[ CAS No. 50890-96-5 ] {[proInfo.proName]}

Name: 50890-96-5|(R)-2-((Methoxycarbonyl)amino)-2-phenylacetic acid|97%
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SKU: A345130
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Quality Control of [ 50890-96-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 50890-96-5 ]

Product Details of [ 50890-96-5 ]

CAS No. :	50890-96-5	MDL No. :	MFCD12796004
Formula :	C₁₀H₁₁NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GOJLQSAREKTKPT-MRVPVSSYSA-N
M.W :	209.20	Pubchem ID :	10910775
Synonyms :

Calculated chemistry of [ 50890-96-5 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.2
Num. rotatable bonds :	5
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	52.08
TPSA :	75.63 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.7 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.68
Log Po/w (XLOGP3) :	1.23
Log Po/w (WLOGP) :	0.84
Log Po/w (MLOGP) :	0.86
Log Po/w (SILICOS-IT) :	0.41
Consensus Log Po/w :	1.0

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.88
Solubility :	2.77 mg/ml ; 0.0132 mol/l
Class :	Very soluble
Log S (Ali) :	-2.42
Solubility :	0.803 mg/ml ; 0.00384 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.95
Solubility :	2.33 mg/ml ; 0.0111 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.07

Safety of [ 50890-96-5 ]

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:

Application In Synthesis of [ 50890-96-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 50890-96-5 ]
Downstream synthetic route of [ 50890-96-5 ]

[ 50890-96-5 ] Synthesis Path-Upstream 1~7

1
[ 875-74-1 ]
[ 79-22-1 ]
[ 50890-96-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydroxide In water at 0℃; for 1.33333 h;	To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 niL) at 0⁰C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting reaction was allowed to stir at 0⁰C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgSO₄, filtered and concentrated in vacuo to provide Int-2a (12.6 g, 91percent), which was used without further purification.
91%	Stage #1: With sodium hydroxide In water at 0℃; for 1 h; Stage #2: With hydrogenchloride In water	To a 0°C solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 rnmol) in water (60 mL) was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting reaction was allowed to stir at 0°C for 1 hour and then acidified with concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) 3/4nd the combined organic extracts were dried over MgS0₄, filtered-and concentrated in vacuo to provide Compound Int-5 (12.6 g, 91percent), which was used without farther purification.
91%	With sodium hydroxide In water at 0℃; for 1 h;	To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 °C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0 °C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgS0₄, filtered and concentrated in vacuo to provide Compound Int-2a (12.6 g, 91percent), which was used without further purification.

91%	With sodium hydroxide In water at 0℃; for 1 h;	To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 °C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0 °C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgS0₄, filtered and concentrated in vacuo to provide Compound Int-2a (12.6 g, 91percent), which was used without further purification.
91%	Stage #1: With sodium hydroxide In water at 0 - 20℃; for 1.33 h; Stage #2: With hydrogenchloride In water	EXAMPLE 2; To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 °C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting reaction was allowed to stir at 0 °C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgS0₄, filtered and concentrated in vacuo to provide compound Int-2a ( 12.6 g, 91percent), which was used without further purification.
91%	With sodium hydroxide In water at 0℃; for 1.33333 h;	EXAMPLE 2Preparation of Intermediate Compound Int-2a To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 °C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0 °C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgS0₄, filtered and concentrated in vacuo to provide Compound Int-2a (12.6 g, 91percent), which was used without further purification.
91%	With sodium hydroxide In water at 0℃; for 1.33333 h;	EXAMPLE 2Preparation of Intermediate Compound Int-2a To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 °C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0 °C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgS0₄, filtered and concentrated in vacuo to provide Compound Int-2a (12.6 g, 91percent), which was used without further purification.
80%	With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃;	D-(-)-α-Phenylglycine (0.165 mmol) was dissolvedin tetrahydrofuran (500 mL), followed by the addition of NaHCO3 (0.496 mmol) in water (500 mL), and then theaddition of methylchloroformate (0.182 mmol) at room temperature. The reaction mixture was stirred at room temperatureovernight. The mixture was acidified to pH = 3 with HCl (1N) and the volatile was concentrated in vacuo. The aqueouslayer was extracted with ethyl acetate and the organic layer was dried over MgSO4, filtered, and concentrated in vacuoto give compound 31 as a pale yellow solid in 80percent yield. MS (ESI, EI+) m/z = 209 (MH+).
67%	With sodium carbonate; sodium hydroxide In water at 20℃; for 3.25 h; Cooling with ice	5.1.1.1 (R)-2-((Methoxycarbonyl)amino)-2-phenylacetic acid (9) Na₂CO₃ (0.55 g, 5.2 mmol) was added to an aq NaOH (10 mL of 1 M/H₂O, 10 mmol) solution of d-phenylglycine (1.500 g, 10.0 mmol) and the resulting solution was cooled in an ice-water bath. Methyl chloroformate (0.85 mL, 11.0 mmol) was added dropwise, then the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 3.25 h. The reaction mixture was washed with ether (3 * 18 mL), and the aqueous phase was cooled in an ice-water bath and acidified with conc. HCl to a pH range of 1-2, and extracted with CH₂Cl₂ (3 * 18 mL). The organic phase was dried (MgSO₄), filtered, and concentrated in vacuo, and the resulting oil residue was treated with diethyl ether/hexanes (∼5:4 ratio; 10 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (∼1:3 ratio) and dried in vacuo to provide 9 as a fluffy white solid (1.4 g, 67percent). ¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): 12.79 (br s, 1H), 7.96 (d, J = 12, 1H), 7.40-7.29 (m, 5H), 5.13 (d, J = 12, 1H), 3.55 (s, 3H).
67%	With sodium carbonate; sodium hydroxide In water at 20℃; for 3.25 h; Cooling with ice	General procedure: Na₂CO₃ (276mg, 2.6mmol) was added to aq NaOH (5mL of 1M/H₂O, 5mmol) solution of d-valine (586mg, 5.00mmol) and the resulting solution was cooled with ice-water bath. Methyl chloroformate (0.420mL, 5.40mmol) was added dropwise, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 3.25h. The reaction mixture was washed with ether (3×9mL), and the aqueous phase was cooled with ice-water bath and acidified with conc HCl to a pH region of 1–2, and extracted with CH₂Cl₂ (3×9mL). The organic phase was dried (MgSO₄), filtered, and concentrated in vacuo to afford Cap-1 as a white solid (760mg, 87percent).
67%	With sodium carbonate; sodium hydroxide In water at 20℃; for 3.25 h; Cooling with ice	Sodium carbonate (0.55 g, 5.2 mmol) Was added to D-phenylglycine (1.500 g, 10.0 mmol) Of sodium hydroxide aqueous solution (10 mL of 1 M / H 2 O, 10 mmol) The reaction mixture was cooled in an ice-water bath. Methylene chloroformate (0.85 mL, 11.0 mmol) was added in small portions, The ice bath was removed and the reaction mixture was stirred at room temperature for 3.25 hours. The reaction mixture was washed with ether (3 X 18 mL) and the water layer was cooled in an ice bath and then acidified to pH 1-2 by addition of con.HCl and extracted with dichloromethane (3 X 18 mL) . The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo and the resulting oil residue was treated with diethyl ether / hexane (5/4, 10 mL) to give a precipitate. The resulting precipitate was filtered, washed with diethyl ether / hexane (1/3) and then dried under vacuum to obtain the target compound (R) -2- (methoxycarbonylamino) -2- phenylacetic acid (1.4 g, 67percent yield) as a white solid.
63%	With sodium carbonate; sodium hydroxide In water at 20℃; for 3.25 h; Cooling with ice	Example 6 [(S)-1-((S)-2-{5-[4'-({(S)-1-[(S)-1-((R)-2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonyl}-amino)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester Sodium carbonate (2.10 g, 19.80 mmol) was added to a solution of sodium hydroxide (1.32 g, 33.10 mmol) and (R)-2-amino-2-phenylacetic acid (5.00 g, 33.10 mmol) in water (25 ml). Cool the solution in an ice bath and add methyl chloroformate (3.44 g, 36.40 mmol) dropwise over 15 min. After the addition was complete the ice bath was removed and the reaction stirred at room temperature for 3 h. The reaction mixture was washed with ether and the aqueous phase acidified with concentrated HCl to a pH of 1-2. The aqueous phase was extracted with methylene chloride and washed with water and a saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated to afford, (R)-2-(methoxycarbonylamino)-2-phenylacetic acid as a white solid, (4.35 g, 63percent): ESI-LRMS m/e calcd for C₁₀H₁₁NO₄ [M⁺] 209. found 210 [M+H⁺].
62%	With sodium hydroxide In water; toluene at 20℃; for 12 h; Cooling with ice	(R)-2-(methoxycarbonylamino)-2-phenylacetic acid To a mixture of (R)-2-amino-2-phenylacetic acid (9.2 g, 60.9 mmol), sodium hydroxide (4.87 g, 122 mmol), water (100 mL), and toluene (100 mL) cooled in ice-water bath was added dropwise methyl chloroformate (6.33 g, 66.9 mmol). The mixture was then warmed to room temperature and stirred for 12 h. The organic phase was separated. The aqueous phase was acidified with 6 N HCl at 0° C., and extracted with EtOAc. The EtOAc solution was washed with water and brine, dried over sodium sulfate, filtered and evaporated to give a white solid product. The product was recrystallized from ethyl acetate to give pure crystalline product, (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (7.9 g, 62percent): ESI-LRMS m/e calcd for C₁₀H₁₁NO₄ [M⁺] 209, found 208 [M-H⁺].

Reference： [1] Patent: WO2010/132538, 2010, A1, . Location in patent: Page/Page column 102-103
[2] Patent: WO2011/87740, 2011, A1, . Location in patent: Page/Page column 73; 74
[3] Patent: WO2012/40923, 2012, A1, . Location in patent: Page/Page column 71
[4] Patent: WO2012/50848, 2012, A1, . Location in patent: Page/Page column 70-71
[5] Patent: WO2012/125926, 2012, A2, . Location in patent: Page/Page column 34
[6] Patent: WO2013/39876, 2013, A1, . Location in patent: Page/Page column 62-63
[7] Patent: WO2013/39878, 2013, A1, . Location in patent: Page/Page column 58; 59
[8] Patent: EP2513113, 2018, B1, . Location in patent: Paragraph 0288; 0290; 0291
[9] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 3, p. 255 - 258
[10] European Journal of Medicinal Chemistry, 2015, vol. 101, p. 163 - 178
[11] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 87 - 100
[12] Patent: KR2017/31307, 2017, A, . Location in patent: Paragraph 0169-0171
[13] RSC Advances, 2018, vol. 8, # 55, p. 31803 - 31821
[14] Patent: US2015/166514, 2015, A1, . Location in patent: Paragraph 0177
[15] Patent: US2012/230951, 2012, A1, . Location in patent: Page/Page column 115
[16] Patent: WO2010/138791, 2010, A1, . Location in patent: Page/Page column 75
[17] Patent: WO2010/138790, 2010, A1, . Location in patent: Page/Page column 39-40
[18] Patent: WO2011/54834, 2011, A1, . Location in patent: Page/Page column 50
[19] Patent: WO2012/41227, 2012, A1, . Location in patent: Page/Page column 64
[20] Patent: WO2012/41014, 2012, A1, . Location in patent: Page/Page column 80-81
[21] Patent: WO2012/40924, 2012, A1, . Location in patent: Example 2
[22] Patent: US2012/219594, 2012, A1,
[23] Patent: EP2545060, 2015, B1, . Location in patent: Paragraph 0230; 0231

2
[ 1007877-76-0 ]
[ 50890-96-5 ]

Yield	Reaction Conditions	Operation in experiment
5.57 g	With trifluoroacetic acid In dichloromethane for 22 h; Cooling with ice	TFA (16 mL) was added dropwise to a cooled (ice/water) CH2Cl2 (160 mL) solution of the above product over7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotectionwas still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (∼1:3 ratio; 30 mL) anddried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9° [c=3.7 mg/mL in H2O; λ=589nm]. 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 12.84 (br s, 1H), 7.96 (d, J=8.3, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3,1H), 3.55 (s, 3H). LC (Cond. I): RT=1.01 min; >95 percent homogeneity index; LC/MS: Anal. Calcd. for [M+H]+C10H12NO4210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]+C10H12NO4 210.0766; found 210.0756.

Reference： [1] Patent: US2009/233925, 2009, A1, . Location in patent: Page/Page column 20
[2] Patent: WO2010/17401, 2010, A1, . Location in patent: Page/Page column 188
[3] Patent: WO2010/120621, 2010, A1, . Location in patent: Page/Page column 85; 86
[4] Patent: WO2010/138488, 2010, A1, . Location in patent: Page/Page column 79-80
[5] Patent: WO2010/138368, 2010, A1, . Location in patent: Page/Page column 38-39
[6] Patent: WO2011/60000, 2011, A1, . Location in patent: Page/Page column 124-125
[7] Patent: WO2011/59850, 2011, A1, . Location in patent: Page/Page column 40
[8] Patent: WO2011/75439, 2011, A1, . Location in patent: Page/Page column 35
[9] Patent: WO2012/18325, 2012, A1, . Location in patent: Page/Page column 37-38
[10] Patent: WO2012/39717, 2012, A1, . Location in patent: Page/Page column 185-186
[11] Patent: EP2328865, 2017, B1, . Location in patent: Paragraph 0340; 0342
[12] Patent: US2008/44379, 2008, A1, . Location in patent: Page/Page column 35
[13] Patent: US2008/44380, 2008, A1, . Location in patent: Page/Page column 34
[14] Patent: WO2008/144380, 2008, A1, . Location in patent: Page/Page column 49
[15] Patent: WO2009/102318, 2009, A1, . Location in patent: Page/Page column 45
[16] Patent: US2010/249190, 2010, A1, . Location in patent: Page/Page column 28-29
[17] Patent: WO2010/117635, 2010, A1, . Location in patent: Page/Page column 158

3
[ 79-22-1 ]
[ 50890-96-5 ]

Reference： [1] Patent: US2012/252721, 2012, A1,

4
[ 2935-35-5 ]
[ 79-22-1 ]
[ 50890-96-5 ]

Reference： [1] Patent: US2011/150827, 2011, A1,

5
[ 5817-70-9 ]
[ 50890-96-5 ]

Reference： [1] Synlett, 1999, # 7, p. 1106 - 1108

6
[ 21116-73-4 ]
[ 50890-96-5 ]

Reference： [1] Synlett, 1999, # 7, p. 1106 - 1108

7
[ 53934-78-4 ]
[ 50890-96-5 ]

Reference： [1] Patent: WO2010/117635, 2010, A1,

[ 50890-96-5 ] Synthesis Path-Downstream 1~58

1
[ 1007877-76-0 ]
[ 50890-96-5 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In dichloromethane; for 22.1h;Cooling with ice/water;	TFA (16 mL) was added dropwise to a cooled (ice/water) CH2Cl2 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (1:3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c=3.7 mg/l mL in H2O; lambda=589 nm]. 1H NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.84 (br s, 1H), 7.96 (d, J=8.3, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3, 1H), 3.55 (s, 3H). LC (Cond. I): RT=1.01 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C10N12NO4 210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]+ C10H12NO4 210.0766; found 210.0756.
	With trifluoroacetic acid; In dichloromethane; for 22h;	TFA (16 mL) was added dropwise to a cooled (ice/water) CH2Cl2 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (-1 :3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c=3.7 mg/mL in H2O; lambda=589 ran]. 1H NMR (DMSO-de, 5=2.5 ppm, 400 MHz): delta 12.84 (br s, IH), 7.96 (d, /=8.3, IH), 7.41-7.29 (m, 5H), 5.14 (d, /=8.3, IH), 3.55 (s, 3H). LC (Cond. I): RT=LOl min; >95 % homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ Cs0Hi2NO4 210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]+ Ci0Hi2NO4 210.0766; found 210.0756.
	With trifluoroacetic acid; In dichloromethane;Cooling with ice;	ClCO2Me (3.2 mL, 41.4 raraol) was added dropwise to a cooled (ice/water) THF (410 mL) semi-solution of (R)- tert-butyl 2-araino-2-phenylacetate/HCl (9.877 g, 40.52 mraol) and diisopropylethylamine (14.2 raL, 81.52 mmol) over 6 mill, and stirred at similar temperature for 5.5 hours. The volatile component was removed in vacuo, and the residue was partitioned between water (100 mL) and ethyl acetate (200 mL) . The organic layer was washed with IN HCl (25 mL) and saturated NaHCO3 solution (30 mL) , dried (MgSO4) , filtered, and concentrated in vacuo. The resultant colorless oil was triturated from hexanes, filtered and washed with hexanes (100 mL) to provide (R) - tert-butyl 2- (methoxycarbonylamino) -2-phenylacetate as a white solid (7.7 g) . 1H NMR (DMSO-d6, delta = 2.5 ppm, 400 MHz) : 7.98 (d, J=8.0 , IH), 7.37-7.29 (m, 5H), 5.09 (d, J=B, IH), 3.56 (s, 3H), 1.33 (s, 9H) . LC (Cond. I) : RT=I.53 min; -90 % homogeneity index; LC/MS : Anal. Calcd. for [M+Na]+ Ci4Hi9NNaO4: 288.12; found 288.15.TFA (16 mL) was added dropwise to a cooled (ice/water) CH2Cl2 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed85 in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (-1:3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g) , Optical rotation: -176.9 [c=3.7 mg/mL in H2O; lambda=589 nm] . 1H NMR (DMSO-d6, 6 = 2.5 ppm, 400 MHz) : delta 12.84 (br s, IH) , 7.96 {d, J=8.3, IH), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3, IH), 3.55 (s, 3H) . LC (Cond. I) : RT=LOl rain; >;95 % homogeneity index; LC/MS : Anal. Calcd. for [M+H] + C10Hi2NO4 210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]+ Ci0Hi2NO4 210.0766; found 210.0756.

