Synthesis method of N-cyano amide compound

Abstract

The invention discloses a synthesis method of N-cyano amides, which comprises the following steps: in an organic solvent, in the presence of alkali, carrying out N-cyanation reaction on an amide N-OTs compound a and TMSCN to generate a target compound b; the method has the advantages that the operation is simple, the raw materials are easy to obtain, the cost is low, the toxicity is low, the compatibility is strong, the product structure is diversified, the reaction condition is mild, the large-scale production is easy to realize and the like, and the method has important significance on rapid synthesis and application of the N-cyano amide compound.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing N-cyanoamide compounds, belonging to the technical field of organic synthesis. Background Art

[0002] N-cyanoamide compounds are an important class of nitrogen-containing compounds with diverse biological activities, such as insecticidal activity, bactericidal activity [1] , cathepsin inhibitory activity [2] etc., and are widely used in the fields of pesticides and pharmaceuticals. In addition, N-cyanoamide is an important chemical raw material and an intermediate for organic synthesis drugs [3] , and is also a good metal ligand [4] . N-cyanoamide compounds have broad application prospects in the fields of pesticides, pharmaceuticals, dyes, and organic synthesis.

[0003] The traditional method for synthesizing N-cyanoamide compounds is to first synthesize various amides, and then undergo a substitution reaction with cyanogen bromide to obtain N-cyanoamide compounds, or first synthesize various aliphatic amines or aromatic amines, then undergo a substitution reaction with cyanogen bromide, and then undergo an acylation reaction with an acyl chloride compound to obtain N-cyanoamide compounds [5] .

[0004]

[0005] However, traditional methods have significant limitations. The use of highly toxic reagents (cyanogen bromide, BrCN), BrCN is a highly toxic and volatile compound, posing a great health hazard to operators, and strict protective measures and special equipment are required. In addition, BrCN is difficult to store and handle, easily hydrolyzes to form toxic hydrogen cyanide (HCN), requires strict anhydrous conditions for storage, and cyanide-containing waste needs to be treated after the reaction, increasing costs and environmental risks. The reaction conditions are harsh, temperature and pH sensitive, and the reaction of BrCN usually requires low temperature (such as 0 °C) and strictly controlled alkaline conditions, otherwise side reactions (such as over-substitution or hydrolysis) are likely to occur. Limitations on substrates, if the substrate contains sensitive functional groups (such as hydroxyl, mercapto), non-selective reactions may occur. Substrates with large steric hindrance (such as aromatic amines or large steric hindrance aliphatic amines) have low reaction activity, resulting in a decrease in yield. Low efficiency of multi-step synthesis and intermediate stability problems. In the first method, the reaction of amide with BrCN may produce unstable N-cyanoamide, which needs to be quickly separated or used directly. In the second method, the cyanamide intermediate may decompose due to improper storage or reaction conditions. Cumulative by-products, multi-step reactions (such as amine → cyanamide → acylation) may introduce more impurities, requiring complex purification steps (such as column chromatography), reducing the overall yield. Selectivity challenges and poor regioselectivity. If the substrate contains multiple nucleophilic sites (such as polyamino compounds), BrCN may attack non-target sites, generating a mixture of isomers. Amines and BrCN may produce disubstituted products (such as N,N-dicyanoamine). In the acylation step, the acyl chloride may attack the cyano group rather than the amino group (strict condition control is required). Poor functional group compatibility and sensitive group limitations. Acidic / basic groups (such as carboxylic acid, phenolic hydroxyl) in the substrate may conflict with the reaction conditions. Reducing groups (such as thiol) may be oxidized by BrCN. Difficulty in introducing complex structures, limited applicability to drug molecules with multiple functional groups (such as natural product derivatives). Moreover, BrCN is expensive and requires special transportation and storage. Waste treatment pressure, the treatment of cyanide-containing waste needs to comply with strict environmental protection regulations, increasing the industrial production cost. Difficulty in large-scale production, the low temperature or strict anhydrous conditions at the laboratory scale are difficult to achieve efficiently in industrial production. Process complexity, multi-step reactions require multiple separation and purification steps, increasing equipment investment and time costs.

[0006] In summary, although the traditional synthesis methods of N-cyanoamide compounds are relatively direct, they have many limitations in terms of cost, safety, selectivity, operation complexity, high toxicity, and environmental impact. Therefore, developing a synthesis method of N-cyanoamide compounds that does not involve BrCN and aliphatic or aromatic amines can avoid the various disadvantages of traditional synthesis methods.

[0007] This method first prepares amide N-OTs compounds by existing synthesis methods [6,7] , and uses these compounds as raw materials to synthesize N-cyanoamide compounds.

[0008]

References

[0009] [1] Zhu, Y.; Loso, M. R.; Watson, G. B.; Sparks, T. C.; Rogers, R.B.; Huang, J. Z.; Gerwick, B. C.; Babcock, J. M.; Kelley, D.; Hegde, V. B.;Nugent, B. M.; Renga, J. M.; Denholm, I.; Gorman, K.; DeBoer, G. J.; Hasler,J.; Meade, T.; Thomas, J. D. J. Agric. Food Chem. 2011, 59, 2950.

