Name: 308242-23-1|(S)-Methyl 3-(7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propanoate|97%
Brand: Ambeed
SKU: A526680
Price: 15.0 USD
Availability: InStock
Rating: 93 (40 reviews)

2
[ 308242-23-1 ]
[ 1674-56-2 ]
[ 308243-54-1 ]

Yield	Reaction Conditions	Operation in experiment
37%	With di-morpholin-4-yl-phosphinic acid chloride; sodium hydride In tetrahydrofuran; dichloromethane; dimethyl sulfoxide	Ic-8 Methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a] [ 1,4]benzodiazepin-4-yl]propanoate Example Ic-8 Methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a] [ 1,4]benzodiazepin-4-yl]propanoate A solution of the C7-bromo-benzodiazepine Ex I-10 (7.31 g, 18.2 mmol) in THF (21 mL) was added to a suspension of NaH (870 mg of 60% oil dispersion, 21.8 mmol) in THF (70 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, warmed to room temperature and stirred for 30 min, then cooled to 0 °C. Bis-morpholinophosphorochloridate (6.48 g, 25.5 mmol) was added, the mixture was allowed to warm to room temperature over 4.5 h, and the mixture was filtered with additional THF (ca. 10 mL). A mixture of the filtrate and DL-1-amino-2-propanol (2.80 mL, 36.4 mmol) was stirred at room temperature for 18 h and concentrated under reduced pressure. The residue was diluted with EtOAc (ca. 250 mL), washed with saturated aqueous NaHCO3 (1 x 75 mL), H2O (2 x 75 mL), saturated aqueous NaCl (1 x 75 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by flash chromatography, elution with 19:1 EtOAc-MeOH, gave 3.06 g (37%) of the adduct as a foam; ESIMS 459 (M+H, base). A mixture of DMSO (1.88 mL, 26.6 mmol) and oxalyl chloride (1.16 mL, 13.3 mmol) in CH2Cl2 (40 mL) was stirred at -78 °C for 30 min. A solution of the alcohol prepared above (3.05 g, 6.64 mmol) in CH2Cl2 (26 mL) was added. The reaction mixture was warmed to -15 °C and stirred 1 h, cooled to -78 °C, treated with Et3N (5.55 mL, 39.9 mmol), and allowed to warm to room temperature over 3 h. The mixture was diluted with EtOAc (ca. 500 mL), washed with saturated aqueous NaHCO3 (1 x 100 mL), H2O (1 x 100 mL), saturated aqueous NaCl (1 x 100 mL), dried (Na2SO4), and concentrated under reduced pressure to give a foam. A mixture of this foam and a catalytic amount of p-toluenesulfonic acid was stirred at room temperature for 18h, neutralized by the addition of saturated aqueous NaHCO3 and diluted with EtOAc (ca. 500 mL). The layers were separated and the organic phase was washed with saturated aqueous NaHCO3 (1 x 100 mL), H2O (2 x 100 mL), saturated aqueous NaCl (1 x 100 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by flash chromatography, elution with 19:1 EtOAc-MeOH, gave 2.56 g (88%) of Ic-8 as a foam; 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 4.6 Hz, 1H), 8.17 (d J = 7.8 Hz, 1H), 7.79 (dd, J = 7.7, 6.2 Hz, 1H), 7.71 (dd, J = 8.6, 2.2 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 7.5, 5.0 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.86 (s, 1H), 4.05 (m, 1 H), 3.67 (s, 3H), 2.80 (comp, 4H), 2.34 (s, 3H); ESIMS 461 (M+Na, base), 439 (M+H); Anal. calcd. for C21H19BrN4O2-0.25 H2O: C, 58.63; H, 4.43; N, 12.62. Found: C, 56.88; H, 4.43; N, 12.23. Example 1 c-8 was formulated in an aqueous vehicle at a concentration of 10 mg/ml.

Reference： [1]Current Patent Assignee: PAION AG - EP1183243, 2006, B1 Location in patent: Page/Page column 36; 37

3
[ 1563-56-0 ]
[ 308242-23-1 ]

Reference： [1]Patent: WO2011/32692,2011,A1
[2]Patent: EP2305647,2011,A1
[3]Patent: CN108264499,2018,A
[4]Patent: US2018/312511,2018,A1

4
[ 308242-23-1 ]
[ 308242-62-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: lithium dipropan-2-ylazanide / n-heptane; tetrahydrofuran; ethylbenzene / 3.25 h / -18 - 0 °C / Inert atmosphere; Industry scale 1.2: 2.75 h / -5 - 0 °C / Industry scale 2.1: n-heptane; tetrahydrofuran; ethylbenzene / 42.83 h / -2 - 20 °C 2.2: Industry scale 3.1: Dess-Martin periodane / butanone / 30 - 43 °C
	Multi-step reaction with 4 steps 1.1: lithium dipropan-2-ylazanide / n-heptane; tetrahydrofuran; ethylbenzene / 3.25 h / -18 - 0 °C / Inert atmosphere; Industry scale 1.2: 2.75 h / -5 - 0 °C / Industry scale 2.1: n-heptane; tetrahydrofuran; ethylbenzene / 42.83 h / -2 - 20 °C 2.2: Industry scale 3.1: Sodium hydrogenocarbonate; sodium chlorine monoxide; sodium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane; water monomer / 0 °C 4.1: toluene-4-sulfonic acid / chloroform-d1 / 72 h / Reflux
	Multi-step reaction with 3 steps 1.1: lithium dipropan-2-ylazanide / n-heptane; tetrahydrofuran; ethylbenzene / 3.25 h / -18 - 0 °C / Inert atmosphere 1.2: 2.75 h / -5 - 0 °C 2.1: tetrahydrofuran / 42.83 h / -2 - 20 °C 3.1: Dess-Martin periodane / butanone / 30 - 43 °C

	Multi-step reaction with 4 steps 1.1: lithium dipropan-2-ylazanide / n-heptane; tetrahydrofuran; ethylbenzene / 3.25 h / -18 - 0 °C / Inert atmosphere 1.2: 2.75 h / -5 - 0 °C 2.1: tetrahydrofuran / 42.83 h / -2 - 20 °C 3.1: 2,2,6,6-tetramethyl-1-piperidinyloxy free radical; Sodium hydrogenocarbonate; sodium chlorine monoxide; sodium bromide / dichloromethane 4.1: toluene-4-sulfonic acid / chloroform / 72 h / Reflux
	Multi-step reaction with 3 steps 1.1: 2-bromo-pyridine / dichloromethane 1.2: -20 - -15 °C 2.1: dichloromethane / 0.5 h / -20 - -15 °C 2.2: -20 - -15 °C 3.1: hydrogenchloride / methanol / 15 - 25 °C
	Multi-step reaction with 5 steps 1: phosphorous pentasulfide / acetonitrile; tetrahydrofuran / 2 h / 20 °C / Large scale 2: tetrahydrofuran / 3 h / 0 - 50 °C / Large scale 3: glacial acetic acid; NaNO₂ / methanol / 4 h / 0 - 20 °C / Large scale 4: chloroform / 5 h / 20 °C 5: chromium(VI) oxide; sulfuric acid / acetone / 2 h / 0 - 20 °C / Large scale

Reference： [1]Current Patent Assignee: PAION AG - WO2011/32692, 2011, A1
[2]Current Patent Assignee: PAION AG - WO2011/32692, 2011, A1
[3]Current Patent Assignee: PAION AG - EP2305647, 2011, A1
[4]Current Patent Assignee: PAION AG - EP2305647, 2011, A1
[5]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2018/148361, 2018, A1
[6]Current Patent Assignee: HANA PHARM - WO2021/256679, 2021, A1

5
[ 308242-23-1 ]
[ 1275616-61-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / n-heptane; tetrahydrofuran; ethylbenzene / 3.25 h / -18 - 0 °C / Inert atmosphere; Industry scale 1.2: 2.75 h / -5 - 0 °C / Industry scale 2.1: n-heptane; tetrahydrofuran; ethylbenzene / 42.83 h / -2 - 20 °C 2.2: Industry scale 3.1: sodium hydrogencarbonate; sodium hypochlorite; sodium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane; water / 0 °C
	Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / n-heptane; tetrahydrofuran; ethylbenzene / 3.25 h / -18 - 0 °C / Inert atmosphere 1.2: 2.75 h / -5 - 0 °C 2.1: tetrahydrofuran / 42.83 h / -2 - 20 °C 3.1: 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hydrogencarbonate; sodium hypochlorite; sodium bromide / dichloromethane