	With trifluoroacetic acid; In dichloromethane;Cooling with ice;	TFA (16 mL) was added dropwise to a cooled (ice/water) CH2Cl2 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (~1 :3 ratio; 30 mL)-and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c=3.7 mg/mL in H2O; lambda=589 nm]. 1H NMR (DMSO-d6, delta= 2.5 ppm, 400 MHz): delta 12.84 (br s, IH), 7.96 (d, J=E 3, IH), 7.41-7.29 (m, 5H)5 5.14 (d, J=8.3, IH), 3.55 (s, 3H). LC (Cond. I): RT=LOl min; >;95 % homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C10H12NO4 210.08; found 210.17; HRMS: Anal.Calcd. for [M+H]+ C10H12NO4 210.0766; found 210.0756.
	With trifluoroacetic acid; In dichloromethane; for 22h;Cooling with ice;	TFA (16 mL) was added dropwise to a cooled (ice/water) CH2CI2 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) andhexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (~1 :3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c=3.7 mg/mL in H2O; lambda=589 ran]. 1H NMR (DMSO-d6,6=2.5 ppm, 400 MHz): delta 12.84 (br s, IH), 7.96 (d, /=8.3, IH), 7.41-7.29 (m, 5H)S 5.14 (d, /=8.3, IH), 3.55 (s, 3H). LC (Cond. I): RT=LOl min; >;95 % homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C10H12NO4 210.08; found 210.17; HRMS:Anal. Calcd. for [M+Hf C10H12NO4 210.0766; found 210.0756.
	With trifluoroacetic acid; In dichloromethane; for 20h;Cooling with ice;	ClC02Me (3.2 mL, 41.4 mmol) was added dropwise to a cooled(ice/water) THF (410 mL) semi-solution of (R)-/er/-butyl 2-amino-2- phenylacetate/HCl (9.877 g, 40.52 mmol) and diisopropylethylamine (14.2 mL, 81.52 mmol) over 6 min, and stirred at similar temperature for 5.5 hours. The volatile component was removed in vacuo, and the residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with IN HC1 (25 mL) and saturated NaHC03 solution (30 mL), dried (MgS04), filtered, and concentrated in vacuo. The resultant colorless oil was triturated from hexanes, filtered and washed with hexanes (100 mL) to provide (R)-/er/-butyl 2- (methoxycarbonylamino)-2-phenylacetate as a white solid (7.7 g). XH NMR (DMSO- d6, delta=2.5 ppm, 400 MHz): 7.98 (d, J=8.0, IH), 7.37-7.29 (m, 5H), 5.09 (d, J=8, IH), 3.56 (s, 3H), 1.33 (s, 9H). LC (Cond. I): RT=1.53 min; -90 % homogeneity index; LC/MS: Anal. Calcd. for [M+Na Ci4H19 a04: 288.12; found 288.15.[00285] TFA (16 mL) was added dropwise to a cooled (ice/water) CH2C12 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (~1 :3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c=3.7 mg/mL in H20; lambda=589 nm]. ¾ NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.84 (br s, 1H), 7.96 (d, J=8.3, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3, 1H), 3.55 (s, 3H). LC (Cond. I): RT=1.01 min; >95 % homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ Ci0H12NO4 210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]+ Ci0H12NO4 210.0766; found 210.0756.
	With trifluoroacetic acid; In dichloromethane; for 22.14h;Cooling with ice/water;	TFA (16 mL) was added dropwise to a cooled (ice/water) CH2C12 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (~1 :3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c=3.7 mg/mL in H20; lambda=589 nm]. 1H NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.84 (br s, IH), 7.96 (d, J=8.3, IH), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3, IH), 3.55 (s, 3H). LC (Condition I): RT=1.01 min; >95 % homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C10H12N04 210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]+ C10H12NO4 210.0766; found 210.0756.
	With trifluoroacetic acid; In dichloromethane; for 22h;Cooling with ice;	[00136] TFA (16 mL) was added dropwise to a cooled (ice/water) CH2CI2 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (~1 :3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c=3.7 mg/mL in H20; lambda=589 nm]. XH NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.84 (br s,IH), 7.96 (d, J=8.3, IH), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3, IH), 3.55 (s, 3H). LC (Condition I): RT=1.01 min; >95 % homogeneity index; LC-MS: Anal. Calcd. for[M+H]+ CioH12N04 210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]+ Ci0H12NO4 210.0766; found 210.0756. -5
	With trifluoroacetic acid; In dichloromethane; for 22h;Cooling with ice;	TFA (16 mL) was added dropwise to a cooled (ice/water) CH2CI2 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (~1:3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c=3.7 mg/mL in H20; lambda=589 nm]. XH NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.84 (br s, 1H), 7.96 (d, J=8.3, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3, 1H), 3.55 (s, 3H). LC (Cond. I): RT=1.01 min; >95 % homogeneity index; LC/MS: Anal. Calcd. for [M+H Ci0H12NO4 210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]+ Ci0Hi2NO4 210.0766; found 210.0756. -5
5.57 g	With trifluoroacetic acid; In dichloromethane; for 22h;Cooling with ice;	TFA (16 mL) was added dropwise to a cooled (ice/water) CH2Cl2 (160 mL) solution of the above product over7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotectionwas still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (?1:3 ratio; 30 mL) anddried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c=3.7 mg/mL in H2O; lambda=589nm]. 1H NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.84 (br s, 1H), 7.96 (d, J=8.3, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3,1H), 3.55 (s, 3H). LC (Cond. I): RT=1.01 min; >95 % homogeneity index; LC/MS: Anal. Calcd. for [M+H]+C10H12NO4210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]+C10H12NO4 210.0766; found 210.0756.
	With trifluoroacetic acid; In dichloromethane; at 0℃; for 22.1167h;	TFA (16 mL) was added dropwise to a cooled (ice/water) CH2Cl2 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (1:3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c=3.7 mg/mL in H2O; lambda=589 nm]. 1H NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.84 (br s, 1H), 7.96 (d, J=8.3, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3, 1H), 3.55 (s, 3H). LC (Cond. 1): RT=1.01 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C10H12NO4 210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]+ C10H12NO4 210.0766; found 210.0756.
	With trifluoroacetic acid; In dichloromethane; at 0℃; for 22h;	TFA (16 mL) was added dropwise to a cooled (ice/water) CH2Cl2 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (1:3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c=3.7 mg/mL in H2O; lambda=589 nm]. 1H NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.84 (br s, 1H), 7.96 (d, J=8.3, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3, 1H), 3.55 (s, 3H). LC (Cond. 1): RT=1.01 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C10H12NO4 210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]+ C10H12NO4 210.0766; found 210.0756.
	With trifluoroacetic acid; In dichloromethane; at 0℃; for 22.1167h;	TFA (16 mL) was added dropwise to a cooled (ice/water) CH2Cl2 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (~1:3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c=3.7 mg/mL in H2O; lambda=589 nm]. 1H NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.84 (br s, IH), 7.96 (d, J=8.3, IH), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3, IH), 3.55 (s, 3H). LC (Cond. I): RT=LOl min; >95 % homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ Ci0H12NO4 210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]+ Ci0Hi2NO4 210.0766; found 210.0756.
	With trifluoroacetic acid; In dichloromethane; for 22.1167h;Cooling with ice/water;	TFA (16 mL) was added dropwise to a cooled (ice/water) CH2Cl2 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (~1:3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c = 3.7 mg/mL in H2O; lambda = 589 nm]. 1H NMR (DMSO-d6, delta = 2.5 ppm, 400 MHz): delta 12.84 (br s, IH), 7.96 (d, J = 8.3, IH), 7.41-7.29 (m, 5H), 5.14 (d, J = 8.3, IH), 3.55 (s, 3H). LC (Cond. 1): RT = 1.01 min; >95 % homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ Ci0Hi2NO4 210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]+ Ci0Hi2NO4 210.0766; found 210.0756.
	With trifluoroacetic acid; In dichloromethane;Cooling with ice-water bath;	TFA (16 mL) was added dropwise to a cooled (ice/water) CH2Cl2 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (1:3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c=3.7 mg/mL in H2O; lambda=589 nm]. 1HNMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.84 (br s, 1H), 7.96 (d, J=8.3, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3, 1H), 3.55 (s, 3H). LC (Cond. 1): RT=1.01 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C10H12NO4 210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]+ C10H12NO4 210.0766; found 210.0756.
	With trifluoroacetic acid; In dichloromethane;Cooling with ice;	TFA (16 mL) was added dropwise to a cooled (ice/water) CH2Cl2 (160 mL) solution of the above product over 7 minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (-1 :3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 [c-3.7 mg/mL in H2O; lambda-589 ran]. 1H NMR (DMSO~d6, 6=2.5 ppm, 400 MHz): delta 12.84 (br s, IH), 7.96 (d, /=8.3, IH), 7.41-7.29 (m, 5H), 5.14 (d, /=8.3, IH), 3.55 (s, 3H). LC (Cond. I): RT-LOl min; >;95 % homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C10Hi2NO4 210.08; found 210.17; HRMS: Anal. Calcd. for [MH-H]+ C10Hs2NO4 210.0766; found 210.0756.

Reference： [1]Patent: US2009/233925,2009,A1 .Location in patent: Page/Page column 20
[2]Patent: WO2010/17401,2010,A1 .Location in patent: Page/Page column 188
[3]Patent: WO2010/120621,2010,A1 .Location in patent: Page/Page column 85; 86
[4]Patent: WO2010/138488,2010,A1 .Location in patent: Page/Page column 79-80
[5]Patent: WO2010/138368,2010,A1 .Location in patent: Page/Page column 38-39
[6]Patent: WO2011/60000,2011,A1 .Location in patent: Page/Page column 124-125
[7]Patent: WO2011/59850,2011,A1 .Location in patent: Page/Page column 40
[8]Patent: WO2011/75439,2011,A1 .Location in patent: Page/Page column 35
[9]Patent: WO2012/18325,2012,A1 .Location in patent: Page/Page column 37-38
[10]Patent: WO2012/39717,2012,A1 .Location in patent: Page/Page column 185-186
[11]Patent: EP2328865,2017,B1 .Location in patent: Paragraph 0340; 0342
[12]Patent: US2008/44379,2008,A1 .Location in patent: Page/Page column 35
[13]Patent: US2008/44380,2008,A1 .Location in patent: Page/Page column 34
[14]Patent: WO2008/144380,2008,A1 .Location in patent: Page/Page column 49
[15]Patent: WO2009/102318,2009,A1 .Location in patent: Page/Page column 45
[16]Patent: US2010/249190,2010,A1 .Location in patent: Page/Page column 28-29
[17]Patent: WO2010/117635,2010,A1 .Location in patent: Page/Page column 158

2
[ 5817-70-9 ]
[ 50890-96-5 ]

Reference： [1]Synlett,1999,p. 1106 - 1108

3
4,4'-bis(3-((S)-pyrrolidin-2yl)-1H-pyrazol-5-yl)biphenyl bistrifloroacetate [ No CAS ]
[ 50890-96-5 ]
[ 1085706-55-3 ]

Yield	Reaction Conditions	Operation in experiment
29%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 4h;	To a solution of the TFA salt of 4,4'-bis(3-((S>pyrrolidin-2-yl)-lH-pyrazol-5- yl)biphenyl (9a) (0.040 g, 0.0613 mmol), fR>2-(methoxycarbonylamino)-2- phenylacetic acid cap-4 (0.033 g, 0.158 mmol) and etaATU (0.061 g, 0.160 mmol) in DMF (2mL) at room temperature was added i-Pr2NEt (0.21 mL, 1.23 mmol). The mixture was allowed to stir at room temperature for 4 hours and then the crude reaction mixture was directly purified by preparative etaPLC (Ceta3CN:eta2O:TFA) and then repurified by preparative HPLC (CH3CN:H2O:NH4OAc) to give the title compound (30) (0.014 g, 29%) as a white fluffy solid. 1H NMR (400 MHz, DMSO- d6) delta 13.05 - 13.30 (m, IH), 12.63 - 12.85 (m, IH), 7.73 - 7.81 (m, 9H), 7.30 - 7.43 (m, 8H), 7.03 (s, br, IH), 6.93 (m, 0.7H), 6.76 (s, 0.3H), 6.62 (s, 0.7H), 6.43 (s,0.3H), 5.87 (s, 0.5H), 5.44 - 5.49 (m, 2H), 5.31 (s, br, 0.5H), 5.05 - 5.18 (m, 1.7H), 4.71 - 4.73 (m, 0.3H), 3.91 (s, IH), 3.71 - 3.75 (m, IH), 3.55 (s, 3H), 3.53 (s, 3H), <n="39"/>3.53 (m, obscured, IH), 3.18 (s, IH), 1.88 - 2.01 (m, 8H). LCMS: Anal. Calcd. for C46H46N8O6: 809; found: 810 (M+H)+.

Reference： [1]Patent: WO2008/144380,2008,A1 .Location in patent: Page/Page column 36-37

4
(x)C₂HF₃O₂*C₃₇H₄₁N₇O₃ [ No CAS ]
[ 50890-96-5 ]
[ 1228968-13-5 ]

Yield	Reaction Conditions	Operation in experiment
46%	With N-ethyl-N,N-diisopropylamine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 2h;	To a mixture of the TFA salt (200 mg, 0.17 mmol) in DMF (2 mL) and THF (1 mL) was added DIPEA (0.23 mL, 1.38 mmol), followed by N-Moc-D-Phg-OH (47 mg, 0.23 mmol) and DMTMM (72 mg, 0.26 mmol). After stirring at rt for 2 h, the reaction mixture was slowly dropped into H2O while stirring. The resulting precipitate was collected by filtration. The crude product was purified by prep-HPLC to afford 10 (65 mg, 46% yield). NMR (CDCI3, 400 MHz) delta 7.70-7.20 (m, 13H), 6.06 (d, 1H), 5.44 (m, 2H), 5.28 (m, 3H), 4.38 (m, 1H), 3.90-3.64 (m, 10H), 3.22 (m, 1H), 3.04 (m, 1H), 2.90 (m, 2H), 2.74 (m, 4H), 2.40-1.90 (m, 6H), 1.10-0.92 (m, 6H) ppm. LC-MS (ESI): m/z 823.4 (M+H)+.
46%	With N-ethyl-N,N-diisopropylamine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 2h;	Step i. To a mixture of the TFA salt (200 mg, 0.17 mmol) in DMF (2 mL) andTHF (1 mL) was added DIPEA (0.23 mL, 1.38 mmol), followed by N-Moc-D-Phg-OH (47 mg, 0.23 mmol) and DMTMM (72 mg, 0.26 mmol). After stirring at rt for 2 h, the reaction mixture was slowly dropped into H2O while stirring. The resulting precipitate was collected by filtration. The crude product was purified by prep-HPLC to afford 10 (65 mg, 46% yield). 1H NMR (CDCl3, 400 MHz) delta 7.70-7.20 (m, 13H), 6.06 (d, 1H), 5.44 (m, 2H), 5.28 (m, 3H), 4.38 (m, 1H), 3.90-3.64 (m, 10H), 3.22 (m, 1H), 3.04 (m, 1H), 2.90 (m, 2H), 2.74 (m, 4H), 2.40-1.90 (m, 6H), 1.10-0.92 (m, 6H) ppm. LC-MS (ESI): m/z 823.4 (M+H)+.

Reference： [1]Patent: WO2011/150243,2011,A1 .Location in patent: Page/Page column 147; 149
[2]Patent: WO2010/65668,2010,A1 .Location in patent: Page/Page column 149

5
C₂₅H₂₅Cl₃N₆O₂*(x)ClH [ No CAS ]
[ 50890-96-5 ]
[ 1228968-50-0 ]

Yield	Reaction Conditions	Operation in experiment
59%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h;	Step b. To a solution of 6' (150 mg, 0.23 mmol) in 2 mL DMF was added DIPEA (0.3 mL, 1.15 mmol) followed by N-Moc-D-Phg-OH (58 mg, 0.27 mmol) and HATU (100 mg, 0.27 mmol). The mixture was stirred at rt for Ih and then partitioned between H2O and DCM. The organic phase was washed successively with H2O (4 x 2 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to obtain a crude residue. The residue was purified by Prep-TLC to give T (100 mg, 59% yield). 1H NMR (500 MHz, CDCl3) delta 1.65 - 1.95 (m, 4H), 2.05 - 2.23 (m, 4H), 3.01 - 3.06 (m, 1H), 3.15 - 3.23 (m, 1H), 3.61 - 3.78 (s + m, 7H), 4.79 - 4.82 (m, 2H), 5.03 - 5.42 (m, 3H), 6.01 (d, 1H), 7.21 - 7.71 (m, 14H) ppm; LC-MS (ESI): m/z calcd. for C35H34Cl3N7O5 737.17, found 737.8.

