Name: CDI
Brand: Ambeed
SKU: A691302
Rating: 4.8 (27 reviews)

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CDI Crosslinker is a highly reactive carboxylating agent. CDI Crosslinker can be used as a coupling reagent.

4.5 *For Research Use Only !

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Quality Control of CDI Purity: 98% SDS Specification

COA

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Product Citations Show More

Colon-Targeted β3-Adrenoceptor Agonist Mirabegron Enhances Anticolitic Potency of the Drug via Potentiating the Nrf2-HO-1 Pathway

Kim, Jaejeong ; Kang, Changyu ; Yoo, Jin-Wook ; Yoon, In-Soo ; Jung, Yunjin ;

DOI: 10.1021/acs.molpharmaceut.4c01041 PubMed ID: 40241685 Mol. Pharmaceutics,2025,22(5):2431-2445.

Abstract: The selective agonist of β₂-adrenergic receptor mirabegron (MBG), clinically used to treat overactive bladders, exerts beneficial effects in animal models of colitis. Here, we aimed to enhance the therapeutic activity and safety of MBG as an anticolitic drug by implementing colon-targeted drug delivery using a prodrug approach. MBG was azo-linked with salicylic acid (SA) to yield SA-conjugated MBG (MAS), which was conjugated with aspartic acid (Asp) and glutamic acid (Glu) to yield more hydrophilic derivatives: Asp-conjugated MAS (MAS-Asp) and Glu-conjugated MAS (MAS-Glu). MBG derivatives reduced the distribution coefficient and cell permeability of MBG, which were greater with the amino acid-conjugated MAS than with MAS. MBG derivatives were cleaved to release MBG in the cecal contents. Upon oral gavage, compared with MBG, MBG derivatives delivered greater amounts of MBG to the cecum while limiting the systemic absorption of MBG, and the amino acid-conjugated MAS exhibited a greater performance than MAS. In a rat colitis model, MBG derivatives were more effective than MBG in ameliorating colonic damage and inflammation, and the amino acid-conjugated MAS was more potent than MAS. MAS-Glu was therapeutically superior to sulfasalazine, a current drug to treat inflammatory bowel disease, against rat colitis. Moreover, MBG activated the anti-inflammatory nuclear factor erythroid 2-related factor 2 (Nrf2)-hemeoxygenase (HO)-1 pathway in inflamed colonic tissue, and the MAS-Glu-mediated amelioration of colitis was significantly compromised by an HO-1 inhibitor. Taken together, colon-targeted delivery of MBG may enhance the anticolitic activity, reduce the risk of systemic side effects of MBG, and elicit the therapeutic effects, at least partly by activating the Nrf2-HO-1 pathway.

Keywords: colon-targeted drug delivery ; prodrug ; mirabegron ; inflammatory bowel disease ; beta-3 adrenergic receptor ; nuclear factor erythroid 2-related factor 2

Purchased from AmBeed: 23150-65-4 ; 32213-95-9 ; 53902-12-8 ; 530-62-1

N-Salicyloyl acidic amino acids are a promising colon-specific promoiety of riluzole against rat colitis

Kim, Jaejeong ; Kang, Changyu ; Jung, Yunjin ;

DOI: 10.1007/s40005-024-00710-w J. Pharm. Investig.,2024.

Abstract: Purpose: In our previous study, riluzole (RLZ) azo-linked to salicylic acid (RAS) was prepared as a colon-targeted RLZ prodrug against rat colitis. However, RAS was not a satisfactory colon-targeted prodrug because of its non-negligible systemic absorption, leading to low colonic delivery efficiency and the ability to limit the systemic absorption of RLZ. This study aimed to improve the colon specificity and anticolitic activity of RAS. Methods: Salicylic acid (SA) was conjugated with the acidic amino acids aspartic acid (Asp) and glutamic acid (Glu) and subsequently azo-coupled with RLZ to yield Asp-conjugated RAS (RAS-Asp) and Glu-conjugated RAS (RAS-Glu). Results: Amino acid-conjugated RAS lowered the distribution coefficient and cell permeability of RAS while exhibiting a release profile of RLZ similar to that of RAS in the cecal contents. Upon oral gavage, amino acid-conjugated RAS delivered a larger amount of RLZ to the cecum than RAS. The ability of amino acid-conjugated RAS to limit the systemic absorption of RLZ was greater than that of RAS. No significant differences were observed in the colon-specific performance between RAS-Asp and RAS-Glu. In a DNBS-induced rat colitis model, amino acid-conjugated RAS was more effective than RAS in ameliorating colonic damage and inflammation and modulating the anti-inflammatory GSK3β-IL-10 pathway in the inflamed colon, without a significant difference between RAS-Asp and RAS-Glu. Conclusion: Conjugation of acidic amino acids with RAS improved the colon specificity, anticolitic activity, and safety of RAS. N-Salicyloyl acidic amino acids may act as high-performance colon-specific promiety for a candidate drug modifiable to a colon-targeted prodrug with an azo bond as a colon-specific link.

Keywords: Riluzole ; Colon-targeted prodrug ; Colitis ; Acidic amino acids ; High performance colon-specific promoiety

Purchased from AmBeed: 23150-65-4 ; 1744-22-5 ; 32213-95-9 ; 530-62-1

Colon-Targeted Poly (ADP-Ribose) Polymerase Inhibitors Synergize Therapeutic Effects of Mesalazine Against Rat Colitis Induced by 2, 4-Dinitrobenzenesulfonic Acid

Kang, Changyu ; Kim, Jaejeong ; Jeong, Yeonhee ; Yoo, Jin-Wook ; Jung, Yunjin ;

DOI: 10.3390/pharmaceutics16121546 Pharmaceutics,2024,16(12):1546.

