[ CAS No. 616-30-8 ]

Name: 616-30-8|3-Amino-1,2-propanediol|95%
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Quality Control of [ 616-30-8 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 616-30-8 ]

CAS No. :	616-30-8	MDL No. :	MFCD00008140
Formula :	C₃H₉NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KQIGMPWTAHJUMN-UHFFFAOYSA-N
M.W :	91.11	Pubchem ID :	73561
Synonyms :

Calculated chemistry of [ 616-30-8 ]

Physicochemical Properties

Num. heavy atoms :	6
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	3.0
Molar Refractivity :	21.57
TPSA :	66.48 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) :	-8.29 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.43
Log Po/w (XLOGP3) :	-2.02
Log Po/w (WLOGP) :	-1.7
Log Po/w (MLOGP) :	-1.51
Log Po/w (SILICOS-IT) :	-1.2
Consensus Log Po/w :	-1.2

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	3.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	1.0
Solubility :	911.0 mg/ml ; 9.99 mol/l
Class :	Highly soluble
Log S (Ali) :	1.15
Solubility :	1280.0 mg/ml ; 14.1 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	0.87
Solubility :	669.0 mg/ml ; 7.35 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.29

Safety of [ 616-30-8 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P501-P264-P280-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P405	UN#:	2735
Hazard Statements:	H314	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 616-30-8 ]

* 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 [ 616-30-8 ]
Downstream synthetic route of [ 616-30-8 ]

[ 616-30-8 ] Synthesis Path-Upstream 1~20

1
[ 58-55-9 ]
[ 616-30-8 ]
[ 479-18-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: at 65 - 85℃; for 2 h; Stage #2: at 55℃; for 2.66667 h;	In a reaction vessel equipped with a stirrer, a reflux condenser, a dropping funnel, and a thermometer, a mass fraction of20percent potassium bisulfite solution 300ml, stannous chloride 0.7lmo 1,Control the stirring speed 160rpm, raise the temperature of the solution to 65 ° C, slowly add theophylline (2) 0.56mol, increase the solution temperature to 85 ° C, the reaction 120min, reduce the solution temperature to 55 ° C,Dropping 3-amine-1,2-propanediol (3) 1.4mol, after adding the reaction for 160min,Increase the temperature of the solution to 140 ° C, continue to reaction 70min, 1.9kPa vacuum distillation, remove water, after cooling, the qualityThe amount of 45percent hexane heating reflux, so that all the condensate dissolved, hot filter, filter cake with a mass fraction of 75percentEthyl acetate washing, washing liquid cooling after the precipitation of solid, pumping, sodium bromide solution washing,85percent acetonitrile in the mass fraction, in the mass fraction of 98percent nitromethane in the recrystallization,Crystalline 7- (2,3-dihydroxypropyl) - theophylline 126.598, yield 89percent

Reference： [1] Patent: CN105461719, 2016, A, . Location in patent: Paragraph 0013-0014

2
[ 96-24-2 ]
[ 616-30-8 ]

Yield	Reaction Conditions	Operation in experiment
67.4%	With ammonia; sodium hydroxide In water at 18 - 42℃; for 0.399667 h;	Example 1 - Synthesis of APDThe microreactor described above was used for the synthesis.The reagents were injected at flow rates of:1-CPD (cone. 99percent in water, 3.0 ml/min),NaOH (cone. 10percent, 1 1.6 ml/min) and NH₃ (cone. 25percent, 56.4 ml/min).This gave a residence time of 2.87 minutes for the glycidol formation in the first and second chambers, and 21.1 minutes for the aminolysis in the fourth to tenth chambers, giving a total residence time of 23.98 minutes. The temperature was held at about 42 °C in the first and second chambers, and about 18 °C in the fourth to tenth chambers. In the Teflon tubing collection part the temperature was about 22 °C (ambient temperature). Samples were collected after 50 minutes from the starting point. The yield was 67.4 areapercent APD based on the amount of 1-CPD used.

Reference： [1] Patent: WO2012/108777, 2012, A1, . Location in patent: Page/Page column 7-8
[2] Patent: US2226534, 1937, ,
[3] Journal of Organic Chemistry, 1962, vol. 27, p. 2231 - 2233
[4] Patent: CN104610074, 2016, B, . Location in patent: Paragraph 0017; 0023-0025

3
[ 56-82-6 ]
[ 616-30-8 ]

Yield	Reaction Conditions	Operation in experiment
94.5%	With ammonia In water	EXAMPLE 3 The corresponding ketimine is obtained analogously to Example 1 from glyceraldehyde and ammonia in water. After 10percent by weight, relative to the amount of glyceraldehyde, of a 10percent palladium/active charcoal catalyst has been added, hydrogenation is carried out at 50° and a hydrogen pressure of 65 bar. The mixture is filtered and evaporated and the residue is distilled, giving 1-amino-2,3-propanediol in a yield of 94.5percent of theory.

Reference： [1] Patent: US5023379, 1991, A,
[2] Angewandte Chemie - International Edition, 2017, vol. 56, # 11, p. 3050 - 3054[3] Angew. Chem., 2017, vol. 129, # 11, p. 3096 - 3100,5

4
[ 556-52-5 ]
[ 616-30-8 ]

Reference： [1] Patent: EP1201644, 2002, A2, . Location in patent: Page 15-16; 21-23
[2] Patent: DE107510, , ,
[3] Chemische Berichte, 1899, vol. 32, p. 752

5
[ 93372-65-7 ]
[ 616-30-8 ]

Reference： [1] Journal of the American Chemical Society, 1951, vol. 73, p. 4404

6
[ 818-63-3 ]
[ 616-30-8 ]

Reference： [1] Monatshefte fuer Chemie, 1898, vol. 19, p. 574

7
[ 7664-41-7 ]
[ 556-52-5 ]
[ 616-30-8 ]

Reference： [1] Patent: DE107510, , ,
[2] Chemische Berichte, 1899, vol. 32, p. 752

8
[ 616-30-8 ]
[ 61278-21-5 ]
[ 66211-46-9 ]

Reference： [1] Patent: WO2010/148191, 2010, A2, . Location in patent: Page/Page column 45-49; 59
[2] Journal of Polymer Science, Part A: Polymer Chemistry, 2010, vol. 48, # 6, p. 1324 - 1331

9
[ 616-30-8 ]
[ 565-71-9 ]

Reference： [1] Journal of Organic Chemistry, 1985, vol. 50, # 11, p. 1992 - 1994

10
[ 616-30-8 ]
[ 37441-29-5 ]
[ 76801-93-9 ]

Reference： [1] Journal of Organic Chemistry, 1994, vol. 59, # 6, p. 1344 - 1350

11
[ 616-30-8 ]
[ 90-05-1 ]
[ 93-14-1 ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: at 50℃; for 3 h; Reflux Stage #2: at 90℃; for 5 h;	Equipped with a stirrer, a thermometer, a reflux condenser, a reaction vessel, 1.5mol sodium sulfite was added, the mass fraction of 20percent potassium chloride solution 300ml, controlling the stirring speed of 160 rpm, was slowly added guaiacol (2) 1.3mol, solution temperature rises to 50 , holding 3h, was added 3-amine 1,2-propanediol (3) 1.7mol, increasing the solution temperature 90 , maintained under stirring 5h, the temperature of the solution is reduced to 15 , allowed to stand for 25h after removing the aqueous layer delamination, the mass fraction of oil was added 200ml of 25percent solution of sodium bromide, mass fraction of 35percent oxalic acid solution was adjusted to maintain the pH at 7, after cooling the precipitated solid was suction filtered, washed with a solution of potassium nitrate, mass fraction washed with 70percent nitro methane in the mass fraction of 98percent propylene eye recrystallized to give crystals of 3- (o-methoxyphenoxy) -1,2-propanediol 185.33g, yield 72percent.

Reference： [1] Patent: CN105566073, 2016, A, . Location in patent: Paragraph 0013; 0014

12
[ 616-30-8 ]
[ 24424-99-5 ]
[ 89711-08-0 ]

Reference： [1] Patent: WO2017/136871, 2017, A1, . Location in patent: Paragraph 0186
[2] Patent: WO2018/157190, 2018, A1, . Location in patent: Paragraph 0179

13
[ 7790-21-8 ]
[ 1378293-39-0 ]
[ 616-30-8 ]
[ 24424-99-5 ]
[ 89711-08-0 ]

Reference： [1] Patent: US6414112, 2002, B1,
[2] Patent: US5714331, 1998, A,
[3] Patent: US5719262, 1998, A,
[4] Patent: US6710164, 2004, B1,

14
[ 7790-21-8 ]
[ 616-30-8 ]
[ 24424-99-5 ]
[ 137618-48-5 ]
[ 89711-08-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With hydrogenchloride; sodium hydroxide In water; ethyl acetate	(a) Preparation of (bocamino)acetaldehyde 3-Amino-1,2-propanediol (80.0 g; 0.88 mol) was dissolved in water (1500 ml) and the solution was cooled to 4° C., whereafter Boc anhydride (230 g; 1.05 mol) was added at once. The solution was gently heated to room temperature with a water bath. The pH was kept at 10.5 by the dropwise addition of sodium hydroxide. Over the course of the reaction a total of 70.2 g NaOH, dissolved in 480 ml water, was added. After stirring overnight, ethyl acetate (1000 ml) was added and the mixture was cooled to 0° C. and the pH was adjusted to 2.5 by the addition of 4 M hydrochloric acid. The ethyl acetate layer was removed and the acidic aqueous solution was extracted with more ethyl acetate (8500 ml). The combined ethyl acetate solution was reduced to a volume of 1500 ml using a rotary evaporator. The resulting solution was washed with half saturated potassium hydrogen sulphate (1500 ml) and then with saturated sodium chloride. It then was dried over magnesium sulphate and evaporated to dryness, in vacuo. Yield. 145.3 g (86percent) 3-Bocamino-1,2-propanediol (144.7 g; 0.757 mol) was suspended in water (750 ml) and potassium periodate (191.5 g; 0.833 mol) was added. The mixture was stirred under nitrogen for 2.5 h and the precipitated potassium iodate was removed by filtration and washed once with water (100 ml). The aqueous phase was extracted with chloroform (6400 ml). The chloroform extracts were dried and evaporated to dryness, in vacuo. Yield 102 g (93percent) of an oil. The (bocamino)acetaldehyde was purified by kugelrohr distillation at 84° C. and 0.3 mmHg in two portions. The yield 79 g (77percent) of a colorless oil.

Reference： [1] Patent: US6713602, 2004, B1,

15
[ 616-30-8 ]
[ 61278-21-5 ]
[ 66211-46-9 ]

Reference： [1] Patent: WO2010/148191, 2010, A2, . Location in patent: Page/Page column 45-49; 59
[2] Journal of Polymer Science, Part A: Polymer Chemistry, 2010, vol. 48, # 6, p. 1324 - 1331

16
[ 616-30-8 ]
[ 24424-99-5 ]
[ 137618-48-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide In <i>tert</i>-butyl alcohol at 0 - 20℃; for 5 h;	3 g (1.0 eq., 32.93 mmol) of the 3-amino-1,2-propane diol 23 was dissolved in 20 mL of tert-BuOH and 20 mL of 1 M NaOH, and under ice cooling, added with 20 mL of tert-BuOH solution containing 7.19 g (1.0 eq., 32.93 mmol) of Boc₂O. After that, it was stirred for 5 hours at room temperature. After confirming by TLC the disappearance of the reacting materials, it was concentrated under reduced pressure by using an evaporator in water bath at 50° C. Then, the reaction solution was neutralized by using 1 M HCl. Liquid fractionation extraction of the neutralized solution was performed 3 times by adding ethyl acetate and water, and the collected organic layer was washed with a saturated aqueous solution of NaCl. After drying over magnesium sulfate, it was concentrated under reduced pressure by using an evaporator in water bath at 40° C. As a result, the desired compound 2 was obtained in an amount of 6.3 g (yield: quant.). ¹H-NMR signal assignment is given in the following.¹H-NMR (500 MHz, CDCl₃) δ1.45 (9H, s), 2.68-2.71 (1H, br), 2.75-2.81 (1H, br), 3.20 (2H, dd), 3.63 (2H, dd), 3.71 (1H, m) 4.91 (1H, br).
99%	With triethylamine In methanol at 20 - 50℃; for 1.33333 h;	1-aminopropane-2,3-diol (5 g, 55 mmol) was dissolved in methanol (200 ml) followed by dropwise addition of triethylamine (0.5 ml per mmol of amine) and di-tert-butyl dicarbonate [(BOC)2O] wherein BOC corresponds to tertbutyloxycarbonyl (17.97 g, 82 mmol). The reaction medium was heated at 40-50° C. for 20 min then stirred at room temperature for 1 hour. After evaporation of the solvent, the colorless oily residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 95:5) to give the desired compound in the form of a colorless oil which crystallized slowly. Yield: 99percent Rf (dichloromethane/methanol 9:1): 0.39 IR: νNH 3350 cm^-1; νCO ester 1746 cm^-1; νCO amide 1682 cm^-1MP<15° C. NMR (1H, CDCl₃):1.44 (s, 9H, CH₃(BOC)); 3.16-3.31 (m, 2H, BOCNH-CH₂-CH-CH₂-OH); 3.44 (multiplet, 2H, OH); 3.16-3.31 (m, 2H, BOCNH-CH₂-CH-CH₂-OH); 3.71-3.78 (m,1H, BOCNH-CH₂-CH-CH₂-OH); 5.24 (m, 1H, -NHBOC). MS (MALDI-TOF): M+23=214 (M+Na⁺)
99%	With triethylamine In methanol at 20 - 50℃; for 1.33333 h;	Example 22; Preparation of 1-amino-2,3-di(tetradecylthioacetylthio)propane hydrochloride; Preparation of 1-(tert-butyloxycarbonylamino)propane-2,3-diol (example 22a); 1-aminopropane-2,3-diol (5 g, 55 mmol) was dissolved in methanol (200 ml) followed by dropwise addition of triethylamine (0.5 ml per mmol of amine) and di-tert-butyl dicarbonate [(BOC)2O] (wherein BOC corresponds to tertbutyloxycarbonyl) (17.97 g, 82 mmol). The reaction medium was heated at 40-50° C. for 20 min then stirred at room temperature for 1 hour. After evaporation of the solvent, the colorless oily residue was purified by chromatography on silica gel (eluent : dichloromethane/methanol 95:5) to give the desired compound in the form of a colorless oil which crystallized slowly. Yield: 99percent Rf (dichloromethane/methanol 9:1): 0.39 IR: vNH 3350 cm^-1; vCO ester 1746 cm^-1; vCO amide 1682 cm^-1MP<15° C. NMR (¹H, CDCl₃): 1.44 (s, 9H, CH₃(BOC)); 3.16-3.31 (m, 2H, BOCNH-CH₂-CH-CH₂-OH); 3.44 (multiplet, 2H, OH); 3.16-3.31 (m, 2H, BOCNH-CH₂-CH-CH₂-OH); 3.71-3.78 (m, 1H, BOCNH-CH₂-CH-CH₂-OH); 5.24 (m, 1H, -NHBOC). MS (MALDI-TOF): M+23=214 (M+Na⁺)

99%	With triethylamine In methanol at 20 - 50℃; for 1.33333 h;	Preparation of 1-(tert-butyloxycarbonylamino)propane-2,3-diol (example 17a) 1-aminopropane-2,3-diol (5 g, 55 mmol) was dissolved in methanol (200 ml) followed by dropwise addition of triethylamine (0.5 ml per mmol of amine) and di-tert-butyl dicarbonate [(BOC)2O] wherein BOC corresponds to tertbutyloxycarbonyl (17.97 g, 82 mmol). The reaction medium was heated at 40-50° C. for 20 min then stirred at room temperature for 1 hour. After evaporation of the solvent, the colorless oily residue was purified by chromatography on silica gel (eluent:dichloromethane/methanol 95:5) to give the desired compound in the form of a colorless oil which crystallized slowly. Yield: 99percent Rf (dichloromethane/methanol 9:1): 0.39 IR: νNH 3350 cm^-1; νCO ester 1746 cm^-1; νCO amide 1682 cm^-1
97%	at 40℃; for 16 h;	Step 1 tert-Butyl 2,3-dihydroxypropylcarbamate: di-tert-Butyl dicarbonate (43.6 g; 200 mmol; 1.00 equiv) was added in several batches to a solution of 3-aminopropane-1,2-diol (18.2 g; 200 mmol; 1.00 equiv) in acetonitrile (200 mL). The mixture was stirred at about 40° C. for about 16 hours. The resulting mixture was concentrated in vacuo to give the title product as colorless oil (37 g; 97percent yield). LC-MS: m/z=192 (MH)⁺.
96%	With triethylamine In methanol at 20 - 50℃; for 12.33 h;	Intermediate A1A: tert-Butyl(2,3-dihydroxypropyl)carbamate The above Intermediate was synthesized according to a patent literature procedure reported in U.S. Publication No. 2006/69156 A1 (2006). To a solution of 3-aminopropane-1,2-diol (10.0 g, 110 mmol) in MeOH (407 mL) was added Boc₂O (35.9 g, 165 mmol) and TEA (55 mL, 395 mmol) and the reaction mixture was heated at 50° C. for 20 min., followed by stirring at room temperature for 12 h. The reaction was then concentrated under reduced pressure to provide a residue. It was purified by silica gel chromatography (330 g REDISEP® column, eluting with 5percent MeOH in DCM). Fractions containing the product were combined and evaporated to afford Intermediate A1A (20.14 g, 96percent) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.61 (br. s., 1H), 4.63 (d, J=4.9 Hz, 1H), 4.47 (t, J=5.6 Hz, 1H), 3.45 (d, J=5.6 Hz, 1H), 3.31-3.23 (m, 2H), 3.09-2.98 (m, 1H), 2.85 (d, J=6.6 Hz, 1H), 1.38 (s, 9H).
94%	With triethylamine In methanol; dichloromethane at 23℃;	(+/-)-3-amino-1,2-propanediol (11.29 g, 124 mmol) was dissolved in CH2Cl2:CH3OH (1:5) (1 M) and triethylamine (2 mL, 14.7 mmol) was added. Di-tert-butyl dicarbonate (32.5 g, 149 mmol) was dissolved in dichloromethane (0.8 M, 186 mL) and added slowly to the reaction mixture. The resulting reaction was stirred at 23 °C for 2 h, followed by TLC analysis that showed a full consumption of the starting material. The reaction mixture was evaporated under reduced pressure, and the residue was purified by column chromatography with EtOA/:Hexanes 1:4, then dried on high vacuum to yield 11 as a white solid (23.7 g, 94 percent yield). 1H NMR (500 MHz, CDCl3) δ 5.28 – 4.96 (m, 1H), 3.83 – 3.73 (m, 1H), 3.60 (qd, J = 11.7, 4.9 Hz, 2H), 3.44 (s, 1H), 3.27 (dt, J = 12.9, 6.0 Hz, 2H), 1.46 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 157.45 , 80.13 , 71.37 , 63.58, 28.35 , 27.42.