Reference： [1]Patent: WO2010/65668,2010,A1 .Location in patent: Page/Page column 113

6
[ 1239649-51-4 ]
[ 50890-96-5 ]
[ 1228668-83-4 ]

Yield	Reaction Conditions	Operation in experiment
81%		Example 1-2.Step 2a. A solution of the compound from step Ic (79.0 mg, 0.122 mmol) in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) rt for 30 minutes. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z = 449.39 [M+H]+. Example 1-3.A mixture of the crude compound from step 2a (0.122 mmol at most) and (R)- (methoxycarbonyl)amino phenyl acetic acid (prepared according to WO 2008/021927, 76.4 mg, 0.366 mmol) in DMF (3 mL) was treated with HATU (0.102 g, 0.268 mmol) in the presence of DIPEA (0.30 mL, 2.44 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown sirup. It was purified by flash column chromatographyPAGE 99 OF 191 (silica, CH2Cl2-MeOH) to give the title compound as a yellow solid (82.4 mg, 2 steps 81%). ESIMS m/z = 831.59 [M+H]+.

Reference： [1]Patent: WO2010/91413,2010,A1 .Location in patent: Page/Page column 99-100

7
[ 1239656-74-6 ]
[ 50890-96-5 ]
[ 1239656-75-7 ]

Yield	Reaction Conditions	Operation in experiment
79%		Example 2-3 a.Step 3a-a. A solution of the compound of Example la-a (8.7 mg, 13.8 mumol) in 1,4- dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) rt for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z = 427.39 [M+H]+.Step 3a-b. A mixture of the crude compound of step 3a-a (13.8 mumol at most) and (R)- (methoxycarbonyl)amino phenyl acetic acid (prepared according to WO 2008/021927, 7.2 mg, 34.5 mumol) in DMF (3 mL) was treated with HATU (12.0 mg, 31.7 mumol) in the presence of DIPEA (34.4 muL, 0.276 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown sirup. It was purified by flash column chromatography (silica, CH2Cl2-MeOH) to give the title compound as a very light yellow solid (8.8 mg, 2 steps 79%). ESIMS m/z = 809.30 [M+H]+.

Reference： [1]Patent: WO2010/91413,2010,A1 .Location in patent: Page/Page column 120

8
2,6-bis-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)benzo[1,2-d:4,5-d']bis[1,3]thiazole tetratrifluoroacetate [ No CAS ]
[ 50890-96-5 ]
dimethyl ([1,3]thiazolo[5,4-f][1,3]benzothiazole-2,6-diylbis(1H-imidazole-4,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate bistrifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.4%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h;	HATU (43.6 mg, 0.115 mraol) was added to a stirred solution of 2, 6-bis (2- ( (2S) -2-pyrrolidinyl) -lH-imidazol- 5-yl)benzo[l,2-d:4,5-d']bis [1, 3] thiazole (27 mg, 0.029 ramol) , (R) -2- {methoxycarbonylamino) -2-phenylacetic acid (24.6 mg, 0.118 mmol) and DIEA (0.051 mL, 0.29 mmol} in dimethylformamide (2 mL) . The reaction was stirred for 16 h at room temperature. The reaction mixture was diluted with methanol (2 mL) and water (2 mL) , stirred for 15 min at room temperature and concentrated to dryness in vacuo. The residue was purified by preparative HPLC (acetonitrile/ water/ 0.1% TFA) to afford dimethyl ( [1, 3] thiazolo [5, 4-f] [1, 3]benzothiazole- 2,6-diylbis (lH-imidazole-4 , 2-diyl (2S) -2, 1- pyrrolidinediyl ( (IR) ~2~oxo-l-phenyl-2 , 1- ethanediyl) ) ) biscarbamate, bistrifluoroacetate (14.9 mg, 0.014 mmol, 47.4 % yield) as a pale yellow solid.76 LC-MS retention time 1.41 min; m/z 867.2 (MH+) . LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Sunfire 5u Cl 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 4 mL/rain, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% water / 0.1% TFA and solvent B was 90% acetonitrile / 10% water / 0.1% TFA. MS data was determined using a Mi?romass Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD~d4) 6 ppm 8.46 - 8.60 (m, 2H) , 7.32 - 7.52 (m, 10H) , 7.00 - 7.10 (m, 2H) , 5.55 (s, 2H) , 5.27 (dd, J=S.2, 3.4 Hz, 2H) , 4.03 (t,J=IO.8 Hz, 2H) , 3.58 - 3.78 (m, 8H) , 2.24 - 2.41 (m, 2H) , 2.10 - 2.24 (m, 4H) , 1.84 - 2.01 (m, 2H) .

Reference： [1]Patent: WO2010/120621,2010,A1 .Location in patent: Page/Page column 76; 77

9
[ 875-74-1 ]
[ 79-22-1 ]
[ 50890-96-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydroxide; In water; at 0℃; for 1.5h;	D-phenylglycine(20g, 32.2mmol)An aqueous solution (120 ml) of sodium hydroxide (42.4 g, 0.53 mol) was cooled to 0 C with an ice bath.Methyl chloroformate (10.4 ml, 266 mmol) was added dropwise over 30 minutes with stirring.After the reaction mixture was stirred at 0 C for 1 hour,Acidified with pre-cooled concentrated hydrochloric acid (50 ml, 600 mmol).The mixture was extracted with ethyl acetate (3×150 mL).Dry over anhydrous magnesium sulfate, filter,Concentrated under reduced pressureWhite solid S1-5(25.3g, 92%).
91%	With sodium hydroxide; In water; at 0℃; for 1.33333h;	To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 niL) at 00C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting reaction was allowed to stir at 00C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to provide Int-2a (12.6 g, 91%), which was used without further purification.
91%		To a 0C solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 rnmol) in water (60 mL) was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting reaction was allowed to stir at 0C for 1 hour and then acidified with concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) ¾nd the combined organic extracts were dried over MgS04, filtered-and concentrated in vacuo to provide Compound Int-5 (12.6 g, 91%), which was used without farther purification.

91%	With sodium hydroxide; In water; at 0℃; for 1h;	To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0 C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgS04, filtered and concentrated in vacuo to provide Compound Int-2a (12.6 g, 91%), which was used without further purification.
91%	With sodium hydroxide; In water; at 0℃; for 1h;	To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0 C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgS04, filtered and concentrated in vacuo to provide Compound Int-2a (12.6 g, 91%), which was used without further purification.
91%		EXAMPLE 2; To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting reaction was allowed to stir at 0 C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgS04, filtered and concentrated in vacuo to provide compound Int-2a ( 12.6 g, 91%), which was used without further purification.
91%	With sodium hydroxide; In water; at 0℃; for 1.33333h;	EXAMPLE 2Preparation of Intermediate Compound Int-2a To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0 C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgS04, filtered and concentrated in vacuo to provide Compound Int-2a (12.6 g, 91%), which was used without further purification.
91%	With sodium hydroxide; In water; at 0℃; for 1.33333h;	EXAMPLE 2Preparation of Intermediate Compound Int-2a To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0 C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgS04, filtered and concentrated in vacuo to provide Compound Int-2a (12.6 g, 91%), which was used without further purification.
80%	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃;	D-(-)-alpha-Phenylglycine (0.165 mmol) was dissolvedin tetrahydrofuran (500 mL), followed by the addition of NaHCO3 (0.496 mmol) in water (500 mL), and then theaddition of methylchloroformate (0.182 mmol) at room temperature. The reaction mixture was stirred at room temperatureovernight. The mixture was acidified to pH = 3 with HCl (1N) and the volatile was concentrated in vacuo. The aqueouslayer was extracted with ethyl acetate and the organic layer was dried over MgSO4, filtered, and concentrated in vacuoto give compound 31 as a pale yellow solid in 80% yield. MS (ESI, EI+) m/z = 209 (MH+).
67%	With sodium carbonate; sodium hydroxide; In water; at 20℃; for 3.25h;Cooling with ice;	5.1.1.1 (R)-2-((Methoxycarbonyl)amino)-2-phenylacetic acid (9) Na2CO3 (0.55 g, 5.2 mmol) was added to an aq NaOH (10 mL of 1 M/H2O, 10 mmol) solution of d-phenylglycine (1.500 g, 10.0 mmol) and the resulting solution was cooled in an ice-water bath. Methyl chloroformate (0.85 mL, 11.0 mmol) was added dropwise, then the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 3.25 h. The reaction mixture was washed with ether (3 * 18 mL), and the aqueous phase was cooled in an ice-water bath and acidified with conc. HCl to a pH range of 1-2, and extracted with CH2Cl2 (3 * 18 mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo, and the resulting oil residue was treated with diethyl ether/hexanes (?5:4 ratio; 10 mL) to provide a precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (?1:3 ratio) and dried in vacuo to provide 9 as a fluffy white solid (1.4 g, 67%). 1H NMR (DMSO-d6, delta = 2.5 ppm, 500 MHz): 12.79 (br s, 1H), 7.96 (d, J = 12, 1H), 7.40-7.29 (m, 5H), 5.13 (d, J = 12, 1H), 3.55 (s, 3H).
67%	With sodium carbonate; sodium hydroxide; In water; at 20℃; for 3.25h;Cooling with ice;	General procedure: Na2CO3 (276mg, 2.6mmol) was added to aq NaOH (5mL of 1M/H2O, 5mmol) solution of d-valine (586mg, 5.00mmol) and the resulting solution was cooled with ice-water bath. Methyl chloroformate (0.420mL, 5.40mmol) was added dropwise, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 3.25h. The reaction mixture was washed with ether (3×9mL), and the aqueous phase was cooled with ice-water bath and acidified with conc HCl to a pH region of 1-2, and extracted with CH2Cl2 (3×9mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo to afford Cap-1 as a white solid (760mg, 87%).
67%	With sodium carbonate; sodium hydroxide; In water; at 20℃; for 3.25h;Cooling with ice;	Sodium carbonate (0.55 g, 5.2 mmol) Was added to D-phenylglycine (1.500 g, 10.0 mmol) Of sodium hydroxide aqueous solution (10 mL of 1 M / H 2 O, 10 mmol) The reaction mixture was cooled in an ice-water bath. Methylene chloroformate (0.85 mL, 11.0 mmol) was added in small portions, The ice bath was removed and the reaction mixture was stirred at room temperature for 3.25 hours. The reaction mixture was washed with ether (3 X 18 mL) and the water layer was cooled in an ice bath and then acidified to pH 1-2 by addition of con.HCl and extracted with dichloromethane (3 X 18 mL) . The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo and the resulting oil residue was treated with diethyl ether / hexane (5/4, 10 mL) to give a precipitate. The resulting precipitate was filtered, washed with diethyl ether / hexane (1/3) and then dried under vacuum to obtain the target compound (R) -2- (methoxycarbonylamino) -2- phenylacetic acid (1.4 g, 67% yield) as a white solid.
63%	With sodium carbonate; sodium hydroxide; In water; at 20℃; for 3.25h;Cooling with ice;	Example 6 [(S)-1-((S)-2-{5-[4'-({(S)-1-[(S)-1-((R)-2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonyl}-amino)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester Sodium carbonate (2.10 g, 19.80 mmol) was added to a solution of sodium hydroxide (1.32 g, 33.10 mmol) and (R)-2-amino-2-phenylacetic acid (5.00 g, 33.10 mmol) in water (25 ml). Cool the solution in an ice bath and add methyl chloroformate (3.44 g, 36.40 mmol) dropwise over 15 min. After the addition was complete the ice bath was removed and the reaction stirred at room temperature for 3 h. The reaction mixture was washed with ether and the aqueous phase acidified with concentrated HCl to a pH of 1-2. The aqueous phase was extracted with methylene chloride and washed with water and a saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated to afford, (R)-2-(methoxycarbonylamino)-2-phenylacetic acid as a white solid, (4.35 g, 63%): ESI-LRMS m/e calcd for C10H11NO4 [M+] 209. found 210 [M+H+].
62%	With sodium hydroxide; In water; toluene; at 20℃; for 12h;Cooling with ice;	(R)-2-(methoxycarbonylamino)-2-phenylacetic acid To a mixture of (R)-2-amino-2-phenylacetic acid (9.2 g, 60.9 mmol), sodium hydroxide (4.87 g, 122 mmol), water (100 mL), and toluene (100 mL) cooled in ice-water bath was added dropwise methyl chloroformate (6.33 g, 66.9 mmol). The mixture was then warmed to room temperature and stirred for 12 h. The organic phase was separated. The aqueous phase was acidified with 6 N HCl at 0 C., and extracted with EtOAc. The EtOAc solution was washed with water and brine, dried over sodium sulfate, filtered and evaporated to give a white solid product. The product was recrystallized from ethyl acetate to give pure crystalline product, (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (7.9 g, 62%): ESI-LRMS m/e calcd for C10H11NO4 [M+] 209, found 208 [M-H+].
		To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 0C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0 0C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to provide Compound Int-2a (12.6 g, 91%), which was used without further purification.
		EXAMPLE 2Preparation of Intermediate Compound Int-2a nt-2aTo a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 niL) at O0C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting reaction was allowed to stir at 00C for 1 hour, and then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to provide compound Int- 2a ( 12.6 g, 91 %), which was used without further purification.
		2b.11 Synthesis of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid; To a solution of (R)-2-amino-2-phenylacetic acid (14 g, 92.6 mmol) in water (250 mL) was added LiOH (14.8 g, 618.7 mmol) at 0C and the mixture was stirred for 15 minutes. To this solution, methyl chloroformate (17.9 mL, 231.5 mmol) was added drop wise and the mixture was stirred for 2 hours at 0C. The mixture was then acidified until pH 1 with concentrated HC1. The mixture was extracted with EtOAc and the organic phase was concentrated in vacuum. The residue was dried overnight in vacuum, resulting in (i?)-2-(methoxycarbonylamino)-2-phenylacetic acid (11.8 g; 60.9 mmol).
		EXAMPLE 2Preparation of Intermediate Compound Int-2a Int-2aTo a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0 C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgS04, filtered and concentrated in vacuo to provide Int-2a (12.6 g, 91%), which was used without further purification.
		To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0 C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgS04, filtered and concentrated in vacuo to provide Compound Int-2a (12.6 g, 91%), which was used without further purification
		EXAMPLE 2Preparation of Intermediate Compound Int-2a Int-2aTo a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0 C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgS04, filtered and concentrated in vacuo to provide Int-2a (12.6 g, 91%), which was used without further purification.
	With LiOH; In water;	2b.11 Synthesis of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid To a solution of (R)-2-amino-2-phenylacetic acid (14 g, 92.6 mmol) in water (250 mL) was added LiOH (14.8 g, 618.7 mmol) at 0 C. and the mixture was stirred for 15 minutes. To this solution, methyl chloroformate (17.9 mL, 231.5 mmol) was added drop wise and the mixture was stirred for 2 hours at 0 C. The mixture was then acidified until pH 1 with concentrated HCl. The mixture was extracted with EtOAc and the organic phase was concentrated in vacuum. The residue was dried overnight in vacuum, resulting in (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (11.8 g; 60.9 mmol).
	With sodium hydroxide; In water; at 0℃; for 1.33333h;	EXAMPLE 2 Preparation of Intermediate Compound Int-2a (0230) (0231) To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0 C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to provide Compound Int-2a (12.6 g, 91%), which was used without further purification.

Reference： [1]Patent: CN109232612,2019,A .Location in patent: Paragraph 0090; 0091; 0092
[2]Patent: WO2010/132538,2010,A1 .Location in patent: Page/Page column 102-103
[3]Patent: WO2011/87740,2011,A1 .Location in patent: Page/Page column 73; 74
[4]Patent: WO2012/40923,2012,A1 .Location in patent: Page/Page column 71
[5]Patent: WO2012/50848,2012,A1 .Location in patent: Page/Page column 70-71
[6]Patent: WO2012/125926,2012,A2 .Location in patent: Page/Page column 34
[7]Patent: WO2013/39876,2013,A1 .Location in patent: Page/Page column 62-63
[8]Patent: WO2013/39878,2013,A1 .Location in patent: Page/Page column 58; 59
[9]Patent: EP2513113,2018,B1 .Location in patent: Paragraph 0288; 0290; 0291
[10]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 255 - 258
[11]European Journal of Medicinal Chemistry,2015,vol. 101,p. 163 - 178
[12]European Journal of Medicinal Chemistry,2017,vol. 125,p. 87 - 100
[13]Patent: KR2017/31307,2017,A .Location in patent: Paragraph 0169-0171
[14]RSC Advances,2018,vol. 8,p. 31803 - 31821
[15]Patent: US2015/166514,2015,A1 .Location in patent: Paragraph 0177
[16]Patent: US2012/230951,2012,A1 .Location in patent: Page/Page column 115
[17]Patent: WO2010/138791,2010,A1 .Location in patent: Page/Page column 75
[18]Patent: WO2010/138790,2010,A1 .Location in patent: Page/Page column 39-40
[19]Patent: WO2011/54834,2011,A1 .Location in patent: Page/Page column 50
[20]Patent: WO2012/41227,2012,A1 .Location in patent: Page/Page column 64
[21]Patent: WO2012/41014,2012,A1 .Location in patent: Page/Page column 80-81
[22]Patent: WO2012/40924,2012,A1 .Location in patent: Example 2
[23]Patent: US2012/219594,2012,A1
[24]Patent: EP2545060,2015,B1 .Location in patent: Paragraph 0230; 0231

10
[ 1255936-24-3 ]
[ 50890-96-5 ]
[ 1255936-26-5 ]

Yield	Reaction Conditions	Operation in experiment
68%	With HATU; In N,N-dimethyl-formamide; at 20℃; for 15h;	A solutin of compound Int-8e (1.0 g, 3.42 mmol), compound Int-8a (0.95 g, 4.54 mmol), HATU (1.3g, 3.42 mmol), and DMF (10 mL) was allowed to stir at room temperature for about 15 hours. The solution was then diluted with ethyl acetate (100 mL), washed with brine (3 X 40 mL), dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified using an 80 g silica gel column/ Combi-Flash system (0-5% methanol in dichloromethane) to provide compound Int-8b as a gel (1.12g, 68%).
68%	With HATU; In N,N-dimethyl-formamide; at 20℃; for 15h;	A solution of compound Int-9e (1.0 g, 3.42 mmol), compound Int-13a (0.95 g, 4.54 mmol), HATU (1.3g, 3.42 mmol), and DMF (10 mL) was allowed to stir at room temperature for about 15 hours. The solution was then diluted with ethyl acetate (100 mL), washed with brine (3 X 40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified using an 80 g silica gel column/ Combi- Flash system (0-5% methanol in dichloromethane) to provide Compound I?t-13b as a gel (1.12g, 68%).
68%	With HATU; In N,N-dimethyl-formamide; at 20℃; for 15h;	EXAMPLE 14 Preparation of Intermediate Compound Int-14b (0319) (0320) A solution of compound Int-9e (1.0 g, 3.42 mmol), compound Int-14a (0.95 g, 4.54 mmol), HATU (1.3g, 3.42 mmol), and DMF (10 mL) was allowed to stir at room temperature for about 15 hours. The solution was then diluted with ethyl acetate (100 mL), washed with brine (3 X 40 mL), dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified using an 80 g silica gel column/Combi-Flash system (0-5% methanol in dichloromethane) to provide Compound Int-14b as a gel (1.12g, 68%).