Reference： [1]Current Patent Assignee: PAION AG - WO2011/32692, 2011, A1
[2]Current Patent Assignee: PAION AG - EP2305647, 2011, A1

6
[ 308242-23-1 ]
3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propionic acid methyl ester benzene sulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: lithium diisopropyl amide / n-heptane; tetrahydrofuran; ethylbenzene / 3.25 h / -18 - 0 °C / Inert atmosphere; Industry scale 1.2: 2.75 h / -5 - 0 °C / Industry scale 2.1: n-heptane; tetrahydrofuran; ethylbenzene / 42.83 h / -2 - 20 °C 2.2: Industry scale 3.1: Dess-Martin periodane / butanone / 30 - 43 °C 4.1: ethyl acetate; ethanol / 1.67 h
	Multi-step reaction with 4 steps 1.1: lithium diisopropyl amide / n-heptane; tetrahydrofuran; ethylbenzene / 3.25 h / -18 - 0 °C / Inert atmosphere; Industry scale 1.2: 2.75 h / -5 - 0 °C / Industry scale 2.1: n-heptane; tetrahydrofuran; ethylbenzene / 42.83 h / -2 - 20 °C 2.2: Industry scale 3.1: sodium hydrogencarbonate; sodium hypochlorite; sodium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane; water / 0 °C 4.1: ethyl acetate; ethanol / 1.08 h
	Multi-step reaction with 5 steps 1.1: lithium diisopropyl amide / n-heptane; tetrahydrofuran; ethylbenzene / 3.25 h / -18 - 0 °C / Inert atmosphere; Industry scale 1.2: 2.75 h / -5 - 0 °C / Industry scale 2.1: n-heptane; tetrahydrofuran; ethylbenzene / 42.83 h / -2 - 20 °C 2.2: Industry scale 3.1: sodium hydrogencarbonate; sodium hypochlorite; sodium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane; water / 0 °C 4.1: toluene-4-sulfonic acid / chloroform-d1 / 72 h / Reflux 5.1: ethyl acetate; ethanol / 1.67 h

	Multi-step reaction with 4 steps 1.1: lithium diisopropyl amide / n-heptane; tetrahydrofuran; ethylbenzene / 3.25 h / -18 - 0 °C / Inert atmosphere 1.2: 2.75 h / -5 - 0 °C 2.1: tetrahydrofuran / 42.83 h / -2 - 20 °C 3.1: Dess-Martin periodane / butanone / 30 - 43 °C 4.1: ethyl acetate; ethanol / 1.67 h
	Multi-step reaction with 4 steps 1.1: lithium diisopropyl amide / n-heptane; tetrahydrofuran; ethylbenzene / 3.25 h / -18 - 0 °C / Inert atmosphere 1.2: 2.75 h / -5 - 0 °C 2.1: tetrahydrofuran / 42.83 h / -2 - 20 °C 3.1: 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hydrogencarbonate; sodium hypochlorite; sodium bromide / dichloromethane 4.1: ethyl acetate; ethanol / 1.08 h
	Multi-step reaction with 5 steps 1.1: lithium diisopropyl amide / n-heptane; tetrahydrofuran; ethylbenzene / 3.25 h / -18 - 0 °C / Inert atmosphere 1.2: 2.75 h / -5 - 0 °C 2.1: tetrahydrofuran / 42.83 h / -2 - 20 °C 3.1: 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hydrogencarbonate; sodium hypochlorite; sodium bromide / dichloromethane 4.1: toluene-4-sulfonic acid / chloroform / 72 h / Reflux 5.1: ethyl acetate; ethanol / 1.67 h

Reference： [1]Current Patent Assignee: PAION AG - WO2011/32692, 2011, A1
[2]Current Patent Assignee: PAION AG - WO2011/32692, 2011, A1
[3]Current Patent Assignee: PAION AG - WO2011/32692, 2011, A1
[4]Current Patent Assignee: PAION AG - EP2305647, 2011, A1
[5]Current Patent Assignee: PAION AG - EP2305647, 2011, A1
[6]Current Patent Assignee: PAION AG - EP2305647, 2011, A1

7
[ 308242-23-1 ]
[ 1275616-59-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / n-heptane; tetrahydrofuran; ethylbenzene / 3.25 h / -18 - 0 °C / Inert atmosphere; Industry scale 1.2: 2.75 h / -5 - 0 °C / Industry scale 2.1: n-heptane; tetrahydrofuran; ethylbenzene / 42.83 h / -2 - 20 °C 2.2: Industry scale
	Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / n-heptane; tetrahydrofuran; ethylbenzene / 3.25 h / -18 - 0 °C / Inert atmosphere 1.2: 2.75 h / -5 - 0 °C 2.1: tetrahydrofuran / 42.83 h / -2 - 20 °C

Reference： [1]Current Patent Assignee: PAION AG - WO2011/32692, 2011, A1
[2]Current Patent Assignee: PAION AG - EP2305647, 2011, A1

8
[ 308242-23-1 ]
[ 7264-90-6 ]
[ 1275616-60-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3S)-3-(7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propionic acid methyl ester With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -18 - 0℃; for 3.25h; Inert atmosphere; Industry scale; Stage #2: di-morpholin-4-yl-phosphinic acid chloride In tetrahydrofuran; n-heptane; ethylbenzene at -5 - 0℃; for 2.75h; Industry scale;	A4 Preparation of 3-[(S)-7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1 H-1 ,4-benzodiazepin- 3-yl]-propionic acid methyl ester of formula (E)1.36 kg (3.39 mol) compound of formula (D) was suspended in 3500 ml dry tetrahydrofurane (THF) under argon and cooled down to -18 °C. A 2M solution of lithium diisopropylamide LDA (3.4 mol) in 1700 ml THF/heptane/ethylbenzene was added over a period of 90 minutes. The addition was exothermic and the temperature was controlled to be between -10 and -5 °C. The mixture was then stirred for 105 minutes at 0°C, followed by the portionwise addition of bis-morpholinophosphoryl- chloridate BMPC (1.74 kg; 6.78 mol) over 15 minutes. The brown suspension was stirred for 150 minutes and the temperature held between -5 and Q°C An analytical amount of the main product isolated by chromatography was found to have the following NMR data:1 H-NMR (CDCI3, 300 MHz) 8.68 (ddd, 1 H, J= 4.8, 1.7, 0.9); 7.96 (dt, 1 H, J= 7.9, 1.0); 7.8 (td, 1 H, J= 7.7, 1.8); 7.67 (dd, 1 H, J= 8.6, 2.3); 7.57 (d, 1 H, J= 2.0); 7.41 (ddd, 1 H, J= 7.5, 4.8, 1.2); 7.36 (d, 1 H, J= 8.6); 7.2 (m, 1H); 3.85- 3.65 (m, 8H + 3H ) 3.33-3.19 (m, 8H); 2.76-2.45 (m, 4H), corresponding to the compound of formula (E1 )
	Stage #1: (3S)-3-(7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propionic acid methyl ester With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -18 - 0℃; for 3.25h; Inert atmosphere; Stage #2: di-morpholin-4-yl-phosphinic acid chloride In tetrahydrofuran; n-heptane; ethylbenzene at -5 - 0℃; for 2.75h;	A.4 1.36 kg (3.39 mol) compound of formula (D) was suspended in 3500 ml dry tetrahydrofurane (THF) under argon and cooled down to -18 °C. A 2M solution of lithium diisopropylamide LDA (3.4 mol) in 1700 ml THF/heptane/ethylbenzene was added over a period of 90 minutes. The addition was exothermic and the temperature was controlled to be between -10 and -5 °C. The mixture was then stirred for 105 minutes at 0°C, followed by the portionwise addition of bis-morpholinophosphorylchloridate BMPC (1.74 kg; 6.78 mol) over 15 minutes. The brown suspension was stirred for 150 minutes and the temperature held between -5 and 0°C. An analytical amount of the main product isolated by chromatography was found to have the following NMR data: 1H-NMR (COCl3, 300 MHz) 8.68 (ddd, 1H, J= 4.8, 1.7, 0.9); 7.96 (dt, 1H, J= 7.9, 1.0); 7.8 (td, 1H, J= 7.7, 1.8); 7.67 (dd, 1H, J= 8.6, 2.3); 7.57 (d, 1H, J= 2.0); 7.41 (ddd, 1H. J= 7.5, 4.8, 1.2); 7.36 (d, 1H, J= 8.6); 7.2 (m, 1H); 3.85- 3.65 (m, 8H + 3H) 3.33-3.19 (m, 8H); 2.76-2.45 (m, 4H), corresponding to the compound of formula (E1)
	Stage #1: (3S)-3-(7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propionic acid methyl ester With lithium hexamethyldisilazane In tetrahydrofuran at -30℃; for 2h; Inert atmosphere; Stage #2: di-morpholin-4-yl-phosphinic acid chloride In tetrahydrofuran at -10 - 0℃; for 4h; Inert atmosphere;	2.1 (S)-3-(7-Bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4] was added to the reaction flask. Aza [image]-3-yl)methyl propionate (800 g) and tetrahydrofuran (6.8 kg) were stirred and dissolved under argon atmosphere. The reaction solution was cooled to -30 ° C, and a solution of (2.4 L) of 1 M bis(trimethylsilyl)amide lithium (LiHMDS) in THF (2.5 kg) was added dropwise thereto, and the reaction was exothermed and dripped after about 1 hour. During the control period, the temperature did not exceed -20 ° C, and the mixture was stirred at -20 ° C for further 1 hour. Then, dimorpholinylphosphinic acid chloride (1.2 kg) was added portionwise over 30 min, and the mixture was stirred at -10 ° C to 0 ° C for 4 h.