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 2, p. 623 - 627
[2] Patent: US2016/151506, 2016, A1, . Location in patent: Paragraph 0308-0312
[3] Canadian Journal of Chemistry, 1997, vol. 75, # 7, p. 942 - 948
[4] Patent: US2006/69156, 2006, A1, . Location in patent: Page/Page column 26
[5] Patent: US2006/154984, 2006, A1, . Location in patent: Page/Page column 41
[6] Patent: US2006/35977, 2006, A1, . Location in patent: Page/Page column 28
[7] Angewandte Chemie - International Edition, 2015, vol. 54, # 40, p. 11696 - 11700[8] Angew. Chem., 2015, vol. 127, # 40, p. 11862 - 11866,5
[9] Patent: US2010/9950, 2010, A1, . Location in patent: Page/Page column 23
[10] Patent: US9273058, 2016, B2, . Location in patent: Page/Page column 449; 453
[11] MedChemComm, 2017, vol. 8, # 11, p. 2050 - 2054
[12] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4969 - 4974
[13] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 20, p. 4509 - 4512
[14] Journal of the American Chemical Society, 2015, vol. 137, # 39, p. 12442 - 12445
[15] Synthesis, 1998, # 8, p. 1113 - 1118
[16] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 2, p. 445 - 451
[17] Journal of the American Chemical Society, 2005, vol. 127, # 10, p. 3339 - 3345
[18] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 8, p. 1972 - 1982
[19] Journal of Medicinal Chemistry, 2006, vol. 49, # 3, p. 1191 - 1197
[20] Chemistry - A European Journal, 2000, vol. 6, # 22, p. 4211 - 4217
[21] Patent: EP720615, 2000, B1,
[22] Patent: EP2119718, 2009, A1, . Location in patent: Page/Page column 84-85
[23] RSC Advances, 2013, vol. 3, # 19, p. 6771 - 6774
[24] Patent: WO2013/163675, 2013, A1, . Location in patent: Paragraph 00181
[25] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5756 - 5763
[26] Patent: WO2016/206101, 2016, A1, . Location in patent: Page/Page column 193
[27] Patent: WO2018/175927, 2018, A2, . Location in patent: Paragraph 00299

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[ 24424-99-5 ]
[ 137618-48-5 ]

Reference： [1] Patent: US5539082, 1996, A,

18
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[ 7517-99-9 ]

Reference： [1] Journal of Organic Chemistry, 1996, vol. 61, # 12, p. 4175 - 4179

19
[ 616-30-8 ]
[ 32315-10-9 ]
[ 7517-99-9 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 16, p. 2345 - 2352
[2] Farmaco, 2004, vol. 59, # 9, p. 685 - 690

20
[ 616-30-8 ]
[ 105-58-8 ]
[ 7517-99-9 ]

Reference： [1] Agricultural and Biological Chemistry, 1985, vol. 49, # 5, p. 1509 - 1512

[ 616-30-8 ] Synthesis Path-Downstream 1~68

1
[ 96-24-2 ]
[ 616-30-8 ]

Yield	Reaction Conditions	Operation in experiment
67.4%	With ammonia; sodium hydroxide; In water; at 18 - 42℃; for 0.399667h;	Example 1 - Synthesis of APDThe microreactor described above was used for the synthesis.The reagents were injected at flow rates of:1-CPD (cone. 99% in water, 3.0 ml/min),NaOH (cone. 10%, 1 1.6 ml/min) and NH3 (cone. 25%, 56.4 ml/min).This gave a residence time of 2.87 minutes for the glycidol formation in the first and second chambers, and 21.1 minutes for the aminolysis in the fourth to tenth chambers, giving a total residence time of 23.98 minutes. The temperature was held at about 42 C in the first and second chambers, and about 18 C in the fourth to tenth chambers. In the Teflon tubing collection part the temperature was about 22 C (ambient temperature). Samples were collected after 50 minutes from the starting point. The yield was 67.4 area% APD based on the amount of 1-CPD used.
	With ammonium hydroxide; hydroquinone; N-nitrosodiphenylamine; In ethanol; at 45 - 60℃; under 1125.11 - 1650.17 Torr; for 4h;Large scale;	The 700kg 3-chloro-1,2-propylene glycol was pumped into 5000L stainless steel ammoniation reactor with stirring and mechanical seal, then 3500L, 25% by weight of ammonia water, and the preparation of the ammoniation catalyst is added to the ammoniation reactor, using the stirring side of the heating method, the temperature is controlled at 45~50 C, pressure control at 0.15MPa, the reaction 1.5h, and then heated to 50~55 C, the pressure control at 0.18MPa, the reaction 2h, and then heated to 55~60 C, the pressure control at 0.22MPa, the reaction 0.5h, ammoniation reaction is completed.

Reference： [1]Patent: WO2012/108777,2012,A1 .Location in patent: Page/Page column 7-8
[2]Patent: US2226534,1937,
[3]Journal of Organic Chemistry,1962,vol. 27,p. 2231 - 2233
[4]Patent: CN104610074,2016,B .Location in patent: Paragraph 0017; 0023-0025

2
[ 127-88-8 ]
[ 616-30-8 ]
[ 904214-05-7 ]

Yield	Reaction Conditions	Operation in experiment
54%	With triethylamine; In isopropyl alcohol; at 20℃; for 24h;	<strong>[616-30-8]3-amino-1,2-propanediol</strong> (5.54 g, 60.8 mmol) was dissolved in 100 mLIsopropanol,Dichlorophosphoryl mustard (15.7 g, 60.8 mmol)And triethylamine (12.3 g, 121.6 mmol) were added and stirred at room temperature for 24 hours. After the reaction, filter, filter The solution was evaporated to dryness and extracted three times with ethyl acetate and water (150 mL x 3). The organic layers were combined and washed three times with saturated sodium chloride solution, Dried over anhydrous sodium sulfate and concentrated, and the column was separated (dichloromethane: methanol = 40: 1) to give 9.08 g of an off-white solid in 54% yield.Mp: 98 C.

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 3044 - 3052
[2]Patent: CN106986895,2017,A .Location in patent: Paragraph 0042; 0043; 0044; 0045; 0046; 0047
[3]Archiv der Pharmazie,1986,vol. 319,p. 1023 - 1027

3
[ 4316-94-3 ]
[ 616-30-8 ]
[ 85446-45-3 ]

Reference： [1]European Journal of Medicinal Chemistry,1982,vol. 17,p. 569 - 576

4
[ 616-30-8 ]
[ 32315-10-9 ]
[ 7517-99-9 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1994,p. 2345 - 2352
[2]Il Farmaco,2004,vol. 59,p. 685 - 690

5
[ 616-30-8 ]
[ 24424-99-5 ]
[ 137618-48-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; In tert-butyl alcohol; at 0 - 20℃; for 5h;	3 g (1.0 eq., 32.93 mmol) of the 3-amino-1,2-propane diol 23 was dissolved in 20 mL of tert-BuOH and 20 mL of 1 M NaOH, and under ice cooling, added with 20 mL of tert-BuOH solution containing 7.19 g (1.0 eq., 32.93 mmol) of Boc2O. After that, it was stirred for 5 hours at room temperature. After confirming by TLC the disappearance of the reacting materials, it was concentrated under reduced pressure by using an evaporator in water bath at 50 C. Then, the reaction solution was neutralized by using 1 M HCl. Liquid fractionation extraction of the neutralized solution was performed 3 times by adding ethyl acetate and water, and the collected organic layer was washed with a saturated aqueous solution of NaCl. After drying over magnesium sulfate, it was concentrated under reduced pressure by using an evaporator in water bath at 40 C. As a result, the desired compound 2 was obtained in an amount of 6.3 g (yield: quant.). 1H-NMR signal assignment is given in the following.1H-NMR (500 MHz, CDCl3) delta1.45 (9H, s), 2.68-2.71 (1H, br), 2.75-2.81 (1H, br), 3.20 (2H, dd), 3.63 (2H, dd), 3.71 (1H, m) 4.91 (1H, br).
99%	With triethylamine; In methanol; at 20 - 50℃; for 1.33333h;	1-aminopropane-2,3-diol (5 g, 55 mmol) was dissolved in methanol (200 ml) followed by dropwise addition of triethylamine (0.5 ml per mmol of amine) and di-tert-butyl dicarbonate [(BOC)2O] wherein BOC corresponds to tertbutyloxycarbonyl (17.97 g, 82 mmol). The reaction medium was heated at 40-50 C. for 20 min then stirred at room temperature for 1 hour. After evaporation of the solvent, the colorless oily residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 95:5) to give the desired compound in the form of a colorless oil which crystallized slowly. Yield: 99% Rf (dichloromethane/methanol 9:1): 0.39 IR: nuNH 3350 cm-1; nuCO ester 1746 cm-1; nuCO amide 1682 cm-1 MP<15 C. NMR (1H, CDCl3):1.44 (s, 9H, CH3 (BOC)); 3.16-3.31 (m, 2H, BOCNH-CH2-CH-CH2-OH); 3.44 (multiplet, 2H, OH); 3.16-3.31 (m, 2H, BOCNH-CH2-CH-CH2-OH); 3.71-3.78 (m,1H, BOCNH-CH2-CH-CH2-OH); 5.24 (m, 1H, -NHBOC). MS (MALDI-TOF): M+23=214 (M+Na+)
99%	With triethylamine; In methanol; at 20 - 50℃; for 1.33333h;	Example 22; Preparation of 1-amino-2,3-di(tetradecylthioacetylthio)propane hydrochloride; Preparation of 1-(tert-butyloxycarbonylamino)propane-2,3-diol (example 22a); 1-aminopropane-2,3-diol (5 g, 55 mmol) was dissolved in methanol (200 ml) followed by dropwise addition of triethylamine (0.5 ml per mmol of amine) and di-tert-butyl dicarbonate [(BOC)2O] (wherein BOC corresponds to tertbutyloxycarbonyl) (17.97 g, 82 mmol). The reaction medium was heated at 40-50 C. for 20 min then stirred at room temperature for 1 hour. After evaporation of the solvent, the colorless oily residue was purified by chromatography on silica gel (eluent : dichloromethane/methanol 95:5) to give the desired compound in the form of a colorless oil which crystallized slowly. Yield: 99% Rf (dichloromethane/methanol 9:1): 0.39 IR: vNH 3350 cm-1; vCO ester 1746 cm-1; vCO amide 1682 cm-1 MP<15 C. NMR (1H, CDCl3): 1.44 (s, 9H, CH3 (BOC)); 3.16-3.31 (m, 2H, BOCNH-CH2-CH-CH2-OH); 3.44 (multiplet, 2H, OH); 3.16-3.31 (m, 2H, BOCNH-CH2-CH-CH2-OH); 3.71-3.78 (m, 1H, BOCNH-CH2-CH-CH2-OH); 5.24 (m, 1H, -NHBOC). MS (MALDI-TOF): M+23=214 (M+Na+)

