Name: 756525-91-4|2,2-Dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid|97%
Brand: Ambeed
SKU: A108006
Rating: 91 (22 reviews)

1
[ 756525-91-4 ]
[ 1012048-05-3 ]
[ 1012050-70-2 ]

Yield	Reaction Conditions	Operation in experiment
46%	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: RGD-C₂ With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 6h;	2,2-Dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid 39 (35 mg, 0.096 mmol) was dissolved in N,N'-dimethylformamide (DMF) (2 mL) and treated with N-hydroxysuccinimide (NHS) (11 mg, 0.096 mmol) and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) (18.4 mg, 0.096 mmol) at room temperature. After stirring for 1 hr, a solution of compound 1 (30 mg, 0.048 mmol) in DMF (1 mL) and N,N'-diisopropylethylamine (DIPEA) (20 μL, 0.12 mmol) were added to the reaction mixture and stirred for 6 hr. LC/MS shows all the starting material was consumed. Solvent was removed under high vacuum, and residue was dissolved in water (10 mL) and methanol (2 mL). After filtration, the desired product was isolated by semi-preparative HPLC. The collected fractions were combined and lyophilized to afford compound 40 (21 mg, 46%) as a white fluffy powder. MS (m/z) (ESI): 975.3 [M+H]+.

Reference： [1]Current Patent Assignee: SIEMENS AG - US2008/213175, 2008, A1 Location in patent: Page/Page column 64

2
[ 756525-91-4 ]
[ 74-88-4 ]
[ 1260431-01-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.416667h; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran; mineral oil at 20℃; for 4.5h;	11.5 11.5. Preparation of 3-r2-(2-{2-r2-(tert-butoxycarbonyl-methyl-amino)-ethoxy1-ethoxy}- ethoxy)-ethoxy1-propionic acidMolecular Weight =379.45Molecular Formula =C17H33N08Under magnetic stirring, at RT, under an inert atmosphere of Ar, a solution of 330 mg of commercially available 3-(2-{2-[2-(2-tert-butoxycarbonylamino-ethoxy)-ethoxy]-ethoxy}-ethoxy)- propionic acid in 4 ml of THF is cooled down to about 0°C with a water-ice-sodium chloride. 72.2 mg of NaH (70% in oil) are slowly added, and 25 min later 0.174 ml of Mel. Cooling bath is removed, and after 3 hrs at RT, 120 mg of NaH and 0.2 ml of Mel are added. After 1.5 hr at RT, a diluted aqueous solution of acetic acid is added in order to achieve a pH between 5 and 6. The crude reaction mixture is diluted with AcOEt (30 ml), washed with water (2x20 ml), with brine (10 ml), and the organic phase is dried on MgS04, filtered and evaporated under RP. 227 mg of 3-[2- (2-{2-[2-(tert-butoxycarbonyl-methyl-amino)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-propionic acid are obtained as a colourless oil. Mass spectra (A) : tR = 1.02 min ; [M+H]+ : m/z 280, 380.
	With sodium hydride In tetrahydrofuran at 0 - 20℃; for 12h;	6.9 6.9. 3-[2-(2-{2-[2-((tert-Butoxycarbonyl)(methyl)amino)ethoxy]ethoxy}ethoxy)ethoxy]-propanoic acid 85.4 mg of NaH are added portionwise to a solution, cooled to 0° C., of 520 mg of 3-[2-(2-{2-[2-((tert-butoxycarbonyl)amino)ethoxy]ethoxy}ethoxy)ethoxy]propanoic acid in 14 ml of THF. After stirring for 5 min, 150 μl of iodomethane are added. The mixture is then stirred at AT for 2 h and then an additional 150 μl of iodomethane are added. After 12 h at AT, the mixture is hydrolysed and then brought to acidic pH by addition of aqueous acetic acid at 0° C. The aqueous phase is extracted 3* with AcOEt, the combined organic phases are dried over MgSO4 and concentrated under RP, and the crude product obtained is reacted again according to the same protocol with 85 mg of NaH and 176 μl of iodomethane for an additional 2 h. 500 mg of 3-[2-(2-{2-[2-((tert-butoxycarbonyl)(methyl)amino)ethoxy]ethoxy}ethoxy)ethoxy]propanoic acid are thus obtained. LC/MS (F): rt=1.01 min; [M+H]+: m/z 380.

Reference： [1]Current Patent Assignee: SANOFI - WO2011/39721, 2011, A1 Location in patent: Page/Page column 32-33
[2]Current Patent Assignee: SANOFI - US2012/244172, 2012, A1 Location in patent: Page/Page column 45

3
[ 756525-91-4 ]
[ 1255942-06-3 ]
[ 1255942-12-1 ]

Yield	Reaction Conditions	Operation in experiment
		Aza-dibenzocyclooctyne-PEG4-amine (ADIBO-PEG4-amine, 9). EDC (0.75 g, 4.68 mmol) was added to a solution of Boc-NH-(CH2CH2O)4-CH2CH2CO2H (PCT International Application Publication No. WO 2009/053339 A2; Pessi et al.) (1.57 g, 4.32 mmol) in CH2Cl2 (15 mL) and DTRA (0.7 g, 5.4 mmol) at room temperature and stirred for 15 minutes. A solution of ADIBO-amine 7 (1 g, 3.6 mmol) in CH2Cl2 (1 mL) was added to the reaction mixture and stirred for 4 hours, at which time the solvent was removed under reduced pressure and the crude product purified by chromatography (ethyl acetate:hexanes 1:1 to 9:1) to provide 1.8 g (2.8 mmol, 80%) of crude N-Boc-protected ADIBO-PEG4-amine (9-Boc) as yellow oil.A solution of TFA (0.48 g, 4.2 mmol) in THF (15 mL) was added to a solution of 9-Boc (1.8 g, 2.8 mmol) in THF (30 mL) at room temperature. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The residue was purified by chromatography (CH2Cl2:MeOH 10:1 to 10:4) to provide 1.15 g (2.2 mmol, 79%) of ADIBO-PEG4-amine (9) as slightly yellow oil. 1H-NMR (500 MHz): 7.67 (d, J=7.5 Hz, 1H), 7.43-7.34 (m, 5H), 7.31 (t, J=7.5 Hz, 1H), 7.29-7.24 (m, 1H), 6.95-6.88 (m, 1H), 5.13 (d, J=14 Hz, 1H), 4.45-4.2 (br s, 2H), 3.7-3.5 (m, 22H), 3.37-3.2 (m, 3H), 2.68 (t, J=5 Hz, 2H), 2.57-2.42 (m, 1H), 2.4-2.32 (m, 2H), 2.02-1.92 (1H); 13C-NMR (100 MHz, CDCl3): 172.13, 171.21, 151.20, 148.16, 129.3, 129.2, 128.78, 128.44, 128.31, 127.9, 127.29, 127.25, 125.68, 123.16, 122.55, 114.81, 107.92, 70.46, 70.39, 70.35, 70.32, 70.30, 70.26, 70.1, 55.62. 48.86, 36.69, 35.41, 34.67; FIRMS (ESI+) m/z calcd for C29H38N3O6 [M+H] 524.2761. found 524.2756.

Reference： [1]Bioconjugate Chemistry,2010,vol. 21,p. 2076 - 2085
[2]Patent: US2012/29186,2012,A1 .Location in patent: Page/Page column 7

4
[ 756525-91-4 ]
[ 1351946-91-2 ]
[ 1351946-92-3 ]

Yield	Reaction Conditions	Operation in experiment
70%		14 Preparation 14 Preparation 14 tert-butyl (19-{5-[(2S)-1-methylpyrrolidin-2-yl]pyridin-3-yl}-15-oxo-3,6,9,12-tetraoxa-16-azanonadec-1-yl)carbamate The title compound was prepared by the general method described above for preparation 13, using 3-(2-{2-[2-(2-tert-Butoxycarbonylamino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-propionic acid instead of trans-4-tert-butoxycarbonyl-cyclohexane carboxylic acid, to yield a pale yellow gum (180 mg, 70%). 1H NMR (400 MHz, CDCl3) δ=1.41 (s, 9H), 1.65-1.76 (m, H), 1.78-1.86 (m, 3H), 1.88-2.01 (m, H), 2.13-2.21 (m, 4H), 2.25-2.32 (m, H), 2.44-2.47 (t, 2H), 2.61-2.65 (t, 2H), 3.03-3.07 (t, H), 3.19-3.29 (m, 6H), 3.49-3.52 (t, 2H), 3.57-3.62 (m, 11H), 3.70-3.73 (t, 2H), 5.21 (brm, H), 6.66 (brm, H), 7.51 (t, H), 8.30-8.31 (d, H),] 8.33 (d, H). MS, m/z=445 ES+ [M+H]+, 445 Cl [M+H]+

Reference： [1]Current Patent Assignee: PFIZER INC - US2011/300174, 2011, A1

5
[ 756525-91-4 ]
[ 1351947-13-1 ]
[ 1351947-23-3 ]

Yield	Reaction Conditions	Operation in experiment
56%		45 Preparation 45 Preparation 45 tert-butyl [18-({5-[(2S)-1-methylpyrrolidin-2-yl]pyridin-3-yl}oxy)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadec-1-yl]carbamate The title compound was prepared by the general method described above for preparation 35, using 3-(2-{2-[2-(2-tert-Butoxycarbonylamino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-propionic acid instead of trans-4-tert-butoxycarbonyl-cyclohexane carboxylic acid, to yield an orange gum (80 mg, 56%). 1H NMR (400 MHz, CDCl3) δ=1.42 (s, 9H), 2.03-2.20 (m, 3H), 2.38-2.50 (m, 6H), 2.85-2.91 (m, 1H), 3.19-3.22 (m, 2H), 3.47-3.50 (t, 2H), 3.53-3.63 (m, 15H), 3.71-3.74 (t, 2H), 3.84-3.92 (m, 1H), 4.17-4.19 (t, 2H), 7.58-7.59 (m, 1H), 8.20-8.21 (d, 1H), 8.28 (d, 1H). MS m/z=570 ES+ [M+H]+, 570 Cl [M+H]+

Reference： [1]Current Patent Assignee: PFIZER INC - US2011/300174, 2011, A1

6
[ 173998-77-1 ]
[ 756525-91-4 ]
[ 1334181-91-7 ]

Reference： [1]ChemMedChem,2011,vol. 6,p. 1727 - 1738
[2]ChemMedChem,2013,vol. 8,p. 587 - 593

7
[ 7724-12-1 ]
[ 756525-91-4 ]
[ 1439931-86-8 ]

Yield	Reaction Conditions	Operation in experiment
1.4 g		Example 33. Bis(piperidineazepino)-6-((2-(2-(2-(2-(6-carboxyamido-2- cyanobenzothiazolyl)ethoxy)ethoxy)ethoxy)ethyl)carbamoyl)rhodamine (PBI 5122) [00194] To a solution of t-boc-N-amido-dPEG®4-acid (Quanta BioDesign, lg) and N- methylmorpholine (0.3 mL) in THF (25 mL), isobutyl chloroformate (0.36 mL) was added. After stirring for 30min, <strong>[7724-12-1]6-amino-2-cyanobenzothiazole</strong> (White et. al., J. Am. Chem. Soc. 88, 2015 (1966), 0.48g) was added, and the reaction stirred overnight. The reaction was then filtered, and the eluent concentrated. The crude reaction purified over silica gel (gradient of MeOH in CH2C12) to provide a clear oil (1.4 g).

Reference： [1]Patent: WO2013/78244,2013,A1 .Location in patent: Paragraph 00193-00194

8
[ 756525-91-4 ]
[ 1520890-12-3 ]
[ 1520890-16-7 ]

Yield	Reaction Conditions	Operation in experiment
52%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 20℃; for 18h; Inert atmosphere;	26 rac-(2-{2-[2-(2-{3-Oxo-3-[4-(9-oxo-l ,4, 9,10-tetrahydro-2H-3-oxa-10-aza-phenanthren- 2-yl)-piperidin-l-yl]-propoxy} -ethoxy)-ethoxy]-ethoxy} -ethyl) -carbamic acid tert-butyl ester A mixture of HBTU (74.3 mg, 0.196 mmol), Hunig's base (0.132 ml, 0.753 mmol), 2- piperidin-4-yl-l ,2,4,10-tetrahydro-3-oxa-10-aza-phenanthren-9-one trifluoroacetate (60 mg, 0.151 mmol), 3-(2-{2-[2-(2-tert-butoxycarbonylamino-ethoxy)-ethoxy]-ethoxy}-ethoxy)- propionic acid (71.5 mg, 0.196 mmol,) in NMP (1.8 mL) was stirred at room temperature for 18 h. The resulting mixture was diluted with ethyl acetate, poured into 0.1 M sodium hydroxide, and extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, washed with H20 (2 x 50 mL), dried over MgS04, and concentrated in vacuo to afford (2-{2-[2-(2-{3-Oxo-3- [4-(9-oxo-l ,4, 9,10-tetrahydro-2H-3-oxa-10-aza-phenanthren-2-yl)-piperidin-l-yl]-propoxy}- ethoxy)-ethoxy]-ethoxy} -ethyl) -carbamic acid tert-butyl ester as an off-white solid (50 mg, 52%). 'H NMR (DMSO-de) δ: 11.24 (s, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.60 - 7.78 (m, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 6.74 (t, J = 4.7 Hz, 1H), 4.90 (d, J = 14.4 Hz, 1H), 4.59 (d, J = 14.7 Hz, 1H), 4.43 (br. d, J = 12.8 Hz, 1H), 3.93 (br. d, J = 14.0 Hz, 1H), 3.61 (t, J = 6.8 Hz, 2H), 3.33 - 3.38 (m, 2H), 3.03 (q, J = 6.0 Hz, 2H), 2.85 - 2.99 (m, 1H), 2.56 (td, J = 6.8, 2.3 Hz, 2H), 1.92 (br. t, J = 12.8 Hz, 1H), 1.65 - 1.82 (m, 1H), 1.50 - 1.65 (m, 1H), 1.35 (s, 9H), 1.00 - 1.15 (m, 1H). MS calcd. for C33H49N3O9 [(M-H) ] 630.8, obsd. 630.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2013/189904, 2013, A1 Location in patent: Page/Page column 58; 59

9
[ 756525-91-4 ]
[ 1263045-16-4 ]

Reference： [1]Patent: WO2014/100762,2014,A1

10
[ 756525-91-4 ]
[ 76-05-1 ]
[ 1615234-93-9 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane at 20℃;	The BOC protective group in commercially available t-blc-N-amido-dPEG4-acid was removed by treatment with TFA to give the TFA salt of the amine, which was reacted with previously synthesized NHS ester.
	In dichloromethane at 20℃;	1 Example 1: Materials and Methods for Examples 2-6 [0277] Referring to the scheme of synthesis of Compound O, β-alanine was treated with maleic anhydride in DMF and the acid so obtained was reacted with N-hydroxysuccinimide (NHS) under DCC coupling to give NHS-ester. The BOC protective group in commercially available t-boc-N-amido-dPEG4-acid was removed by treatment with TFA to give the TFA salt of the amine, which was reacted with previously synthesized NHS ester. The carboxylic acid so obtained was isolated and was coupled with N-hydroxysuccinimide using EDCI to furnish NHS ester Compound O.

Reference： [1]Current Patent Assignee: ALTRUBIO INC - WO2014/100762, 2014, A1 Location in patent: Paragraph 240; 248
[2]Current Patent Assignee: ALTRUBIO INC - WO2015/196167, 2015, A1 Location in patent: Paragraph 0269; 0277

11
[ 756525-91-4 ]
[ 97682-37-6 ]
(S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-[3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoyl]piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In dichloromethane at 20℃; for 24h;	2.4 To a stirred solution of (S)-4, 1 1 -diethyl-4-hydroxy-3, 14-dioxo-3,4, 12, 14-tetra- hydro-1 H-pyrano[3',4':6,7]indolizino[1 ,2-b]quinolin-9-yl piperazine-1 -carboxylate of Formula 7 (60 mg, 0.12 mmol)Formula 7 in dry methylene chloride (6 ml) 15-Boc-amino)-4,7, 10, 13-tetraoxapentadecanoic acid (43 mg, 0.12 mmol), (benzotriazol-1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (57 mg, 0.13 mmol) and triethylamine (0.035 ml, 0.26) are added. The mixture is stirred at room temperature for 24 hours, then the solvent is evaporated, and the residue is purified on a silica gel column eluting with ethyl acetate - methanol 5: 1 , to obtain (S)-4, 1 1 -diethyl-4-hydroxy-3, 14- dioxo-3,4, 12, 14-tetrahydro-1 H-pyrano[3',4':6,7]indolizino[1 ,2-b]quinolin-9-yl 4-[3-[2- [2- [2- [2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]- propanoyl] piperazine-1 -carboxylate [or 4-(2,2-dimethyl-4-oxo-3,8, 1 1 , 14, 17- pentaoxa-5-azaicosan-20-oyl)piperazine-1 -carboxylate] (Formula 8), yield 99 mg (99%).