Stage #1: (3S)-3-(7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propionic acid methyl ester With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: di-morpholin-4-yl-phosphinic acid chloride In tetrahydrofuran for 1h;

2.3 Step 3. Preparation of (S)-methyl 3-(7-bromo-2-((2-hydroxyethyl)amino)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-yl)propanoate (Compound 2e) (S)-Methyl 3-(7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propanoate (compound 2c, 1 g, 2.49 mmol) was dissolved in dried THF (10 mL). The solution was cooled to 0° C., NaH (149.2 mg, 3.73 mmol) was added, and the reaction mixture was stirred for 30 min. Morpholinyl chlorophosphate (1.27 g, 4.98 mmol) was added, and the reaction mixture was stirred for 1 h until LCMS indicated that the reaction was completed. 2-Aminoethanol (609 mg, 9.96 mmol) was added, and the reaction mixture was stirred for 3 h until LCMS indicated that the reaction was completed. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water for three times, dried and concentrated. The residue was purified through preparative TLC to obtain (S)-methyl 3-(7-bromo-2-((2-hydroxyethyl)amino)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-yl)propanoate (compound 2e, 300 mg, yield: 27.3%).

Reference： [1]Current Patent Assignee: PAION AG - WO2011/32692, 2011, A1 Location in patent: Page/Page column 17-18
[2]Current Patent Assignee: PAION AG - EP2305647, 2011, A1 Location in patent: Page/Page column 10
[3]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - CN108264499, 2018, A Location in patent: Paragraph 0050-0051; 0087-0088; 0090; 0092
[4]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - US2018/312511, 2018, A1 Location in patent: Paragraph 22-23; 24-36; 39-40; 43-46

9
[ 1275616-57-3 ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: hydrogenchloride; methanol / 1,4-dioxane / 3.25 h / 10 - 20 °C 2: sodium hydrogencarbonate / 1,4-dioxane; acetonitrile; methanol / 15 - 20 °C

Reference： [1]Current Patent Assignee: PAION AG - EP2305647, 2011, A1

10
[ 1275616-58-4 ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In 1,4-dioxane; methanol; acetonitrile at 15 - 20℃;	A.3 449 g (5343 mmol) of sodium hydrogen carbonate were suspended in 2000 ml of acetonitrile under vigorous stirring. The solution of the compound of formula (C) obtained in Example A2 above (1743 g, 763 mmol) was added to that suspension in 4 equal portions at room temperature over a period of 30 minutes (actual solvent ratio methanol/1,4-dioxane/acetonitrile: 3/4/10). The temperature decreased to 15 °C, with an intensive gas development and a slight foaming after addition of each portion. The colour switched after each addition from orange (colour of the hydrochloric solution) to yellow-green. The yellow-green solution was stirred at a temperature of about 15 °C for 3 hours 40 minutes. The reaction mixture was filtered over a thin layer of celite, washed with acetonitrile and evaporated in vacuo at 50 °C bath temperature, yielding 424 g of viscous resin, The resin was dissolved in 1500 ml of 2-propanol at 85 °C. After cooling the precipitated solid was isolated by filtration and washed with 2-propanol and dried at a temperature of 35 °C in vacuo to give the product as a yellow crystalline solid (215.8g. 528mmol) having the following NMR data: 1H-NMR (CDCl3, 300 MHz) 8.69 (s, 1H); 8.52 (dq, 1H, J= 4.8. 1.6, 0.8); 7.99 (dt, 1H, J= 8.0, 1.0); 7.73 (td, 1H J= 7.8, 1.8);7.54-7.43(m, 2H) 7.28 (qd, 1H, J= 7.6, 4.8, 1.0); 6.93(d, 1H, J=8.6); 3.67 (dd, 1H J= 7.6, 6.1); 3.60 (s, 3H) 2.66-2.34 (m, 4H), corresponding to the compound of formula (D).

Reference： [1]Current Patent Assignee: PAION AG - EP2305647, 2011, A1 Location in patent: Page/Page column 9-10

11
[ 45214-91-3 ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: dicyclohexyl-carbodiimide / dichloromethane / 41 h / -10 - 0 °C 2: hydrogenchloride / 1,4-dioxane; methanol / 3.25 h / 10 - 15 °C / Industry scale 3: sodium hydrogencarbonate / acetonitrile / 4.17 h / 15 - 20 °C / Industry scale
	Multi-step reaction with 3 steps 1: dicyclohexyl-carbodiimide / dichloromethane / -10 - 0 °C 2: hydrogenchloride; methanol / 1,4-dioxane / 3.25 h / 10 - 20 °C 3: sodium hydrogencarbonate / 1,4-dioxane; acetonitrile; methanol / 15 - 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; 4-methyl-morpholine / N,N-dimethyl-formamide / 0.5 h / Cooling with ice 2: trifluoroacetic acid / dichloromethane / Cooling with ice

Reference： [1]Current Patent Assignee: PAION AG - WO2011/32692, 2011, A1
[2]Current Patent Assignee: PAION AG - EP2305647, 2011, A1
[3]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - US2018/312511, 2018, A1

12
C₂₃H₂₅BrN₂O₇ [ No CAS ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane; methanol / 3.25 h / 10 - 15 °C / Industry scale 2: sodium hydrogencarbonate / acetonitrile / 4.17 h / 15 - 20 °C / Industry scale

Reference： [1]Current Patent Assignee: PAION AG - WO2011/32692, 2011, A1

13
C₁₈H₁₇BrN₂O₅*ClH [ No CAS ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In acetonitrile at 15 - 20℃; for 4.16667h; Industry scale;	A3 Example A3:Preparation of 3-[(S)-7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1 H-1 ,4-benzodiazepin- 3-yl]-propionic acid methyl ester of formula (D) 449 g (5343 mmol) bf sodium hydrogen carbonate were suspended in 2000 ml of acetonitrile under vigorous stirring. The solution of the compound of formula (C) obtained in Example A2 above (1743 g, 763 mmol) was added to that suspension in 4 equal portions at room temperature over a period of 30 minutes (actual solvent ratio methanol/1 ,4-dioxane/acetonitrile: 3/4/10). The temperature decreased to 15 °C, with an intensive gas development and a slight foaming after addition of each portion. The colour switched after each addition from orange (colour of the hydrochloric solution) to yellow-green. The yellow-green solution was stirred at a temperature of about 15 °C for 3 hours 40 minutes. The reaction mixture was filtered over a thin layer of celite, washed with acetonitrile and evaporated in vacuo at 50 °C bath temperature, yielding 424 g of viscous resin, The resin was dissolved in 1500 ml of 2-propanol at 85 °C. After cooling the precipitated solid was isolated by filtration and washed with 2-propanol and dried at a temperature of 35 °C in vacuo to give the product as a yellow crystalline solid (215.8g, 528mmol) having the following NMR data:1 H-NMR (CDCI3, 300 MHz) 8.69 (s, 1 H); 8.52 (dq, 1 H, J= 4.8, 1.6, 0.8); 7.99 (dt, 1 H, J= 8.0, 1.0); 7.73 (td, 1 H J= 7.8, 1.8);7.54-7.43(m, 2H) 7.28 (qd, 1 H, J= 7.6, 4.8, 1.0); 6.93(d, 1 H, J=8.6); 3.67 (dd, 1 H J= 7.6, 6.1); 3.60 (s, 3H) 2.66-2.34 (m, 4H), corresponding to the compound of formula (D).