99%	With triethylamine; In methanol; at 20 - 50℃; for 1.33333h;	Preparation of 1-(tert-butyloxycarbonylamino)propane-2,3-diol (example 17a) 1-aminopropane-2,3-diol (5 g, 55 mmol) was dissolved in methanol (200 ml) followed by dropwise addition of triethylamine (0.5 ml per mmol of amine) and di-tert-butyl dicarbonate [(BOC)2O] wherein BOC corresponds to tertbutyloxycarbonyl (17.97 g, 82 mmol). The reaction medium was heated at 40-50 C. for 20 min then stirred at room temperature for 1 hour. After evaporation of the solvent, the colorless oily residue was purified by chromatography on silica gel (eluent:dichloromethane/methanol 95:5) to give the desired compound in the form of a colorless oil which crystallized slowly. Yield: 99% Rf (dichloromethane/methanol 9:1): 0.39 IR: nuNH 3350 cm-1; nuCO ester 1746 cm-1; nuCO amide 1682 cm-1
97%	In acetonitrile; at 40℃; for 16h;	Step 1 tert-Butyl 2,3-dihydroxypropylcarbamate: di-tert-Butyl dicarbonate (43.6 g; 200 mmol; 1.00 equiv) was added in several batches to a solution of 3-aminopropane-1,2-diol (18.2 g; 200 mmol; 1.00 equiv) in acetonitrile (200 mL). The mixture was stirred at about 40 C. for about 16 hours. The resulting mixture was concentrated in vacuo to give the title product as colorless oil (37 g; 97% yield). LC-MS: m/z=192 (MH)+.
96%	With triethylamine; In methanol; at 20 - 50℃; for 12.33h;	Intermediate A1A: tert-Butyl(2,3-dihydroxypropyl)carbamate The above Intermediate was synthesized according to a patent literature procedure reported in U.S. Publication No. 2006/69156 A1 (2006). To a solution of 3-aminopropane-1,2-diol (10.0 g, 110 mmol) in MeOH (407 mL) was added Boc2O (35.9 g, 165 mmol) and TEA (55 mL, 395 mmol) and the reaction mixture was heated at 50 C. for 20 min., followed by stirring at room temperature for 12 h. The reaction was then concentrated under reduced pressure to provide a residue. It was purified by silica gel chromatography (330 g REDISEP column, eluting with 5% MeOH in DCM). Fractions containing the product were combined and evaporated to afford Intermediate A1A (20.14 g, 96%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) delta ppm 6.61 (br. s., 1H), 4.63 (d, J=4.9 Hz, 1H), 4.47 (t, J=5.6 Hz, 1H), 3.45 (d, J=5.6 Hz, 1H), 3.31-3.23 (m, 2H), 3.09-2.98 (m, 1H), 2.85 (d, J=6.6 Hz, 1H), 1.38 (s, 9H).
94%	With triethylamine; In methanol; dichloromethane; at 23℃;	(+/-)-3-amino-1,2-propanediol (11.29 g, 124 mmol) was dissolved in CH2Cl2:CH3OH (1:5) (1 M) and triethylamine (2 mL, 14.7 mmol) was added. Di-tert-butyl dicarbonate (32.5 g, 149 mmol) was dissolved in dichloromethane (0.8 M, 186 mL) and added slowly to the reaction mixture. The resulting reaction was stirred at 23 C for 2 h, followed by TLC analysis that showed a full consumption of the starting material. The reaction mixture was evaporated under reduced pressure, and the residue was purified by column chromatography with EtOA/:Hexanes 1:4, then dried on high vacuum to yield 11 as a white solid (23.7 g, 94 % yield). 1H NMR (500 MHz, CDCl3) delta 5.28 - 4.96 (m, 1H), 3.83 - 3.73 (m, 1H), 3.60 (qd, J = 11.7, 4.9 Hz, 2H), 3.44 (s, 1H), 3.27 (dt, J = 12.9, 6.0 Hz, 2H), 1.46 (s, 9H). 13C NMR (126 MHz, CDCl3) delta 157.45 , 80.13 , 71.37 , 63.58, 28.35 , 27.42.
	With hydrogenchloride; sodium hydroxide; In water; ethyl acetate;	3-t-butoxycarbonylamino-1,2-propanediol (II) 3-amino-1,2-propanediol (10g, 0.11moles) was dissolved in water (250mL). The solution was cooled to 0C and Boc anhydride (25g. 0.12 moles) added in one portion. The reaction mixture was brought to room temperature and the pH maintained at 10.5 using NaOH (2M) until the pH remained constant. The reaction mixture was stirred for a further 16h. at room temperature then EtOAc (200mL) added and the pH adjusted to 2.5 using HCl (4M) at 0C. The phases were separated and the aqueous phase extracted with EtOAc (10x150mL). The combined organic phases were dried (MgSO4) then evaporated in vacuo to yield V as an oil. The product solidified upon freezing (20.4g, 97%). Rf=0.75(A), 0.60(B), FAB MS 192 (M+1)+, 1H n.m.r. (200MHz, CDCl3); 1.39(s,9H,Boc Me), 3.14(broad, 2H, CH2), 3.52(m,2H,CH2), 3.68(m,1H,CH), 4.75(s,2H,2xOH), 5.52(m,1H,NH). 13C n.m.r. (50MHz, CDCl3); 28.17(Me), 42.55(NCH2), 63.48(CH2), 71.08(CH), 79.76(quaternary C), 157.1(C=O).
	With triethylamine; In methanol; dichloromethane; at 20 - 25℃;	EXAMPLE 2-27: Production of (S)-4-amino-13-hydroxy-18,20-dimethyl-7-thia-3,5,11,15-tetraazatricyclo [15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-10,16-dione (Compound 31) [Show Image] Step 1: Preparation of ((S)-2,3-dihydroxypropyl)carbamic acid tert-butyl ester [Show Image] (R)-3-Aminopropane-1,2-diol (3.02 g, 33.09 mmol) was dissolved in a mixed solvent of dichloromethane (5 ml) and methanol (25 ml), and then triethylamine (553 mul, 3.97 mmol) was added thereto. A dichloromethane (11 ml) solution of di-t-butyl bicarbonate (9.12 ml, 39.71 mmol) was dropwise added to the mixture at room temperature. After the mixed solution was stirred at room temperature for five hours, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate =2:3) to yield ((S)-2,3-dihydroxypropyl)carbamic acid tert-butyl ester (5.00 g). Physicochemical properties of ((S)-2,3-dihydroxypropyl)carbamic acid tert-butyl ester: Molecular weight: 191.Chemical shift value delta in 1H-NMR (270 MHz, in chloroform-d): 1.45 (9H, s), 2.78 (1H, d), 2.84 (1H, t), 3.19-3.36 (2H, m), 3.52-3.67 (2H, m), 3.69-3.80 (1H, m), 4.93 (1H, brs).
	With triethylamine; In methanol; at 20℃;	To a stirred solution of 3-amino-1,2-propanediol (10.0 g, 0.1 1 mol) and triethylamine (23 mL, 0.17 mol) in MeOH (200 mL) at room temperature was added di-tert-butyl dicarbonate (26.4 g, 0.12 mol). The resulting solution was left to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure then co-evaporated with toluene to remove all the MeOH. The crude residue was taken up in CH2Cl2 and, after cooling to 0C, imidazole and tert-butyl-(chloro)dimethylsilane were sequentially added. The resulting mixture was left to stir at this temperature for 2h. The reaction mixture was partitioned between water (100 mL) and CH2Cl2 (70 mL) and the aqueous layer was extracted with further CH2Cl2 (2 x 70 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude residue was purified over silica gel eluting with n-hexane followed by 10 % ethyl acetate in hexanes to afford tert-butyl 3-(tert-butyldimethylsilyloxy)-2-hydroxypropylcarbamate (32.6 g, 97.3%) as a colourless oil. 1H-NMR (300 MHz, CDCl3) 5ppm: 0.09 (6 H, s), 0.91 (9 H, s), 1.46 (9 H, s), 2.86 (1 H, br d, J 4.2 Hz), 3.13 (1 H, ddd, J 14.1 , 6.7, 5.3 Hz), 3.30 - 3.43 (1 H, m), 3.54 (1 H, dd, J 10.1 , 6.2 Hz), 3.66 (1 H, dd, J 10.1 , 4.5 Hz), 3.70 - 3.80 (1 H, m), 4.98 (1 H, br s).
	With triethylamine; In dichloromethane; at 0 - 20℃;	General procedure: Diethanolamine 3 (or threoninol 5, 3-amino-1,2-propanediol 6)(0.047 mol) was dissolved in CH2Cl2 and triethylamine (9.60 g,0.095 mol) was slowly added. The solution was cooled to 0 C,and (Boc)2O (12.45 g, 0.057 mol) was added dropwise. Then themixed solution was left for stirring at room temperature overnight.The solvent was removed under reduce pressure to afford crudeproduct, which was further purified by silica gel column chromatography(CH2Cl2/CH3OH = 10/1, v/v) to give compound 3a (or5a, 6a).
	With triethylamine; In methanol; at 20℃; for 6h;	A solution of 3-aminopropane-1,2-diol (20 g, 220 mmol), TEA (61.2 ml, 439 mmol) and BOC2O (61.2 ml, 263 mmol) in MeOH (200 ml) was stirred at ambient temperature for 6 hr. The reaction mixture was concentrated under vacuum to give crude product. The residue was purified by silica gel Isolute Flash Si; 20 g prepacked column chromatography, eluted with methanol/dichloromethane (with 0.1% TFA) = 1/10. The combined organic fractions were concentrated under reduced pressure to give the title compound. ?H NMR (CDC13, 400 MHZ):3.76-3.73 (m, 1H), 3.60-3.57 (m, 2H), 3.28-3.25 (m, 2H), 1.45 (s, 9H).
	at 20℃;	For boc protected 3-amino-1 ,2-propanediol, the 3-amino-1 ,2-propanediol can be reacted at RT with a small excess (e.g. 1 .02 - 1 .1 eq.) of di-t-butyl dicarbonate (a.k.a. Boc anhydride) in an aprotic solvent such as DCM or THF. No base is needed and in some cases the reaction can be driven to completion by heating overnight. The product of the reaction can then be evaporated and used without further purification.
	With triethylamine; In methanol; at 20℃; for 5h;	3-Aminopropane-1,2-diol (30 g, 0.33 mol, 1.0 eq) was dissolved in methanol (600 mL) and triethylamine (69 mL, 0.51 mol, 1.5 eq) and di-tert-butyl dicarbonate (79.2 g, 0.36 mol, 1.1 eq), reacted at room temperature for 5 hours. After 1H-NMR, the reaction was complete and the concentration was light.Yellow oily crude (63g crude),Used directly in the next step without purification.
	With triethylamine; In methanol; at 20℃;	Di-/er/-butyl dicarbonate (264 g, 1.21 mol) was added to a stirred solution of 3- aminopropane-l,2-diol (100 g, 1.10 mol) and triethylamine (111 g, 1.10 mol) in MeOH (2000 mL) and the reaction stirred at room temperature overnight. The mixture was concentrated under reduced pressure and residual solvent removed by azeotrope with toluene to yield the crude material /tvV-butyl (2,3-dihydroxypropyl)carbamate (210 g) as a white solid. 1H NMR (400 MHz, CDCl3) d 5.31 (s, 1H), 3.94-3.68 (m, 3H), 3.66-3.51 (m, 2H), 3.39-3.09 (m, 2H), 1.45 (s, 9H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 623 - 627
[2]Patent: US2016/151506,2016,A1 .Location in patent: Paragraph 0308-0312
[3]Canadian Journal of Chemistry,1997,vol. 75,p. 942 - 948
[4]Patent: US2006/69156,2006,A1 .Location in patent: Page/Page column 26
[5]Patent: US2006/154984,2006,A1 .Location in patent: Page/Page column 41
[6]Patent: US2006/35977,2006,A1 .Location in patent: Page/Page column 28
[7]Angewandte Chemie - International Edition,2015,vol. 54,p. 11696 - 11700
Angew. Chem.,2015,vol. 127,p. 11862 - 11866,5
[8]Patent: US2010/9950,2010,A1 .Location in patent: Page/Page column 23
[9]Patent: US9273058,2016,B2 .Location in patent: Page/Page column 449; 453
[10]MedChemComm,2017,vol. 8,p. 2050 - 2054
[11]Journal of Medicinal Chemistry,2014,vol. 57,p. 4969 - 4974
[12]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 4509 - 4512
[13]Journal of the American Chemical Society,2015,vol. 137,p. 12442 - 12445
[14]Journal of the American Chemical Society,2020,vol. 141,p. 2703 - 2712
[15]Synthesis,1998,p. 1113 - 1118
[16]Journal of Heterocyclic Chemistry,2008,vol. 45,p. 445 - 451
[17]Journal of the American Chemical Society,2005,vol. 127,p. 3339 - 3345
[18]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1972 - 1982
[19]Journal of Medicinal Chemistry,2006,vol. 49,p. 1191 - 1197
[20]Chemistry - A European Journal,2000,vol. 6,p. 4211 - 4217
[21]Patent: EP720615,2000,B1
[22]Patent: EP2119718,2009,A1 .Location in patent: Page/Page column 84-85
[23]RSC Advances,2013,vol. 3,p. 6771 - 6774
[24]Patent: WO2013/163675,2013,A1 .Location in patent: Paragraph 00181
[25]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5756 - 5763
[26]Patent: WO2016/206101,2016,A1 .Location in patent: Page/Page column 193
[27]Patent: WO2018/175927,2018,A2 .Location in patent: Paragraph 00299
[28]Patent: CN109810041,2019,A .Location in patent: Paragraph 0203; 0207-0210
[29]Patent: WO2019/241751,2019,A1 .Location in patent: Paragraph 00367

6
[ 616-30-8 ]
[ 87885-43-6 ]
[ 87885-48-1 ]

Reference： [1]Journal of Heterocyclic Chemistry,1983,vol. 20,p. 947 - 950

7
[ 616-30-8 ]
[ 565-71-9 ]

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 1992 - 1994

8
[ 616-30-8 ]
[ 105-58-8 ]
[ 7517-99-9 ]

Reference： [1]Agricultural and Biological Chemistry,1985,vol. 49,p. 1509 - 1512

9
[ 868-84-8 ]
[ 616-30-8 ]
[ 7517-99-9 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 4175 - 4179

10
[ 40106-98-7 ]
[ 616-30-8 ]
3-(5-Nitro-quinolin-4-ylamino)-propane-1,2-diol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1381 - 1390

11
[ 616-30-8 ]
[ 82911-69-1 ]
[ 167700-44-9 ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium hydrogencarbonate; sodium carbonate; In water; acetone; at 20℃;	For Fmoc protected 3-amino-1 ,2-propanediol, 9-fluorenylmethoxysuccinimidyl carbonate (Fmoc-O-Su) was suspended in acetone (about 1 .2 mL acetone per mmol Fmoc-O-Su) with stirring. To the stirring solution at RT was added dropwise a solution containing 3-amino-1 ,2-propanediol (about 1 .1 mmol per mmol of Fmoc-O-Su) dissolved in a mixture of acetone and water (about 4 to 1 acetone to water; and in a ratio of about 0.8- 1 .0 mL per mmol of 3-amino-1 ,2-propanediol - but other ratios will work as well). When complete, a solution containing NaHC03 and Na2C03 (in a ratio of about 1 mmol NaHC03 and 0.5 mmol Na2C03 per mmol of Fmoc-O-Su) dissolved in deionized water (in a ratio of about 1 ml_ deionized water per 1 mL of acetone originally added to the Fmoc-O-Su) was added dropwise to the stirring mixture. After stirring and analysis by TLC (indicating the reaction was complete), a solution containing enough HCI (dissolved in about 0.3 mL water per 1 mL of acetone originally added to the Fmoc-O-Su) to completely neutralize the NaHC03 and Na2C03 was added dropwise over 30 minutes to one hour. The reaction was then concentrated on a rotoevaporator to remove acetone and the residue partitioned with EtOAc/deionized water/acetone (4/2/0.5) in a ratio of about 2.2 mL of this mixture per 1 mL of acetone originally added to the Fmoc-O-Su). The layers were separated and the aqueous layer extracted 3 times with more EtOAc. The combined organic layers were then extracted with a solution containing 3 parts brine and one part water. The organic layer was then dried over MgS04 (granular), filtered and evaporated to a solid. The product was recrystallized from 9/1 acetonitrile/water.
	With sodium hydrogencarbonate; In water; acetone;	10 mmol <strong>[616-30-8]3-amino-1,2-propanediol</strong> was dissolved in 50 ml water, 10 mmol sodium bicarbonate was added, and then 10 mmol Fmoc-OSul was dissolved in 100 ml of acetone, slowly added dropwise and stirred overnight. Acetone was distilled off by rotary evaporation. 8.0 mmol of the above product was dissolved in a dichloromethane/toluene mixed solvent; 8.0 mmol CDI was dissolved in toluene, and the two were slowly added dropwise under protection by nitrogen to react at 25 C. for 12 hours. 1 mmol dodecylamine was dissolved in 5 ml toluene solution, and the mixture was slowly added dropwise to the aforesaid reaction solution, and reaction was further carried out at 25 C. for 24 hours. 3.0 mmol sodium hydroxide was added to the reaction solution to react for 1 hour. After completion of the reaction, the solvent was removed by rotary evaporation at 70 C., followed by recrystallization with acetonitrile/water (v/v=5:1), to obtain pale yellow solid, which was dried under vacuum. The resultant was recrystallized with DMF once again, to obtain a double long carbon chain intermediate R12.

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 4958 - 4961
[2]Patent: WO2018/175927,2018,A2 .Location in patent: Paragraph 00298; 00300; 00301
[3]Helvetica Chimica Acta,1999,vol. 82,p. 2130 - 2140
[4]PLoS ONE,2015,vol. 10
[5]Journal of Materials Chemistry B,2017,vol. 5,p. 7963 - 7973
[6]Patent: US2017/355667,2017,A1 .Location in patent: Paragraph 0060

12
[ 616-30-8 ]
[ 268205-33-0 ]
[ 2566-22-5 ]
<i>N</i>-[1-(2,3-dihydroxy-propylcarbamoyl)-2-phenyl-ethyl]-benzamide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2000,vol. 65,p. 1672 - 1679

13
[ 7732-18-5 ]
[ 62037-46-1 ]
silver oxide [ No CAS ]
[ 616-30-8 ]

Reference： [1]Hoppe-Seyler's Zeitschrift fur Physiologische Chemie,1926,vol. 158,p. 56

14
[ 2004-07-1 ]
[ 616-30-8 ]
[ 103842-19-9 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4135 - 4150

15
[ 616-30-8 ]
[ 383-63-1 ]
[ 125348-23-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	In tetrahydrofuran;	1) Preparation of N-(2,3-dihydroxypropyl)-2,2,2-trifluoroacetamide 15 g of 3-aminopropan-1,2-diol (164.6 mmol) were solubilized in 100 ml of tetrahydrofuran in a round-bottomed flask provided with a magnetic bar. The reaction mixture was then cooled to 0 C. on an ice bath and 21.5 ml of ethyl trifluoroacetate (181.1 mmol) were gradually added. The reaction mixture was stirred for 2 hours at room temperature. The crude reaction product was then evaporated to dryness. 29 g of a pure colorless oil were thus obtained (yield: 95%), that product was used without further purification.
91%	In acetonitrile; for 4h;Inert atmosphere;	2,2,2-Trifluoro-iV-(2,3-dihydroxypropyl) acetamide (1). To a stirred mixture of 3- amino-l,2-propanediol (18.80 g, 0.21 mol) in acetonitrile (120 mL) under argon was added dropwise ethyl trifluoroacetate (34.30 g, 0.24 mol). After 4 h, the solvent was evaporated, and the residue was dissolved in ethyl acetate (200 ml), washed with aqueous KHS04 and brine, then dried over MgS0 , and concentrated to yield 34.90 g (91%) of 2,2,2-trifluoro-N-(2,3- dihydroxypropyl)-acetamide as colorless oil. 1H NMR (300MHz, CD3OD): £(ppm) 3.27-3.29 (m, 2H, NH-G), 3.47-3.49 (m, 2H, C-OH), 3.70-3.78 (m, 1H, CH-OH), 7.60 (b, 1H, NH).
83.4%	In acetonitrile; at 20℃; for 12h;Inert atmosphere; Cooling with ice;	(1) Under a nitrogen atmosphere, a 250 ml round-mouth reaction bottle is used as a reaction vessel.15.49 g (0.17 mol) of <strong>[616-30-8]3-amino-1,2-propanediol</strong> was added thereto, and dissolved in 100 ml of acetonitrile. The mixture was ice-cooled, and 36.23 g of ethyl trifluoroacetate was slowly added dropwise thereto, and the mixture was stirred at room temperature for 12 hours. The solvent was removed by rotary evaporation, and then 300 ml of ethyl acetate was added to dissolve the product after rotary evaporation. The product was washed once with 100 ml of 10% ammonium sulfate solution and 100 ml of saturated sodium chloride solution, and the organic phase was collected, dried over anhydrous sulfuric acid, and filtered. The filtrate was concentrated under vacuum to give the compound 2,2,2-trifluoro-N-(2,3-dihydroxypropyl)acetamide 26.53 g, yield: 83.4%;

Reference： [1]Patent: US2002/91242,2002,A1
[2]MedChemComm,2017,vol. 8,p. 2050 - 2054
[3]Polymer,2011,vol. 52,p. 921 - 932
[4]Patent: WO2013/155173,2013,A2 .Location in patent: Page/Page column 19
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16
[ 1194-21-4 ]
[ 616-30-8 ]
2-amino-6-[(2,3-dihydroxypropyl)amino]-4(3H)-pyrimidinone [ No CAS ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 943 - 959

17
[ 616-30-8 ]
[ 7139-02-8 ]
3-[6-(2,3-dihydroxy-propylamino)-4,8-di-piperidin-1-yl-pyrimido[5,4-<i>d</i>]pyrimidin-2-ylamino]-propane-1,2-diol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 4905 - 4922

18
[ 616-30-8 ]
[ 87736-89-8 ]
[ 881015-65-2 ]

Reference： [1]Heterocycles,2005,vol. 66,p. 531 - 534

19
[ 616-30-8 ]
[ 16523-31-2 ]
2-(2,3-dihydroxy-propylamino)-4-(2,3-dihydroxy-propylimino)-5-hydroxy-cyclohexa-2,5-dienone [ No CAS ]

Reference： [1]Chemistry - A European Journal,2005,vol. 11,p. 7237 - 7246

20
[ 616-30-8 ]
[ 130296-37-6 ]
[ 874942-71-9 ]