Reference： [1]Patent: WO2010/132538,2010,A1 .Location in patent: Page/Page column 107
[2]Patent: WO2010/138791,2010,A1 .Location in patent: Page/Page column 96
[3]Patent: EP2545060,2015,B1 .Location in patent: Paragraph 0319; 0320

11
[ 1307303-89-4 ]
[ 76-05-1 ]
[ 50890-96-5 ]
dimethyl (2,2'-bi-1,3-thiazole-5,5'-diylbis(1H-imidazole-4,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%		HATU (135 mg, 0.356 mmol) was added to a stirred solution of 5,5'-bis(2- ((2S)-2-pyrrolidinyl)-lH-imidazol-4-yl)-2,2'-bi-l,3-thiazole (40 mg, 0.091 mmol), <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (76 mg, 0.37 mmol) and DIEA (0.16 mL, 0.91 mmol) in dimethylformamide (2 mL) at room temperature. The reaction was stirred for 16 h, diluted with methanol (2 mL) and water (2 mL), stirred for 15 min and concentrated to dryness in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire C18 column 30 X 150 mm 5u, eluted with a gradient of 10 to 70 % acetonitrile/water/0.1 % TFA) to yield a trifluoroacetate salt of dimethyl (2,2'-bi-l,3-thiazole-5,5'-diylbis(lH-imidazole-4,2-diyl(2S)-2, l- pyrrolidinediyl((lR)-2-oxo-l-phenyl-2,l-ethanediyl)))biscarbamate (37 mg, 0.036 mmol, 39 % yield) as a yellow solid.[00184] LC-MS retention time 1.21 min; m/z 821.1 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nm. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/ 100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS Platform for LC in electrospray mode. XH NMR (400 MHz, MeOD-d4) delta ppm 8.29 (s, 2H), 7.87 (s, 2H), 7.48- 7.06 (m, 10H), 5.52 - 5.49 (m, 2H), 5.27 (dd, J=8.0, 3.8 Hz, 2H), 4.06 - 3.97 (m, 2H), 3.67 - 3.63 (m, 2H), 3.64 (s, 6H), 2.43 - 2.30 (m, 2H), 2.22 - 1.90 (m, 6H).

Reference： [1]Patent: WO2011/60000,2011,A1 .Location in patent: Page/Page column 68-69

12
[ 1228968-49-7 ]
[ 50890-96-5 ]
[ 1228968-50-0 ]

Yield	Reaction Conditions	Operation in experiment
59%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h;	To a solution of 6' (150 mg, 0.23 mmol) in 2 mL DMF was added DIPEA (0.3 mL, 1.15 mmol) followed by N-Moc-D-Phg-OH (58 mg, 0.27 mmol) and HATU (100 mg, 0.27 mmol). The mixture was stirred at rt for lh and then partitioned between ¾0 and DCM. The organic phase was washed successively with ¾0 (4 x 2 mL), dried over anhydrous Na2S04, and concentrated in vacuo to obtain a crude residue. The residue was purified by Prep-TLC to give T (100 mg, 59% yield). NMR (500 MHz, CDC13) delta 1.65 - 1.95 (m, 4H), 2.05 - 2.23 (m, 4H), 3.01 - 3.06 (m, 1H), 3.15 - 3.23 (m, 1H), 3.61 - 3.78 (s + m, 7H), 4.79 - 4.82 (m, 2H), 5.03 - 5.42 (m, 3H), 6.01 (d, 1H), 7.21 - 7.71 (m, 14H) ppm; LC-MS (ESI): m/z calcd. for C35H34Cl3N705 737.17, found 737.8.

Reference： [1]Patent: WO2011/150243,2011,A1 .Location in patent: Page/Page column 112; 113

13
[ 1378383-00-6 ]
[ 50890-96-5 ]
[ 1377035-29-4 ]

Yield	Reaction Conditions	Operation in experiment
26%		A mixture of (5)- benzyl 2-(5-(8-(2-((5}-l-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-lH- imidazol-5-yl)-6H-dibenzo [c,h]chromen-2-yl)- 1 H-imidazol-2-yl)pyrrolidine- 1 -carboxylate (260 mg, 0.33 mmol), 33% HBr in acetic acid (1 mL) and dichloromethane (4 mL) was vigorously stirred at room temperature for 30 minutes and then thoroughly concentrated. The crude material was diluted with dichloromethane and concentrated, letting the resulting residue sit under vacuum overnight. To this residue were sequentially added dichloromethane (2.4 mL), dimethylformamide (0.6 mL), (i?)-2-(methoxycarbonylamino)-2-phenylacetic acid (88 mg, 0.42 mmol), and COMU (154 mg, 0.36 mmol) and diisopropylethylamine (0.16 mL, 0.9 mmol). After stirring for 30 minutes at room temperature the reaction was diluted with ethyl acetate and washed sequentially with saturated aqueous NaHC03 solution, water and brine. The organic layer was dried (MgS04), then filtered through a freebasing column (Stratospheres PL- HC03MP SPE, Part No.: PL3540-C603). The filtrate was concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H20 + 0.1% HC02H) to yield methyl (R)-2-{{S)- 2-(5-(8-(2-((5}-l-((5)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-lH- imidazol-5 -yl)-6H-dibenzo [c, h] chromen-2-yl)- 1 H-imidazol-2-yl)pyrrolidin- 1 -yl)-2-oxo- 1 - phenylethylcarbamate (72 mg, 26%). LCMS-ESI+: calculated for C48H5oN807: 850.96; observed [M+l]+: 851.93.

Reference： [1]Patent: WO2012/68234,2012,A2 .Location in patent: Page/Page column 585; 586; 588

14
[ 1378383-10-8 ]
[ 50890-96-5 ]
[ 1377039-03-6 ]

Yield	Reaction Conditions	Operation in experiment
55%		To a solution of (£)- benzyl 2-(5-(4'-(2-((5}- 1 -((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)- /H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-7H-imidazol-2-yl)pyrrolidine-l-carboxylate (0.28 g, 0.37 mmol), potassium carbonate (105 mg, 0.75 mmol) and water (1 drop) in ethanol (5 mL) was added 10% palladium on carbon (200 mg). The reaction flask was flushed with argon for 2 minutes. Hydrogen gas was bubbled through the reaction mixture for 10 minutes. The reaction was stirred under hydrogen gas for 18 hours, and then flushed with argon. The mixture was diluted with methanol and filtered through Celite. The filtrate was concentrated and used without purification in the next step. This residue was dissolved in a 5:1 mixture ofdichloromethane:dimethylformamide (4.3 mL) and cooled to 0 C. To the solution were sequentially added <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (98 mg, 0.47 mmol) and COMU (202 mg, 0.47 mmol). After one hour, the reaction was diluted with acetonitrile (2 mL) and methanol (2 mL). To this solution was added ten drops of 5M aqueous NaOH solution and stirring was continued for 30 minutes. The reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined aqueous washings were extracted three times with ethyl acetate, and the combined organic layers were dried (MgS04) and concentrated. The crude material was purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H20 + 0.1% HC02H), followed by flash column chromatography to yield methyl (R)-2-((5)-2-(5-(4'-(2-((5)- 1 -((R)-2-methoxycarbonylamino-3 - methylbu1anoyl)pyrrolidin-2-yl)-lH-berizo[i¾imidazol-6-yl)biphenyl-4-yl)-lH-imidazol-2- yl)pyrrolidin-l-yl)-2-oxo-l-phenylethylcarbamate (165 mg, 55%). LCMS-ESf1": calculated for C47H5oN806: 822.95; observed [M+l]+: 823.87.

Reference： [1]Patent: WO2012/68234,2012,A2 .Location in patent: Page/Page column 591; 593; 594

15
[ 1378383-23-3 ]
[ 50890-96-5 ]
[ 1377040-19-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of (S)-benzyl 2- (5-(7-(2-((5 -l-((5)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-lH- benzo[<flimidazol-6-yl)-dibenzo[ ),£¾thiophen-3-yl)-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (0.19 g, 0.24 mmol), potassium carbonate (70 mg, 0.50 mmol) and water (1 drop) in ethanol (3.5 mL) was added 10% palladium on carbon (175 mg). The reaction flask was flushed with argon for 2 minutes. Hydrogen gas was bubbled through the reaction mixture for 10 minutes. The reaction was stirred under hydrogen gas for 18 hours, and then flushed with argon. The mixture was diluted with methanol and filtered through Celite. The filtrate was concentrated and used without purification in the next step. This residue was dissolved in a 5: 1 mixture ofdichloromethane:dimethylformamide (3.0 mL) and cooled to 0 C. To the solution were sequentially added (i?)-2-(methoxycarbonylamino)-2-phenylacetic acid (76 mg, 0.36 mmol) and COMU (150 mg, 0.35 mmol). After one hour, the reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined aqueous washings were extracted three times with ethyl acetate, and the combined organic layers were dried (MgS04) and concentrated. The crude material was purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H20 + 0.1% TFA) to yield methyl (R)-2-((S)-2-(5-(7-(2-((S l-((S)-2- methoxycarbonylamino-3 -methylbutanoyl)pyrrolidin-2-yl)- 1 H-benzo [i/]imidazol-6- yl)dibenzo[Z>, < ]thiophen-3 -yl)- 1 H-imidazol-2-yl)pyrrolidin- 1 -yl)-2-oxo- 1 -phenylethylcarbamate (95 mg, 47%). LCMS-ESf : calculated for C47H48N806S: 853.00; observed [M+l]+: 853.85.

Reference： [1]Patent: WO2012/68234,2012,A2 .Location in patent: Page/Page column 596; 598; 599

16
[ 1416718-23-4 ]
[ 50890-96-5 ]
[ 1416718-28-9 ]

Yield	Reaction Conditions	Operation in experiment
62%	With N-ethyl-N,N-diisopropylamine;HATU; In N,N-dimethyl-formamide; at 20℃; for 4h;	N,N'-Diisopropylethylamine (556 mg, 4.30 mmol) was added to a solution of 1-(4-bromo-phenyl)-3-(S)-pyrrolidine-2-carbonyl)-urea hydrochloride (500 mg, 1.43 mmol), <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (BMS patent) (300 mg, 1.43 mmol) and HATU (545 mg, 1.43 mmol) in DMF (10 mL). After the addition was complete the reaction was stirred at room temperature for 4 h. The reaction was diluted with ethyl acetate and washed with water, 2N hydrochloric acid, a saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated to afford, ((R)-2-{(S)-2-[3-(4-Bromo-phenyl)-ureidocarbonyl]-pyrrolidin-1-yl}-2-oxo-1-phenyl-ethyl)-carbamic acid methyl ester as a clear colorless oil, (448 mg, 62%): ESI-LRMS m/e calcd for C22H23BrN4O5 [M+] 503. found 531 [M+H+].

Reference： [1]Patent: US2012/328565,2012,A1 .Location in patent: Page/Page column 19

17
[ 1416718-33-6 ]
[ 50890-96-5 ]
[ 1416718-34-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine;HATU; In N,N-dimethyl-formamide; at 20℃; for 4h;	N,N'-Diisopropylethylamine (233 mg, 1.80 mmol) was added to a solution of 1-(6-bromo-pyridin-3-yl)-3-(S)-pyrrolidine-2-carbonyl)-urea hydrochloride (210 mg, 0.60), <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (BMS patent) (126 mg, 0.60 mmol) and HATU (228 mg, 0.60 mmol) in DMF (10 mL). After the addition was complete the reaction was stirred at room temperature for 4 h. The reaction was diluted with ethyl acetate and washed with water, 0.5N hydrochloric acid, a saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated to afford, ((R)-2-{(S)-2-[3-(6-Bromo-pyridin-3-yl)-ureidocarbonyl]-pyrrolidin-1-yl}-2-oxo-1-phenyl-ethyl)-carbamic acid methyl ester as a yellow solid, (284 mg, 94%): ESI-LRMS m/e calcd for C21H22BrN5O5 [M+] 504. found 505 [M+H+].

Reference： [1]Patent: US2012/328565,2012,A1 .Location in patent: Page/Page column 23

18
{(S)-2-methyl-1-[(S)-2-(5-{4'-[(S)-3-(pyrrolidine-2-carbonyl)ureidomethyl]biphenyl-4-yl}-1H-imidazol-2-yl)pyrrolidine-1-carbonyl]propyl}carbamic acid methyl ester dihydrochloride [ No CAS ]
[ 50890-96-5 ]
[ 1416718-20-1 ]

Yield	Reaction Conditions	Operation in experiment
16.4%	With N-ethyl-N,N-diisopropylamine;HATU; In N,N-dimethyl-formamide; at 23℃; for 16h;	Example 11 ((S)-1-{(S)-2-[5-(4'-{3-[(S)-1-((R)-2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidine-2-carbonyl]-ureidomethyl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester A suspension of methyl (2S)-3-methyl-1-oxo-1-((2S)-2-(5-(4'-((3-pyrrolidine-2-carbonylureido)methyl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate dihydrochloride (118.9 mg, 114 mumol) (prepared in the example 10), in DMF (5 ml) to give a light brown suspension and (S)-2-(methoxycarbonylamino)-2-phenylacetic acid (23.8 mg, 114 mmol), HATU (44.2 mg, 114 mumol, Eq: 1.00) in DMF (2.5 ml) were added. Then, the mixture was treated with N,N'-diisopropylethylamine (59.5 mul, 342 mumol). The reaction mixture was stirred for 16 h at 23 C. The reaction mixture, after aqueous work up using ethyl acetate/water followed by purification by reverse phase HPLC using a 50 g Polaris C18A column eluting with CH3CN/water (30% to 100%) gradient to afford ((S)-1-{(S)-2-[5-(4'-{3-[(S)-1-((R)-2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidine-2-carbonyl]-ureidomethyl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as off-white powder. (15.9 mg, yield-16.4%). ESI-LRMS m/e calcd for C43H50N8O8 [M+] 806. found 807 [M+H+]. 1H NMR (500 MHz, DMSO-d6) delta 11.51 (br. s., 1H), 10.18 (br. s., 1H), 8.55 (br. s., 1H), 7.78 (d, J=7.81 Hz, 2H), 7.55-7.71 (m, 4H), 7.22-7.54 (m, 7H), 5.67 (d, J=0.98 Hz, 1H), 5.46 (d, J=7.81 Hz, 1H), 5.11 (br. s., 1H), 4.42 (br. s., 2H), 4.06-4.16 (m, 1H), 3.66-3.86 (m, 2H), 3.48-3.59 (m, 6H), 3.18 (d, J=8.30 Hz, 1H), 1.66-2.28 (m, 8H), 0.77-0.95 (m, 6H).