Reference： [1]Current Patent Assignee: PAION AG - WO2011/32692, 2011, A1 Location in patent: Page/Page column 16-17

14
[ 308242-23-1 ]
[ 1001415-66-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: lithium diisopropyl amide; di-morpholin-4-yl-phosphinic acid chloride / tetrahydrofuran / 0 °C 2: sodium hydrogencarbonate; potassium bromide; sodium hypochlorite; 2-azatricyclo[3.3.1.1^3,7]dec-2-yloxidanyl / acetic acid methyl ester; toluene; water / 1 h / 0 °C 3: methanol / 50 °C
	Multi-step reaction with 3 steps 1: lithium diisopropyl amide / n-heptane; tetrahydrofuran / 2 h / -25 - -5 °C / Inert atmosphere 2: tetrahydrofuran / 16 h / -5 - 20 °C 3: acetone / 3 h / 20 - 50 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: PAION AG - US2016/9680, 2016, A1
[2]Current Patent Assignee: MOEHS IBERICA - WO2019/72944, 2019, A1

15
[ 308242-23-1 ]
[ 1674-56-2 ]
3-[(S)-7-bromo-2-(2-hydroxypropylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61.74%	Stage #1: (3S)-3-(7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propionic acid methyl ester With lithium diisopropyl amide In tetrahydrofuran at -10 - 0℃; for 1h; Inert atmosphere; Stage #2: With di-morpholin-4-yl-phosphinic acid chloride In tetrahydrofuran at 0℃; for 3h; Inert atmosphere; Stage #3: 3-amino-2-propanol In tetrahydrofuran at -2 - 25℃; for 18h; Inert atmosphere;	1; 3; 5-6; 1 3-[(S)-7-Bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diaza-3-yl]- Methyl propionate Preparation: (3S)-7-bromo-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-propionic acid methyl ester (10g, 0.025mol) dissolved in 23g of tetrahydrofuran, and the temperature is reduced to -10°C under nitrogen protection; Slowly add 11.2g of lithium diisopropylamide dropwise, Control the temperature at -10-5, after the addition, increase the temperature to 0 for reaction; After stirring for 1h, add di-morpholinophosphoryl chloride (12.7g, 0.05mol), keep it at 0 and react for 3h; Dissolve 1-amino-2-propanol (5.5g, 0.073mol) in 10g tetrahydrofuran and add dropwise to the system, control the temperature at -24, After dripping, heat to 25°C and stir for 2h; Dissolve 1-amino-2-propanol (1g, 0.013mol) in 1g tetrahydrofuran and add dropwise to the system, stir at 25°C for 16h; TLC analysis determines the end of the reaction. After the reaction is complete, the system is spin-dried. Add 70g of dichloromethane and 66g of saturated sodium bicarbonate solution to the residue, stir for 20min; separate the liquids, wash the organic phase with 35g of saturated ammonium chloride solution and 35g of purified water; combine the water phases, Extract with 20g of dichloromethane; combine the organic phases, spin dry, add 40g of methyl tert-butyl ether, heat to dissolve and slowly reduce to 0-5°C. Crystallize for 1h; filter and drain, the filter cake is rinsed with a small amount of methyl tert-butyl ether and dried under reduced pressure at 45°C for 8h to obtain 7.05g of off-white solid. The yield is 61.74%, and the purity is 99.12%.
	With di-morpholin-4-yl-phosphinic acid chloride; lithium diisopropyl amide In tetrahydrofuran at 0℃;	1; 2.1 Example 1 Reaction from 3-[(S)-7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propionic acid methyl ester (Compound (D)) to 3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid methyl ester (Compound (EM)) To Compound (D) (1.0 mmol) in 1.0 mL of tetrahydrofuran was added bismorpholinophosphoryl chloridate (BMPC) (1.2 mmol). At 0° C. or less, a tetrahydrofuran solution (1.8 M, 1.0 mmol, 0.56 mL) of lithium diisopropylamide was added dropwise to the reaction mixture. At 0° C., a solution of 1-aminopropan-2-ol (1.3 mmol) in 0.4 mL of tetrahydrofuran was added dropwise to the reaction mixture. The resulting reaction mixture was stirred overnight at 0° C. To the reaction mixture of Example 1 were added about 16 mL of t-butyl methyl ether and about 10 mL of an aqueous solution of ammonium chloride (concentration: 25%) to separate it into layers. The organic layer thus obtained was washed with about 10 mL of an aqueous solution of ammonium chloride and then washed with water so as to decrease the weight ratio of an ammonium ion content in the organic layer to 170 ppm or less relative to Compound (EM). The organic layer thus obtained was concentrated to about 1.0 mL under reduced pressure. Toluene was added to the organic layer, followed by concentration under reduced pressure to about 1.0 mL. The toluene solution thus obtained was cooled to 0° C. The solid thus precipitated was collected by filtration and then dried to obtain Compound (EM) having the following physical properties. The measurement procedure of an ammonium ion content will be described later. TLC: Rf 0.35 (ethyl acetate); 1H-NMR (CDCl3): δ 8.70-8.60 (m, 1H), 7.88-7.82 (m, 1H), 7.81-7.75 (m, 1H), 7.53-7.47 (m, 1H), 7.40-7.33 (m, 2H), 7.15-7.10 (m, 1H), 5.71-5.65 (m, 1H), 5.20-4.70 (m, 1H), 4.15-3.95 (m, 1H), 3.71 (s, 3H), 3.48-3.38 (m, 1H), 3.33-3.14 (m, 1H), 3.30-3.20 (m, 1H), 2.85-2.73 (m, 1H), 2.66-2.35 (m, 3H), 1.20-1.18 (m, 3H). HPLC conditions Column: YMC-Pack ODS-AQ (length: 25 cm, inner diameter: 4.6 mm, particle size: 3 μm, YMC) Column temperature: 25° C. Mobile phase: 10 mM aqueous potassium dihydrogen phosphate solution/acetonitrile=55/45 Flow rate: 0.7 mL/min Detector: UV 230 nm Injection amount: 5 μL Analysis time: 40 minutes The retention time under the above-mentioned conditions is 12.3 minutes and 12.8 minutes.