Reference： [1]Collection of Czechoslovak Chemical Communications,2006,vol. 71,p. 625 - 634
[2]Angewandte Chemie - International Edition,2006,vol. 45,p. 4444 - 4447

21
[ 616-30-8 ]
[ 3939-09-1 ]
[ 908117-06-6 ]

Yield	Reaction Conditions	Operation in experiment
41.4%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 200℃; for 0.116667h;Microwave irradiation;	A mixture of 2, 4-Difluoro-benzonitrile (1.39 g, 10 mmol) , 3- amino-propane-1, 2-diol (0.911 g, 10 mmol) , and ethyl- diisopropyl-amine (1.74 mL) in DMSO (10 itiL) was microwaved at 200 0C for 7 min. Then the reaction mixture was poured into a saturated NH4Cl aq. solution (100 mL) , extracted with EtOAc (3x100 mL) , dried over Na2SCu, filtered, concentrated. The crude mixture was purified by flash silica gel chromatography (EtOAc-Hexane 1:1) to give 2- (2, 3-Dihydroxy-propylamino) -4- fluoro-benzonitrile (0.87 g, 41.4% yield). LCMS (m/z) : M+H = 211.To a mixture of 6, 6-Dimethyl-3-trifluoromethyl-l, 5, 6, 7- tetrahydro-indazol-4-one (0.961 g, 4.14 mmol, 1 eq) and NaH (99 ?ig, 4.14 mmol, 1 eq) in dimethyl acetamide (20 mL) was added slowly 2- (2, 3-Dihydroxy-propylamino) -4-fluoro- benzonitrile (0.87 g, 4.14 mmol, 1 eq) . Then the reaction mixture was stirred at 150 C overnight, cooled, poured into saturated NH4Cl aq. solution (100 mL) , extracted by EtOAc(3x150 mL) , dried over Na2SO4, filtered, concentrated. The crude product was purified by flash silica gel chromatography, eluted by EtOAc to give 2- (2, 3-Dihydroxy-propylamino) -4- (6, 6- dimethyl-4-oxo-3-trifluoromethyl-4 , 5,6, 7-tetrahydro-indazol-l- yl)-benzonitrile (1.7g, 97% yield). LCMS (m/z): M+H = 423. 2- (2, 3-Dihydroxy-propylamino) -4- (6, 6-dimethyl-4-oxo-3- trifluoromethyl-4, 5, 6, 7-tetrahydro-indazol-l-yl) -benzonitrile (1.7 g, 4 mmol, 1 eq) , NaOH (806 mg, 20 mmol, 5 eq) , and H2O2 EPO <DP n="118"/>(3 iriL) were dissolved in EtOH-water (4:1) (40 itiL) . The mixture was microwaved at 120 C for 15 min, then concentrated to dryness, and purified by flash chromatography, eluted by 10% MeOH in EtOAc to give pure 2- (2, 3-Dihydroxy-propylamino) - 4- (6, beta-dimethyl-4-oxo-3-trifluoromethyl-4, 5, 6, 7-tetrahydro- indazol-1-y l)-benzamide (0.52 g, 29% yield). LCMS (m/z) : M+H = 441.

Reference： [1]Patent: WO2006/91963,2006,A1 .Location in patent: Page/Page column 115-117

22
aqueous sodium chloride [ No CAS ]
[ 616-30-8 ]
[ 24424-99-5 ]
[ 137618-48-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; potassium hydrogen sulphate; In water; ethyl acetate;	EXAMPLE 14 3-(Boc-amino)-1,2-propanediol, 18 3-Amino-1,2-propanediol (40.00 g, 0.440 mol, 1.0 eqv) was dissolved in water (1000 ml) and cooled to 0 C., and di-tert-butyl dicarbonate (115.0 g, 0.526 mol, 1.2 eqv) was added in one portion. The reaction mixture was heated to room temperature on a water bath with stirring. The pH was maintained at 10.5 with a solution of sodium hydroxide (17.56 g, 0.440 mol, 1.0 eqv) in water (120 ml). When the addition of aqueous sodium hydroxide was completed, the reaction mixture was stirred overnight at room temperature. Subsequently, ethyl acetate (750 ml) was added to the reaction mixture followed by cooling to 0 C. and the pH was adjusted to 2.5 with 4N sulfuric acid with vigorous stirring. The phases were separated. The water phase was washed with additional ethyl acetate (6350 ml). The volume of the organic phase was reduced to 900 ml by evaporation under reduced pressure and washed with a saturated aqueous solution of potassium hydrogen sulfate diluted to twice its volume (11000 ml) and with saturated aqueous sodium chloride (1*500 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure to yield 50.12 9 (60%) of the title compound. The product could be solidified by evaporation from methylene chloride and subsequent freezing. 1 H-NMR (CDCl3 /TMS): delta=1.43 (s, 9H, Me3 C), 3.25 (m, 2H, CH2), 3.57 (m, 2H, CH2), 3.73 (m, 1H, CH). 13 C-NMR (CDCl3 /TMS): delta=28.2 (Me3 C), 42.6 (CH2), 63.5, 71.1 (CH2 OH, CHOH), 79.5 (Me3 C), 157.0 (C=O).

Reference： [1]Patent: US5539082,1996,A

23
[ 616-30-8 ]
[ 16806-93-2 ]
[ 186963-75-7 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol;	a) Preparation of 4-oxo-4,5,6,7-tetrahydro-1-N-(beta,gamma-dihydroxypropyl)indole 9.4 g of 2,3-dihydroxypropylamine were added to a solution of 13.6 g of <strong>[16806-93-2]4-oxo-4,5,6,7-tetrahydrobenzofuran</strong> in 200 cm3 of ethanol. The reaction medium was heated at 150° C. for 9 hours. After evaporation of the solvent and purification of the crude product on silica gel (ethyl acetate/methanol=9/1), 11.2 g of 4-oxo-4,5,6,7-tetrahydro-1-N-(beta,gamma-dihydroxypropyl)indole were recovered in the form of an oil.

Reference： [1]Patent: US5704948,1998,A

24
[ 111453-26-0 ]
[ 616-30-8 ]
[ 111453-35-1 ]

Yield	Reaction Conditions	Operation in experiment
87.9%	With triethylamine; In tetrahydrofuran; ISOPROPYLAMIDE; water;	5-(N-2,3-Diacetoxypropylacetamido)-2,4,6-triiodo-N-(2-acetoxyethyl)-isophthalamic acid chloride (IV) into: 5-(N-2,3-Diacetoxypropylacetamido)-2,4,6-triiodo-N-(2-acetoxyethyl)-N'-(2,3-dihydroxypropyl)-isophthalamide (VII) The title compound (IV) (86.25 g, 100 mMoles) was dissolved in dimethylacetamide (200 ml) to which triethylamine (13.9 g, 100 mMoles) and <strong>[616-30-8]3-amino-1,2-propanediol</strong> (10.93 g, 120 mMoles) were added. The reaction was stirred at room temperature for 8 hr to completion by TLC. The solvent was evaporated in vacuo and the product dissolved in tetrahydrofuran (75 ml) and partitioned with water saturated with sodium chloride. The organic extract was washed with brine:1N hydrochloric acid (9:1, 50 ml 2), followed by brine:water (1:1) (50 ml 2) and finally brine (40 ml *1). The organic layer was dried over MgSO4 and the solvent was removed to give 80.6 g of the product (VII) as an off-white foam (87.9% yield).
87.9%	With triethylamine; In ISOPROPYLAMIDE; at 20℃; for 8h;	The compound from the preceding stage (86.25 g, 100 mmol) was dissolved in dimethylacetamide (200 ml), where triethylamine (13.9 g, 100 mmol) and 3-amino- 1,2-propanediol (10.93 g, 120 mmol) were added. The reaction mixture was stirred at ambient temperature for 8 hours until the reaction was at an end by TLC monitoring. The solvent was evaporated under vacuum and the product was dissolved in tetrahydrofuran (75 ml) to which sodium chloride solution had been added. The organic extract was washed with a sodium chloride solution/ IN hydrochloric acid mixture (9:1, 50 ml x 2), subsequently with a sodium chloride solution/water (1:1) mixture (50 ml x 2) and finally with sodium chloride solution (40 ml x 1). The organic layer was dried over MgSO4 and the solvent removed to give 80.6 g of the product in the form of a virtually white foam (87.9% yield).

Reference： [1]Patent: US4954348,1990,A
[2]Patent: WO2007/116039,2007,A1 .Location in patent: Page/Page column 8; Fig.1

25
[ 56-82-6 ]
[ 616-30-8 ]

Yield	Reaction Conditions	Operation in experiment
94.5%	With ammonia;active charcoal; palladium; In water;	EXAMPLE 3 The corresponding ketimine is obtained analogously to Example 1 from glyceraldehyde and ammonia in water. After 10% by weight, relative to the amount of glyceraldehyde, of a 10% palladium/active charcoal catalyst has been added, hydrogenation is carried out at 50 and a hydrogen pressure of 65 bar. The mixture is filtered and evaporated and the residue is distilled, giving 1-amino-2,3-propanediol in a yield of 94.5% of theory.

Reference： [1]Patent: US5023379,1991,A
[2]Angewandte Chemie - International Edition,2017,vol. 56,p. 3050 - 3054
Angew. Chem.,2017,vol. 129,p. 3096 - 3100,5

26
[ 2004-07-1 ]
[ 616-30-8 ]
(R,S)-N₆-[Dihydroxypropyl]-2-amino-adenosine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;	EXAMPLE 8 (R,S)-N6 -[Dihydroxypropyl]-2-amino-adenosine The title compound was prepared as in Example 1 using 3.0 g (10 mmol) 2-amino-6-chloropurineriboside, 0.9 g (10 mmol) 2,3-dihydroxypropylamine and 1.0 g (10 mmol) triethylamine. the product was collected as a glass. Analysis for (C13 H20 N6 O6) Calcd: C=43.82, H=5.66, N=23.58; Found: C=43.21, H=5.85, N=22.73.

Reference： [1]Patent: US4616003,1986,A

27
[ 616-30-8 ]
[ 601-88-7 ]
[ 113864-77-0 ]

Yield	Reaction Conditions	Operation in experiment
	In 1-methyl-pyrrolidin-2-one; isopropyl alcohol;	EXAMPLE 7 Preparation of 2-(beta,gamma-dihydroxypropyl)amino-6-chloronitrobenzene STR15 0.2 mole (38.4 g) of <strong>[601-88-7]2,6-dichloronitrobenzene</strong> and 0.6 mole (54.6 g) of 3-aminopropane-1,2-diol in 200 ml of 1-methyl-2-pyrrolidone are heated to 80° C. The reaction mixture is diluted with ice. The product expected precipitates. After recrystallizing from isopropanol, it melts at 126° C. Analysis of the product obtained gives the following results:

Reference： [1]Patent: US4845293,1989,A

28
[ 1955-46-0 ]
[ 616-30-8 ]
[ 122731-58-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In methanol; water;	a)5-Nitro-N-(2,3-dihydroxypropyl)isophthalic acid monoamide To a solution of 5-nitroisophthalic acid monomethyl ester (22.5 g, 0.1 moles) in methanol (100 mL), triethylamine (10.1 g, 0.1 moles) and 3-amino-1,2-propanediol (10.02 g, 0.11 moles) were added with stirring and heated at solvent reflux for three hours. The solution was evaporated to dryness under reducedpressure. The residue was treated with cold water, filtered, and washed with cold water. The white solid was dried in vacuo to obtain 5-nitro-N-(2,3-dihydroxypropyl)isophthalic acid monoamide (26.9 g, 95%). The product was used in the next step without purification.
86%	With potassium tert-butylate; In tert-butyl alcohol;Inert atmosphere; Reflux;	A 50 mL round bottom flask equipped with a condenser, an electric stirrer and a thermometer was charged with 400 mg of monomethyl 5-nitro-isophthalate and 4 mL of t-butanol was added and the solid was not dissolved at room temperature with stirring.194 mg3-amino-1,2-propanediol andPotassium tert-butoxide 598 mg,The solid is dissolved, the solution color from white to brown,In a nitrogen atmosphere,The mixture was heated to reflux and the reaction was stopped by TLC. The operation was as follows: 1 drop of H2O was added and 1 H2O was added to adjust the pH value to 1 with concentrated HCl. After the reaction with the starting point (developing solvent CH3OH: CH2Cl2: glacial acetic acid = 2: 1: After filtering, the filter cake was washed with a small amount of tert-butanol, dried, and weighed 434mg, and the mixture was stirred at room temperature for 1 hour. After the reaction, Yield 86%.
82%	In acetonitrile; at 75 - 80℃; for 7h;	The reaction flask was charged with 3-methoxycarbonyl-5-nitrobenzoic acid (formula II, 45 g, 0.2 mol)Was added to acetonitrile (180 mL) and dissolved,Then 3-amino-1,2-propanediol (54.6 g, 0.6 mol) was added,The reaction solution was heated to 75-80 C,Reaction for 7 hours.After the reaction,The reaction solution was added to 500 ml of 1N hydrochloric acid,0-10 C crystallization overnight,filter,The filter cake is washed once with the appropriate amount of water and ethyl acetate,To give 3 - ((2,3-dihydroxypropyl) carbamoyl) -5-nitrobenzoic acid (formula III-1, 46.6 g)Yield 82%Purity ?99%.

Reference： [1]Patent: EP1186305,2002,A1
[2]Patent: CN105254521,2016,A .Location in patent: Paragraph 0027
[3]Patent: CN106366016,2017,A .Location in patent: Paragraph 0092; 0093; 0094

29
[ 616-30-8 ]
[ 13290-96-5 ]
[ 76820-34-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	In methanol;	f) 5-Nitro-N,N'-bis-(2,3-dihydroxypropyl)isophthalamide To a solution of <strong>[13290-96-5]5-nitroisophthalic acid dimethyl ester</strong> (23.92 g, 0.1 moles) in methanol (100 mL), 3-amino-1,2-propanediol (16.52 g, 0.22 moles) was added with stirring and heated at solvent reflux for four hours. The solution was evaporated to dryness under reduced pressure. The crude was crystallized inmethanol/ethyl ether, filtered off, and dried in vacuo to obtain 5-nitro-N,N'-bis-(2,3-dihydroxypropyl)isophthalamide (30.3 g, 85%).
	With sodium methylate; In methanol; for 80.0h;	Dimethyl 5-nitroisophthalate (150 g, 0.628 mol) and 3-aminopropane-l,2-diol (143 g, 1.57 mol) is dissolved in methanol (1200 mL), then sodium methoxide (18 g, 0.333 mol) is added, the mixture obtained is stirred for 80 h. The pH is adjusted to 5.5-6.5 using acetic acid, the mixture heated to 40 C. Methanol is removed by distillation initially under normal pressure then under reduced pressure until the mixture is a syrup. Water is added to the mixture to a total volume of 1200 mL to obtain the aqueous solution of N,N'-bis-(2,3- dihydroxypropyl)-5-nitroisophthalamide.
	With sodium methylate; In methanol; at 25 - 30℃; for 2.0h;	[0037] Diamide was prepared at various reaction temperatures ranging from 25 C. to 108 C., and at ratios of APD to diamide of 2.10:1 and 2.08:1, according to the reaction conditions reported in Table 3a, below. Experiments 1-4 were run at a diester concentration of 1.00 mole per liter in the solvent 2-methoxyethanol. Experiments 5-8 we run at a diester concentration of 3.22 moles per liter in the solvent methanol. The analytical results obtained are reported in Table 3b, below. (?Exp.? refers to experiment number, ?Temp.? is the reaction temperature in C., ?Time? is the reaction time in hours, ?Ratio? is the molar equivalent ratio of APD to diester, ?NaOMe:Diest.? is molar equivalent ratio of sodium methoxide to diester. Acid Amide, Amide Ester and Diester are reported in % purity by HPLC. [0038] The HPLC profiles for experiments 1-3 run at 65 C. and 108 C. showed an increased number of minor peaks as compared to experiments 4-8 run at 25-30 C. and 45-50 C., indicating that the higher reaction temperature, qualitatively, generated a larger number of impurities. In particular, an HPLC chromatogram for experiment 1, depicted in FIG. 1, shows minor peaks at 1.698, 13.255, 14.409, 14.786 and 15.400 minutes whereas an HPLC chromatogram for experiment 5, depicted in FIG. 2, shows an absence of such minor peaks. Further, the diamide prepared at 65 C. and 108 C. had an increase in color as compared to the lower temperature reactions.

With sodium methylate; In methanol; at 20 - 50℃;

ccording to the molar ratio of dimethyl 5-nitro-1,3-phthalic acid to 2,3-dihydroxypropylamine:1.2 Prepare raw materials. Will be 50gDimethyl 5-nitro-1,3-phthalate was placedIn a 500 ml reaction flask, add 80 ml of methanol.Stir well,22.8 g of 2,3-dihydroxypropylamine was added dropwise.Add 5g sodium methoxide dropwise at room temperature.Keep the temperature at 20-50 C for 20-40 hours.HPLC detection of raw materials ? 0.1% reaction,Cool down to room temperature and adjust the pH to 6 with hydrochloric acid.Add 250mL of water,Mixing to obtain about 450 ML of transesterification reaction solution,Used in the next hydrogenation reduction reaction.