Reference： [1]Current Patent Assignee: ADAMED SP. Z.O.O. - WO2014/141094, 2014, A1 Location in patent: Page/Page column 60

12
[ 756525-91-4 ]
4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl (S)-4-(aminomethyl)cyclohexanecarboxylate [ No CAS ]
(S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(21,21-dimethyl-3,19-dioxo-6,9,12,15,20-pentaoxa-2,18-diazadocosyl)cyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In dichloromethane at 20℃; for 24h;	2.3 To the solution of 4, 1 1 -diethyl-4-hydroxy-3, 14-dioxo-3,4, 12, 14-tetrahydro-1 H- pyrano[3',4':6,7]indolizino[1 ,2-b]quinolin-9-yl (1 R,4S)-(S)-4-(aminomethyl)- cyclohexanecarboxylate (170 mg, 0.33 mmol) in dry methylene chloride, 15-(Boc- amino)-4,7, 10, 13-tetraoxapentadecanoic acid (120 mg, 0.33 mmol), (benzo- triazol-1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (150 mg, 0.34 mmol) and triethylamine (0.09 ml) are added. The mixture is stirred at room temperature for 24 hours, then the solvent is evaporated, and the residue is purified on a silica gel column eluting with ethyl acetate - methanol 5 : 1 , to obtain (S)-4, 1 1 -diethyl-4-hydroxy-3, 14-dioxo-3,4, 12, 14-tetrahydro-1 H-pyrano- [3',4':6,7]indolizino[1 ,2-b]quinolin-9-yl (1 R,4S)-4-(21 ,21 -dimethyl-3, 19-dioxo- 6,9, 12, 15,20-pentaoxa-2, 18-diazadocosyl)cyclohexanecarboxylate (Formula 4), yield 280 mg (96%)

Reference： [1]Current Patent Assignee: ADAMED SP. Z.O.O. - WO2014/141094, 2014, A1 Location in patent: Page/Page column 58; 59

13
[ 756525-91-4 ]
[ 2450-71-7 ]
tert-butyl(15-oxo-3,6,9,12-tetraoxa-16-azanonadeca-18-yne-1-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 3h;	Synthesis of Intermediate: tert-butyl(15-oxo-3,6,9,12-tetraoxa-16- azanonadeca-18-in-1-yl)carbamate (I3) EDCI (263 mg, 1.37mmol, the equivalent of 1, dichlomethane (10 ml) of propagyl amine (88μL, 1.37mmol, 1 equiv.) and T-boc-N-amidophenol-dPEG (registered trademark) 4-acid (365.42mmol, 1.37mmol, 1 equivalent) is added to the solution. A reaction material 3 time after stirring at room temperature, is confirmed by TLC complete conversion. The reaction mixture is diluted with dichlomethane, washed with water and salt water. In dehydrated organic layer is magnesium sulfate, filtering, and removed by a rotary evaporator under reduced pressure, excessive dichlomethane. The residual flash column chromatography on obtd. (silica gel; gradient, from 10% methanol in dichlomethane 0%). According to collect pure fraction, a rotary evaporator under reduced pressure, excessive eluent by removing, product I3 (490 mg, 89%) is obtained.
72%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	(a) Amide coupling EDCI (5.25 g, 27.4 mmol, 1 eq) was added to a solution of propargylamine 1 (1.75 mL1.51 g, 27.4 mmol, 1 eq), and Boc-amino-PEG4-acid 2 (10 g, 27.4 mmol, 1 eq) in DCM (200 mL). The reaction proceeded rapidly and was complete after 2 hours at room temperature (TLC, DCM/MeOH, 90/10, ninhydrin/heat). The solution was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over magnesium sulphate and the DCM was removed by rotoevaporation under vacuum. The residue was purified by manual flash chromatography (gradient 2% methanol to 3% methanol in DCM) to give 4 as a clear oil (yield 7.95g, 72%).
71%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; Inert atmosphere;	6.a.i (i) tert-Butyl (15-oxo-3,6,9,12-tetraoxa-16-azanonadec-18-yn-1-yl)carbamate (27) (i) tert-Butyl (15-oxo-3,6,9,12-tetraoxa-16-azanonadec-18-yn-1-yl)carbamate (27) EDCI (263 mg, 1.37 mmol) was added to a stirred solution of t-boc-N-amido-dPEG4-acid (26) (500 mg, 1.37 mmol, Stratech Scientific Limited) and propargylamine (88 μL, 76 mg, 1.37 mmol) in dry DCM (10 mL) at room temperature. The reaction mixture was stirred under an argon atmosphere for 16 hours at which point analysis by LC/MS showed a substantial amount of desired product at retention time 1.26 minutes (ES+) m/z 403 ([M+H]+, ˜50% relative intensity), 425 ([M+Na]+, ˜100% relative intensity), note that both starting material and product had weak UV absorption (214 and 254 nm) and were best detected on ES+TIC. The reaction mixture was diluted with DCM (100 mL) and washed with H2O (30 mL), brine (40 mL), dried (MgSO4), filtered and evaporated in vacuo to provide the crude product. Purification by flash chromatography (gradient elution in 1% increments: 100% DCM to 98:2 v/v DCM/MeOH) gave the amide 27 as an oil (392 mg, 71% yield).

71%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; Inert atmosphere;	2.B EDCI (263 mg, 1.37 mmol) was added to a stirred solution of i-boc-N-amido-dPEG4-acid (26) (500 mg, 1.37 mmol, Stratech Scientific Limited) and propargylamine (88 μ, 76 mg, 1.37 mmol) in dry DCM (10 mL) at room temperature. The reaction mixture was stirred under an argon atmosphere for 16 hours at which point analysis by LC/MS showed a substantial amount of desired product at retention time 1.26 minutes (ES+) mlz 403 ([ + Η]+ , -50% relative intensity), 425 ([ + Na]+ -100% relative intensity), note that both starting material and product had weak UV absorption (214 and 254 nm) and were best detected on ES+ TIC. The reaction mixture was diluted with DCM (100 mL) and washed with H20 (30 mL), brine (40 mL), dried (MgS04), filtered and evaporated in vacuo to provide the crude product. Purification by flash chromatography (gradient elution in 1% increments: 100% DCM to 98:2 v/v DCM/MeOH) gave the amide 27 as an oil (392 mg, 71% yield).
71%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; Inert atmosphere;

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - JP2016/510806, 2016, A Location in patent: Paragraph 0385
[2]Tiberghien, Arnaud C.; Gregson, Stephen J.; Masterson, Luke A.; Levy, Jean-Noel; Kemp, Gary C.; Adams, Lauren R.; Patel, Neki V.; Howard, Philip W. [Tetrahedron Letters, 2017, vol. 58, # 46, p. 4363 - 4366]
[3]Current Patent Assignee: ASTRAZENECA PLC; ROCHE HOLDING AG - US2014/294868, 2014, A1 Location in patent: Paragraph 0643; 0644
[4]Current Patent Assignee: ROCHE HOLDING AG - WO2016/44396, 2016, A1 Location in patent: Paragraph 00383; 00384
[5]Gregson, Stephen J.; Masterson, Luke A.; Wei, Binqing; Pillow, Thomas H.; Spencer, Susan D.; Kang, Gyoung-Dong; Yu, Shang-Fan; Raab, Helga; Lau, Jeffrey; Li, Guangmin; Lewis Phillips, Gail D.; Gunzner-Toste, Janet; Safina, Brian S.; Ohri, Rachana; Darwish, Martine; Kozak, Katherine R.; Dela Cruz-Chuh, Josefa; Polson, Andrew; Flygare, John A.; Howard, Philip W. [Journal of Medicinal Chemistry, 2017, vol. 60, # 23, p. 9490 - 9507]

14
[ 756525-91-4 ]
(E)-4-(4-(2-aminoethyl)piperazin-1-yl)-1-(4-(4-(4-phenoxyphenoxy)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)piperidin-1-yl)but-2-en-1-one [ No CAS ]
tert-butyl (E)-(15-oxo-18-(4-(4-oxo-4-(4-(4-(4-phenoxyphenoxy)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)piperidin-1-yl)but-2-en-1-yl)piperazin-1-yl)-3,6,9,12-tetraoxa-16-azaoctadecyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33.4%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane; ethyl acetate at 20℃; for 6h;	77 tert-butyl (E)-(15-oxo-18-(4-(4-oxo-4-(4-(4-(4-phenoxyphenoxy)-5H-pyrrolor3,2- d1pyrimidin-5-yl)piperidin-l-yl)but-2-en-l-yl)piperazin-l-yl)-3,6,9,12-tetraoxa-16- azaoctadecvDcarbamate To a stirred solution of (E)-4-[4-(2-Amino-ethyl)-piperazin- l-yl]-l-{4-[4-(4-phenoxy-phenoxy)- pyrrolo[3,2-d]pyrimidin-5-yl]-piperidin- l-yl}-but-2-en- l-one (1.00 g; 1.29 mmol; 1.00 eq.) in dry DCM (13.30 g; 10.00 ml; 10.00 V) was added 3-(2-{2-[2-(2-tert-Butoxycarbonylamino- ethoxy)-ethoxy]-ethoxy}-ethoxy)-propionic acid (0.58 g; 1.55 mmol; 1.20 eq.) followed by Triethyl amine (0.40 g; 0.55 ml; 3.87 mmol; 3.00 eq.) at RT. The reaction mixture was cooled to 0-5°C and T3P was added (50% in Ethyl acetate) (1.23 g; 1.22 ml; 1.93 mmol; 1.50 eq.). The reaction mixture was stirred at RT for 6h. The reaction was monitored by TLC. The reaction mixture was diluted with 10% NaHC03 solution and extracted with DCM. The organic layer was washed with water (25mL), brine (25 mL) and dried over anhydrous sodium sulphate. The crude product was purfied by column chromatography (60-120 silica) using chloroform and methanol as eluent (2-5%) to afford [2-(2-{2-[2-(2-{2-[4-((E)-4-Oxo-4-{4-[4-(4-phenoxy-phenoxy)- pyrrolo[3,2-d]pyrimidin-5-yl] -piperidin- 1 -yl } -but-2-enyl)-piperazin- 1 -yl] -ethylcarbamoyl } - ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethyl]-carbamic acid tert-butyl ester (0.43 g; 0.43 mmol; 33.4 %; colorless gum). MS: m/z = 930[M+H]+. IH NMR (400 MHz, DMSO-d6):8.31 (s, IH), 8.02 (d, J = 4.00 Hz, IH), 7.74 (t, J = 4.00 Hz, IH), 7.39-7.35 (m, 2H), 7.34-7.33 (m, 2H), 7.17-7.10 (m, IH), 7.10-7.04 (m, 4H), 6.75-6.70 (m, IH), 6.66-6.55 (m, 3H), 5.04-5.00 (m, IH), 4.55-4.53 (m, IH), 4.30-4.20 (m, IH), 3.58-3.50 (m, 2H), 3.48-3.47 (m, 12H), 3.46-3.37 (m, 2H), 3.35-3.32 (m, IH), 3.32-3.30 (m, 2H), 3.15-3.12 (m, 4H), 2.55-2.50 (m, IH), 2.49-2.48 (m, 10H), 2.28-2.20 (m, 2H), 1.98- 1.90 (m, 2H), 1.35 (s, 9H).

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2015/17502, 2015, A1 Location in patent: Paragraph 00323

15
[ 756525-91-4 ]
rac-tyrosine benzyl ester p-toluenesulfonate [ No CAS ]
t-boc-NH-dPEG4-CO-Tyr-OBn [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 5 - 20℃;	A 250mL 4-neck round bottom flask was charged with magnetic stir bar, thermo probe, boc-dPEG4-acid (34.3g, 94 mmol) dissolved in anhydrous CH2CI2 (250ml_), HOBT (2.61 g, 17.1 mmol), diisopropyethyl amine (DIEA, 13.23g, 102 mmol), and benzyl ester of tyrosine tosylate salt (37.8g, 85.0 mmol). The suspension was cooled to 5°C in an ice/water bath. Solid coupling reagent (EDC, 24.54g, 128 mmol) was added to this suspension portion wise. The ice/water bath was removed and the reaction was allowed to warm to room temperature overnight. The reaction was monitored by TLC (in CH2Cl2/MeOH=9/1 ) and after it was complete it was washed with water (4x30ml_). The organic layer was dried over magnesium sulfate and filtered over a bed of celite (1 Og). The CH2CI2 was removed under reduced pressure to give 52g (98%) of product as viscous oil. 1H NMR (400 MHz, CDCI3, δ): 7.29 (m, 5H, benzyl), 6.94 (s, 1 H, NH), 6.78 (d, 2H, tyrosine), 6.68 (d, 2H, tyrosine), 5.23 (s, 1 H, CH2OCO), 5.20 (s, 1 H, NH), 5.07 (m, 2H, OCH2CO), 4.85 (m, 1 H, CHN), 3.58 (m, 16H, CH20), 2.98 (d, 2H, CH2N), 2.42 (m, 2H, CH2), 2.48 (m, 2H, CH2CO), 1.36 (s, 9H, CH3)

Reference： [1]Current Patent Assignee: EQIP; EQUIP - WO2015/23979, 2015, A1 Location in patent: Page/Page column 76-77

16
[ 756525-91-4 ]
[ 1222999-46-3 ]
tert-butyl (15-oxo-15-(4-(4-(2-oxo-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3,6,9,12-tetraoxapentadecyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42.2 mg	With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 6h;	7 tert-Butyl (15-oxo-15-(4-(4-(2-oxo-9-(quinolin-3-yl)benzo[h][l,6]naphthyridin- 1 (2H)-yl)-2- (trifluoromethyl)phenyl)piperazin- 1 -yl)-3 ,6,9, 12-tetraoxapentadecyl)carbamate (15b) To a solution of fert-butyl 4-(4-((6-bromo-3-formylquinolin-4-yl)amino)-2- (trifluoromethyl)phenyl)piperazine-l-carboxylate (14b, 50.6 mg, 0.078 mmol) in 3 mL of dichloroethane was added 1 mL of TFA. The mixture was stirred at room temperature for 2 h. The solvent was removed under vacuum and the residue was dissolved in 5 mL of DMF. To this solution was added triethylamine (19.3 mg, 0.191 mmol), 2,2-dimethyl-4-oxo- 3,8,1 1,14,17- pentaoxa-5-azaicosan-20-oic acid (29.8 mg, 0.082 mmol), and HATU (35.4 mg, 0.093 mmol). The resulted mixture was stirred at room temperature for 6 h. The crude mixture was purified by column chromatography through CI 8 column using 5-100% ACN (containing 0.1% TFA)/water (containing 0.1% TFA) as eluent. The combined pure fractions were neutralized using 1 N NaOH solution, extracted with ethyl acetate (3x50 mL). The organic layer was dried over MgS04, filtered, and concentrated to give 15a (42.2 mg, 60%). 1H NMR (400 MHz, DMSO-c) δ 9.21 (s, 1H), 8.59 (d, J = 2.3 Hz, 1H), 8.36 (d, J = 9.5 Hz, 1H), 8.28 (dd, J = 2.3, 0.8 Hz, 1H), 8.25-8.13 (m, 2H), 8.10-7.96 (m, 3H), 7.63-7.90 (m, 4H), 7.13 (d, J = 1.7 Hz, 1H), 6.97 (d, J = 9.4 Hz, 1H), 6.73 (t, J = 5.5 Hz, 1H), 3.71-3.43 (m, 19H), 3.35 (t, J = 6.0 Hz, 1H), 3.04 (q, J = 6.0 Hz, 2H), 2.67-2.74 (m, 3H), 2.51 -2.62 (m, 3H), 1.36 (s, 9H); LC/MS: (electrospray +ve), mlz 899.3 (MH)+, tR = 5.43 min, UV254 >95%.

Reference： [1]Current Patent Assignee: LOYOLA UNIVERSITY CHICAGO; GOVERNMENT OF THE UNITED STATES - WO2015/73804, 2015, A2 Location in patent: Paragraph 0275

17
[ 756525-91-4 ]
[ 1222999-58-7 ]
tert-butyl (15-(4-(4-(9-(6-aminopyridin-3-yl)-2-oxobenzo[h][1,6]naphthyridin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46.1 mg	With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 6h;	7 tert-Butyl (15-(4-(4-(9-(6-aminopyridin-3-yl)-2-oxobenzo[h][l,6]naphthyridin- 1 (2H)-yl)-2- (trifluoromethyl)phenyl)piperazin- 1 -yl)- 15-oxo-3 ,6,9,12- tetraoxapentadecyl)carbamate (15a) To a solution of tert-butyl 4-(4-(9-(6-aminopyridin-3-yl)-2- oxobenzo[h] [ 1 ,6]naphthyridin- 1 (2H)- yl)-2-(trifluoromethyl)phenyl)piperazine- 1 -carboxylate (14a, 57.2 mg, 0.093 mmol) in 3 mL of dichloroethane was added 1 mL of TFA. The mixture was stirred at room temperature for 2 h. The solvent was removed under vacuum and the residue was dissolved in 5 mL of DMF. To this solution was added triethylamine (40 mg, 0.40 mmol), 2,2-dimethyl-4-oxo-3, 8,1 1 ,14,17- pentaoxa-5-azaicosan-20-oic acid (35.6 mg, 0.097 mmol), and HATU (51.7 mg, 0.1 1 1 mmol). The resulted mixture was stirred at room temperature for 6 h. The crude mixture was purified by column chromatography through C18 column using 5-100% ACN (containing 0.1% TFA)/water (containing 0.1% TFA) as eluent. The combined pure fractions were neutralized using 1 N NaOH solution, extracted with ethyl acetate (3x50 mL). The organic layer was dried over MgSC-4, filtered, and concentrated to give 15a (46.1 mg, 58%). 1H NMR (400 MHz, DMSO- d6) δ 9.09 (s, 1H), 8.30 (d, J= 9.4 Hz, 1H), 8.05 (d, J= 8.7 Hz, 1H), 7.99-7.87 (m, 2H), 7.79-7.69 (m, 3H), 7.14 (dd, J= 8.6, 2.6 Hz, 1H), 6.98-6.88 (m, 2H), 6.74 (t, J= 5.9 Hz, 1H), 6.42 (dd, J= 8.6, 0.8 Hz, 1H), 6.19 (s, 2H), 3.61 -3.70 (m, 5H), 3.45-3.55 (m, 10H), 3.23- 3.38 (m, 5H), 2.87-3.07 (m, 5H), 2.63-2.70 (m, 3H), 1.36 (s, 9H); LC/MS: (electrospray +ve), mlz 864.3 (MH)+, tR = 4.40 min, UV254 = 100%.