Reference： [1]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN112321594, 2021, A Location in patent: Paragraph 0032-0041; 0046-0049; 0053-0067
[2]Current Patent Assignee: PAION AG - US2016/9680, 2016, A1 Location in patent: Paragraph 0146-0158

16
methyl (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-[4-bromo-2-(pyridine-2-carbonyl)phenyl]carbamoyl}butanoate [ No CAS ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
89.9%	With morpholine In N,N-dimethyl-formamide at 5 - 30℃; for 2.5h;	1-13 Embodiment 2 The preparation method of remazolam intermediate Ia Add N,N-dimethylformamide (15.6g) to the reaction flask, turn on stirring,Add Intermediate IIa (8.3g), cool to 510,Morpholine (4.1 g) was added, the addition was completed, and the temperature was controlled to 22-29 °C for 2 h.After the reaction was completed, the reaction solution was cooled to 0-5°C,Stir for 20min, suction filtration to obtain the N,N-dimethylformamide filtrate of Ia.The filtrate was poured into a mixed solvent of 10% aqueous sodium chloride solution (152 g) and n-heptane (90 g), and stirred at 0 to 15° C. for 1 h.Crude intermediate Ia was obtained by centrifugation.Add ethyl acetate (14g) to the glass reaction flask, add the crude product of Intermediate Ia, heat up to reflux, slowly add n-heptane (85g), after the addition, heat up to 60°C and stir for 1h, then reduce the system to 20 30° C., stirring for crystallization for 2 h, centrifugation, and drying of the filter cake to obtain off-white powder. Yield 89.9%, HPLC: 97.11%.
48.2%	With morpholine In dichloromethane at 20℃; for 20h;	1.3 methyl (S)-3-(7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-3-yl)propionate Add 20% morpholine/dichloromethane (35 mL) to the oil and stir to dissolve.React at room temperature for about 20 hours,Washed four times after the reaction,Wash morpholine, dry and concentrate, column chromatography(eluent: CH2Cl2→CH2Cl2:CH3OH=100:1 to 50:1, by volume) to give crude product (3.7 g, yield 63.7%, HPLC >96%).After adding isopropanol (15 mL), it was heated to dissolve, and the mixture was stirred and crystallized at room temperature, and filtered to give the object product (2.8 g, yield: 48.2%, HPLC: 99.84%).
	With triethylamine In dichloromethane at 40 - 45℃;	4 Comparative Example 4. Obtaining 3-[(3S)-7-bromo-2-oxo-5-(pyridin-2-yl) -2, 3-dihydro-1H- [1,4] -benzodiazepin-3-yl]propionic acid methyl ester of formula (D) from methyl (4S)-4-(fluorenyl-9-methoxycarbonylamino)-5-[4-bromo-2-(pyridine-2-carbonyl) aniline] -5-oxo-pentanoate 16.8 g (26 mmol) of methyl (4S)-4-(fluorenyl-9-methoxycarbonylamino) -5- [4-bromo-2- (pyridine-2-carbonyl)aniline]-5-oxo-pentanoate were dissolved in 80 mL of dichloromethane, and 48.8 g (482 mmol) of triethylamine were added. Once the addition ended, the obtained mixture was kept under stirring overnight at a temperature between 40 and 45°C.Once it no longer had to be kept under the aforementionedconditions, the reaction mixture was concentrated by means of avacuum to obtain a residue to which 40 mL of acetone were added. It was heated at reflux, obtaining a homogenous mixture which was cooled at a temperature of about 20°C. The resulting solid was filtered and washed with acetone, yielding a product thatcontained 62% 3-[(3S)-7-bromo-2-oxo-5-(pyridin-2-yl)-2,3- dihydro-1H-[1,4]-benzodiazepin-3-yl] propionic acid methyl ester of formula (D) . This solid was recrystallized into isopropanol, obtaining 4.2 g (40%) of the desired product with a purity of 94%. The purity of the obtained products was analyzed by means of the ultra high performance liquid chromatography technique inWaters Acquity HClass equipment, equipped with a variable wave detector and temperature-controlled oven for the column.

Reference： [1]Current Patent Assignee: CHENGDU EASTON BIOPHARMACEUTICALS CO LTD;SICHUAN QINGMU PHARMACEUTICAL CO LTD - CN114644612, 2022, A Location in patent: Paragraph 0061-0099
[2]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - CN108264499, 2018, A Location in patent: Paragraph 0050-0051; 0075-0076; 0084-0086
[3]Current Patent Assignee: MOEHS IBERICA - WO2019/72944, 2019, A1 Location in patent: Page/Page column 40; 41

17
[ 308242-23-1 ]
3-((3S)-7-bromo-2-((2-hydroxypropyl)amino)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-yl) propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -30 °C / Inert atmosphere 1.2: 4 h / -10 - 0 °C / Inert atmosphere 2.1: 20 h / 0 °C
	Multi-step reaction with 4 steps 1: phosphorous pentasulfide / acetonitrile; tetrahydrofuran / 2 h / 20 °C / Large scale 2: tetrahydrofuran / 3 h / 0 - 50 °C / Large scale 3: glacial acetic acid; NaNO₂ / methanol / 4 h / 0 - 20 °C / Large scale 4: chloroform / 5 h / 20 °C

Reference： [1]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - CN108264499, 2018, A
[2]Current Patent Assignee: HANA PHARM - WO2021/256679, 2021, A1

18
[ 308242-23-1 ]
methyl (S)-3-(8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine -4-yl)propionate tosylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -30 °C / Inert atmosphere 1.2: 4 h / -10 - 0 °C / Inert atmosphere 2.1: 20 h / 0 °C 3.1: oxalyl dichloride / dichloromethane; dimethyl sulfoxide / 3 h / -70 - -60 °C 3.2: 3 h / 20 °C 3.3: 16 h / 25 °C

Reference： [1]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - CN108264499, 2018, A

19
[ 5794-88-7 ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / -40 °C / Inert atmosphere 1.2: 3 h / 0 - 10 °C / Inert atmosphere 2.1: dicyclohexyl-carbodiimide / dichloromethane / 48 h / -10 - 0 °C 3.1: morpholine / dichloromethane / 20 h / 20 °C

Reference： [1]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - CN108264499, 2018, A

20
[ 109-04-6 ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / -40 °C / Inert atmosphere 1.2: 3 h / 0 - 10 °C / Inert atmosphere 2.1: dicyclohexyl-carbodiimide / dichloromethane / 48 h / -10 - 0 °C 3.1: morpholine / dichloromethane / 20 h / 20 °C

Reference： [1]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - CN108264499, 2018, A

21
[ 308242-23-1 ]
[ 358-23-6 ]
(S)-3-(2-(methoxycarbonyl)ethyl)-7-bromo-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-2-yl trifluoromethanesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3S)-3-(7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propionic acid methyl ester With 2-bromo-pyridine In dichloromethane Stage #2: trifluoromethylsulfonic anhydride In dichloromethane at -20 - -15℃;	1-b Example 1-b: Preparation of compound of methyl-3 -((S)-2-(2.2-dimethoxypropylamino)-7- bromo-5 -(pyridin-2-yl)-3H-benzo [el [1.41 diazepin-3 -yl)propanoate) (formula-ITT- 13’) from compound of formula-TV (3 S)-(7-BroMo-2-oxo-5-pyridin-2-yl-2, 3 -dihydro- 1H-benzo[e] [1,4] diazepin-3 -yl)-propionic acid Methyl ester (Compound of formula TV, S enantiomer,25.0 gr) and dichloromethane (“IVIDC”, 375 ml) were charged into a clean, dry 4 neck RBF. The reaction mixture was stirred for 5-10 minutes at temperature of 20-25°C and a clear solution was obtained. 2-bromo pyridine (29.46 gr) was added to the solution and the obtained reaction mixture was stirred for 5-10 minutes. The obtained reaction mass was cooled down to a temperature of -15° to -20°C. Then, Triflic anhydride (26.32 gr) was slowly added, over a period of 30-45 minutes to the cooled reaction mass, at the same temperature of-15° to -20°C. After the addition was completed, the obtained reaction mixture was stirred for 30-45 minutes, at the same temperature of -15° to -20°C. The reaction progress was monitored by HPLC (monitor intermediate (S)-3 -(2-(methoxycarbonyl)ethyl)-7-bromo-5 - (pyridin-2-yl)-3H-benzo [e] [1,4] diazepin-2-yl trifluoromethanesulfonate formation). Afterwards, 1-amino-2,2-dimethoxypropane (14.81 gr) in dichloromethane (2 vol, 50 mL) solution was slowly added over a period of about 30 minutes to the reaction mixture at temperature of -15° to -20°C. After complete addition, Triethylamine (31.44 gr) was slowly added over a period of about 30 minutes at the same temperature of -15° to -20°C, and the obtained mixture was stirred at temperature of -15° to -20°C for 60-120 minutes. The reaction progress was monitored by HPLC. After the reaction was completed, ammonium chloride solution (20%, 125 ml) was added, and the temperature was raised to 15-20°C; the obtained mixture was stirred for 30 minutes. The organic layer was separated, washed with DM water (125 ml) and re-separated. The organic layer was then concentrated to volume of 1-1.5 vol, at a temperature below 45°C. Toluene (50m1) was added to the reaction mass, and then stripped out 1 vol under vacuum at a temperature below 60°C. Then, Toluene (50m1) was added and the obtained mixture was heated to temperature of 60-65°C, and was stirred at this temperature for 30-45 minutes. Heating was discontinued and the reaction mass was slowly cooled to temperature of 0-10°C, and was stirred for 3-4 hours - crystallization occurred. The obtained suspension was stirred at temperature of 0-10°C for 3 0-45 minutes. The obtained solid was filtered and washed twice with pre-cooled (temperature of about 5-10 °C) toluene (12.5 ml X 2 times), and suck-dried for 20-30 minutes. The wet solid was further dried under vacuum at temperature of 40-45°C for 6-8 hours. Yield (dry): 26.5 gm (85%)