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 1181 - 1190
[2]Patent: EP1186305,2002,A1
[3]Patent: WO2013/63737,2013,A1 .Location in patent: Page/Page column 14; 15
[4]Patent: US2014/200367,2014,A1 .Location in patent: Paragraph 0037-0038
[5]Patent: CN109912445,2019,A .Location in patent: Paragraph 0032; 0033; 0034

30
[ 916225-31-5 ]
[ 616-30-8 ]
N-{5-[2-bromo-5-(2,3-dihydroxypropylsulfamoyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; In dichloromethane; at 20℃;	4-[2-(acetylamino)^-methyl-l,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (500 mg; 1.2 mmol; 1 eq), is dissolved in anhydrous DCM (30 ml). The reaction is put under nitrogen. Triethylamine (0.34 ml; 2.41 mmol; 2 eq) and 2,2-dimethyl-l,3-dioxolane-4-methanamine (0.31 ml; 2.41 mmol; 2 eq) are added successively and the reaction mixture is stirred overnight at room temperature. It is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (3650 mg; 94%).M (ESI): 509.57; M+(ESI):511.2. HPLC (method A), Rt: 3.36 min (purity: 89.2%).

Reference： [1]Patent: WO2006/125803,2006,A1 .Location in patent: Page/Page column 70

31
[ 7790-21-8 ]
[ 616-30-8 ]
[ 24424-99-5 ]
[ 137618-48-5 ]
[ 89711-08-0 ]

Yield	Reaction Conditions	Operation in experiment
102 g (93%)	With hydrogenchloride; sodium hydroxide; In water; ethyl acetate;	(a) Preparation of (bocamino)acetaldehyde 3-Amino-1,2-propanediol (80.0 g; 0.88 mol) was dissolved in water (1500 ml) and the solution was cooled to 4 C., whereafter Boc anhydride (230 g; 1.05 mol) was added at once. The solution was gently heated to room temperature with a water bath. The pH was kept at 10.5 by the dropwise addition of sodium hydroxide. Over the course of the reaction a total of 70.2 g NaOH, dissolved in 480 ml water, was added. After stirring overnight, ethyl acetate (1000 ml) was added and the mixture was cooled to 0 C. and the pH was adjusted to 2.5 by the addition of 4 M hydrochloric acid. The ethyl acetate layer was removed and the acidic aqueous solution was extracted with more ethyl acetate (8500 ml). The combined ethyl acetate solution was reduced to a volume of 1500 ml using a rotary evaporator. The resulting solution was washed with half saturated potassium hydrogen sulphate (1500 ml) and then with saturated sodium chloride. It then was dried over magnesium sulphate and evaporated to dryness, in vacuo. Yield. 145.3 g (86%) 3-Bocamino-1,2-propanediol (144.7 g; 0.757 mol) was suspended in water (750 ml) and potassium periodate (191.5 g; 0.833 mol) was added. The mixture was stirred under nitrogen for 2.5 h and the precipitated potassium iodate was removed by filtration and washed once with water (100 ml). The aqueous phase was extracted with chloroform (6400 ml). The chloroform extracts were dried and evaporated to dryness, in vacuo. Yield 102 g (93%) of an oil. The (bocamino)acetaldehyde was purified by kugelrohr distillation at 84 C. and 0.3 mmHg in two portions. The yield 79 g (77%) of a colorless oil.

Reference： [1]Patent: US6713602,2004,B1

32
[ 616-30-8 ]
[ 606-21-3 ]
[ 1173983-56-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine; In tetrahydrofuran; at 20℃; for 40h;	Reference Example 85 3-[(2,6-Dinitrophenyl)amino]propane-1,2-diol To a stirred solution of 2-chloro-1,3-dinitrobenzene (4.05 g, 20.0 mmol) and triethylamine (3.35 mL, 24.0 mmol) in tetrahydrofuran (70 mL) was added a solution of 3-amino-1,2-propandiol (3.64 g, 40.0 mmol) in tetrahydrofuran (10 mL) at room temperature. After 40 hr, the reaction mixture was diluted with water, extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluding with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound (5.02 g, 19.6 mmol, 98%) as a yellow solid. 1H NMR (CDCl3) delta 1.83 (brs, 1H), 2.46-2.58 (m, 1H), 3.00-3.19 (m, 2H), 3.54-3.67 (m, 1H), 3.69-3.80 (m, 1H), 3.91-4.03 (m, 1H), 6.78 (t, J=8.2 Hz, 1H), 8.19 (d, J=8.2 Hz, 2H), 8.75 (brs, 1H). MS Calcd.: 257; MS Found: 258 (M+H).

Reference： [1]Patent: US2009/186879,2009,A1 .Location in patent: Page/Page column 66

33
[ 616-30-8 ]
[ 152120-55-3 ]
C₂₀H₂₃N₃O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	In tetrahydrofuran; at 25℃; for 15h;	To the solution of 3-aminopropane-1,2-diol (3.0 g, 32.9 mmol, 2.54 mL, 1.00 eq) in THF (60 mL) was added N,N-di-CBZ-1H-pyrazole-1-carbamidine (11.2 g, 29.6 mmol, 0.90 eq). Then the reaction was stirred at 25 C for 15 hrs. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel chromatography to give Compound 68 (12 g, 86%) as white solid.?H NMR 400 MHz CDC13 oe 11.70 (s, 1H), 8.66 (s, 1H), 7.56 (d, J= 3.6 Hz, 2H), 7.40- 7.32 (m, 9H), 6.34-6.31 (m, 1H), 5.20 (s, 2H), 5.13 (s, 2H), 3.83-3.79 (m, 1H), 3.66-3.52 (m, 4H).

Reference： [1]Patent: WO2017/160569,2017,A1 .Location in patent: Paragraph 00456; 00457
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 1632 - 1635

34
[ 616-30-8 ]
[ 534-03-2 ]
[ 37441-29-5 ]
[ 1096689-22-3 ]

Yield	Reaction Conditions	Operation in experiment
57%		At 2C a mantled reactor with mechanical stirrer, dropping funnel and inner thermometer was charged with DMA (640 ml), triethylamine (224 ml, 161.3 g, 1.59 mol) and 5-Amino-2,4,6-triiodo-isophthalic acid dichloride (320 g, 537 mmol). The mixture was stirred and cooled to -24C. A solution of 1-amino-2,3- dihydroxypropane (49,92 g, 548 mmol) in DMA (160 ml) was added slowly to keep the inner temperature below -19C. The mixture was stirred at a temperature gradient from -24C to OC in 24h. A solution of serinol (60 g, 658 mmol) in DMA (160 ml) was added slowly and the mixture was stirred at a temperature gradient from 0C to 4OC in 2Oh. The mixture was stirred at 22 C for 1day and precipitated triethylamine hydrochloride was filtered off. Evaporation at 60C/25 mbar left a viscous liquid residue (586 g) which was diluted with water (350 ml). Salts andexcess amines were removed by treatment with ion exchangers Amberlite200C (143 ml), IRA67 (148 ml) and IRA900 (56 ml) followed by filtration. The ion exchangers were washed with water (2 x 400 ml). Some seeding crystals were added to the combined aqueous phase and the solution was stirred slowly at 22C for 9 days. The precipitate was isolated by filtration. The filter cake was re- suspended in water (240 ml) and stirred for 1day. The suspension was filtered and the filter cake was dried in air (216 g, 57% yield, 88,6% HPLC purity). The crude product was purified by preparative HPLC (column: selfpacked Luna C18, 10 mum 250 x 100 mm, solvents: A = water and B = acetonitrile; gradient 5-10 % B over 10 min, hold 10 min; flow 350 ml/ min, UV detection at 244 nm and 254 nm). Relevant fractions were combined and freeze dried to yield 5-amino-N1-(1 ,3-dihydroxypropan- 2-yl)-N3-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide
		At 2C a mantled reactor with mechanical stirrer, dropping funnel and inner thermometer was charged with DMA (640 ml), triethylamine (224 ml, 161.3 g, 1.59 mol) and 5-Amino-2,4,6-triiodo-isophthalic acid dichloride (320 g, 537 mmol). The mixture was stirred and cooled to -24C. A solution of 1-amino-2,3- dihydroxypropane (49,92 g, 548 mmol) in DMA (160 ml) was added slowly to keep the inner temperature below -19C. The mixture was stirred at a temperature gradient from -24C to 00C in 24h. A solution of serinol (60 g, 658 mmol) in DMA (160 ml) was added slowly and the mixture was stirred at a temperature gradient from 00C to 400C in 2Oh. The mixture was stirred at 22 0C for 1 day and precipitated triethylamine hydrochloride was filtered off. Evaporation at 60C/25 mbar left a viscous liquid residue (586 g) which was diluted with water (350 ml). Salts and excess amines were removed by treatment with ion exchangers Amberlite200C (143 ml), IRA67 (148 ml) and IRA900 (56 ml) followed by filtration. The ion exchangers were washed with water (2 x 400 ml). Some seeding crystals were added to the combined aqueous phase and the solution was stirred slowly at 22C for 9 days. The precipitate was isolated by filtration. The filter cake was re- suspended in water (240 ml) and stirred for 1day. The suspension was filtered and the filter cake was dried in air (216 g, 57% yield, 88,6% HPLC purity). The crude product was purified by preparative HPLC (column: selfpacked Luna C18, 10 mum 250 x 100 mm, solvents: A = water and B = acetonitrile; gradient 5-10 % B over 10 min, hold 10 min; flow 350 ml/ min, UV detection at 244 nm and 254 nm). Relevant <n="34"/>fractions were combined and freeze dried to yield 5-amino-N1-(1 ,3-dihydroxypropan- 2-yl)-N3-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. LC-ESI-MS) m/z 705.9 [M+H]+ corresponding to the wanted structure. 1 H-NMR 500 MHz (solvent: DMSO-dtheta, ref. TMS): side chain 1 : 8.34 ppm (m, NH), 7.91 ppm (m, NH), 4.8-4.4 ppm (m, OH), 3.70 ppm (m, CH), 3.49 ppm (m, CH2), 3.39 ppm (m, CH2), 3.31 ppm (m, NCH2), 3.14 ppm (m, NCH2), side chain 2: 8.09 ppm (d, NH), 7.58 ppm (m, NH), 4.8-4.4 ppm (m, OH), 3.82 ppm (m, CH), 3.65 ppm (m, CH2), 3.53 ppm (m, CH2), side chain 3: 5.46 ppm (m, NH2).
	With triethylamine; In water; 2,4-dichlorophenoxyacetic acid dimethylamine;	a) 5-amino-N1-(1,3-dihydroxypropan-2-yl)-N3-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide At 2 C. a mantled reactor with mechanical stirrer, dropping funnel and inner thermometer was charged with DMA (640 ml), triethylamine (224 ml, 161.3 g, 1.59 mol) and 5-Amino-2,4,6-triiodo-isophthalic acid dichloride (320 g, 537 mmol). The mixture was stirred and cooled to -24 C. A solution of 1-amino-2,3-dihydroxypropane (49.92 g, 548 mmol) in DMA (160 ml) was added slowly to keep the inner temperature below -19 C. The mixture was stirred at a temperature gradient from -24 C. to 0 C. in 24 h. A solution of serinol (60 g, 658 mmol) in DMA (160 ml) was added slowly and the mixture was stirred at a temperature gradient from 0 C. to 40 C. in 20 h. The mixture was stirred at 22 C. for 1 day and precipitated triethylamine hydrochloride was filtered off. Evaporation at 60 C./25 mbar left a viscous liquid residue (586 g) which was diluted with water (350 ml). Salts and excess amines were removed by treatment with ion exchangers Amberlite200C (143 ml), IRA67 (148 ml) and IRA900 (56 ml) followed by filtration. The ion exchangers were washed with water (2400 ml). Some seeding crystals were added to the combined aqueous phase and the solution was stirred slowly at 22 C. for 9 days. The precipitate was isolated by filtration. The filter cake was re-suspended in water (240 ml) and stirred for 1 day. The suspension was filtered and the filter cake was dried in air (216 g, 57% yield, 88.6% HPLC purity). The crude product was purified by preparative HPLC (column: selfpacked Luna C18, 10 mum 250100 mm, solvents: A=water and B=acetonitrile; gradient 5-10% B over 10 min, hold 10 min; flow 350 ml/min, UV detection at 244 nm and 254 nm). Relevant fractions were combined and freeze dried to yield 5-amino-N1-(1,3-dihydroxypropan-2-yl)-N3-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. LC-ESI-MS) m/z 705.9 [M+H]+ corresponding to the wanted structure. 1H-NMR 500 MHz (solvent: DMSO-d6, ref. TMS): side chain 1: 8.34 ppm (m, NH), 7.91 ppm (m, NH), 4.8-4.4 ppm (m, OH), 3.70 ppm (m, CH), 3.49 ppm (m, CH2), 3.39 ppm (m, CH2), 3.31 ppm (m, NCH2), 3.14 ppm (m, NCH2), side chain 2: 8.09 ppm (d, NH), 7.58 ppm (m, NH), 4.8-4.4 ppm (m, OH), 3.82 ppm (m, CH), 3.65 ppm (m, CH2), 3.53 ppm (m, CH2), side chain 3: 5.46 ppm (m, NH2).

Reference： [1]Patent: JP5830589,2015,B2 .Location in patent: Paragraph 0163
[2]Patent: WO2009/106551,2009,A2 .Location in patent: Page/Page column 32-33
[3]Patent: US2011/52504,2011,A1

35
[ 76350-03-3 ]
[ 616-30-8 ]
[ 76350-04-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With dmap; at 30℃; for 10h;	In a 500 mL reactor, a filtrate (Compound II), DMAP 0.2 g (0.00164 mol), was added.9.5 g (0.104 mol) of aminoglycerol, heated to 30 C, reacted for 10 h,After completion of the reaction, the temperature was lowered to 5 C to obtain a crude iopromide intermediate.The crude product was recrystallized from ethylene glycol diethyl ether to give a purified iopromide intermediate 68.6 g, HPLC ? 99.5%, yield 95%.
81%	With triethylamine; In 1,4-dioxane; isopropyl alcohol; at 0 - 10℃;	Step 2[129]2.02 L of 1,4-dioxane and 1.01 L of isopropanol were added to 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride which was recovered in step 1. The mixture was dissolved and cooled to 0 to 10. 0.155 kg of triethylamine was added, and 0.142 kg of <strong>[616-30-8]3-amino-1,2-propanediol</strong> dissolved in 1.01 L of isopropanol was added dropwise. The mixture was stirred for 1 to 2 hours while maintaining the same temperature. After completion of the reaction, the resultant was concentrated below 40. After concentration, 10.1 L of ethyl acetate and 10.1 L of water were added and stirred. The mixture was cooled to 3, and aged for 1 hour, and then crystals were filtered and dried under vacuum at 40 to 60 to obtain the title compound with a yield of 31%. The title compound was obtained with a yield of 81% through the first and second reactions.[130]1H NMR(DMSO-D6, 500MHz) : 10.15 (d, NH), 8.72 (t, NH), 4.03 (s, 2H), 3.70 (d, 2H), 3.49 (d, 4H), 3.20~3.14 (m, 2H)
65%	With triethylamine; In N,N-dimethyl acetamide; at -10℃; for 10h;	5-methoxyacetamido-2,4,6-triiodoisophthaloyl chloride (formula III) (60.0 g, 0.09 mol) was dissolved in 400 ml of DMA,Add triethylamine (9.07 g, 0.09 mol),Cool down to below -10 C,200 ml of DMA-dissolved <strong>[616-30-8]3-amino-1,2-propanediol</strong> (8.18 g 0.09 mol) solution was slowly added dropwise, and the reaction was continued at -10 C for 10 h. Filtering,The filtrate was distilled to remove most of the DMA under reduced pressure, and then the CH 2 Cl 2 solution was added dropwise.A white solid was isolated, suction filtered, dried 42.2 g,The yield was 65%.