Reference： [1]Current Patent Assignee: LOYOLA UNIVERSITY CHICAGO; GOVERNMENT OF THE UNITED STATES - WO2015/73804, 2015, A2 Location in patent: Paragraph 0272-0273

18
[ 756525-91-4 ]
(2S,3S,4R)-3,4-bis-tert-butyldimethylsilyloxy-2-hexacosanoylamino-1-(2,3,4-tri-O-benzyl-6-hydroxy-α-D-galactopyranosyl)octadecane [ No CAS ]
(2S,3S,4R)-3,4-bis-tert-butyldimethylsilyloxy-2-hexacosanoylamino-1-(2,3,4-tri-O-benzyl-6-carbonyl-1-ethyl-2-(tri-1-ethanoyl)1-ethanoyl-2-(tert-butoxy-carbonyl)amino)-α-D-galactopyranosyloctadecane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: (2S,3S,4R)-3,4-bis-tert-butyldimethylsilyloxy-2-hexacosanoylamino-1-(2,3,4-tri-O-benzyl-6-hydroxy-α-D-galactopyranosyl)octadecane In N,N-dimethyl-formamide for 5h;	(25,35,4R)-3,4-His-tert-butyldimethylsilyloxy-2-hexacosanoylamino- 1 -(2,3,4-tri-O-benzyl-6-(carbo- nyl-1 -ethyl-2-(tri(1 -ethanoyl)1 -ethanoyl-2-(tert-bu-toxy-carbonyl)amino)-a-D-galactopyranosyl)octadecane (37) 10266] To a solution of 38 (18 mg, 0.05 mmol) in DMF (5 mE) was added O-(Henzotriazol- 1 -yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate TETU (16.1 mg, 0.05) and diisopropylethylamine (12.9 mg, 17 pi, 0.1 mmol). The mixture was stirred for 30 mm at tt. Then a mixture of36 (50 mg, 0.04 mmol) in DMF (1 ml) was added to the reaction mixture and stirred for 5 hours. Subsequently, the reaction mixture was diluted with CH2C12 (15 mE) and the resulting mixture was washed with 5% HC1 (2x3 mE), 1M NaHCO3 (3x3 mE) and water (2x3 mE). The organic layer was collected, dried (MgSO4), filtered and concentrated to give the crude ester product which was purified by flash column chromatography on silica gel (gradient hexanes/EtOAc=8: 1 - 1:1) to yield the linker-equipped glycolipid 37(40mg, 63%) as a colorless oil. HR ESI Calcd for C99H174N2O16Si2 [M+H]: 1705.6272. found: 1705.6231.

Reference： [1]Current Patent Assignee: UNIVERSITY OF BASEL; MAX-PLANCK-GESELLSCHAFT ZUR FÖRDERUNG DER WISSENSCHAFT E.V.; UNIVERSITY HOSPITAL BASEL - US2015/238597, 2015, A1 Location in patent: Paragraph 0266

19
[ 756525-91-4 ]
N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-{1-[(4-methylpiperidin-4-yl)methyl]-1H-pyrazol-4-yl}thiophene-2-carboxamide [ No CAS ]
5-(1-[1-(15-amino-4,7,10,13-tetraoxapentadecan-1-oyl)-4-methylpiperidin-4-yl]methyl}-1H-pyrazol-4-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiophene-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid; N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-{1-[(4-methylpiperidin-4-yl)methyl]-1H-pyrazol-4-yl}thiophene-2-carboxamide With 4-methyl-morpholine; HATU at 20℃; for 3h; Stage #2: With hydrogenchloride In 1,4-dioxane	1165 Example 1165 5-(1-[1-(15-amino-4,7,10,13-tetraoxapentadecan-1-oyl)-4-methylpiperidin-4-yl]methyl}-1H-pyrazol-4-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiophene-2-carboxamide Example 1165 5-(1-[1-(15-amino-4,7,10,13-tetraoxapentadecan-1-oyl)-4-methylpiperidin-4-yl]methyl}-1H-pyrazol-4-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiophene-2-carboxamide (5914) A suspension of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-{1-[(4-methylpiperidin-4-yl)methyl]-1H-pyrazol-4-yl}thiophene-2-carboxamide (0.139 g, 0.274 mmol), 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid (0.100 g, 0.274 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.104 g, 0.274 mmol) and 4-methylmorpholine (0.105 ml, 0.958 mmol) was stirred at room temperature for 3 hours. The reaction mixture was purified directly by normal phase chromatography and the resulting material was treated with HCl/dioxane (4 M) then concentrated to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 14.71 (s, 1H), 9.58 (t, J=6.0 Hz, 1H), 8.89 (d, J=7.0 Hz, 1H), 8.35 (d, J=1.9 Hz, 1H), 8.16 (d, J=2.1 Hz, 2H), 8.06 (s, 3H), 7.92 (d, J=3.9 Hz, 1H), 7.83 (s, 2H), 7.50 (dd, J=7.0, 1.2 Hz, 1H), 7.26 (d, J=3.8 Hz, 1H), 4.64 (d, J=5.8 Hz, 2H), 4.05 (s, 2H), 3.80 (dd, J=11.8, 6.8 Hz, 2H), 3.66-3.58 (m, 4H), 3.55 (dd, J=9.2, 4.4 Hz, 4H), 3.50 (t, J=7.5 Hz, 8H), 3.37-3.26 (m, 1H), 3.23-3.13 (m, 1H), 2.99-2.90 (m, 2H), 2.55 (t, J=6.6 Hz, 2H), 1.53-1.19 (m, 4H), 0.95 (s, 3H); MS (ESI(+)) m/e 682 (M+H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC; POTISEK STEPHANIE L - US9187472, 2015, B2 Location in patent: Page/Page column 643-644

20
[ 756525-91-4 ]
(2S)-4-[[(2R,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]amino]-2-(tertbutoxycarbonylamino)-4-oxobutanoic acid [ No CAS ]
3-[2-[2-[2-[2-[[(2S)-4-[[(2R,3R,4R,5S,6R)]-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]amino-2-(tert-butoxycarbonylamino)-4-oxobutanoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid With hydrogenchloride In 1,4-dioxane at 20℃; for 1h; Stage #2: (2S)-4-[[(2R,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]amino]-2-(tertbutoxycarbonylamino)-4-oxobutanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In 1,4-dioxane; N,N-dimethyl-formamide at 20℃; for 0.51h;	1.1-5 (1-5A) Synthesis of 3-[2-[2-[2-[2-[[(2S)-4-[[(2R,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]amino-2-(tert-butoxycarbonylamino)-4-oxobutanoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (compound 1-5A: compound of the following formula) (1-5A) Synthesis of 3-[2-[2-[2-[2-[[(2S)-4-[[(2R,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]amino-2-(tert-butoxycarbonylamino)-4-oxobutanoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (compound 1-5A: compound of the following formula) (0155) (0156) 3-[2-[2-[2-[2-(tert-Butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (200 mg, 0.547 mmol) was dissolved in a solution of 4 N hydrochloric acid in dioxane (2 mL), and the solution was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dried in a vacuum pump to obtain a crude product of the intermediate as a light brown oil (165 mg). (0157) (2S)-4-[[(2R,3R,4R,5S,6R)-3-Acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]amino]-2-(tert-butoxycarbonylamino)-4-oxobutanoic acid (158 mg, 0.364 mmol) produced according to the approach of J. Am. Chem. Soc., 1999, 121, 284-290 and HATU (138 mg, 0.364 mmol) were dissolved in N,N-dimethylformamide (3 mL). To the solution, N,N-diisopropylethylamine (128 µL, 0.728 mmol) was added, and the mixture was stirred at room temperature for 1 minute. This solution was added to the obtained crude product (54.9 mg) of the intermediate, further N,N-diisopropylethylamine (128 µL, 0.728 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was diluted with water, and the resulting product was separated and purified by reverse-phase HPLC (GL Sciences Inc., Inertsil ODS-3) using a 0.1% aqueous trifluoroacetic acid solution and a 0.1% solution of trifluoroacetic acid in acetonitrile as eluents to obtain the title compound 1-5A as a white solid (53 mg, yield through 2 steps: 43%). ESI-LC-MS: Calcd for C28H50N4O15: [M+H]+ 683, Found 683.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2949665, 2015, A1 Location in patent: Paragraph 0155; 0156; 0157

21
[ 6066-82-6 ]
[ 756525-91-4 ]
2,5-dioxopyrrolidin-1-yl 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 18h;
	With dicyclohexyl-carbodiimide In dichloromethane
	With dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 2h;	1.1 1 .1 . Biotin-Peg-NH-Boc S2168 (other batch S2166) The commercial product, 15-(t-Butyloxycarbonyl) amino-4,7,10,13-teraoxa-pentadecanoic acid (Boc-NHPeg4-OH; 358 mg, 0.98 mmol) was dissolved in 6.5 ml of CH2CI2 and cooled to 0°C in an ice-water bath. N-hydroxy succinimide (NHS; 147 mg, 1 .27 mmol) and Dicyclohexylcarbodiimide (DCC; 262 mg, 1 .3 mmol) were added to the reaction mixture and stirred at 0°C for 10 min. and then 2 h at room temperature, monitoring the disappearance of the acid by TLC analysis. The reaction mixture was diluted with 10 ml of CH2CI2, then cooled and filtered to remove the DCU and the organic phases were gently concentrated to of the initial volume (4 ml). Next, to the activated solution, 5-(Biotinamido)pentylamine ,(322 mg, 0.98 mmol) dissolved in 0.5 ml of DMF and 165 μΙ of TEA (0.98 mmol) was added and the reaction mixture was stirred at room temperature overnight. The organic solvent was evaporated under high vacuum and the obtained crude product was dissolved in with CH2CI2 (40 ml). It, after workup by washing with 0.1 N HCI, water, NaHC03 5%, (7 ml) and with brine (7 ml), was dried over anhydrous Na2S04, filtered and concentrated. Finally it was purified by silica gel chromatography (CH2Cl2/MeOH 9:1 ) to give a white solid (428mg, yield 65 %). The structure was confirmed by 1H-NMR spectroscopy analysis (500 MHz): δ [ppm, D20 (d2)], 4.61 (dd, 1 H biot); 4.42 (dd, 1 H, biot); 3.32 (1 H, m, -OCH2CH2CO-); 3.68 (12H, s, - CH2CH20-) 3.58 (2H, m, -CH2NHCO-); 3.28 (t, 2H 2.97 (dd, biot.); 2.75 (1 H, dd, biot.)2.15 (2H, t, -CH2C02NH-); 1 .76-1 .3 (22H, m, -CH2-, biot + -OtBu); and Mass spectroscopy Q-Tof (m/z); [M+Na+]= 698.36; [M+K+] =714.32 and was used without further purification.

	With dicyclohexyl-carbodiimide In dichloromethane at 20℃;	2 Synthesis of 17: A solution of Boc-15-amino-4,7,10,l-tetraoxapentadecanoic acid (0.365g g, 1 mmol) and N-hydroxysuccinimide (0.115 g, 1 mmol) in CH2CI2 (4 mL) was added dicyclohexylcarbodiimide (0.206 g, lmmol). After stirring at room temperature overnight, the mixture was filtered and the filtrate was evaporated to give compound 17.
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;

Reference： [1]Camodeca, Caterina; Nuti, Elisa; Tosetti, Francesca; Poggi, Alessandro; D'Arrigo, Cristina; Zocchi, Maria Raffaella; Rossello, Armando [ChemMedChem, 2018, vol. 13, # 19, p. 2119 - 2131]
[2]Current Patent Assignee: NORTHWESTERN UNIVERSITY (ILLINOIS); THE JOHNS HOPKINS UNIVERSITY - WO2015/171792, 2015, A1 Location in patent: Page/Page column 85
[3]Current Patent Assignee: ESSETIFIN SPA - WO2018/188990, 2018, A1 Location in patent: Page/Page column 35-36
[4]Current Patent Assignee: THE JOHNS HOPKINS UNIVERSITY - WO2018/232280, 2018, A1 Location in patent: Page/Page column 55
[5]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/257998, 2020, A1 Location in patent: Page/Page column 222

22
[ 55750-62-4 ]
[ 756525-91-4 ]
[ 1263045-16-4 ]

Yield	Reaction Conditions	Operation in experiment
0.227 g		Synthesis of linker-drugReferring to the scheme of synthesis of Compound O, beta-alanine was treated with maleic anhydride in DMF and the acid so obtained was reacted with N-hydroxysuccinimide (NHS) under DCC coupling to give NHS-ester. The BOC protective group in commercially available t-boc-N-amido-dPEG4-acid was removed by treatment with TFA to give the TFA salt of the amine, which was reacted with previously synthesized NHS ester. The carboxylic acid so obtained was isolated and was coupled with N-hydroxysuccinimide using EDCI to furnish NHS ester Compound O.

Reference： [1]Patent: WO2015/196089,2015,A1 .Location in patent: Paragraph 0273; 0281

23
[ 756525-91-4 ]
2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol [ No CAS ]
[ 76-05-1 ]
tert-butyl (15-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate 2,2,2-trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid; 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: trifluoroacetic acid In water; acetonitrile	249.1 Step 1: tert-butyl (15-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-15- oxo-3,6,9,12-tetraoxapentadecyl)carbamate 2,2,2-trifluoroacetate A disposable reaction tube was charged with 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (68 mg, 0.2488 mmol), 2,2-dimethyl-4-oxo-3 ,8, 11,14,1 7-pentaoxa-5-azaicosan-20-oic acid (100 mg, 0.2737 mmol), anda stir bar for the addition of dimethylformamide (2 mL). N-ethyl-N-isopropylpropan-2-amine (0.086 mL, 0.498 mmol) was added, followed by 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)- 1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (114 mg, 0.299 mmol), and the solution stirred at room temperature 2 h. The reaction mixture was diluted with water and purified by prep-HPLC (eluting with a gradient of water acetonitrile 0.1% trifluoroacetic acid). Purefractions were pooled and lyophilized to provide the title compound as an off-white amorphous solid (70 mg). LCMS MZ (M+H) 619.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; MORPHOSYS AG - WO2016/138114, 2016, A1 Location in patent: Page/Page column 173; 174

24
[ 756525-91-4 ]
[ 1351397-21-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate / acetonitrile / 0.5 h / 80 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 0 - 20 °C
	Multi-step reaction with 2 steps 1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 20 °C / Cooling with ice 2: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C
	Multi-step reaction with 2 steps 1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 20 °C / Cooling with ice 2: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: BIK THERAPEUTICS - CN102985413, 2016, B
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/257998, 2020, A1
[3]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2021/212638, 2021, A1

25
[ 756525-91-4 ]
[ 100-44-7 ]
[ 1351397-20-0 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In acetonitrile at 80℃; for 0.5h; Inert atmosphere;	2.1 Preparation Example 1 Preparation of 1-amino-3,6,9,12-tetraoxa-pentadecane-15-acid benzyl ester (7) (step 1)(224 mg, 0.61 mmol, 5) was dissolved in acetonitrile (5 mL) under an argon atmosphere at 0 & lt; 0 & gt; C under argon atmosphere. , Cesium carbonate (CsC03, 596 mg, 1.83 mmol) and thionyl chloride (211 μL, 1.83 mmol) were added and the reaction mixture was stirred at 80 ° C for 30 minutes and then cooled to room temperature. The solvent was removed in vacuo and the pure compound (6) was obtained by column chromatography.

Reference： [1]Current Patent Assignee: BIK THERAPEUTICS - CN102985413, 2016, B Location in patent: Paragraph 0146-0150

26
[ 756525-91-4 ]
S-[2-({(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}amino)-2-oxoethyl]-L-cysteine [ No CAS ]
N-(15-amino-4,7,10,13-tetraoxapentadecan-1-oyl)-S-[2-({(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}[pyrrolidin-3-ylmethyl]amino)-2-oxoethyl]cystein trifluoroacetat [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid; S-[2-({(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}amino)-2-oxoethyl]-L-cysteine With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide Stage #2: With zinc(II) chloride In 2,2,2-trifluoroethanol at 50℃; for 3h;	The title compound was obtained by coupling of intermediate C90 with 2,2-dimethyl-4-oxo- 3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid in DMF in the presence of HAUl and N,Ndiisopropylethylamine and subsequent removal of the Roe groups using 6 equivalents of zinc chloride in2,2,2 trifluorethanol under heating for 3 h to 50°C. After addition of 6 equivalents of EDTA the product was purified by HPLC.LC-MS (Method 1): R1 = 0.80 mm; MS (ESIpos): mz = 846 (M+H)+.