Reference： [1]Patent: US2012/328565,2012,A1 .Location in patent: Page/Page column 26-27

19
C₃₉H₄₅N₇O₅*(x)ClH [ No CAS ]
[ 50890-96-5 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
65 mg	With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h;	PY Methyl {(2S)-l-[(2S,5S)-2-(9-{2-[(2S,4S)-l-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4- (methoxymethyl)pyrrolidin-2-yl]-lH-imidazol-5-yl}-l,ll- dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-2-yl)-5-methylpyrrolidin-l-yl]-3-methyl- 1 -oxobutan-2-yl} carbamate A solution of tert-butyl (2S,4S)-2-[5-(2- {(2S,5S)-l -[N-(methoxycarbonyl)-L-valyl]-5- methylpyrrolidin-2-yl}-l,l l-dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-9-yl)-lH- imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-l -carboxylate (150 mg, 0.19 mmol) in 1.25 N HCI in EtOH (3 mL) was stirred overnight then heated to 50 °C for 3h. The reaction was concentrated and the crude material dissolved in DMF (2 mL). To this solution was added a solution of (R)-2- (methoxycarbonylamino)-2-phenylacetic acid (52 mg, 0.25 mmol) and COMU (90 mg, 0.21 mmol). To the resulting solution was added diisopropylethylamine (0.099 mL, 0.57 mmol). After stirring for 2h at room temperature, the reaction was quenched with IN HCI (0.200 mL) and purified by HPLC. After lyophilization, the TFA salt was dissolved in EtOAc and washed with saturated NaHCOs. The organic phase was dried over Na2S04 and concentrated. The free base was then dissolved in MeCN/H20 and lyophilized to afford methyl {(2S)-l -[(2S,5S)-2-(9- {2-[(2S,4S)-l - {(2R)-2- [(methoxycarbonyl)amino]-2-phenylacetyl} -4-(methoxymethyl)pyrrolidin-2-yl]-lH-imidazol-5-yl} - l , l l -dihydroisochromeno[4',3':6,7]naphtho[l ,2-d]imidazol-2-yl)-5-methylpyrrolidin-l -yl]-3-methyl- l -oxobutan-2-yl} carbamate (65 mg, 39%). LCMS-ESI+: calculated for C49H54N808: 882.4; observed [M+l ]+: 884.1. Diagnostic peaks in NMR 'H NMR (CD3OD): 8.28 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.91 -7.01 (m, 10H), 3.62 (s, 3H), 3.34 (s, 3H), 3.23 (s, 3H), 1.56 (d, 3H), 1.03 (d, 3H), 0.94 (d, 3H).

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/75029, 2013, A1 Location in patent: Page/Page column 207; 208

20
C₃₆H₃₉N₇O₄*(x)ClH [ No CAS ]
[ 50890-96-5 ]
[ 1377604-57-3 ]

Yield	Reaction Conditions	Operation in experiment
45%	With 1-[(1-(cyano-?2-?ethoxy-?2-?oxoethylidenaminooxy)?dimethylamino-?morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;	[l-(2-{5-[2-(l-[(Methoxycarbonyl)amino](phenyl)acetyl}pyrrolidin-2-yl)-l,ll- dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-9-yl]-lH-imidazol-2-yl}pyrrolidin-l-yl)-3- methyl-l-oxobutan-2-yl]carbamic acidA solution of tert-butyl 2-[9-(2-{l-[N-(methoxycarbonyl)valyl]pyrrolidin-2-yl}-lH-imidazol- 5-yl)-l , 11 -dihydroisochromeno[4',3':6,7]naphtho[l ,2-d]imidazol-2-yl]pyrrolidine-l -carboxylate (462 mg, 0.63 mmol), ethanol (6 mL) and concentrated HC1 (2 mL) was heated to 60 C for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to this material was added a solution of (R)-2-(methoxycarbonylamino)-2- phenylacetic acid (172 mg, 0.82 mmol) and COMU (311 mg, 073 mmol) in DMF (6 mL). To the resulting solution was added diisopropylethylamine (330 L, 1.89 mmol). After stirring for 18 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2S04), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 45%ACN/H20 + 0.1% TFA). The product fractions were lyophilized to give [l-(2-{5-[2-(l- { [(methoxycarbonyl)amino] (phenyl)acetyl} pyrrolidin-2-yl)-l , 11- dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-9-yl]-lH-imidazol-2-yl}pyrrolidin-l-yl)-3 methyl- l-oxobutan-2-yl]carbamic acid (231 mg, 45%). LCMS-ESI+: calculated for C46H48N8078: 824.92; observed [M+l]+: 826.00

Reference： [1]Patent: WO2013/75029,2013,A1 .Location in patent: Page/Page column 57

21
C₃₈H₄₃N₇O₅*(x)ClH [ No CAS ]
[ 50890-96-5 ]
[ 1377048-01-5 ]

Yield	Reaction Conditions	Operation in experiment
39%	With 1-[(1-(cyano-?2-?ethoxy-?2-?oxoethylidenaminooxy)?dimethylamino-?morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;	methyl {2- [2- {9- [2-(l- {2- [(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-lH- imidazol-5-yl]-l,ll-dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-2-yl}-4- (methoxymethyl)pyrrolidin-l-yl]-2-oxo-l-phenylethyl}carbamate A solution of (2S,4S)-tert-butyl 2-(9-(2-((S)-l -((S)-2-(methoxycarbonylamino)-3- methylbutanoyl)pyrrolidin-2-yl)-lH-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)- 4-(methoxymethyl)pyrrolidine-l -carboxylate (196 mg, 0.25 mmol), ethanol (3 mL) and concentrated HC1 (1 mL) was heated to 60 C for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to this material was added a solution of <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (69 mg, 0.33 mmol) and COMU (124 mg, 029 mmol) in DMF (4 mL). To the resulting solution was added diisopropylethylamine (130 0.76 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2S04), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 45% ACN/H20 + 0.1% TFA). The product fractions were lyophilized to give methyl {2-[2- {9-[2-(l- {2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-lH- imidazol-5-yl]-l , 11 -dihydroisochromeno[4',3':6,7]naphtho[l ,2-d]imidazol-2-yl} -4- (methoxymethyl)pyrrolidin-l -yl]-2-oxo-l -phenylethyl}carbamate (84 mg, 39%>). LCMS-ESI+:calculated for C48H52N808: 868.98; observed [M+l]+: 870.11

Reference： [1]Patent: WO2013/75029,2013,A1 .Location in patent: Page/Page column 63

22
C₃₉H₄₃N₇O₅*(x)ClH [ No CAS ]
[ 50890-96-5 ]
methyl {2-[2-{9-[2-(2-{2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With 1-[(1-(cyano-?2-?ethoxy-?2-?oxoethylidenaminooxy)?dimethylamino-?morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;	methyl {2-[2-{9-[2-(2-{2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[3.1.0]hex-3- yl)-lH-imidazol-5-yl]-l,ll-dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-2-yl}-4- (methoxymethyl)pyrrolidin- 1 -yl] -2-oxo-l -phenylethyl} carbamate :A solution of (2S,4S)-tert-butyl 2-(9-(2-((S)-l -((S)-2-(methoxycarbonylamino)-3- methylbutanoyl)azabicyclo[3.1.0]hexan-3-yl)-lH-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9- d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-l-carboxylate (196 mg, 0.25 mmol), ethanol (3 mL) and concentrated HC1 (1 mL) was heated to 60 C for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to this material was added a solution of <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (69 mg, 0.33 mmol) and COMU (124 mg, 029 mmol) in DMF (4 mL). To the resulting solution was addeddiisopropylethylamine (130 mu?^, 0.76 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2S04), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 45% ACN/H20 + 0.1% TFA). The product fractions were lyophilized to give methyl {2-[2- {9-[2-(2- {2-[(methoxycarbonyl)amino]-3- methylbutanoyl} -2-azabicyclo[3.1.0]hex-3 -yl)-l H-imidazol-5-yl] -1 , 11- dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-2-yl} -4-(methoxymethyl)pyrrolidin-l-yl]-2- oxo-1 -phenylethyl} carbamate (84 mg, 39%). LCMS-ESI+: calculated for C49H52N808: 880.99; observed [M+l]+: 882.09

Reference： [1]Patent: WO2013/75029,2013,A1 .Location in patent: Page/Page column 66

23
[ 1378389-33-3 ]
[ 50890-96-5 ]
[ 1377049-54-1 ]

Yield	Reaction Conditions	Operation in experiment
35%		A solution of (2S,4S)-tert-butyl 2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxy late (170 mg, 0.22 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 C. for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to this material was added a solution of <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (59 mg, 0.28 mmol) and COMU (108 mg, 025 mmol) in DMF (3 mL). To the resulting solution was added diisopropylethylamine (110 muL, 0.66 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 44% ACN/H2O+0.1% TFA). The product fractions were lyophilized to give methyl {(1R)-2-[(2S,4R)-2-(9-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4?,3?:6,7]-naphtho[1,2-d]imidazol-2-yl}-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-phenylethyl}carbamate (67 mg, 35%). MS (ESI) m/z 870 [M+H]+. 1H NMR (400 MHz, dmso) delta 8.71 (s, 1H), 8.20 (d, 1H, J=8.4 Hz), 8.01 (m, 1H), 7.91-7.64 (m, 6H), 7.38-7.28 (m, 6H), 6.85 (s, 1H), 5.51 (d, 1H, J=7.2 Hz), 5.39-5.29 (m, 3H), 5.13-5.09 (m, 1H), 4.11-3.04 (m, 15H), 2.77-1.98 (m, 8H), 0.79 (dd, 6H, J=6.8 Hz, J=12.8 Hz)

Reference： [1]Patent: US2013/309196,2013,A1 .Location in patent: Paragraph 0272

24
(2S,4S)-tert-butyl 2-(9-chloro-4,5-dihydro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate [ No CAS ]
[ 50890-96-5 ]
[ 1377048-54-8 ]

Yield	Reaction Conditions	Operation in experiment
56%		A solution of (2S,4S)-tert-butyl 2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-1,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (156 mg, 0.18 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 C. for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to (90 mg, 0.12 mmol) of this material was added a solution of <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (34 mg, 0.16 mmol) and COMU (61 mg, 014 mmol) in DMF (2 mL). To the resulting solution was added diisopropylethylamine (60 muL, 0.37 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 49% ACN/H2O+0.1% TFA). The product fractions were lyophilized to give methyl {(2S)-2-[[(2S,4S)-2-{9-[2-((2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-y]-1,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (62 mg, 56%). MS (ESI) m/z 920 [M+H]+. 1H NMR (400 MHz, dmso) delta 8.73 (s, 1H), 8.17 (d, 2H, J=8.4 Hz), 7.94 (d, 3H, J=8.8 Hz), 7.84-7.67 (m, 6H), 7.37-7.29 (m, 6H), 5.48 (d, 1H, J=7.6 Hz), 5.35-5.20 (m, 5H), 4.14-3.12 (m, 15H), 2.52-1.92 (m, 8H), 0.80 (dd, 6H, J=6.8 Hz, J=6.4 Hz)

Reference： [1]Patent: US2013/309196,2013,A1 .Location in patent: Paragraph 0279

25
[ 1378389-43-5 ]
[ 50890-96-5 ]
[ 1377049-57-4 ]

Yield	Reaction Conditions	Operation in experiment
44%		A solution tert-butyl (2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxy carbonyl)-L-valyl]-pyrrolidin-2-yl}-1,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-carboxylate (122 mg, 0.16 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 C. for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (3 mL). This solution was concentrated and to this material was added a solution of <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (43 mg, 0.2 mmol) and COMU (77 mg, 018 mmol) in DMF (3 mL). To the resulting solution was added diisopropylethylamine (80 muL, 0.37 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 44% ACN/H2O+0.1% TFA). The product fractions were lyophilized to give methyl {(1R)-2-[(2S,4S)-2-(5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-pyrrolidin-2-yl]-1,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-[(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (60 mg, 44%). MS (ESI) m/z 870 [M+H]+. 1H NMR (400 MHz, dmso) delta 8.71 (s, 1H), 8.22 (d, 1H, J=8 Hz), 8.09 (m, 1H), 7.88-7.63 (m, 6H), 7.36-7.29 (m, 6H), 5.41 (d, 1H, J=8.4 Hz), 5.30-5.24 (m, 2H), 5.14-5.10 (m, 1H), 4.13-3.09 (m, 15H), 2.47-1.80 (m, 8H), 0.80 (dd, 6H, J=6.4 Hz, J=23 Hz)

Reference： [1]Patent: US2013/309196,2013,A1 .Location in patent: Paragraph 0284

26
[ 1378389-51-5 ]
[ 50890-96-5 ]
[ 1377049-90-5 ]

Yield	Reaction Conditions	Operation in experiment
63%		A solution (1R,3S,5R)-tert-butyl 3-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methoxymethylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (101 mg, 0.16 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 C. for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (3 mL). This solution was concentrated and to this material was added a solution of <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (35 mg, 0.17 mmol) and COMU (63 mg, 015 mmol) in DMF (3 mL). To the resulting solution was added diisopropylethylamine (70 muL, 0.38 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 44% ACN/H2O+0.1% TFA). The product fractions were lyophilized to give methyl methyl {(1R)-2-[(1R,3S,5R)-2-(9-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methoxymethylpyrrolidin-2-yl]-1H-imidazol-5 yl}-1,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-3-yl]-2-oxo-1-phenylethyl}carbamate (71 mg, 63). MS (ESI) m/z 882 [M+H]+. 1H NMR (400 MHz, dmso) delta 8.66 (s, 1H), 8.17 (d, 1H, J=8.8 Hz), 8.04 (s, 1H), 7.87-7.59 (m, 6H), 7.39-7.22 (m, 6H), 5.72 (d, 1H, J=7.6 Hz), 5.68 (s, 1H), 5.25 (s, 1H), 5.13-5.01 (m, 2H), 4.12-4.00 (m, 2H), 3.81-3.00 (m, 13H), 2.60 (m, 1H), 2.43-2.37 (m, 3H), 1.92-1.82 (m, 3H), 0.83-0.58 (m, 7H), 0.59 (s, 1H), 0.00 (s, 1H)

Reference： [1]Patent: US2013/309196,2013,A1 .Location in patent: Paragraph 0287

27
[ 1378391-45-7 ]
[ 50890-96-5 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
65 mg	Stage #1: tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate With hydrogenchloride In ethanol at 50℃; for 3h; Stage #2: (2R)-2-[(methoxycarbonyl)amino]-2-phenylacetic acid With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h;	CY A solution of tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (150 mg, 0.19 mmol) in 1.25 N HCl in EtOH (3 mL) was stirred overnight then heated to 50° C. for 3 h. The reaction was concentrated and the crude material dissolved in DMF (2 mL). To this solution was added a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (52 mg, 0.25 mmol) and COMU (90 mg, 0.21 mmol). To the resulting solution was added diisopropylethylamine (0.099 mL, 0.57 mmol). After stirring for 2 h at room temperature, the reaction was quenched with 1N HCl (0.200 mL) and purified by HPLC. After lyophilization, the TFA salt was dissolved in EtOAc and washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The free base was then dissolved in MeCN/H2O and lyophilized to afford methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (65 mg, 39%). LCMS-ESI+: calculated for C49H54N8O8: 882.4; observed [M+1]+: 884.1. Diagnostic peaks in NMR 1H NMR (CD3OD): 8.28 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.91-7.01 (m, 10H), 3.62 (s, 3H), 3.34 (s, 3H), 3.23 (s, 3H), 1.56 (d, 3H), 1.03 (d, 3H), 0.94 (d, 3H)

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2013/309196, 2013, A1 Location in patent: Paragraph 0491

28
tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-4-cyclopropyl-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate [ No CAS ]
[ 50890-96-5 ]
methyl {(1R)-2-[(2S,4S)-2-(4-cyclopropyl-5-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%		To a solution of tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-4-cyclopropyl-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (0.13 g, 0.15 mmol) in a mixture of CH2Cl2 (3.0 mL) and methanol (0.25 mL) was added HCl (in dioxanes, 4M, 1.1 mL, 4.40 mmol). The resulting solution was stirred at 40 C. for 1 h, and concentrated in vacuo. The resulting solid was slurried in CH2Cl2 (3.0 mL), and <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (0.05 g, 0.23 mmol) and diisopropylethylamine (0.1 mL, 0.57 mmol) were added. The reaction was cooled to -40 C. (MeCN/CO2 bath) and COMU (0.11 g, 0.25 mmol) was added. The resulting solution was allowed to warm to room temperature over 30 min, and stirred at room temperature for 1.5 h. The reaction was diluted with CH2Cl2 and washed with aqueous sodium bicarbonate. The aqueous layer was backextracted with CH2Cl2, and the combined organic layers were dried (Na2SO4) and concentrated. The crude oil was purified by reverse phase HPLC (Gemini, 10?58% MeCN/H2O (0.1% TFA)). The desired fractions were combined with MeOH and concentrated to remove volatiles. The resulting solution was basified with aqueous sodium bicarbonate (sat.). The resulting slurry was stirred at room temperature for 30 min, filtered (nylon membrane filter (0.45 um)), and washed with water. The solid was dried in vacuo to provide methyl {(1R)-2-[(2S,4S)-2-(4-cyclopropyl-5-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (0.05 g, 38%). LCMS-ESI+: calc'd for C52H58N8O8: 922.44 (M+); Found: 923.69 (M+H+). [0648] 1H NMR (400 MHz, cd3od) delta (Mixture of rotomers) 8.28 (s, 2H), 7.93 (s, 2H), 7.74-7.52 (m, 3H), 7.52-7.32 (m, 3H), 7.27-7.07 (m, 4H), 5.48-5.38 (m, 2H), 4.10-3.98 (m, 2H), 3.67-3.48 (m, 4H), 3.42-3.34 (m, 6H), 3.06 (s, 3H), 2.43-2.16 (m, 4H), 2.16-1.61 (m, 8H), 1.55-1.32 (m, 3H), 1.02-0.50 (m, 11H).