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2018/148361, 2018, A1 Location in patent: Page/Page column 00133

22
[ 308242-23-1 ]
(3S)-3-[7-bromo-2-(2,2-dimethoxypropylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3- yl]propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 2-bromo-pyridine / dichloromethane 1.2: -20 - -15 °C 2.1: dichloromethane / 0.5 h / -20 - -15 °C 2.2: -20 - -15 °C
	Multi-step reaction with 2 steps 1: lithium diisopropyl amide / n-heptane; tetrahydrofuran / 2 h / -25 - -5 °C / Inert atmosphere 2: tetrahydrofuran / 16 h / -5 - 20 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2018/148361, 2018, A1
[2]Current Patent Assignee: MOEHS IBERICA - WO2019/72944, 2019, A1

23
[ 308242-23-1 ]
methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazol[1,2-a][1,4]benzodiazepine-4-yl]propionate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 2-bromo-pyridine / dichloromethane 1.2: -20 - -15 °C 2.1: dichloromethane / 0.5 h / -20 - -15 °C 2.2: -20 - -15 °C 3.1: hydrogenchloride / methanol / 15 - 25 °C 4.1: hydrogenchloride / ethyl acetate / 0.17 h / 20 - 30 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2018/148361, 2018, A1

24
[ 308242-23-1 ]
remimazolam dihydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 2-bromo-pyridine / dichloromethane 1.2: -20 - -15 °C 2.1: dichloromethane / 0.5 h / -20 - -15 °C 2.2: -20 - -15 °C 3.1: hydrogenchloride / methanol / 15 - 25 °C 4.1: hydrogen bromide / acetone / 1 h / 20 - 25 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2018/148361, 2018, A1

25
[ 308242-23-1 ]
(x)C₄H₄O₄*C₂₁H₁₉BrN₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 2-bromo-pyridine / dichloromethane 1.2: -20 - -15 °C 2.1: dichloromethane / 0.5 h / -20 - -15 °C 2.2: -20 - -15 °C 3.1: hydrogenchloride / methanol / 15 - 25 °C 4.1: ethanol / 20 - 30 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2018/148361, 2018, A1

26
[ 308242-23-1 ]
(x)C₂H₂O₄*C₂₁H₁₉BrN₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 2-bromo-pyridine / dichloromethane 1.2: -20 - -15 °C 2.1: dichloromethane / 0.5 h / -20 - -15 °C 2.2: -20 - -15 °C 3.1: hydrogenchloride / methanol / 15 - 25 °C 4.1: acetone / 0.17 h / 20 - 30 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2018/148361, 2018, A1

27
[ 308242-23-1 ]
methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazol[1,2-a][1,4]benzodiazepine-4-yl]propionate mesylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 2-bromo-pyridine / dichloromethane 1.2: -20 - -15 °C 2.1: dichloromethane / 0.5 h / -20 - -15 °C 2.2: -20 - -15 °C 3.1: hydrogenchloride / methanol / 15 - 25 °C 4.1: acetone / 2 h / 20 - 25 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2018/148361, 2018, A1

28
[ 308242-23-1 ]
C₂₁H₁₉BrN₄O₂*C₁₀H₁₆O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 2-bromo-pyridine / dichloromethane 1.2: -20 - -15 °C 2.1: dichloromethane / 0.5 h / -20 - -15 °C 2.2: -20 - -15 °C 3.1: hydrogenchloride / methanol / 15 - 25 °C 4.1: acetone / 2 h / 20 - 25 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2018/148361, 2018, A1

29
[ 308242-23-1 ]
methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazol[1,2-a][1,4]benzodiazepine-4-yl]propionate hydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 2-bromo-pyridine / dichloromethane 1.2: -20 - -15 °C 2.1: dichloromethane / 0.5 h / -20 - -15 °C 2.2: -20 - -15 °C 3.1: hydrogenchloride / methanol / 15 - 25 °C 4.1: hydrogen bromide / acetone; water / 2.33 h / 20 - 25 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2018/148361, 2018, A1

30
(S)-methyl 5-((4-bromo-2-nicotinoylphenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate [ No CAS ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
53%	With trifluoroacetic acid In dichloromethane Cooling with ice;	2.2 Step 2. Preparation of (S)-methyl 3-(7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propanoate (Compound 2c) (S)-Methyl 5-((4-bromo-2-nicotinoylphenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate (compound 2b, 10 g, 19 mmol) was dissolved in DCM (30 m), and trifluoroacetic acid (10 mL) was added in an ice bath. After LCMS indicated that the reaction was completed, the solvent was removed by evaporation. The residue was dissolved in methanol (50 mL), and was adjusted to pH 10 with Na2CO3. The mixture was stirred at room temperature overnight before EtOH was removed by evaporation. The mixture was extracted with ethyl acetate (30 mL*4). The ethyl acetate layer was dried over Na2SO4, and concentrated. The residue was purified through silica gel column chromatography to obtain (S)-methyl 3-(7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propanoate (compound 2c, 4.1 g, yield: 53%).

Reference： [1]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - US2018/312511, 2018, A1 Location in patent: Paragraph 0250; 0252

31
[ 308242-23-1 ]
(S)-methyl 3-(8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 1.2: 1 h 2.1: 1,4-dioxane / 7 h / 20 - 100 °C

Reference： [1]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - US2018/312511, 2018, A1

32
[ 308242-23-1 ]
(S)-methyl 3-(8-bromo-1-cyclopropyl-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 1.2: 1 h 2.1: 1,4-dioxane / 5 h / 100 °C

Reference： [1]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - US2018/312511, 2018, A1

33
[ 308242-23-1 ]
(S)-methyl 3-(8-bromo-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 1.2: 1 h 2.1: 1,4-dioxane / 5 h / 100 °C

Reference： [1]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - US2018/312511, 2018, A1

34
[ 308242-23-1 ]
(S)-methyl 3-(8-bromo-1-deuteromethyl-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 1.2: 1 h 2.1: 1,4-dioxane / 5 h / 100 °C

Reference： [1]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - US2018/312511, 2018, A1

35
[ 308242-23-1 ]
(S)-methyl 3-(8-bromo-1-(methoxymethyl)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 1.2: 1 h 2.1: 1,4-dioxane / 20 h / 100 °C

Reference： [1]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - US2018/312511, 2018, A1

36
[ 308242-23-1 ]
(S)-methyl 3-(7-bromo-2-((2-hydroxyethyl)amino)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-yl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 1.2: 1 h 2.1: 3 h

Reference： [1]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - US2018/312511, 2018, A1

37
[ 308242-23-1 ]
(S)-methyl 3-(8-bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 1.2: 1 h 2.1: 3 h 3.1: silica gel; dipyridinium dichromate / acetonitrile / 2 h

Reference： [1]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - US2018/312511, 2018, A1

38
[ 308242-23-1 ]
methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazol[1,2-a][1,4]benzodiazepine-4-yl]propionate sulfate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 2-bromo-pyridine / dichloromethane 1.2: -20 - -15 °C 2.1: dichloromethane / 0.5 h / -20 - -15 °C 2.2: -20 - -15 °C 3.1: hydrogenchloride / methanol / 15 - 25 °C 4.1: sulfuric acid / acetone / 0.17 h / 20 - 30 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2018/148361, 2018, A1

39
(2S)-2-(fluorenyl-9-methoxycarbonylamino)-5-methoxy-5-oxopentanoic acid [ No CAS ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 3 h / 15 - 20 °C 2: dichloromethane / 0.5 h / 0 - 10 °C / Reflux 3: triethylamine / dichloromethane / 40 - 45 °C

Reference： [1]Current Patent Assignee: MOEHS IBERICA S L - WO2019/20790, 2019, A1