[0010] [2] (a)Lainé, D.; Palovich, M.; McCleland, B.; Petitjean, E.; Delhom,I.; Xie, H.; Deng, J.; Lin, G.; Davis, R.; Jolit, A.; Nevins, N.; Zhao, B.;Villa, J.; Schneck, J.; McDevitt, P.; Midgett, R.; Kmett, C.; Umbrecht, S.;Peck, B.; Davis, A. B.; Bettoun, D. ACS Med. Chem. Lett. 2011, 2, 142. (b)Falgueyrat, J.-P.; Oballa, R. M.; Okamoto, O.; Wesolowski, G.; Aubin, Y.;Rydzewski, R. M.; Prasit, P.; Riendau, D.; Rodan, S. B.; Percival, M. D. J.Med. Chem. 2001, 44, 94.

[0011] [3] Feldman, P. L.; Brackeen, M. F.; Cowan, D. J.; Marron, B. E.; Schoenen, F. J.; Stafford, J. A.; Suh, E. M.; Domanico, P. L.; Rose, D.; Leesnitzer, M. A.; Brawley, E. S.; Strickland, A. B.; Vergese, M. W.; Connolly, K. M.; Bateman-Fite, R.; Noel, S. L.; Sekut, L.; Stimpson, S. A. J. Med. Chem. 1995, 38, 1505.

[0012] [4] Crutchley, R. J. Coord. Chem. Rev. 2001, 219, 125.

[0013] [5] Servais, A.; Azzouz, M.; Lopes, D.; Courillon, C.; Malacria, M. Angew. Chem., Int. Ed. 2007, 46, 576 - 579;

[0014] [6] Ortiz Jr G X, Hemric B N, Wang Q. Direct and selective 3 - amidation of indoles using electrophilic N - [(benzenesulfonyl) oxy] amides[J]. Organic Letters, 2017, 19(6): 1314 - 1317.

[0015] [7] Carpino L A, Xia J, Zhang C, et al. Organophosphorus and nitro - substituted sulfonate esters of 1 - hydroxy - 7 - azabenzotriazole as highly efficient fast - acting peptide coupling reagents[J]. The Journal of Organic Chemistry, 2004, 69(1): 62 - 71. SUMMARY OF THE INVENTION

[0016] In view of the above problems existing in the prior art, the present invention provides a method for synthesizing N-cyanoamide compounds to promote the application of such compounds. This method has the advantages of simple operation, readily available raw materials, low cost, low toxicity, strong compatibility, diverse product structures, mild reaction conditions, and easy large-scale production, and is of great significance for the rapid synthesis and application of N-cyanoamide compounds.

[0017] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0018] The method for synthesizing N-cyanoamide compounds of the present invention is to carry out an N-cyanation reaction between amide N-OTs compounds a and TMSCN in an organic solvent in the presence of a base to form the target compound b.

[0019] The reaction route is as follows:

[0020]

[0021] Wherein:

[0022] R 1 is selected from any one of substituted or unsubstituted C1-C13 hydrocarbon groups (including alkyl, alkenyl, alkynyl), substituted or unsubstituted aryl groups, and substituted or unsubstituted cycloalkyl groups. The substituents include one or more of alkyl substitution, alkoxy substitution, halogen substitution, heteroatom substitution, cyano substitution, sulfonyl substitution, ester substitution, etc.

[0023] Further, R 1 is selected from C1-C13 alkyl groups, phenyl groups, , , , , , , , , , , , , , , , , , , , , , , , , , , , , any one of; R 3 is selected from any one of methyl, methoxy, tert-butyl, chlorine, bromine, fluorine, cyano, trifluoromethyl, methyl formate, and alkynyl.

[0024] R 2 is selected from substituted or unsubstituted C1-C18 hydrocarbon groups (including alkyl, alkenyl, and alkynyl), and substituted or unsubstituted cycloalkyl groups; the substituents include one or more of alkyl substitution, cycloalkyl substitution, alkoxy substitution, halogen substitution, heteroatom substitution, aryl substitution, sulfonyl substitution, ester group substitution, etc.

[0025] Furthermore, R 2 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , any one of.

[0026] Furthermore, the target compound b is selected from, but not limited to, any one of the compounds with the following structures:

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035] Furthermore, in the N-cyanation reaction, the molar ratio of the amide N-OTs compound a to TMSCN is from 1:1.5 to 1:2.5, and the molar ratio of the amide N-OTs compound a to the base is from 1:2 to 1:3.

[0036] Furthermore, the base used in the N-cyanation reaction is selected from any one of CsF, KF, RbF, etc., and CsF is further preferred.

[0037] Furthermore, the solvent used in the N-cyanation reaction can be any one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, etc., and acetonitrile is further preferred.

[0038] Furthermore, according to the reaction substrates with different structures, the reaction temperature of the N-cyanation reaction can be 0°C to 80°C, and 0°C to 50°C is further preferred.

[0039] Furthermore, according to the reaction substrates with different structures, the reaction time of the N-cyanation reaction can be 2 to 20 h.

[0040] The synthesis method of the N-cyanoamide compound of the present invention specifically includes the following steps:

[0041] Add the N-OTs amide compound a and the base into a reaction vessel, add an appropriate amount of solvent, then add TMSCN, react under the conditions of 0°C to 50°C, and after the reaction is completed, separate and purify by column chromatography or recrystallization to obtain the target compound b.