	With triethylamine; In N,N-dimethyl acetamide; at 0 - 5℃; for 8h;	5-amino-2,4,6-triiodoisophthalic acid dichloride (13.7 kg, 23 mol) was dissolved in dimethylacetamide (17.2 kg) and the mixture was cooled to 15 C . Methoxyacetyl chloride (3.74 kg, 34.5 mol) was added dropwise thereto for 2 hours, and then the mixture was stirred for 15 hours. After confirming the disappearance of the starting material by HPLC analysis for reaction, methylene chloride (45.7 kg) and water (11.5 kg) were subsequently added to the reaction mixture upon being stirred, and then the stirring was stopped and the layers became separated. The obtained organic layer was washed with aqueous sodium bicarbonate solution and concentrated by distillation under reduced pressure. To a solution of the obtained concentrate dissolved in dimethylacetamide (43.1 kg), triethylamine (1.95 kg, 19.32 mol) was added and then a solution of 2,3-dihydroxypropylamine (1.47 kg, 16.13 mol) dissolved in dimethylacetamide (10.78 kg) was added dropwise thereto for 5 hours with maintaining 0 to 5 C . After additional 3 hours with stirring, the reaction mixture was concentrated by distillation under reduced pressure and to the concentrate, methylene dichloride (213.33 kg) was added dropwise for 5 hours to form solid. The solid was filtered and the title compound was obtained as a white solid (10.98 kg, yield 66.1 %).
	With triethylamine; In ISOPROPYLAMIDE; at 0 - 5℃; for 8h;Industry scale;	Example 1Synthesis of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride (Formula 4)5-amino-2,4,6-triiodoisophthalic acid dichloride (13.7 kg, 23 mol) was dissolved in dimethylacetamide (17.2 kg) and the mixture was cooled to 15 C. Methoxyacetyl chloride (3.74 kg, 34.5 mol) was added dropwise thereto for 2 hours, and then the mixture was stirred for 15 hours. After confirming the disappearance of the starting material by HPLC analysis for reaction, methylene chloride (45.7 kg) and water (11.5 kg) were subsequently added to the reaction mixture upon being stirred, and then the stirring was stopped and the layers became separated. The obtained organic layer was washed with aqueous sodium bicarbonate solution and concentrated by distillation under reduced pressure. To a solution of the obtained concentrate dissolved in dimethylacetamide (43.1 kg), triethylamine (1.95 kg, 19.32 mol) was added and then a solution of 2,3-dihydroxypropylamine (1.47 kg, 16.13 mol) dissolved in dimethylacetamide (10.78 kg) was added dropwise thereto for 5 hours with maintaining 0 to 5 C. After additional 3 hours with stirring, the reaction mixture was concentrated by distillation under reduced pressure and to the concentrate, methylene dichloride (213.33 kg) was added dropwise for 5 hours to form solid. The solid was filtered and the title compound was obtained as a white solid (10.98 kg, yield 66.1%).1H NMR (dmso-d6, 500 MHz) 10.2, 10.06 (2s, 1H); 8.79, 8.71, 8.63 (3t, 1H); 4.54.0 (br, 2H); 4.04, 4.00 (2s, 2H); 3.713.66 (m, 1H); 3.48, 3.47 (2s, 3H); 3.403.36 (m, 2H); 3.363.27 (m, 1H); 3.23.09 (m, 1H)

Reference： [1]Patent: CN110078636,2019,A .Location in patent: Paragraph 0038-0039; 0041-0042; 0043; 0045; 0046; 0048-0060
[2]Patent: WO2015/60657,2015,A1 .Location in patent: Paragraph 128-130
[3]Patent: CN105017062,2018,B .Location in patent: Paragraph 0037; 0038
[4]Patent: WO2009/134030,2009,A1 .Location in patent: Page/Page column 10-11
[5]Patent: US2011/34730,2011,A1 .Location in patent: Page/Page column 6

36
[ 616-30-8 ]
[ 61278-21-5 ]
[ 66211-46-9 ]

Yield	Reaction Conditions	Operation in experiment
	With chiral stationary phase including isopropyl-functionalized CF6; In methanol; acetic acid; triethylamine; acetonitrile; at 20℃;Purification / work up;	In addition to the foregoing, numerous other chromatographic separations using a column bonded with a CSP including a derivatized cyclofructan residue were carried out. Tables 5-9 list some additional examples of chromatographic separations using a column bonded with a CSP of the present invention. AU examples of chromatographic separations using columns bonded with CSPs of the present invention were carried out using the following experimental conditions and procedures.\|0132\| The high performance liquid chromatography (HPLC) column packing system was composed of an air driven fluid pump (HASKEL, DSTV- 122), an air compressor, a pressure regulator, a low pressure gauge, two high-pressure gauges (10,000 and 6,000 psi), a slurry chamber, check valves, and tubings. The CSPs were slurry packed into a 25 cm x 0.46 cm (inner diameter, I. D.) stainless steel column.\|0133\| The HPLC system was an Agilent 1 100 system (Agilent Technologies, Palo Alto,CA), which consisted of a diode array detector, an autosampler, a binary pump, a temperature- controlled column chamber, and Chemstation software. All chiral analytes were dissolved in ethanol, methanol, or other appropriate mobile phases, as indicated. For the LC analysis, the injection volume and flow rate were 5 muL and 1 mL/min, respectively. Separations were carried out at room temperature (~20 0C) if not specified otherwise. The wavelengths of UV detection were 195, 200, 210, and 254 nm. The mobile phase was degassed by ultrasonication under vacuum for 5 min. Each sample was analyzed in duplicate. Three operation modes (the normal phase mode, polar organic mode, and reversed phase mode) were tested, unless indicated otherwise. In the normal phase mode, heptane with ethanol or isopropanol was used as the mobile phase. In some cases, trifluoroacetic acid (TFA) was used as an additive, as indicated. The mobile phase of the polar organic mode was composed of acetonitrile/methanol and small amounts of acetic acid and triethylamine. Water/acetonitrile or acetonitrile/acetate buffer (20 mM, pH = 4.1 ) was used as the mobile phase in the reversed-phase mode.\|0134\| Two different supercritical fluid chromatographic instruments were used. One was a Berger SFC unit with an FCM 1200 flow control module, a TCM 2100 thermal column module, a dual pump control module, and a column selection valve. The flow rate was 4 mL/min. The cosolvent was composed of methanol/ethanol/isopropanol = 1 : 1 : 1 and 0.2% diethylamine (DEA). The gradient mobile phase composition was 5% cosolvent hold during 0- 0.6 min, 5-60% during 0.6-4.3 min, 60% hold during 4.3-6.3 min, 60%-5% during 6.3-6.9 min, and 5% hold during 6.9-8.0 min. The other SFC system was a Jasco (MD, USA) system comprised of an autosampler unit (AS-2059-SF Plus), a dual pump module (PU-2086 Plus), a column thermostat module (CO-2060 Plus), a UV/Vis detector (UV-2075 Plus), and a back pressure regulator module (SCH-Vch-BP). Unless otherwise specified, the mobile phase was composed of CCVmethanol (0.1 % TFA or 0.1% diethylamine). The flow rate was 3 mL/min.\|0135\| For the calculations of chromatographic data, the "dead time" to was determined by the peak of the refractive index change due to the sample solvent or determined by injecting l ,3,5-tri-/e/-/-butylbenzene in the normal phase mode.

Reference： [1]Patent: WO2010/148191,2010,A2 .Location in patent: Page/Page column 45-49; 59
[2]Journal of Polymer Science, Part A: Polymer Chemistry,2010,vol. 48,p. 1324 - 1331

37
[ 616-30-8 ]
[ 463-40-1 ]
[ 1024589-97-6 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: All fatty acid amides with different acyl chains and amine heads were synthesized using the same procedure but with different precursor compounds. 2-(1H-Benzotriazole-1-yl)-1,2,3,3-tetramethyluronium tetrafluoroborate (TBTU, 1 equiv) was added to a mixture of compound C1 (1 equiv) and triethylamine (TEA, 2 equiv) in EtOAc. After stirring for 1 h at room temperature, isopropylamine (2 equiv) was added and the reaction mixture was stirred for 12 h. The mixture was washed with water, dried and concentrated to give a residue that was purified by reversed-phase HPLC (YMC ODS-H80) eluting with 80% aqueous CH3CN to yield compound 1 (1.5 mg, 63%);

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 1520 - 1527

38
[ 616-30-8 ]
[ 112-86-7 ]
[ 7336-26-7 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: All fatty acid amides with different acyl chains and amine heads were synthesized using the same procedure but with different precursor compounds. 2-(1H-Benzotriazole-1-yl)-1,2,3,3-tetramethyluronium tetrafluoroborate (TBTU, 1 equiv) was added to a mixture of compound C1 (1 equiv) and triethylamine (TEA, 2 equiv) in EtOAc. After stirring for 1 h at room temperature, isopropylamine (2 equiv) was added and the reaction mixture was stirred for 12 h. The mixture was washed with water, dried and concentrated to give a residue that was purified by reversed-phase HPLC (YMC ODS-H80) eluting with 80% aqueous CH3CN to yield compound 1 (1.5 mg, 63%);

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 1520 - 1527

39
[ 616-30-8 ]
[ 1374791-85-1 ]
3-[(E)-2-(4-chlorophenyl)vinyl]-N-(2,3-dihydroxypropyl)-4-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h;	General procedure: To a solution of amines (2.5 equiv) and DIPEA (5 equiv) in CH2Cl2 at room temperature was added a solution of 3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoyl chloride (1 equiv) in CH2Cl2 and the mixture was stirred for 1 h at room temperature. The reaction mixture was washed with saturated aqueous solution of NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, n-hexane/EtOAc) to give the desired products 32a-h.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 1442 - 1460

40
[ 50-00-0 ]
[ 4966-90-9 ]
[ 616-30-8 ]
[ 1394246-43-5 ]

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 54,p. 113 - 122

41
[ 616-30-8 ]
[ 111-81-9 ]
[ 1418298-58-4 ]

Yield	Reaction Conditions	Operation in experiment
77.5%	With sodium methylate; In methanol; at 108 - 117℃; for 5h;	A reflux pipe, a nitrogen inlet with a three way cock,Vent with 3 way cock,A stirring blade with a vacuum seal,In a 1 L 5-necked flask equipped with a thermometer, 317.29 g (1.60 mol) of methyl 10-undecenoate,173.27 g (1.65 mol) of 3-aminopropane-1,2-diol,3.78 g (16.0 mmol) of a 24% sodium methoxide methanol solution was added,Heating and stirring at 108 C. to 117 C. while reducing the pressure at 500 hPa to 50 hPa,While distilling off methanol produced 24.Reacted for 5 hours, cooled to room temperature, added with 290 g of ethanol, stirred,After dilution, an inorganic synthetic adsorbent (trade name "Kyoward 700"Manufactured by Kyowa Chemical Industry Co., Ltd.) was added thereto, and the mixture was heated and stirred at 75 C. for 2 hours, followed by filtration. The obtained filtrate was concentrated with a rotary evaporator, dried in a vacuum desiccator to constant weight,382.80 g (yield: 77.5%) of 3- [N-methyl (10-undecenoylamido)] propane-1,2-diol was obtained as a white paste.The structure of the obtained reaction product was confirmed by 1 H-NMR spectrum and IR spectrum.
77.5%	With sodium methylate; In methanol; at 108 - 117℃; for 5h;	A reflux pipe, a nitrogen inlet with a three-way cock, a vent with a three-way cock,A stirring blade with a vacuum seal,In a 1 L 5-necked flask equipped with a thermometer, 317.29 g (1.60 mol) of methyl 10-undecenoate,173.27 g (1.65 mol) of 3-aminopropane-1,2-diol,3.78 g (16.0 mmol) of a 24% sodium methoxide methanol solution,And the mixture was heated and stirred at 108 C. to 117 C. while depressurizing at 500 hPa to 50 hPa while distilling off methanol produced 24.Reacted for 5 hours, cooled to room temperature, added with 290 g of ethanol, stirred,After dilution, an inorganic synthetic adsorbent (trade name "Kyoward 700"Manufactured by Kyowa Chemical Industry Co., Ltd.) was added thereto, and the mixture was heated and stirred at 75 C. for 2 hours, followed by filtration. The obtained filtrate was concentrated with a rotary evaporator, dried in a vacuum desiccator to a constant weight value,382.80 g (yield: 77.5%) of 3- [N-methyl (10-undecenoylamido)] propane-1,2-diol was obtained as a white paste.The structure of the obtained reaction product was confirmed by 1 H-NMR spectrum and IR spectrum.

Reference： [1]Patent: JP2017/25031,2017,A .Location in patent: Paragraph 0080
[2]Patent: JP2017/25030,2017,A .Location in patent: Paragraph 0079

42
[ 616-30-8 ]
[ 111-81-9 ]
[ 924641-22-5 ]

Yield	Reaction Conditions	Operation in experiment
75.9%	With sodium methylate; In methanol; at 110 - 115℃; under 30.003 - 187.519 Torr; for 9h;	Example 1 Synthesis of 3-(10-Undecenoylamido)propane-1,2-diol In a 1-liter five-necked flask equipped with a reflux condenser, a nitrogen inlet with a three-way stopcock, a vent with a three-way stopcock, agitator blades with a decompression seal, and a thermometer were placed 333.15 g (1.68 mol) of methyl 10-undecenoate, 157.66 g (1.73 mol) of 3-aminopropane-1,2-diol, and 3.78 g (16.8 mmol) of a 24% solution of sodium methoxide in methanol. The mixture was subjected to a reaction by heating with stirring at 110 C. to 115 C. at a reduced pressure of 250 hPa to 40 hPa for 9 hours while distilling off formed methanol, cooled to room temperature, and thereby yielded a pale yellow crude product which is solid at room temperature. This was combined with 396 g of ethanol, heated at 80 C. with stirring, cooled to give crystals, the crystals were separated by filtration, washed two times sequentially with 100 g of and 150 g of ethanol, respectively, dried to a constant weight, and thereby yielded 328.15 g (yield: 75.9%) of 3-(10-undecenoylamido)propane-1,2-diol as a white powder. The structure of the resulting reaction product was identified through a 1H-NMR spectrum and an IR spectrum ().

Reference： [1]Patent: US2013/30208,2013,A1 .Location in patent: Paragraph 0060

43
[ 117-80-6 ]
[ 616-30-8 ]
2-(2,3-dihydroxypropylamino)-3-chloronaphthalene-1,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium carbonate; In ethanol; at 20℃; for 8h;	General procedure: Sodium carbonate (1.52 g) was dissolved in ethanol (30mL) and into the resulting solution,2,3-dichloro-1,4-naphthoquinone (1) and reletad nucleophilles were added slowly in smallportions. Without heating, the mixture was stirred for 8 h. The colour of the solution quicklychanged, and the extent of the reaction was monitored by TLC. Chloroform (30 mL) wasadded to the reaction mixture. The organic layer was separated, washed with water (4 x 30mL), and dried with Na2SO4. After the solvent was evaporated, the residue was purified bycolumn chromatography on silica gel.

Reference： [1]Synthetic Communications,2014,vol. 44,p. 121 - 126
[2]Phosphorus, Sulfur and Silicon and the Related Elements,2020,vol. 195,p. 474 - 480

44
[ 616-30-8 ]
4-undec-1-ynyl-pyridine-2-carboxylic acid [ No CAS ]
C₂₀H₃₀N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 18h;Cooling with ice;	[00099] 2,4-cis-4-Undecyl-piperidine-2-carboxylic acid (2,3-dihydroxypropyl)amide (CYD-1-79). To a solution of CYD-1-10 (100 mg, 0.36 mmol), triethylamine (147 mg, 1.46 mmol) and 3-aminopropane-l,2-diol (42.8 mg, 0.47 mmol) in 10 mL of CH2C12 was added HBTU (276 mg, 0.73 mmol) in an ice-water bath. The reaction mixture was stirred at room temperature for 18 hrs. TLC indicated that the starting material was gone, and a less polar product was produced. The reaction mixture was diluted with CH2C12, washed with water and brine, and dried with anhydrous Na2S04. The solvent was removed under vacuum to give an oil residue. The residue was purified by silica gel column; eluting with 2% Et3N in EtOAc afforded CYD-1-60-1 (125.0 mg, 85%) as a colorless oil. A solution of CYD-1-60-1 (50 mg, 0.14 mmol), 36 of 37% HCl and Pt02 catalyst (79 mg, 0.43 mmol) in 6 mL of methanol and 4 mL of H20 was reduced on a Parr hydrogenator at 60 p.s.i. for 2 days. TLC indicated that the starting material was gone. The platinum solid was filtered and the filtrate was concentrated on vacuum to give an oil residue. The residue was partitioned between CH2C12 (30 ml) and saturated aqueous NaHC03 (10 mL), dried over anhydrous Na2S04, filtered and concentrated to give an oil residue. The residue was purified by silica gel column; eluting with 17% MeOH in CH2C12 afforded CYD-1-79 (28.0 mg, 54%) as a colorless solid; 1H NMR (800 MHz, CDC13) delta 7.44 (d, 1H, J= 24.8 Hz), 3.76 (br s, 4H), 3.56 (m, 1H), 3.51 (d, 1H, J= 11.2 Hz), 3.44 (m, 1H), 3.36 (s, 1H), 3.27 (d, 1H, J= 11.4 Hz), 3.14 (d, 1H, J = 12.0 Hz), 2.65 (t, 1H, J = 12.0 Hz), 2.03 (s, 1H), 1.69 (d, 1H, J = 12.0 Hz), 1.42 (s, 1H), 1.25 (s, 20H), 1.01 (m, 2H), 0.88 (t, 3H, J= 7.2 Hz).
85%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 18h;Cooling with ice;	To a solution of CYD-1-10 (100 mg, 0.36 mmol), triethylamine (147 mg, 1.46 mmol) and 3-aminopropane-1,2-diol (42.8 mg, 0.47 mmol) in 10 mL of CH2Cl2 was added HBTU (276 mg, 0.73 mmol) in an ice-water bath. The reaction mixture was stirred at room temperature for 18 hrs. TLC indicated that the starting material was gone, and a less polar product was produced. The reaction mixture was diluted with CH2Cl2, washed with water and brine, and dried with anhydrous Na2SO4. The solvent was removed under vacuum to give an oil residue. The residue was purified by silica gel column; eluting with 2% Et3N in EtOAc afforded CYD-1-60-1 (125.0 mg, 85%) as a colorless oil. A solution of CYD-1-60-1 (50 mg, 0.14 mmol), 36 muL of 37% HCl and PtO2 catalyst (79 mg, 0.43 mmol) in 6 mL of methanol and 4 mL of H2O was reduced on a Parr hydrogenator at 60 p.s.i. for 2 days. TLC indicated that the starting material was gone. The platinum solid was filtered and the filtrate was concentrated on vacuum to give an oil residue. The residue was partitioned between CH2Cl2 (30 ml) and saturated aqueous NaHCO3 (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give an oil residue. The residue was purified by silica gel column; eluting with 17% MeOH in CH2Cl2 afforded CYD-1-79 (28.0 mg, 54%) as a colorless solid; 1H NMR (800 MHz, CDCl3) delta 7.44 (d, 1H, J=24.8 Hz), 3.76 (br s, 4H), 3.56 (m, 1H), 3.51 (d, 1H, J=11.2 Hz), 3.44 (m, 1H), 3.36 (s, 1H), 3.27 (d, 1H, J=11.4 Hz), 3.14 (d, 1H, J=12.0 Hz), 2.65 (t, 1H, J=12.0 Hz), 2.03 (s, 1H), 1.69 (d, 1H, J=12.0 Hz), 1.42 (s, 1H), 1.25 (s, 20H), 1.01 (m, 2H), 0.88 (t, 3H, J=7.2 Hz).