40
methyl (4S)-4-(fluorenyl-9-methoxycarbonylamino)-5-[4-bromo-2-(pyridin-2-carbonyl)anilino]-5-oxopentanoate [ No CAS ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
62%	With triethylamine In dichloromethane at 40 - 45℃;	4 Comparative Example 4. Obtaining 3-[(3S)-7-bromo-2-oxo-5-(pyridin-2-yl) -2, 3-dihydro-1H- [1,4] -benzodiazepin-3-yl]propionic acid methyl ester of formula (D) from methyl (4S)-4-(fluorenyl-9-methoxycarbonylamino)-5-[4-bromo-2-(pyridin-2-carbonyl) anilino] -5-oxo-pentanoate 16.8 g (26 mmol) of methyl (4S)-4-(fluorenyl-9-methoxycarbonylamino) -5- [4-bromo-2- (pyridin-2-carbonyl) anilino] - 5-oxo-pentanoate were dissolved in 80 ml of dichloromethane and48.8 g (482 mmol) of triethylamine were added. Once the additionended, the obtained mixture was kept under stirring overnight at a temperature between 40 and 45°C.After being kept as described, the reaction mixture was concentrated by means of vacuum to obtain a residue to which 40 ml of acetone were added. It was heated at reflux, obtaining ahomogeneous mixture which was cooled at a temperature of about20°C. The resulting solid was filtered and washed with acetone, yielding a product containing 62% of 3-[(3S)-7-bromo-2-oxo-5- (pyridin-2-yl) -2, 3-dihydro-1H- [1,4] -benzodiazepin-3-yl] propionic acid methyl ester of formula (D) . This solid wasrecrystallized in isopropanol, obtaining 4.2 g (40%) of the desired product with a purity of 94%. The purity of the obtained products was analyzed by means of the ultra-high performance liquid chromatography technique in a Waters Acquity H-Class apparatus provided with a variable wave detector and atemperature-controlled oven for the column.

Reference： [1]Current Patent Assignee: MOEHS IBERICA S L - WO2019/20790, 2019, A1 Location in patent: Page/Page column 23

41
[ 1499-55-4 ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: chloro-trimethyl-silane; N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / 0 - 5 °C / Reflux 1.2: 2.5 h / 0 - 25 °C 2.1: dicyclohexyl-carbodiimide / dichloromethane / 48 h / -10 - 15 °C 3.1: acetic acid; hydrogen bromide / 2 h / 10 - 20 °C
	Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane; N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / 0 - 5 °C / Reflux 1.2: 2 h / 0 - 20 °C 2.1: thionyl chloride / dichloromethane; N,N-dimethyl-formamide / 3 h / 15 - 20 °C 3.1: dichloromethane / 0.5 h / 0 - 10 °C / Reflux 4.1: triethylamine / dichloromethane / 40 - 45 °C
	Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane; N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / 0 - 5 °C / Reflux 1.2: 2.5 h / 0 - 25 °C 2.1: dicyclohexyl-carbodiimide / dichloromethane / 48 h / -10 - 15 °C 3.1: acetic acid; hydrogen bromide / 2 h / 10 - 20 °C 4.1: sodium hydrogencarbonate / dichloromethane; isopropyl alcohol; n-heptane / 25 °C / pH 3.8-4 / Reflux

Reference： [1]Current Patent Assignee: MOEHS IBERICA S L - WO2019/20790, 2019, A1
[2]Current Patent Assignee: MOEHS IBERICA - WO2019/72944, 2019, A1
[3]Current Patent Assignee: MOEHS IBERICA - WO2019/72944, 2019, A1

42
[ 4652-65-7 ]
[ 308242-23-1 ]

Reference： [1]Patent: WO2019/20790,2019,A1
[2]Patent: WO2019/72944,2019,A1

43
methyl (4S)-4-(benzyloxycarbonylamino)-5-[4-bromo-2-(pyridine-2-carbonyl)aniline]-5-oxopentanoate [ No CAS ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
88.2%	With hydrogen bromide; acetic acid at 10 - 20℃; for 2h;	3 Example 3. Obtaining 3-[(3S)-7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-[1,4]-benzodiazepin-3-yl] propionic acid methyl esterof formula (D) 35.0 g (63 mmol) of methyl (4S)-4-(benzyloxycarbonylamino)-5-[4-bromo-2-(pyridin-2-carbonyl)anilino]-5-oxo-pentanoate offormula (I-B) were dissolved in 70 ml of glacial acetic acid. Maintaining the temperature between 10 and 12°C, 45.7 ml (61.9 g, 253 mmol) of a 33 wt% pre-prepared solution of HBr in glacial acetic acid were slowly added. Once the addition ended, the temperature of the obtained mixture was left to increase toabout 20°C and it was kept under stirring for 2 hours between 15 and 20°C.After being kept as described, 120 ml of water and 50 ml of dichloromethane were added. The resulting aqueous phasecontaining methyl (4S) -4-amino-5- [4-bromo-2- (pyridin-2-carbonyl)anilino]-5-oxo-pentanoate hydrobromide salt of formula(I-C) was separated, and the pH thereof was adjusted in therange of 3.8-4 by means of adding sodium bicarbonate at a temperature of about 25°C. Dichloromethane was added and the organic phase containing the reaction product corresponding to 3- [ (3S) -7-bromo-2-oxo-5- (pyridin-2-yl) -2, 3-dihydro-1H- [1,4] -benzodiazepin-3-yl] propionic acid methyl ester of formula (D) was separated. The organic solvent was vacuum-distilled and 50 ml of isopropanol were added on the resulting residue. The obtained mixture was heated at reflux temperature (about 82°C) and 50 ml of n-heptane were then added. The mixture was slowlycooled to about 20°C and the resulting solid is filtered and dried in an oven, finally obtaining 22.4 g (88.2%) of 3-[(3S)-7- bromo-2-oxo-5- (pyridin-2-yl) -2, 3-dihydro-1H- [1,4] -benzodiazepin3-yl] propionic acid methyl ester of formula (D) with a purity of 99.0%. The purity of the obtained products was analyzed bymeans of the ultra-high performance liquid chromatographytechnique in a Waters Acquity H-Class apparatus provided with avariable wave detector and a temperature-controlled oven for thecolumn. Figure 3 shows the 1H-NMR spectrum. 1H-NMR (CDC13, 400MHz) : 9.01 (1H, s) , 8.59 (1H, m) , 8.05 (1H, d) , 7.81 (1H, m)7.58 (1H, m) , 7.5 (1H, d) , 7.36 (1H, m) , 7.02 (1H, d) , 3.74 (1H, m) , 3.67 (3H, s) , 2.67 (2H, m) , 2.50 (2H, m)
	Multi-step reaction with 2 steps 1: acetic acid; hydrogen bromide / 2 h / 10 - 20 °C 2: sodium hydrogencarbonate / dichloromethane; isopropyl alcohol; n-heptane / 25 °C / pH 3.8-4 / Reflux

Reference： [1]Current Patent Assignee: MOEHS IBERICA S L - WO2019/20790, 2019, A1 Location in patent: Page/Page column 18; 19
[2]Current Patent Assignee: MOEHS IBERICA - WO2019/72944, 2019, A1

44
[ 308242-23-1 ]
[ 7264-90-6 ]
3-[(3S)-7-bromo-2-(bis-morpholinophosphoryloxy)-5-(pyridin-2-yl)-[1,4]-benzodiazepin-3-yl]propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With lithium diisopropyl amide In tetrahydrofuran; n-heptane at -25 - -5℃; for 2h; Inert atmosphere;	6 Comparative Example 6. Obtaining 3-[ (3S)-7-bromo-2-(bis- morpholinophosphoryloxy) -5- (pyridin-2-yl) -[1,4] -benzodiazepin-3- yl]-propionic acid methyl ester of formula (El) from the compound of formula (D) 5.5 g (13.67 mmol) of 3-[(3S)-7-bromo-2-oxo-5-(pyridin-2- yl)-2,3-dihydro-1H-[l,4]-benzodiazepin-3-yl] propionic acid methyl ester were dissolved in 30 mL of anhydrous tetrahydrofuran. 7 mL of a commercial 2M lithium diisopropylamide solution in a mixture of tetrahydrofuran and n35 heptane were added slowly, keeping the temperature at about -25°C and under a nitrogen atmosphere. Once the addition ended, the temperature was increased to -5°C, and 28 mL of a solution previously prepared according to the methodology described in Comparative Example 5, corresponding to 6.9 g (27.10 mmol) of bis-morpholinophosphorylchloride (BMPC), were added, maintainingsaid temperature. The obtained mixture was left to develop under stirring in a nitrogen atmosphere for 2 hours at a temperature of about -5°C, the total consumption of the starting product being verified by means of UPLC (ultra performance liquid chromatography)