Reference： [1]Patent: US2013/309196,2013,A1 .Location in patent: Paragraph 0647-0648

29
[ 1378388-46-5 ]
[ 50890-96-5 ]
[ 1377048-01-5 ]

Yield	Reaction Conditions	Operation in experiment
39%		A solution of (2S,4S)-tert-butyl 2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (196 mg, 0.25 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 C. for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to this material was added a solution of <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (69 mg, 0.33 mmol) and COMU (124 mg, 029 mmol) in DMF (4 mL). To the resulting solution was added diisopropylethylamine (130 muL, 0.76 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 45% ACN/H2O+0.1% TFA). The product fractions were lyophilized to give methyl {2-[2-{9-[2-(1-{2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (84 mg, 39%). LCMS-ESI+: calculated for C48H52N8O8: 868.98; observed [M+1]+: 870.11

Reference： [1]Patent: US2013/309196,2013,A1 .Location in patent: Paragraph 0225

30
(2S,4S)-tert-butyl-2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino) methylbutanoyl)azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate [ No CAS ]
[ 50890-96-5 ]
methyl {2-[2-{9-[2-(2-{2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%		A solution of (2S,4S)-tert-butyl 2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (196 mg, 0.25 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 C. for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to this material was added a solution of <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (69 mg, 0.33 mmol) and COMU (124 mg, 029 mmol) in DMF (4 mL). To the resulting solution was added diisopropylethylamine (130 muL, 0.76 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 45% ACN/H2O+0.1% TFA). The product fractions were lyophilized to give methyl {2-[2-{9-[2-(2-{2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (84 mg, 39%). LCMS-ESI+: calculated for C49H52N8O8: 880.99; observed [M+1]+: 882.09

Reference： [1]Patent: US2013/309196,2013,A1 .Location in patent: Paragraph 0230

31
[ 1378389-18-4 ]
[ 50890-96-5 ]
[ 1377048-18-4 ]

Yield	Reaction Conditions	Operation in experiment
39%		A solution of tert-butyl (2S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (145 mg, 0.18 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 C. for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to this material was added a solution of <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (51 mg, 0.24 mmol) and COMU (92 mg, 021 mmol) in DMF (3 mL). To the resulting solution was added diisopropylethylamine (100 muL, 0.56 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 43% ACN/H2O+0.1% TFA). The product fractions were lyophilized to give methyl {(1R)-2-[(2S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (68 mg, 39%). MS (ESI) m/z 870 [M+H]+. 1H NMR (400 MHz, dmso) delta 8.71 (s, 1H), 8.22 (d, 1H, J=8 Hz), 8.09 (m, 1H), 7.88-7.63 (m, 6H), 7.36-7.29 (m, 6H), 5.41 (d, 1H, J=8.4 Hz), 5.30-5.24 (m, 2H), 5.14-5.10 (m, 1H), 4.13-3.09 (m, 15H), 2.47-1.80 (m, 8H), 0.80 (dd, 6H, J=6.4 Hz, J=23 Hz)

Reference： [1]Patent: US2013/309196,2013,A1 .Location in patent: Paragraph 0260

32
[ 1378389-23-1 ]
[ 50890-96-5 ]
[ 1377048-51-5 ]

Yield	Reaction Conditions	Operation in experiment
39%		A solution of tert-butyl (2S,4S)-2-[9-(2-{(2S4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-3,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxy methyl)pyrrolidine-1-carboxylate (182 mg, 0.18 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 C. for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to this material was added a solution of <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (47 mg, 0.23 mmol) and COMU (85 mg, 0.2 mmol) in DMF (3 mL). To the resulting solution was added diisopropylethylamine (90 muL, 0.52 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 49% ACN/H2O+0.1% TFA). The product fractions were lyophilized to give methyl {(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4?,3?:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (32 mg, 39%). MS (ESI) m/z 884 [M+H]+. 1H NMR (400 MHz, dmso) delta 8.70 (s, 1H), 8.21 (d, 1H, J=8 Hz), 8.08 (s, 1H), 7.90-7.64 (m, 6H), 7.34-7.31 (m, 3H), 7.64 (d, 1H, J=8.4 Hz), 5.47 (d, 1H, J=7.6 Hz), 5.28-5.25 (m, 3H), 5.05-5.01 (m, 1H), 4.19-4.04 (m, 3H), 3.67-3.15 (m, 15H), 2.51-2.46 (m, 4H), 1.95-1.92 (m, 2H), 1.82-1.76 (m, 1H), 1.10 (d, 3H, J=6 Hz), 0.75 (dd, 6H, J=6.8 Hz, J=14 Hz)

Reference： [1]Patent: US2013/309196,2013,A1 .Location in patent: Paragraph 0263

33
(S)-N-(4-bromophenyl)-1-((S)-pyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide hydrochloride [ No CAS ]
[ 50890-96-5 ]
methyl (R)-2-((S)-2-((S)-2-(4-bromophenylcarbamoyl)pyrrolidine-1-carbonyl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;	N,N-Diisopropyethylamine (481 mg, 3.72 mmol) was added dropwise at room temperature to a heterogeneous mixture of (S)-N-(4-bromophenyl)-1-((S)-pyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide hydrochloride (500 mg, 1.24 mmol), <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> (260 mg, 1.24 mmol), HATU (472 mg, 1.24 mmol) and DMF (10 ml). After the addition was complete the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water, 1N hydrochloric acid, a saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated to afford, methyl (R)-2-((S)-2-((S)-2-(4-bromophenylcarbamoyl)pyrrolidine-1-carbonyl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate as a yellow solid, (640 mg, 93%): ESI-LRMS m/e calcd for C26H29BrN4O5 [M+] 557. found 558 [M+H+].

Reference： [1]Patent: US2015/166514,2015,A1 .Location in patent: Paragraph 0178

34
C₂₆H₂₆F₃N₃O₃S*2ClH [ No CAS ]
[ 50890-96-5 ]
C₃₆H₃₅F₃N₄O₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		[001991 To a mixure of compound 5-1 (295 mg, 0.5 mmol), compound 5-1-2 (101 mg, 0.S3mmol), EDCI (115mg, 0.6 mmol) and DCM (lOmL) was added DIPEA (0.18 mL, 1 mmol) dropwise at -15 C. The reactionmixture was stirred at -15 C for 1.0 hour and then at 25 C for further 4.0 hours. Then to the reaction was added ammonia (6 mL), and the resulting mixture was stirred for 2 hours. The separated organic phase was washed with water (5 mL x 2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 5 0/1) to give the title compound as a white solid (270mg, 78%). The compound was characterized by the following spectroscopic data:MS (ESI, pos. ion) m/z: 709.2 [M+Hfb; and?H NMR (400 MHz, CDC13): 8.32-8.29 (m, 2H), 7.81 (s, 1H), 7.41-7.39 (m, 2H), 7.35 (s, 1H), 7.27-7.25 (m, 5H), 7.23 (s, 1H), 4.85-4.82 (m, 1H), 4.38-4.35 (m, 1H), 3.70 (s, 3H), 3.59-3.56 (m, 1H), 2.88-2.84 (m, 2H),2.42-2.38 (m, 2H), 2.02-2.00 (m, 2H), 1.70-1.67(m, 4H), 1.45-1.41 (m, 2H), 1.1 (d,J=4.3 Hz, 3H)ppm.
78%		Step 2) the Preparation of Compound 5-2 (0332) To a mixture of compound 5-1 (295 mg, 0.5 mmol), compound 5-1-2 (101 mg, 0.53 mmol), EDCI (115 mg, 0.6 mmol) and DCM (10 mL) was added DIPEA (0.18 mL, 1 mmol) dropwise at -15 C. The reaction mixture was stirred at -15 C. for 1.0 hour and then at 25 C. for further 4.0 hours. Then to the reaction was added ammonia (6 mL), and the resulting mixture was stirred for 2 hours. The separated organic phase was washed with water (5 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a white solid (270 mg, 78%). The compound was characterized by the following spectroscopic data: (0333) MS (ESI, pos. ion) m/z: 709.2 [M+H]+; and (0334) 1H NMR (400 MHz, CDCl3): delta 8.32-8.29 (m, 2H), 7.81 (s, 1H), 7.41-7.39 (m, 2H), 7.35 (s, 1H), 7.27-7.25 (m, 5H), 7.23 (s, 1H), 4.85-4.82 (m, 1H), 4.38-4.35 (m, 1H), 3.70 (s, 3H), 3.59-3.56 (m, 1H), 2.88-2.84 (m, 2H), 2.42-2.38 (m, 2H), 2.02-2.00 (m, 2H), 1.70-1.67 (m, 4H), 1.45-1.41 (m, 2H), 1.1 (d, J=4.3 Hz, 3H) ppm.

Reference： [1]Patent: WO2015/110048,2015,A1 .Location in patent: Paragraph 00199
[2]Patent: US2017/44140,2017,A1 .Location in patent: Paragraph 0329; 0332; 0333; 0334

35
C₁₈H₂₆BN₃O₂*2ClH [ No CAS ]
[ 50890-96-5 ]
C₂₈H₃₅BN₄O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%		[002041 To a mixture of compound 5-3 (386.3 mg, 0.97 mmol), compound 5-10 (184 mg, 1.05 mmol), EDCI (230 mg, 1.2 mmol) and DCM (10 mL) was added DIPEA (0.35 mL, 2 mmol) dropwise at -15 C. The reaction mixture was stirred at -15 C for 1.0 hour and then at 25 C for 4.0 hours. Then to the reaction was added ammonia (6 mL), and the resulting mixture was stirred for 2.0 hours. The separated organic phase was washed with water (5 mL x 2), dried over anhydrous Na2504 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 5 0/1) to give the title compound as a white solid (200 mg, 40%). The compound was characterized by the following spectroscopic data:+MS (ESI, pos. ion) m/z: 519.3[M+Hj ; and?H NMR (400 MHz, CDC13): 8.01 (br.s, 1H), 7.66 (s, 1H), 7.61 (d, J = 4.0 Hz, 1H), 7.20 (d, J = 4.0 Hz, 6H), 4.81-4.79 (m, 1H), 4.63-4.61 (m, 1H), 3.68 (s, 3H), 3.53-3.50 (m, 1H), 2.68-2.65 (m, 1H), 2.38-2.35 (m, 2H), 2.02-1.99(m,2H), 1.25(s, 12H), 1.1 (d,J= 4.0 Hz, 3H)ppm.
40%		Step 2) the Preparation of Compound 6-2 (0348) To a mixture of compound 5-3 (386.3 mg, 0.97 mmol), compound 5-10 (184 mg, 1.05 mmol), EDCI (230 mg, 1.2 mmol) and DCM (10 mL) was added DIPEA (0.35 mL, 2 mmol) dropwise at -15 C. The reaction mixture was stirred at -15 C. for 1.0 hour and then at 25 C. for 4.0 hours. Then to the reaction was added ammonia (6 mL), and the resulting mixture was stirred for 2.0 hours. The separated organic phase was washed with water (5 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a white solid (200 mg, 40%). The compound was characterized by the following spectroscopic data: (0349) MS (ESI, pos. ion) m/z: 519.3 [M+H]+; and (0350) 1H NMR (400 MHz, CDCl3): delta 8.01 (br.s, 1H), 7.66 (s, 1H), 7.61 (d, J=4.0 Hz, 1H), 7.20 (d, J=4.0 Hz, 6H), 4.81-4.79 (m, 1H), 4.63-4.61 (m, 1H), 3.68 (s, 3H), 3.53-3.50 (m, 1H), 2.68-2.65 (m, 1H), 2.38-2.35 (m, 2H), 2.02-1.99 (m, 2H), 1.25 (s, 12H), 1.1 (d, J=4.0 Hz, 3H) ppm.

Reference： [1]Patent: WO2015/110048,2015,A1 .Location in patent: Paragraph 00204
[2]Patent: US2017/44140,2017,A1 .Location in patent: Paragraph 0344; 0348; 0349; 0350

36
(2S,2'S)-di-tert-butyl 2,2'-(([1,1'-biphenyl]-4,4'-diylbis(azanediyl))bis(carbonyl))bis(2-methylpyrrolidine-1-carboxylate) [ No CAS ]
[ 50890-96-5 ]
dimethyl ((1R,1'R)-((2S,2'S)-2,2'-(([1,1'-biphenyl]-4,4'-diylbis(azandiyl))bis(carbonyl))bis(2-methylpyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%		10293] The compound (144 mg, 0.238 mmol) obtained above was loaded in the mixed solvent of CF3 CO2H (1 mE) and CH2C12 (1 mE), followed by stifling at room temperature for 5 hours. The volatile components were eliminated under reduced pressure and CH2C12 (1 mE) solution containing i-Pr2NEt (208 jil, 1.192 mmol) dissolved in there was loaded thereto for 4 minutes. EDC (119 mg, 0.620 mmol) and the compound (100 mg, 0.572 mmol) prepared in Preparative Example 9 were additionally added to the reaction mixture, followed by stirring at room temperature for 75 minutes. The residue was fractionated with CH2C12 and H20. The organic layer was washed with H20 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue proceeded to silica gel mesh, followed by flash chromatography (eluent: EtOAc/hexane mixture) to give the target compound as a white solid (77 mg, yield: 41%).10294] ?H NMR (DMSO-d5, oe=2.5 ppm, 400 MHz): 9.03 (s, 1H), 8.89 (s, 1H), 7.77-7.57 (m, 1OH), 7.40-7.32 (m, 1OH), 5.46 (m, 2H), 3.99 (m, 1H), 3.76 (m, 1H), 3.56 (s, 3H), 3.54 (s, 3H), 3.48 (m, 1H), 3.21 (m, 1H), 2.18-2.08 (m, 2H), 1.91-1.80 (m, 6H), 1.55 (s, 3H), 1.43 (s, 3H);10295] ?3C NMR (DMSO-d5, oe=39.52 ppm, 100 MHz):171.8, 171.7, 168.2, 167.7, 156.4, 156.2, 138.2, 138.0, 137.2,136.5, 134.7, 134.3, 128.7, 128.4, 128.22, 128.17, 127.70,127.68, 126.09, 126.05, 120.9, 120.3, 67.6, 67.5, 57.2, 57.0,51.7, 51.6, 47.7, 47.5, 23.5, 23.1, 20.6, 20.5;10296] EC/MS: Anal. Calcd. For [M+H] C44H48N508:789.3606; found 789.3600.

Reference： [1]Patent: US2016/31810,2016,A1 .Location in patent: Paragraph 0293; 0294; 0295; 0296

37
(2S,2'S)-di-tert-butyl 2,2'-(((9,9-difluoro-9H-fluorene-2,7-diyl)bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) [ No CAS ]
[ 50890-96-5 ]
dimethyl (1R,1'R)-2,2'-((2S,2'S)-2,2'-(9,9-difluoro-9H-fluorene-2,7-diyl)bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dicarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%		Step 2: Preparation of dimethyl((1 R, 1 ?R)-((25,2?S)-2,2?-(((9,9-difluoro-9H-fluorene-2,7-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-2, 1 -diyl))bis(2-oxo-1 -phenylethane-2, 1 -diyl))dicarbamate 10366] (25,2?S)-di-tert-butyl 2,2?-(((9,9-difluoro-9H-fluo- rene-2,7-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine- 1- carboxylate) (27 mg, 0.043 mmol) obtained in step 1 was dissolved in the mixed solvent comprising CF3CO2H (1 mE) and CH2C12 (1 mE), followed by stirring at room temperature for 5 hours. The volatile components were eliminated under vacuum condition. EDC (21 mg, 0.11 mmol) and Cap (22 mg, 0.10 mmol) were added to CH2C12 (1 mE) solution containing i-Pr2NEt (28 mE, 0.22 mmol) dissolved therein for 4 minutes batch, followed by stirring at room temperature for 75 minutes. Then, layer separation was performed with the reaction product by using CH2C12 and H20. The separated organic layer was washed with H20 and brine. The organic layer was dried over Mg504, filtered, and vacuum-concentrated. The residue proceeded to silica gel mesh, followed by flash chromatography (silica gel: EtOAchexane as eluent) to give the target compound as a solid (18 mg, yield: 52%).10367] ?H NMR (DMSO-d5, oe 2.5 ppm, 400 MHz): 10.14 (s, 2H), 8.05 (s, 2H), 7.77 (d, 2H), 7.71 (s, 4H), 7.43-7.10 (m, 1OH), 5.51 (d, 2H), 4.39 (m, 2H), 3.85 (m, 2H), 3.55 (s, 6H),3.21 (m, 2H), 2.06-1.79 (m, 8H).10368] ?3C NMR (DMSO-d5, oe 39.52 ppm, 100 MHz):170.6, 168.5, 156.2, 139.3, 137.3, 137.0, 128.6, 128.4, 128.1,127.9, 127.6, 122.8, 121.2, 114.5,60.8,56.7,51.6,47.0,29.3,24.3.10369] ECMS: Anal. Calcd. For [M+H] C43H42F2N508:809.3105; found 809.3109.

Reference： [1]Patent: US2016/31810,2016,A1 .Location in patent: Paragraph 0365; 0366; 0367; 0368; 0369

38
(2S,2'S)-di-tert-butyl 2,2'-(((3,3'-dimethyl-[1,1'-biphenyl]-4,4'-diyl)bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) [ No CAS ]
[ 50890-96-5 ]
dimethyl ((1R,1'R)-((25,2'S)-2,2'-(((3,3'-dimethyl-[1,1'-biphenyl]-4,4'-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%		10213] The obtained mixture (144 mg, 0.238 mmol) was loaded in the mixed solvent of CF3 CO2H (1 mE) and CH2C12 (1 mE), followed by stirring at room temperature for 5 hours. The volatile components were eliminated under reduced pressure and CH2C12 (1 mE) solution containing i-Pr2NEt (208 jtl, 1.192 mmol) dissolved in there was loaded thereto for 4 minutes. EDC (119 mg, 0.620 mmol) and the compound (100 mg, 0.572 mmol) prepared in Preparative Example 9 were additionally added to the reaction mixture, followed by stirring at room temperature for 75 minutes. The residue was fractionated with CH2C12 and H20. The organic layer was washed with H20 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue proceeded to silica gel mesh, followed by flash chromatography (eluent:EtOAc/hexane mixture) to give the target compound as a white solid (77 mg, yield: 4 1%).10214] ?H NMR (DMSO-d5, oe=2.5 ppm, 400 MHz): 9.31 (s, 2H), 7.74 (d, 2H), 7.54-7.23 (m, 16H), 5.52 (d, 2H), 4.52 (m, 2H), 3.85 (m, 2H), 3.52 (s, 6H), 3.18 (m, 2H), 2.28 (s, 6H), 2.00-1.82 (m, 8H);10215] ?3C NMR (DMSO-d5, oe=39.52 ppm, 100 MHz):170.1, 168.8, 156.1, 137.1, 136.5, 135.4, 132.2, 128.6, 128.2,128.1, 128.0, 125.2, 123.9, 60.6, 56.8, 51.6, 46.9, 29.1, 24.3, 17.9;10216] EC/MS: Anal. Calcd. For [M+H] C44H48N508:789.3606; found 789.3597.