Abstract: Background/Objectives: In addition to oncological applications, poly(ADP-ribose) polymerase (PARP) inhibitors have potential as anti-inflammatory agents. Colon-targeted delivery of PARP inhibitors has been evaluated as a pharmaceutical strategy to enhance their safety and therapeutic efficacy against gut inflammation. Methods: Colon-targeted PARP inhibitors 5-aminoisoquinoline (5-AIQ) and 3-aminobenzamide (3-AB) were designed and synthesized by azo coupling with salicylic acid (SA), yielding 5-AIQ azo-linked with SA (AQSA) and 3-AB azo-linked with SA (ABSA). Additional conjugation of AQSA with acidic amino acids yielded glutamic acid-conjugated AQSA (AQSA-Glu) and aspartic acid-conjugated AQSA, which further increased the hydrophilicity of AQSA. Results: The distribution coefficients of PARP inhibitors were lowered by chemical modifications, which correlated well with drug permeability via the Caco-2 cell monolayer. All derivatives were effectively converted to their corresponding PARP inhibitors in the cecal contents. Compared with observations in the oral administration of PARP inhibitors, AQSA-Glu and ABSA resulted in the accumulation of much greater amounts of each PARP inhibitor in the cecum. ABSA accumulated mesalazine (5-ASA) in the cecum to a similar extent as sulfasalazine (SSZ), a colon-targeted 5-ASA prodrug. In the DNBS-induced rat colitis model, AQSA-Glu enhanced the anticolitic potency of 5-AIQ. Furthermore, ABSA was more effective against rat colitis than SSZ or AQSA-Glu, and the anticolitic effects of AQSA-Glu were augmented by combined treatment with a colon-targeted 5-ASA prodrug. In addition, the colon-targeted delivery of PARP inhibitors substantially reduced their systemic absorption. Conclusions: Colon-targeted PARP inhibitors may improve the therapeutic and toxicological properties of inhibitors and synergize the anticolitic effects of 5-ASA.

Keywords: poly(ADP-ribose) polymerase inhibitor ; colon-targeted drug delivery ; colitis ; mesalazine ; prodrug

Purchased from AmBeed: 23150-65-4 ; 32213-95-9 ; 15722-48-2 ; 530-62-1

Multistep Mechanochemical Synthesis of PZ-1190, a Multitarget Antipsychotic Agent

Canale, Vittorio ; Kaminski, Michal ; Trybala, Wojciech ; Abram, Michal ; Marciniec, Krzysztof ; Bantreil, Xavier , et al.

DOI: 10.1021/acssuschemeng.3c04023 ACS Sustain. Chem. Eng.,2023,11(45):16156-16164.

Abstract: A solid-state approach was used to synthesize compound PZ-1190, a multitarget ligand for serotonin and dopamine receptors with potential antipsychotic activity in rodents. Compared to the classical batch synthesis approach, the developed multistep mechanochem. protocol improved the overall yield (from 32% to 56%), reduced the reaction time (from 42 to 4 h), and decreased the use of toxic reagents and organic solvents. All synthesized intermediates and PZ-1190 were isolated in high purity by extraction without the requirement of chromatog. purification PZ-1190 was obtained in high enantiomeric purity (≥99% ee) with no impact of grinding processes on the integrity of stereocenter. The described procedures represent rare examples of mechanochem. reduction of a carboxylic function, which might open up the possibility to obtain crucial β- and γ-amino alcs. in a sustainable manner. The oxidation of an aliphatic alc. into an aldehyde using mechanochem. has also been reported for the first time. The obtained results confirmed the suitability of mechanochem. as a sustainable and efficient method of synthesizing candidates for preclin. development.

Keywords: Azinesulfonamide derivatives ; Multistep mechanochemicalsynthesis ; Medicinal mechanochemistry ; Green chemistry ; Antipsychotic agents

Purchased from AmBeed: 134441-93-3 ; 13139-15-6 ; 69610-40-8 ; 87691-87-0 ; 56502-01-3 ; 15761-39-4 ; 26250-84-0 ; 82010-31-9 ; 530-62-1 ; 846038-18-4 ; 198493-30-0 ; 88790-38-9 ; 13139-15-6 ; 347146-79-6

N-Succinylaspartic-Acid-Conjugated Riluzole Is a Safe and Potent Colon-Targeted Prodrug of Riluzole against DNBS-Induced Rat Colitis

Kim, Jaejeong ; Kang, Changyu ; Yoo, Jin-Wook ; Yoon, In-Soo ; Jung, Yunjin ;

DOI: 10.3390/pharmaceutics15112638 PubMed ID: 38004616 Pharmaceutics,2023,15(11):2638.

Abstract: In our previous study, riluzole azo-linked to salicylic acid (RAS) was prepared as a colon-targeted prodrug of riluzole (RLZ) to facilitate the repositioning of RLZ as an anticolitic drug. RAS is more effective against rat colitis than RLZ and sulfasalazine, currently used as an anti-inflammatory bowel disease drug. The aim of this study is to further improve colon specificity, anticolitic potency, and safety of RAS. N-succinylaspart-1-ylRLZ (SAR) and N-succinylglutam-1-ylRLZ (SGR) were synthesized and evaluated as a ""me-better"" colon-targeted prodrug of RLZ against rat colitis. SAR but not SGR was converted to RLZ in the cecal contents, whereas both conjugates remained intact in the small intestine. When comparing the colon specificity of SAR with that of RAS, the distribution coefficient and cell permeability of SAR were lower than those of RAS. In parallel, oral SAR delivered a greater amount of RLZ to the cecum of rats than oral RAS. In a DNBS-induced rat model of colitis, oral SAR mitigated colonic damage and inflammation and was more potent than oral RAS. Moreover, upon oral administration, SAR had a greater ability to limit the systemic absorption of RLZ than RAS, indicating a reduced risk of systemic side effects of SAR. Taken together, SAR may be a "me-better" colon-targeted prodrug of RLZ to improve the safety and anticolitic potency of RAS, an azo-type colon-targeted prodrug of RLZ.

Keywords: riluzole ; colon-targeted drug delivery ; colitis ; prodrug ; N-succinylated acidic amino acids

Purchased from AmBeed: 13574-13-5 ; 7536-58-5 ; 1744-22-5 ; 530-62-1

Design and Synthesis of D3R Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies

Tian, Gui-Long ; Hsieh, Chia-Ju ; Taylor, Michelle ; Lee, Ji Youn ; Luedtke, Robert R. ; Mach, Robert H.

DOI: 10.3390/molecules29010123 PubMed ID: 38202706 Molecules,2023,29(1):123.

Abstract: A series of bitopic ligands based on Fallypride with a flexible secondary binding fragment (SBF) were prepared with the goal of preparing a D3R-selective compound The effect of the flexible linker ((R,S)-trans-2a-d), SBFs ((R,S)-trans-2h-j), and the chirality of orthosteric binding fragments (OBFs) ((S,R)-trans-d, (S,R)-trans-i, (S,S)-trans-d, (S,S)-trans-i, (R,R)-trans-d, and (R,R)-trans-i) were evaluated in in vitro binding assays. Computational chem. studies revealed that the interaction of the fragment binding to the SBF increased the distance between the pyrrolidine nitrogen and ASP1103.32 of the D3R, thereby reducing the D3R affinity to a suboptimal level.