Reference： [1]Current Patent Assignee: BAYER AG - WO2016/207090, 2016, A2 Location in patent: Page/Page column 303

27
[ 756525-91-4 ]
Compound L [ No CAS ]
OG₁₇₈₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19 g	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 0.5h; Inert atmosphere; Stage #2: Compound L In acetonitrile at 20℃; for 0.333333h; Cooling with ice;	2 Example 2. Synthesis of Initiator OG1786 [0354] Next, OG1405 was reacted with OG1402 to prepare OG1785 as set forth in FIG. 34. In a 500 ml flask under nitrogen equipped with a stir bar was placed OG1402 (5.5 g), followed by acetonitrile (70 ml), then N,N-diisopropylethylamine (26.3 ml) and T3P solution (see above) (7.9 ml). The solution was stirred at room temperature for 30 minutes, then cooled in an ice water bath and a solution of OG1405 (crude oil from above, 34.5 g) in acetonitrile (70 ml) added. The mixture was warmed to room temperature. After 20 minutes the reaction was cooled in an ice water bath and quenched with water (5 ml). The mixture was then concentrated under vacuum using a rotary evaporator to half volume. Samples were taken for LCMS. (0399) [0355] More water (50 ml), followed by 0.5 M citric acid (75 ml) and isopropyl acetate (175 ml) was added. The mixture was partitioned in 5 minutes. The aqueous was extracted with additional isopropyl acetate (50mL). The combined organics were washed with aqueous citric acid (0.13 M, 30 ml, consist of 10 ml of 0.5 M citric acid and 20 ml water). The organics were then washed with the mixture of saturated sodium chloride (25 ml) and water (25 ml), then finally washed with the saturated sodium chloride (25 ml). They were then dried over sodium sulfate (124 g), filtered and rinsed with isopropyl acetate (30 ml), and concentrated under rotary evaporator to a tan oil (27.3 g). Samples were taken for LCMS analysis. (0400) [0356] The oil was dissolved in acetonitrile/water (3:1, 15 ml/5ml), filtered through an HPLC filter disk (Cole-Parmer PTFE membrane 0.2 μm, product number 02915- 20) and split into three equal portions, each of which were individually purified as follows. (0401) [0357] Portions were loaded onto Redi-Sep Gold C18 column (275 g, SN- 69- 2203-339, Lot 241234-611W) equilibrated at 50% solvent B (acetonitrile)/50% solvent A (water). The material was then purified by reverse phase HPLC with a solvent A: water/solvent B: acetonitrile gradient. Appropriate fractions were pooled and partitioned between dichloromethane (150 ml) and water (5 ml)/saturated sodium chloride (25 ml). The aqueous was extracted twice with dichloromethane (2 x 50 ml). Combined organics were dried over sodium sulfate (60g), filtered and rinsed with dichloromethane (40 ml) and concentrated. Structure and purity were confirmed by various analytics including LCMS: OG1785 was isolated as a foamy solid (R5329, 19.0 g, 83% yield, 95.1% purity (a/a 210 nm), stored under nitrogen at 4°C.
19 g	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 0.5h; Inert atmosphere; Stage #2: Compound L In acetonitrile at 20℃; for 0.333333h; Cooling with ice;	6 Next, OG1405 was reacted with OG1402 to prepare OG1785 as set forth in FIG. 2H. In a 500 ml flask under nitrogen equipped with a stir bar was placed OG1402 (5.5 g), followed by acetonitrile (70 ml), then N,N-diisopropylethylamine (26.3 ml) and T3P solution (see above) (7.9 ml). The solution was stirred at room temperature for 30 minutes, then cooled in an ice water bath and a solution of OG1405 (crude oil from above, 34.5 g) in acetonitrile (70 ml) added. The mixture was warmed to room temperature. After 20 minutes the reaction was cooled in an ice water bath and quenched with water (5 ml). The mixture was then concentrated under vacuum using a rotary evaporator to half volume. Samples were taken for LCMS. (0613) More water (50 ml), followed by 0.5 M citric acid (75 ml) and isopropyl acetate (175 ml) was added. The mixture was partitioned in 5 minutes. The aqueous was extracted with additional isopropyl acetate (50 mL). The combined organics were washed with aqueous citric acid (0.13 M, 30 ml, consist of 10 ml of 0.5 M citric acid and 20 ml water). The organics were then washed with the mixture of saturated sodium chloride (25 ml) and water (25 ml), then finally washed with the saturated sodium chloride (25 ml). They were then dried over sodium sulfate (124 g), filtered and rinsed with isopropyl acetate (30 ml), and concentrated under rotary evaporator to a tan oil (27.3 g). Samples were taken for LCMS analysis. (0614) The oil was dissolved in acetonitrile/water (3:1, 15 ml/5 ml), filtered through an HPLC filter disk (Cole-Parmer PTFE membrane 0.2 μm, product number 02915-20) and split into three equal portions, each of which were individually purified as follows. (0615) Portions were loaded onto Redi-Sep Gold C18 column (275 g, SN-69-2203-339, Lot 241234-611W) equilibrated at 50% solvent B (acetonitrile)/50% solvent A (water). The material was then purified by reverse phase HPLC with a solvent A: water/solvent B: acetonitrile gradient. Appropriate fractions were pooled and partitioned between dichloromethane (150 ml) and water (5 ml)/saturated sodium chloride (25 ml). The aqueous was extracted twice with dichloromethane (2×50 ml). Combined organics were dried over sodium sulfate (60 g), filtered and rinsed with dichloromethane (40 ml) and concentrated. Structure and purity were confirmed by various analytics including LCMS: 0G1785 was isolated as a foamy solid (R5329, 19.0 g, 83% yield, 95.1% purity (a/a 210 nm), stored under nitrogen at 4° C.

Reference： [1]Current Patent Assignee: KODIAK SCIENCES INC - WO2017/117464, 2017, A1 Location in patent: Paragraph 0354-0357
[2]Current Patent Assignee: KODIAK SCIENCES INC - US2019/270806, 2019, A1 Location in patent: Paragraph 0062; 0612-0615

28
[ 756525-91-4 ]
3-(aminomethyl)-N-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)benzamide [ No CAS ]
tert-butyl (1-(3-((2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)carbamoyl)phenyl)-3-oxo-6,9,12,15-tetraoxa-2-azaheptadecan-17-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid With O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.5h; Stage #2: 3-(aminomethyl)-N-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)benzamide In N,N-dimethyl-formamide for 1.5h;	8 Tert-butyl(1-(3-((2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)carbamoyl)phenyl)-3-oxo-6,9,12,15-tetraoxa 2-azaheptadecan-17-yl)carbamate To a solution of 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid (20.0 mg, 0.05 mmol) in 1 mL DMF, O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (19.8 mg, 0.07 mmol) and N,N-diisopropylethylamine (0.03 mL, 0.16 mL) was added. The mixture was stirred for 0.5 hr. A 0.5 mL aliquot was treated with 0.25 M solution of 3-(aminomethyl)-N-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)benzamide (0.1 mL, 0.03 mL). The mixture was stirred for 1.5 hrs before being concentrated to give the product as a yellow oil.

Reference： [1]Current Patent Assignee: PROMEGA CORP - US9702824, 2017, B2 Location in patent: Page/Page column 37; 38

29
[ 756525-91-4 ]
4-(aminomethyl)-N-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)benzamide hydrochloride [ No CAS ]
tert-butyl (1-(4-((2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)carbamoyl)phenyl)-3-oxo-6,9,12,15-tetraoxa-2-azaheptadecan-17-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid With O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.5h; Stage #2: 4-(aminomethyl)-N-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)benzamide hydrochloride In N,N-dimethyl-formamide	8 Tert-butyl(1-(4-((2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)carbamoyl)phenyl)-3-oxo-6,9,12,15-tetraoxa-2-azaheptadecan-17-yl)carbamate To a solution of 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid (20.0 mg, 0.05 mmol) in 1 mL DMF, O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (19.8 mg, 0.07 mmol) and N,N-diisopropylethylamine (0.03 mL, 0.16 mL) was added. The mixture was stirred for 0.5 hr. A 0.5 mL aliquot was treated with 0.25 M solution of 4-(aminomethyl)-N-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)benzamide-HCl (0.1 mL, 0.03 mL). The mixture was stirred overnight before being concentrated to give the product as a yellow oil.

Reference： [1]Current Patent Assignee: PROMEGA CORP - US9702824, 2017, B2 Location in patent: Page/Page column 41; 42

30
[ 756525-91-4 ]
[ 6325-93-5 ]
tert-butyl (15-((4-nitrophenyl)sulfonamido)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18h;
53%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 5h; Inert atmosphere;

Reference： [1]Teng, Mingxing; Jiang, Jie; Ficarro, Scott B.; Seo, Hyuk-Soo; Bae, Jae Hyun; Donovan, Katherine A.; Fischer, Eric S.; Zhang, Tinghu; Dhe-Paganon, Sirano; Marto, Jarrod A.; Gray, Nathanael S. [ACS Medicinal Chemistry Letters, 2021, vol. 12, # 8, p. 1302 - 1307]
[2]Tamura, Tomonori; Song, Zhining; Amaike, Kazuma; Lee, Shin; Yin, Sifei; Kiyonaka, Shigeki; Hamachi, Itaru [Journal of the American Chemical Society, 2017, vol. 139, # 40, p. 14181 - 14191]

31
[ 756525-91-4 ]
(2S)-2-amino-N-[(1S)-1-[(4-{2-[(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-12-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo[10.8.0.02'9.04'8.013,18]icosa-14,17-dien-8-yl]-2-oxoethoxy}phenyl)carbamoyl]ethyl]-3-methylbutanamide [ No CAS ]
C₅₀H₇₂F₂N₄O₁₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.18 g	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid; (2S)-2-amino-N-[(1S)-1-[(4-{2-[(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-12-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo[10.8.0.0<SUP>2</SUP>'<SUP>9</SUP>.0<SUP>4</SUP>'<SUP>8</SUP>.0<SUP>13,18</SUP>]icosa-14,17-dien-8-yl]-2-oxoethoxy}phenyl)carbamoyl]ethyl]-3-methylbutanamide With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane Stage #2: With trifluoroacetic acid In dichloromethane	53 The example demonstrates a method for making Linker-Payload LP14. The following Example refers to FIG. 18. N-[(15)-l-[(15)-l-[(4-{2-[(1^2^4R,6R,8^9^ 11^12R,13^, 195)-12,19- Difluoro- 11 -hydroxy-9, 13 -dimethyl- 16-oxo-6-propyl-5,7- dioxapentacyclo[10.8.0.02'9.04'8.013 8]icosa-14, 17-dien-8-yl]-2- oxoethoxy}phenyl)carbamoyl]ethyl]carbamoyl}-2-methylpropyl]-l-{2-[4-(2,5-dioxo-2,5- dihydro- lH-pyrrol- 1 -yl)phenyl]acetamido} -3,6,9, 12-tetraoxapentadecan- 15-amide (LP14) Compound 34h-2 (0.18 g, 74% yield in 2 steps) was obtained according to the General procedure F ESI m/z: 728 (M + H)+ [0745] Compound LP14 (20 mg, 14% yield in 3 steps from 34h) was obtained as a white solid. ESI: 1189 (M + H)+. 1H NMR (500 MHz, DMSCto) δ 9.81-9.67 (m, 1H), 8.43- 8.13 (m, 2H), 8.03-7.84 (m, 1H), 7.61-7.47 (m, 2H), 7.35 (d, J= 8.4 Hz, 2H), 7.29-7.21 (m, 3H), 7.17 (s, 2H), 6.88-6.81 (m, 2H), 6.33-6.28 (dd, J = 10.1, 1.8 Hz, 1H), 6.11 (s, 1H), 5.71- 5.56 (m, 1H), 5.51 (s, 1H), 5.12 (d, J= 18.5 Hz, 1H), 4.84 (d, J= 18.5 Hz, 1H), 4.79-4.76 (m, 1H), 4.74 (t, J= 4.3 Hz, 2H), 4.38-4.33 (m, 1H), 4.25-4.17 (m, 2H), 3.63-3.55 (m, 2H), 3.52- 3.44 (m, 14H), 3.42 (t, J= 5.8 Hz, 2H), 3.21 (q, J= 5.7 Hz, 1H), 2.69-2.55 (m, 1H), 2.47-2.41 (m, 1H), 2.41-2.34 (m, 1H), 2.29-2.23 (m, 1H), 2.14-2.02 (m, 2H), 1.99-1.90 (m, 1H), 1.82 (d, J= 13.0 Hz, 1H), 1.65-1.53 (m, 4H), 1.49 (s, 3H), 1.47-1.41 (m, 1H), 1.40-1.33 (m, 2H), 1.29 (d, J= 7.1 Hz, 3H), 0.90-0.80 (m, 12H) ppm. Anal. HPLC: 100%, Retention time: 8.45 min (method A).

Reference： [1]Current Patent Assignee: REGENERON PHARMACEUTICALS INC - WO2018/89373, 2018, A2 Location in patent: Paragraph 0742-0745

32
[ 756525-91-4 ]
(S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloro-7-(1-(methylamino)ethyl)pyrazolo[1,5-a]pyrimidin-6-yl)urea hydrochloride [ No CAS ]
tert-butyl (S)-(17-(2-chloro-6-(3-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)ureido)pyrazolo[1,5-a]pyrimidin-7-yl)-16-methyl-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 0.5h;	1 tert-Butyl (5)-(17-(2-chloro-6-(3-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3- yl)ureido)pyrazolo[l,5-a]pyrimidin-7-yl)-16-methyl-15-oxo-3,6,9,12-tetraoxa-16- azaoctadecyl)carbamate: HATU (20 mg, 0.045 mmol), 2,2-dimethyl-4-oxo-3,8, 11,14,17- pentaoxa-5-azaicosan-20-oic acid (10 mg, 0.026 mmol) and DIEA (20 μ, 0.11 mmol) were added to a solution of (S)-l-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloro-7- (l-(methylamino)ethyl)pyrazolo[l,5-a]pyrimidin-6-yl)urea hydrochloride (10 mg, 0.021 mmol) in DMF (3 mL). The reaction was stirred for 30 minutes and the mixture was purified by HPLC to give the title compound (10 mg, 56%) as an oil. MS m/z 795.57 [M+H]+.

Reference： [1]Current Patent Assignee: CORNELL UNIVERSITY - WO2018/85247, 2018, A1 Location in patent: Paragraph 00347

33
[ 756525-91-4 ]
N-(35-amino-3,6,9,12,15,18,21,24,27,30,33-undecaoxapentatriacontyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide [ No CAS ]
tert-butyl (15,53-dioxo-57-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-3,6,9,12,19,22,25,28,31,34,37,40,43,46,49-pentadecaoxa-16,52-diazaheptapentacontyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 18h; Inert atmosphere;	1 1- amino-N-(37-oxo-41-((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4-d]imidazol-4-yl)- 3,6,9,12,15,18,21,24,27,30,33-undecaoxa-36-diazaheptapentacontyl)-3,6,9,12- tetraoxapentadecan-15-amide: Under a nitrogen atmostphere, a solution of 2,2-dimethyl-4-oxo-3,8,l l, 14,17-pentaoxa-5-azaicosan- 20-oic acid (31.6 mg, 0.086 mmol), HATU (33.2 mg, 0.087 mmol), and HOBt (1.324 mg, 8.65 μηιο) was prepared in dichloromethane (DCM) (865 μ) at ambient temperature. The mixture was homogeneous. Afterwards, DIEA (45.3 μ, 0.259 mmol) was delivered. After 10 mins the mixture was treated with N-(35-amino-3,6,9, 12,15, 18,21,24,27,30,33-undecaoxapentatriacontyl)-5- ((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4-d]imidazol-4-yl)pentanamide (66.7 mg, 0.086 mmol) and was allowed to stir for 18 hours. The progress was checked by Open Access LCMS [Shimadzu 10A PE (LC) coupled with Sciex Single Quadrupole 150EX (MS) and Sedere Sedex 75C (ELS)] ((Thermo Hypersil Gold C18, 20x2.1 mm, 1.9 u particle diam.), 1.6 mL/min, gradient from 5-92% CH3CN (0.02 % TFA) / H20 (0.02 %TFA)). The spectra confirmed that the reaction was progressed fairly cleanly and was about 100% complete. The reaction mixture was diluted with DCM and treated with an aqueous work up using 1 : 1 mixture of saturated sodium bicarbonate and water and brine. The organic layer was passed through a phase separator and concentrated to give the desired product, tert- butyl (15,53-dioxo-57-((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4-d]imidazol-4-yl)- 3,6,9, 12, 19,22,25,28,3 l,34,37,40,43,46,49-pentadecaoxa-16,52-diazaheptapentacontyl)carbamate (102 mg, 0.082 mmol, 95 % yield), as a clear colorless oil. Purity was judged >90% and the analytical characterization data of the final material was consistent with the assigned structure. MS (ES) m/e 1119 [M+H]+, rt = 0.83 mins.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2018/134731, 2018, A1 Location in patent: Page/Page column 19

34
[ 756525-91-4 ]
[ 125-73-5 ]
C₃₃H₅₂N₂O₈*ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; trimethylamine In N,N-dimethyl-formamide at 20℃;	CHpCHpC(O))-dextrorphan 54: [0177] To a solution of dextrorphan 1, Boc-NH-(PEG)4-CH2CH2-COOH 50, HOBt and trimethylamine in DMF is added a solution of HBTU in DMF. The reaction mixture is stirred at room temperature. The reaction is quenched with water and the solvent is evaporated under reduced pressure. The residue is taken in EtOAc, and washed with 5% aq. NaHCO3 and brine. The organic part is dried over anhydrous Na2SO4 and is evaporated to dryness to give 53 .