Reference： [1]Patent: WO2013/86266,2013,A2 .Location in patent: Paragraph 00099
[2]Patent: US9533973,2017,B2 .Location in patent: Page/Page column 39-40

45
[ 616-30-8 ]
[ 170838-26-3 ]
C₂₀H₃₀N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20.0℃; for 16.0h;	[000115] N-(2,3-Dihydroxypropyl)-2-(piperidin-4-yl)benzamide (CYD-3-35). To a solution of 2-(l-(/er/-butoxycarbonyl)piperidin-4-yl)benzoic acid (100 mg, 0.32 mmol) and 3- aminopropane-l,2-diol (30 mg, 0.32 mmol) in 5 mL of DMF was added HBTU (161 mg, 0.42 mmol) and DIPEA (105 mg, 0.82 mmol). The resulting mixture was stirred at room temperature for 16 hrs. After that, TLC showed that the starting material was gone. The solvent DMF was removed under vacuum to give a dark oil residue, which was then partitioned between CH2CI2 (50 ml) and 10% NaHS04 solution (10 mL). The organic layer was separated and washed with saturated aqueous NaHCOs (10 mL), dried over anhydrous Na2S04, filtered and concentrated to give an oil residue. This residue was purified with silica gel column; eluting with 3% MeOH in CH2C12 afforded CYD-3-29 (89 mg, 71%) as a colorless gel. CYD-3-29 (89 mg, 0.23 mmol) was dissolved in 1 mL of CH2C12, and then 250 of TFA was added into it. The resulting mixture was stirred at room temperature. After 2 hrs, the solvent was removed under vacuum. The residue was partitioned between CH2C12 (30 ml) and saturated aqueous NaHCOs (10 mL), dried over anhydrous Na2S04, filtered and concentrated to give an oil residue. The residue was purified with preparative TLC; developing with 16% MeOH in CH2C12 afforded CYD-3-35 (35 mg, 53%) as a colorless gel. 1H NMR (600 MHz, CDC13 + CD3OD) delta 7.78 (br s, 1H), 7.46 (m, 2H), 7.39 (d, 1H, J = 7.2 Hz), 7.29 (m, 1H), 3.88 (s, 1H), 3.61 (m, 2H), 3.49 (m, 1H), 3.41 (s, 1H), 3.37 (s, 2H), 3.24 (d, 2H, J = 11.4 Hz), 3.12 (m, 1H), 2.83 (t, 2H, J = 12.0 Hz), 1.93 (m, 2H), 1.98 (q, 2H, J = 12.6 Hz).
71%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20.0℃; for 16.0h;	To a solution of <strong>[170838-26-3]2-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid</strong> (100 mg, 0.32 mmol) and 3-aminopropane-1,2-diol (30 mg, 0.32 mmol) in 5 mL of DMF was added HBTU (161 mg, 0.42 mmol) and DIPEA (105 mg, 0.82 mmol). The resulting mixture was stirred at room temperature for 16 hrs. After that, TLC showed that the starting material was gone. The solvent DMF was removed under vacuum to give a dark oil residue, which was then partitioned between CH2Cl2 (50 ml) and 10% NaHSO4 solution (10 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give an oil residue. This residue was purified with silica gel column; eluting with 3% MeOH in CH2Cl2 afforded CYD-3-29 (89 mg, 71%) as a colorless gel. CYD-3-29 (89 mg, 0.23 mmol) was dissolved in 1 mL of CH2Cl2, and then 250 muL of TFA was added into it. The resulting mixture was stirred at room temperature. After 2 hrs, the solvent was removed under vacuum. The residue was partitioned between CH2Cl2 (30 ml) and saturated aqueous NaHCO3 (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give an oil residue. The residue was purified with preparative TLC; developing with 16% MeOH in CH2Cl2 afforded CYD-3-35 (35 mg, 53%) as a colorless gel. 1H NMR (600 MHz, CDCl3+CD3OD) delta 7.78 (br s, 1H), 7.46 (m, 2H), 7.39 (d, 1H, J=7.2 Hz), 7.29 (m, 1H), 3.88 (s, 1H), 3.61 (m, 2H), 3.49 (m, 1H), 3.41 (s, 1H), 3.37 (s, 2H), 3.24 (d, 2H, J=11.4 Hz), 3.12 (m, 1H), 2.83 (t, 2H, J=12.0 Hz), 1.93 (m, 2H), 1.98 (q, 2H, J=12.6 Hz).

Reference： [1]Patent: WO2013/86266,2013,A2 .Location in patent: Paragraph 000115
[2]Patent: US9533973,2017,B2 .Location in patent: Page/Page column 53-54

46
[ 616-30-8 ]
4-[(tert-butoxy)carbonyl]-1-phenylpiperazine-2-carboxylic acid [ No CAS ]
C₁₉H₂₉N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	[000116] N-(2,3-Dihydroxypropyl)-l-phenylpiperazine-2-carboxamide (CYD-3-49). To a solution of 4-(/er/-butoxycarbonyl)-l-phenylpiperazine-2-carboxylic acid (100 mg, 0.32 mmol) and 3-aminopropane-l,2-diol (30 mg, 0.32 mmol) in 5 mL of DMF was added HBTU (161 mg, 0.42 mmol) and DIPEA (105 mg, 0.82 mmol). The resulting mixture was stirred at room temperature for 16 hrs. After that, TLC showed that the starting material was gone. The solvent DMF was removed under vacuum to give a dark oil residue, which was then partitioned between CH2CI2 (50 ml) and 10% NaHS04 solution (10 mL). The organic layer was separated and washed with saturated aqueous NaHCOs (10 mL), dried over anhydrous Na2S04, filtered and concentrated to give an oil residue. This residue was purified with silica gel column; eluting with 5% MeOH in CH2C12 afforded the amide CYD-3-34 (90 mg, 72%) as colorless gel. CYD-3-34 (90 mg, 0.23 mmol) was dissolved in 1 mL of CH2C12, and then 250 of TFA was added into it. The resulting mixture was stirred at room temperature. After 2 hr, the solvent was removed under vacuum to afford the TFA salt of the amide CYD- 3-49 as a colorless gel (70 mg, 78%). 1H NMR (600 MHz, CDC13 + CD3OD) delta 7.31 (m, 2H), 7.05 (d, 1H, J = 7.8 Hz), 6.97 (m, 1H), 4.54 (s, 1H), 3.68 (m, 2H), 3.58 (m, 2H), 3.36 (m, 5H), 3.27 (m, 2H).
72%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of 4-(tert-butoxycarbonyl)-1-phenylpiperazine-2-carboxylic acid (100 mg, 0.32 mmol) and 3-aminopropane-1,2-diol (30 mg, 0.32 mmol) in 5 mL of DMF was added HBTU (161 mg, 0.42 mmol) and DIPEA (105 mg, 0.82 mmol). The resulting mixture was stirred at room temperature for 16 hrs. After that, TLC showed that the starting material was gone. The solvent DMF was removed under vacuum to give a dark oil residue, which was then partitioned between CH2Cl2 (50 ml) and 10% NaHSO4 solution (10 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give an oil residue. This residue was purified with silica gel column; eluting with 5% MeOH in CH2Cl2 afforded the amide CYD-3-34 (90 mg, 72%) as colorless gel. CYD-3-34 (90 mg, 0.23 mmol) was dissolved in 1 mL of CH2Cl2, and then 250 muL of TFA was added into it. The resulting mixture was stirred at room temperature. After 2 hr, the solvent was removed under vacuum to afford the TFA salt of the amide CYD-3-49 as a colorless gel (70 mg, 78%). 1H NMR (600 MHz, CDCl3+CD3OD) delta 7.31 (m, 2H), 7.05 (d, 1H, J=7.8 Hz), 6.97 (m, 1H), 4.54 (s, 1H), 3.68 (m, 2H), 3.58 (m, 2H), 3.36 (m, 5H), 3.27 (m, 2H).

Reference： [1]Patent: WO2013/86266,2013,A2 .Location in patent: Paragraph 000116
[2]Patent: US9533973,2017,B2 .Location in patent: Page/Page column 55

47
[ 616-30-8 ]
[ 13290-96-5 ]
[ 122731-58-2 ]
[ 76820-34-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In 2-methoxy-ethanol; at 108℃; for 3.0h;	[0037] Diamide was prepared at various reaction temperatures ranging from 25 C. to 108 C., and at ratios of APD to diamide of 2.10:1 and 2.08:1, according to the reaction conditions reported in Table 3a, below. Experiments 1-4 were run at a diester concentration of 1.00 mole per liter in the solvent 2-methoxyethanol. Experiments 5-8 we run at a diester concentration of 3.22 moles per liter in the solvent methanol. The analytical results obtained are reported in Table 3b, below. (?Exp.? refers to experiment number, ?Temp.? is the reaction temperature in C., ?Time? is the reaction time in hours, ?Ratio? is the molar equivalent ratio of APD to diester, ?NaOMe:Diest.? is molar equivalent ratio of sodium methoxide to diester. Acid Amide, Amide Ester and Diester are reported in % purity by HPLC. [0038] The HPLC profiles for experiments 1-3 run at 65 C. and 108 C. showed an increased number of minor peaks as compared to experiments 4-8 run at 25-30 C. and 45-50 C., indicating that the higher reaction temperature, qualitatively, generated a larger number of impurities. In particular, an HPLC chromatogram for experiment 1, depicted in FIG. 1, shows minor peaks at 1.698, 13.255, 14.409, 14.786 and 15.400 minutes whereas an HPLC chromatogram for experiment 5, depicted in FIG. 2, shows an absence of such minor peaks. Further, the diamide prepared at 65 C. and 108 C. had an increase in color as compared to the lower temperature reactions.

Reference： [1]Patent: US2014/200367,2014,A1 .Location in patent: Paragraph 0037-0038

48
[ 616-30-8 ]
[ 90-05-1 ]
[ 93-14-1 ]

Yield	Reaction Conditions	Operation in experiment
72%		Equipped with a stirrer, a thermometer, a reflux condenser, a reaction vessel, 1.5mol sodium sulfite was added, the mass fraction of 20% potassium chloride solution 300ml, controlling the stirring speed of 160 rpm, was slowly added guaiacol (2) 1.3mol, solution temperature rises to 50 , holding 3h, was added 3-amine 1,2-propanediol (3) 1.7mol, increasing the solution temperature 90 , maintained under stirring 5h, the temperature of the solution is reduced to 15 , allowed to stand for 25h after removing the aqueous layer delamination, the mass fraction of oil was added 200ml of 25% solution of sodium bromide, mass fraction of 35% oxalic acid solution was adjusted to maintain the pH at 7, after cooling the precipitated solid was suction filtered, washed with a solution of potassium nitrate, mass fraction washed with 70% nitro methane in the mass fraction of 98% propylene eye recrystallized to give crystals of 3- (o-methoxyphenoxy) -1,2-propanediol 185.33g, yield 72%.

Reference： [1]Patent: CN105566073,2016,A .Location in patent: Paragraph 0013; 0014

49
[ 1955-46-0 ]
[ 616-30-8 ]
methyl 3-((2,3-dihydroxypropyl)carbamoyl)-5-nitrobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The reaction flask was added3-methoxycarbonyl-5-nitrobenzoic acid(Formula VIII) (50 g, 0.222 mol),Add 400 mL of dichloromethaneDissolve it,Dropping at room temperatureOxalyl chloride(28.5 mL, 0.335 mol),After completion of the dropwise addition, stirring was continued for 1-2 hours,The reaction solution was then concentrated,The concentrate was reconstituted with dichloromethane (125 mL)The reaction solution is cooled to below 0 C,A solution of 3-amino-1,2-propanediol (48.5 g, 0.53 mol)The entire dripping process was maintained for 4 hours,After the addition was completed, the mixture was stirred for 0.5 hour,The reaction solution was washed with water,The organic layer was dried over anhydrous sodium sulfate,filter,Concentrated to give methyl 3 - ((2,3-dihydroxypropyl) carbamoyl) -5-nitrobenzoate (Formula VII-1).

Reference： [1]Patent: CN106366015,2017,A .Location in patent: Paragraph 0080; 0081; 0082; 0083

50
[ 616-30-8 ]
[ 1195768-23-0 ]
C₂₆H₂₆F₃N₅O₄S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 60℃;	Dabrafenib modified to feature a diol functional group for further conjugation to PGA was prepared as depicted in Scheme 11, and characterized by 1H-NMR.

Reference： [1]Patent: WO2017/145164,2017,A1 .Location in patent: Page/Page column 77

51
[ 55648-31-2 ]
[ 616-30-8 ]
5-methylamino-N, N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium methylate; In methanol; at 5℃; for 12h;Reflux;	c) In a clean 500ml reaction flask was added 110g of methanol,44.6 g of dimethyl 5-methylaminoisophthalate was added with stirring,40gAmino-1,2-propanediol, 2.2 g of sodium methoxide,After the addition is complete, the mixture is heated to reflux for 4 hours, cooled to 5 C and stirred for 8 hours, filtered, rinsed with cold methanol and dried to yield 64.5 g, yield 94%(Based on 5-methylaminoisophthalic acid dimethyl ester)

Reference： [1]Patent: CN107253918,2017,A .Location in patent: Paragraph 0052; 0059

52
[ 616-30-8 ]
5-[(2-methoxy)acetamido]-3-(2,3-dihydroxy-N-propyl(methyl)carbamoyl)-2,4,6-triiodobenzoyl chloride [ No CAS ]
[ 73334-07-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium carbonate; In N,N-dimethyl acetamide; at 20℃; for 2h;	100 mmol of the compound of formula (III), 120 mmol sodium carbonate, 100 mmol 2,3-dihydroxypropylamine and 150 mL DMAC were added to the reaction flask, and stirred at room temperature for 2h. The solvent was evaporated under reduced pressure, 400 mL of water was added to the residue, saturated sodium hydroxide solution was added, neutralized, eluted with cation exchange column and anion exchange column, the anion exchange column eluate was collected, water was distilled off under reduced pressure, and the obtained white solid was dried at 70C under reduced pressure to obtain compound of formula (I). Yield 92%. Purity by HPLC was 99.7%.

Reference： [1]Patent: CN103965074,2016,B .Location in patent: Paragraph 0029; 0030

53
[ 616-30-8 ]
[ 10436-25-6 ]
tert-butyl 11-(2,3-dihydroxypropylamino)-11-oxoundecylcarbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 174 - 188

54
[ 616-30-8 ]
C₁₅H₁₈N₂O₆ [ No CAS ]
C₁₅H₂₁N₃O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.9%		After the above reaction,Evaporate the solvent under reduced pressureThen dissolve it with 300L anhydrous methanol.Add 40.7 kg of <strong>[616-30-8]3-amino-1,2-propanediol</strong>,1.5kg sodium methoxide,Heat reflux reaction for 6h,After the reaction is completed, cool down to below 30C,200L of 10N sodium hydroxide aqueous solution was added dropwise, and after completion of the dropwise addition, the temperature was raised to 50-65 C. After the reaction was continued for 3-5 h, the temperature was lowered to room temperature, and the pH was adjusted to 2-3 with concentrated hydrochloric acid and the solution was concentrated under reduced pressure to near dryness.After adding 174kg of ethanol, stirring and heating to dissolve, slowly cool to 0~10C and crystallize for 8 hours.After filtration and vacuum drying, 95.4 kg of a compound of the formula (2) was obtained with a yield of 87.9%.

Reference： [1]Patent: CN107400062,2017,A .Location in patent: Paragraph 0047; 0056; 0061; 0066; 0071; 0076; 0081; 0086

55
[ 616-30-8 ]
2-(3-chloroquinolin-6-yl)acetic acid [ No CAS ]
2-(3-chloroquinolin-6-yl)-N-(2,3-dihydroxypropyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	A mixture of (3-chloro-quinolin-6-yl)-acetic acid (2.35 g, 10.60 mmol, 1.0 eq), 3-amino-propane-l,2-diol (1.4 g, 15.90 mmol, 1.5 eq), HATU (6.0 g, 15.90 mmol, 1.5 eq) and Et3N (3.2 g, 31.8 mmol, 3.0 eq) in DMF (20 mL) was stirred at rt overnight. The mixture was concentrated and the resulting residue was washed with EA, dried in vacuo to afford 2-(3-chloro-quinolin-6-yl)-N-(2,3-dihydroxy-propyl)-acetamide (2.7 g, 86%) as a white solid.