Reference： [1]Patent: US2016/31810,2016,A1 .Location in patent: Paragraph 0213; 0214; 0215; 0216

39
(2S,2'S)-di-tert-butyl 2,2'-(((2,2'-dimethyl-[1,1'-biphenyl]-4,4'-diyl)bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) [ No CAS ]
[ 50890-96-5 ]
dimethyl((1R,1'R)-((2S,2'S)-2,2'-(((2,2'-dimethyl-[1,1'-biphenyl]-4,4'-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%		10228] The compound (292 mg, 0.509 mmol) obtained above was loaded in the mixed solvent of CF3 CO2H (2 mE) and CH2C12 (2 mE), followed by stifling at room temperature for 5 hours. The volatile components were eliminated under reduced pressure and CH2C12 (2 mE) solution containing i-Pr2NEt (443 jil, 2.54 mmol) dissolved in there was loaded thereto for 4 minutes. EDC (253 mg, 1.32 mmol) and the compound (256 mg, 1.22 mmol) prepared in Preparative Example 9 were additionally added to the reaction mixture, followed by stifling at room temperature for 75 minutes. The residue was fractionated with CH2C12 and H20. The organic layer was washed with H20 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue proceeded to silica gel mesh, followed by flash chroma0 tography (eluent: EtOAc/hexane mixture) to give the targetcompound as a white solid (292 mg, yield: 73%).10229] ?H NMR (DMSO-d5, oe=2.5 ppm, 400 MHz): 9.84(s, 2H), 7.73 (d, 2H), 7.59 (s, 2H), 7.48-7.14 (m, 12H), 6.87(d, 2H), 5.51 (d, 2H), 4.42 (m, 2H), 3.84 (m, 2H), 3.55 (s, 6H),3.20 (m, 2H), 1.98 (s, 6H), 1.97-1.78 (m, 8H);10230] ?3C NMR (DMSO-d5, oe=39.52 ppm, 100 MHz):170.2, 168.4, 156.1, 137.9, 137.1, 135.8, 135.8, 129.58, 128.62, 128.1, 127.9, 120.5, 116.7, 60.7, 56.8, 51.7, 47.0, 29.4,24.3, 19.8;10231] EC/MS: Anal. Calcd. For [M+H] C44H48N508:789.3606; found 789.3605.

Reference： [1]Patent: US2016/31810,2016,A1 .Location in patent: Paragraph 0228; 0229; 0230; 0231

40
(2S,2'S)-di-tert-butyl 2,2'-(((9H-fluorene-2,7-diyl)bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) [ No CAS ]
[ 50890-96-5 ]
dimethyl ((1R,1'R)-((2S,2’S)-2,2'-(((9H-fluorene-2,7-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane2,1-diyl))dicarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%		10235] The compound (300 mg, 0.51 mmol) obtained above was loaded in the mixed solvent of CF3 CO2H (2 mE) and CH2C12 (2 mE), followed by stifling at room temperature for 5 hours. The volatile components were eliminated under reduced pressure and CH2C12 (2 mE) solution containing i-Pr2NEt (441 jtl, 2.5 mmol) dissolved in there was loaded thereto for 4 minutes. EDC (253 mg, 1.3 mmol) andcompound (255 mg, 1.3 mmol) prepared in Preparative Example 9 were additionally added to the reaction mixture, followed by stifling at room temperature for 75 minutes. The residue was fractionated with CH2C12 and H20. The organic layer was washed with H20 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue proceeded to silica gel mesh, followed by flash chromatography (eluent: EtOAc/hexane mixture) to give the target compound as a white solid (198 mg, yield: 50%).10236] ?H NMR (DMSO-d5, oe=2.5 ppm, 400 MHz): 9.92 (s, 2H), 7.91 (s, 2H), 7.75-7.69 (m, 4H), 7.56 (d, 2H), 7.44- 7.13 (m, 1OH), 5.52 (d, 2H), 4.43 (m, 2H), 3.88-3.83 (m, 2H),3.55 (s, 6H), 3.21 (m, 2H), 2.04-1.78 (m, 8H);10237] ?3C NMR (DMSO-d5, oe=39.52 ppm, 100 MHz):170.2, 168.5, 156.2, 143.6, 137.5, 137.2, 136.4, 128.7, 128.1,127.9, 119.6, 118.1, 116.2, 60.8, 56.8, 51.7, 47.0, 36.7, 29.4, 24.3;10238] EC/MS: Anal. Calcd. For [M+H] C43HN5O8:773.3293; found 773.3296.

Reference： [1]Patent: US2016/31810,2016,A1 .Location in patent: Paragraph 0235; 0236; 0237; 0238

41
(2S,2'S)-Di-tert-butyl 2,2'-(((2,2'-difluoro-[1,1'-biphenyl]-4,4'-diyl)bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) [ No CAS ]
[ 50890-96-5 ]
dimethyl ((1R,1'R)-((2S,2'S)-2,2'-(((2,2'-difluoro-[1,1'-biphenyl]-4,4'-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%		10243] The compound (245 mg, 0.42 mmol) obtained above was loaded in the mixed solvent of CF3 CO2H (2 mE) and CH2C12 (2 mE), followed by stifling at room temperature for 5 hours. The volatile components were eliminated under reduced pressure and CH2C12 (2 mE) solution containing i-Pr2NEt (370 jil, 2.1 mmol) dissolved in there was loaded thereto for 4 minutes. EDC (210 mg, 1.1 mmol) and the compound (212 mg, 1.0 mmol) prepared in Preparative Example 9 were additionally added to the reaction mixture, followed by stifling at room temperature for 75 minutes. The residue was fractionated with CH2C12 and H20. The organic layer was washed with H20 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue proceeded to silica gel mesh, followed by flash chromatography (eluent: EtOAc/hexane mixture) to give the target compound as a white solid (134 mg, yield: 40%).10244] ?H NMR (DMSO-d5, oe=2.5 ppm, 400 MHz): 10.43(s, 2H), 7.74-7.71 (m, 3H), 7.46-7.11 (m, 15H), 5.51 (d, 2H),4.43 (m, 2H), 3.83 (m, 2H), 3.54 (s, 6H), 3.19 (m, 2H),2.05-1.77 (m, 8H);10245] ?3C NMR (DMSO-d5, oe=39.52 ppm, 100 MHz):170.8, 168.4, 160.0, 158.0, 156.1, 140.5, 137.2, 131.6, 128.6,128.5, 128.1, 127.9, 127.6, 117.1, 115.1, 106.3, 106.1, 60.8,56.7, 51.7, 47.0, 29.3, 24.3;10246] ?9F NMR (DMSO-d5, 377 MHz,): oe -73.45;10247] EC/MS: Anal. Calcd. For [M+H] C42H42F2N508:797.3105; found 797.3112.

Reference： [1]Patent: US2016/31810,2016,A1 .Location in patent: Paragraph 0243; 0244; 0245; 0246; 0247

42
(2S,2'S)-di-tert-butyl 2,2'-(((2,2'-dichloro-[1,1'-biphenyl]-4,4'-diyl)bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) [ No CAS ]
[ 50890-96-5 ]
dimethyl ((1R,1'R)-((2S,2'S)-2,2'-(((2,2'-dichloro-[1,1'-biphenyl]-4,4'-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%		10251] The compound (245 mg, 0.4 mmol) obtained above was loaded in the mixed solvent of CF3CO2H (4 mE) and CH2C12 (4 mE), followed by stifling at room temperature for 5 hours. The volatile components were eliminated under reduced pressure and CH2C12 (4 mE) solution containing i-Pr2NEt (347 pi, 2.0 mmol) dissolved in there was loaded thereto for 4 minutes. EDC (199 mg, 1.04 mmol) and the compound (200 mg, 0.96 mmol) prepared in Preparative Example 9 were additionally added to the reaction mixture, followed by stifling at room temperature for 75 minutes. The residue was fractionated with CH2C12 and H20. The organic layer was washed with H20 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue proceeded to silica gel mesh, followed by flash chromatography (eluent: EtOAc/hexane mixture) to give the target compound as a white solid (146 mg, yield: 44%).10252] ?H NMR (DMSO-d5, oe=2.5 ppm, 400 MHz): 10.14(s, 2H), 7.97-7.91 (m, 2H), 7.75 (d, 2H), 7.65-7.55 (m, 2H),7.43-7.12 (m, 12H), 5.51 (d, 2H), 4.39 (m, 2H), 3.84 (m, 2H),3.55 (s, 6H), 3.20 (m, 2H), 2.06-1.79 (m, 8H);10253] ?3C NMR (DMSO-d5, oe=39.52 ppm, 100 MHz):170.8, 168.5, 156.2, 139.9, 137.1, 132.6, 132.1, 131.7, 128.6,128.1, 127.9, 119.3, 117.7, 60.8, 56.73, 51.68, 47.0, 29.3,24.3;10254] EC/MS: Anal. Calcd. For [M+H] C42H42C,2N508:829.2514; found 829.2518.

Reference： [1]Patent: US2016/31810,2016,A1 .Location in patent: Paragraph 0251; 0252; 0253; 0254

43
(2S,2’S)-di-tert-butyl 2,2'-(((2,2'-dibromo-[1,1'-biphenyl]-4,4'-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) [ No CAS ]
[ 50890-96-5 ]
dimethyl ((1R,1'R)-((2S,2'S)-2,2’-(((2,2'-dibromo-[1,1'-biphenyl]-4,4'-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%		10258] The compound (260 mg, 0.353 mmol) obtained above was loaded in the mixed solvent of CF3 CO2H (2 mE) and CH2C12 (2 mE), followed by stifling at room temperature for 5 hours. The volatile components were eliminated under reduced pressure and CH2C12 (4 mE) solution containing i-Pr2NEt (3078 jii, 1.77 mmol) dissolved in there was loaded thereto for 4 minutes. EDC (176 mg, 0.92 mmol) and the compound (177 mg, 0.85 mmol) prepared in Preparative Example 9 were additionally added to the reaction mixture, followed by stifling at room temperature for 75 minutes. The residue was fractionated with CH2C12 and H20. The organic layer was washed with H20 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue proceeded to silica gel mesh, followed by flash chromatography (eluent: EtOAc/hexane mixture) to give the target compound as a white solid (110 mg, yield: 42%).10259] ?H NMR (DMSO-d5, oe=2.5 ppm, 400 MHz): 10.13 (s, 2H), 8.32-8.12 (m, 2H), 7.92-7.61 (m, 4H), 7.41-7.13 (m, 12H), 5.51 (d, 2H), 4.39 (m, 2H), 3.84 (m, 2H), 3.55 (s, 6H),3.52 (m, 2H), 3.19 (m, 2H), 2.05-1.81 (m, 8H);10260] ?3C NMR (DMSO-d5, oe=39.52 ppm, 100 MHz):170.7, 168.5, 156.2, 139.8, 137.1, 135.9, 131.3, 128.6, 128.1,127.9, 123.0, 122.3, 118.1, 60.8, 56.7, 51.7, 47.0,29.3,24.3;10261] EC/MS:Anal. Calcd. For [M+H] C42H42Br2N5O8:917.1504; found 917.1521.

Reference： [1]Patent: US2016/31810,2016,A1 .Location in patent: Paragraph 0258; 0259; 0260; 0261

44
(2R,2'R)-di-tert-butyl 2,2'-(([1,1'-biphenyl]-4,4'-diylbis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) [ No CAS ]
[ 50890-96-5 ]
dimethyl (1R,1'R)-2,2'-((2R,2'R)-2,2'-(biphenyl-4,4'-diylbis(azanediyl))bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dicarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%		10265] The compound (300 mg, 0.52 mmol) obtained above was loaded in the mixed solvent of CF3 CO2H (2 mE) and CH2C12 (2 mE), followed by stifling at room temperature for 5 hours. The volatile components were eliminated under reduced pressure and CH2C12 (3 mE) solution containing i-Pr2NEt (455 jil, 2.6 mmol) dissolved in there was loaded thereto for 4 minutes. EDC (258 mg, 0.620 mmol) and the compound (260 mg, 1.24 mmol) prepared in Preparative Example 9 were additionally added to the reaction mixture, followed by stifling at room temperature for 75 minutes. The residue was fractionated with CH2C12 and H20. The organic layer was washed with H20 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue proceeded to silica gel mesh, followed by flash chromatography (eluent: EtOAc/hexane mixture) to give the target compound as a white solid (171 mg, yield: 57%).10266] ?H NMR (DMSO-d5, oe=2.5 ppm, 400 MHz): 10.14(s, 2H), 7.68-7.60 (m, 9H), 7.46-7.30 (m, 1 1H), 5.49 (d, 2H),4.53 (m, 2H), 3.68 (m, 2H), 3.54 (s, 6H), 3.12 (m, 2H),2.00-2.13 (m, 2H), 1.89-1.82 (m, 6H);10267] ?3C NMR (DMSO-d5, oe=39.52 ppm, 100 MHz):170.2, 168.1, 156.4, 138.2, 136.9, 134.4, 128.4, 128.4, 127.8,126.4, 119.4, 60.6, 56.6, 51.6, 46.9, 29.4, 24.7;10268] EC/MS: Anal. Calcd. For [M+H] C42H44N508:761.3293; found 761.3281.

Reference： [1]Patent: US2016/31810,2016,A1 .Location in patent: Paragraph 0265; 0266; 0267; 0268

45
C₄₄H₅₃N₇O₇ [ No CAS ]
[ 50890-96-5 ]
velpatasvir [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.2%		Under the protection of nitrogen, adding 102g 1a, by adding 500 ml of methylene chloride is dissolved, add 4mol/LHCl the 1,4-dioxane solution 500 ml, stirring the mixture at room temperature for 1 hour, TLC (hexane: ethyl acetate 1:1) board central control, starting material point dematerialised, cessation of the reaction, after concentrating the solvent, by adding <strong>[50890-96-5](R)-2-(methoxycarbonylamino)-2-phenylacetic acid</strong> 29g, COMU 60g, DMF 500mL, diisopropyl ethylamine 223 ml, reaction 25 C 1 hour, add ethyl acetate 1L after dilution, by adding 1L purified water washing 2 times, water-free magnesium sulfate drying, concentrating, adding 500 ml methanol heating 60 C dissolved, slowly dropping 250 ml purified water, precipitated solid, is omitted, cooling to 50 C thermal insulation 1 hour, filtering, cooling to room temperature, concentrated to obtain Velpatasvir (GS-5816) product 90.5g, yield 78.2%.

Reference： [1]Patent: CN105294713,2016,A .Location in patent: Paragraph 0017

46
C₃₈H₄₃N₇O₃*3ClH [ No CAS ]
[ 50890-96-5 ]
C₄₈H₅₂N₈O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; ethyl cyanoglyoxylate-2-oxime; In dichloromethane; at 0 - 20℃; for 2h;	A mixture of compound 3-13 (0.60 g, 0.835 mmol) , compound 3-14 (0.21 g, 1.0 mmol) , EDCI (0.192 g, 1.0 mmol) and ethyl cyanoglyoxylate-2-oxime (0.048 g, 0.334 mmol) in DCM (10 mL) was stirred at 0 , and DIPEA (0.324 g, 2.505 mmol) was added dropwise. After the addition, the mixture was stirred at rt for 2 hours. After the mixture was completed, ammonium hydroxide (2 mL) was added. The resulting mixture was stirred for 1 hour, then partitioned. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE : EtOAc (V : V) 1 : 1) to give the title compound as a gray solid (0.45 g, 64) . 1H NMR (400 MHz, CDCl3) : delta 8.10 (s, 1H) , 7.62 (d, 4H) , 7.36 (m, 4H) , 7.21 (m, 3H) , 5.43 (s, 2H) , 5.10 (s, 2H) , 3.56 (m, 4H) , 3.16 (m, 4H) , 3.10 (m, 4H) , 2.66 (m, 4H) , 2.36 (m, 4H) , 2.09 (m, 6H) , 1.05 (m, 6H) ppm MS-ESI, m/z: 837.7 [M+H]+.