[0042] Compared with the prior art, the present invention has the following significant beneficial effects:

[0043] This method creatively uses the amide N-OTs compound shown in formula a to carry out the N-cyanation reaction with TMSCN to generate the N-cyanoamide compound b, and this process no longer involves the use of BrCN, thus avoiding various disadvantages of the traditional synthesis method of N-cyanoamide compounds.

[0044] All raw materials used in this method are compounds that are inexpensive, readily available, or easy to prepare. Moreover, the reaction conditions are mild and the operation is simple. This makes this method highly compatible, with a wide substrate range, greatly improving the structural diversity of N-cyanoamide compounds and facilitating industrial scale-up production. Detailed implementation mode

[0045] The technical solution of the present invention will be further described in detail and completely below with reference to specific examples.

[0046] Preparation of target compound b

[0047]

[0048] Method A: Add N-alkyl-N-OTs amide (0.1 mmol, 1.0 equiv.), TMSCN (19.6 μL, 0.15 mmol, 1.5 equiv.), CsF (30.4 mg, 0.2 mmol, 2.0 equiv.) and MeCN (2.0 mL) to a 15 mL dry reaction tube equipped with a magnetic stir bar. Then tightly cap the reaction tube and place it in an ice-water bath (0 °C), and stir vigorously for 8 - 20 hours (monitor the conversion of N-alkyl-N-OTs amide by TLC). After the reaction is complete, concentrate under reduced pressure and purify by column chromatography (ethyl acetate / petroleum ether) to obtain the target compound b.

[0049] Method B: Add N-alkyl-N-OTs amide (0.1 mmol, 1.0 equiv.), TMSCN (31.1 μL, 0.25 mmol, 2.5 equiv.), CsF (45.6 mg, 0.3 mmol, 3.0 equiv.) and MeCN (2.0 mL) to a 15 mL dry reaction tube equipped with a magnetic stir bar. Then tightly cap the reaction tube and heat it to 50 °C, and stir vigorously for 2 - 7 hours (monitor the conversion of N-alkyl-N-OTs amide by TLC). After the reaction is complete, concentrate under reduced pressure and purify by column chromatography (ethyl acetate / petroleum ether) to obtain the target compound b.

[0050] After detection:

[0051] Method A: White solid (13.6 mg, 78%). M.P. 55 - 56 °C; 1 H NMR (600MHz, CDCl 3 ) δ 7.72 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 3.35 (s,2H), 2.40 (s, 2H); 13¹³C NMR (151 MHz, CDCl 3 ) δ 168.6, 144.2, 129.3, 128.8, 127.9, 112.0, 35.4, 21.7; IR (ATR) 2972, 2237, 1700, 1285, 1056, 831, 745 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 10 H 11 N 2 O + : 175.0866, found [M+H] + : 175.0859.

[0052] Method A: Colorless oily liquid (0.1 mmol scale: 18.4 mg, 85%; 10 mmol scale: 1.77 g, 82%). 1 ¹H NMR (600 MHz, CDCl 3 ) δ 7.79 - 7.73 (m, 2H), 7.50 - 7.45 (m, 2H), 3.34 (s, 3H), 1.32 (s, 9H); 13 ¹³C NMR (151 MHz, CDCl 3 ) 168.4, 156.9, 128.6, 127.8, 125.6, 112.0, 35.3, 35.1, 31.0; IR (ATR) 2967, 2237, 1702, 1283, 1056, 848, 766, 705 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 13 H 17 N 2 O + : 217.1335, found [M+H] + : 217.1340.

[0053] Method A: White solid (12.2 mg, 64%). M.P. 97 - 99 °C; 1 ¹H NMR (600 MHz, CDCl 3) δ 7.85 - 7.80 (m, 2H), 6.98 - 6.92 (m, 2H), 3.85 (s, 3H), 3.35 (s, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 167.9, 163.6, 131.1, 122.8, 114.0, 112.3, 55.6, 35.5; IR (ATR) 2971, 2235, 1698, 1258, 1057, 841, 735 cm -1 ; HRMS(ESI / [M + H] + ) m / z calcd. for C 10 H 11 N 2 O 2 + : 191.0815, found [M + H] + : 191.0817.

[0054] Method A: White solid (0.1 mmol scale: 11.3 mg, 61%; 15 mmol scale: 1.66 g, 60%). M.P. 78 - 79 °C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.91 - 7.87 (m, 2H), 7.82 - 7.77 (m, 2H), 3.40 (s, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 167.1, 134.6, 132.5, 129.3, 117.5, 116.8, 111.0, 35.5; IR (ATR) 2989, 2240, 1709, 1282, 1065, 851, 733 cm -1 ; HRMS (ESI / [M + H] + ) m / z calcd. for C 10 H 8 N 3 O + : 186.0662, found [M + H] + : 186.0660.

[0055] Method A: White solid (12.8 mg, 56%). M.P. 70 - 71 °C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.94 - 7.90 (m, 2H), 7.79 - 7.74 (m, 2H), 3.41 (s, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 167.6, 134.8 (q, J C-F = 33.2 Hz), 134.0, 129.2, 125.9 (q, J C-F = 3.5 Hz), 123.4 (q, J C-F = 273.0 Hz), 111.3, 35.5; 19 F NMR (564 MHz, CDCl 3 ) δ -63.5; IR (ATR) 2989, 2238, 1705, 1319, 1123, 850, 764, 698 cm -1 ; HRMS(ESI / [M + H] + ) m / z calcd. for C 10 H 8 F 3 N 2 O + : 229.0583, found [M + H] + : 229.0587.

