A Green, Facile, and Practical Preparation of Capsaicin Derivatives with Thiourea Structure

A Green, Facile, and Practical Preparation of Capsaicin Derivatives with Thiourea Structure | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A Green, Facile, and Practical Preparation of Capsaicin Derivatives with Thiourea Structure Lina Chen, Zhenhua Gao, Ye Zhang, Xiandong Dai, Fanhua Meng, Yongbiao Guo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3893887/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 May, 2024 Read the published version in Scientific Reports → Version 1 posted 8 You are reading this latest preprint version Abstract A green, facile, and practical synthetic method of capsaicin derivatives with thiourea structure is developed by using an automated synthetic system, leading to a series of capsaicin derivatives with various electronic properties and functionalities in good to excellent yields. Physical sciences/Chemistry Physical sciences/Chemistry/Green chemistry Physical sciences/Chemistry/Organic chemistry Physical sciences/Chemistry/Synthesis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Capsaicin is an alkaloid found in the Capsaicin family. 1 In general, capsaicin was used for headaches 2 , muscular pain 3 , gastroenteric protection 4 and to improve circulation 5 . In addition, capsaicin and other capsaicinoid compounds showed strong evidence of having promising potential in the fight against many types of cancer 6 . Consequently, many analogues of capsaicin (Fig. 1 ) have been synthesized and evaluated for diverse bioactivities, among which capsaicin derivatives with thiourea structure (CDTS) is highly noteworthy owing to its stronger biological activity and lower synthetic cost. 7 The pioneer work in the field was reported by Walpole et al. who employed EtOAc (Fig. 2 a) or DMF(Fig. 2 b) as the solvent to realize the asymmetric synthesis of CDTS directly from vanilylamine or vanilylamine hydrochloride and Isothiocyanate. 8 However, these method required organic solvent and chromatography fractionation, and also showed low yield. Moreover, because CDTS have strong irrtancy, the column separation process of CDTS will cause environmental pollution and make people feel uncomfortable. To overcome such problems, it is desirable to develop novel, efficient and mild protocol wherever applicable to meet some of the green chemistry principles. Additionally, with the development of automation technology, the automated synthetic systems have been developed to accelerate chemical reasearch. 9 With these systems, several reactions were reported, including Suzuki coupling 10 , Buchwald-Hartwig amination 11 and photordox-catalysed cross coupling 12 . Despite these elegant examples, an automated synthesis of CDTS has yet to be described. Herein, we report on a green, facile, and automatic protocol for preparation of CDTS on a gram scale (Fig. 2 c). Results and discussion Initially, the vanilylamine hydrochloride ( 1) and 1-isothiocyanatoheptane ( 2a ) were chosen as model substrates to optimize the reaction conditions. The reaction of 1 and 2a was carried out in the presence of K 2 CO 3 in EtOH at r.t. for 24 h. The reaction proceeded smoothly to give the thiourea ( 3a ) in 34% yield (Table 1 , entry 1). Then, a series of solvents was evaluated for the condensation reaction (entries 2–6). The results revealed that solvent effect played a crucial role; H 2 O is the best in terms of yields. Encouraged by this result, subsequently, different bases, including KOH, NaOH, Na 2 CO 3 , NaHCO 3 , Na 2 SiO 3 , CeCO 3 and NEt 3 , were examined(entries 7–13), giving good to excellent yields except weak base NaHCO 3 (entry 10), of which Na 2 SiO 3 offered the highest yield (entry 11). It was noteworthy that the reaction hardly occurred in absence of base (entry 14). Additional efforts at reaction optimization(base loading and reaction time)provided the similar levels of selectivity. Finally, the optimized conditions were then concluded as follows: 1 (0.2 mmol), 2a (0.22 mmol) and Na 2 SiO 3 (0.22 mmol) in H 2 O (2 mL) at r.t. for 12 h, and 3a was obtained in 99% yield. Notably, the column chromatographic separation was not required. After simple filtration, 3a were obtained in 84% yields. Table 1. Selected optimization studies [a] Entry Based Solvent 1 / 2a Yield (%) 1 K 2 CO 3 EtOH 1/2 34 2 K 2 CO 3 CCl 4 1/2 2 3 K 2 CO 3 CH 2 Cl 2 1/2 2 4 K 2 CO 3 THF 1/2 4 5 K 2 CO 3 CH 3 CN 1/2 14 6 K 2 CO 3 H 2 O 1/2 93 7 KOH H 2 O 1/2 98 8 NaOH H 2 O 1/2 95 9 Na 2 CO 3 H 2 O 1/2 80 10 NaHCO 3 H 2 O 1/2 9 11 Na 2 SiO 3 H 2 O 1/2 99 12 CeCO 3 H 2 O 1/2 73 13 NEt 3 H 2 O 1/2 89 14 - H 2 O 1/2 1 15 Na 2 SiO 3 H 2 O 1/1.1 99 16 b Na 2 SiO 3 H 2 O 1/1.1 99 17 c Na 2 SiO 3 H 2 O 1/1.1 90 a Reaction conditions: 1a (0.2 mmol), 2a (0.22 or 0.4 mmol), and base (0.22 mmol), in solvent (2 mL) for 24 h.Yield was determined by HPLC analysis. b 12 h. c 8 h. d Isolated yield. With the potential application of this versatile synthetic transformation (green solvents, mild reaction conditions, and simple post processing) to the chemical enterprise, we explored the development of an automated synthetic system to further demonstrate the synthetic utility of this method. As depicted in Fig. 3 , the automated synthetic system manly consists of seven parts: (i) central control unit; (ii) solvents; (iii) syringe pump; (iv) selection valve; (v) reaction moldule; (vi) filter moldule; (vii) vacuum pump. As shown in Fig. 4 a, the vanilylamine hydrochloride ( 1) and isothiocyanatoheptane ( 2a ) were chosen as model substrates to validate the design concept of automated synthetic system and its potential for large scale production of thioureas with high yield. The automated synthetic system is capable of fulfilling the whole process of synthesis of 3a , in which a general six-step sequential unit operation is included as follows (Fig. 4 b): (i) 1a (3 mmol), 2a (3.3 mmol), and Na 2 SiO 3 (3.3 mmol) were added into the reaction moldule. (ii) H 2 O (30 mL) was then injected into reaction moldule, which is predetermined by the program med method using the syring pump and solvent selection value. (iii) The mixture was stired for 12 h at r.t. (iv) The mixture was transferred to filter moldule and filtered by vacuum pump. (v) EtOH was then injected into filter moldule, which is predetermined by the program med method using the syring pump and solvent selection value. (vi) The mixture was stired for 5 min, and then filtered to give the desired thiourea 3a in 84% yield. With the establishment of the optimized reaction conditions and the process of automated synthesis, a series of substrates was explored to determine the generality of this method, and the results are summarized in Fig. 5 . In general, the corresponding thioureas 3a-3y were obtained with good to excellent yields (69%-96%), except 3l (50% yield). The chain length of the alkyl isothiocyanates tended to slightly influenced to the yield ( 3a vs 3b vs 3c vs 3d ). The substituents of benzyl isothiocyanates could contain both electron-withdrawing and electron-donating groups at the para position of benzene rings, for example, -F ( 3f , 90% yield), -Cl ( 3g , 78% yield), -OMe ( 3h , 94% yield). 3,4-disubstituted benzyl isothiocyanate was viable substrate as well ( 3i , 81% yield). Under the standard conditions, product 3j was also smoothly yielded in excellent yields (92%). In contrast to phenylethyl isothiocyanate ( 2j ), substrate 2k bearing a strong electron withdrawing CF 3 group at the at the para position of benzene ring led to a significantly reduction in yield ( 3g , 82% vs. 3k , 50%), while weakly electron withdrawing group (F, and Cl), and electron donating goups (Me, and MeO) at the at the para position of benzene rings had little effect on the yield ( 3l- 3o, 69–90% yield). Moreover, The good tolerance of the halogen atom (F, and Cl)at different positions on the benzene rings demonstrated good compatibility of the protocol( 3l vs. 3p vs. 3q , and 3m vs. 3r vs. 3s ). After that, phenylpropyl isothiocyanates were also investigated, the reaction of substrates 2t and 2u readily took place under the optimized conditions, offering the corresponding products with good yields. Finally, the isothiocyanatobenzene, benzoyl isothiocyanate, and ( R )-(1-isothiocyanatopropyl)benzene were also investigated. Products 3v - 3x were smoothly yielded in 78–87% yields. In summary, we developed a green, efficient, and automatic protocol to prepare capsaicin derivatives with thiourea structures. A series of capsaicin derivatives were obtained in good to excellent yields (up to 96%). This methodology features the ready availability of starting materials, mild reaction conditions, and high functional groups tolerance. Declarations Conflicts of interest There are no conflicts to declare. Author Contribution Yongbiao Guo conceived and directed the project. Lina Chen, Zhenhua Gao and Ye Zhang performed the experiments. Xiandong Dai and Fanhua Meng analyzed the results. Lina Chen and Zhenhua Gao wrote the main manuscript text. All authors reviewed the manuscript. References (a) S. Kosuge, M. Furuta. Agric. Boi. Chem ., 1970, 34, 248; (b) J. Sawynok. Curr. Pharm. Des ., 2005, 11, 2995. (a) J. F. Peppin, K. Majors, L. R. Webster, D. M. Simpson, J. K. Tobias, G. F. Vanhove. J. Pain. Res ., 2011, 4, 385; (b) L. R. Webster, J. K. Tobias, G. F. Vanhove. Diabetes Res. Clin. Pract. , 2011, 93, 187. L. Mason, R. A. Moore, S. Derry, J. E. Edwards, H. J. McQuay. BMJ ., 2004, 328, 991; (b) K.Hempenstall, T. J. Nurmikko, R. W. Johnson, R. P. Hern, A. S. Rice. PLoS Med ., 2005, 2, 164. (a) S. J. Wimalawansa. Peptides, 1993, 104, 485; (b) O. M. Abdel-Salam, J. Szolcsanyi, G. Mozsik. J. Physiol. Paris., 1997, 91, 151. (a) S. Akerman, H. Kaube, P. J. Goadsby. Br. J. Pharmacol., 2003, 140, 718; (b) S. Gupta, S. Akerman, P. R. Saxena, P. J. Goadsby, A. M. van den Brink. Cephalalgia, 2006, 26, 1294. (a) Y. Surh. Mutat. Res., 1999, 428, 305; (b) P. Anandakumar, S. Jagan, S. Kamaraj, G. Ramakrishnan, A. A. Titto, T. Devaki. J. Pharm. Pharmacol., 2008, 60, 803; (c) A. M. Bode, Z. Dong. Cancer Res. , 2011, 71, 2809. X. F. Huang, J. Y. Xue, A. Q. Jiang, H. L. Zhu. Curr. Med. Chem., 2013, 20, 2661. (a) C. S. J. Walpole, R. Wrigglesworth, S. Bevan, E. A. Campbell, A. Dray, I. James, G. A. Hughes, K. J. Masdin, M. N. Perkins, J. Winter. J. Med. Chem ., 1993, 36, 2381. (b) R. Wrigglesworth, C. S. J. Walpole, S. Bevan, E. A. Campbell, A. Dray, G. A. Hughes, I. James, K. J. Masdin, J. Winter. J. Med. Chem ., 1996, 39, 4942. (a) M. Shevlin. Acs Med. Chem. Lett ., 2017, 8, 601; (b) S. W. Krska, D. A. Dirocco, S. D. Dreher, M. Shevlin. Acc Chem. Res. , 2017, 50, 2976. (a) B. J. Reizman, Y. M. Wang, S. L. Buchwald, K. F. Jensen. Chem. Eng. , 2016, 1, 658; (b) D. Perera, J. W. Tucker, S. Brahmbhatt. Science , 2018, 359, 429; (c) W. Beker, R. Roszak, A. Wolos. H. J. Am. Chem . Soc., 2022, 144, 4819. (a) J. Boström, D. G. Brown, R. J. Young, G. M. Keserü. Nat. Rev. Drug. Discov ., 2018, 17, 709. (b) D. T. Ahneman, J. G. Estrada, S. Lin. Science, 2018, 360, 186. (c) S. K. Kashani, J. E. Jessiman, S. G. Newman. Org. Process Res. Dev ., 2020, 24, 1948. (d) B. Li, S. Su, C. Zhu, J. Lin, X. Hu, L. Su, Z. Yu, K. Liao, H. Chen. J. Cheminformatics , 2023, 15, 72. (a) Y. Chen, X. Wang, X. He, Q. An, Z. Zuo. J. Am. Chem. Soc ., 2021, 143, 4896; (b) S. K. Kariofillis, S. Jiang, A. M. Zurański. J. Am. Chem. Soc ., 2022,144, 1045. Additional Declarations No competing interests reported. Supplementary Files Supportinginformation.pdf Cite Share Download PDF Status: Published Journal Publication published 08 May, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 18 Feb, 2024 Reviews received at journal 06 Feb, 2024 Reviewers agreed at journal 06 Feb, 2024 Reviewers invited by journal 05 Feb, 2024 Editor assigned by journal 05 Feb, 2024 Editor invited by journal 02 Feb, 2024 Submission checks completed at journal 01 Feb, 2024 First submitted to journal 24 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3893887","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":270427372,"identity":"5d7b995e-a11c-45be-adfd-2b4c0422019d","order_by":0,"name":"Lina Chen","email":"","orcid":"","institution":"State Key Laboratory of NBC Protection for Civilian","correspondingAuthor":false,"prefix":"","firstName":"Lina","middleName":"","lastName":"Chen","suffix":""},{"id":270427373,"identity":"37923fee-5a49-4323-87a9-06f8666017d2","order_by":1,"name":"Zhenhua Gao","email":"","orcid":"","institution":"State Key Laboratory of NBC Protection for Civilian","correspondingAuthor":false,"prefix":"","firstName":"Zhenhua","middleName":"","lastName":"Gao","suffix":""},{"id":270427374,"identity":"2d526066-77e6-4231-9177-997193118e6d","order_by":2,"name":"Ye Zhang","email":"","orcid":"","institution":"Sichuan University of Science \u0026 Engineering","correspondingAuthor":false,"prefix":"","firstName":"Ye","middleName":"","lastName":"Zhang","suffix":""},{"id":270427375,"identity":"ca395507-72cb-4955-9732-7850406db396","order_by":3,"name":"Xiandong Dai","email":"","orcid":"","institution":"State Key Laboratory of NBC Protection for Civilian","correspondingAuthor":false,"prefix":"","firstName":"Xiandong","middleName":"","lastName":"Dai","suffix":""},{"id":270427376,"identity":"e652f21b-ef47-407c-8fd2-f857dc420b5c","order_by":4,"name":"Fanhua Meng","email":"","orcid":"","institution":"State Key Laboratory of NBC Protection for Civilian","correspondingAuthor":false,"prefix":"","firstName":"Fanhua","middleName":"","lastName":"Meng","suffix":""},{"id":270427377,"identity":"335f2c86-6c12-40e2-8d3f-ba3a88c61a94","order_by":5,"name":"Yongbiao Guo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvklEQVRIie3PMQrCMBjF8a8EMgXimC49w5NApt7EpUXoVMUDdCgIOvYwBWclYBelVyh07VD3guLoII2bQ37z+w+PyPP+U9BPiIVk7NK5Jgxil0Xhka/hmnAlRqvRCrNw2qO5WyiwtLZkiIp4NZ/ctmkH8PRkKevomm3KuSQsc40E4p00CErrkFSDUWeotN4HB+WUSJWbsAQ0GOOuyaA1IYmU5QyJyxcu82VP01PIqn10YxHPJ5+S3+ae53neNy+vNzqcwqJdnAAAAABJRU5ErkJggg==","orcid":"","institution":"State Key Laboratory of NBC Protection for Civilian","correspondingAuthor":true,"prefix":"","firstName":"Yongbiao","middleName":"","lastName":"Guo","suffix":""}],"badges":[],"createdAt":"2024-01-24 11:14:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3893887/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3893887/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-61014-5","type":"published","date":"2024-05-08T04:00:52+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":50558997,"identity":"121b149a-98ee-4a95-94dc-1754779000bc","added_by":"auto","created_at":"2024-02-02 13:37:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":55200,"visible":true,"origin":"","legend":"\u003cp\u003eCapsaicin and its derivatives with thiourea structure\u003c/p\u003e","description":"","filename":"Figure15Page11.png","url":"https://assets-eu.researchsquare.com/files/rs-3893887/v1/4017b96e6a0f452965147079.png"},{"id":50559165,"identity":"b48bb659-3b46-4634-af9d-dcc08c3077f4","added_by":"auto","created_at":"2024-02-02 13:45:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":79779,"visible":true,"origin":"","legend":"\u003cp\u003ePrevious studies and our work\u003c/p\u003e","description":"","filename":"Figure15Page12.png","url":"https://assets-eu.researchsquare.com/files/rs-3893887/v1/239ea75c920494829062b6df.png"},{"id":50559002,"identity":"fd69d18d-4e41-4465-b717-7e1db793b9ee","added_by":"auto","created_at":"2024-02-02 13:37:22","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":247283,"visible":true,"origin":"","legend":"\u003cp\u003ePhotograph (a) and schematic (b) of the automated synthetic system\u003c/p\u003e","description":"","filename":"Figure15Page13.png","url":"https://assets-eu.researchsquare.com/files/rs-3893887/v1/7012b1efc2fb35db71c1301b.png"},{"id":50559000,"identity":"bca5a162-a32a-46a5-aef9-1fbbda796e17","added_by":"auto","created_at":"2024-02-02 13:37:22","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":19209,"visible":true,"origin":"","legend":"\u003cp\u003ea. Gram-scale synthesis of \u003cstrong\u003e3a\u003c/strong\u003e. b. The representation of general six-step unit operation for \u003cstrong\u003e3a\u003c/strong\u003e synthesis\u003c/p\u003e","description":"","filename":"Figure15Page14.png","url":"https://assets-eu.researchsquare.com/files/rs-3893887/v1/cf9ae04109e4d83969dcb4b2.png"},{"id":50559001,"identity":"7f5db244-a045-4dcc-bd68-de42442e2411","added_by":"auto","created_at":"2024-02-02 13:37:22","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":43675,"visible":true,"origin":"","legend":"\u003cp\u003eScope of substituted isothiocyanates. \u003csup\u003ea\u003c/sup\u003eReaction conditions: \u003cstrong\u003e1\u003c/strong\u003e (3 mmol), \u003cstrong\u003e2\u003c/strong\u003e (3.3 mmol) and Na\u003csub\u003e2\u003c/sub\u003eSiO\u003csub\u003e3\u003c/sub\u003e (3.3 mmol) in H\u003csub\u003e2\u003c/sub\u003eO (30 mL) for 12 h (r.t.). Filtered yields\u003c/p\u003e","description":"","filename":"Figure15Page15.png","url":"https://assets-eu.researchsquare.com/files/rs-3893887/v1/e62a764c426738653c631eb2.png"},{"id":56140418,"identity":"0647692e-b447-4582-b6fe-e4d3af8c7b6b","added_by":"auto","created_at":"2024-05-09 04:24:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":927502,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3893887/v1/926b6340-355a-4571-a842-a8e9f0e99d5a.pdf"},{"id":50559003,"identity":"d61d361a-1240-4957-9d8f-2cd75eaadae7","added_by":"auto","created_at":"2024-02-02 13:37:22","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":4502443,"visible":true,"origin":"","legend":"","description":"","filename":"Supportinginformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3893887/v1/832bf045ab81efdc69e90b66.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Green, Facile, and Practical Preparation of Capsaicin Derivatives with Thiourea Structure","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCapsaicin is an alkaloid found in the Capsaicin family.\u003csup\u003e1\u003c/sup\u003e In general, capsaicin was used for headaches\u003csup\u003e2\u003c/sup\u003e, muscular pain\u003csup\u003e3\u003c/sup\u003e, gastroenteric protection\u003csup\u003e4\u003c/sup\u003e and to improve circulation\u003csup\u003e5\u003c/sup\u003e. In addition, capsaicin and other capsaicinoid compounds showed strong evidence of having promising potential in the fight against many types of cancer\u003csup\u003e6\u003c/sup\u003e. Consequently, many analogues of capsaicin (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) have been synthesized and evaluated for diverse bioactivities, among which capsaicin derivatives with thiourea structure (CDTS) is highly noteworthy owing to its stronger biological activity and lower synthetic cost.\u003csup\u003e7\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe pioneer work in the field was reported by Walpole et al. who employed EtOAc (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea) or DMF(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb) as the solvent to realize the asymmetric synthesis of CDTS directly from vanilylamine or vanilylamine hydrochloride and Isothiocyanate.\u003csup\u003e8\u003c/sup\u003e However, these method required organic solvent and chromatography fractionation, and also showed low yield. Moreover, because CDTS have strong irrtancy, the column separation process of CDTS will cause environmental pollution and make people feel uncomfortable. To overcome such problems, it is desirable to develop novel, efficient and mild protocol wherever applicable to meet some of the green chemistry principles.\u003c/p\u003e \u003cp\u003eAdditionally, with the development of automation technology, the automated synthetic systems have been developed to accelerate chemical reasearch.\u003csup\u003e9\u003c/sup\u003e With these systems, several reactions were reported, including Suzuki coupling\u003csup\u003e10\u003c/sup\u003e, Buchwald-Hartwig amination\u003csup\u003e11\u003c/sup\u003e and photordox-catalysed cross coupling\u003csup\u003e12\u003c/sup\u003e. Despite these elegant examples, an automated synthesis of CDTS has yet to be described. Herein, we report on a green, facile, and automatic protocol for preparation of CDTS on a gram scale (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Results and discussion","content":"\u003cp\u003eInitially, the vanilylamine hydrochloride (\u003cb\u003e1)\u003c/b\u003e and 1-isothiocyanatoheptane (\u003cb\u003e2a\u003c/b\u003e) were chosen as model substrates to optimize the reaction conditions. The reaction of \u003cb\u003e1\u003c/b\u003e and \u003cb\u003e2a\u003c/b\u003e was carried out in the presence of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e in EtOH at r.t. for 24 h. The reaction proceeded smoothly to give the thiourea (\u003cb\u003e3a\u003c/b\u003e) in 34% yield (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, entry 1). Then, a series of solvents was evaluated for the condensation reaction (entries 2\u0026ndash;6). The results revealed that solvent effect played a crucial role; H\u003csub\u003e2\u003c/sub\u003eO is the best in terms of yields. Encouraged by this result, subsequently, different bases, including KOH, NaOH, Na\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e, NaHCO\u003csub\u003e3\u003c/sub\u003e, Na\u003csub\u003e2\u003c/sub\u003eSiO\u003csub\u003e3\u003c/sub\u003e, CeCO\u003csub\u003e3\u003c/sub\u003e and NEt\u003csub\u003e3\u003c/sub\u003e, were examined(entries 7\u0026ndash;13), giving good to excellent yields except weak base NaHCO\u003csub\u003e3\u003c/sub\u003e(entry 10), of which Na\u003csub\u003e2\u003c/sub\u003eSiO\u003csub\u003e3\u003c/sub\u003e offered the highest yield (entry 11). It was noteworthy that the reaction hardly occurred in absence of base (entry 14). Additional efforts at reaction optimization(base loading and reaction time)provided the similar levels of selectivity. Finally, the optimized conditions were then concluded as follows: \u003cb\u003e1\u003c/b\u003e (0.2 mmol), \u003cb\u003e2a\u003c/b\u003e (0.22 mmol) and Na\u003csub\u003e2\u003c/sub\u003eSiO\u003csub\u003e3\u003c/sub\u003e(0.22 mmol) in H\u003csub\u003e2\u003c/sub\u003eO (2 mL) at r.t. for 12 h, and \u003cb\u003e3a\u003c/b\u003e was obtained in 99% yield. Notably, the column chromatographic separation was not required. After simple filtration, \u003cb\u003e3a\u003c/b\u003e were obtained in 84% yields.\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Selected optimization studies \u003csup\u003e[a]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"data:image/png;base64,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\"\u003e\u003c/p\u003e\n\u003cdiv align=\"\" style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\n \u003ctable style=\"width:88.64%;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:16.08%;border-top:black;border-left:white;border-bottom: windowtext;border-right:white;border-style:solid;border-width:1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.25pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eEntry\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:22.78%;border-top:solid black 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right: solid white 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.25pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:10px;\"\u003eBased\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:26.06%;border-top:solid black 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right: solid white 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.25pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eSolvent\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: 1pt solid black;border-left: none;border-bottom: 1pt solid black;border-right: none;padding: 0in 5.4pt;height: 12.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:10px;\"\u003e1\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"font-size:10px;\"\u003e/\u003cstrong\u003e2a\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: 1pt solid black;border-left: none;border-bottom: 1pt solid black;border-right: none;padding: 0in 5.4pt;height: 12.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eYield (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eK\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eEtOH\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e1/2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e34\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;background: rgb(198, 217, 241);padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: rgb(198, 217, 241);padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eK\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: rgb(198, 217, 241);padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eCCl\u003csub\u003e4\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: rgb(198, 217, 241);padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e1/2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: rgb(198, 217, 241);padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eK\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eCH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e1/2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eK\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eTHF\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e1/2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;background: rgb(198, 217, 241);padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e5\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: rgb(198, 217, 241);padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eK\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: rgb(198, 217, 241);padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eCH\u003csub\u003e3\u003c/sub\u003eCN\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: rgb(198, 217, 241);padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e1/2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: rgb(198, 217, 241);padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e14\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e6\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eK\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e1/2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e93\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eKOH\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e1/2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e98\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eNaOH\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e1/2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e95\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e9\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eNa\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e1/2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e80\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e10\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eNaHCO\u003csub\u003e3\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e1/2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e9\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e11\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eNa\u003csub\u003e2\u003c/sub\u003eSiO\u003csub\u003e3\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e1/2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e99\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e12\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eCeCO\u003csub\u003e3\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e1/2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e73\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e13\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eNEt\u003csub\u003e3\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e1/2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e89\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e14\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e1/2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e15\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eNa\u003csub\u003e2\u003c/sub\u003eSiO\u003csub\u003e3\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e1/1.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 11.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e99\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-right: 1pt solid white;border-bottom: 1pt solid white;border-left: 1pt solid white;border-image: initial;border-top: none;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e16\u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eNa\u003csub\u003e2\u003c/sub\u003eSiO\u003csub\u003e3\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e1/1.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid white;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e99\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.08%;border-top: none;border-left: 1pt solid white;border-bottom: 1pt solid black;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e17\u003csup\u003ec\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.78%;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eNa\u003csub\u003e2\u003c/sub\u003eSiO\u003csub\u003e3\u003c/sub\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.06%;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.34%;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e1/1.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.74%;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid white;background: white;padding: 0in 5.4pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:11.0pt;font-size:11px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:10px;color:black;\"\u003e90\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eReaction conditions: \u003cstrong\u003e1a\u003c/strong\u003e (0.2 mmol), \u003cstrong\u003e2a\u003c/strong\u003e (0.22 or 0.4 mmol), and base (0.22 mmol), in solvent (2 mL) for 24 h.Yield was determined by HPLC analysis. \u003csup\u003eb\u003c/sup\u003e12 h. \u003csup\u003ec\u003c/sup\u003e8 h. \u003csup\u003ed\u003c/sup\u003eIsolated yield.\u003c/p\u003e \u003cp\u003eWith the potential application of this versatile synthetic transformation (green solvents, mild reaction conditions, and simple post processing) to the chemical enterprise, we explored the development of an automated synthetic system to further demonstrate the synthetic utility of this method. As depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, the automated synthetic system manly consists of seven parts: (i) central control unit; (ii) solvents; (iii) syringe pump; (iv) selection valve; (v) reaction moldule; (vi) filter moldule; (vii) vacuum pump.\u003c/p\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea, the vanilylamine hydrochloride (\u003cb\u003e1)\u003c/b\u003e and isothiocyanatoheptane (\u003cb\u003e2a\u003c/b\u003e) were chosen as model substrates to validate the design concept of automated synthetic system and its potential for large scale production of thioureas with high yield. The automated synthetic system is capable of fulfilling the whole process of synthesis of \u003cb\u003e3a\u003c/b\u003e, in which a general six-step sequential unit operation is included as follows (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb): (i) \u003cb\u003e1a\u003c/b\u003e (3 mmol), \u003cb\u003e2a\u003c/b\u003e (3.3 mmol), and Na\u003csub\u003e2\u003c/sub\u003eSiO\u003csub\u003e3\u003c/sub\u003e (3.3 mmol) were added into the reaction moldule. (ii) H\u003csub\u003e2\u003c/sub\u003eO (30 mL) was then injected into reaction moldule, which is predetermined by the program med method using the syring pump and solvent selection value. (iii) The mixture was stired for 12 h at r.t. (iv) The mixture was transferred to filter moldule and filtered by vacuum pump. (v) EtOH was then injected into filter moldule, which is predetermined by the program med method using the syring pump and solvent selection value. (vi) The mixture was stired for 5 min, and then filtered to give the desired thiourea \u003cb\u003e3a\u003c/b\u003e in 84% yield.\u003c/p\u003e \u003cp\u003eWith the establishment of the optimized reaction conditions and the process of automated synthesis, a series of substrates was explored to determine the generality of this method, and the results are summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. In general, the corresponding thioureas \u003cb\u003e3a-3y\u003c/b\u003e were obtained with good to excellent yields (69%-96%), except \u003cb\u003e3l\u003c/b\u003e (50% yield). The chain length of the alkyl isothiocyanates tended to slightly influenced to the yield (\u003cb\u003e3a\u003c/b\u003e vs \u003cb\u003e3b\u003c/b\u003e vs \u003cb\u003e3c\u003c/b\u003e vs \u003cb\u003e3d\u003c/b\u003e). The substituents of benzyl isothiocyanates could contain both electron-withdrawing and electron-donating groups at the para position of benzene rings, for example, -F (\u003cb\u003e3f\u003c/b\u003e, 90% yield), -Cl (\u003cb\u003e3g\u003c/b\u003e, 78% yield), -OMe (\u003cb\u003e3h\u003c/b\u003e, 94% yield). 3,4-disubstituted benzyl isothiocyanate was viable substrate as well (\u003cb\u003e3i\u003c/b\u003e, 81% yield). Under the standard conditions, product \u003cb\u003e3j\u003c/b\u003e was also smoothly yielded in excellent yields (92%). In contrast to phenylethyl isothiocyanate (\u003cb\u003e2j\u003c/b\u003e), substrate \u003cb\u003e2k\u003c/b\u003e bearing a strong electron withdrawing CF\u003csub\u003e3\u003c/sub\u003e group at the at the para position of benzene ring led to a significantly reduction in yield (\u003cb\u003e3g\u003c/b\u003e, 82% \u003cem\u003evs.\u003c/em\u003e \u003cb\u003e3k\u003c/b\u003e, 50%), while weakly electron withdrawing group (F, and Cl), and electron donating goups (Me, and MeO) at the at the para position of benzene rings had little effect on the yield (\u003cb\u003e3l-\u003c/b\u003e3o, 69\u0026ndash;90% yield). Moreover, The good tolerance of the halogen atom (F, and Cl)at different positions on the benzene rings demonstrated good compatibility of the protocol(\u003cb\u003e3l\u003c/b\u003e \u003cem\u003evs.\u003c/em\u003e \u003cb\u003e3p\u003c/b\u003e \u003cem\u003evs.\u003c/em\u003e \u003cb\u003e3q\u003c/b\u003e, and \u003cb\u003e3m\u003c/b\u003e \u003cem\u003evs.\u003c/em\u003e \u003cb\u003e3r\u003c/b\u003e \u003cem\u003evs.\u003c/em\u003e \u003cb\u003e3s\u003c/b\u003e). After that, phenylpropyl isothiocyanates were also investigated, the reaction of substrates \u003cb\u003e2t\u003c/b\u003e and \u003cb\u003e2u\u003c/b\u003e readily took place under the optimized conditions, offering the corresponding products with good yields. Finally, the isothiocyanatobenzene, benzoyl isothiocyanate, and (\u003cem\u003eR\u003c/em\u003e)-(1-isothiocyanatopropyl)benzene were also investigated. Products \u003cb\u003e3v\u003c/b\u003e-\u003cb\u003e3x\u003c/b\u003e were smoothly yielded in 78\u0026ndash;87% yields.\u003c/p\u003e \u003cp\u003eIn summary, we developed a green, efficient, and automatic protocol to prepare capsaicin derivatives with thiourea structures. A series of capsaicin derivatives were obtained in good to excellent yields (up to 96%). This methodology features the ready availability of starting materials, mild reaction conditions, and high functional groups tolerance.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflicts of interest\u003c/h2\u003e \u003cp\u003eThere are no conflicts to declare.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eYongbiao Guo conceived and directed the project. Lina Chen, Zhenhua Gao and Ye Zhang performed the experiments. Xiandong Dai and Fanhua Meng analyzed the results. Lina Chen and Zhenhua Gao wrote the main manuscript text. All authors reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e(a) S. Kosuge, M. Furuta. \u003cem\u003eAgric. Boi. Chem\u003c/em\u003e., 1970, 34, 248; (b) J. Sawynok. \u003cem\u003eCurr. Pharm. Des\u003c/em\u003e., 2005, 11, 2995.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e(a) J. F. Peppin, K. Majors, L. R. Webster, D. M. Simpson, J. K. Tobias, G. F. Vanhove. \u003cem\u003eJ. Pain. Res\u003c/em\u003e., 2011, 4, 385; (b) L. R. Webster, J. K. Tobias, G. F. Vanhove. \u003cem\u003eDiabetes Res. Clin. Pract.\u003c/em\u003e, 2011, 93, 187.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eL. Mason, R. A. Moore, S. Derry, J. E. Edwards, H. J. McQuay. \u003cem\u003eBMJ\u003c/em\u003e., 2004, 328, 991; (b) K.Hempenstall, T. J. Nurmikko, R. W. Johnson, R. P. Hern, A. S. Rice. \u003cem\u003ePLoS Med\u003c/em\u003e., 2005, 2, 164.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e(a) S. J. Wimalawansa. Peptides, 1993, 104, 485; (b) O. M. Abdel-Salam, J. Szolcsanyi, G. Mozsik. J. Physiol. Paris., 1997, 91, 151.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e(a) S. Akerman, H. Kaube, P. J. Goadsby. Br. J. Pharmacol., 2003, 140, 718; (b) S. Gupta, S. Akerman, P. R. Saxena, P. J. Goadsby, A. M. van den Brink. Cephalalgia, 2006, 26, 1294.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e(a) Y. Surh. Mutat. Res., 1999, 428, 305; (b) P. Anandakumar, S. Jagan, S. Kamaraj, G. Ramakrishnan, A. A. Titto, T. Devaki. J. Pharm. Pharmacol., 2008, 60, 803; (c) A. M. Bode, Z. Dong. \u003cem\u003eCancer Res.\u003c/em\u003e, 2011, 71, 2809.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eX. F. Huang, J. Y. Xue, A. Q. Jiang, H. L. Zhu. Curr. Med. Chem., 2013, 20, 2661.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e(a) C. S. J. Walpole, R. Wrigglesworth, S. Bevan, E. A. Campbell, A. Dray, I. James, G. A. Hughes, K. J. Masdin, M. N. Perkins, J. Winter. \u003cem\u003eJ. Med. Chem\u003c/em\u003e., 1993, 36, 2381. (b) R. Wrigglesworth, C. S. J. Walpole, S. Bevan, E. A. Campbell, A. Dray, G. A. Hughes, I. James, K. J. Masdin, J. Winter. \u003cem\u003eJ. Med. Chem\u003c/em\u003e., 1996, 39, 4942.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e(a) M. Shevlin. \u003cem\u003eAcs Med. Chem. Lett\u003c/em\u003e., 2017, 8, 601; (b) S. W. Krska, D. A. Dirocco, S. D. Dreher, M. Shevlin. \u003cem\u003eAcc Chem. Res.\u003c/em\u003e, 2017, 50, 2976.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e(a) B. J. Reizman, Y. M. Wang, S. L. Buchwald, K. F. Jensen. \u003cem\u003eChem. Eng.\u003c/em\u003e, 2016, 1, 658; (b) D. Perera, J. W. Tucker, S. Brahmbhatt. \u003cem\u003eScience\u003c/em\u003e, 2018, 359, 429; (c) W. Beker, R. Roszak, A. Wolos. H. \u003cem\u003eJ. Am. Chem\u003c/em\u003e. Soc., 2022, 144, 4819.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e(a) J. Bostr\u0026ouml;m, D. G. Brown, R. J. Young, G. M. Keser\u0026uuml;. \u003cem\u003eNat. Rev.\u003c/em\u003e Drug. \u003cem\u003eDiscov\u003c/em\u003e., 2018, 17, 709. (b) D. T. Ahneman, J. G. Estrada, S. Lin. Science, 2018, 360, 186. (c) S. K. Kashani, J. E. Jessiman, S. G. Newman. \u003cem\u003eOrg. Process Res. Dev\u003c/em\u003e., 2020, 24, 1948. (d) B. Li, S. Su, C. Zhu, J. Lin, X. Hu, L. Su, Z. Yu, K. Liao, H. Chen. \u003cem\u003eJ. Cheminformatics\u003c/em\u003e, 2023, 15, 72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e(a) Y. Chen, X. Wang, X. He, Q. An, Z. Zuo. \u003cem\u003eJ. Am. Chem. Soc\u003c/em\u003e., 2021, 143, 4896; (b) S. K. Kariofillis, S. Jiang, A. M. Zurański. \u003cem\u003eJ. Am. Chem. Soc\u003c/em\u003e., 2022,144, 1045.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3893887/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3893887/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"A green, facile, and practical synthetic method of capsaicin derivatives with thiourea structure is developed by using an automated synthetic system, leading to a series of capsaicin derivatives with various electronic properties and functionalities in good to excellent yields.","manuscriptTitle":"A Green, Facile, and Practical Preparation of Capsaicin Derivatives with Thiourea Structure","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-02 13:37:17","doi":"10.21203/rs.3.rs-3893887/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-02-18T05:02:25+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-02-06T16:20:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5e8c186c-6218-45c4-a79d-05b579b9955d","date":"2024-02-06T07:31:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-05T19:59:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-05T17:11:43+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-02-02T16:52:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-02-01T09:47:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-01-24T11:05:37+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d81fe36f-ed46-4755-9567-68806f38c0d9","owner":[],"postedDate":"February 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":28504941,"name":"Physical sciences/Chemistry"},{"id":28504942,"name":"Physical sciences/Chemistry/Green chemistry"},{"id":28504943,"name":"Physical sciences/Chemistry/Organic chemistry"},{"id":28504944,"name":"Physical sciences/Chemistry/Synthesis"}],"tags":[],"updatedAt":"2024-05-09T04:00:53+00:00","versionOfRecord":{"articleIdentity":"rs-3893887","link":"https://doi.org/10.1038/s41598-024-61014-5","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-05-08 04:00:52","publishedOnDateReadable":"May 8th, 2024"},"versionCreatedAt":"2024-02-02 13:37:17","video":"","vorDoi":"10.1038/s41598-024-61014-5","vorDoiUrl":"https://doi.org/10.1038/s41598-024-61014-5","workflowStages":[]},"version":"v1","identity":"rs-3893887","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3893887","identity":"rs-3893887","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}