Keywords: dopamine 2 receptor ; dopamine 3 receptor ; flexible linker ; bitopic ligands ; molecular dynamic simulation

Purchased from AmBeed: 530-62-1

Product Details of CDI

CAS No. :	530-62-1
Formula :	C₇H₆N₄O
M.W :	162.15
SMILES Code :	O=C(N1C=CN=C1)N2C=CN=C2
MDL No. :	MFCD00005286
InChI Key :	PFKFTWBEEFSNDU-UHFFFAOYSA-N
Pubchem ID :	68263

Safety of CDI

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H302-H314-H360
Precautionary Statements:	P201-P202-P260-P264-P270-P280-P301+P312+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P308+P313-P363-P405-P501
Class:	8
UN#:	3263
Packing Group:	Ⅱ

Application In Synthesis of CDI

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

Upstream synthesis route of [ 530-62-1 ]
Downstream synthetic route of [ 530-62-1 ]

[ 530-62-1 ] Synthesis Path-Upstream 1~6

1
[ 530-62-1 ]
[ 102-51-2 ]
[ 2080-75-3 ]

References: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 3, p. 719 - 723.

2
[ 40372-61-0 ]
[ 530-62-1 ]
[ 5579-85-1 ]

Yield	Reaction Conditions	Operation in experiment
82%	at 80℃; for 3 h;	Intermediate 8: 6-Bromo-5-chlo H)-one A mixture of 2-amino-5-bromo-4-chlorophenol (Intermediate 7, 8.4 g, 37.8 mmol), N,N-carbonyldiimidazole (12.2 g, 75.6 mmol) in THF (250 mL), was heated at 80 °C for 3 h. The solvent was removed under vacuum and the residue purified by column chromatography (silica: 200 - 400 mesh, 100 g) eluting with petroleum ether/ ethyl acetate from 9:1 to 5:1 ) to give 6-bromo-5-chlorobenzo[d]oxazol-2(3H)-one as an orange solid (7.7 g, 82percent). LCMS (A): Rt 1.49 min, MH⁺ 248/250.

References: [1] Patent: WO2015/91647, 2015, A1, . Location in patent: Page/Page column 42.

3
[ 15403-22-2 ]
[ 106-95-6 ]
[ 530-62-1 ]
[ 113100-86-0 ]

References: [1] Patent: US2002/65308, 2002, A1, .

4
[ 71-41-0 ]
[ 530-62-1 ]
[ 161599-46-8 ]
[ 162204-20-8 ]

Yield	Reaction Conditions	Operation in experiment
91.6%	at 20℃; for 4 h;	To a 1000 ml reaction flask, 600 ml of methylene chloride, 84.8 g of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, 48.6 g of carbonyldiimidazole, and 25.2 g of n-pentanol were charged. The reaction was carried out at 20° C. for 4 hours. The end of the reaction was monitored by TLC (developer, dichloromethane:methanol=20:1). 220 ml of 10percent hydrochloric acid solution was added to the reaction mixture. The organic layer was separated, washed with 220 ml of purified water, and separated. The organic layer was controlled at a bath temperature of 60° C., and the organic layer was concentrated under reduced pressure to dryness. To the residue was added 160 ml of ethyl acetate and 320 ml of n-hexane was stirred for 30 minutes. The temperature was lowered to 10° C. or lower, and suction filtration was started to obtain a white solid. °C, 104.8 g of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-n-pentyloxycarbonyl cytidine was dried, yielding 91.6percent, purity 99.7percent.

References: [1] Patent: CN107936075, 2018, A, . Location in patent: Paragraph 0024-0026.

5
[ 17626-40-3 ]
[ 530-62-1 ]
[ 221289-88-9 ]

Yield	Reaction Conditions	Operation in experiment
24%	for 16 h; Inert atmosphere	To a stined solution of 3, 4-diammobenzanitrile (IC; 200 mg, 1.5 mmol) in THF (10 mL) under argon atmosphere was added carbonyl diimidazole (243 mg, 1.5 mmol) at RT and stirred for 16 h. The volatile were concentrated raider reduced pressure. The crude material was purified by silica gel column chromatography (eiuent: 40percent Acetone Hexane) to afford compound ID (60 mg, 0.37 mmol, 24percent) as an off-white solid. H NMR (400 MHz, DMSO- : δ 11.16 (b s_; IH), 11.04 (br s, IH), 7.39 (dd, 7= 8. L 1.6 Hz, IH), 7.30 (s, IH), 7.06 (d, 7 = 8.2 Hz. IH).
1.5 g	at 0 - 25℃; for 18 h;	To a stirred solution of 3,4-diaminobenzonitrile (1 .40 g, 10.5 mmol) in tetrahydrofuran (70 mL) at 0 °C was added 1 ,1’-carbonyldiimidazole (2.22 g, 13.7 mmol), then the mixture was warmed to 25 °C and stirred for 18 h. The mixture was treated with ethyl acetate (100 mL), washed with 1 N HCI (20 mL x 2) and saturated aqueous sodium chloride solution (30 mL), then dried over anhydrous sodium sulfate,filtered and concentrated to give 2-oxo-1 ,3-dihydrobenzimidazole-5-carbonitrile (1 .50 g) as a pale yellow solid, which was used in next step directly.
0.211 g	at 125℃; for 2 h;	Step a. To a solution of 3,4-diaminobenzonitrile (CAS Number 17626-40-3; 0.400 g, 3.00 mmol) in toluene (5 ml) was added CDI (0.633 g, 3.907 mmol) at rt. The resulting reaction mixture was heated at 125°C for 2 h. The resulting reaction mixture was diluted with water (100 ml) and basified using 1M NaOH solution. The resulting mixture was extracted with EtOAc (3 x 100 ml) and the combined organic layer was dried over Na₂S0₄, filtered and concentrated under reduced pressure yielding 2- oxo-2,3-dihydro-lH-benzo[d]imidazole-5-carbonitrile (0.211 g, 1.327 mmol). LCMS: Method F, 4.066 min, MS: ES- 158.00; NMR (400 MHz, DMSO-d6) δ ppm: 11.19 (s, 1 H), 11.06 (s, 1 H), 7.40 (dd, J=8.0, 1.2 Hz, 1 H), 7.31 (d, J=1.2 Hz, 1 H), 7.07 (d, J=8.0 Hz, 1 H).