[0056] Method A: White solid (18.2 mg, 76%). M.P. 74 - 76 °C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.70 - 7.64 (m, 2H), 7.64 - 7.59 (m, 2H), 3.35 (s, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 167.7, 132.0, 130.2, 129.5, 128.3, 111.5, 35.4; IR (ATR) 2989, 2238, 1705, 1281, 1056, 837, 745 cm -1 ; HRMS (ESI / [M + H]+ ) Calculated m / z for C 9 H 8 BrN 2 O + : 238.9815, found [M+H] + : 238.9816.

[0057] Method A: White solid (8.7 mg, 44%). M.P. 65 - 66 °C; 1 1H NMR (600 MHz, CDCl 3 ) δ 7.79 - 7.73 (m, 2H), 7.49 - 7.43 (m, 2H), 3.37 (s, 3H); 13 13C NMR (151 MHz, CDCl 3 ) δ 167.6, 139.8, 130.2, 129.1, 129.0, 111.6, 35.5; IR (ATR) 2971, 2238, 1703, 1283, 1056, 841, 748 cm -1 ; HRMS (ESI / [M+H] + ) Calculated m / z for C 9 H 8 ClN 2 O + : 195.0320, found [M+H] + : 195.0325.

[0058] Method A: Colorless oily liquid (11.9 mg, 67%). 1 1H NMR (600 MHz, CDCl 3 ) δ7.61 (ddt, J = 7.7, 1.7, 0.8 Hz, 1H), 7.51 - 7.43 (m, 2H), 7.29 (tt, J = 8.4,1.7 Hz, 1H), 3.37 (s, 3H); 13 13C NMR (151 MHz, CDCl 3 ) δ 167.4 (d, J C-F = 2.8 Hz),162.4 (d, J C-F = 249.3 Hz), 132.6 (d, J C-F= 7.4 Hz), 130.6 (d, J C-F = 7.7 Hz),124.4 (d, J C-F = 3.4 Hz), 120.4 (d, J C-F = 21.3 Hz), 116.0 (d, J C-F = 23.9 Hz),111.4, 35.5; 19 F NMR (565 MHz, CDCl 3 ) δ -110.5; IR (ATR) 2971, 2235,1709, 1290, 1056, 835, 739 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 9 H 8 FN 2 O + :179.0615, found [M+H] + : 179.0619.

[0059] Method A: Pale yellow liquid (13.1 mg, 71%). 1 H NMR (600 MHz, CDCl 3 ) δ7.89 (t, J = 1.8 Hz, 1H), 7.77 (dt, J = 8.0, 1.5 Hz, 1H), 7.68 (dt, J = 7.8,1.4 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 3.37 (s, 3H), 3.16 (s, 1H); 13 C NMR(151 MHz, CDCl 3 ) δ 167.8, 136.5, 132.3, 131.1, 128.8, 128.6, 123.2, 111.5,82.0, 79.2, 35.5; IR (ATR) 2986, 2236, 1708, 1290, 1061, 796, 734 cm -1 ;HRMS (ESI / [M+H] + ) m / z calcd. for C 11 H 9 N 2 O+ : 185.0709, found [M+H] + : 185.0713.

[0060] Method A: White solid (14.4 mg, 66%). M.P. 92 - 93 °C; 1 H NMR (600MHz, CDCl 3 ) δ 8.19 - 8.11 (m, 2H), 7.91 - 7.81 (m, 2H), 3.95 (s, 3H), 3.40 (s, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 168.0, 165.9, 134.6, 134.2, 129.9, 128.7, 111.4, 52.7, 35.5; IR (ATR) 2988, 2240, 1710, 1277, 1109, 1057, 733 cm -1 ;HRMS (ESI / [M+H] + ) m / z calcd. for C 11 H 11 N 2 O 3 + : 219.0764, found [M+H] + : 219.0769.

[0061] Method A: White solid (11.3 mg, 54%). M.P. 157 - 159 °C; 1 H NMR (600MHz, CDCl 3 ) δ 8.40 (dd, J = 1.8, 0.9 Hz, 1H), 7.98 - 7.92 (m, 2H), 7.92 - 7.88 (m, 1H), 7.82 (dd, J = 8.5, 1.9 Hz, 1H), 7.63 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.58 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 3.45 (s, 3H); 13 C NMR (151 MHz,CDCl 3) δ 168.8, 135.5, 132.1, 130.2, 129.4, 128.9, 128.8, 128.0(128.01),128.0(127.95), 127.4, 124.4, 112.0, 35.6; IR (ATR) 2972, 2349, 1727,1675, 1265, 1066, 736 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 13 H 11 N 2 O + :211.0866, found [M+H] + : 211.0867.

[0062] Method A: White solid (17.5 mg, 70%). M.P. 118 - 119 °C; 1 H NMR (600MHz, CDCl 3 ) δ 7.06 (s, 2H), 3.89 (s, 3H), 3.88 (s, 6H), 3.36 (s, 3H); 13 C NMR(151 MHz, CDCl 3 ) δ 167.9, 153.1, 142.4, 125.2, 111.9, 106.5, 61.0, 56.4,35.6; IR (ATR) 2969, 2232, 1705, 1416, 1336, 1127, 736 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 12 H 15 N 2 O 4 + : 251.1026, found [M+H] + : 251.1035.

[0063] Method A: White solid (10.2 mg, 68%). M.P. 59 - 60 °C; 1 H NMR (600 MHz,CDCl 3) δ 7.67 - 7.65 (m, 1H), 7.53 (d, J = 3.5 Hz, 1H), 6.58 (dd, J = 3.7, 1.7 Hz, 1H), 3.37 (s, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 156.6, 147.3, 143.9, 120.5, 112.5, 111.2, 35.4; IR (ATR) 2988, 2238, 1697, 1468, 1315, 1066, 887, 734 cm -1 ; HRMS (ESI / [M + H] + ) m / z calcd. for C 7 H 7 N 2 O 2 + : 151.0502, found [M + H] + : 151.0503.

[0064] Method A: Colorless oily liquid (11.5 mg, 69%). 1 H NMR (600 MHz, CDCl 3 ) δ 8.11 (dd, J = 4.0, 1.0 Hz, 1H), 7.69 (dd, J = 5.0, 1.0 Hz, 1H), 7.14 (dd, J = 5.0, 3.9 Hz, 1H), 3.38 (s, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 160.7, 134.4, 133.8, 133.7, 128.3, 111.9, 35.9; IR (ATR) 2971, 2236, 1676, 1414, 1312, 1276, 842, 729 cm -1 ; HRMS (ESI / [M + H] + ) m / z calcd. for C 7 H 7 N 2 OS + : 167.0274, found [M + H] + : 167.0274.

[0065] Method A: White solid (17.1 mg, 79%). M.P. 102 - 104 °C; 1 H NMR (600 MHz, CDCl 3 ) δ 8.41 (s, 1H), 8.21 (d, J = 8.2 Hz, 1H), 7.88 (dt, J = 8.1, 1.0 Hz, 1H), 7.49 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.43 (td, J = 7.6, 7.0, 1.3 Hz, 1H), 3.41 (s, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 162.4, 139.4, 136.9, 134.8, 125.8, 125.7, 124.2, 122.5, 112.0, 35.1; IR (ATR) 2989, 2233, 1696, 1238, 1062, 767, 736 cm -1 ; HRMS (ESI / [M + H] + ) m / z calcd. for C 11 H 9 N 2 OS + : 217.0430, found [M + H] + : 217.0435.

[0066] Method A: Colorless oily liquid (10.9 mg, 54%). 1 H NMR (600 MHz, CDCl 3 ) δ 7.30 (t, J = 7.6 Hz, 2H), 7.20 (dd, J = 17.1, 7.4 Hz, 3H), 3.15 (s, 3H), 2.71 - 2.66 (m, 4H), 2.04 (p, J = 7.4 Hz, 2H); 13 C NMR (151 MHz, CDCl 3 ) δ 172.3, 140.8, 128.6, 128.5, 126.3, 111.2, 34.8, 33.6, 33.5, 25.9; IR (ATR) 2958, 2233, 1725, 1227, 1090, 740, 700 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 12 H 15 N 2 O + : 203.1179, found [M+H] + : 203.1176.

[0067] Method A: White solid (17.2 mg, 79%). M.P. 49 - 51 °C; 1 H NMR(600 MHz, CDCl 3 ) δ 7.15 - 7.11 (m, 2H), 6.85 - 6.82 (m, 2H), 3.78 (s, 3H), 3.15(s, 3H), 2.95 (br s, 4H); 13 C NMR (151 MHz, CDCl 3 ) δ 171.8, 158.3, 131.5,129.4, 114.1, 111.2, 55.3, 36.3, 33.6, 29.6; IR (ATR) 2971, 2235, 1728,1513, 1246, 826, 733 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 12 H 15 N 2 O 2 + :219.1128, found [M+H] + : 219.1129.

[0068] Method A: Pale yellow liquid (14.0 mg, 74%). 1 H NMR (600 MHz, CDCl 3 ) δ8.46 - 8.43 (m, 2H), 7.52 (d, J = 7.9 Hz, 1H), 7.20 (dd, J = 7.9, 4.8 Hz, 1H),3.13 (s, 3H), 2.97 (s, 4H); 13¹³C NMR (151 MHz, CDCl 3 ) δ 171.1, 149.9, 148.2, 136.0, 134.9, 123.5, 110.9, 35.4, 33.7, 27.4; IR (ATR) 2970, 2235, 1726, 1425, 1084, 732, 713 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 10 H 12 N 3 O + : 190.0975, found [M+H] + : 190.0981.

[0069] Method A: Pale yellow liquid (13.3 mg, 83%). 1 ¹H NMR (600 MHz, CDCl 3 ) δ 3.53 (t, J = 5.8 Hz, 2H), 3.15 (s, 3H), 2.68 (t, J = 6.6 Hz, 2H), 1.82 (dq, J = 6.6, 3.3, 2.6 Hz, 4H); 13 ¹³C NMR (151 MHz, CDCl 3 ) δ 171.9, 111.1, 44.3, 33.6, 33.3, 31.5, 21.7; IR (ATR) 2970, 2234, 1726, 1225, 1066, 796, 734 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 7 H 12 ClN 2 O + : 175.0633, found [M+H] + : 175.0634.

[0070] Method A: White solid (24.2 mg, 91%). M.P. 102 - 103 °C; 1 ¹H NMR (600 MHz, CDCl 3) δ 3.17 (s, 3H), 2.65 (t, J = 7.5 Hz, 2H), 1.68 (p, J = 7.4 Hz, 2H), 1.36 - 1.21 (m, 20H), 0.87 (t, J = 6.9 Hz, 3H); 13 C NMR (151MHz, CDCl 3 ) δ 172.7, 111.4, 34.3, 33.7, 32.0, 29.8, 29.7, 29.7, 29.5, 29.4, 29.3, 29.0, 24.6, 22.8, 14.2; IR (neat) 2916, 2234, 1719, 1076, 738 cm -1 ;HRMS (ESI / [M + H] + ) m / z calcd. for C 16 H 31 N 2 O + : 267.2431, found [M + H] + :267.2434.

[0071] Method A: Colorless oily liquid (9.4 mg, 68%). 1 H NMR (600 MHz, CDCl 3 ) δ5.81 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.13 - 5.07 (m, 1H), 5.04 (dt, J = 10.1, 1.3 Hz, 1H), 3.18 (s, 3H), 2.77 (t, J = 7.4 Hz, 2H), 2.46 - 2.41 (m, 2H); 13 C NMR (151 MHz, CDCl 3 ) δ 171.9, 135.6, 116.6, 111.2, 33.7, 33.6, 28.4; IR(ATR) 2988, 2235, 1728, 1266, 1078, 920, 734 cm -1 ; HRMS (ESI / [M + K] + ) m / z calcd. for C 7 H 10 KN 2 O+ : 177.0425, found [M + H] + : 177.0434.

[0072] Method A: Colorless oily liquid (10.4 mg, 75%). 1 1H NMR (600 MHz, CDCl 3 ) δ3.62 (p, J = 8.4 Hz, 1H), 3.17 (s, 3H), 2.41 - 2.29 (m, 4H), 2.05 (dq, J =11.4, 8.9 Hz, 1H), 1.96 - 1.88 (m, 1H); 13 13C NMR (151 MHz, CDCl 3 ) δ 174.5, 111.2,38.2, 33.8, 25.1, 18.1; IR (ATR) 2970, 2234, 1722, 1257, 1218, 735 cm -1 ;HRMS (ESI / [M+H] + ) m / z calcd. for C 7 H 11 N 2 O + : 139.0866, found [M+H] + : 139.0866.

[0073] Method B: White solid (11.3 mg, 63%). M.P. 49 - 50 °C; 1 1H NMR (600MHz, CDCl 3 ) δ 3.13 (d, J = 1.6 Hz, 3H), 1.66 (s, 1H), 1.23 (dd, J = 4.6, 1.7Hz, 12H); 13 13C NMR (151 MHz, CDCl 3 ) δ 170.6, 112.3, 35.5, 33.5, 32.3, 23.3,16.9; IR (ATR) 2989, 2231, 1708, 1218, 1097, 1038, 736 cm -1 ; HRMS (ESI / [M+H] +) m / z calcd. for C 10 H 17 N 2 O + : 181.1335, found [M+H] + : 181.1327.

[0074] Method B: White solid (11.8 mg, 59%). M.P. 55 - 56 °C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.39 - 7.35 (m, 3H), 7.35 - 7.27 (m, 2H), 3.16 (s, 3H), 1.54 - 1.51 (m, 2H), 1.34 - 1.31 (m, 2H); 13 C NMR (151 MHz, CDCl 3 ) δ 172.2, 137.2, 129.0, 128.4, 128.0, 110.6, 35.2, 31.1, 29.8, 14.6; IR (ATR) 2971, 2236, 1716, 1308, 1067, 734, 698 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 12 H 13 N 2 O + : 201.1022, found [M+H] + : 201.1016.

[0075] Method B: White solid (12.8 mg, 69%). M.P. 96 - 97 °C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.87 (d, J = 15.4 Hz, 1H), 7.59 (dd, J = 7.9, 1.6 Hz, 2H), 7.46 - 7.40 (m, 3H), 7.11 (d, J = 15.3 Hz, 1H), 3.30 (s, 3H); 13 C NMR (151 MHz, CDCl 3) δ 165.0, 148.5, 133.7, 131.5, 129.2, 128.8, 113.7, 111.4, 34.0; IR(ATR) 2988, 2234, 1701, 1630, 1337, 1223, 763, 736 cm -1 ; HRMS (ESI / [M+H] + )m / z calcd. for C 11 H 11 N 2 O + : 187.0866, found [M+H] + : 187.0863.

[0076] Method A: Colorless oily liquid (0.1 mmol scale: 13.6 mg, 63%; 15 mmol scale: 2.27 g, 70%). 1 H NMR (600 MHz, CDCl 3 ) δ 7.79 (d, J = 7.9 Hz, 2H), 7.63 - 7.56 (m, 1H), 7.48 (t, J = 7.7 Hz, 2H), 3.81 - 3.75 (m, 2H), 1.77–1.68 (m, 3H), 0.99 (d, J = 6.6 Hz, 6H); 13 C NMR (151 MHz, CDCl 3 ) δ 168.6, 133.2, 131.3, 128.7, 128.7, 111.3, 46.4, 36.3, 25.8, 22.4; IR (ATR) 2987, 2236, 1706, 1368, 733, 701 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 13 H 17 N 2 O + : 217.1335, found [M+H] + : 217.1331.

[0077] Method A: Colorless oily liquid (17.6 mg, 82%). 11H NMR (600 MHz, CDCl 3 ) δ7.83 - 7.73 (m, 2H), 7.58 (tq, J = 7.1, 1.3 Hz, 1H), 7.48 (ddt, J = 9.0, 7.6, 1.5 Hz, 2H), 3.79 (d, J = 7.6 Hz, 2H), 2.83 (hept, J = 7.8 Hz, 1H), 2.19 (dtd, J = 10.0, 8.0, 3.8 Hz, 2H), 2.04–1.91 (m, 2H), 1.90 - 1.83 (m, 2H); 13 13C NMR (151 MHz, CDCl 3 ) δ 168.8, 133.2, 131.2, 128.7, 128.6, 111.4, 52.5, 33.7, 26.0, 18.5; IR (ATR) 2973, 2232, 1704, 1272, 1076, 734, 704 cm -1 ; HRMS(ESI / [M + H] + ) m / z calcd. for C 13 H 15 N 2 O + : 215.1179, found [M + H] + : 215.1180.

[0078] Method A: Colorless oily liquid (12.3 mg, 61%). 1 1H NMR (600 MHz, CDCl 3 ) δ 7.30 (t, J = 7.6 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 6.7 Hz, 2H), 3.59 (t, J = 7.3 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.36 (s, 3H), 2.03 (p, J = 7.6 Hz, 2H); 13 13C NMR (151 MHz, CDCl 3 ) δ 169.4, 140.2, 128.7, 128.4, 126.4, 111.0, 45.8, 32.6, 29.1, 22.3; IR (ATR) 2971, 2240, 1653, 1242, 1047, 737, 693 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 12 H 15 N 2 O + : 203.1179, found [M+H] + : 203.1172.

[0079] Method A: Colorless oily liquid (14.2 mg, 51%). 1 H NMR (600 MHz, CDCl 3 ) δ 7.80 (d, J = 6.9 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.21 (d, J = 7.0 Hz, 3H), 3.79 (t, J = 7.2 Hz, 2H), 2.71 (t, J = 7.6 Hz, 2H), 1.87 (p, J = 8.2, 7.6 Hz, 2H), 1.78 (p, J = 7.2, 6.7 Hz, 2H); 13 C NMR (151 MHz, CDCl 3 ) δ 168.5, 141.6, 133.2, 131.2, 128.69, 128.65, 128.6, 128.5, 126.1, 111.2, 47.7, 35.4, 28.2, 27.2; IR (ATR) 2920, 2232, 1703, 1270, 1060, 734, 698 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 18 H 19 N 2 O + : 279.1492, found [M+H] + : 279.1487.

[0080] Method A: Colorless oily liquid (25.0 mg, 81%). 1 H NMR (600 MHz,CDCl 3 ) δ 7.87-7.76 (m, 2H), 7.65-7.55 (m, 1H), 7.49 (t, J = 7.8 Hz, 2H),7.15-7.08 (m, 2H), 6.93-6.76 (m, 2H), 3.82-3.76 (m, 5H), 2.65 (t, J = 7.6 Hz,2H), 1.85 (p, J = 7.6, 7.0 Hz, 2H), 1.76-1.70 (m, 2H); 13 C NMR (151 MHz,CDCl 3 ) δ 168.5, 158.0, 133.6, 133.2, 131.2, 129.4, 128.7, 128.6, 113.9,111.2, 55.3, 47.7, 34.4, 28.4, 27.2; IR (ATR) 2930, 2220, 1711, 1512,1244, 1036, 735, 701 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 19 H 21 N 2 O 2 + :309.1598, found [M+H] + : 309.1599.

[0081] Method A: Colorless oily liquid (17.6 mg, 76%). 1 H NMR (600 MHz, CDCl 3 )δ 7.79 (dq, J = 8.5, 1.4 Hz, 2H), 7.58 (tt, J = 7.1, 1.3 Hz, 1H), 7.51-7.45(m, 2H), 3.94-3.83 (m, 2H), 3.48 (dqd, J = 8.2, 6.3, 4.5 Hz, 1H), 3.34 (s,3H), 1.99-1.86 (m, 2H), 1.21 (d, J = 6.1 Hz, 3H); 1313C NMR (151 MHz, CDCl 3 ) δ168.6, 133.2, 131.3, 128.7, 128.7, 111.4, 74.1, 56.2, 45.3, 34.5, 19.0; IR(ATR) 2973, 2232, 1704, 1277, 1074, 734, 702 cm -1 ; HRMS (ESI / [M+H] + ) m / zcalcd. for C 13 H 17 N 2 O 2 + : 233.1285, found [M+H] + : 233.1290.