Reference： [1]Current Patent Assignee: KEMPHARM INC - WO2018/191477, 2018, A1 Location in patent: Paragraph 0177

35
[ 756525-91-4 ]
Levorphanol [ No CAS ]
C₃₃H₅₂N₂O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide; butan-1-ol at 20℃; for 24h;	3-(H2N-PEG4-CH2CH2C(O))-levorphanol 54: To a solution of levorphanol 1 (0.103 g, 0.4 mmol), Boc-NH-(PEG)4-CH2CH2- COOH 50 (0.16 g, 0.44 mmol), HOBt (0.06 g, 0.44 mmol) and trimethylamine (0.17 mL, 1.2 mmol) in DMF ( 6mL) was added a solution of HBTU (0.166g, 0.44 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with water (1 mL) and the solvent was evaporated under reduced pressure. The residue was taken in EtOAc (110 mL), washed with 5% aq. NaHCO3 (2 x 60 mL) and brine (1 x 60 mL). The organic part was dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by preparative HPLC to give 53.

Reference： [1]Current Patent Assignee: KEMPHARM INC - WO2018/191472, 2018, A1 Location in patent: Paragraph 0180

36
[ 107-35-7 ]
[ 756525-91-4 ]
1-ammonio-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecane-18-sulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid With di(succinimido) carbonate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; Inert atmosphere; Stage #2: Tau In tetrahydrofuran; water at 20℃;	1 -ammonio-1 5-oxo-3,6,9,1 2-tetraoxa-1 6-azaoctadecane-18-Compound 36:sulfonate To a solution of 15-(Boc-amino)-4,7,10,13-tetraoxapentadecanoic acid (500 mg, 1 .3 mmol) in THE (5 mL) were added, under Ar, DIEA (438.4 pL, 2.6 mmol) and DSC(381 .6 mg, 1 .43 mmol). The reaction medium was stirred for 6 h at RT then 50 mg of DSC were added and the stirring was carried on at RT overnight. At that time, taurine (821 .6 mg, 6.5 mmol) and H20 (1 mL) were added to the reaction medium. Thereaction medium was stirred at RT overnight, concentrated in vacuo and purified by preparative LCMS on a 5 pm 018 SunFire column (Waters, 30 x 100 mm, gradient elution MeCN + 0.07% TFA/H20 + 0.07% TEA) to give 341 mg of compound 36 (70%).RMN 1H (400 MHz, ö in ppm, DMSO-d6): 2.28 (t, J = 6.5 Hz, 2 H); 2.60 (m, 2 H); 2.99(m, 2 H); 3.32 (m, 2 H); 3.45 to 3.65 (m, 16 H); 7.77 (broad m, 4 H).IR spectrum as aKBr pellet; main absorption bands in reciprocal centimeters: 3000; 1780; 1648; 1556;1200-1170; 1200; 1100; 1040.

Reference： [1]Current Patent Assignee: SANOFI - WO2018/206635, 2018, A1 Location in patent: Page/Page column 193; 194

37
[ 756525-91-4 ]
[ 57-88-5 ]
[ 1147885-57-1 ]

Yield	Reaction Conditions	Operation in experiment
75%	With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃;	3 Cholest-5-en-3-yl 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oate (1): N-t-boc-amido-dPEG4 acid (1g, 2.7 mmol, Product N° 10220, Quanta BioDesign, Ltd.) was added to a solution of cholesterol (0.99g, 2.7 mmol) in 40 mL of CH2Cl2, followed by N,N'-diisopropylcarbodiimide (0.43 mL, 3.2 mmol) and 4-dimethylamino-pyridine (16 mg, 5%). The mixture was stirred at room temperature overnight and the solvent was evaporated under vacuo. The crude was dissolved in EtOAc, washed with HCl 1N, saturated NH4Cl and brine, dried over Na2SO4, filtered and concentrated. The crude was purified by flash column chromatography (BIOTAGE) on silica gel with a gradient 25-50% EtOAc in petroleum ether to afford 1.48 g of desired compound as incolor oil (Yield 75%).

Reference： [1]Current Patent Assignee: MERCK & CO INC - EP2205283, 2019, B1 Location in patent: Paragraph 0093; 0094

38
[ 756525-91-4 ]
[ 115416-38-1 ]
C₃₁H₅₇N₅O₉S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 2.16667h; Stage #2: N-(5-aminopentyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazole-4-yl)pentanamide With triethylamine In N,N-dimethyl-formamide at 20℃;	Biotinylated Linker (2) [Biotin-Peg4-NH2] Step I. Coupling reaction The commercial 15-(t-Butyloxycarbonyl) amino-4,7,10,13-tetraoxa-pentadecanoic acid BocNH-Peg4-OH (358 mg, 0.98 mmol) was dissolved in 6.5 mL of CH2Cl2 and cooled to 0°C then treated with N-hydroxy succinimide (NHS 147 mg, 1.3 mmol), and N,N’-dicyclohexylcarbodiimide (DCC) (262 mg, 1.3 mmol) and stirred at 0°C for 10 min and 2 h at rt, monitoring the disappearance of the acid by TLC. The reaction mixture was diluted with 10 mL of CH2Cl2, then cooled and filtered to remove the N,N’-Dicyclohexylurea (DCU) and the organic phase concentrated to of the initial volume (4 mL) was treated with 5-(Biotinamido)pentylamine 1 (322 mg, 0.98 mmol) dissolved in 0.5 mL of DMF and 165 μl of TEA (0.98 mmol) and the reaction mixture stirred at rt overnight. After concentration under high vacuum the crude product obtained was dissolved in with CH2Cl2 (40 mL), worked up by washing with 0.1N HCl, H2O, NaHCO3 5%, (7 mL) and with brine (7 mL), dried over anhydrous Na2SO4, concentrated and finally purified by silica gel chromatography (CH2Cl2/MeOH 9:1) to give a white solid intermediate 8 (428mg, yield 65 %). Its structure was confirmed by 1H-NMR spectroscopy analysis (500 MHz): δ [ppm, D2O (d2)], 4.61 (dd, 1H biot.); 4.42 (dd, 1H, biot.); 3.32 (1H, m, -OCH2CH2CO-); 3.68 (12H, s, - CH2CH2O-) 3.58 (2H, m, -CH2NHCO-); 3.28 (t, 2H 2.97 (dd, biot.); 2.75 (1H, d, biot.)2.15 (2H, t, -CH2CO2NH-); 1.76-1.3 (22H, m, -CH2-, biotin + -OtBu); and mass spectroscopy Q-Tof (m/z); [M+Na+]= 698.36; [M+K+] =714.32 and it was used without further purification.

Reference： [1]Esposito, Emiliano; Vlodavsky, Israel; Barash, Uri; Roscilli, Giuseppe; Milazzo, Ferdinando M.; Giannini, Giuseppe; Naggi, Annamaria [European Journal of Medicinal Chemistry, 2020, vol. 186]

39
[ 756525-91-4 ]
[ 1439934-41-4 ]
tert-butyl (15-(4-(4-((5-chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.3%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 3h;	<strong>[1439934-41-4]2-((5-chloro-2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide</strong> (200.0 mg, 0.46 mmol) and 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid (250.0 mg, 0.69 mmol) and HATU (208.4 mg, 0.55 mmol) were taken up in DMF (5 mL), and N,N-diisopropylethylamine (238.7 muL, 1.37 mmol) was added. The mixture was stirred for 3 hrs, and volatiles removed under reduced pressure. The crude was taken up in a minimum volume of dichloromethane, absorbed on Celite, and dried to a free flowing solid. The mixture was subjected to silica gel flash chromatography giving the desired product (192.0 mg, 53.3%) as a white solid. MS (ESI+) m/z calc'd for [M+H]+ C38H54ClN8O8: 785.38, found 785.60.

Reference： [1]Patent: US2020/3771,2020,A1 .Location in patent: Paragraph 0888

40
benzyl (E)-2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicos-18-en-20-oate [ No CAS ]
[ 756525-91-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With palladium 10% on activated carbon; hydrogen In tetrahydrofuran for 24h;

Reference： [1]Song, Fengbin; Chen, Lu; Lin, Ronghui; Salter, Rhys [Journal of labelled compounds and radiopharmaceuticals, 2020, vol. 63, # 1, p. 15 - 24]

41
[ 756525-91-4 ]
1-amino-3,6,9,12-tetraoxapentadecan-15-oic acid hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride In 1,4-dioxane at 20℃; for 2h;

Reference： [1]Song, Fengbin; Chen, Lu; Lin, Ronghui; Salter, Rhys [Journal of labelled compounds and radiopharmaceuticals, 2020, vol. 63, # 1, p. 15 - 24]

42
[ 106984-09-2 ]
[ 756525-91-4 ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2020,vol. 63,p. 15 - 24

43
[ 756525-91-4 ]
[ 744203-61-0 ]
C₂₆H₅₁ClN₂O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;

Reference： [1]Cheng, Yangyang; Derivery, Emmanuel; González-Gaitán, Marcos; López-Andarias, Javier; Laurent, Quentin; Matile, Stefan; Moreau, Dimitri; Saarbach, Jacques; Sakai, Naomi; Winssinger, Nicolas [Journal of the American Chemical Society, 2020, vol. 142, # 10, p. 4784 - 4792]

44
[ 756525-91-4 ]
C₂₁H₄₃ClN₂O₇*C₂HF₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 1 h / 20 °C 2: dichloromethane / 2 h

Reference： [1]Cheng, Yangyang; Derivery, Emmanuel; González-Gaitán, Marcos; López-Andarias, Javier; Laurent, Quentin; Matile, Stefan; Moreau, Dimitri; Saarbach, Jacques; Sakai, Naomi; Winssinger, Nicolas [Journal of the American Chemical Society, 2020, vol. 142, # 10, p. 4784 - 4792]

45
[ 756525-91-4 ]
C₃₁H₅₉ClN₄O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 1 h / 20 °C 2: dichloromethane / 2 h 3: triethylamine / dichloromethane / 1 h / 20 °C

Reference： [1]Cheng, Yangyang; Derivery, Emmanuel; González-Gaitán, Marcos; López-Andarias, Javier; Laurent, Quentin; Matile, Stefan; Moreau, Dimitri; Saarbach, Jacques; Sakai, Naomi; Winssinger, Nicolas [Journal of the American Chemical Society, 2020, vol. 142, # 10, p. 4784 - 4792]

46
[ 756525-91-4 ]
[ 142685-25-4 ]
C₂₂H₃₁F₄NO₈ [ No CAS ]

Reference： [1]Nuclear Medicine and Biology,2021,vol. 92,p. 217 - 227

47
[ 756525-91-4 ]
(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-ammonium 2,2,2-trifluoroacetate [ No CAS ]
C₃₉H₆₁N₅O₁₀S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; 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 0 - 20℃; for 1h;

Reference： [1]Wang, Mingliang; Lu, Jianfeng; Wang, Mi; Yang, Chao-Yie; Wang, Shaomeng [Journal of Medicinal Chemistry, 2020, vol. 63, # 14, p. 7510 - 7528]

48
[ 756525-91-4 ]
C₁₉H₂₂ClN₅*2C₂HF₃O₂ [ No CAS ]
C₃₅H₅₁ClN₆O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; 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 22℃; for 1.5h;
100%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 22℃; for 1.5h;	A 25 mL flask, equipped with stir bar, was charged with S006 (7.0 mg, 15 mmol), 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid (8 mg, 20 μmol), HATU (7 mg,0.02 mmol), DIPEA (15 μL, 0.10 mmol), and DMF (6 mL). The resulting light-yellow solutionwas stirred at 22°C for 1.5 hours, at which point, HPLC indicated complete consumption of thestaring material, and the solvent removed under reduced pressure. The crude residue was purifiedby preparative HPLC (C18, 5 → 95% MeCN/H2O, 0.05% TFA) yielding 11 mg (quantitative) ofcarbamate S007 as a yellow oil.

Reference： [1]Current Patent Assignee: PROMEGA CORP - WO2020/117954, 2020, A2 Location in patent: Page/Page column 17; 54; 55
[2]Boursier, Michelle E.; Hall, Mary P.; Hurst, Robin; Killoran, Michael P.; Kirkland, Thomas A.; Levin, Sergiy; Machleidt, Thomas; Ohana, Rachel Friedman; Zimmerman, Kristopher [Molecules, 2021, vol. 26, # 10]

49
[ 756525-91-4 ]
C₂₀H₂₃ClN₄O [ No CAS ]
C₃₆H₅₂ClN₅O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine; 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 22℃; for 18h;	flask, equipped with stir bar, was charged with SL-1519 (25 mg, 37 pmol), 2,2-dimethyl-4-oxo- 3,8,ll,14,17-pentaoxa-5-azaicosan-20-oic acid (31 mg, 84 pmol), HATU (32 mg, 84 pmol), DIPEA (66 pL, 0.47 mmol), and DMF (6 mL). The resulting light yellow solution was stirred at 22 °C for 18 hours, at which point, HPLC indicated complete consumption of the staring material, and the solvent removed under reduced pressure. The crude residue was purified by preparative HPLC (C18, 5 95% MeChWHO, 0.05% TFA) yielding 41 mg (85% yield) of carbamate SL-1520 as a clear oil. *H NMR (400 MHz, DMSO-d6) d 9.58 (br. s, 1H), 8.05 (t, J = 5.8 Hz, 1H), 7.68 (dd, J = 8.7, 2.6 Hz, 1H), 7.57 (d, J = 2.6 Hz, 1H), 7.44 (d, J = 8.7 Hz,1H), 7.23 (dd, J = 7.8, 1.5 Hz, 1H), 7.18 - 6.90 (m, 3H), 6.75 (t, J = 5.7 Hz, 1H), 3.61 (t, J = 6.4 Hz, 2H), 3.57 - 3.44 (m, 16H), 3.36 (t, J = 6.2 Hz, 2H), 3.26 (s, 2H), 3.17 - 3.09 (m, 4H), 3.05 (q, J = 6.0 Hz, 2H), 2.35 (d, J = 6.4 Hz, 2H), 1.97 - 1.73 (m, 2H), 1.37 (s, 9H); MS (ESI) calc’d for CseHssCINsOs [M+H]+718.36 found 718.41.

Reference： [1]Current Patent Assignee: PROMEGA CORP - WO2020/117954, 2020, A2 Location in patent: Page/Page column 17; 58

50
[ 756525-91-4 ]
C₁₉H₂₅N₅S [ No CAS ]
C₃₅H₅₄N₆O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With 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 22℃; for 3h;

Reference： [1]Current Patent Assignee: PROMEGA CORP - WO2020/117954, 2020, A2 Location in patent: Page/Page column 17; 60-61

51
[ 756525-91-4 ]
C₂₃H₂₉N₃O*2C₂HF₃O₂ [ No CAS ]
C₃₉H₅₈N₄O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 22℃; for 17h;	A 25 mL flask, equipped with stir bar, was charged with S039 (5.2 mg, 8.8 μmol), 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid (4.0 mg, 11 μmol), HATU (4.2mg, 11 μmol), EtN(iPr)2 (11 μL, 62 μmol), and DMF (6 mL). The resulting light-yellow solutionwas stirred at 22°C for 17 hours at which point, HPLC indicated complete consumption of thestaring material and the solvent was removed under reduced pressure. The crude residue waspurified by preparative HPLC (C18, 5 → 95% MeCN/H2O, 0.05% TFA), yielding 3.8 mg (61%yield) of amide S042 as a clear oil.
3.8 mg	With N-ethyl-N,N-diisopropylamine; 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 22℃; for 17h;	A 25 mL flask, equipped with stir bar, was charged with SL-1842 (5.2 mg, 8.8 pmol),2,2-dimethyl-4-oxo-3,8,ll,14,17-pentaoxa-5-azaicosan-20-oic acid (4.0 mg, 11 pmol), HATU (4.2 mg, 11 pmol), EtN(iPr)2(11 pL, 62 pmol), and DMF (6 mL). The resulting light-yellow solution was stirred at 22°C for 17 hours at which point, HPLC indicated complete consumption of the staring material and the solvent was removed under reduced pressure. The crude residue was purified by preparative HPLC (Cl 8, 5 95% MeCN/H20, 0.05% TFA), yielding 3.8 mg (61% yield) of amide SL-1846 as a clear oil. 1H NMR (400 MHz, MeOD) d 7.64 (dd, J = 8.0, 1.9 Hz, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.37 - 7.23 (m, 3H), 7.20 (dd, J = 6.8, 1.6 Hz, 1H), 5.92 (t, J = 7.3 Hz, 1H), 3.71 (t, J = 6.0 Hz, 2H), 3.59 - 3.37 (m, 20H), 3.29 - 3.13 (m, 4H), 3.03 (q, J = 15.7, 14.5 Hz, 1H), 2.82 (m, 7H), 2.61 (t, J = 9.2 Hz, 2H), 2.45 (t, J = 6.0 Hz, 2H), 1.44 (s, 9H); HRMS (ESI) calc’d for C39H59N4O8 [M+H]+711.4333 found 711.4329. Single peak on HPLC at 254 nm.

Reference： [1]Boursier, Michelle E.; Hall, Mary P.; Hurst, Robin; Killoran, Michael P.; Kirkland, Thomas A.; Levin, Sergiy; Machleidt, Thomas; Ohana, Rachel Friedman; Zimmerman, Kristopher [Molecules, 2021, vol. 26, # 10]
[2]Current Patent Assignee: PROMEGA CORP - WO2020/117954, 2020, A2 Location in patent: Page/Page column 80; 81

52
[ 756525-91-4 ]
C₂₀H₂₄ClN₅*C₂HF₃O₂ [ No CAS ]
C₃₆H₅₃ClN₆O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With 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 22℃; for 1h;
100%	With triethylamine; HATU In N,N-dimethyl-formamide at 22℃; for 1h;	A 25 mL flask, equipped with stir bar, was charged with S001 (12 mg, 25 μmol), 2,2-dimethyl-4 oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid (14 mg, 37 μmol), HATU (12 mg,31 μmol), NEt3 (24 μL, 0.17 mmol), and DMF (6 mL). The resulting light-yellow solution wasstirred at 22°C for 1 hour, at which point, HPLC indicated complete consumption of the staringmaterial, and the solvent removed under reduced pressure. The crude residue was purified bypreparative HPLC (C18, 5 → 95% MeCN/H2O, 0.05% TFA) yielding 18 mg (quantitative yield)of amide S002 as a yellow oil.

Reference： [1]Current Patent Assignee: PROMEGA CORP - WO2020/117954, 2020, A2 Location in patent: Page/Page column 17; 43
[2]Boursier, Michelle E.; Hall, Mary P.; Hurst, Robin; Killoran, Michael P.; Kirkland, Thomas A.; Levin, Sergiy; Machleidt, Thomas; Ohana, Rachel Friedman; Zimmerman, Kristopher [Molecules, 2021, vol. 26, # 10]

53
[ 756525-91-4 ]
[ 1448297-52-6 ]
tert-butyl ((S)-17-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-18,18-dimethyl-15-oxo-3,6,9,12-tetraoxa-16-azanonadecyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; triethylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	tert-butyl ((S)-17-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-18,18-dimethyl-15-oxo-3,6,9,12-tetraoxa- 16-azanonadecyl)carbamate 3-[2-[2-[2-[2-(tert-Butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (94 mg, 0.255 mmol) was dissolved in DMF (20 ml) and treated with HATU (97 mg, 0.255 mmol) and triethylamine (97 m, 0.697 mmol) followed by (2S,4R)-l-[(2S)-2-amino- 3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2- carboxamide (100 mg, 0.232 mmol). The reaction was stirred at r.t. overnight, diluted with water (20 ml) and extracted with ethyl acetate (2 x 15 ml). The organic layers were combined, washed with 2 M HCL (10 ml) and 10% LiCl (aq) (2 x 10 ml), dried over MgSCri and concentred in vacuo. The residue was purified by column chromatography eluting with 5% MeOH/DCM to yield the title compound (166 mg, 92%). HRMS: calc. [M+H]+ forC38H59N5OIOS = 778.4055; found = 778.4243 [M+H]+.
	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dimethyl sulfoxide at 20℃;

Reference： [1]Current Patent Assignee: YALE UNIVERSITY - WO2020/198055, 2020, A1 Location in patent: Page/Page column 174; 178-179
[2]Cahuzac, Kaitlyn M.; Chen, Xian; Jin, Jian; Liu, Jing; Parsons, Ramon E.; Shen, Yudao; Wang, Li; Xie, Ling; Xu, Jia; Yu, Xufen [Journal of Medicinal Chemistry, 2021, vol. 64, # 24, p. 18054 - 18081]

54
[ 756525-91-4 ]
(2S,4R)-1-((S)-1-amino-17-(tert-butyl)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecan-18-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; triethylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / 20 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
	Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / dimethyl sulfoxide / 20 °C 2: trifluoroacetic acid / water / 20 °C

Reference： [1]Current Patent Assignee: YALE UNIVERSITY - WO2020/198055, 2020, A1
[2]Dölle, Anja; Adhikari, Bikash; Krämer, Andreas; Weckesser, Janik; Berner, Nicola; Berger, Lena-Marie; Diebold, Mathias; Szewczyk, Magdalena M.; Barsyte-Lovejoy, Dalia; Arrowsmith, Cheryl H.; Gebel, Jakob; Löhr, Frank; Dötsch, Volker; Eilers, Martin; Heinzlmeir, Stephanie; Kuster, Bernhard; Sotriffer, Christoph; Wolf, Elmar; Knapp, Stefan [Journal of Medicinal Chemistry, 2021, vol. 64, # 15, p. 10682 - 10710]
[3]Cahuzac, Kaitlyn M.; Chen, Xian; Jin, Jian; Liu, Jing; Parsons, Ramon E.; Shen, Yudao; Wang, Li; Xie, Ling; Xu, Jia; Yu, Xufen [Journal of Medicinal Chemistry, 2021, vol. 64, # 24, p. 18054 - 18081]

55
[ 756525-91-4 ]
C₂₅H₃₁N₅O₄ [ No CAS ]
C₄₁H₆₀N₆O₁₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide	5.i CMP2 is synthesized by combining the targeting moiety, TM10 with 100, followed by coupling with (R)-tert-Bu4- DOTAGA and labeling with cold lutetium as shown below.

Reference： [1]Current Patent Assignee: ROCK CREEK ADVISORS LLC - WO2020/205948, 2020, A1 Location in patent: Paragraph 0275

56
[ 756525-91-4 ]
C₆₈H₇₉F₂N₁₅O₁₃S₂ [ No CAS ]
C₈₀H₁₀₂F₂N₁₆O₁₈S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.72 mg	With ethyl (2E)-cyano(hydroxyimino)ethanoate; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 48h;

Reference： [1]Alleyne, Candice; Amin, Rupesh P.; Bhatt, Bhavana; Bianchi, Elisabetta; Blain, J. Craig; Boyer, Nicolas; Branca, Danila; Embrey, Mark W.; Ha, Sookhee N.; Jette, Kelli; Johns, Douglas G.; Kerekes, Angela D.; Koeplinger, Kenneth A.; Laplaca, Derek; Li, Nianyu; Murphy, Beth; Orth, Peter; Ricardo, Alonso; Salowe, Scott; Seyb, Kathleen; Shahripour, Aurash; Stringer, Joseph R.; Sun, Yili; Tracy, Rodger; Wu, Chengwei; Xiong, Yusheng; Youm, Hyewon; Zokian, Hratch J.; Tucker, Thomas J. [Journal of Medicinal Chemistry, 2020, vol. 63, # 22, p. 13796 - 13824]

57
[ 756525-91-4 ]
4-(3-aminopropyl)-7-fluoro-1-thioxo-2,4-dihydro[1,2,4]triazolo[4,3-a]quinazolin-5(1H)-one [ No CAS ]
tert-butyl (19-(7-fluoro-5-oxo-1-thioxo-1,2-dihydro[1,2,4]triazolo[4,3-a]quinazolin-4(5H)-yl)-15-oxo-3,6,9,12-tetraoxa-16-azanonadecyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; Inert atmosphere; Stage #2: 4-(3-aminopropyl)-7-fluoro-1-thioxo-2,4-dihydro[1,2,4]triazolo[4,3-a]quinazolin-5(1H)-one With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; Inert atmosphere;

Reference： [1]Alverez, Celeste N.; Park, Jung-Eun; Toti, Kiran S.; Xia, Yangliu; Krausz, Kristopher W.; Rai, Ganesha; Bang, Jeong K.; Gonzalez, Frank J.; Jacobson, Kenneth A.; Lee, Kyung S. [Journal of Medicinal Chemistry, 2020, vol. 63, # 22, p. 14087 - 14117]

58
[ 756525-91-4 ]
C₄₅H₇₉N₃O₁₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 2: potassium carbonate / water / Cooling with ice 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / Cooling with ice
	Multi-step reaction with 3 steps 1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 20 °C / Cooling with ice 2: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / Cooling with ice
	Multi-step reaction with 3 steps 1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 20 °C / Cooling with ice 2: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 2 h

Multi-step reaction with 5 steps 1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 20 °C / Cooling with ice 2: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 4: potassium carbonate / water; tetrahydrofuran / 20 °C / Cooling with ice 5: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 2 h

Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/257998, 2020, A1
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/257998, 2020, A1
[3]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2021/212638, 2021, A1
[4]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2021/212638, 2021, A1

59
[ 756525-91-4 ]
[ 100-39-0 ]
[ 1351397-20-0 ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 20℃; Cooling with ice;
69%	With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 20℃; Cooling with ice;

Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/257998, 2020, A1 Location in patent: Page/Page column 221-222
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2021/212638, 2021, A1 Location in patent: Page/Page column 191

60
[ 663921-15-1 ]
[ 24424-99-5 ]
[ 756525-91-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate In tetrahydrofuran; water at 20℃; Cooling with ice;
3.8 g	With potassium carbonate In tetrahydrofuran; water at 20℃; Cooling with ice;

Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/257998, 2020, A1 Location in patent: Page/Page column 221
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2021/212638, 2021, A1 Location in patent: Page/Page column 190-191

61
[ 1032900-25-6 ]
[ 756525-91-4 ]
C₄₄H₆₅ClN₆O₁₀S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h; Stage #2: 5-chloro-N²-{5-methyl-4-(piperidin-4-yl)-2-[(propan-2-yl)oxy]phenyl}-N⁴-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine With triethylamine In dichloromethane at 25℃; for 1h;	General procedure: N-tert-Butoxycarbonyl-beta-alanine (4.1mg, 21.5μmol) in dichloromethane (300μL) with EDCI (6.9mg, 35.8μmol) and NHS (4.1mg, 35.8μmol) stirred for 1h at room temperature, then the mixed reaction was added to the mixture solution of triethylamine (9.1mg, 12.5μL, 89.5μmol) and Ceritinib (1) (10mg, 17.9μmol) and stirred at 25°C for another 1h (monitored by TLC). After removal of the solvent, the residue was extracted with ethyl acetate (3×1mL), and the organic phase was washed with saturated sodium chloride. The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure to afford crude product 3a. Product 3a (7.3mg, 10μmol) was dissolved in dichloromethane (500μL), followed by the addition of trifluoroacetic acid (500μL). The mixture was stirred for 1h at room temperature, which was diluted with water (2mL) after removal of the solvent under reduced pressure, and then NaHCO3 aqueous solution was added dropwise until the solution was alkalized to pH 8-9. The aqueous phase was extracted with AcOEt (3×3mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product 4a. A solution containing MPA (2) (9.3mg, 15μmol), 2-(7-aza-1H-benzotriazole-1-yl)1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 7.6mg20μmoland dry DMSO (300μL) was cooled to 0°C. Product 4a (6.3mg, 10μmol) and DIPEA (6.5mg, 8.7μL, 50μmol) were added to the solution. The reaction mixture was stirred at room temperature for 2h. Subsequently, the crude product 5a was separated and purified by semi-preparative chromatography and the purified product 5a was confirmed by mass spectrometry. At last, the absorption and fluorescence spectra of YQ-L-5a was detected. The 1H NMR spectra of YQ-L-5a was showed in Supplemental Fig. 2.

Reference： [1]Xu, Haoran; Zhao, Yue; Gao, Xin; Wang, Fang; Gu, Yueqing [European Journal of Medicinal Chemistry, 2021, vol. 219]

62
[ 756525-91-4 ]
[ 1448189-80-7 ]
tert-butyl ((S)-17-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-18,18-dimethyl-15-oxo-3,6,9,12-tetraoxa-16-azanonadecyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With N-ethyl-N,N-diisopropylamine; 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℃; for 4h; Inert atmosphere;

Reference： [1]Dölle, Anja; Adhikari, Bikash; Krämer, Andreas; Weckesser, Janik; Berner, Nicola; Berger, Lena-Marie; Diebold, Mathias; Szewczyk, Magdalena M.; Barsyte-Lovejoy, Dalia; Arrowsmith, Cheryl H.; Gebel, Jakob; Löhr, Frank; Dötsch, Volker; Eilers, Martin; Heinzlmeir, Stephanie; Kuster, Bernhard; Sotriffer, Christoph; Wolf, Elmar; Knapp, Stefan [Journal of Medicinal Chemistry, 2021, vol. 64, # 15, p. 10682 - 10710]

63
[ 756525-91-4 ]
[ 140872-99-7 ]
C₃₅H₅₉N₇O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid 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 0.0833333h; Stage #2: N-(2-aminoethyl)-N'-cyano-N''-<3-<3-(1-piperidinylmethyl)phenoxy>propyl>guanidine In N,N-dimethyl-formamide for 18h;	To a solution of 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic-acid (65 mg, 0.18 mmol) in DMF (2.5 mL) was added HBTU (74 mg, 0.20 mmol) followed by DIPEA (46 μL, 0.36 mmol). The mixture was stirred at room temperature for 5 minutes and S102 (64 mg, 0.18 mmol) was added. The reaction mixture was stirred for 18 hours and the solvent was removed under vacuum. The crude yellow oil was purified by silica gel chromatography purified (5% 1M NH3 in MeOH/DCM) to provide 233 mg (81% yield) of carbamate S103 as a yellow oil.

Reference： [1]Boursier, Michelle E.; Hall, Mary P.; Hurst, Robin; Killoran, Michael P.; Kirkland, Thomas A.; Levin, Sergiy; Machleidt, Thomas; Ohana, Rachel Friedman; Zimmerman, Kristopher [Molecules, 2021, vol. 26, # 10]

64
[ 756525-91-4 ]
C₂₁H₂₆N₆O₂*2C₂HF₃O₂ [ No CAS ]
C₃₇H₅₅N₇O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 22℃; for 3h;	A 25 mL flask, equipped with stir bar, was charged with S107 (46 mg, 63 μmol), 2,2-dimethyl-4 oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid (29 mg, 78 μmol), HATU (30 mg, 78 μmol), EtN(iPr)2 (110 μL, 0.62 mmol), and DMF (6 mL). The resulting light-yellow solution was stirred at 22°C for 3 hours, at which point, HPLC indicated complete consumption of the staring material, and the solvent removed under reduced pressure. The crude residue was purified by preparative HPLC (C18, 5 → 95% MeCN/H2O, 0.05% TFA) yielding 25 mg (54% yield) of amide S108 as a clear oil.

Reference： [1]Boursier, Michelle E.; Hall, Mary P.; Hurst, Robin; Killoran, Michael P.; Kirkland, Thomas A.; Levin, Sergiy; Machleidt, Thomas; Ohana, Rachel Friedman; Zimmerman, Kristopher [Molecules, 2021, vol. 26, # 10]

65
[ 756525-91-4 ]
[ 894-71-3 ]
C₃₅H₅₀N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 22℃; for 6h;	A 25 mL flask, equipped with stir bar, was charged with Nortiptyline HCl (24 mg, 80μmol), 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid (37 mg, 100 μmol),HATU (38 mg, 100 μmol), EtN(iPr)2 (100 μL, 570 μmol), and DMF (8 mL). The resulting lightyellowsolution was stirred at 22°C for 6 hours at which point, HPLC indicated completeconsumption of the staring material and the solvent was removed under reduced pressure. Thecrude residue was purified by preparative HPLC (C18, 5 → 95% MeCN/H2O, 0.05% TFA),yielding 31 mg (63% yield) of amide NRT-01 as a clear residue.

Reference： [1]Boursier, Michelle E.; Hall, Mary P.; Hurst, Robin; Killoran, Michael P.; Kirkland, Thomas A.; Levin, Sergiy; Machleidt, Thomas; Ohana, Rachel Friedman; Zimmerman, Kristopher [Molecules, 2021, vol. 26, # 10]

66
[ 756525-91-4 ]
C₂₀H₂₃ClN₄O*2C₂HF₃O₂ [ No CAS ]
C₃₆H₅₂ClN₅O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 22℃; for 18h;	25 mL flask, equipped with stir bar, was charged with S081 (25 mg, 37 μmol), 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid (31 mg, 84 μmol), HATU (32 mg, 84 μmol), DIPEA (66 μL, 0.47 mmol), and DMF (6 mL). The resulting light-yellow solution was stirred at 22°C for 18 hours, at which point, HPLC indicated complete consumption of the staring material, and the solvent removed under reduced pressure. The crude residue was purified by preparative HPLC (C18, 5 → 95% MeCN/H2O, 0.05% TFA) yielding 41 mg (85% yield) of carbamate S082 as a clear oil.

Reference： [1]Boursier, Michelle E.; Hall, Mary P.; Hurst, Robin; Killoran, Michael P.; Kirkland, Thomas A.; Levin, Sergiy; Machleidt, Thomas; Ohana, Rachel Friedman; Zimmerman, Kristopher [Molecules, 2021, vol. 26, # 10]

67
[ 756525-91-4 ]
C₁₉H₂₅N₅S*2C₂HF₃O₂ [ No CAS ]
C₃₅H₅₄N₆O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 22℃; for 3h;	A 25 mL flask, equipped with stir bar, was charged with S087 (4.2 mg, 12 mmol), 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid (5.4 mg, 15 μmol), HATU (5.6 mg, 15 μmol), DIPEA (16 μL, 11 μmmol), and DMF (6 mL). The resulting light-yellow solution was stirred at 22°C for 3 hours, at which point, HPLC indicated complete consumption of the staring material, and the solvent removed under reduced pressure. The crude residue was purified by preparative HPLC (C18, 5 → 95% MeCN/H2O, 0.05% TFA) yielding 9 mg (quantitative) of carbamate S088 as a yellow oil.