References: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3719 - 3742.
[2] Patent: WO2017/117393, 2017, A1, . Location in patent: Page/Page column 263.
[3] Patent: EP2003132, 2008, A1, . Location in patent: Page/Page column 23.
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 17, p. 5392 - 5395.
[5] Patent: WO2018/81167, 2018, A1, . Location in patent: Page/Page column 244.
[6] Patent: WO2018/60742, 2018, A1, . Location in patent: Page/Page column 62-63.

6
[ 825619-30-5 ]
[ 530-62-1 ]
[ 765-30-0 ]
[ 896466-04-9 ]

References: [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 2, p. 379 - 388.

[ 530-62-1 ] Synthesis Path-Downstream 1~35

1
[ 102735-53-5 ]
[ 530-62-1 ]
[ 766-17-6 ]
[ 177913-96-1 ]

References: [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 2313 - 2330.

2
[ 453-71-4 ]
[ 53308-95-5 ]
[ 109-73-9 ]
[ 530-62-1 ]
p-FC₆H₄CH₂-X, X = Br, I [ No CAS ]
1-butyl-3-(4-fluoro-benzyl)-5-(4-propyl-4,5-dihydro-1<i>H</i>-imidazol-2-yl)-1,3-dihydro-benzoimidazol-2-one [ No CAS ]

References: [1]Tetrahedron,2002,vol. 58,p. 2095 - 2100.

3
[ 20845-34-5 ]
[ 530-62-1 ]
2-imidazol-1-ylmethyl-1-methyl-piperidine [ No CAS ]
imidazole-1-carboxylic acid 1-methyl-piperidin-2-ylmethyl ester [ No CAS ]
carbonic acid bis-(1-methyl-piperidin-2-ylmethyl) ester [ No CAS ]

References: [1]Synthesis,2004,p. 2540 - 2544.

4
[ 68176-57-8 ]
[ 530-62-1 ]
[ 99840-59-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	In tetrahydrofuran; at 0 - 20℃; for 12h;	At 0 C,To 4-tert-butylbenzene-1,2-diamine (I-9, 5.02 g, 30.5 mmol)Add in tetrahydrofuran (400mL) solution1,1'-carbonyldiimidazole (CDI, 5.43 g, 33.6 mmol),The resulting solution was stirred at room temperature for 12 hours.Then diluted with diisopropyl ether (50 mL),The mixture was stirred for a further 30 minutes at room temperature.White precipitates gradually appear,Filter and collect products,Wash with diisopropyl ether (50 mL),Vacuum drying,4.05 g (yield: 70%) of 5-tert-butyl-1H-benzo[d]imidazole-2(3H)-one (IX-1),It is a white solid.
	In tetrahydrofuran; dichloromethane; at 20℃; for 6.5h;	General procedure: To a solution of 4-methyl-1,2-phenylenediamine (25 g, 0.205 mol) in tetrahydrofuran (375 mL) was added dropwise a solution of 1,1'-carbonyldiimidazole (36.5 g, 0.225 mol) in dichloromethane (375 mL). After stirring for 6.5 h at ambient temperature, to the reaction mixture was added diisopropyl ether (375 mL). After stirring at ambient temperature, the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether and dried in vacuo to give 5-methyl-1,3-dihydrobenzimidazol-2-one (24.6 g, 70.1%).

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3719 - 3742.
[2]Patent: CN110092804,2019,A .Location in patent: Paragraph 0189; 0193; 0194.
[3]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 719 - 723.
[4]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1071 - 1074.

5
[ 53308-95-5 ]
[ 530-62-1 ]
[1-(imidazole-1-carbonyl)-butyl]-carbamic acid <i>tert</i>-butyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 544 - 559.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9396 - 9408.

6
[ 530-62-1 ]
[ 107867-51-6 ]
[ 438190-87-5 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane;	B. 6-Trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one Add 1,1'-carbonyldiimidazole (1.0 g, 6.17 mmol)to a solution of <strong>[107867-51-6]5-trifluoromethyl-pyridine-2,3 diamine</strong> (0.90 g, 5.08 mmol) in CH2Cl2 (10 mL) and stir at room temperature for 18 hours. Heat the solution to reflux for 2 hours and filter the precipitate to obtain 6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one.

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3719 - 3742.
[2]Patent: US2003/36652,2003,A1 .

7
[ 95-24-9 ]
[ 116668-47-4 ]
[ 530-62-1 ]
6-[3-(6-chloro-benzothiazol-2-yl)-ureido]-naphthalene-2-carboxylic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4657 - 4660.

8
[ 116668-47-4 ]
[ 530-62-1 ]
[ 1744-22-5 ]
6-[3-(6-trifluoromethoxy-benzothiazol-2-yl)-ureido]-naphthalene-2-carboxylic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4657 - 4660.

9
[ 530-62-1 ]
[ 159622-10-3 ]
C₁₄H₁₉N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; for 0.75 - 0.833333h;Heating / reflux;Product distribution / selectivity;	Step 2: Preparation of cyclopropanesulfonic acid (1-(R)-tert-butoxycarbonylamino-2-(S)-vinylcyclopropanecarbonyl)-amide A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); LC-MS (retention time: 1.70 minutes, method B), MS m/z 331 (M++H).; 1b. Preparation of P1-P1' sulfamide derivative To a solution of (1R,2S) 1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid (217 mg, 1.194 mmol) in THF (5 mL), was added CDI (290 mg, 1.791 mmol) and the reaction mixture was heated under reflux for 45 minutes. In another round-bottomed flask, LiHMDS (1.0M solution in hexanes, 2.4 mL, 2.4 mmol) was added to a solution of N-ethylmethylsulfamide (330 mg, 2.388 mmol) in THF (5 mL) and the reaction mixture was stirred at room temperature for 1 hour. Two reaction mixtures were added together and stirred at room temperature for 2 hours. Water was added to quench the reaction and the reaction solution was extracted with ethyl acetate. The organic layer was separated and dried over MgSO4. Filtration and concentration of the solvent gave crude product which was purified by preparative HPLC to afford desired N-Boc protected N-acylsulfamide. The Boc protecting group was then removed as the compound was dissolved in 4N HCl solution in dioxane (2 mL) and stirred at room temperature for 4 hours. Evaporation of solution give brownish oil as the HCl salt. (112 mg, 33percent yield). 1H NMR (400 Mz, CD3OD) delta 1.16 (t, J=7.21 Hz, 3H), 1.68 (dd, J=10.03, 7.83 Hz, 1H), 2.15 (m, 1H), 2.37 (m, 1H), 2.89 (s, 3H), 3.30 (m, 2H), 5.31 (d, J=10.27 Hz, 1H), 5.42 (d, J=17.12 Hz, 3H), 5.68 (m, 1H). LC-MS (retention time: 0.883 minutes.), MS m/z 270 (M+Na+).; A solution of the product of Step 7a (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropanesulfonic acid amide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and the THF was evaporated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the combined organic extracts dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1:1) provided the desired compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40 S column (eluted 9percent acetone in dichloromethane) to provide a second batch of the desired compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); LC/MS (MH+, 331).;
	In tetrahydrofuran; at 20℃; for 3h;Product distribution / selectivity;	Example 58 Preparation of Compound 58 Step 1. To a solution N-Boc-vinylcyclopropane carboxylic acid, the product of step 7a, Example 7, (1.83 g, 8.05 mmol) and THF (32 mL) was added 1,1'-carbonyldiimidazole (1.44 g, 8.86 mmol). After stirring at room temperature for 3 hours, the reaction mixture was treated with N,N-dimethylsulfamide (1.0 g, 8.05 mmol) followed by DBU (2.45 g, 16.1 mmol) and it was stirred at room temperature for an additional 15 hours. The reaction was then diluted with EtOAc (50 mL) and was washed with 2.x.25 mL 1N aqueous HCl. The aqueous layer was extracted with 2.x.50 mL EtOAc. The combined organic portion was washed with H2O (25 mL) and brine, dried over MgSO4, filtered, and concentrated to a light yellow solid (2.6 g, 97percent yield) which was used without further purification. LC-MS, MS m/z 356 (M++Na).
	In tetrahydrofuran; for 0.833333h;Heating / reflux;	Preparation of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with 1N NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with 1N HCl until pH 4 and extracted with ethyl acetate (3.x.40 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (2.62 g, 87percent). 1H NMR: (DMSO-d6) delta 1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); MS m/z 228 (M++H).

In tetrahydrofuran; for 1 - 2h;Heating / reflux;Product distribution / selectivity;

Step 1; [(lR,2S)-l-(2-Amino-benzenesulfonylaminocarbonyl)-2-vinyl-cyclopropyl]-carbamic acid tert-butyl ester; To a solution of 6.3 g (28 mmol) (lR,2S)-l-tert-Butoxycarbonylamino-2-vinyl-cyclopropane- <n="155"/>carboxylic acid (prepared according to WO 2000009558 Al) in 90 mL abs. THF is added 6.95 g (42 mmol) CDI and the mixture is refluxed for 2 h. After cooling to rt 5.1 g (29 mmol) 2-Aminobenzenesulfonamide and 6.5 g (42 mmol) DBU is added and stirring is continued for 45 min. The reaction mixture is diluted with 250 mL EtOAc and washed with 100 mL 0.5 N HCl and brine. The organic phase is dried with Na2SO4, filtered and the solvent is removed in vacuo. The residue is purified by FC on silica (eluent: CH2Cl2/Me0H 98:2) to give the title compound as a colorless solid. HPLC (method A) tR = 3.99 min TLC, Rf (CH2Cl2/Me0H 19:1) = 0.35 MS (method D): 382 [M+H]; Step 7; 12-{l-[((lR,2S)-l-tert-Butoxycarbonylamino-2-vinyl-cyclopropanecarbonyl)-su.famoyl]- cyclopropylj-dodecanoic acid methyl ester; <n="256"/>A mixture of 610 mg (2.7 mmol) (lR,2S)-l-tert-Butoxycarbonylamino-2-vinyl- cyclopropane-carboxylic acid and 687 mg (4.0 mmol) CDI in 20 mL THF is refluxed for 1 h. The reaction mixture is cooled to RT and 0.6 mL (4.0 mmol) DBU and a mixture of 806 mg (2.4 mmol) 12-(l-Sulfamoyl-cyclopropyl)-dodecanoic acid methyl ester in 5 mL THF is added. The mixture is stirred at RT overnight, concentrated in vacuo, taken up in EtOAc and washed with 0.1 M aq. HCl. The combined organic phases are dried over Na2SO4 and concentrated in vacuo. The residue is purified by FC on silica (Eluent: EtOAc/hexane 1:3) to give the title compound.LC-MS (method E) tR = 5.132 min, M-H = 543.3 HPLC (method C) tR = 4.472 min; Step 4; Methyl 12-[[({(lR,2S)-l-[(tert-butoxycarbonyl)amino]-2- vinylcyclopropyl}carbonyl)amino]-sulfonyl}(methyl)amino]dodecanoate; A mixture of 1.41 g (6.2 mmol) (lR,2S)-l-tert-Butoxycarbonylamino-2-vinyl-cyclopropane- carboxylic acid and 1.52 mg (9.31 mmol) CDI in 30 mL THF is refluxed for 1 h. In a second flask to a mixture of 3.0 g (9.31 mmol) of the title compound obtained in step 3 in 30 mL THF 9.3 mL (9.3 mmol) LiHMDS (1 M in THF) is added at 0°C and the mixture is stirred for 30 min. Both mixtures are combined and stirred at RT overnight. Water is added and the mixture is extracted with DCM (3x). The combined organic layers are dried over Na2SO4 and concentrated in vacuo. The residue is purified by FC (silica gel, eluent: EtOAc/hexane 1 :3) to give the title compound. LC-MS (method E) tR = 4.728 min, M-H = 530.2

References: [1]Patent: US2006/183694,2006,A1 .Location in patent: Page/Page column 33; 44-45.
[2]Patent: US2006/183694,2006,A1 .Location in patent: Page/Page column 56.
[3]Patent: US2007/99825,2007,A1 .Location in patent: Page/Page column 36.
[4]Patent: WO2008/101665,2008,A1 .Location in patent: Page/Page column 153-154; 254-255; 260.

10
[ 499-49-0 ]
[ 530-62-1 ]
di-tert-butyl toluene-3,5-dicarboxylate [ No CAS ]
3,5-dicarboxybenzyl methanethiosulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; tert-butyl alcohol;	3,5-Dicarboxybenzyl Methanethiosulfonate (1c). 1,1'-Carbonyldiimidazole (6.67 g, 0.0411 mol) was added to a solution of <strong>[499-49-0]toluene-3,5-dicarboxylic acid</strong> (2) (3.364 g, 0.0187 mol) in DMF (30 mL) and the resulting mixture stirred at 40° C. under N2. After 1.5 h DBU (6.15 mIL, 0.041 mol) and t-BuOH (7.7 mL, 0.0822 mol) were added. After 24 h the solution was cooled, ether (150 mL) added and the mixture acidified (HCl (aq.), 1.5 M). The ethereal layer was separated and the aqueous layer further extracted (ether, 150 mL). The organic fractions were combined, washed with water and 10percent K2CO3 (aq.), dried (MgSO4), filtered and the solvent removed. The residue was purified by flash chromatography (EtOAc:hexane, 1:50) to afford a colorless oil which solidified upon standing to give di-tert-butyl toluene-3,5-dicarboxylate (4.58 g, 84percent) as a white solid; mp 86.5-87.5° C. (hexane); IR (film) 1712 cm-1 (C=O), 1606, 1476 cm-1 (Ar C=C); 1H NMR (CDCl3) delta 1.60 (s, 18H, C(CH3)3), 2.43 (s, 3H, CH3), 7.95 (br s, 2H, H-2, H-6), 8.38 (br s, 1H, H-4); 13C NMR (CDCl3) delta 21.4 (CH3), 28.2 (C(H3)3), 81.4 ((CH3)3), 127.7, 132.1, 133.7, 138.1 (Ar), 165.2 (COO).

References: [1]Patent: US2002/127695,2002,A1 .

11
[ 6624-49-3 ]
[ 100959-19-1 ]
[ 530-62-1 ]
[ 311346-55-1 ]

Yield	Reaction Conditions	Operation in experiment
377 mg (70%)	With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide;	Example 18 Preparation of N-(trans-4-methylcyclohexyl)isoquinoline-3-carboxamide (406) A solution of <strong>[6624-49-3]isoquinoline-3-carboxylic acid</strong> (346 mg, 2 mmol), and 1,1'-carbonyldiimidazole (325 mg, 2 mmol) in dimethylformamide (4 mL) was heated at 50° C. for 1 hour. After this time, trans-4-methylcyclohexylamine hydrochloride (300 mg, 2 mmol), and N,N-diisopropylethylamine (0.523 mL, 3 mmol) were added and the mixture heated at 50° C. for 16 hours. The reaction mixture was cooled, and diluted with ethyl acetate (20 mL). The organic solution was washed with water (3*15 mL), brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated to afford 377 mg (70percent) of 406: rt=9.65 min.; m/z (rel. int.) 268 (M+, 9), 240 (6), 223 (16), 211 (17), 197 (13), 173 (22), 156 (55), 128 (100), 112 (38), 101 (15), 77 (10).

References: [1]Patent: US6429207,2002,B1 .

12
[ 3471-31-6 ]
[ 6269-89-2 ]
[ 530-62-1 ]
[ 214124-59-1 ]

Yield	Reaction Conditions	Operation in experiment
91%	In tetrahydrofuran; dichloromethane; water; ethyl acetate; N,N-dimethyl-formamide;	14.1 1-[(5-methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-nitrophenyl)-piperazine In a 100 ml flask, 1.62 g (10 mmoles) of 1.1'-carbonyl-diimidazole is added to a solution of 2.05 g (10 mmoles) of 5-methoxyindole-3-acetic acid in 10 ml of THF. After one hour of agitation at ambient temperature, a solution of 1-(4-nitrophenyl)piperazine in 10 ml of DMF is added dropwise. Agitation is continued for 15 hours. The reaction medium is then concentrated under vacuum and the evaporation residue is precipitated from 50 ml of an ethyl acetate/water mixture (1/1). After filtration, the solid is rinsed successively with 50 ml of water, 50 ml of ethyl acetate and 50 ml of dichloromethane. After drying under vacuum, a yellow powder is obtained with a yield of 91percent. Melting point: 239-240° C. NMR 1H (100 MHz, DMSO d6, delta): 10.90 (m, 1H, NH); 7.63 (m, 4H, Ph-NO2); 7.40-7.15 (m, 3H, indol); 6.87 (dd, 1H indol, Jotho=8.7 Hz, Jmeta=2.8 Hz); 3.90 (s, 2H, CH2-CO); 3.88 (s, 3H, OCH3); 3.79 (m, 4H, piperazine); 3.50 (m, 4H, piperazine).
91%		14.1) 1-[(5-methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-nitrophenyl)piperazine: In a 100 ml flask, 1.62 g (10 mmoles) of 1.1'-carbonyl-diimidazole is added to a solution of 2.05 g (10 mmoles) of 5-methoxyindole-3-acetic acid in 10 ml of THF. After one hour of agitation at ambient temperature, a solution of 1-(4-nitrophenyl)piperazine in 10 ml of DMF is added dropwise. Agitation is continued for 15 hours. The reaction medium is then concentrated under vacuum and the evaporation residue is precipitated from 50 ml of an ethyl acetate/water mixture (1/1). After filtration, the solid is rinsed successively with 50 ml of water, 50 ml of ethyl acetate and 50 ml of dichloromethane. After drying under vacuum, a yellow powder is obtained with a yield of 91percent. Melting point: 239-240° C. NMR 1H (100 MHz, DMSO d6, delta): 10.90 (m, 1H, NH); 7.63 (m, 4H, Ph-NO2); 7.40-7.15 (m, 3H, indol); 6.87 (dd, 1H indol, Jortho=8.7 Hz, Jmeta=2.8 Hz); 3.90 (s, 2H, CH2-CO); 3.88 (s, 3H, OCH3); 3.79 (m, 4H, piperazine); 3.50 (m, 4H, piperazine).

References: [1]Patent: US6809088,2004,B2 .
[2]Patent: US6340700,2002,B1 .Location in patent: Page column 31.

13
[ 5369-19-7 ]
[ 530-62-1 ]
C₁₄H₁₇N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; for 12h;	Example 4; l-(3-tert-Butyl-phenyl)- 3-{4-[2-(3-Hydroxy-propylamino)-pyrimidin-4-yloxy]- phenyl}-urea172 mg (1.06 mmol) l.T-Carbonyl-diimidazol (CDI) were given to a solution of 144 mg (0.964 mmol) 3-t-butylaniline in 4.0 ml dichloromethane and stirred for 12 h. A solution of 263 mg (0.964 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2- ylamino]-propan-l-ol in 6.0 ml dichloromethane was added within 30 min. and the mixture stirred for 12 h at r.t. The reaction mixture was filtered, the filtrate evaporated and the residue purified by chromatography on silica gel (dichloromethane/methanol 95:5). The obtained material was washed with ether and the precipitate was isolated by filtration and dried. Yield: 170 mg (41percent) of the title compound. MS: 436.1 (ESI+), 434.07(ESI-).eta-NMR(400Hz, [DJDMSO): delta = 1.26(s, 9H, t-Bu), 1.59 (quintet, 2H, CH2-CH2- CH2), 3.2 (br, 2H, CH2-NH), 3.39 (br, 2H, CH2-OH), 4.37 (br, IH, OH), 6.04(br, IH, 5-H-pyrimidine), 7.00(d, IH, Ar-^-Bu), 7.04(br, IH, CH2NH), 7.08(d, 2H, 3- H/5-H-Ar-NH), 7.20(t, IH, 5-H-Ar-t-Bu), 7.29(d, IH, Ar-t-Bu), 7.46(s, IH, 2-H- Ar-t-Bu), 7.47(d, 2H, 2-H/6-H-Ar-NH), 8.12(d, IH, 6-H-pyrimidine), 8.64(s, IH, urea-NH), 8.68(s, IH, urea-NH).

References: [1]Patent: WO2008/77548,2008,A1 .Location in patent: Page/Page column 31.

14
[ 56-91-7 ]
[ 530-62-1 ]
[ 123986-64-1 ]
[ 1160823-18-6 ]

Yield	Reaction Conditions	Operation in experiment
		4-[([(4-[(tert-butoxycarbonyl)amino methyl}benzyl)oxy]carbonyl}amino) methyl]benzoic acid. To a suspension of CDI (340 mgd, 2.1 mmol) in THF (1.6 mL) was added tert-butyl [4-(hydroxymethyl)benzyl]carbamate (500 mg, 2.1 mmol)) in THF (0.7 mL) and the mixture was aged for 1 hour at ambient temperature. The resulting mixture was then added to a stirring solution of 4-(aminomethyl)benzoic acid (320 mg, 2.1 mmol), TEA (0.3 mL, 2.1 mmol), and DBU (0.3 mL, 2.1 mmol)) in THF (3.5 mL). After stirring at ambient temperature for 5 hours the reaction mixture was concentrated in vacuo, diluted with water, then acidified with HCl. The white precipitate was filtered away, washed with water then dissolved in DCM:EtOAc (some MeOH was added for solubility) dried over anhydrous MgSO4 and concentrated in vacuo to give the title compound. cal'd [M+Na]+437, exp. 437

References: [1]Patent: US2009/156825,2009,A1 .Location in patent: Page/Page column 18-19.

15
[ 124-40-3 ]
[ 530-62-1 ]
[ 17583-10-7 ]
[ 79891-47-7 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of <strong>[17583-10-7]2-amino-5,6-dihydro-4H-benzothiazol-7-one</strong> (10 g, 59 mmol), DBU (18 mL, 0.12 mol) and CDI (24 g, 0.15 mol) in 400 mL acetonitrile is stirred for 5 h at 100 0C. Then dimethylamine (150 mL, 2M in TetaF) is added and the reaction mixture is stirred overnight at 100 0C. The reaction mixture is concentrated under reduced pressure and the residue is poured in water. The mixture is acidified to peta 5 with 6 M HCl in water and extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The residue is triturated with diethyl ether. Yield: 9.1 g.

References: [1]Patent: WO2009/112565,2009,A1 .Location in patent: Page/Page column 29.

16
[ 1223404-88-3 ]
[ 31560-06-2 ]
[ 530-62-1 ]
[ 1223404-67-8 ]

Yield	Reaction Conditions	Operation in experiment
86%		Example 92; (lS.4S)-N-(5-((R)-2-(2.5-difluorophenvnpyrrolidin-l-vnpyrazolori.5-alpyrimidin-3- vD-Sigma-oxa-S-azabicvclo^^.?heptane-S-carboxamide; [00515] To a DCM (1.0 niL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l- yl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 50 mg, 0.16 mmol) was added CDI (51 mg, 0.32 mmol) at ambient temperature in one portion. After stirring 90 minutes, (lS,4S)-2- oxa-5-azabicyclo[2.2.1]heptane hydrochloride (43 mg, 0.32 mmol) was added in one portion, followed by DIEA (0.083 mL, 0.48 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a pale-yellowish powder (60 mg, 86% yield). MS (apci) m/z = 441.2 (M+H).

References: [1]Patent: WO2010/48314,2010,A1 .Location in patent: Page/Page column 95-96.

17
[ 530-62-1 ]
[ 302348-51-2 ]
[ 1262015-14-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	In dichloromethane; at 20℃;Inert atmosphere;	Compound 2 (660 mg, 2.82 mmol) was dissolved in 10 mL of dry CH2Cl2.Then, N,N'-carbonyldiimidazole (915 mg, 5.64 mmol) was added, and the mixture was stirred at room temperature for 1-2 h under N2. After the reaction was completed, 40 ml of CH 2 Cl 2 was added, and the mixture was washed three times with an equal amount of 1 M HCl solution, and the organic phase was dried over anhydrous sodium sulfate.Concentrated under reduced pressure to give a white solid 787mg, yield 85%.
	In dichloromethane; at 20℃; for 2h;	2.07 g of 1,1'-carbonyldiimidazole and 2.07 g of 4- (hydroxymethyl) phenylboronic pinicole ester(4- (hydroxymethyl) phenylboronic acid pinacol ester) was dissolved in 20 mL of dichloromethane (DCM)And allowed to react at room temperature for 2 hours. The product was named 1 and 1 was obtained by silica gel chromatography using an eluent of 1: 1 mixture of ethyl acetate and hexane.

References: [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 561 - 565.
Angew. Chem.,2019,vol. 131,p. 571 - 575,5.
[2]Patent: CN108148098,2018,A .Location in patent: Paragraph 0058; 0061; 0062.
[3]Journal of the American Chemical Society,2014,vol. 136,p. 14742 - 14745.
[4]Journal of the American Chemical Society,2011,vol. 133,p. 756 - 758.
[5]Journal of the American Chemical Society,2018,vol. 140,p. 1235 - 1238.
[6]Patent: KR101963327,2019,B1 .Location in patent: Paragraph 0099; 0100; 0102-0104.

18
[ 122889-11-6 ]
[ 530-62-1 ]
C₂₈H₂₅N₃O₄ [ No CAS ]

References: [1]Protein and Peptide Letters,2011,vol. 18,p. 1093 - 1098.

19
[ 7149-75-9 ]
[ 530-62-1 ]
C₁₁H₁₀ClN₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 20℃; for 1h;	General procedure: A mixture of 4-chloro-3-(trifluoromethyl)aniline or its derivatives and CDI in dry CH2Cl2 (5mL) was stirred for 1h at room temperature, then compound 6 (194mg, 0.69mmol) or its derivatives was added. The mixture was allowed to stir for an additional 1h to afford white precipitates. The solid was collected by filtration under vacuum, washed with water for three times and dried under vaccum to give compound 7a?7m and 7p?7r [13], but 7m and 7n was synthesis by a condensation reaction between benzoic acid and compound 6 promoted by EDCI. The yields of all compounds were between 65.7percent and 82.4percent. The general synthetic route is depicted in Scheme 1.

References: [1]Chinese Chemical Letters,2014,vol. 25,p. 351 - 354.

20
[ 1409950-08-8 ]
[ 6674-22-2 ]
[ 530-62-1 ]
[ 159622-10-3 ]
[ 1409964-03-9 ]

Yield	Reaction Conditions	Operation in experiment
96%	With hydrogenchloride; In N,N-dimethyl-formamide;	Step 4 To a solution of <strong>[159622-10-3](1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid</strong> (7.5 g, 33 mmol) in DMF (50 mL) was added 1,1'-carbonyldiimidazole ("CDI", 10.7 g, 66.0 mmol) and the reaction mass was heated at 55° C. for 4 h. To this reaction mass was added 1-fluoromethylcyclopropane-1-sulfonamide (6.5 g, 42.9 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene ("DBU", 6.0 mL, 43 mmol). The reaction mixture was stirred at 55° C. for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH ?2 by using aq. 1.5 N HCl solution. The precipitated solid was isolated via filtration and washed with water to afford tert-butyl (1R,2S)-1-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate as off-white solid (11.5 g, 96percent). MS: MS m/z 361.4 (M+-1).
96%	With hydrogenchloride; In N,N-dimethyl-formamide;	Step 4: Preparation of tert-butyl (1R,2S)-1-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate To a solution of <strong>[159622-10-3](1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid</strong> (7.5 g, 33 mmol) in DMF (50 mL) was added 1,1'-carbonyldiimidazole ("CDI", 10.7 g, 66.0 mmol) and the reaction mass was heated at 55° C. for 4 h. To this reaction mass was added 1-fluoromethylcyclopropane-1-sulfonamide (6.5 g, 42.9 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene ("DBU", 6.0 mL, 43 mmol). The reaction mixture was stirred at 55° C. for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH ?2 by using aq. 1.5 N HCl solutions. The precipitated solid was isolated via filtration and washed with water to afford tert-butyl (1R,2S)-1-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate as off-white solid (11.5 g, 96percent). MS:MS m/z 361.4 (M+-1).

References: [1]Patent: US2014/127156,2014,A1 .Location in patent: Page/Page column.
[2]Patent: US2015/376233,2015,A1 .

21
[ 608-32-2 ]
[ 530-62-1 ]
[ 75370-65-9 ]

Yield	Reaction Conditions	Operation in experiment
42%	In acetonitrile; at 20 - 70℃;	Step 2 4-Amino-1,3-dihydrobenzoimidazol-2-one 0.53 g (6.5 mmol, 2 eq) of N-N'-carbonyliimidazole were added portionwise to 450.7 mg (3.24 mmol, 1 eq) of <strong>[608-32-2]benzene-1,2,3-triamine</strong> in solution in 30 ml of acetonitrile. The reaction medium was stirred at ambient temperature for 6 hours and then heated at 70° C. overnight. The reaction was stopped by adding 50 ml of water and then extracted with ethyl acetate. The organic phases were combined, and dried over sodium sulfate. The solvents were evaporated off and then the residue was purified by chromatography on silica gel (dichloromethane/methanol/aqueous ammonia: 95/5/2). 229.9 mg of 4-amino-1,3-dihydrobenzoimidazol-2-one were obtained. Yield=42percent.

References: [1]Patent: US2014/309208,2014,A1 .Location in patent: Paragraph 0319; 0321.

22
[ 444731-72-0 ]
[ 6973-09-7 ]
[ 530-62-1 ]
N-(2,3-dimethyl-2H-indazol-6-yl)-N'-(3-sulfamoyl-4-methylphenyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49.8%		2- Methyl-5-amino-benzenesulfonamide (1.86g, 10mmol) in drydichloromethane (20 mL) was added CDI (1.62g, 10mmol), under nitrogen at roomtemperature the reaction 3h, Example 1 was slowly added dropwise the obtained2,3-dimethyl--2H- indazol-6-amine (1.61g, 10mmol) in dichloromethane (10 mL)solution was reacted at room temperature 3h. Cooled to 10 ° C, suctionfiltered, washed with dichloromethane (10mL × 2), recrystallized from ethanolto give 1.86 g of an off-white solid, yield 49.8percent.

References: [1]Patent: CN103739550,2016,B .Location in patent: Paragraph 0141-0144.

23
[ 25475-67-6 ]
4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)aniline [ No CAS ]
[ 530-62-1 ]
N-(quinolin-3-yl)-N'-(4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)urea [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 5099 - 5119.

24
[ 6296-99-7 ]
[ 69843-13-6 ]
[ 530-62-1 ]
diethyl 2-((3-(1-methyl-1H-pyrazol-4-yl)ureido)methylene)malonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%		Step 1. Diethyl 2-((3-(1-methyl-1H-pyrazol-4-yl)ureido)methylene)malonate A mixture of 1-methyl-1H-pyrazol-4-amine (0.097 g, 1.0 mmol) and 1,1'-carbonyldiimidazole (0.178 g, 1.100 mmol) in DMSO (1 mL) was stirred at rt for 1 h, then diethyl 2-(aminomethylene)malonate (0.187 g, 1.00 mmol) was added to the solution. The reaction mixture was stirred at 80° C. overnight, cooled to rt, and directly purified via column chromatography (0percent to 100percent EtOAc in hexanes) to afford the product (0.204 g, 66percent). LCMS calcd for C13H19N4O5 (M+H)+: m/z=311.1. Found: 311.2.

References: [1]Patent: US2017/275290,2017,A1 .Location in patent: Paragraph 1103; 1104.

25
[ 530-62-1 ]
[ 302348-51-2 ]
C₁₆H₂₁BN₂O₃ [ No CAS ]

References: [1]Angewandte Chemie - International Edition,2017,vol. 56,p. 14025 - 14030.
Angew. Chem.,2017,vol. 129,p. 14213 - 14218,6.

26
[ 23687-26-5 ]
[ 5649-08-1 ]
[ 530-62-1 ]
1-(isoquinolin-6-yl)-3-(2-oxo-2-(piperidin-1-yl)ethyl)urea [ No CAS ]