Reference： [1]Patent: WO2016/141890,2016,A1 .Location in patent: Paragraph 00232; 00237

47
C₃₉H₄₅N₇O₃*3ClH [ No CAS ]
[ 50890-96-5 ]
C₄₉H₅₄N₈O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; ethyl cyanoglyoxylate-2-oxime; In dichloromethane; at 0 - 20℃; for 2h;	A mixture of compound 4-13 (0.60 g, 0.92 mmol) , compound 3-14 (0.23 g, 1.1 mmol) , EDCI (0.21 g, 1.1 mmol) and ethyl cyanoglyoxylate-2-oxime (0.06 g, 0.37 mmol) in DCM (10 mL) was stirred at 0 , and DIPEA (0.360 g, 2.8 mmol) was added dropwise. After the addition, the mixture was stirred at rt for 2 hours. After the reaction was complete, ammonium hydroxide (2 mL) was added. The resulting mixture was stirred for 1 hour, then partitioned. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE : EtOAc (V : V) 1 : 1) to give the title compound as a gray solid (0.40 g, 50) . 1H NMR (400 MHz, CDCl3) : delta 8.10 (s, 1H) , 7.62 (d, 4H) , 7.36 (m, 4H) , 7.21 (m, 3H) , 5.43 (s, 2H) , 5.10 (s, 2H) , 3.56 (m, 4H) , 3.16 (m, 4H) , 3.10 (m, 4H) , 2.66 (m, 4H) , 2.36 (m, 3H) , 2.09 (m, 6H) , 1.59 (m, 3H) , 1.05 (m, 6H) ppm MS-ESI, m/z: 852.5 [M+H]+.

Reference： [1]Patent: WO2016/141890,2016,A1 .Location in patent: Paragraph 00237; 00242

48
C₄₁H₄₉N₇O₄ [ No CAS ]
[ 50890-96-5 ]
C₅₁H₅₈N₈O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; ethyl cyanoglyoxylate-2-oxime; In dichloromethane; at 0 - 20℃; for 2h;	A mixture of compound 5-8 (0.55 g, 0.72 mmol) , compound 3-14 (0.178 g, 0.852 mmol) , EDCI (0.163 g, 0.852 mmol) and ethyl cyanoglyoxylate-2-oxime (0.04 g, 0.284 mmol) in DCM (10 mL) was stirred at 0 , and DIPEA (0.275 g, 2.13 mmol) was added dropwise. After the addition, the mixture was stirred at rt for 2 hours. After the reaction was complete, ammonium hydroxide (2 mL) was added. The resulting mixture was stirred for 1 hour, then partitoned. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE : EtOAc (V : V) 1 : 3) to give the title compound as a gray solid (0.35 g, 55) . 1H NMR (400 MHz, CDCl3) : delta 8.10 (s, 1H) , 7.52 (d, 4H) , 7.36 (m, 4H) , 7.31 (m, 3H) , 5.43 (s, 2H) , 5.10 (s, 2H) , 3.56 (m, 4H) , 3.21 (m, 5H) , 3.09 (m, 4H) , 3.01 (m, 4H) , 2.66 (m, 4H) , 2.26 (m, 2H) , 2.09 (m, 6H) , 1.59 (m, 3H) , 1.05 (m, 6H) ppm MS-ESI, m/z: 896.0 [M+H]+.

Reference： [1]Patent: WO2016/141890,2016,A1 .Location in patent: Paragraph 00242; 00248

49
tert-butyl (S)-2-((4-((4-((R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)phenyl)sulfonyl)phenyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]
[ 50890-96-5 ]
C₄₂H₄₄N₆O₁₀S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%		(S) -2 - ((4 - ((4 - ((R) -1- (tert- Butoxycarbonyl) pyrrolidin- Carboxamido) phenyl) sulfonyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (172 mg, 0.268 mmol) Was dissolved in a mixed solution (4 mL) of trifluoroacetic acid / dichloromethane (1/1) And the mixture was stirred at room temperature for 30 minutes. After concentrating the solvent in vacuo, the concentrated reaction product, Ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (133 mg, 0.696 mmol), Hydroxybenzotriazole hydrate (90.1 mg, 0.667 mmol) And the compound obtained in Preparation Example 3 (R) -2- (methoxycarbonylamino) -2-phenylacetic acid (134 mg, 0.642 mmol) was blanketed over a period of 4 minutes N, N-Diisopropylethylamine (233 mL, 1.28 mmol) In dichloromethane (10 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to give the desired compound (111 mg, 50% yield) as a white solid.

Reference： [1]Patent: KR2017/31307,2017,A .Location in patent: Paragraph 0374-0376

50
tert-butyl (S)-2-(((4-((4-((R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)phenoxy)sulfonyl)oxy)phenyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]
[ 50890-96-5 ]
bis(4-((S)-1-((R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)pyrrolidine-2-carboxamido)phenyl)sulphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%		(S) -2 - ((4 - ((4- ((R) -1- (tert-Butoxycarbonyl) pyrrolidine- 2- carboxamido) phenoxy) Sulfonyl) Oxy) phenyl) carbamoyl) pyrrolidine-1-carboxylate (50.0 mg, 0.0741 mmol) Was dissolved in a trifluoroacetic acid / dichloromethane (1/1) mixed solution (2 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (64.5 mg, 0.193 mmol) Hydroxybenzotriazole hydrate (26.0 mg, 0.193 mmol) And (R) -2- (methoxycarbonylamino) -2-phenylacetic acid obtained in Preparation Example 3 (37.2 mg, 0.178 mmol) was added to N, N-diisopropylethylamine (64.5 mL, 0.371 mmol) in dichloromethane (5 mL) and stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue Purification via flash column chromatography on silica gel using dichloromethane: methanol as mobile phase gave the desired compound (37.6 mg, 59% yield) as a white solid.

Reference： [1]Patent: KR2017/31307,2017,A .Location in patent: Paragraph 0379-0381

51
di-tert-butyl 2,2'-(((sulfonylbis(oxy))bis(3,1-phenylene))bis(1H-imidazole-5,2-diyl))(2S,2'S)-bis(pyrrolidine-1-carboxylate) [ No CAS ]
[ 50890-96-5 ]
bis(3-(2-((S)-1-((R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)sulfate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		In Production Example 25 The resulting di-tert-butyl 2,2 '- (((sulfonylbis (oxy)) bis (3,1-phenylene)) bis (1H-imidazol-5,2-diyl)) (2S, 2'S) (Pyrrolidine-1-carboxylate) (185 mg, 0.256 mmol) Was dissolved in a trifluoroacetic acid / dichloromethane (1/1) mixed solution (6 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (128 mg, 0.667 mmol), hydroxybenzotriazole hydrate (90.1 mg, 0.667 mmol), and the compound obtained in Preparation Example 3 (R) -2- (methoxycarbonylamino) -2-phenylacetic acid (129 mg, 0.615 mmol) Was added to dichloromethane (10 mL) of N, N-diisopropylethylamine (223 mL, 1.28 mmol) collectively over 4 minutes, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was washed with anhydrous sulfuric acid Dried with citric acid, filtered and concentrated in vacuo. The residue was chromatographed using dichloromethane: methanol as the mobile phase Purification via silica gel flash column chromatography gave the desired compound (97.2 mg, 67% yield) as a yellow solid .

Reference： [1]Patent: KR2017/31307,2017,A .Location in patent: Paragraph 0414-0416

52
(2S,2'S)-di-tert-butyl 2,2'-(5,5'-(4,4'-sulfonylbis(oxy))bis(4,1-phenylene)bis(1H-imidazol-5,2-diyl))dipyrrolidine-1-carboxylate [ No CAS ]
[ 50890-96-5 ]
bis(4-(2-((S)-1-((R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)sulfate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%		Di-tert-butyl 2,2 '- (((sulfonylbis (oxy)) bis (4,1-phenylene)) bis (1H-imidazol-5,2-diyl)) (2S, 2'S) -bis (pyrrolidine-1-carboxylate) (105 mg, 0.145 mmol) Was dissolved in a mixed solution (6 mL) of trifluoroacetic acid / dichloromethane (1/1) , And the mixture was stirred at room temperature for 30 minutes. After concentrating the solvent in vacuo, the concentrated reaction product, Ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (72.6 mg, 0.349 mmol), Hydroxybenzotriazole hydrate (51.2 mg, 0.379 mmol) And the compound obtained in Preparation Example 3 (R) -2- (methoxycarbonylamino) -2-phenylacetic acid (75.2 mg, 0.350 mmol) Was added to a solution of N, N-diisopropylethylamine (127 [mu] L, 0.728 mmol) Was added to dichloromethane (5 mL) and stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid and extracted with dichloromethane And extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue is dissolved in dichloro Methanol: The residue was purified by silica gel flash column chromatography using methanol as mobile phase to obtain the desired compound (56.1 Mg, 43% yield) as a white solid.

Reference： [1]Patent: KR2017/31307,2017,A .Location in patent: Paragraph 0399-0401

53
C₂₆H₂₇NO₆ [ No CAS ]
[ 50890-96-5 ]
C₃₆H₃₆N₂O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In N,N-dimethyl-formamide; at 20 - 25℃;Industrial scale;	Compound 13 (2.21 kg, 4.92 mol, 1.0 eq)Soluble in N, N-dimethylformamide (DMF) to be used.Compound 9 (1.3 kg, 1.1 eq),The mass concentration of 50% propyl phosphoric anhydride (T3P)N, N-dimethylformamide (DMF) solution (5.02 kg, 1.1 eq)(Said mass concentration refers to the mass of propyl phosphoric anhydride as propyl phosphoric anhydride N, N- dimethylformamide total mass percentage),Dissolved in DMF, reduced to 0-10 ,The solution was dropped into the above configuration, stirring at 20 ~ 25 5-6 hours,TLC showed complete reaction of compound 13, reduced to 5-10 C, dropped into water, 5-10 C,Stirred for 2-3 hours, filtered, the filter cake washed with water, dried,3.06 kg of compound 12 was obtained in a yield of 97.0% and an HPLC purity of 98.71%.

Reference： [1]Patent: CN107573355,2018,A .Location in patent: Paragraph 0236-239

54
C₂₆H₂₆BrNO₆ [ No CAS ]
[ 50890-96-5 ]
C₃₆H₃₅BrN₂O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In N,N-dimethyl-formamide; at 20 - 25℃;Industrial scale;	Compound 10 (1.52 kg, 2.87 mol, 1.0 eq) was dissolved in N, N-dimethylformamide (DMF) for use.Compound 9 (661 g, 1.1 eq),The mass concentration of 50% propyl phosphoric anhydride (T3P)N, N-dimethylformamide (DMF) solution (2.02 kg, 1.1 eq)(Said mass concentration refers to the mass of propyl phosphoric anhydride as propyl phosphoric anhydride N, N- dimethylformamide total mass percentage),Dissolved in DMF, dropped to 0-10 , the solution was dropped into the above configuration, stirring at 20 ~ 25 5-6 hours,TLC showed complete reaction of compound 10, reduced to 5-10 C, dropped into water, 5-10 C,Stirred for 2-3 hours, filtered, the filter cake washed with water, dried,1.96 kg of compound 8 was obtained with a yield of 95.0% and an HPLC purity of 98.28%

Reference： [1]Patent: CN107573355,2018,A .Location in patent: Paragraph 0229-0232

55
(2S,4S)-2-[5-(2-{(2S,4S)-1-{N-(methoxycarbonyl)-L-valyl}-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromene[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine [ No CAS ]
[ 50890-96-5 ]
[ 1377049-84-7 ]

Yield	Reaction Conditions	Operation in experiment
270 mg	With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 1h;	1.3 In a mixed solvent of 16 ml of dichloromethane and 4 ml of methanol, 660 mg of i-2 was added and stirred to dissolve;Then 4 ml of 4M HCl in dioxane was added and the reaction mixture was stirred for 2 h then evaporated to dryness under reduced pressure.(2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-5-Methylpyrrolidin-2-yl}-1,11-dihydroisochromene [4',3':6,7]naphtho[1,2-d]imidazol-9-yl)- 1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine (i-3); plusInto 20 ml of DMF, stir to dissolve, then add 170 mg (0.21 mmol) of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid,400 mg (0.21 mmol) COMU; 0.7 ml (1.05 mmol) DIPEA was added dropwise with stirring. Stir the reaction for 1 h and add methanol/acetic acidEster (1:9) mixture, washed sequentially with saturated NaHCO3, brine; the organic phase was dried over anhydrous MgSO4 overnight, filtered, and depressurizedconcentrate;Purified by HPLCMethyl {(1R)-2-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-Methylbutyryl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromene [4',3':6,7]naphtho[1,2-d]imidazole -9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (i-4 )270mg.
270 mg	With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 1h;	5.3 The third step: In a mixed solvent of 16 ml of dichloromethane and 4 ml of methanol, add 660 mg of i-2 and stir to dissolve; then add 4 ml of 4M HCl in dioxane, stir the reaction mixture for 2 hours, and then evaporate under reduced pressure. ,Acquired (2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-prolyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromene [4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H- Imidazol-2-yl]-4-(methoxymethyl)pyrrolidine (i-3)Add 20ml DMF, stir to dissolve, then add 170mg (0.21mmol)(R)-2-(Methoxycarbonylamino)-2-phenylacetic acid, 400 mg (0.21 mmol) COMU; 0.7 ml (1.05 mmol) DIPEA was added dropwise with stirring. The reaction was stirred for 1 h, a mixture of methanol/ethyl acetate (1:9) was added and washed sequentially with saturated NaHCO3, brine; the organic phase was dried over anhydrous MgSO4 overnight, filtered, and depressurized Concentration; purification by HPLC yields I'270 mg.

Reference： [1]Current Patent Assignee: BEIJING MEIBEITA PHARMACEUTICAL RES - CN107540679, 2018, A Location in patent: Paragraph 0042; 0045
[2]Current Patent Assignee: BEIJING MEIBEITA PHARMACEUTICAL RES - CN107556324, 2018, A Location in patent: Paragraph 0041; 0042; 0045

56
(S)-2-{5-[4-(6-{(S)-2-[(1-(S)-2-methoxycarbonylamino-3-methylbutyryl)pyrrolidin-2-yl]-1H-imidazol-4-yl}thieno[3,2-b]thiophen-3-yl)phenyl]-1H-imidazol-2-yl}pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]
[ 50890-96-5 ]
[ 1312547-19-5 ]

Yield	Reaction Conditions	Operation in experiment
74%		Intermediate E79 (0.132 mmol) was dissolved in methanol (2.6 mL) and 4N HClin dioxane (2.64 mL) was added. The mixture was stirred 1 hr at room temperature before concentration under reducedpressure. The residue was dissolved in DMF (2.6 mL) and the mixture was cooled down to -10 C. TEA (0.924 mmol),intermediate 31 (0.139 mmol), and HATU (0.172 mmol) were added and the mixture was stirred at -10 C for 1 hr. Ethylacetate was added and the mixture was washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was filtered on a SCX-2 column and purified by silica gel chromatography(eluent: DCM-DCM/MeOH 97/3) to give compound A169 as a beige solid in 74% yield. 1H NMR (CDCl3, 400MHz) delta (ppm) 0.89-0.91 (m, 6H), 1.40-2.42 (m, 8H), 3.08-3.24 (m, 3H), 3.67 (m, 3H), 3.71 (m, 4H), 3.88-3.89 (m, 1H),4.34-4.38 (m, 1H), 5.30-5.32 (m, 1H), 5.42-5.45 (m, 3H), 6.03-6.04 (m, 1H), 7.26-8.14 (m, 16H), 10.65 (m, 1H); MS (ESI,EI+) m/z = 885.8 (MH+).

Reference： [1]Patent: EP2513113,2018,B1 .Location in patent: Paragraph 0378; 0379; 0382

57
{2-methyl-(S)-1-[2-(S)-(5-{4-[6-((S)-2-pyrrolidin-2-yl-3H-benzoimidazol-5-yl)thieno[3,2-b]thiophen-3-yl]phenyl}-1H-imidazol-2-yl)pyrrolidine-1-carbonyl]propyl}carbamic acid methyl ester hydrochloride salt [ No CAS ]
[ 50890-96-5 ]
[ 1312547-21-9 ]

Yield	Reaction Conditions	Operation in experiment
41%	With triethylamine; HATU; In N,N-dimethyl-formamide; at -10℃; for 0.5h;	Intermediate E47 (0.178 mmol) was dissolved in DMF (3.6 mL) and the mixturewas cooled down to -10 C. TEA (1.246 mmol), intermediate 31 (0.187 mmol), and HATU (0.231 mmol) were addedand the mixture was stirred at -10 C during 30 min. Ethyl acetate was added and the mixture was washed with water.The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was filteredon a SCX-2 column and the filtrate was purified by silica gel chromatography (eluent: DCM to DCM/MeOH 5%) andRP18 (H2O to ACN/H2O 60%) to give compound A172 as a white solid in 41% yield. 1H NMR (DMSO-d6, 400 MHz) delta(ppm) 0.86 (d, 3H), 0.91 (d, 3H), 1.85-2.15 (m, 8H), 3.19 (m, 1H), 3.53 (s, 6H), 3.81 (m, 2H), 3.94 (m, 1H), 4.05 (m, 1H), 5.08 (m, 1H), 5.17 (m, 1H), 5.23 (m, 1H), 6.82 (m, 1H), 7.26-7.46 (m, 6H), 7.52-7.72 (m, 4H), 7.73-7.91 (m, 4H), 7.93-8.12(m, 3H), 11.83 (s, 1H), 12.29 (s, 1H); MS (ESI, EI+) m/z = 886.2 (MH+).

Reference： [1]Patent: EP2513113,2018,B1 .Location in patent: Paragraph 0374; 0375; 0377

58
[ 53934-78-4 ]
[ 50890-96-5 ]

Reference： [1]Patent: WO2010/117635,2010,A1

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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

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[ 50890-96-5 ] Synthesis Path-Upstream 1~7

[ 50890-96-5 ] Synthesis Path-Downstream 1~58

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Amino Acid Derivatives

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