Reference： [1]Boursier, Michelle E.; Hall, Mary P.; Hurst, Robin; Killoran, Michael P.; Kirkland, Thomas A.; Levin, Sergiy; Machleidt, Thomas; Ohana, Rachel Friedman; Zimmerman, Kristopher [Molecules, 2021, vol. 26, # 10]

68
[ 756525-91-4 ]
2-methoxyindolizine [ No CAS ]
tert-butyl (15-(2-methoxyindolizin-3-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.6%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 30℃; for 20h; Inert atmosphere;

Reference： [1]Watanabe, Kenji; Terao, Nodoka; Niwa, Takashi; Hosoya, Takamitsu [Journal of Organic Chemistry, 2021, vol. 86, # 17, p. 11822 - 11834]

69
[ 756525-91-4 ]
(2S)-N-[(3S)-1-(4-aminobenzoyl)-5-[(2-methoxy-1-naphthyl)methyl]-4-oxo-2,3-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide [ No CAS ]
tert-butyl (15-((4-((S)-5-((2-methoxynaphthalen-1-yl)methyl)-3-((S)-2-(methylamino)propanamido)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-1-carbonyl)phenyl)amino)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10.4 mg	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; water at 20℃;

Reference： [1]Besten, Willem Den; Blaquiere, Nicole; Dueber, Erin; Fairbrother, Wayne J.; Goncharov, Tatiana; Helgason, Elizabeth; Izrael-Tomasevic, Anita; Mulvihill, Melinda M.; Phung, Wilson; Prakash, Sumit; Staben, Steven T.; Verma, Kshitij; Vucic, Domagoj; Wertz, Ingrid; Yamazoe, Sayumi; Yu, Kebing [Journal of the American Chemical Society, 2021, vol. 143, # 28, p. 10571 - 10575]

70
[ 756525-91-4 ]
(2S)-N-[(3S)-1-(4-aminobenzoyl)-5-[(2-methoxy-1-naphthyl)methyl]-4-oxo-2,3-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide [ No CAS ]
1-amino-N-(4-((S)-5-((2-methoxynaphthalen-1-yl)methyl)-3-((S)-2-(methylamino)propanamido)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-1-carbonyl)phenyl)-3,6,9,12-tetraoxapentadecan-15-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / tetrahydrofuran; water / 20 °C 2: trifluoroacetic acid / dichloromethane / 0.25 h / 20 °C

Reference： [1]Besten, Willem Den; Blaquiere, Nicole; Dueber, Erin; Fairbrother, Wayne J.; Goncharov, Tatiana; Helgason, Elizabeth; Izrael-Tomasevic, Anita; Mulvihill, Melinda M.; Phung, Wilson; Prakash, Sumit; Staben, Steven T.; Verma, Kshitij; Vucic, Domagoj; Wertz, Ingrid; Yamazoe, Sayumi; Yu, Kebing [Journal of the American Chemical Society, 2021, vol. 143, # 28, p. 10571 - 10575]

71
[ 756525-91-4 ]
7-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-3-([(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one monohydrochloride [ No CAS ]
tert-butyl N-[14-([(3R)-1-[1-cyclopropyl-6-fluoro-3-([(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]pyrrolidin-3-yl]methyl}carbamoyl)-3,6,9,12-tetraoxatetradecan-1-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 24h;	15A Preparation of tert-butyl N-[14-([(3R)-1-[1-cyclopropyl-6-fluoro-3-([(3S)-1-(6-methylpyridin-3- yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]pyr- rolidin-3-yl]methyl}carbamoyl)-3,6,9,12-tetraoxatetradecan-1-yl]carbamate 1-[(tert-butoxy)carbonyl]amino}-3,6,9,12-tetraoxapentadecan-15-oic acid (0.207 g, 1.5 eq) and HATU ( 0.172 g, 1.2 eq.) were dissolved in dry DMF( 5.0 ml ) then 7-[(3R)-3-(aminomethyl)pyr- rolidin-1-yl]-1-cyclopropyl-6-fluoro-3-([(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyri- din-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one (Example 15) ( 0.230 g, 1.0 eq.) and TEA ( 0.160 ml, 3.0 eq.) were added, reaction was stirred at RT for 24 h. Crude was evaporated and extracted (DCM / NaOH aq). Organic layers were combined, dried over Na2SO4, filtered and evaporated. Product was purified by FCC (SiHP; DCM : MeOH). The titled compound was obtained (0.30 g, yield 84%) as a brown oil. ESI-MS: 957.9 [M+H]+

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA - WO2021/116446, 2021, A1 Location in patent: Page/Page column 264

72
[ 756525-91-4 ]
C₂₇H₃₀N₆O₃ [ No CAS ]
C₄₃H₅₉N₇O₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	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 20h;

Reference： [1]Yokoo, Hidetomo; Shibata, Norihito; Endo, Akinori; Ito, Takahito; Yanase, Yuta; Murakami, Yuki; Fujii, Kiyonaga; Hamamura, Kengo; Saeki, Yasushi; Naito, Mikihiko; Aritake, Kosuke; Demizu, Yosuke [Journal of Medicinal Chemistry, 2021, vol. 64, # 21, p. 15868 - 15882]

73
[ 756525-91-4 ]
C₂₄H₃₀N₆O₃ [ No CAS ]
C₄₀H₅₉N₇O₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide	1 Synthesis of compound 9: Put In the above compound 8 and 5,8,11,14-tetraoxa-2-azaheptadecandioic acid-1-tert-butyl ester (0.19g, 1.0mmol), HATU (0.38g, 1.0mmol) and N,N-diisopropylethylamine (0.26g, 2.0mmol) and 10mL N,N-dimethylformamide. The reaction mixture was stirred overnight, and the solvent was distilled off under reduced pressure to obtain a crude product. After purification on a silica gel column (dichloromethane/methanol=50:1), a white solid compound 9 was obtained with a yield of 64%.

Reference： [1]Current Patent Assignee: SHANGHAI LANNACHENG BIOTECHNOLOGY - CN113582975, 2021, A Location in patent: Paragraph 0103; 0118-0119; 0123

74
[ 756525-91-4 ]
(2S,4R)-1-((2S,25S)-2-(tert-butyl)-25-(4-chlorophenyl)-26-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4,20,26-trioxo-7,10,13,16-tetraoxa-3,19,23-triazahexacosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide trifluoroacetic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / dimethyl sulfoxide / 20 °C 2: trifluoroacetic acid / water / 20 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / dimethyl sulfoxide / 12 h / 20 °C

Reference： [1]Cahuzac, Kaitlyn M.; Chen, Xian; Jin, Jian; Liu, Jing; Parsons, Ramon E.; Shen, Yudao; Wang, Li; Xie, Ling; Xu, Jia; Yu, Xufen [Journal of Medicinal Chemistry, 2021, vol. 64, # 24, p. 18054 - 18081]

75
[ 756525-91-4 ]
C₆₀H₈₆N₁₂O₁₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / dimethyl sulfoxide / 20 °C 2: trifluoroacetic acid / water / 20 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / dimethyl sulfoxide / 12 h / 20 °C

Reference： [1]Cahuzac, Kaitlyn M.; Chen, Xian; Jin, Jian; Liu, Jing; Parsons, Ramon E.; Shen, Yudao; Wang, Li; Xie, Ling; Xu, Jia; Yu, Xufen [Journal of Medicinal Chemistry, 2021, vol. 64, # 24, p. 18054 - 18081]

76
[ 756525-91-4 ]
(2S,4R)-1-((S)-27-((2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxy-3-methylbut-1-yn-1-yl)-1H-imidazo[4,5-c]pyridin-7-yl)oxy)-2-(tert-butyl)-4,20-dioxo-7,10,13,16-tetraoxa-3,19,24-triazaheptacosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide trifluoroacetic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / dimethyl sulfoxide / 20 °C 2: trifluoroacetic acid / water / 20 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / dimethyl sulfoxide / 12 h / 20 °C 4: dichloromethane / 0.5 h / 20 °C

Reference： [1]Cahuzac, Kaitlyn M.; Chen, Xian; Jin, Jian; Liu, Jing; Parsons, Ramon E.; Shen, Yudao; Wang, Li; Xie, Ling; Xu, Jia; Yu, Xufen [Journal of Medicinal Chemistry, 2021, vol. 64, # 24, p. 18054 - 18081]

77
[ 756525-91-4 ]
3,5-bis(5-(methylthio)-1,3,4-oxadiazol-2-yl)aniline [ No CAS ]
C₂₈H₄₀N₆O₉S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine; ethyl cyanoglyoxylate-2-oxime In N,N-dimethyl-formamide at 50℃; for 18h; Inert atmosphere;	To continue efforts to search for a higher yielding route forward, bis(methyl thioether) 7 was used as a starting point to test a new set of peptide coupling conditions: oxyma with 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) (FIG. 11A and FIG. 11B). At room temperature, this reaction yielded <10% of the desired product (compound 11), with mass spectrometry revealing the presence of unreacted starting material 7 as well as the O-acylisourea-activated EDC intermediate. Suspecting that the EDC intermediate was trapped in a step with an energy barrier that was impassable at room temperature, we repeated the same reaction at 50° C. This time, the PEGylated product 11 was obtained in 55% yield. To complete the sequence, 11 was then oxidized with mCPBA to create bis(methylsulfonyl) 12 in 73% yield, and-finally-compound 12 was deprotected to provide DiPODS (DiPODS-PEG4-NH2) in 90% yield. This synthesis was concluded with an 8-step synthetic route to produce DiPODS with a cumulative yield of 15%. As synthesized, DiPODS is modular and can be coupled to any number of different bifunctional chelators, dyes, or other payloads. The primary amine of DiPODS can be reacted with a number of electrophilic bioconjugation reagents such as activated esters or phenyl-isothiocyanates.

Reference： [1]Current Patent Assignee: CITY UNIVERSITY OF NEW YORK - US2022/24904, 2022, A1 Location in patent: Paragraph 0031; 0067; 0072

78
[ 756525-91-4 ]
heptadecan-9-yl 8-((8-(nonyloxy)-8-oxooctyl)amino)octanoate [ No CAS ]
nonyl 8-[3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoyl-[8-(1-octylnonoxy)-8-oxooctyl]amino]octanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.4%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane; N,N-dimethyl-formamide at 20℃; for 18h;	21.1 Step (1) To the solution of nonyl 8-[[8-(l-octylnonoxy)-8-oxo-octyl]amino]octanoate (1.00 g, 1.51 mmol) in anhydrous DMF (10 mL) and anhydrous DCM (2 mL) was added 3-[2-[2-[2- [2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (551 mg, 1.51 mmol), HATU(0.859 g,2.26 mmol) and DIPEA(0.389 g,3.01 mmol). The mixture was stirred at room temperature for 18 h. TLC (4% methanol in DCM) indicated that the reaction was finished. The solvent was removed under vacuum and the residue was partitioned between H2O (20 mL) and ethyl acetate (250 mL). The organic layer was washed with brine (50 mL3), dried over Na2SC>4. The residue was purified by flash chromatography column eluted with 0% to 3%(2%) methanol in dichloromethane to give nonyl 8-[3-[2-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoyl-[8-(l-octylnonoxy)-8-oxo- octyl]amino]octanoate (1.319 g, 1.3 mmol, 86.4% yield). 1H NMR (500 MHz, CDCL) d 5.12 (s, 1H), 4.90 - 4.82 (m, 1H), 4.08 - 4.01 (m, 2H), 3.78 (t, J = 6.8 Hz, 2H), 3.69 - 3.60 (m, 12H), 3.55 (t, J = 5.0 Hz, 2H), 3.36 - 3.16 (m, 6H), 2.62 (t, J = 6.7 Hz, 2H), 2.33 - 2.23 (m, 4H), 1.65 - 1.47 (m, 14H), 1.44 (s, 9H), 1.35 - 1.23 (m, 48H), 0.90 - 0.85 (m, 9H).
86.4%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane; N,N-dimethyl-formamide at 20℃; for 18h;	21.1 Step (1) To the solution of nonyl 8-[[8-(l-octylnonoxy)-8-oxo-octyl]amino]octanoate (1.00 g, 1.51 mmol) in anhydrous DMF (10 mL) and anhydrous DCM (2 mL) was added 3-[2-[2-[2- [2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (551 mg, 1.51 mmol), HATU(0.859 g,2.26 mmol) and DIPEA(0.389 g,3.01 mmol). The mixture was stirred at room temperature for 18 h. TLC (4% methanol in DCM) indicated that the reaction was finished. The solvent was removed under vacuum and the residue was partitioned between H2O (20 mL) and ethyl acetate (250 mL). The organic layer was washed with brine (50 mL3), dried over Na2SC>4. The residue was purified by flash chromatography column eluted with 0% to 3%(2%) methanol in dichloromethane to give nonyl 8-[3-[2-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoyl-[8-(l-octylnonoxy)-8-oxo- octyl]amino]octanoate (1.319 g, 1.3 mmol, 86.4% yield). 1H NMR (500 MHz, CDCL) d 5.12 (s, 1H), 4.90 - 4.82 (m, 1H), 4.08 - 4.01 (m, 2H), 3.78 (t, J = 6.8 Hz, 2H), 3.69 - 3.60 (m, 12H), 3.55 (t, J = 5.0 Hz, 2H), 3.36 - 3.16 (m, 6H), 2.62 (t, J = 6.7 Hz, 2H), 2.33 - 2.23 (m, 4H), 1.65 - 1.47 (m, 14H), 1.44 (s, 9H), 1.35 - 1.23 (m, 48H), 0.90 - 0.85 (m, 9H).

Reference： [1]Current Patent Assignee: SANOFI - WO2022/13443, 2022, A1 Location in patent: Page/Page column 157; 158
[2]Current Patent Assignee: SANOFI - WO2022/13443, 2022, A1 Location in patent: Page/Page column 157; 158

79
[ 756525-91-4 ]
heptadecan-9-yl ((2-aminoethyl)(8-(nonyloxy)-8-oxooctyl)amino)octanoate [ No CAS ]
nonyl 8-[2-[3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]ethyl-[8-(1-octylnonoxy)-8-oxooctyl]amino]octanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64.8%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 18h;	22.3 Step (3) To a solution of nonyl 8-[2-aminoethyl-[8-(l-octylnonoxy)-8-oxo- octyl]amino]octanoate (1.33 g, 0.00187 mol) in dichloromethane (10 ml) was added 3-[2- [2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (0.684 g, 0.00187mol), DIPEA (0.484 g, 0.00375 mol),HATU (1.07 g, 0.00281 mol). The mixture was stirred at 25°C for 18 h. After reaction, the mixture was diluted with DCM (100 ml), washed with water (300 ml x2), brine (300 ml), dried over NaiSCU. The organic was concentrated and purified by flash chromatography column eluted with 20% ethyl acetate in petroleum ether to give nonyl 8-[2-[3-[2-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]ethyl-[8- (1- octylnonoxy)-8-oxo-octyl]amino]octanoate (1.28 g, yield 64.8 %) as a colourless oil. lH NMR (500 MHz, CDCI3) d 5.14 - 5.06 (m, 1H), 4.91 - 4.81 (m, 1H), 4.09 - 4.01 (m, 2H), 3.80 - 3.70 (m, 3H), 3.68 - 3.59 (m, 14H), 3.56 - 3.50 (m, 2H), 3.41 - 3.22(m, 4H), 2.51 - 2.41 (m, 4H), 2.32 - 2.24 (m, 4H), 2.05 - 1.85 (m, 2H), 1.65 - 1.57 (m, 6H), 1.53 - 1.40 (m, 17H), 1.37 - 1.22 (m, 48H), 0.92 - 0.83 (m, 9H).
64.8%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 18h;	22.3 Step (3) To a solution of nonyl 8-[2-aminoethyl-[8-(l-octylnonoxy)-8-oxo- octyl]amino]octanoate (1.33 g, 0.00187 mol) in dichloromethane (10 ml) was added 3-[2- [2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (0.684 g, 0.00187mol), DIPEA (0.484 g, 0.00375 mol),HATU (1.07 g, 0.00281 mol). The mixture was stirred at 25°C for 18 h. After reaction, the mixture was diluted with DCM (100 ml), washed with water (300 ml x2), brine (300 ml), dried over NaiSCU. The organic was concentrated and purified by flash chromatography column eluted with 20% ethyl acetate in petroleum ether to give nonyl 8-[2-[3-[2-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]ethyl-[8- (1- octylnonoxy)-8-oxo-octyl]amino]octanoate (1.28 g, yield 64.8 %) as a colourless oil. lH NMR (500 MHz, CDCI3) d 5.14 - 5.06 (m, 1H), 4.91 - 4.81 (m, 1H), 4.09 - 4.01 (m, 2H), 3.80 - 3.70 (m, 3H), 3.68 - 3.59 (m, 14H), 3.56 - 3.50 (m, 2H), 3.41 - 3.22(m, 4H), 2.51 - 2.41 (m, 4H), 2.32 - 2.24 (m, 4H), 2.05 - 1.85 (m, 2H), 1.65 - 1.57 (m, 6H), 1.53 - 1.40 (m, 17H), 1.37 - 1.22 (m, 48H), 0.92 - 0.83 (m, 9H).

Reference： [1]Current Patent Assignee: SANOFI - WO2022/13443, 2022, A1 Location in patent: Page/Page column 159; 160
[2]Current Patent Assignee: SANOFI - WO2022/13443, 2022, A1 Location in patent: Page/Page column 159; 160

80
[ 756525-91-4 ]
heptadecan-9-yl 8-((2-hydroxyethyl)(8-(nonyloxy)-8-oxooctyl)amino)octanoate [ No CAS ]
nonyl 8-[2-[3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoyloxy]ethyl-[8-(1-octylnonoxy)-8-oxo-octyl]amino]octanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.6%	With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 18h;	19.1 Synthesis of compound (XX) Step (1) To a solution of nonyl 8-[2-hydroxyethyl-[8-(l-octylnonoxy)-8-oxo- octyl]amino]octanoate (1.00 g, 1.41 mmol) and 3- [2- [2- [2- [2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (0.772 g,2.11 mmol) in dry DCM (10 mL) was added DMAP (17.2 mg, 0.141 mmol), DIPEA (0.218 g,1.69 mmol) and then added EDCI(0.324 g,1.69 mmol) at 0°C. The reaction was stirred at room temperature for 18 hrs. TLC indicated that the starting material was disappeared and a new spot formed. Water (20 mL) was added to quench the reaction and the mixture was extracted with DCM (50 mL). The organic layer was washed with saturated sodium bicarbonate and dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-5% CH3OH in DCM (3%)) to give nonyl 8-[2-[3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy] ethoxy]ethoxy]ethoxy]propanoyloxy]ethyl-[8-(l-octylnonoxy)-8-oxo-octyl]amino]octanoate (1.126 g, 1.06 mmol, 75.6 %yield) as colorless oil. 1H NMR (400 MHz, CDC13) d 5.07 (s, 1H), 4.92 - 4.81 (m, 1H), 4.16 - 4.02 (m, 4H), 3.78 - 3.72 (m, 2H), 3.68 - 3.58 (m, 12H), 3.58 - 3.50 (m, 2H), 3.37 - 3.26 (m, 2H), 2.71 - 2.57 (m, 4H), 2.47 - 2.38 (m, 4H), 2.33 - 2.24 (m, 4H), 1.66 - 1.56 (m, 6H), 1.53 - 1.22 (m, 65H), 0.92 - 0.83 (m, 9H).
75.6%	With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 18h;	19.1 Synthesis of compound (XX) Step (1) To a solution of nonyl 8-[2-hydroxyethyl-[8-(l-octylnonoxy)-8-oxo- octyl]amino]octanoate (1.00 g, 1.41 mmol) and 3- [2- [2- [2- [2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (0.772 g,2.11 mmol) in dry DCM (10 mL) was added DMAP (17.2 mg, 0.141 mmol), DIPEA (0.218 g,1.69 mmol) and then added EDCI(0.324 g,1.69 mmol) at 0°C. The reaction was stirred at room temperature for 18 hrs. TLC indicated that the starting material was disappeared and a new spot formed. Water (20 mL) was added to quench the reaction and the mixture was extracted with DCM (50 mL). The organic layer was washed with saturated sodium bicarbonate and dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-5% CH3OH in DCM (3%)) to give nonyl 8-[2-[3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy] ethoxy]ethoxy]ethoxy]propanoyloxy]ethyl-[8-(l-octylnonoxy)-8-oxo-octyl]amino]octanoate (1.126 g, 1.06 mmol, 75.6 %yield) as colorless oil. 1H NMR (400 MHz, CDC13) d 5.07 (s, 1H), 4.92 - 4.81 (m, 1H), 4.16 - 4.02 (m, 4H), 3.78 - 3.72 (m, 2H), 3.68 - 3.58 (m, 12H), 3.58 - 3.50 (m, 2H), 3.37 - 3.26 (m, 2H), 2.71 - 2.57 (m, 4H), 2.47 - 2.38 (m, 4H), 2.33 - 2.24 (m, 4H), 1.66 - 1.56 (m, 6H), 1.53 - 1.22 (m, 65H), 0.92 - 0.83 (m, 9H).

Reference： [1]Current Patent Assignee: SANOFI - WO2022/13443, 2022, A1 Location in patent: Page/Page column 149; 150
[2]Current Patent Assignee: SANOFI - WO2022/13443, 2022, A1 Location in patent: Page/Page column 149; 150

81
[ 756525-91-4 ]
N-[2,3-bis[(Z)-octadec-9-enoxy]propyl]octan-1-amine [ No CAS ]
tert-butyl N-[2-[2-[2-[2-[3-[2,3-bis[(Z)-octadec-9-enoxy]propyloctylamino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.5%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 16h;	14.3 Step (3) A mixture of 3- [2- [2- [2- [2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (0.4 g, 1.09 mmol), bis(dimethylamino)methylene-(triazolo[4,5-b]pyridin-3-yl)oxonium;hexafluorophosphate (0.624 g, 1.64 mmol), DIEA (0.283 g, 2.19 mmol) and N-[2,3-bis[(Z)-octadec-9- enoxy]propyl]octan-l -amine (0.771 g, 1.09 mmol) in DCM (10 mL) was stirred for 16 h at ambient temperature. The mixture was poured into DCM (100 mL). The organic layer was washed with 1 N HC1, sat NaCl, dried over NaS04 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with l:81ethyl acetate /petroleum ether to give tert-butyl N-[2-[2-[2-[2-[3-[2,3-bis[(Z)-octadec-9-enoxy]propyl-octyl-amino]-3-oxo- propoxy] ethoxy] ethoxy] ethoxy]ethyl]carbamate (0.95 g, 82.5%) as colourless oil.1H NMR (400 MHz, CDC13) d 5.36 (dt, J = 10.6, 4.7 Hz, 3H), 3.84 - 3.16 (m, 31H), 2.69 - 2.61 (m, 2H), 2.07 - 1.93 (m, 6H), 1.60 - 1.47 (m, 6H), 1.44 (s, 9H), 1.23 (d, J = 33.4 Hz, 56H), 0.91 - 0.85 (m, 9H).
82.5%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 16h;	14.3 Step (3) A mixture of 3- [2- [2- [2- [2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (0.4 g, 1.09 mmol), bis(dimethylamino)methylene-(triazolo[4,5-b]pyridin-3-yl)oxonium;hexafluorophosphate (0.624 g, 1.64 mmol), DIEA (0.283 g, 2.19 mmol) and N-[2,3-bis[(Z)-octadec-9- enoxy]propyl]octan-l -amine (0.771 g, 1.09 mmol) in DCM (10 mL) was stirred for 16 h at ambient temperature. The mixture was poured into DCM (100 mL). The organic layer was washed with 1 N HC1, sat NaCl, dried over NaS04 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with l:81ethyl acetate /petroleum ether to give tert-butyl N-[2-[2-[2-[2-[3-[2,3-bis[(Z)-octadec-9-enoxy]propyl-octyl-amino]-3-oxo- propoxy] ethoxy] ethoxy] ethoxy]ethyl]carbamate (0.95 g, 82.5%) as colourless oil.1H NMR (400 MHz, CDC13) d 5.36 (dt, J = 10.6, 4.7 Hz, 3H), 3.84 - 3.16 (m, 31H), 2.69 - 2.61 (m, 2H), 2.07 - 1.93 (m, 6H), 1.60 - 1.47 (m, 6H), 1.44 (s, 9H), 1.23 (d, J = 33.4 Hz, 56H), 0.91 - 0.85 (m, 9H).

Reference： [1]Current Patent Assignee: SANOFI - WO2022/13443, 2022, A1 Location in patent: Page/Page column 125-128
[2]Current Patent Assignee: SANOFI - WO2022/13443, 2022, A1 Location in patent: Page/Page column 125-128

82
[ 756525-91-4 ]
1,3-bis(2-azidoethoxy)-2-[(2-azidoethoxy)methyl]propan-2-amine [ No CAS ]
tert-butyl N-(14-[1 3-bis(2-azidoethoxy)-2-[(2-azidoethoxy)methyl]propan-2-yl]carbamoyl}-3,6,9,12-tetraoxatetradecan-1-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid With 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℃; for 0.0833333h; Stage #2: 1,3-bis(2-azidoethoxy)-2-[(2-azidoethoxy)methyl]propan-2-amine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h;	16.16C Example 160: teit-Butyl N-(1 4-[1 ,3-bis(2-azidoethoxy)-2-[(2-azidoethoxy) methyl] propan-2-yl]carbamoyl}-3,6, 9,1 2-tetraoxatetradecan- 1 -yl)carbamate (BL3-6) To a solution of compound BL3-5 (53 mg, 0.14 mmol) in DMF (3 mL) was added HATU (69 mg, 0.18 mmol), and the mixture was stirred at RT for 5 minutes. To the stirred solution were added a solution of crude compound BL3-4 (43 mg), which was obtained above, in DMF (1 mL) and DIPEA (50 mg, 0.39 mmol) successively. The resulting mixture was stirred at RT for an hour. Reaction completion was monitored by LCMS. The reaction solution was directly purified by reversed phase flash chromatography (0-100% acetonitrile in aq. ammonium bicarbonate (10 mM)) to give compound BL3-6 (65 mg, 73% yield in 2 steps) as a colorless oil. ESI m/z: 676.4 (M + H).
73%	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid With 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℃; for 0.0833333h; Stage #2: 1,3-bis(2-azidoethoxy)-2-[(2-azidoethoxy)methyl]propan-2-amine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h;	16.16C Example 160: teit-Butyl N-(1 4-[1 ,3-bis(2-azidoethoxy)-2-[(2-azidoethoxy) methyl] propan-2-yl]carbamoyl}-3,6, 9,1 2-tetraoxatetradecan- 1 -yl)carbamate (BL3-6) To a solution of compound BL3-5 (53 mg, 0.14 mmol) in DMF (3 mL) was added HATU (69 mg, 0.18 mmol), and the mixture was stirred at RT for 5 minutes. To the stirred solution were added a solution of crude compound BL3-4 (43 mg), which was obtained above, in DMF (1 mL) and DIPEA (50 mg, 0.39 mmol) successively. The resulting mixture was stirred at RT for an hour. Reaction completion was monitored by LCMS. The reaction solution was directly purified by reversed phase flash chromatography (0-100% acetonitrile in aq. ammonium bicarbonate (10 mM)) to give compound BL3-6 (65 mg, 73% yield in 2 steps) as a colorless oil. ESI m/z: 676.4 (M + H).

Reference： [1]Current Patent Assignee: REGENERON PHARMACEUTICALS INC - WO2022/15656, 2022, A1 Location in patent: Paragraph 0775; 0776; 0781; 0782
[2]Current Patent Assignee: REGENERON PHARMACEUTICALS INC - WO2022/15656, 2022, A1 Location in patent: Paragraph 0775; 0776; 0781; 0782

83
[ 756525-91-4 ]
[ 191732-72-6 ]
C₂₉H₄₂N₄O₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 1h;

Reference： [1]Barr, Haim; Gabizon, Ronen; Gurwicz, Neta; London, Nir; Prasad, Pragati Kishore; Reddi, Rambabu N.; Resnick, Efrat; Rogel, Adi; Shulman, Ziv [Journal of the American Chemical Society, 2021, vol. 143, # 48, p. 20095 - 20108]

84
[ 756525-91-4 ]
1-amino-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-3,6,9,12-tetraoxapentadecan-15-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 25 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 25 °C

Reference： [1]Barr, Haim; Gabizon, Ronen; Gurwicz, Neta; London, Nir; Prasad, Pragati Kishore; Reddi, Rambabu N.; Resnick, Efrat; Rogel, Adi; Shulman, Ziv [Journal of the American Chemical Society, 2021, vol. 143, # 48, p. 20095 - 20108]

85
[ 756525-91-4 ]
1-(2-(((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)methyl)acrylamido)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-3,6,9,12-tetraoxapentadecan-15-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 25 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 25 °C 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 25 °C

Reference： [1]Barr, Haim; Gabizon, Ronen; Gurwicz, Neta; London, Nir; Prasad, Pragati Kishore; Reddi, Rambabu N.; Resnick, Efrat; Rogel, Adi; Shulman, Ziv [Journal of the American Chemical Society, 2021, vol. 143, # 48, p. 20095 - 20108]

86
[ 756525-91-4 ]
C₈₄H₈₈N₁₁O₁₀Pol [ No CAS ]
C₁₀₀H₁₁₇N₁₂O₁₇Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; ethyl cyanoglyoxylate-2-oxime In N,N-dimethyl-formamide at 20℃; for 2h; Further stages;

Reference： [1]Chen, Kuo-Ting; Dalm, Simone U.; Haeck, Joost; Handula, Maryana; Seimbille, Yann; Verhoeven, Marjolein; de Jong, Marion [Pharmaceutics, 2022, vol. 14, # 1]

87
[ 756525-91-4 ]
C₈₄H₈₈N₁₁O₁₀Pol [ No CAS ]
C₉₅H₁₀₉N₁₂O₁₅Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid; C₈₄H₈₈N₁₁O₁₀Pol With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; ethyl cyanoglyoxylate-2-oxime In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: With piperidine In N,N-dimethyl-formamide Further stages;

Reference： [1]Chen, Kuo-Ting; Dalm, Simone U.; Haeck, Joost; Handula, Maryana; Seimbille, Yann; Verhoeven, Marjolein; de Jong, Marion [Pharmaceutics, 2022, vol. 14, # 1]

88
[ 756525-91-4 ]
(x)C₂HF₃O₂*C₂₂H₃₀N₄O₃S [ No CAS ]
tert‐butyl N‐(14‐[(2S)‐1‐[(2S,4R)‐4‐hydroxy‐2‐([4‐(4‐methyl‐1,3‐thiazol‐5‐yl)phenyl]methyl}carbamoyl)pyrrolidin‐1‐yl]‐3,3‐dimethyl‐1‐oxobutan‐2‐yl]carbamoyl}‐3,6,9,12‐tetraoxatetradecan‐1‐yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43 mg	With N-ethyl-N,N-diisopropylamine; 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℃; for 18h;	General method C for amide coupling. General procedure: The deprotected amine TFA salt (1.00 eq.) was dissolved in N,N-dimethylformamide (DMF) (2 mL). The carboxylic acid (1.00 eq.) was then added to the solution, followed by hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) (1.10 eq.) and DIPEA (4.00 eq.). The reaction mixture was then stirred at room temperature for 18 h before water was added. It was then extracted three times with DCM, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was then purified by column chromatography on silica gel using a gradient of 5 to 30% of methanol in dichloromethane.
43 mg	With N-ethyl-N,N-diisopropylamine; 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℃; for 18h;	General method C for amide coupling. General procedure: The deprotected amine TFA salt (1.00 eq.) was dissolved in N,N-dimethylformamide (DMF) (2 mL). The carboxylic acid (1.00 eq.) was then added to the solution, followed by hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) (1.10 eq.) and DIPEA (4.00 eq.). The reaction mixture was then stirred at room temperature for 18 h before water was added. It was then extracted three times with DCM, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was then purified by column chromatography on silica gel using a gradient of 5 to 30% of methanol in dichloromethane.

Reference： [1]Aublette, Marine C.; Gadd, Morgan S.; Harrison, Tom A.; Thorpe, Elizabeth J. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 64]
[2]Aublette, Marine C.; Gadd, Morgan S.; Harrison, Tom A.; Thorpe, Elizabeth J. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 64]

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	756525-91-4	MDL No. :	MFCD07781254
Formula :	C₁₆H₃₁NO₈	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YEIYIPDFZMLJQH-UHFFFAOYSA-N
M.W :	365.42	Pubchem ID :	2756001
Synonyms :		Chemical Name :	2,2-Dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid

Num. heavy atoms :	25
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.88
Num. rotatable bonds :	18
Num. H-bond acceptors :	8.0
Num. H-bond donors :	2.0
Molar Refractivity :	89.65
TPSA :	112.55 Å²

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) :	-8.64 cm/s

Log Po/w (iLOGP) :	3.73
Log Po/w (XLOGP3) :	-0.16
Log Po/w (WLOGP) :	1.05
Log Po/w (MLOGP) :	-0.44
Log Po/w (SILICOS-IT) :	1.75
Consensus Log Po/w :	1.19

[ CAS No. 756525-91-4 ] {[proInfo.proName]}

Quality Control of [ 756525-91-4 ]

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[ 756525-91-4 ] Synthesis Path-Upstream 1~1

[ 756525-91-4 ] Synthesis Path-Downstream 1~88

Related Functional Groups of
[ 756525-91-4 ]

Aliphatic Chain Hydrocarbons

Ethers

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Lipinski :	0.0
Ghose :	None
Veber :	1.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Log S (ESOL) :	-0.82
Solubility :	55.7 mg/ml ; 0.152 mol/l
Class :	Very soluble
Log S (Ali) :	-1.75
Solubility :	6.52 mg/ml ; 0.0178 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.17
Solubility :	0.25 mg/ml ; 0.000684 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	3.63

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

Precautionary Statements-General
Code	Phrase
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P222	Do not allow contact with air.
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P233	Keep container tightly closed.
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Code	Phrase
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P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
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P370	In case of fire:
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P372	Explosion risk in case of fire.
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P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
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P401
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P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
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[ CAS No. 756525-91-4 ] {[proInfo.proName]}

Quality Control of [ 756525-91-4 ]

Related Doc. of [ 756525-91-4 ]

Product Details of [ 756525-91-4 ]

Calculated chemistry of [ 756525-91-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 756525-91-4 ]

Application In Synthesis of [ 756525-91-4 ]

[ 756525-91-4 ] Synthesis Path-Upstream 1~1

[ 756525-91-4 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 756525-91-4 ]

Aliphatic Chain Hydrocarbons

Ethers

Amides

Amines

Carboxylic Acids

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 756525-91-4 ]