Reference： [1]Patent: WO2018/11628,2018,A1 .Location in patent: Paragraph 00460

56
[ 616-30-8 ]
4,4'-[(6-chloro-1,3,5-triazine-2,4-diyl)bis(iminomethylene)]dibenzene sulfonamide [ No CAS ]
4,4'-[{6-[(2,3-dihydroxypropyl)amino]-1,3,5-triazine-2,4-diyl}bis(iminomethylene)]dibenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.9%		General procedure: Uncatalyzed reactions were performed according to the methodology published previously in [39].Catalyzed reactions were performed according to the general method: Appropriate disubstituteds-triazine derivative (1 mmol) was dissolved in 10 mL of DMF. Then 1 mmol (0.138 g) of solid anhydrouspotassium carbonate was added in small portions and the mixture was stirred for 10 min. Then 1 mmolof the appropriate nucleophile was added portion wise. Finally, 2.5% mol. of supported Cu(I) ions(312 mg of catalyst) was added into the reaction mixture. The reaction mixture was then stirred at100 C until the maximum conversion of starting nucleophile was achieved (monitored by TLC).After completion of the reaction, the catalyst and salt were filtered o. Crushed ice was then added intothe solution and the formed precipitate was collected by filtration. The crude product was dissolved inhot acetone and precipitated by the addition of isopropyl alcohol.
45.5%		General procedure: One equivalent (eq) of starting compound (4-16) was dissolvedin DMF as a solvent. Then 1 eq of solid anhydrous potassium carbonate was added in portions. After 10 min of stirring 1 eq of the appropriate nucleophile was added also in portions. Reaction was stirred at 100C until disappearance of starting material (monitored by TLC: CH3OH was used as eluent, detection with UV light and ninhydrin). After completion of the reaction was crushed ice added to the reaction mixture and the precipitate formed was collected by filtration. Purification of a crude product was made by the procedure mentioned in paragraph 4. 5.

Reference： [1]Molecules,2019,vol. 24
[2]Bioorganic Chemistry,2018,vol. 77,p. 25 - 37

57
[ 616-30-8 ]
methyl 4-(4-[4-(aminosulfonyl)benzyl]amino}-6-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate [ No CAS ]
methyl 4-{4-[4-(aminosulfonyl)benzyl]amino}-6-[(2,3-dihydroxy propyl)amino]-1,3,5-triazin-2-yl}piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%		General procedure: Uncatalyzed reactions were performed according to the methodology published previously in [39].Catalyzed reactions were performed according to the general method: Appropriate disubstituteds-triazine derivative (1 mmol) was dissolved in 10 mL of DMF. Then 1 mmol (0.138 g) of solid anhydrouspotassium carbonate was added in small portions and the mixture was stirred for 10 min. Then 1 mmolof the appropriate nucleophile was added portion wise. Finally, 2.5% mol. of supported Cu(I) ions(312 mg of catalyst) was added into the reaction mixture. The reaction mixture was then stirred at100 C until the maximum conversion of starting nucleophile was achieved (monitored by TLC).After completion of the reaction, the catalyst and salt were filtered o. Crushed ice was then added intothe solution and the formed precipitate was collected by filtration. The crude product was dissolved inhot acetone and precipitated by the addition of isopropyl alcohol.
20.2%		General procedure: One equivalent (eq) of starting compound (4-16) was dissolvedin DMF as a solvent. Then 1 eq of solid anhydrous potassium carbonate was added in portions. After 10 min of stirring 1 eq of the appropriate nucleophile was added also in portions. Reaction was stirred at 100C until disappearance of starting material (monitored by TLC: CH3OH was used as eluent, detection with UV light and ninhydrin). After completion of the reaction was crushed ice added to the reaction mixture and the precipitate formed was collected by filtration. Purification of a crude product was made by the procedure mentioned in paragraph 4. 5.

Reference： [1]Molecules,2019,vol. 24
[2]Bioorganic Chemistry,2018,vol. 77,p. 25 - 37

58
[ 616-30-8 ]
methyl [4-(4-[4-(aminosulfonyl)benzyl]amino}-6-chloro-1,3,5-triazin-2-yl)piperazin-1-yl]acetate [ No CAS ]
methyl (4-{4-[4-(aminosulfonyl)benzyl]amino}-6-[(2,3-dihydroxypropyl)amino]-1,3,5-triazin-2-yl}piperazin-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.9%		General procedure: Uncatalyzed reactions were performed according to the methodology published previously in [39].Catalyzed reactions were performed according to the general method: Appropriate disubstituteds-triazine derivative (1 mmol) was dissolved in 10 mL of DMF. Then 1 mmol (0.138 g) of solid anhydrouspotassium carbonate was added in small portions and the mixture was stirred for 10 min. Then 1 mmolof the appropriate nucleophile was added portion wise. Finally, 2.5% mol. of supported Cu(I) ions(312 mg of catalyst) was added into the reaction mixture. The reaction mixture was then stirred at100 C until the maximum conversion of starting nucleophile was achieved (monitored by TLC).After completion of the reaction, the catalyst and salt were filtered o. Crushed ice was then added intothe solution and the formed precipitate was collected by filtration. The crude product was dissolved inhot acetone and precipitated by the addition of isopropyl alcohol.
27.1%		General procedure: One equivalent (eq) of starting compound (4-16) was dissolvedin DMF as a solvent. Then 1 eq of solid anhydrous potassium carbonate was added in portions. After 10 min of stirring 1 eq of the appropriate nucleophile was added also in portions. Reaction was stirred at 100C until disappearance of starting material (monitored by TLC: CH3OH was used as eluent, detection with UV light and ninhydrin). After completion of the reaction was crushed ice added to the reaction mixture and the precipitate formed was collected by filtration. Purification of a crude product was made by the procedure mentioned in paragraph 4. 5.

Reference： [1]Molecules,2019,vol. 24
[2]Bioorganic Chemistry,2018,vol. 77,p. 25 - 37

59
[ 616-30-8 ]
4-[({4-chloro-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)methyl]benzenesulfonamide [ No CAS ]
4-[({4-[(2,3-dihydroxypropyl)amino]-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)methyl]benzene-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54.8%		General procedure: Uncatalyzed reactions were performed according to the methodology published previously in [39].Catalyzed reactions were performed according to the general method: Appropriate disubstituteds-triazine derivative (1 mmol) was dissolved in 10 mL of DMF. Then 1 mmol (0.138 g) of solid anhydrouspotassium carbonate was added in small portions and the mixture was stirred for 10 min. Then 1 mmolof the appropriate nucleophile was added portion wise. Finally, 2.5% mol. of supported Cu(I) ions(312 mg of catalyst) was added into the reaction mixture. The reaction mixture was then stirred at100 C until the maximum conversion of starting nucleophile was achieved (monitored by TLC).After completion of the reaction, the catalyst and salt were filtered o. Crushed ice was then added intothe solution and the formed precipitate was collected by filtration. The crude product was dissolved inhot acetone and precipitated by the addition of isopropyl alcohol.
24.6%		General procedure: One equivalent (eq) of starting compound (4-16) was dissolvedin DMF as a solvent. Then 1 eq of solid anhydrous potassium carbonate was added in portions. After 10 min of stirring 1 eq of the appropriate nucleophile was added also in portions. Reaction was stirred at 100C until disappearance of starting material (monitored by TLC: CH3OH was used as eluent, detection with UV light and ninhydrin). After completion of the reaction was crushed ice added to the reaction mixture and the precipitate formed was collected by filtration. Purification of a crude product was made by the procedure mentioned in paragraph 4. 5.

Reference： [1]Molecules,2019,vol. 24
[2]Bioorganic Chemistry,2018,vol. 77,p. 25 - 37

60
[ 616-30-8 ]
(R)-1-(3-((3'-(3-bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol [ No CAS ]
3-((3-((3'-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)amino)propane-1,2-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-ethyl-N,N-diisopropylamine; In methanol; at 60 - 70℃; for 48h;Inert atmosphere;	A mixture of 3-aminopropane-1,2-diol (61 mg, 0.670 mmol) and (R)-1-(3-((3'-(3- bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (70 muL, 0.401 mmol) was heated at 60-70 C for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-mum (0394) particles;Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; (0395) Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10- 50% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a mixture of diastereomers: (19.2 mg, 93%). LC/MS Condition E: ret time 1.09 min; m/e = 473 (M+H)+. LC/MS Condition F: ret time 1.11 min; m/e = 473 (M+H)+.

Reference： [1]Patent: WO2018/44963,2018,A1 .Location in patent: Page/Page column 84

61
[ 616-30-8 ]
3,3'-bis(3-bromopropoxy)-2,2'-dimethyl-1,1'-biphenyl [ No CAS ]
3,3'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(propane-3,1-diyl))bis(azanediyl))bis(propane-1,2-diol) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; methanol; at 65℃; for 72h;Inert atmosphere;	A mixture of 3-aminopropane-1,2-diol (84 mg, 0.922 mmol) and 3,3'-bis(3- bromopropoxy)-2,2'-dimethyl-1,1'-biphenyl (20 mg, 0.044 mmol) in methanol (0.5 mL), THF (0.5 mL) and N,N-diisopropylethylamine (30 muL, 0.172 mmol) was heated at 65 C for 72 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-mum particles;Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 2-42% B over 20 minutes, then a 5- minute hold at 100% B; Flow: 20 mL/min to give the pure title compound as a mixture of diastereoisomers: (19.4 mg, 90%). LC/MS Condition E: ret time 1.07 min; m/e = 477 (M+H)+. LC/MS Condition F: ret time 1.10 min; m/e = 477 (M+H)+.

Reference： [1]Patent: WO2018/44963,2018,A1 .Location in patent: Page/Page column 97-98

62
[ 616-30-8 ]
[ 99-96-7 ]
C₁₀H₁₃NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 12h;	Compound 8 (1.38 g, 10 mmol),1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride(EDC.HCL, 1.91 g, 10 mmol),N-hydroxysuccinimide (NHS, 1.15 g, 10 mmol),Compound 4 (0.91 g, 10 mmol) was dissolved in DMF (30 mL)The reaction was carried out for 12 hours at room temperature. The reaction solution was stopped with an aqueous solution of sodium hydrogencarbonate.The aqueous phase is extracted with methylene chloride.The organic phase was washed with saturated brine and dried over sodium sulfate.Obtained residue column chromatography to obtain compound 9(1.58 g, 75%).
75%	With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 12h;	Compound 2 (1.38 g, 10 mmol),1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (EDC.HCL, 1.91 g, 10 mmol), N-hydroxysuccinimide (NHS, 1.15 g, 10 mmol) ,Compound 1 (0.91 g, 10 mmol) was dissolved in DMF (30 mL)The reaction was carried out for 12 hours at room temperature. Evaporating the solvent of the reaction solution under reduced pressure,The resulting residue was subjected to column chromatography to give Compound 3 (1. 5 g, 75%).

Reference： [1]Patent: CN108264523,2018,A .Location in patent: Paragraph 0035; 006; 0037
[2]Patent: CN108264522,2018,A .Location in patent: Paragraph 0023; 0024; 0025

63
[ 616-30-8 ]
[ 13290-96-5 ]
methyl 3-((2,3-dihydroxypropyl)carbamoyl)-5-nitrobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	In methanol; at 20 - 65℃; for 24.5h;	71.7 g (0.3 mol) of the compound of formula (II) (R1 is -CH3) was placed in a reaction flask at room temperature, and 617 mL was added.Methanol, stirred to a white suspension, heated to 60-65 C in an oil bath, and dissolved in 32.7 g (0.36 mol, 1.2 eq) of amino glycerol100mL of methanol, then slowly added dropwise to the solution, 4.5 hours after the completion of the addition, constant temperature reaction for 20 hours, TLC test product is notSignificant changes occur again, the solution is cooled to room temperature, the pH is adjusted to 6-7 with acetic acid, 717 mL of pure water is added, and stirred for a few minutes (or stirredAdd pure water under mixing, filter, solid recovery, dry to obtain 12.3g, the filtrate was extracted with ethyl acetate (200mL × 4 times), combined withThe organic phase was washed with water (MgSO 3×3×).The product (i.e., the compound of formula (III)) 41.4 g, yield 56%, HPLC > 98%,.In this embodiment, R3NH2 is serinol, and the remaining raw materials, amounts and steps are the same as those in Example 1, and will not be described again.There is still HPLC >98%.

Reference： [1]Patent: CN108341750,2018,A .Location in patent: Paragraph 0039-0042

64
[ 616-30-8 ]
C₈₆H₁₄₉NO₃₂ [ No CAS ]
C₈₃H₁₅₃NO₃₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.6%	With hydrogenchloride; sodium hydrogencarbonate; sodium carbonate; In dichloromethane; at 20℃; for 16h;pH 9.0;	1.72 g of TPGS-pNC was weighed into a 50 mL round bottom flask.After 10mL of dichloromethane is dissolved,It was steamed under reduced pressure to form a film.Join<strong>[616-30-8]3-amino-1,2-propanediol</strong> hydrochloride solution(APD, 0.18g, 5mL 0.01mol/L HCl) hydrated for 20min, continue to add 20mL pH9.0,A buffer solution of Na2CO3-NaHCO3 at a concentration of 0.2 mmoL.After reacting for 16 h at room temperature,Put the reaction solution in a dialysis bag,Dialysis with deionized water for 48h,Change the water every 12 hours.After the end of dialysis,Freeze-dried,That is,The yield was 89.6%

Reference： [1]Patent: CN108245683,2018,A .Location in patent: Paragraph 0077; 0080

65
[ 616-30-8 ]
2-((3,5-bis(chlorocarbonyl)-2,4,6-triiodophenyl)(2-hydroxyethyl)amino)-2-oxoethyl acetate [ No CAS ]
2-((3,5-bis((2,3-dihydroxypropyl)carbamoyl)-2,4,6-triiodophenyl)(2-hydroxyethyl)amino)-2-oxoethyl acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In N,N-dimethyl acetamide; at 20℃; for 24h;Cooling;	1.32 g (2.14 eq) of isoserinol was added to 5 ml of dimethylacetamide (DMAc), 2.01 ml (2.14 eq) of triethylamine was added and the mixture was cooled. To another vessel was added 5 g (6.758 mmol) of 2 - ((3,5-bis (chlorocarbonyl) -2,4,6-triiodophenyl) (2-hydroxyethyl) amino) -2-oxoethyl acetate) And 15 ml of dimethylacetamide (DMAc) were added to the reaction solution. After reaction at room temperature for 24 hours, the resulting salt was filtered. The filtrate was concentrated under reduced pressure using a vacuum pump at 70 C and then the concentrate was crystallized from chloroform to give 5.45 g of 2 - ((3,5-bis ((2,3-dihydroxypropyl) carbamoyl) (2-hydroxyethyl) amino) -2-oxoethyl acetate (95%).

Reference： [1]Patent: KR2018/73981,2018,A .Location in patent: Paragraph 0100; 0107; 0108

66
[ 22195-47-7 ]
[ 616-30-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	With sulfuric acid; In water; at 70℃; for 3h;	A flask was charged with 539 g of a 50% aqueous solution of H2S04 and 655.5 g (2,2-dimethyl-1 ,3-dioxolan-4-yl) methanamine obtained in example 1 were added dropwise within 2 h at 70C. After complete addition, stirring was continued at 70 C for 1 h. During addition and stirring,acetone was removed continuously by distillation. Acetone removal was completed under reduced pressure and the solution was then treated at ambient temperature with 444.4 g of a 50% aqueous solution of NaOH. The precipitate was removed by filtration and the filter cake was washed with ca. 300 mL of ethanol. The combined filtrates were concentrated under reduced pressure and the residue was distilled. 406 g (89% yield) of 3-aminopropane-1 ,2-diol (APD)were collected.
89%	With sulfuric acid; In water; at 70℃; for 3h;	A flask was charged with 539 g of a 50% aqueous solution of H2S04 and 655.5 g (2,2-dimethyl- 1 ,3-dioxolan-4-yl)methanamine obtained in example 1 were added dropwise within 2 h at 70 00. After complete addition, stirring was continued at 70 00 for 1 h. During addition and stirring, acetone was removed continuously by distillation. Acetone removal was completed under reducedpressure and the solution was then treated at ambient temperature with 444.4 g of a 50% aqueous solution of NaOH. The precipitate was removed by filtration and the filter cake was washed with ca. 300 mL of Ethanol. The combined filtrates were concentrated under reduced pressure and the residue was distilled. 406 g (89% yield) of 3-aminopropane-1 ,2-diol (APD) were collected.

Reference： [1]Patent: WO2019/20466,2019,A1 .Location in patent: Page/Page column 7
[2]Patent: WO2019/20488,2019,A1 .Location in patent: Page/Page column 9; 10

67
[ 616-30-8 ]
[ 1229006-11-4 ]
[ 77-78-1 ]
[ 1206102-07-9 ]

Reference： [1]Organic Process Research and Development,2019,vol. 23,p. 565 - 570

68
[ 616-30-8 ]
[ 796871-27-7 ]
4-[2-({4-chloro-6-[(2,3-dihydroxypropyl)amino]-1,3,5-triazin-2-yl}amino)ethyl]benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.2%		General procedure: Uncatalyzed reactions were performed according to the methodology published previously in [39].Catalyzed reactions were performed according to the general method: Starting dichlorotriazinylbenzenesulfonamide (1 mmol; 0.320 g of 4-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]-benzene-1-sulfonamide,0.334 g of 4-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]methyl}-benzene-1-sulfonamide or 0.348 g of4-{2-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]ethyl}benzene-1-sulfonamide) was dissolved in 10 mL ofDMF. Then 1 mmol (0.138 g) of solid anhydrous potassium carbonate was added in small portions andthe mixture was stirred for 10 min. Then 1 mmol of the appropriate nucleophile was added portionwise. Finally, 2.5% mol of supported Cu(I) ions (312 mg of catalyst) were added into the reactionmixture. Reaction was stirred at 35 C until the maximum conversion of starting reactants was achieved(monitored by TLC). After completion of a reaction, the catalyst and salt were filtered o. Crushed icewas then added into the solution and the formed precipitate was collected by filtration. The crudeproduct was dissolved in hot acetone and precipitated by the addition of isopropyl alcohol.

Reference： [1]Molecules,2019,vol. 24
[2]Molecules,2020,vol. 25

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Code	Phrase
H400	Very toxic to aquatic life
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H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 616-30-8 ]

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