Reference： [1]Current Patent Assignee: MOEHS IBERICA - WO2019/72944, 2019, A1 Location in patent: Page/Page column 41; 42

45
methyl (4S)-4-amino-5-[4-bromo-2-(pyridine-2-carbonyl) aniline]-5-oxopentanoate hydrobromide salt [ No CAS ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
88.2%	With sodium hydrogencarbonate In n-heptane; dichloromethane; isopropyl alcohol at 25℃; Reflux;	3 Example 3. Obtaining 3-[(3S)-7-bromo-2-oxo-5-(pyridin-2-yl)-2,3- dihydro-1H-[1,4]-benzodiazepin-3-yl] propionic acid methyl ester of formula (D) 35.0 g (63 mmol) of methyl (4S)-4-(benzyloxycarbonylamino)-5- [4-bromo-2- (pyridine-2-carbonyl) aniline] -5-oxo-pentanoate offormula (I-B) were dissolved in 70 mL of glacial acetic acid.45.7 mL (61.9 g, 253 mmol) of a previously prepared 33% byweight solution of HBr in glacial acetic acid were added slowly,keeping the temperature between 10 and 12°C. Once the additionended, the temperature of the mixture obtained was left to go up to about 20°C, and it was kept under stirring for 2 hours between 15 and 20°C.Once it no longer had to be kept under the aforementioned conditions, 120 mL of water and 50 mL of dichloromethane wereadded. The resulting aqueous phase containing methyl (4S)-4- amino-5- [4-bromo-2- (pyridine-2-carbonyl) aniline] -5-oxo- pentanoate hydrobromide salt of formula (I-C) was separated, and the pH thereof was adjusted to the range of 3.8-4 by means of adding sodium bicarbonate at a temperature of about 25°C.Dichloromethane was added, and the organic phase containing the reaction product corresponding to 3-[(3S)-7-bromo-2-oxo-5- (pyridin-2-yl) -2, 3-dihydro-1H- [1,4] -benzodiazepin-3-yl] propionic acid methyl ester of formula (D) was separated. The organic solvent was vacuum-distilled, and 50 mL of isopropanolwere added to the resulting residue. The obtained mixture was heated at the reflux temperature (about 82°C), and 50 mL of nheptane were then added. The mixture was cooled slowly to about 20°C, and the resulting solid was filtered and oven-dried, finally obtaining 22.4 g (88.2%) of 3-[(3S)-7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-[1,4]-benzodiazepin-3-yl] propionic acid methyl ester of formula (D) with a purity of99.0%. The purity of the obtained products was analyzed by means of the ultra high performance liquid chromatography technique in Waters Acquity HClass equipment, equipped with a variable wavedetector and temperature-controlled oven for the column. Figure3 shows the 1H-NMR spectrum. 1H-NMR (CDC13, 400 MHz) 6 (ppm)9.01 (1H, s) , 8.59 (1H, m) , 8.05 (1H, d) , 7.81 (1H, m) , 7.58(1H, m) , 7.5 (1H, d) , 7.36 (1H, m) , 7.02 (1H, d) , 3.74 (1H, m)3.67 (3H, s) , 2.67 (2H, m) , 2.50 (2H, m)

Reference： [1]Current Patent Assignee: MOEHS IBERICA - WO2019/72944, 2019, A1 Location in patent: Page/Page column 36; 37

46
(S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-methoxy-5-oxopentanoic acid [ No CAS ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: thionyl chloride / dichloromethane; N,N-dimethyl-formamide / 3 h / 15 - 20 °C 2: dichloromethane / 0.5 h / 0 - 10 °C / Reflux 3: triethylamine / dichloromethane / 40 - 45 °C

Reference： [1]Current Patent Assignee: MOEHS IBERICA - WO2019/72944, 2019, A1

47
[ 308243-40-5 ]
[ 308242-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: dichloromethane / 0.5 h / 0 - 10 °C / Reflux 2: triethylamine / dichloromethane / 40 - 45 °C

Reference： [1]Current Patent Assignee: MOEHS IBERICA - WO2019/72944, 2019, A1

48
[ 308242-23-1 ]
(S)-3-(7-bromo-5-(pyridin-2-yl)-2-thioso-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl) propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With phosphorous pentasulfide In tetrahydrofuran; acetonitrile at 20℃; for 2h; Large scale;	1-1 Example 1-1: Preparation of compound of formula 3 3-[(S)-7-Bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-propionic acid methyl ester (Formula 2 ) 3 kg were suspended in a mixed solution of 11.7 L of acetonitrile (30 equivalents relative to 1 equivalent of compound of Formula 2) and 15 L of tetrahydrofuran (25 equivalents of compound of Formula 2). 3.32 kg of phosphorus pentasulfide (2 equivalents relative to 1 equivalent of the compound of Formula 2) was added to the reaction mixture and stirred at 20±5° C. for 2 hours. To the reaction mixture, 10 L of dichloromethane and 10 L of purified water were added to the organic layer (compound of Formula 3; (S)-3-(7-bromo-5-(pyridin-2-yl)-2-thioso-2; 3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propionic acid methyl ester) was extracted. After drying and filtration over anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure.

Reference： [1]Current Patent Assignee: HANA PHARM - WO2021/256679, 2021, A1 Location in patent: Paragraph 137-138

49
[ 308242-23-1 ]
(S)-3-(7-bromo-2-(methylamino)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-yl) propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: phosphorous pentasulfide / acetonitrile; tetrahydrofuran / 2 h / 20 °C / Large scale 2: tetrahydrofuran / 3 h / 0 - 50 °C / Large scale

Reference： [1]Current Patent Assignee: HANA PHARM - WO2021/256679, 2021, A1

50
[ 308242-23-1 ]
(S)-3-(7-bromo-2-(methyl(nitroso)amino)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-yl) propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: phosphorous pentasulfide / acetonitrile; tetrahydrofuran / 2 h / 20 °C / Large scale 2: tetrahydrofuran / 3 h / 0 - 50 °C / Large scale 3: glacial acetic acid; NaNO₂ / methanol / 4 h / 0 - 20 °C / Large scale

Reference： [1]Current Patent Assignee: HANA PHARM - WO2021/256679, 2021, A1

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	308242-23-1	MDL No. :	N/A
Formula :	C₁₈H₁₆BrN₃O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PITXBYGUVDYTBQ-HNNXBMFYSA-N
M.W :	402.24	Pubchem ID :	58780386
Synonyms :

Num. heavy atoms :	25
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.22
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	104.05
TPSA :	80.65 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-7.14 cm/s

Log Po/w (iLOGP) :	2.81
Log Po/w (XLOGP3) :	2.27
Log Po/w (WLOGP) :	2.0
Log Po/w (MLOGP) :	1.5
Log Po/w (SILICOS-IT) :	3.95
Consensus Log Po/w :	2.51

[ CAS No. 308242-23-1 ] {[proInfo.proName]}

Quality Control of [ 308242-23-1 ]

Related Doc. of [ 308242-23-1 ]

Product Details of [ 308242-23-1 ]

Calculated chemistry of [ 308242-23-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 308242-23-1 ]

Application In Synthesis of [ 308242-23-1 ]

[ 308242-23-1 ] Synthesis Path-Downstream 1~50

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 :	0.55

Log S (ESOL) :	-3.79
Solubility :	0.0654 mg/ml ; 0.000162 mol/l
Class :	Soluble
Log S (Ali) :	-3.6
Solubility :	0.101 mg/ml ; 0.000251 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-6.77
Solubility :	0.0000678 mg/ml ; 0.000000169 mol/l
Class :	Poorly soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.68

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

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
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P270	Do not eat, drink or smoke when using this product.
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P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
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P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
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P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling