[ CAS No. 71432-55-8 ] {[proInfo.proName]}

Name: 71432-55-8|tert-Butyl N,N'-diisopropylcarbamimidate|95% T
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Quality Control of [ 71432-55-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 71432-55-8 ]

Product Details of [ 71432-55-8 ]

CAS No. :	71432-55-8	MDL No. :	MFCD06657672
Formula :	C₁₁H₂₄N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FESDUDPSRMWIDL-UHFFFAOYSA-N
M.W :	200.32	Pubchem ID :	11041782
Synonyms :

Calculated chemistry of [ 71432-55-8 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.91
Num. rotatable bonds :	5
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	62.6
TPSA :	33.62 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.67 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.98
Log Po/w (XLOGP3) :	2.61
Log Po/w (WLOGP) :	2.56
Log Po/w (MLOGP) :	2.4
Log Po/w (SILICOS-IT) :	2.14
Consensus Log Po/w :	2.54

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.4
Solubility :	0.804 mg/ml ; 0.00402 mol/l
Class :	Soluble
Log S (Ali) :	-2.97
Solubility :	0.217 mg/ml ; 0.00108 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.63
Solubility :	0.473 mg/ml ; 0.00236 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.43

Safety of [ 71432-55-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 71432-55-8 ]

* 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 [ 71432-55-8 ]
Downstream synthetic route of [ 71432-55-8 ]

[ 71432-55-8 ] Synthesis Path-Upstream 1~7

1
[ 693-13-0 ]
[ 75-65-0 ]
[ 71432-55-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	at 20℃; for 14 h; Inert atmosphere	CuCl (63.4mg, 0.64mmol,1 molpercentforN,N’-diisopropylcarbodiimide) was added to a solution of N,N’-diisopropylcarbodiimide(10.0mL, 63.9mmol, 1.0 eq) in tBuOH (6.97mL, 73.5mmol, 1.15 eq). The reactionmixture was stirred for 14 h at room temperature and subsequently distilledunder reduced pressure (80°C, 25mmHg). The title compoundwas obtained as a colorless oil(10.4g, 51.9mmol, 81percent); 1H NMR (300 MHz, CDCl3) d 3.80-3.58(1H, m, CH), 3.31-2.97 (1H, m, CH), 1.44 (9H, s, tBu), 1.19-1.01 (12H, m, Me2×2).
78.1%	for 96 h;	Theisolated compounds 1 and 2 were synthesized according toa modified procedure.19) In brief, N,N′-diisopropyl-O-tertbutylisourea (6) was obtained from the reaction of diisopropylcarbodiimide (DIC) (5) (40.8 g, 323 mmol) and tert-butylalcohol (27.8 g, 375 mmol) with a catalytic amount of copper(I) chloride for 4 d (yield: 78.1percent). Malate 7 was thereafter obtained by adding excess 6 (38.8 g, 194 mmol) to a solution of(-) malic acid (3.6 g, 26.9 mmol) in dichloromethane (300 mL)at room temperature (yield: 14.0percent). Acetylation of commercially available p-coumaric acid (3) (1 g, 6.0 mmol) by treatment with acetic anhydride (1.74 mL, 18.4 mmol) in pyridine(10 mL) gave 4-O-acetyl coumaric acid (8) (yield: 78percent). Thecoupling reaction of the obtained coumaric acid derivative(8) (1.0 g, 5.05 mmol) and malate 7 (1.2 g, 5.05 mmol) in thepresence of DIC (0.65 mL) and N,N-dimethyl-4-aminopyridine(DMAP) (255.6 mg) afforded the condensation product (9)(yield: 18.3percent). Hydrolysis of compound 9 by treatment withtrifluoroacetic acid (TFA) followed by removal of the acetylgroup under acidic conditions (3 M HCl–acetone, reflux) gavep-coumaroyl malate (2) (total yield: 11.0percent). Methylation of 2was achieved by treatment of MeOH involving 5percent sulfuricacid (H2SO4) in reflux to obtain compound 1 (total yield:4.6percent).
78.1%	for 96 h;	The isolated compounds 1 and 2 were synthesized according to a modified procedure.19) In brief, N,N-diisopropyl-O-tertbutylisourea(6) was obtained from the reaction of diisopropylcarbodiimide(DIC) (5) (40.8 g, 323 mmol) and tert-butylalcohol (27.8 g, 375 mmol) with a catalytic amount of copper(I) chloride for 4 d (yield: 78.1percent). Malate 7 was thereafter obtainedby adding excess 6 (38.8 g, 194 mmol) to a solution of(−) malic acid (3.6 g, 26.9 mmol) in dichloromethane (300 mL)at room temperature (yield: 14.0percent). Acetylation of commercially available p-coumaric acid (3) (1 g, 6.0 mmol) by treatment with acetic anhydride (1.74 mL, 18.4 mmol) in pyridine(10 mL) gave 4-O-acetyl coumaric acid (8) (yield: 78percent). The coupling reaction of the obtained coumaric acid derivative(8) (1.0 g, 5.05 mmol) and malate 7 (1.2 g, 5.05 mmol) in thepresence of DIC (0.65 mL) and N,N-dimethyl-4-aminopyridine(DMAP) (255.6 mg) afforded the condensation product (9)(yield: 18.3percent). Hydrolysis of compound 9 by treatment with trifluoroacetic acid (TFA) followed by removal of the acetylgroup under acidic conditions (3 M HCl–acetone, reflux) gavep-coumaroyl malate (2) (total yield: 11.0percent). Methylation of 2was achieved by treatment of MeOH involving 5percent sulfuricacid (H2SO4) in reflux to obtain compound 1 (total yield:4.6percent)

Reference： [1] Organic Letters, 2005, vol. 7, # 13, p. 2615 - 2618
[2] Chemistry - A European Journal, 2007, vol. 13, # 30, p. 8543 - 8563
[3] Beilstein Journal of Organic Chemistry, 2011, vol. 7, p. 1486 - 1493
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4204 - 4219
[5] Patent: EP2952517, 2015, A1, . Location in patent: Paragraph 0217
[6] Tetrahedron Letters, 2014, vol. 55, # 46, p. 6343 - 6346
[7] Chemical and Pharmaceutical Bulletin, 2017, vol. 85, # 12, p. 1191 - 1194
[8] Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 12, p. 1191 - 1194
[9] Chemical Communications, 2018, vol. 54, # 22, p. 2785 - 2787
[10] Synthesis, 2009, # 21, p. 3571 - 3578
[11] Organometallics, 2017, vol. 36, # 7, p. 1296 - 1302
[12] Justus Liebigs Annalen der Chemie, 1955, vol. 597, p. 235,237
[13] Journal of Organic Chemistry, 1994, vol. 59, # 8, p. 2261 - 2266
[14] Journal of the American Chemical Society, 2000, vol. 122, # 50, p. 12458 - 12468
[15] Tetrahedron, 2005, vol. 61, # 15, p. 3725 - 3731
[16] Patent: WO2007/99317, 2007, A1, . Location in patent: Page/Page column 98
[17] Patent: WO2006/14429, 2006, A2, . Location in patent: Page/Page column 13-14
[18] Journal of Organic Chemistry, 2010, vol. 75, # 20, p. 6953 - 6960
[19] Tetrahedron, 2011, vol. 67, # 12, p. 2338 - 2347
[20] Phosphorus, Sulfur and Silicon and the Related Elements, 2012, vol. 187, # 5, p. 632 - 640
[21] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 15, p. 4830 - 4837
[22] European Journal of Medicinal Chemistry, 2013, vol. 65, p. 256 - 275
[23] Organic Process Research and Development, 2006, vol. 10, # 3, p. 534 - 538
[24] Organic Letters, 2015, vol. 17, # 18, p. 4620 - 4623
[25] Journal of the American Chemical Society, 2016, vol. 138, # 7, p. 2114 - 2117
[26] Angewandte Chemie - International Edition, 2018, vol. 57, # 12, p. 3084 - 3088[27] Angew. Chem., 2018, vol. 130, p. 3138 - 3142,5

2
[ 777031-92-2 ]
[ 75-65-0 ]
[ 71432-55-8 ]

Reference： [1] Patent: WO2005/35525, 2005, A2, . Location in patent: Page/Page column 57

3
[ 71432-55-8 ]
[ 619-66-9 ]
[ 65874-27-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 12, p. 3435 - 3439

4
[ 2067-33-6 ]
[ 71432-55-8 ]
[ 88987-42-2 ]

Yield	Reaction Conditions	Operation in experiment
7.4 g	for 120 h;	Diisopropylcarbodiimide (25.2 g; 0.2 mol), tert-butyl alcohol (14.8 g; 0.2 mol) and CuCl (0.5 g) was stirred overnight at rt. 5-Bromovaleric acid (10.0 g; 55.7 mmol) was dissolved in 150 mL of dichloromethane, and the crude tert-butyl isourea generated in situ was added in 15 equal portions (approximately 3 mL of each) over the period of 5 days. Any increase in the temperature of the reaction mixture above 30 °C led to a rapid decomposition of the alkylating agent. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography on silica gel using a linear gradient of diethyl ether in petroleum ether. Yield: 7.4 g (56percent). Colorless liquid, Rf = 0.81 (S8). ¹H NMR (600 MHz, CDCl3): δ = 3.42 (t, J = 6.7 Hz, 2H), 2.25 (t, J = 7.4 Hz, 2H), 1.88 (m, 2H), 1.74 (m, 2H), 1.45 (s, 9H, t-Bu). ¹³C NMR (150.9 MHz, CDCl3): δ = 172.47 (-CO-O), 80.28, 34.47, 33.14, 31.95, 28.04 (3C), 23.60. IR (film) νmax (cm^-1): 1729 vs (C=O); 2978 m, 2934 m, 1367 s (CH3). 1156 vs (C-O). HRMS (ESI) calc for C₉H₁₇O₂BrNa [M + Na]⁺ 259.03041, found: 259.03037.

Reference： [1] European Journal of Medicinal Chemistry, 2013, vol. 65, p. 256 - 275

5
[ 71432-55-8 ]
[ 2799-07-7 ]
[ 76587-61-6 ]

Reference： [1] Journal of Organic Chemistry, 1994, vol. 59, # 11, p. 3216 - 3218

6
[ 71432-55-8 ]
[ 193751-54-1 ]

Reference： [1] Tetrahedron Letters, 1998, vol. 39, # 20, p. 3357 - 3358

7
[ 71432-55-8 ]
[ 5398-44-7 ]
[ 75308-46-2 ]

Reference： [1] Patent: US2003/144303, 2003, A1,

[ 71432-55-8 ] Synthesis Path-Downstream 1~60

1
[ 693-13-0 ]
[ 75-65-0 ]
[ 71432-55-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	With copper(l) chloride; at 20℃; for 14h;Inert atmosphere;	CuCl (63.4mg, 0.64mmol,1 mol%forN,N?-diisopropylcarbodiimide) was added to a solution of N,N?-diisopropylcarbodiimide(10.0mL, 63.9mmol, 1.0 eq) in tBuOH (6.97mL, 73.5mmol, 1.15 eq). The reactionmixture was stirred for 14 h at room temperature and subsequently distilledunder reduced pressure (80C, 25mmHg). The title compoundwas obtained as a colorless oil(10.4g, 51.9mmol, 81%); 1H NMR (300 MHz, CDCl3) d 3.80-3.58(1H, m, CH), 3.31-2.97 (1H, m, CH), 1.44 (9H, s, tBu), 1.19-1.01 (12H, m, Me2×2).
78.1%	With copper(l) chloride; for 96h;	Theisolated compounds 1 and 2 were synthesized according toa modified procedure.19) In brief, N,N?-diisopropyl-O-tertbutylisourea (6) was obtained from the reaction of diisopropylcarbodiimide (DIC) (5) (40.8 g, 323 mmol) and tert-butylalcohol (27.8 g, 375 mmol) with a catalytic amount of copper(I) chloride for 4 d (yield: 78.1%). Malate 7 was thereafter obtained by adding excess 6 (38.8 g, 194 mmol) to a solution of(-) malic acid (3.6 g, 26.9 mmol) in dichloromethane (300 mL)at room temperature (yield: 14.0%). Acetylation of commercially available p-coumaric acid (3) (1 g, 6.0 mmol) by treatment with acetic anhydride (1.74 mL, 18.4 mmol) in pyridine(10 mL) gave 4-O-acetyl coumaric acid (8) (yield: 78%). Thecoupling reaction of the obtained coumaric acid derivative(8) (1.0 g, 5.05 mmol) and malate 7 (1.2 g, 5.05 mmol) in thepresence of DIC (0.65 mL) and N,N-dimethyl-4-aminopyridine(DMAP) (255.6 mg) afforded the condensation product (9)(yield: 18.3%). Hydrolysis of compound 9 by treatment withtrifluoroacetic acid (TFA) followed by removal of the acetylgroup under acidic conditions (3 M HCl-acetone, reflux) gavep-coumaroyl malate (2) (total yield: 11.0%). Methylation of 2was achieved by treatment of MeOH involving 5% sulfuricacid (H2SO4) in reflux to obtain compound 1 (total yield:4.6%).
78.1%	With copper(l) chloride; for 96h;	The isolated compounds 1 and 2 were synthesized according to a modified procedure.19) In brief, N,N-diisopropyl-O-tertbutylisourea(6) was obtained from the reaction of diisopropylcarbodiimide(DIC) (5) (40.8 g, 323 mmol) and tert-butylalcohol (27.8 g, 375 mmol) with a catalytic amount of copper(I) chloride for 4 d (yield: 78.1%). Malate 7 was thereafter obtainedby adding excess 6 (38.8 g, 194 mmol) to a solution of(-) malic acid (3.6 g, 26.9 mmol) in dichloromethane (300 mL)at room temperature (yield: 14.0%). Acetylation of commercially available p-coumaric acid (3) (1 g, 6.0 mmol) by treatment with acetic anhydride (1.74 mL, 18.4 mmol) in pyridine(10 mL) gave 4-O-acetyl coumaric acid (8) (yield: 78%). The coupling reaction of the obtained coumaric acid derivative(8) (1.0 g, 5.05 mmol) and malate 7 (1.2 g, 5.05 mmol) in thepresence of DIC (0.65 mL) and N,N-dimethyl-4-aminopyridine(DMAP) (255.6 mg) afforded the condensation product (9)(yield: 18.3%). Hydrolysis of compound 9 by treatment with trifluoroacetic acid (TFA) followed by removal of the acetylgroup under acidic conditions (3 M HCl-acetone, reflux) gavep-coumaroyl malate (2) (total yield: 11.0%). Methylation of 2was achieved by treatment of MeOH involving 5% sulfuricacid (H2SO4) in reflux to obtain compound 1 (total yield:4.6%)

	With copper(l) chloride; at 17 - 25℃; for 48h;	2-tert-Butyl-l,3-diisopropylisourea [629 g; obtained as a liquid by the reaction of diisopropylcarbodiimide (496 ml), tert-butanol (303 ml) and cuprous chloride (4.71 g) at ambient temperature under argon for 48 hours and filtration of the mixture] was added to a stirred suspension of 2-(5-benzyloxypyridin-2-yl)acetic acid (84.1 g) in methylene chloride (1.4 litres) and the mixture was stirred at ambient temperature for 48 hours. The resultant precipitate was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica using increasingly polar solvent mixtures of methylene chloride and ethyl acetate (100:0 up to 19:1) as eluent. There was thus obtained tert-butyl 2-(5-benzyloxypyridin-2-yl)acetate (63.7 g) as an oil which crystallised upon standing; 1H NMR: (DMSOd6) 1.4 (s, 9H), 3.65 (s, 2H), 5.2 (s, 2H), 7.25 (d, IH), 7.4 (m, 6H), 8.25 (d, IH).
	With copper(l) chloride; at 20℃; for 24h;	To synthesize compound 5 of Figure 2, O-tert-butyl-N,N'- diisopropylisourea was made according to Rapoport et al., J. Org. Chem., 1993, 58, 2369- 2376, incorporated by reference herein. In brief, 10 mL (1.0 equiv) of N,N'- diisopropylcarbodiimide was added to 7.1 mL (1.15 equiv) of t-butanol. 64 mg of CuCl was added and the reaction was stirred at ambient temperature for 24 h. 1.73 mL (7.25 mmol) O- tert-butyl-N,N'-diisopropylisourea was added to 1.0 g (4.87 mmol) of t-BOC-L-serine in 10.0 mL dry CH2Cl2. The reaction was refiuxed for 24 h before an additional 1.73 mL (7.25 mmol) O-tert-butyl-N,N'-diisopropylisourea was added to the reaction mixture, which was refiuxed for another 24 h. Solvents were removed under vacuum, and residues were redissolved in CH2Cl2, which was followed by a silica gel filtration for removal of N,N'- diiospropylurea. The filtrate solvent was removed and approximately 1.0 g of the t-butyl ester of t-BOC L-serine was achieved (yield 79%). Selective deprotection of the t-BOC moiety was achieved according to Han et al., J. Pept. Res. 2001, 58(4), 338-341, incorporated by reference herein, by exposing the t-butyl ester and t-BOC-protected L-serine to 4 M HCl in dioxane at 0 0C for 0.5 h. Solvent was removed under vacuum, and 751 mg of t-butyl ester-protected L-serine was obtained as a white crystalline compound. 751 mg (3.8 mmol) L-serine t-butylester, 826 mg (3.8 mmol) t-BOC L-valine, and 425 muL (3.05 mmol) TEA were dissolved in 15.0 mL dry CH2Cl2 to achieve the desired conjugation between the two amino acids, 695 mg (3.37 mmol) DCC and 434 mg (3.21 mmol) HOBt, was added, and the reaction was stirred at room temperature for 18 h. N,N'-dicyclohexylurea was filtered off and the crude product was concentrated under vacuum. The crude product was dissolved in 50 mL of DCM. An aqueous workup was performed using 25 mL sat. NaHCO3 followed by 30 mL HPLC water before obtaining the desired dipeptide as a foamy film in 48% yield (650 mg). This product was used as obtained without further purification. [0045] To prepare compound 5 of Figure 2, 135 mg (0.428 mmol) cidofovir was exposed to 135 mg (1.04 mmol) DIEA and dissolved in 4 mL DMF. A HPMPC-DIEA salt was obtained after solvent was removed under vacuum. 650 mg (1.8 mmol) dipeptide (t- BOC-Val-Ser-t-butyl described above) was added to a reaction flask containing the HPMPC- DIEA salt and 4 mL dry DMF. 660 mg (1.27 mmol) PyBOP and 425 muL (2.44 mmol) DIEA were added, and the reaction took place stirring under N2 (g) at 40 0C for 1 h. An additional 330 mg (0.635 mmol) PyBOP was added and left for 3 additional hours. Solvents were removed under vacuum, and a silica gel column chromatography purification was performed [eluent; CH2Cl2: acetone:methanol, 20:10:1.]. Solvent was removed and deprotection of the t-BOC and t-butoxy groups was performed in 4 mL of CH2Cl2 in the presence of 2 mL of 99% TFA for 3 h at room temperature. Solvents were removed under vacuum and ether was added to precipitate the final compound, 5, which was filtered by methanol on a funnel containing a silica gel layer. Preparative HPLC purification on a C- 18 column (5 mum, 100. A, 21.4x250 mm by Varian) was obtained using a mobile phase containing 0.1 M TEA and 3.5% acetonitrile at pH 6.7 adjusted with acetic acid. A fraction of the sample was purified by preparative HPLC methods and evaluated by NMR and HR-MS techniques. 1H NMR (CD3OD): delta 0.94 (6H, m), 2.10 (IH, m), 2.94-5.73 (1OH, m), 5.73 (IH, m), 7.40 (IH, m). 31P NMR (CD3OD): delta 14.3 and 15.6 (IP, 2s). Exact mass (Ci6H26N5O8P); 447.1519 m/z
	With copper(l) chloride; at 20℃;	General procedure: CuCl (2 mol %) was added to a stirred solution of alcohol 3 (5.5 mmol) and DIC (5.5 mmol). Stirring was continued for 22-24 h at 20 C. The resulting product was transferred into a syringe and was added over a period of 90 min in a dropwise manner at 24 C (for 3a) or at 0 C (for 3b,c) to a solution of 3-hydroxy-5-(4-methoxyphenyl)-4-methylthiazole-2(3H)-thione (MAnTTOH; 2) (1 mmol) in CH2Cl2 (2 mL). After complete addition, solids were removed by filtration to afford a clear solution, which was concentrated under reduced pressure. The remaining oil was purified by column chromatography (SiO2) using the eluent gradient (EG) specified below.
	With copper(l) chloride; at 20℃; for 12h;Inert atmosphere;	DIC (12.1 mL, 77.8 mmol) was added to a mixture of CuCl (140 mg, 1.4 mmol) and tert-butanol (29.9 mL, 312.6 mmol) and the mixture was stirred at room temperature for 12 h. The volatile components were removed under reduced pressure. The solid was dissolved in THF (25 mL) and 5-methoxy-2-methyl-1H-indole-3-acetic acid (2) (7.0 g, 31.9 mmol) was added and the mixture stirred at room temperature for 2 h. The solvent was evaporated and the solid was purified by column chromatography with a mixture of hexanes (80-100 C) and ethyl acetate (3:1). The solvent was removed under reduced pressure to yield a white solid. Yield: 7.2 g (82%).
	With copper(l) chloride; In 1,4-dioxane; water; at 20℃; for 12h;	Di-tert-butyl dicarbonate (1.2 equiv.,16.0 g; 73.3 mmol) in 50 mL dioxane was added drop-wise to a vigorously stirred solution of trans-4-hydroxy-L-proline (8.0 g; 61.0 mmol) in 10% aqueous Na2CO3 (80 mL) at 0 C, and the reaction was stirred overnight at room temperature. After the reaction was complete (TLC in the S H1 system), the solution was acidified by saturated aq. citric acid to pH4, and the product was extracted with EtOAc (three times with 200 mL, then five times with 100 mL). The combined extracts were dried over Na2SO4 and were then evaporated in vacuo to give a viscous colorless oil (16 g, Rf 0.6 in the S H1 system). The crude product 56 was used directly in the next step without furtherpurification. Diisopropylcarbodiimide (18.9 mL, 122 mmol, 2 equiv.) and CuCl (0.121 g, 1.22 mmol, 0.02 equiv.) was added to tert-butanol (11.5 mL,122 mmol, 2 equiv.), and the mixture was stirred for 12 h at roomtemperature to allow the formation of O-tert-butyl-N,N'-diisopropylisourea(ca. 122 mmol, 2 equiv.). A solution of crude 56 in dichloromethane (50 mL) was slowly added to the isourea upon cooling to 0 C, and the reaction mixture was heated to reflux for 1 d. A third equivalent of isourea (61 mmol) was then added, and the reaction was heated for an additional day. After the reaction mixture cooled, the precipitated urea was filtered off, and then, the filtrate was evaporated and dissolved in toluene (200 mL). The second crop of urea was filtered off, and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography on silica (elution with a linear gradient of EtOAc in toluene) to give compound 57. Yield 11.64 g (66% over 2 steps). Pale yellow oil.Rf 0.85 (S H3). Mixture of conformers at N-CO bond (~ 2:1); Major e 1H NMR (600 MHz, CDCl3): delta = 4.45 (m, 1H), 4.27 (t, J 8.2and 7.4 Hz, 1H), 3.59 (dd, J 11.6 and 4.3 Hz, 1H), 3.54 (ddd, J 11.6,2.3 and 1.6 Hz, 1H), 3.00 (bd, J 3.2 Hz, 1H, OH), 2.30 (dddd, J 13.3,8.2, 3.3 and 1.6 Hz, 1H), 2.03 (ddd, J 13.3, 7.4 and 5.0 Hz, 1H), 1.46(s, 9H, t-Bu), 1.43 (s, 9H, t-Bu). 13C NMR (150.9 MHz, CDCl3):d 172.15 (eCOeO), 154.23 (NeCOeO), 81.10, 80.16, 69.10, 58.48,54.52, 39.06, 28.27 (3C), 27.93 (3C). Minor - 1H NMR (600 MHz,CDCl3): delta = 4.46 (m, 1H), 4.30 (dd, J 8.2 and 7.0 Hz, 1H), 3.60 (dd,J 11.4 and 4.9 Hz, 1H), 3.42 (ddd, J 11.6, 2.7 and 1.5 Hz, 1H), 2.91(bd, J 3.7 Hz, 1H, OH), 2.24 (dddd, J 13.4, 8.2, 3.8 and 1.5 Hz, 1H),2.05 (ddd, J 13.4, 7.0 and 5.2 Hz, 1H), 1.46 (s, 9H, t-Bu), 1.45 (s, 9H,t-Bu). 13C NMR (150.9 MHz, CDCl3): d 172.07 (-CO-O), 154.42(N-CO-O), 81.18, 79.84, 69.98, 58.41, 54.60, 38.32, 28.32 (3C), 27.85(3C). IR gammamax/cm-1 (CCl4): 3446 m br (OH); 2980 s, 1478 m, 1393 vs,1367 vs (CH3); 2933 m (CH2); 1744 vs (C=O ester); 1704 vs (C=O carbamate); 1169 vs (C-O); 1087 s (C-OH). HRMS (ESI) calculatedfor (M + Na)+ C14H25O5NNa 310.1625, found 310.1624.
		Isourea reagent preparation: CuCI (2.02g, 0.02x wt) was charged to reactor 1. A charge of 0.01 to 0. lOx wt CuC1 can be used. Alternative Cu(I) salts such as CuBr or Cu can be used. N,N?-diisopropylcarbodiimide (126.8mL, 1.27x vol) was charged to reactor I. Alternative initial charges of N,N?-diisopropyLcarbodiimide can be used (0 to 3.17x vol). A 4% 02 atmosphere was established in reactor 1. An atmosphere of up to 22% 02 can be used. The reaction mixture was agitated at 25 C for 1 hour while maintaining a vessel atmosphere of 4%02. A temperature of 10 to 40 C can be used. A vessel atmosphere of up to 22% 02 can be used. An agitation time of 0 to 12 hours can be used. N,N?-diisopropylcarbodiimide (190.2mL, 1.9x vol) was charged to reactor 1 while maintaining a temperature of 30 C. Alternative secondary charges ofN,N?-diisopropylcarbodiimide can be used (0 to 3.17x vol). A temperature of 10 to 40 C could be used. Tert-butanol (182g. 1.82x wt) was charged to reactor 1 while maintaining a temperature of 30 C. Alternative charges of tert-butanol (1.51 to 3 .02x wt) can be used. A temperature of 10 to 40 C can be used. A 4% 02 atmosphere was re-established and reactor 1 was sealed. A vessel atmosphere of up to 22% 02 can be used. Reactor 1 was agitated at 25 C for 12 hours while maintaining a vessel atmosphere of 4% 02. A vessel atmosphere of up to 22% 02 can be used. A temperature of 10 to 40 C can be used. A reaction time of 4 to 72 hours can be used.

Reference： [1]Organic Letters,2005,vol. 7,p. 2615 - 2618
[2]Chemistry - A European Journal,2007,vol. 13,p. 8543 - 8563
[3]Beilstein Journal of Organic Chemistry,2011,vol. 7,p. 1486 - 1493
[4]Journal of Medicinal Chemistry,2015,vol. 58,p. 4204 - 4219
[5]Patent: EP2952517,2015,A1 .Location in patent: Paragraph 0217
[6]Tetrahedron Letters,2014,vol. 55,p. 6343 - 6346
[7]Chemical and Pharmaceutical Bulletin,2017,vol. 85,p. 1191 - 1194
[8]Chemical and pharmaceutical bulletin,2017,vol. 65,p. 1191 - 1194
[9]Chemical Communications,2018,vol. 54,p. 2785 - 2787
[10]Synthesis,2009,p. 3571 - 3578
[11]Organometallics,2017,vol. 36,p. 1296 - 1302
[12]Justus Liebigs Annalen der Chemie,1955,vol. 597,p. 235,237
[13]Journal of Organic Chemistry,1994,vol. 59,p. 2261 - 2266
[14]Journal of the American Chemical Society,2000,vol. 122,p. 12458 - 12468
[15]Tetrahedron,2005,vol. 61,p. 3725 - 3731
[16]Patent: WO2007/99317,2007,A1 .Location in patent: Page/Page column 98
[17]Patent: WO2006/14429,2006,A2 .Location in patent: Page/Page column 13-14
[18]Journal of Organic Chemistry,2010,vol. 75,p. 6953 - 6960
[19]Tetrahedron,2011,vol. 67,p. 2338 - 2347
[20]Phosphorus, Sulfur and Silicon and the Related Elements,2012,vol. 187,p. 632 - 640
[21]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 4830 - 4837
[22]European Journal of Medicinal Chemistry,2013,vol. 65,p. 256 - 275
[23]Organic Process Research and Development,2006,vol. 10,p. 534 - 538
[24]Organic Letters,2015,vol. 17,p. 4620 - 4623
[25]Journal of the American Chemical Society,2016,vol. 138,p. 2114 - 2117
[26]Angewandte Chemie - International Edition,2018,vol. 57,p. 3084 - 3088
Angew. Chem.,2018,vol. 130,p. 3138 - 3142,5
[27]Patent: WO2019/40109,2019,A1 .Location in patent: Paragraph 00337

2
[ 6027-13-0 ]
[ 71432-55-8 ]
(S)-2-Amino-4-mercapto-butyric acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 3216 - 3218

3
[ 71432-55-8 ]
[ 3316-09-4 ]
[ 141993-05-7 ]

Reference： [1]European Journal of Medicinal Chemistry,1992,vol. 27,p. 131 - 140

4
[ 71432-55-8 ]
[ 2799-07-7 ]
[ 76587-61-6 ]

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 3216 - 3218

5
[ 71432-55-8 ]
[ 138682-84-5 ]
[ 144358-24-7 ]

Reference： [1]Tetrahedron Letters,1993,vol. 34,p. 975 - 978
[2]Journal of Organic Chemistry,1996,vol. 61,p. 9115 - 9125
[3]Journal of Medicinal Chemistry,1994,vol. 37,p. 4031 - 4051

6
[ 71432-55-8 ]
[ 71-00-1 ]
[ 759432-08-1 ]

Reference： [1]Gibson, Frank S.; Bergmeier, Stephen C.; Rapoport, Henry [Journal of Organic Chemistry, 1994, vol. 59, # 11, p. 3216 - 3218]

7
[ 71432-55-8 ]
[ 54-12-6 ]
[ 16874-09-2 ]

Reference： [1]Gibson, Frank S.; Bergmeier, Stephen C.; Rapoport, Henry [Journal of Organic Chemistry, 1994, vol. 59, # 11, p. 3216 - 3218]

8
[ 71432-55-8 ]
[ 13726-69-7 ]
[ 170850-75-6 ]

Yield	Reaction Conditions	Operation in experiment
11.64 g	With sodium carbonate; In dichloromethane; at 0℃; for 48h;Reflux;	Di-tert-butyl dicarbonate (1.2 equiv.,16.0 g; 73.3 mmol) in 50 mL dioxane was added drop-wise to a vigorously stirred solution of trans-4-hydroxy-L-proline (8.0 g; 61.0 mmol) in 10% aqueous Na2CO3 (80 mL) at 0 C, and the reaction was stirred overnight at room temperature. After the reaction was complete (TLC in the S H1 system), the solution was acidified by saturated aq. citric acid to pH4, and the product was extracted with EtOAc (three times with 200 mL, then five times with 100 mL). The combined extracts were dried over Na2SO4 and were then evaporated in vacuo to give a viscous colorless oil (16 g, Rf 0.6 in the S H1 system). The crude product 56 was used directly in the next step without furtherpurification. Diisopropylcarbodiimide (18.9 mL, 122 mmol, 2 equiv.) and CuCl (0.121 g, 1.22 mmol, 0.02 equiv.) was added to tert-butanol (11.5 mL,122 mmol, 2 equiv.), and the mixture was stirred for 12 h at roomtemperature to allow the formation of O-tert-butyl-N,N'-diisopropylisourea(ca. 122 mmol, 2 equiv.). A solution of crude 56 in dichloromethane (50 mL) was slowly added to the isourea upon cooling to 0 C, and the reaction mixture was heated to reflux for 1 d. A third equivalent of isourea (61 mmol) was then added, and the reaction was heated for an additional day. After the reaction mixture cooled, the precipitated urea was filtered off, and then, the filtrate was evaporated and dissolved in toluene (200 mL). The second crop of urea was filtered off, and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography on silica (elution with a linear gradient of EtOAc in toluene) to give compound 57. Yield 11.64 g (66% over 2 steps). Pale yellow oil.Rf 0.85 (S H3). Mixture of conformers at N-CO bond (~ 2:1); Major e 1H NMR (600 MHz, CDCl3): delta = 4.45 (m, 1H), 4.27 (t, J 8.2and 7.4 Hz, 1H), 3.59 (dd, J 11.6 and 4.3 Hz, 1H), 3.54 (ddd, J 11.6,2.3 and 1.6 Hz, 1H), 3.00 (bd, J 3.2 Hz, 1H, OH), 2.30 (dddd, J 13.3,8.2, 3.3 and 1.6 Hz, 1H), 2.03 (ddd, J 13.3, 7.4 and 5.0 Hz, 1H), 1.46(s, 9H, t-Bu), 1.43 (s, 9H, t-Bu). 13C NMR (150.9 MHz, CDCl3):d 172.15 (eCOeO), 154.23 (NeCOeO), 81.10, 80.16, 69.10, 58.48,54.52, 39.06, 28.27 (3C), 27.93 (3C). Minor - 1H NMR (600 MHz,CDCl3): delta = 4.46 (m, 1H), 4.30 (dd, J 8.2 and 7.0 Hz, 1H), 3.60 (dd,J 11.4 and 4.9 Hz, 1H), 3.42 (ddd, J 11.6, 2.7 and 1.5 Hz, 1H), 2.91(bd, J 3.7 Hz, 1H, OH), 2.24 (dddd, J 13.4, 8.2, 3.8 and 1.5 Hz, 1H),2.05 (ddd, J 13.4, 7.0 and 5.2 Hz, 1H), 1.46 (s, 9H, t-Bu), 1.45 (s, 9H,t-Bu). 13C NMR (150.9 MHz, CDCl3): d 172.07 (-CO-O), 154.42(N-CO-O), 81.18, 79.84, 69.98, 58.41, 54.60, 38.32, 28.32 (3C), 27.85(3C). IR gammamax/cm-1 (CCl4): 3446 m br (OH); 2980 s, 1478 m, 1393 vs,1367 vs (CH3); 2933 m (CH2); 1744 vs (C=O ester); 1704 vs (C=O carbamate); 1169 vs (C-O); 1087 s (C-OH). HRMS (ESI) calculatedfor (M + Na)+ C14H25O5NNa 310.1625, found 310.1624.

Reference： [1]Tetrahedron Asymmetry,1998,vol. 9,p. 71 - 77
[2]Journal of Organic Chemistry,2017,vol. 82,p. 8419 - 8425
[3]Beilstein Journal of Organic Chemistry,2011,vol. 7,p. 1486 - 1493
[4]Tetrahedron,2005,vol. 61,p. 3725 - 3731
[5]European Journal of Medicinal Chemistry,2013,vol. 65,p. 256 - 275
[6]Organic Letters,2015,vol. 17,p. 4620 - 4623

9
[ 71432-55-8 ]
Cyclopent-3-enecarbonyl azide [ No CAS ]
[ 193751-54-1 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 3357 - 3358

10
[ 71432-55-8 ]
[ 77611-37-1 ]
[ 213176-15-9 ]

Reference： [1]Tetrahedron,1999,vol. 55,p. 63 - 88

11
[ 71432-55-8 ]
[ 2480-93-5 ]
[ 53054-02-7 ]

Reference： [1]Tetrahedron,2001,vol. 57,p. 4759 - 4766
[2]Organic Letters,2012,vol. 14,p. 4678 - 4681
[3]Tetrahedron Letters,1999,vol. 40,p. 2569 - 2572

12
[ 71432-55-8 ]
[ 5241-64-5 ]
[ 158008-94-7 ]

Reference： [1]Organic Letters,2002,vol. 4,p. 2961 - 2963

13
[ 71432-55-8 ]
[ 147266-92-0 ]
[ 862996-27-8 ]

Reference： [1]Journal of Organic Chemistry,2005,vol. 70,p. 6447 - 6453

14
[ 282092-84-6 ]
[ 71432-55-8 ]
[ 282092-85-7 ]

Reference： [1]Journal of the American Chemical Society,2000,vol. 122,p. 4247 - 4248

15
[ 7733-29-1 ]
[ 71432-55-8 ]
N^α-benzyloxycarbonyl-N^δ-(tert-butoxycarbonyl)-ornithine tert-butyl ester [ No CAS ]

Reference： [1]Organic Letters,2006,vol. 8,p. 3865 - 3868

16
[ 71432-55-8 ]
[ 619-66-9 ]
[ 65874-27-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3435 - 3439

17
[ 71432-55-8 ]
[ 619-21-6 ]
[ 247186-56-7 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; <i>tert</i>-butyl alcohol at 20℃; for 16h;

Reference： [1]Maruoka, Hiroshi; Muto, Tsuyoshi; Tanaka, Taisaku; Imajo, Seiichi; Tomimori, Yoshiaki; Fukuda, Yoshiaki; Nakatsuka, Takashi [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 12, p. 3435 - 3439]

18
[ 636-61-3 ]
[ 71432-55-8 ]
[ 157594-60-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	In dichloromethane; at 20℃; for 48h;Inert atmosphere;	N,N'-Diisopropyl-O-tert-butylisourea (30.00?g, 149.90?mmol, 6.7 eq.) was added to the suspension of (R)-malic acid (3.00?g, 22.40?mmol, 1.0 eq.) in DCM (150.0?mL). After stirring at rt for 48?h, the mixture was filtered through a short pad of celite. The filtrate was concentrated in vacuo and dissolved in EtOAc (100.0?mL). The solution was washed with 1?M HCl (aq.), sat. NaHCO3 (aq.), brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Cyh:EtOAc?=?9:1, v/v) to obtain ester 7 as colorless oil (4.06?g, 16.50?mmol, 74%). [alpha]25D +6.2 (c 0.87, CHCl3); IR (ATR) numax 3500, 2979, 2935, 1727, 1367, 1252, 1144, 1101?cm-1; 1H NMR (400?MHz, CDCl3) delta 4.29 (dd, J?=?5.9, 4.5?Hz, 1H), 2.71 (dd, J?=?16.3, 4.5?Hz, 1H), 2.63 (dd, J?=?16.3, 5.9?Hz, 1H), 1.45 (s, 9H), 1.44 (s, 9H); 13C NMR (100?MHz, CDCl3) delta 172.8, 169.8, 82.6, 81.3, 67.6, 39.9, 28.1, 28.0; EIMS m/z (%) 269.1 [M+Na]+ (52), 515.3 [2M + Na]+ (40); HREIMS m/z 269.1359 [M+Na]+ (calcd for C12H22NaO5+, 269.1365); Rf?=?0.51 (Cyh:EtOAc?=?4:1, v/v).

Reference： [1]Australian Journal of Chemistry,2009,vol. 62,p. 676 - 682
[2]Tetrahedron,2019,vol. 75,p. 4479 - 4485
[3]Synthetic Communications,2013,vol. 43,p. 1345 - 1350
[4]Heterocycles,2007,vol. 72,p. 181 - 185
[5]Journal of Organic Chemistry,2008,vol. 73,p. 9692 - 9697

19
[ 857732-39-9 ]
[ 71432-55-8 ]
[ 857732-40-2 ]

Reference： [1]Organic and Biomolecular Chemistry,2007,vol. 5,p. 2826 - 2834
[2]Journal of Antibiotics,2018,vol. 71,p. 234 - 239

20
C₁₇H₂₂O₆ [ No CAS ]
[ 71432-55-8 ]
C₂₁H₃₀O₆ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2007,vol. 5,p. 2826 - 2834

21
[ 71432-55-8 ]
[ 13504-86-4 ]
[ 224321-05-5 ]

Yield	Reaction Conditions	Operation in experiment
81%	In tetrahydrofuran; at 0 - 20℃; for 24.5h;	Example 1 Preparation of compound 59 4-Hydroxy-pyrrolidine-1, 2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester (3) [0155] Commercially available (Bachem) Z-Hydroxy- proline (l) (10g, 42.51mmols) was dissolved 90mls of THF (tetrahydrofuran) and was cooled to 0 C with an ice water bath. To this was added previously prepared tert- butyl N, N'-diisopropyl-imidocarbamate (2) (27ml, 135mmol) via a dropping funnel over 30 minutes. After addition the cooling bath was removed and the reaction stirred at ambient temperature for 24 hours. The volume of the reaction was reduced and then diethyl ether was added prior to washing with saturated sodium bicarbonate, then 0.5M hydrochloric acid, then water, and finally with brine. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 15g of crude material. Material was run through a plug of Si02 and eluted with 45% EtOAc-Hexanes to give 4-Hydroxy-pyrrolidine-1, 2- dicarboxylic acid 1-benzyl ester 2-tert-butyl ester 3 as a colorless oil 11. Og (81%)

Reference： [1]Patent: WO2005/35525,2005,A2 .Location in patent: Page/Page column 57

22
[ 503414-71-9 ]
[ 71432-55-8 ]
[ 503415-52-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	In tetrahydrofuran; at 20℃; for 16h;	[0230] To a solution of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(4-pyridyl) benzoic acid (500 mg, 1.1820 mmol) in tetrahydrofuran (THF) (20 ml) was added 2-tert-butyl-1,3-diisopropylurea (2.36 g, 11.8 mmol) followed by stirring at room temperature for 16 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give tert-butyl 5(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(4-pyridyl) benzoate (400 mg, 0.8350 mmol, 70%). The compound was dissolved in a mixed solvent of acetonitrile (30 ml) and water (10 ml), then CAN (1.12 g, 2.0437 mmol) was added thereto and the mixture was stirred for-3 hours. [0231] The reaction solution was poured into water, neutralized with a 1N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (methylene chloride:methanol=95:5) to give tert-butyl 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)-2-(4-pyridyl)benzoate (251 mg, 0.5590 mmol, 67%). The compound (251 mg, 0.5590 mmol) was dissolved in formic acid (10 ml) and stirred at room temperature for 6 hours. The residue obtained by evaporation of the solvent was washed with ether to give the title compound (202 mg, 0.5139 mmol, 92%). (The overall yield: 43%)

Reference： [1]Patent: US2004/39061,2004,A1 .Location in patent: Page/Page column 18

23
[ 847608-22-4 ]
[ 71432-55-8 ]
[ 847373-15-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	In tetrahydrofuran; at 20℃; for 2.5h;Heating / reflux;	2-tert-Butyl-1,3-diisopropylisourea (8.04 g, 40.1 mmol) was added to a mixture of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid hydrochloride salt (24) (2.91 g, 7.31 mmol) in THF (165 mL). After stirring for 2 hours at room temperature and 30 minutes at reflux, the reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with 10% K2CO3 and brine, dried (Na2SO4) and concentrated. The resulting residue was dissolved in CH2Cl2 and filtered. The filtrate was concentrated and purified by flash column chromatography using the Biotage system (CH2Cl2) to give the desired product (40) (3.28 g, 78%).

Reference： [1]Patent: US2005/49419,2005,A1 .Location in patent: Page/Page column 30

24
[ 252357-29-2 ]
[ 71432-55-8 ]
[ 252357-30-5 ]

Yield	Reaction Conditions	Operation in experiment
72%	In dichloromethane;Heating / reflux;	1.5 g (10.78 mmol) of (R) 2-Amino-4,4-difluoro butanoic acid (prepared as described in Winkler et al, Synthesis 1419, 1996) was dissolved in aqueous half saturated Na2CO3 (50 mL) and cooled to 0 C. A solution of (benzyloxy-carbonyloxy)succinimide (2.69 g, 10.78 mmol) in dioxane (50 mL) was added dropwise over 30 min. The resulting suspension was stirred overnight at room temperature. After evaporation of the dioxane under reduced pressure, water (20 mL) and EtOAc (150 mL) were added. The aqueous phase was brought to pH 2 by addition of 1 N HCl, the organic phase was separated, washed with brine and dried. Evaporation gave 2.85 g (97%) of a colourless oil.This material (950 mg; 3.55 mmol) was dissolved in dichloromethane (15 mL) and N,N'-isopropyl-O-tert-butyl isourea (1.42 g, 7.10 mmol) was added dropwise. The solution was brought to gentle reflux. After 8 h another 1.42 g of the isourea was added and reflux was continued overnight. The diisopropylurea was removed by filtration, and the residue purified by flash chromatography (petroleum ether/ethyl acetate 10:1) to give a colourless oil (844 mg; 72%). 1H-NMR (DMSO-d6) delta 1.38 (s, 9H), 2.14-2.28 (m, 2H), 4.08 (m, 1H), 5.03 (d, J=12.6 Hz, 1H), ), 5.06 (d, J=12.6 Hz, 1H), 6.10 (tt, J=4.7, 56.2 Hz, 1H), 7.27-7.39 (m, 5H), 7.79 (d, J=8.1 Hz, 1H); 13C-NMR (DMSO-d6) delta 27.4, 34.9 (t, J=22.5 Hz), 49.5, 65.5, 81.2, 115.9 (t, J=238 Hz), 127.7, 127.8, 128.3, 136.7, 135.8, 169.8; 19F-NMR (DMSO-d6) delta -115.1 (d, J=283 Hz), -115.8 (d, J=283 Hz); MS m/z 330 (M+: +H).300 mg (0.91 mmol) of this material were hydrogenated over 10% palladium-on-charcoal in methanol (10 mL). After 5 h, the catalyst was removed by filtration, then some ethyl acetate and a 1 N solution of hydrochloric acid in diethyl ether (1.37 mL) were added. After evaporation in vacuo the title compound (203 mg; 96%) was obtained as an off-white solid; mp 153-154 C.; 1H-NMR (DMSO) delta 1.44 (s, 9H), 2.38-2.50 (m, 2H), 4.03 (t, J=6.2 Hz, 1H), 6.35 (tt, J=4.3, 55.6 Hz, 1H), 8.85 (bs, 3H); 13C-NMR (DMSO-d6) delta 27.3, 34.3 (t, J=23.3 Hz), 47.6, 83.4, 114.9 (t, J=238 Hz), 167.0; 19F-NMR (DMSO-d6) delta -114.5 (d, J=285 Hz), -115.3 (d, J=285 Hz); MS m/z 196 (M++H).

Reference： [1]Patent: US6867284,2005,B1 .Location in patent: Page/Page column 28-29

25
[ 10349-57-2 ]
[ 71432-55-8 ]
[ 403605-43-6 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 0 - 20℃; for 16h;	Preparation of Intermediate Quinoline-6-carboxylic acid ter-butyl ester; To a solution of 2-tert-butyl-1, 3-diisopropyl-isourea, prepared in accordance with the method described in Mathias, L. J., Synthesis, 1979,561, (115 g, 575 mM, 5 equiv) in CH2C12 (200 mL) at 0 C, A-1 was added in one portion (19. 9g, 115 mM, 1 equiv). The ice-bath was removed and the mixture was allowed to warm to room temperature and was stirred at that temperature overnight (16 h). The mixture was cooled to 0 C and a precipitate that formed was removed by filtration. The filtrate was washed with 10% aqueous citric acid, and aqueous NaHC03, dried over MgSO4, filtered and concentrated to give B-1 as an oil. The oil was purified by filtration through a plug of silica gel, eluting with 20% ethyl acetate in hexanes.

Reference： [1]Patent: WO2005/80373,2005,A1 .Location in patent: Page/Page column 68
[2]Organic Process Research and Development,2006,vol. 10,p. 534 - 538

26
[ 71432-55-8 ]
[ 10314-98-4 ]
[ 882738-24-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	In dichloromethane; at 20℃; for 1.5h;	To a solution of l-[(benzyloxy)carbonyl]piperidine-4-carboxylic acid in DCM (0.2 M), 3 eq of tert-butyl N,N-diisopropylimidocarbamate were added and the mixture was stirred at RT. After 30 min, a further 1.5 eq of ferf-butyl N,N-diisopropylimidocarbamate were added and the solution stirred for an additional hour. The solution was filtered through a pad of celite and then through a pad of silica gel to give the product (83 %); MS (ES+) m/z 320 (M+H)+

Reference： [1]Patent: WO2006/38039,2006,A1 .Location in patent: Page/Page column 17; 29

27
[ 898227-78-6 ]
[ 71432-55-8 ]
[ 898227-79-7 ]

Yield	Reaction Conditions	Operation in experiment
35%	In tetrahydrofuran; for 20.0h;Heating / reflux;	(d) tert -Butyl 6-chloro-5-cyano-2-methylnicotinate; A solution of 6-Chloro-5-cyano-2-metih.ylnicotinic acid (6.10 g, 31.0 mmol) and tert-butyl N,N'-isopropylcarbamimidate (18.6 g, 93.1 mmol) in THF (150 mL) was heated to reflux for 20 h. The reaction mixture was cooled to room temperature, concentrated and diluted with DCM (300 mL). The resulting precipitate was removed by filtration through silica gel and discarded. The supernatant was concentrated, diluted with EtOAc (400 mL), washed with saturated NH4Cl (2 x 200 mL), saturated NaHCO3 (2 x 200 mL), brine (200 mL), dried (Mg5O4), passed through silica gel and concentrated. Flash chromatography (50 % DCM/hexanes) furnished tert-butyl 6-chloro-5-cyano-2-methylnicotinate as a solid. Yield: 2.75 g (35 %).1HNMR (400 MHz, CDCi): 5 1.61 (9H/s), 2.87 (3H, s), 8.39 (1H, s). M5 m/z: 254 (M+l).

Reference： [1]Patent: WO2006/73361,2006,A1 .Location in patent: Page/Page column 142

28
[ 898228-77-8 ]
[ 71432-55-8 ]
[ 898228-78-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	In tetrahydrofuran; for 1h;Heating / reflux;	(b) tert -Butyl 5-chloro -6-(4-(methoxycarbonyl)piperidin-1-yl)nicotinate; A solution of 5-chloro-6-(4-(methoxycarbonyl)piperidin-1-yl)nicotinic acid (2.01 g, 6.73 mmol) and tert-butyl N,N'-diisopropylcarbamimidate (21.6 g, 107 mmol) in THF (100 mL) was heated to reflux for 1 h. After cooling to room temperature, the resulting precipitate was removed by filtration through silica gel and discarded. The supernatant was concentrated. Flash chromatography (5 % EtOAc/hexanes) furnished tert-butyl 5-chloro-6-(4- (methoxycarbonyl)piperidin- 1 -yl)nicotinate. Yield: 1.91 g (80 %). EPO <DP n="190"/>1HNMR (400 MHz, CDCh): 5 1.57 (9H, s), 1.85-1.95 (2H, m), 2.01-2.05 (2H, m), 2.52-2.60 (1H, m), 2.96-3.03 (2H, m), 3.71 (3H, s), 4.00-4.05 (2H, m), 8.05 (1H, d, J= 2.7 Hz), 8.69 (1H, d, J =-2.7 Hz). M5 m/z: 355 (M+l).

Reference： [1]Patent: WO2006/73361,2006,A1 .Location in patent: Page/Page column 188-189

29
[ 71432-55-8 ]
[ 5398-44-7 ]
[ 75308-46-2 ]

Yield	Reaction Conditions	Operation in experiment
73%	In tetrahydrofuran;	Step 1 To a solution of 2,6-dichloropyridine-4-carboxylic acid (8.28 g, 43.1 mmol, Aldrich) in dry THF (30 ml) was added N,N'-diisopropyl-O-t-butylisourea (17 ml, 3.6 M) dropwise over 1 minute. The resulting mixture was stirred at room temperature overnight. The material was then heated to 65 C. and additional N,N'-diisopropyl-O-t-butylisourea (10 ml) was added dropwise. The mixture was stirred for 1 hour and cooled to room temperature. After removing volatiles, the remainder was purified by flash silica gel column (EtOAc/hexanes 5:95 followed by 7.5:92.5)affording tert-butyl-2,6-dichloro-4-pyridine carboxylate (7.83 g, 73%) as a white solid. MS (ES+): 248.

Reference： [1]Patent: US2003/144303,2003,A1

30
[ 86-90-8 ]
[ 71432-55-8 ]
1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride [ No CAS ]
1-[4-bromo-2-(tert-butoxycarbonyl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With hydrogenchloride; N-ethyl-N,N-diisopropylamine; In dichloromethane;	Referential Example 26 1-[4-Bromo-2-(tert-butoxycarbonyl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine In dichloromethane (200 ml), <strong>[86-90-8]4-bromophthalic anhydride</strong> (1.96 g) and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (3.00 g) were suspended under ice cooling. To the resulting suspension, diisopropylethylamine (3.76 ml) was added, followed by stirring for 20 minutes. To the reaction mixture, dilute hydrochloric acid and dichloromethane were added. The organic layer so separated was dried over anhydrous sodium sulfate. The solvent was concentrated so that the volume was reduced to 200 ml. To the concentrate, N,N'-diisopropyl-O-tert-butylisourea (2.6 g) was added under ice cooling and the resulting mixture was stirred at room temperature for 3 days. Dilute hydrochloric acid and dichloromethane were added to the reaction mixture. The organic layer so separated was dried over anhydrous sodium sulfate. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1~1:1), whereby the title compound (1.78 g, 35%) was obtained as a colorless solid. 1H-NMR (CDCl3) delta: 1.30(9H,s), 2.90-3.40(6H,m), 3.80-4.00(2H,m), 7.01(1H,d,J=8.3 Hz), 7.59(1H,dd,J=8.3,2.0 Hz), 7.61(1H,dd,J=8.3,2.0 Hz), 7.76(1H,dd,J=8.8,2.0 Hz), 7.85-7.95(3H,m), 8.00(1H,d,J=2.0 Hz), 8.29(1H,br s).
35%	With hydrogenchloride; N-ethyl-N,N-diisopropylamine; In dichloromethane;	[Referential Example 26] 1-[4-Bromo-2-(tert-butoxycarbonyl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine In dichloromethane (200 ml), <strong>[86-90-8]4-bromophthalic anhydride</strong> (1.96 g) and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (3.00 g) were suspendedunder ice cooling. To the resulting suspension, diisopropylethylamine (3.76 ml) was added, followed by stirring for 20 minutes. To the reaction mixture, dilute hydrochloric acid and dichloromethane were added. The organic layer so separated was dried over anhydrous sodium sulfate. The solvent was concentrated so that the volume was reduced to 200 ml. To the concentrate, N,N'-diisopropyl-O-tert-butylisourea (2.6 g) was added under ice cooling and the resulting mixture was stirred at room temperature for 3 days. Dilute hydrochloric acid and dichloromethane were added to the reaction mixture. The organic layer so separated was dried over anhydrous sodium sulfate. The residue was purified by chromatography on a silica gel column (hexane: ethyl acetate = 3:1 ~ 1:1), whereby the title compound (1.78 g, 35%) was obtained as a colorless solid. 1H-NMR (CDCl3) delta: 1.30(9H,s), 2.90-3.40(6H,m), 3.80-4.00(2H,m), 7.01(1H,d,J=8.3Hz), 7.59(1H,dd,J=8.3,2.0Hz), 7.61(1H,dd,J=8.3,2.0Hz), 7.76(1H,dd,J=8.8,2.0Hz), 7.85-7.95(3H,m), 8.00(1H,d,J=2.0Hz), 8.29(1H,br s).

Reference： [1]Patent: US6525042,2003,B1
[2]Patent: EP1104754,2001,A1

31
[ 494799-17-6 ]
[ 71432-55-8 ]
[ 879498-89-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	In dichloromethane; for 52h;Heating / reflux;	Example 8; (2E)-3-{4-[({1-[({3-cycIohexyI-1-[2-(4-methylpiperazin-1-yI)-2- oxoethyl]-2-phenyl-1H-indol-6-yl}carbonyl)amino]cyclopentyl }carbonyl) amino]rhohenyI}acryli acid; Step 1; tert-butyl 3-cycIohexyl-1H-indole-6-carboxylate; A solution of 3-cycIohexenyl-1H -indole-6-carboxylic acid (1 eq., prepared as described in Example 1, Step 1) in dry DCM (0,19 M) was treated with tert-butyl N,N'-diisopropylimidocarbamate (2 eq.). The resulting clear solution was heated at reflux for 36 h. Addition of a further equivalent of isourea was required after 16 h to drive the reaction to completion. After cooling down the solvent was evaporated giving a residue that was purified by silica gel chromatography (Flashmaster Personal, PE: EtOAc, 30:1) affording tert-butyl 3-cyclohexyl-1H-indole-6-carboxylate (75percent)
58%	In dichloromethane; for 19h;Heating / reflux;	Step 4: tert-butyl S-cvclohexyl-lH-indole--carboxylate; 2 eq of tert-buty\\ N,N-diisopropylimidocarbamate (prepared according to literature precedent: Synthesis1979, 561) were added to a solution of 3-cyclohexyl-l//-indole-6-carboxylic acid (prepared as described in published International patent application WO2004087714) in CH2Cl2 (0.4 M) and the mixture heated at reflux under N2 for 16 h. A further 2.5 eq of tert-butyl N,N-diisopropylimidocarbamate were then added portionwise over 3 h, with heating being resumed after each addition. The reaction mixture was then filtered whilst hot through a pad of celite and the filtrate concentrated in vacuo. The residue was purified by flash chromatography (5percent EtOAc/PE) to afford the title compound (58 percent); MS (ES") m/z 298 (M-H)".

Reference： [1]Patent: WO2006/29912,2006,A1 .Location in patent: Page/Page column 37
[2]Patent: WO2006/46030,2006,A2 .Location in patent: Page/Page column 28

32
[ 848243-87-8 ]
[ 71432-55-8 ]
[ 914497-89-5 ]

Yield	Reaction Conditions	Operation in experiment
57%	In dichloromethane; for 36h;Heating / reflux;	A suspension of 6-cyclohexyl-4H-thieno[3,2-Z>]pyrrole-2-carboxylic acid (1 eq., prepared as described in WO2005/023819) in dry CH2Cl2 (0.19 M) was treated with terf-butyl NN'-diisopropylimidocarbamate (2 eq.). The resulting clear solution was heated to reflux for 20 h. Addition of a further equivalent of EPO <DP n="23"/>isourea was required after 16 h to drive the reaction to complete conversion. After cooling down the solvent was evaporated in vacuo giving a residue that was purified by flash chromatography (PE:EtOAc, 10: 1) affording the title compound (57%). 1H-NMR (400 MHz, DMSCW6, 300 K, delta) 11.12 (bs, IH), 7.55 (s, IH), 7.08 (s, IH), 2.60-2.50 (m, IH), 1.99-1.67 (m, 5H), 1.51 (s, 9H), 1.45-1.19 (m, 5H). MS (ES+) 5 m/z: 306 [M+H]+.

Reference： [1]Patent: WO2006/119975,2006,A1 .Location in patent: Page/Page column 21-22
[2]Tetrahedron Letters,2009,vol. 50,p. 1625 - 1628

33
[ 71432-55-8 ]
[ 3262-72-4 ]
[ 71630-31-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	In dichloromethane; at 0 - 20℃;Inert atmosphere;	Commercially available tert-(butoxycarbonyl)-L-serine 1 (18 g, 88 mmol) was dissolved in dichloromethane (DCM, 150 mL) and cooled to 0 C under argon. tert-Butyl N,N?-diisopropylcarbamimdate (53 g, 0.26 mmol; prepared as described by West6) was added in three portions over 5 min. Reaction was stirred overnight at rt. The reaction was stirred with hexanes (200 mL) for 30 min, then filtered through celite and concentrated under reduced pressure. Reaction was purified using a silica plug and eluted with a gradient of 25%-50% ethyl acetate (EtOAc) in hexanes. Product containing fractions were pooled and concentrated under reduced pressure. Yield: 22.3 g (97%). 1H NMR (CDCl3) d 5.70-5.52 (m, 1H), 4.40 (s, 1H), 4.14-3.89 (m, 2H), 1.65-1.35 (m, 18H).
74%	In dichloromethane; for 5h;Reflux;	To a solution of 2-(S)-((tert-butoxycarbonyl)amino)-3-hydroxypropionic acid 8 (498 mg, 2.44 mmol, 1.0 equiv) in CH2Cl2 (5 mL) was added 2-tert-butyl-1,3-diisopropyl-isourea (0.9 mL, 3.66 mmol, 1.5 equiv). The solution was stirred and refluxed for 3 h, and then 2-tert-butyl-1,3-diisopropyl-isourea (0.9 mL, 3.66 mmol, 1.5 equiv) was added to the reaction mixture again. After stirring for 2 h at reflux, the mixture was evaporated in vacuo. The residue was filtered through a short column of silica gel eluting EtOAc, and the filtrate was concentrated. Purification by silica gel column chromatography (hexane/EtOAc = 5/1) afforded 9 as a colorless solid (470 mg, 1.80 mmol, 74%); Rf 0.61 (hexane/EtOAc = 1/1); [alpha]25D=-20.8 [alpha]D25=-20.8 (c 1.6, EtOH) {lit. value: [alpha]22D=-22.5 [alpha]D22=-22.5 (c 1.8, EtOH)25}; IR (KBr, cm-1) 3322, 3171, 2976, 2890, 1700, 1478, 1365, 1294, 1186, 1060, 930, 854, 791, 755, 694, 585, 437; 1H NMR (300 MHz, CDCl3) delta 5.40 (1H, br s, NH), 4.26 (1H, br s, H14), 3.90-3.89 (2H, d, J = 3.81 Hz, H13), 1.48 (9H, s, tBu), 1.45 (9H, s, tBu); Anal. Calcd for C12H23NO5: C, 55.2; H, 8.9; N, 5.4. Found: C, 55.5; H, 8.4; N, 5.4.
	In dichloromethane; for 48h;Heating / reflux;	To synthesize compound 5 of Figure 2, O-tert-butyl-N,N'- diisopropylisourea was made according to Rapoport et al., J. Org. Chem., 1993, 58, 2369- 2376, incorporated by reference herein. In brief, 10 mL (1.0 equiv) of N,N'- diisopropylcarbodiimide was added to 7.1 mL (1.15 equiv) of t-butanol. 64 mg of CuCl was added and the reaction was stirred at ambient temperature for 24 h. 1.73 mL (7.25 mmol) O- tert-butyl-N,N'-diisopropylisourea was added to 1.0 g (4.87 mmol) of t-BOC-L-serine in 10.0 mL dry CH2Cl2. The reaction was refiuxed for 24 h before an additional 1.73 mL (7.25 mmol) O-tert-butyl-N,N'-diisopropylisourea was added to the reaction mixture, which was refiuxed for another 24 h. Solvents were removed under vacuum, and residues were redissolved in CH2Cl2, which was followed by a silica gel filtration for removal of N,N'- diiospropylurea. The filtrate solvent was removed and approximately 1.0 g of the t-butyl ester of t-BOC L-serine was achieved (yield 79%). Selective deprotection of the t-BOC moiety was achieved according to Han et al., J. Pept. Res. 2001, 58(4), 338-341, incorporated by reference herein, by exposing the t-butyl ester and t-BOC-protected L-serine to 4 M HCl in dioxane at 0 0C for 0.5 h. Solvent was removed under vacuum, and 751 mg of t-butyl ester-protected L-serine was obtained as a white crystalline compound. 751 mg (3.8 mmol) L-serine t-butylester, 826 mg (3.8 mmol) t-BOC L-valine, and 425 muL (3.05 mmol) TEA were dissolved in 15.0 mL dry CH2Cl2 to achieve the desired conjugation between the two amino acids, 695 mg (3.37 mmol) DCC and 434 mg (3.21 mmol) HOBt, was added, and the reaction was stirred at room temperature for 18 h. N,N'-dicyclohexylurea was filtered off and the crude product was concentrated under vacuum. The crude product was dissolved in 50 mL of DCM. An aqueous workup was performed using 25 mL sat. NaHCO3 followed by 30 mL HPLC water before obtaining the desired dipeptide as a foamy film in 48% yield (650 mg). This product was used as obtained without further purification. [0045] To prepare compound 5 of Figure 2, 135 mg (0.428 mmol) cidofovir was exposed to 135 mg (1.04 mmol) DIEA and dissolved in 4 mL DMF. A HPMPC-DIEA salt was obtained after solvent was removed under vacuum. 650 mg (1.8 mmol) dipeptide (t- BOC-Val-Ser-t-butyl described above) was added to a reaction flask containing the HPMPC- DIEA salt and 4 mL dry DMF. 660 mg (1.27 mmol) PyBOP and 425 muL (2.44 mmol) DIEA were added, and the reaction took place stirring under N2 (g) at 40 0C for 1 h. An additional 330 mg (0.635 mmol) PyBOP was added and left for 3 additional hours. Solvents were removed under vacuum, and a silica gel column chromatography purification was performed [eluent; CH2Cl2: acetone:methanol, 20:10:1.]. Solvent was removed and deprotection of the t-BOC and t-butoxy groups was performed in 4 mL of CH2Cl2 in the presence of 2 mL of 99% TFA for 3 h at room temperature. Solvents were removed under vacuum and ether was added to precipitate the final compound, 5, which was filtered by methanol on a funnel containing a silica gel layer. Preparative HPLC purification on a C- 18 column (5 mum, 100. A, 21.4x250 mm by Varian) was obtained using a mobile phase containing 0.1 M TEA and 3.5% acetonitrile at pH 6.7 adjusted with acetic acid. A fraction of the sample was purified by preparative HPLC methods and evaluated by NMR and HR-MS techniques. 1H NMR (CD3OD): delta 0.94 (6H, m), 2.10 (IH, m), 2.94-5.73 (1OH, m), 5.73 (IH, m), 7.40 (IH, m). 31P NMR (CD3OD): delta 14.3 and 15.6 (IP, 2s). Exact mass (Ci6H26N5O8P); 447.1519 m/z

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2254 - 2258
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 7358 - 7373
[3]Tetrahedron Asymmetry,2012,vol. 23,p. 1557 - 1563
[4]Patent: WO2006/14429,2006,A2 .Location in patent: Page/Page column 13-14
[5]Journal of Medicinal Chemistry,2015,vol. 58,p. 4204 - 4219

34
[ 474019-94-8 ]
[ 71432-55-8 ]
[ 947688-59-7 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 17 - 25℃; for 48h;	2-tert-Butyl-l,3-diisopropylisourea [629 g; obtained as a liquid by the reaction of diisopropylcarbodiimide (496 ml), tert-butanol (303 ml) and cuprous chloride (4.71 g) at ambient temperature under argon for 48 hours and filtration of the mixture] was added to a stirred suspension of 2-(5-benzyloxypyridin-2-yl)acetic acid (84.1 g) in methylene chloride (1.4 litres) and the mixture was stirred at ambient temperature for 48 hours. The resultant precipitate was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica using increasingly polar solvent mixtures of methylene chloride and ethyl acetate (100:0 up to 19:1) as eluent. There was thus obtained tert-butyl 2-(5-benzyloxypyridin-2-yl)acetate (63.7 g) as an oil which crystallised upon standing; 1H NMR: (DMSOd6) 1.4 (s, 9H), 3.65 (s, 2H), 5.2 (s, 2H), 7.25 (d, IH), 7.4 (m, 6H), 8.25 (d, IH).

Reference： [1]Patent: WO2007/99317,2007,A1 .Location in patent: Page/Page column 98
[2]Patent: US2009/76075,2009,A1 .Location in patent: Page/Page column 36

35
[ 71432-55-8 ]
[ 1043880-78-9 ]
[ 1037369-00-8 ]

Yield	Reaction Conditions	Operation in experiment
		[Reference Example 204]; (3S, 4S) -4-AlIyI-1-benzyloxycarbonylpyrrolidine-3 -carboxy1ic acid tert-butyl ester; [Formula 320]Oxalyl dichloride (48.0 mL, 559 mmol) was dissolved in dichloromethane (1000 mL) . Dimethyl sulfoxide (39.7 mL, 559 mmol) was added dropwise at -70C, and the mixture was stirred for 15 hours. A solution of (3S, 4S) -3-allyl-l- benzyloxycarbonyl-4-hydroxymethylpyrrolidine (140 g, 508 mmol) in dichloromethane (400 mL) was added dropwise to the <n="502"/>reaction solution, and the mixture was stirred for 50 minutes. Triethylamine (354 mL, 2.54 mol) was added dropwise to the reaction solution, and then the mixture was stirred at -10C for 10 minutes. The reaction solution was extracted with water and dichloromethane. Then, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.The resulting residue was dissolved in a mixed solution of tert-butyl alcohol (250 mL) and tetrahydrofuran (750 mL) . 2-Methyl-2-butene (538 mL, 5.08 mol) was added and then a suspension of sodium chlorite (60.3 g, 533 mmol) and sodium dihydrogenphosphate dihydrate (238 g, 1.52 mol) in water(250 ml) was added at 0C, and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and then a IN hydrochloric acid solution was added, followed by extraction with diethyl ether. The organic layer was washed with a 5% sodium thiosulfate solution and brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure.The resulting residue was dissolved in dichloromethane (1000 mL) . N, N1 -Diisopropyl-O-tert-butylisourea (509 g, 2.54 mol) was added dropwise, and the mixture was stirred at 50C for four hours and then at room temperature for 15 hours. The precipitated solid was filtered off, and then <n="503"/>the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate = 10:1 -> 4:1) to give 126 g of the title compound as a colorless oil. 1H-NMR (400 MHz, CDCl3) delta: 7.36-7.31 (5H, m) , 5.81-5.65 (IH, m) , 5.14-5.07 (2H, m) , 5.06-5.00 (2H, m) , 3.77-3.63 (2H, m) , 3.58-3.49 (IH, m) , 3.13-3.01 (IH, m) , 2.71-2.59 (IH, m) , 2.48 (IH, brs) , 2.36-2.26 (IH, m) , 2.16-2.04 (IH, m) , 1.45 (9H, s) .

Reference： [1]Patent: WO2008/82009,2008,A2 .Location in patent: Page/Page column 500-502

36
[ 71432-55-8 ]
[ 1038386-81-0 ]
[ 1038386-82-1 ]

Yield	Reaction Conditions	Operation in experiment
88%	In dichloromethane; for 6h;Heating / reflux;	Part E:A mixture of compound 7 (1.05 g, 3.6 mmol) and 2-terf-butyl-1 ,3- diisopropylisourea (6 g, 29.2 mmol) in dichloromethane (60 mL) was heated at reflux for 6 hours and then cooled to room temperature. LC-MS analysis of the reaction indicated that the reaction was complete. The resulting precipitate was removed by filtration and washed through with dichloromethane. The filtrate was concentrated, and purified by flash column chromatography (SiO2, dichloromethane / ethyl acetate - 100:1 ) to afford compound 8 as a white foam (1.22 g, 88 % yield). HPLC-MS tR = <n="74"/>2.42 min (UV254 nm); mass calculated for formula C21 H24N2O4S 400.1 , observed LCMS m/z 401.2 (M+H).

Reference： [1]Patent: WO2008/82490,2008,A2 .Location in patent: Page/Page column 72; 73

37
[ 97-67-6 ]
[ 71432-55-8 ]
(2S)-2-hydroxybutenedioic acid di(tert-butyl) ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14.0%	In dichloromethane; at 20℃;	Theisolated compounds 1 and 2 were synthesized according toa modified procedure.19) In brief, N,N?-diisopropyl-O-tertbutylisourea (6) was obtained from the reaction of diisopropylcarbodiimide (DIC) (5) (40.8 g, 323 mmol) and tert-butylalcohol (27.8 g, 375 mmol) with a catalytic amount of copper(I) chloride for 4 d (yield: 78.1%). Malate 7 was thereafter obtained by adding excess 6 (38.8 g, 194 mmol) to a solution of(-) malic acid (3.6 g, 26.9 mmol) in dichloromethane (300 mL)at room temperature (yield: 14.0%). Acetylation of commercially available p-coumaric acid (3) (1 g, 6.0 mmol) by treatment with acetic anhydride (1.74 mL, 18.4 mmol) in pyridine(10 mL) gave 4-O-acetyl coumaric acid (8) (yield: 78%). Thecoupling reaction of the obtained coumaric acid derivative(8) (1.0 g, 5.05 mmol) and malate 7 (1.2 g, 5.05 mmol) in thepresence of DIC (0.65 mL) and N,N-dimethyl-4-aminopyridine(DMAP) (255.6 mg) afforded the condensation product (9)(yield: 18.3%). Hydrolysis of compound 9 by treatment withtrifluoroacetic acid (TFA) followed by removal of the acetylgroup under acidic conditions (3 M HCl-acetone, reflux) gavep-coumaroyl malate (2) (total yield: 11.0%). Methylation of 2was achieved by treatment of MeOH involving 5% sulfuricacid (H2SO4) in reflux to obtain compound 1 (total yield:4.6%).
14%	In dichloromethane; at 20℃;	The isolated compounds 1 and 2 were synthesized according to a modified procedure.19) In brief, N,N-diisopropyl-O-tertbutylisourea(6) was obtained from the reaction of diisopropylcarbodiimide(DIC) (5) (40.8 g, 323 mmol) and tert-butylalcohol (27.8 g, 375 mmol) with a catalytic amount of copper(I) chloride for 4 d (yield: 78.1%). Malate 7 was thereafter obtainedby adding excess 6 (38.8 g, 194 mmol) to a solution of(-) malic acid (3.6 g, 26.9 mmol) in dichloromethane (300 mL)at room temperature (yield: 14.0%). Acetylation of commercially available p-coumaric acid (3) (1 g, 6.0 mmol) by treatment with acetic anhydride (1.74 mL, 18.4 mmol) in pyridine(10 mL) gave 4-O-acetyl coumaric acid (8) (yield: 78%). The coupling reaction of the obtained coumaric acid derivative(8) (1.0 g, 5.05 mmol) and malate 7 (1.2 g, 5.05 mmol) in thepresence of DIC (0.65 mL) and N,N-dimethyl-4-aminopyridine(DMAP) (255.6 mg) afforded the condensation product (9)(yield: 18.3%). Hydrolysis of compound 9 by treatment with trifluoroacetic acid (TFA) followed by removal of the acetylgroup under acidic conditions (3 M HCl-acetone, reflux) gavep-coumaroyl malate (2) (total yield: 11.0%). Methylation of 2was achieved by treatment of MeOH involving 5% sulfuricacid (H2SO4) in reflux to obtain compound 1 (total yield:4.6%)

Reference： [1]Synthesis,2009,p. 3571 - 3578
[2]Synthetic Communications,2013,vol. 43,p. 1345 - 1350
[3]Chemical and Pharmaceutical Bulletin,2017,vol. 85,p. 1191 - 1194
[4]Chemical and pharmaceutical bulletin,2017,vol. 65,p. 1191 - 1194
[5]Angewandte Chemie - International Edition,2008,vol. 47,p. 5451 - 5455

38
[ 71432-55-8 ]
[ 943859-05-0 ]
[ 1073132-31-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	In dichloromethane; for 48h;Inert atmosphere; Reflux;	N,N'-diisopropyl-O-tert-butylisourea (1.68?g, 8.40?mmol, 10.0 eq) was added to a solution of acid 10 (0.29?g, 0.84?mmol, 1.0 eq.) in DCM (18.0?mL). The reaction mixture was refluxed for 48?h and then filtered through a short pad of celite. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (Cyh:EtOAC?=?4:1, v/v) to obtain ester 11 as colorless syrup (0.32?g, 0.78?mmol, 94%). [alpha]25D +15.6 (c 0.32, Et2O); IR (ATR) numax 2979, 1730, 1368, 1222, 1144?cm-1; 1H NMR (400?MHz, CDCl3) delta 5.15 (d, J?=?3.5?Hz, 1H), 3.36 (ddd, J?=?9.6, 5.1, 3.3?Hz, 1H), 2.67 (dd, J?=?16.7, 9.6?Hz, 1H), 2.38 (dd, J?=?16.8, 5.2?Hz, 1H), 2.11 (s, 3H), 1.49 (s, 9H), 1.48 (s, 9H), 1.47 (s, 9H); 13C NMR (100?MHz, CDCl3) delta 170.5, 169.9, 169.1, 166.7, 82.8, 81.9, 80.9, 72.1, 43.7, 33.7, 28.0, 28.0, 28.0, 20.5; EIMS m/z (%) 420.3 [M + NH4]+ (24); HREIMS m/z 425.2145 [M+Na]+ (calcd for C20H34NaO8+, 425.2151); Rf?=?0.74 (Cyh:EtOAc?=?4:1, v/v).

Reference： [1]Tetrahedron,2019,vol. 75,p. 4479 - 4485
[2]Journal of Organic Chemistry,2008,vol. 73,p. 9692 - 9697

39
[ 71432-55-8 ]
[ 1094537-91-3 ]
(1S,3R,4S,5R,6R,7R)-3,4-di-tert-butyl 5-methyl 7-benzyloxy-1-((4R,5R)-4-benzyloxy-5-methyl-6-phenylhexyl)-4,6-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate [ No CAS ]
C₄₈H₆₄O₁₂ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 17281 - 17283

40
[ 71432-55-8 ]
[ 2389-45-9 ]
[ 135727-85-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	In dichloromethane; at 0 - 20℃; for 53h;	(0131) (0132) A commercially available compound 3 (1.00 g, 2.62 mmol) was dissolved in dichloromethane (5.00 mL), and after being cooled to 0 degree C, O-tBu-N, N'-diisopropyl isourea (1.57 g, 1.77 mL, 7.88 mmol) was added thereto. The mixture was warmed back to the room temperature and was stirred for 27 hours, and then, O-tBu-N, N'-diisopropyl isourea (1.57 g, 1.77 mL, 7.88 mmol) was added again, and was stirred for 26 hours. The reaction solution was concentrated under the reduced pressure and the solvent was distilled away, and then a solid material was removed through a short column. The residue was isolated and purified through the silica gel column chromatography (hexane:ethyl acetate = 2:3) to obtain the compound 4 at 98 % (1.1278 g).
98%	In dichloromethane; at 0 - 20℃; for 53h;Inert atmosphere;	O-tert-Butyl-N,N?-diisopropyl isourea (1.77 ml, 7.88 mmol, 3.0 eq) was added to a solution of6-(benzyloxycarbony)-amino-2-(S)-4-[(tert-butoxycarbonyl)amino]-hexanoic acid (3, 1.00 g, 2.62 mmol, 1.0 eq) dissolvedin CH2Cl2(5 mL) at 0 C. After stirring for 27h,anadditional amount ofO-tert-butyl-N,N?-diisopropyl isourea(1.77 ml, 7.88 mmol, 3.0 eq) was added at room temperature.After stirring for 26h, the reaction mixture wasfiltered through a short column of silica gel eluting withethyl acetate(EtOAc). Purification on silica gel columnchromatography (hexane/EtOAc = 2:3) afforded4as a colorlesssolid (1.13 g, 2.59 mmol, 98%); Rf0.64 (hexane/EtOAc = 2:3); [a]D205.50 (c1.0, CHCl3)[lit.value: [a]D205.10 (c 0.98,CHCl3)]4;1H NMR (300 MHz, CDCl3) d 7.42-7.30 (5H, m, Cbz), 5.09 (2H, s, Cbz), 5.07-4.95 (1H, m, NH), 4.90-4.69 (1H, m, NH), 4.24-4.06 (1H, m, H16), 3.19 (2H, dd, J = 6.3, 6.3Hz, H7), 1.89-1.52 (6H, m, H8/9/10), 1.45 (9H, s, tBu), 1.43 (9H, s, Boc).

Reference： [1]Organic Letters,2014,vol. 16,p. 1672 - 1675
[2]Patent: EP2952504,2015,A1 .Location in patent: Paragraph 0131-0132
[3]Tetrahedron Letters,2014,vol. 55,p. 6343 - 6346
[4]Angewandte Chemie - International Edition,2009,vol. 48,p. 1633 - 1635

41
[ 71432-55-8 ]
[ 83-40-9 ]
[ 4128-37-4 ]
[ 115-11-7 ]
[ 221646-18-0 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 4753 - 4762

42
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid [ No CAS ]
[ 71432-55-8 ]
[ 1166831-37-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	In tetrahydrofuran at 20℃; for 16h;	1.5.235.A 2-(4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetic acid (0.250 g, 0.954 mmol) was dissolved in 10 mis of dry THF. To this solution was added (Z)-tert-butyl N,N'- diisopropylcarbamimidate (3.82 g, 19.08 mmol) and the mixture was allowed to stir at room temperature for 16 hours. The mixture was then filtered, filtrate concentrated under reduced pressure and purified by a 5Og Snap cartridge (Biotage, 10% EtOAc/Hexanes) to give 280 mgs (92%) of tert-butyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetate as a thick oil.

Reference： [1]Current Patent Assignee: PFIZER INC; BRISTOL-MYERS SQUIBB CO - WO2011/22508, 2011, A2 Location in patent: Page/Page column 103

43
[ 71432-55-8 ]
[ 2882-15-7 ]
[ 1226-02-4 ]

Yield	Reaction Conditions	Operation in experiment
7.2 g	In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere;	DIC (12.1 mL, 77.8 mmol) was added to a mixture of CuCl (140 mg, 1.4 mmol) and tert-butanol (29.9 mL, 312.6 mmol) and the mixture was stirred at room temperature for 12 h. The volatile components were removed under reduced pressure. The solid was dissolved in THF (25 mL) and 5-methoxy-2-methyl-1H-indole-3-acetic acid (2) (7.0 g, 31.9 mmol) was added and the mixture stirred at room temperature for 2 h. The solvent was evaporated and the solid was purified by column chromatography with a mixture of hexanes (80-100 C) and ethyl acetate (3:1). The solvent was removed under reduced pressure to yield a white solid. Yield: 7.2 g (82%); elemental Anal. Calcd for C16H21NO3: C, 69.80; H, 7.69. Found: C, 69.57; H, 7.67; mp: 110-111 C; ESI MS (-) (CH3COCH3): m/z: 274.0 (100%, [M-H]-); 1H NMR (CDCl3, ppm): 7.75 (s, vbr, NHindole), 7.14 (d, 3JHH = 8 Hz, 1H, CHindole), 7.00 (d, 4JHH = 2 Hz, 1H, CHindole), 6.76 (dd, 3JHH = 8 Hz, 4JHH = 2 Hz, 1H, CHindole), 3.85 (s, 3H, OCH3), 3.54 (s, 2H, CH2), 2.39 (s, 3H, CH3), 1.43 (s, 9H, C(CH3)3); 13C{1H} NMR (CDCl3, ppm): 171.4 (COO), 154.0 (CindoleO), 133.5 (Cindole), 130.2 (Cindole), 129.1 (Cindole), 110.9 (CindoleH), 110.9 (CindoleH), 105.0 (Cindole), 100.6 (CindoleH), 80.5 (C(CH3)3), 55.9 (OCH3), 31.9 (CH2), 28.1 (C(CH3)3), 11.9 (CH3); IR (selected, KBr, cm-1): = 3342 (s, nu(N-H)), 3005 (w), 2980 (w), 2965 (w), 2914 (w), 2837 (w), 2047 (w), 1722 (s, nu(CO)).

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 4830 - 4837

44
[ 71432-55-8 ]
[ 1069110-51-5 ]
[ 1069110-52-6 ]

Yield	Reaction Conditions	Operation in experiment
73%	In dichloromethane; at 20℃;	A mixture of 6 (70 mg, 0.17 mmol), <strong>[71432-55-8]2-tert-butyl-1,3-diisopropylisourea</strong> (200 mg, 1.0 mmol) and CH2Cl2 (4 mL) was stirred overnight at room temperature. The precipitate was removed by filtration and washed with CH2Cl2. The filtrate was concentrated, and the residue was purified by chromatography on silica gel using hexane/EtOAc (85: 15) to give 7 as pale yellow oil (58 mg, 73%). 1H NMR (500 MHz, CDCl3) delta 8.64 (s, 1H), 8.49 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.68 (dd, J = 7.0, 2.5 Hz, 1H), 7.39-7.30 (m, 2H), 7.21-7.18 (m, 1H), 7.15 (t, J = 8.5 Hz, 1H), 6.99 (t, J = 8.5 Hz, 1H), 5.80-5.72 (m, 1H), 4.99-4.90 (m, 2H), 4.68 (t, J = 7.0 Hz,, 1H), 2.60-2.53 (m, 1H), 2.14-2.06 (m, 3H), 1.69 (s, 9H), 1.51-1.30 (m, 2H).

Reference： [1]Patent: WO2008/121836,2008,A1 .Location in patent: Page/Page column 62; 85

45
[ 71432-55-8 ]
[ 40371-50-4 ]
[ 849773-54-2 ]

Yield	Reaction Conditions	Operation in experiment
68%	In dichloromethane for 20h; Reflux;

Reference： [1]Mashiach, Roi; Meijler, Michael M. [Organic Letters, 2013, vol. 15, # 7, p. 1702 - 1705]

46
[ 71432-55-8 ]
[ 1407156-09-5 ]
[ 1407156-10-8 ]

Yield	Reaction Conditions	Operation in experiment
39%	In dichloromethane; at 20℃;	Compound 23a (10.19 g, 24.0 mmol) in dichloromethane (100 mL) was added with Compound 23b (9.62 g, 48.0 mmol) and stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was added with water and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, and dried over anhydrous magnesium sulfate. Inorganic substances were filtered off, and the filtrate was dried under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to yield Compound 23c (4.45 g, 39%) as an orange oil. 1H-NMR (CDCl3) delta: 1.55 (9H, s), 2.54 (1H, t, J = 6.65 Hz), 3.80 (3H, s), 3.83 (3H, s), 4.52 (2H, d, J = 6.65 Hz), 5.00 (2H, s), 5.05 (2H, s), 6.81 (2H, d, J = 8.66 Hz), 6.90 (2H, d, J = 8.66 Hz), 7.00 (1H, d, J = 8.28 Hz), 7.08 (1H, d, J = 8.28 Hz), 7.29 (2H, d, J = 8.53 Hz), 7.35 (2H, d, J = 8.53 Hz).
39%	In dichloromethane; at 20℃;Inert atmosphere;	To a solution of Compound 56a (10.19g, 24.0 mmol) in dichloromethane (100 mL) was added Compound 56b (9.62g, 48.0 mmol), and then the mixture was stirred at room temperature over night. The solvent was removed by evaporation and to the residue was added water and ethyl acetate. The organic layer separated was washed with water and brine, and then dried over MgS04, filtered and concentrated.' The residue was purified by column chromatography on silica gel eluted with n-hexane/ethyl acetate to afford Compound 56c (4.45g, 39%) as an oil substance. 1H-NMR (CDC13) delta: 1.55 (9H, s), 2.54 (1H, t, J = 6.65 Hz), 3.80 (3H, s), 3.83 (3H, s), 4.52 (2H, d, J= 6.65 Hz), 5.00 (2H, s), 5.05 (2H, s), 6.81 (2H, d, J= '8.66· Hz), 6.90 (2H, d, J = 8.66 Hz), 7.00 (1H, d, J= 8.28 Hz), 7.08 (1H, d, J= 8.28 Hz), 7.29 (2H, d, J = 8.53 Hz), 7.35 (2H, d, J = 8.53 Hz) .
39%	In dichloromethane; at 20℃;	In a mixture of dichloromethane (100 mL)Compound 56b (9.62 g, 48.0 mmol) was added to a solution of compound 56a (10.19 g, 24.0 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed by evaporation and water and ethyl acetate were added to the residue. The organic layer was separated, washed with water and brine, then dried over MgSO 4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with n-hexane / ethyl acetate to afford compound 56c (4.45 g, 39%) as an oil.

Reference： [1]Patent: EP2703406,2014,A1 .Location in patent: Paragraph 0266
[2]Patent: WO2014/68388,2014,A1 .Location in patent: Paragraph 0368
[3]Patent: JP6377570,2018,B2 .Location in patent: Paragraph 0490; 0491

47
[ 71432-55-8 ]
C₁₀H₁₃NO₅ [ No CAS ]
[ 1585241-84-4 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; In dichloromethane; at 20℃; for 15h;	To a stirred solution of 32(500 mg, 2.07 mmol) in THF (4 mL) was added 1 Maqueous KOH (4.15 mL, 4.15 mmol). The resulting mixture was stirred at 40C for 3 h. Then the mixture was concentrated under reduced pressure. The crude material including carboxylic acid (33) was applied to the following reaction without further purification.To a stirred suspension of the crude material including 33in CH2Cl2(5 mL) were added NH4Cl (277 mg, 5.18 mmol) and N,N?-diisopropyl-O-tert-butylisourea (1.63 mL, 7.25 mmol) at room temperature. The resulting mixture was stirred at room temperature for 15 h. Then the reaction mixture was filtered and concentrated under reduced pressure. The crude material including tert-butyl ester 34was applied to the following reaction without further purification.

Reference： [1]Organic Letters,2014,vol. 16,p. 1980 - 1983
[2]Chemical and Pharmaceutical Bulletin,2016,vol. 64,p. 723 - 732

48
[ 71432-55-8 ]
[ 1610839-55-8 ]
[ 1610839-62-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	In dichloromethane; at 20 - 50℃; for 21h;	To a stirred solution of 5 (0.032g, 0.141mmol) in CH2Cl2 (1.4mL) was added N,N?-diisopropyl-O-tert-butyl isourea (0.0085, 0.424mmol, 3.0 equiv), and the reaction mixture was stirred at room temperature for 18h, then stirred at 50C for 3h. The reaction mixture was evaporated and dried under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate=20:1) to afford product 17 (0.036g, 0.128mmol, 90%) as a white solid: Rf=0.4 (hexane/ethyl acetate=10:1); 1H NMR (400MHz, CDCl3) delta 5.23 (1H, s), 4.85 (1H, s), 3.72 (3H, s), 2.22 (1H, m), 2.13 (1H, m), 1.68-1.58 (2H, m), 1.46 (9H, s), 1.47-1.39 (2H, m), 1.10 (3H, s), 1.03 (3H, s); 13C NMR (400MHz, CDCl3) delta 172.6, 170.5, 151.3, 113.0, 82.0, 62.7, 52.3, 39.9, 36.7, 33.0, 30.2, 29.5, 27.7, 18.7; IR (neat) numax 2948, 1724, 1633, 1456, 1392, 1367, 1300, 1251, 1213, 1161, 1138, 1062, 1022, 991, 952cm-1; HRMS-ESI [M+Na]+ calculated for C16H26O4Na: 305.1723, found: 305.1723; [alpha]19D=-6.8[alpha]D19=-6.8 (c 0.65, CHCl3).

Reference： [1]Tetrahedron Asymmetry,2014,vol. 25,p. 718 - 724

49
[ 71432-55-8 ]
[ 3262-72-4 ]
[ 71630-31-4 ]

Yield	Reaction Conditions	Operation in experiment
66%	In dichloromethane;Inert atmosphere; Reflux;	A solution of Boc-D-serine (2g, 9.75 mmol) in dry DCM (20 mL) was treated with 2-tert-butyl-l,3-diisopropylisourea (3.5 mL, 15.5 mmol) under nitrogen and the reaction was stirred at reflux overnight. The reaction was not complete. An additional portion of 2-tert-butyl-l,3-diisopropylisourea (3.5 mL, 15.5 mmol) was added and the reaction was stirred at reflux for 36 h. The reaction was cooled to room temperature, and the resulting suspension diluted with 40% ether/hexane, filtered and the solid washed with 40% ether/hexane. The combined filtrate and washes were concentrated under reduced pressure and the resulting residue purified by flash chromatography (0-30% EtOAc in hexanes gradient) to provide tert-butyl (tert-butoxycarbonyl)-D-serinate (1.69 g, 66% yield). 1H NMR (300 MHz, Chloroform-d) delta 5.43 (br. s, 1H), 4.27 (br. s, 1H), 3.91 (dd, J = 6.1, 3.9 Hz, 2H), 2.41 (br. s, 1H), 1.50 (s, 9H), 1.47 (s, 9H).

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 250 - 255
[2]Patent: WO2018/136935,2018,A1 .Location in patent: Paragraph 00289
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 4204 - 4219
[4]Journal of Medicinal Chemistry,2018,vol. 61,p. 7358 - 7373

50
[ 71432-55-8 ]
[ 2592-18-9 ]
tert-butyl 2-(tert-butoxycarbonylamino)-3-hydroxybutanoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 4204 - 4219

51
[ 71432-55-8 ]
[ 147266-92-0 ]
[ 862996-27-8 ]

Reference： [1]Chemistry - A European Journal,2015,vol. 21,p. 3682 - 3690

52
[ 71432-55-8 ]
[ 111223-31-5 ]
(S)-tert-butyl 6-((tert-butoxycarbonyl)amino)-2-hydroxyhexanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	In dichloromethane; at 20℃; for 36h;	(S)-6- ((tert-butoxycarbonyl)amino)-2-hydroxyhexanoic acid 14 (250 mg, 1.00 mmol) was mixed with tert-butyl-1,3-diisopropylisourea (600 mg, 3.00 mmol) in 2 mL anhydrous methylene chloride. The reaction was sealed and kept at room temperature for 36 h.135 mg (S)-tert-butyl 6-((tert-butoxycarbonyl)amino)-2-hydroxyhexanoate was obtained after flash column chromatography and the yield was 44 %. (?H NMR (400 MHz, CDC13): oe 4.56(br, 1H), 4.06(dd, Ji = 7.2 Hz, J2 = 4.4 Hz, 1H), 3.14(m, 2H), 2.25(br, 1H), 1.83-1.75(m, 1H), 1.65-1.35(m, 23H); ?3CNMR(125 MHz, CDC13): oe174.6, 156.1, 82.5, 79.2, 70.4, 40.6, 34.0, 29.8, 28.5, 28.1, 22.0. MS: Calculated for[C,5H30NO], 304.2118 [M+H] Found 304.2147.

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 206 - 218
[2]Patent: WO2016/65142,2016,A2 .Location in patent: Page/Page column 56

53
[ 71432-55-8 ]
6-hydroxy-6-methylheptanoic acid [ No CAS ]
6-hydroxy-6-methylheptanoic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	In dichloromethane; at 40℃;Inert atmosphere;	To a 100 mL 3 -neck round bottom flask equipped with a magnetic stirrer, addition funnel, condenser, thermocouple and nitrogen inlet was charged 6-Hydroxy-6-methyl-heptanoic acid 19 (0.68 g; 4.2 mmol) and DCM (30 mL). This solution was stirred at ambient temperature and the Nu,Nu'-diisopropyl-O-ieri-butyl isourea (2.6 g; 13 mmol) was added dropwise via addition funnel. The reaction was stirred overnight and then heated to 40 C for 3 h. The solvent was removed and the crude product was purified on a silica gel flash column eluting with 0-50% ethyl acetate in hexanes, and product fractions evaporated in vacuo giving the title compound as a clear colorless oil (0.28 g, 30% yield). 1H-NMR (500 MHz, CDC13): delta 2.25 - 2.21 (t, 2H), 1.63 - 1.57 (q, 2H), 1.49 - 1.46 (m, 2H), 1.44 (m, 9H), 1.41 - 1.36 (m, 2H), 1.21 (s, 6H).

Reference： [1]Patent: WO2015/187596,2015,A2 .Location in patent: Paragraph 00251; 00252

54
[ 71432-55-8 ]
C₂₇H₅₂O₃Si [ No CAS ]
C₃₀H₅₆O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%		A solution of the diene 28 (40 mg, 0.09 mmol) in CH2Cl2 (2 ml) and MeOH(17 mul) was cooled to - 78 C and ozone was bubbled through the solution untila blue colour persisted. Me2S (105 mg, 1.7 mmol) was added and the solutionallowed to warm to RT for 30 min and then concentrated under reducedpressure. The crude dialdehyde was dissolved in tBuOH (2.1 ml) and 2-methyl-2-butene (420 mul) and a solution of 80% NaClO2 (150 mg, 1.65 mmol) andNaH2PO4 (91 mg, 0.75 mmol) in water (0.7 ml) was added and the biphasicsolution was stirred for 16 h.Water and EtOAc were added and the phases wereseparated and the aqueous phase was adjusted to pH 2 with HCl and furtherextracted with EtOAc. The combined organic extracts were washed with brine,dried and concentrated and the crude diacid was dissolved in CH2Cl2 (1.5 ml)and treated with N,N?-diisopropyl-O-tert-butylisourea (400 mg, 0.5 ml) for16 h. The resulting suspension was filtered through a pad of Celite and thefiltrate was concentrated and the crude product was purified by flashchromatography (5% EtOAc/petrol) to give triester ent-11 (13 mg, 27%) as acolourless oil. [alpha]D25 -3.2 (c 0.42, CH2Cl2); the IR and NMR spectra wereidentical to those for the (+)-enantiomer; HRMS (ESI): calculated forC30H56O7Na [M+Na]+ 551.39183; found 551.39178.

Reference： [1]Journal of Antibiotics,2018,vol. 71,p. 234 - 239

55
[ 71432-55-8 ]
[ 938-63-6 ]
4-tert-butoxy-2,3,5,6-tetrafluoroaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane at 20℃; Inert atmosphere;	1 Step 1: Synthesis of 4-tert-butoxy-2,3,5,6-tetrafluoroaniline (154) To a stirred solution of 4- amino-2,3,5,6-tetrafluorophenol (152) (0.445 g, 2.46 mmol) in CH2C12 at room temperatureunder N2 was added 1 molar equivalent of 2-tert-butyl-1,3-diisopropylisourea (2.63 g, 13.13 mmol, 2.95 mL) every 2 hours until the total 5 equiv was added and the reaction is allowed to stir overnight. LC-MS monitor suggests no starting material retention. TLC in 20% EtOAc/Hexanes suggests complete conversion from starting material. One component of interest O.5rF. Rotovap CH2C12 and triturate in Hexanes, overnight Filter. Set insolublediisopropylurea byproduct aside. Rotovap organics to give a dark brown oil that is dried under high vac to give (0.5 ig, 87.5%) desired product as a dark brown gum in >90% purity. LC-MS (ES+): RT 8.856 mi mlz 238.0 [MHjb. ‘H NMR (400 MI-Tz, CD3CN) 4.27 (s, 1H), 1.25 - 1.18 (m, 6H).
	In dichloromethane at 20℃; Inert atmosphere;	Step 1: Synthesis of 4-tert-butoxy-2,3,5,6-tetrafluoroaniline (154) To a stirred solution of 4- amino-2,3,5,6-tetrafluorophenol (152) (0.445 g, 2.46 mmol) in CH2Cl2 at room temperature under N2 was added 1 molar equivalent of 2-tert-butyl-1,3-diisopropylisourea (2.63 g, 13.13 mmol, 2.95 mL) every 2 hours until the total 5 equiv was added and the reaction is allowed to stir overnight. LC-MS monitor suggests no starting material retention. TLC in 20% (0447) EtOAc/Hexanes suggests complete conversion from starting material. One component of interest ~0.5rF. Rotovap CH2Cl2 and triturate in Hexanes, overnight Filter. Set insoluble diisopropylurea byproduct aside. Rotovap organics to give a dark brown oil that is dried under high vac to give (0.51g, 87.5%) desired product as a dark brown gum in >90% purity. LC-MS (ES+): RT 8.856 min, m/z 238.0 [M-H]+. 1H NMR (400 MHz, CD3CN) d 4.27 (s, 1H), 1.25- 1.18 (m, 6H).

Reference： [1]Current Patent Assignee: YALE UNIVERSITY - WO2019/23621, 2019, A1 Location in patent: Page/Page column 77
[2]Current Patent Assignee: YALE UNIVERSITY - WO2020/154672, 2020, A1 Location in patent: Page/Page column 67-68

56
[ 71432-55-8 ]
2-(4-(4-(hydroxymethyl)pyrimidin-2-yl)cyclohex-3-en-1-yl)acetic acid [ No CAS ]
(S*)-tert-butyl 2-(4-(4-(hydroxymethyl)pyrimidin-2-yl)cyclohex-3-en-1-yl)acetate [ No CAS ]
(R*)-tert-butyl 2-(4-(4-(hydroxymethyl)pyrimidin-2-yl)cyclohex-3-en-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; In dichloromethane; tert-butyl alcohol; at 0 - 20℃;	To a solution of Example 35A (690 mg) in dichloromethane (6.9 mL) and Zeri-butanol (6.9 mL) was added ammonium chloride (445 mg), and the reaction was cooled to 0 C. 2-te -Butyl-l,3- diisopropylisourea (1.7 g) was added, and the reaction was warmed to room temperature and stirred overnight. Additional ammonium chloride (445 mg) and 2-ri-butyl-l ,3-diisopropylisourea (1.6 g) were added, and the reaction was stirred overnight. Additional ammonium chloride (445 mg) and 2-ieri-butyl- 1,3-diisopropylisourea (1.6 g) were added. The reaction was stirred for 5 hours. The reaction was diluted with saturated aqueous ammonium chloride and ethyl acetate. The mixture was filtered over diatomaceous earth, and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by normal phase MPLC on a Teledyne Isco CombiFlash Rf+ 24 g gold silica gel column eluting with 0-65% ethyl acetate in heptanes to give a mixture of enantiomers. The mixture was purified by chiral SFC using a Chiralpak AD-H column (30 x 250 mm, 5 micron) to give the title compound of arbitrarily assigned stereochemistry. Analytical SFC analysis using a Chiralpak AD-H column (5-50% methanol over 10 minutes) gave a retention time of 6.21 minutes. 'H NMR (400 MHz,dimethylsulfoxide-rfi) delta ppm 8.70 (d, 1H), 7.34 (d, 1H), 7.23-7.09 (m, 1H), 5.57 (br s, 1H), 4.52 (d, 2H), 2.78-2.60 (m, 1H), 2.46-2.29 (m, 2H), 2.22 (d, 2H), 2.07-1.76 (m, 3H), 1.49-1.27 (m, 10H).

Reference： [1]Patent: WO2019/35927,2019,A1 .Location in patent: Paragraph 00394; 00395; 00396

57
[ 71432-55-8 ]
[ 61172-66-5 ]
[ 1253913-81-3 ]

Yield	Reaction Conditions	Operation in experiment
51%	In dichloromethane; at 0 - 20℃;Inert atmosphere;	(S)-2-((tert-Butoxycarbonyl)amino)pent-4-ynoic acid (1.43 g, 6.72 mmol) was dissolved in DCM (14.0 mL). Reaction was cooled to 0 C under argon. tert-Butyl (Z)-N,N?-diisopropylcarbamimidate (1.35 g, 6.72 mmol; prepared as described by West6) was added in three portions over 5 min. Reaction was then left to stir overnight at rt. The reaction was then stirred with hexanes (20 mL) for 30 min, then filtered through celite and concentrated under reduced pressure. Reaction was purified by flash column chromatography using 10% EtOAc/Hexanes. Product containing fractions were pooled and concentrated under reduced pressure. Yield: 0.915 g (51%).1H NMR (CDCl3) d 5.35 (s, 1H), 4.37 (m, 1H), 2.72 (m, 2H), 2.04 (m, 1H), 1.50 (s, 9H), 1.47 (s, 9H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2254 - 2258

58
[ 625-72-9 ]
[ 71432-55-8 ]
[ 110171-06-7 ]

Yield	Reaction Conditions	Operation in experiment
39%	In dichloromethane; at 5 - 20℃; for 65h;	Commercially available ie/t-butyl (Z)- V,/V?-diisopropyl-carbamimidate (28.9 g, 144 mmol) was added dropwise to a solution of 40 (5 g, 48.0 mmol) in dichloromethane (100 mL) at 5 C. The reaction mixture was stirred at rt for 65 h, with formation of a heavy white suspension. The suspension was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure with additional precipitation of solid. The precipitate was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash chromatography (Interchim system, SorbTech 220 g silica gel column, gradient of 23-30% ethyl acetate-hexanes) to afford 41 (3.0 g, 39% yield) as a clear oil.

Reference： [1]Patent: WO2019/183564,2019,A1 .Location in patent: Paragraph 238; 239

59
[ 71432-55-8 ]
3'-(benzyloxy)-6'-hydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-5-carboxylic acid [ No CAS ]
tert-butyl 3'-(benzyloxy)-6'-hydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		To a stirred solution of 0.49 g (1.05 mmol, 1.0 eq) of 3 in pyridine (5 mL) was added 149 muL (1.58 mmol, 1.5 eq) of acetic anhydride. The solution was stirred at room temperature for 2 h until judged complete by LCMS. The solution was concentrated, the resulting residue acidified with 1 N HCl, extracted with ethyl acetate (3), washed with brine, and passed through a phase separator (Biotage). The solution was concentrated in vacuo and the residue was dissolved in dichloromethane (5 mL). To this solution was added 630 mg (3.15 mmol, 3.0 eq) of O-t-Bu-DIIU. The solution was stirred for 48 h at room temperature. The resulting suspension was filtered, the solids washed with dichloromethane, the organics combined and concentrated, and the residue dissolved in methanol (5 mL). To this solution was added 1.1 mL (5.25 mmol, 5.0 eq) of 25% sodium methoxide in methanol. The mixture was stirred for 20 min at room temperature, quenched with 1 N HCl, concentrated and extracted with ethyl acetate (3). The organic layers were combined, washed with brine, passed through a phase separator (Biotage), and concentrated in vacuo. The residue was purified by flash chromatography to provide 0.37 g (68%) of S1. 1H NMR (400 MHz, CDCl3) delta 8.62 (s, 1H), 8.29 (dd, J=8.02 Hz, J=1.34 Hz, 1H), 7.44-7.30 (m, 5H), 7.21 (d, J=8.04 Hz, 1H), 6.83 (d, J=2.08 Hz, 1H), 6.74 (d, J=2.00 Hz, 1H), 6.70-6.62 (m, 2H), 6.57-6.50 (m, 2H), 5.07 (s, 2H), 1.64 (s, 9H); 13C NMR (100 MHz, CDCl3) delta 169.5, 164.4, 160.8, 158.6, 156.6, 152.6, 136.3, 136.2, 134.2, 129.2, 129.1, 128.8, 127.6, 127.1, 126.6, 124.3, 112.7, 112.6, 110.7, 110.3, 103.4, 102.1, 84.7, 82.7, 70.4, 28.3; LRMS calculated for C32H26O7 [M+H]+ m/z: 523.2, measured 523.6.

Reference： [1]Patent: US2019/308991,2019,A1 .Location in patent: Paragraph 0101; 0108

60
[ 40371-50-4 ]
[ 71432-55-8 ]
[ 849773-54-2 ]

Yield	Reaction Conditions	Operation in experiment
74%	In dichloromethane for 20h; Inert atmosphere; Reflux;	tert-Butyl (2S)-4-[(benzyloxy)carbonyl]amino}-2-hydroxybutanoate ((S)-S5) According to a procedureby Mashiach and Meijler[8] a solution of S4 (1.00 g, 3.95 mmol) and tert-butyl-(Z)-N,N'-diisopropylcarbamimidate(3.5 M, 1.13 mL, 0.79 g, 3.95 mmol) in abs. CH2Cl2 (30 mL) under inert gasatmosphere was heated at reflux for 20 h. After cooling to room temperature, the suspension was filteredand rinsed with CH2Cl2 (50 mL). The filtrate was concentrated under reduced pressure and the residuewas purified by chromatography on SiO2 hexanes/EtOAc (7 : 3) to give S5 (894 mg, 2.92 mmol, 74%) asa colorless solid, mp. 44 °C.

Reference： [1]Altevogt, Luca; Baro, Angelika; Bilitewski, Ursula; Freund, Marcel; Laschat, Sabine; Lin, Yulin; Rudolf, Richard; Seubert, Philipp [Synlett, 2020, vol. 31, # 12, p. 1177 - 1181]

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