[0082] Method A: Colorless oily liquid (20.8 mg, 82%). 1 1H NMR (600 MHz,CDCl 3 ) δ 7.86-7.78 (m, 2H), 7.64-7.56 (m, 1H), 7.52-7.44 (m, 2H), 3.88 (t, J= 6.8 Hz, 2H), 2.66 (tt, J = 6.8, 2.4 Hz, 2H), 2.16 (tt, J = 7.2, 2.4 Hz,2H), 1.46 (dtd, J = 8.5, 7.1, 5.6 Hz, 2H), 1.41-1.34 (m, 2H), 0.87 (t, J =7.3 Hz, 3H); 13 13C NMR (151 MHz, CDCl 3 ) δ 168.4, 133.3, 131.0, 128.7(128.73),128.7(128.69), 111.0, 83.7, 74.5, 47.1, 30.8, 22.0, 18.4, 18.4, 13.7; IR(ATR) 2960, 2235, 1706, 1274, 788, 700 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd.for C 16 H 19 N 2 O+ : 255.1492, found [M+H] + : 255.1490.

[0083] Method A: Colorless oily liquid (12.7 mg, 64%). 1 H NMR (600 MHz, CDCl 3 ) δ7.89 - 7.75 (m, 2H), 7.66 - 7.55 (m, 1H), 7.54 - 7.44 (m, 2H), 3.94 (t, J = 6.8 Hz,2H), 2.72 (td, J = 6.8, 2.7 Hz, 2H), 2.12 (t, J = 2.6 Hz, 1H); 13 C NMR (151MHz, CDCl 3 ) δ 168.4, 133.4, 130.8, 128.8, 128.8, 111.0, 78.9, 71.6, 46.5,18.1; IR (ATR) 2971, 2236, 1706, 1275, 1076, 736, 701 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 12 H 11 N 2 O + : 199.0866, found [M+H] + : 199.0856.

[0084] Method A: Pale yellow liquid (19.2 mg, 84%). 1 H NMR (600 MHz, CDCl 3 ) δ7.78 (dd, J = 8.2, 1.5 Hz, 2H), 7.61 - 7.55 (m, 1H), 7.51 - 7.45 (m, 2H), 5.64 - 5.57 (m, 1H), 5.35 (dtd, J = 10.6, 7.3, 1.4 Hz, 1H), 3.79 (t, J = 7.1 Hz,2H), 2.56 (q, J = 7.1 Hz, 2H), 2.14 - 2.08 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H); 1313C NMR (151 MHz, CDCl 3 ) δ 168.6, 136.2, 133.2, 131.2, 128.7, 128.6, 122.8,111.3, 47.6, 25.7, 20.8, 14.3; IR (ATR) 2968, 2233, 1703, 1275, 700 cm -1 ;HRMS (ESI / [M+H] + ) m / z calcd. for C 14 H 17 N 2 O + : 229.1335, found [M+H] + : 229.1328.

[0085] Method A: Pale yellow liquid (17.3 mg, 61%). 1 1H NMR (600 MHz,CDCl 3 ) δ 7.80 (d, J = 7.7 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.8Hz, 2H), 5.88 - 5.74 (m, 1H), 5.00 (dt, J = 17.0, 2.0 Hz, 1H), 4.93 (dd, J =10.2, 2.3 Hz, 1H), 3.80 - 3.71 (m, 2H), 2.04 (q, J = 7.2 Hz, 2H), 1.80 (p, J =8.2, 7.4 Hz, 2H), 1.46 - 1.27 (m, 10H); 13 13C NMR (151 MHz, CDCl 3 ) δ 168.6, 139.2,133.2, 131.2, 128.7, 128.6, 114.3, 111.3, 47.9, 33.8, 29.3, 29.1, 29.0, 28.9,27.6, 26.4; IR (ATR) 2927, 2232, 1705, 1274, 1076, 735, 701 cm -1 ; HRMS(ESI / [M+H] + ) m / z calcd. for C 18 H 25 N2 O + : 285.1961, found [M+H] + : 285.1962.

[0086] Method A: Pale yellow liquid (23.3 mg, 59%). 1 HNMR (600 MHz, CDCl 3 ) δ 7.80 (d, J = 7.7 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 5.36 (dtt, J = 18.1, 7.7, 4.1 Hz, 4H), 3.76 (t, J = 7.4 Hz, 2H), 2.78 (t, J = 6.9 Hz, 2H), 2.05 (qd, J = 7.1, 3.2 Hz, 4H), 1.81 (p, J = 7.4 Hz, 2H), 1.46 - 1.24 (m, 18H), 0.89 (t, J = 6.9 Hz, 3H); 13 C NMR(151 MHz, CDCl 3 ) δ 168.6, 133.2, 131.2, 130.3, 130.1, 128.7, 128.6, 128.2, 128.0, 111.3, 47.9, 31.6, 29.7, 29.4(29.45), 29.4(29.43), 29.3, 29.2, 27.6, 27.3(27.30), 27.3(27.29), 26.4, 25.7, 22.7, 14.2; IR (ATR) 2927, 2232, 1705, 1273, 1076, 736, 700 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 26 H 39 N 2 O + :395.3057, found [M+H] + : 395.3060.

[0087] Method A: White solid (20.8 mg, 83%). M.P. 39 - 41 °C; 11H NMR (600MHz, CDCl 3 ) δ 7.80 (d, J = 7.7 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.49 (t, J= 7.7 Hz, 2H), 3.78 (t, J = 7.3 Hz, 2H), 3.56 (t, J = 6.5 Hz, 2H), 1.85 (h, J= 7.3, 6.9 Hz, 4H), 1.59 (h, J = 7.7, 7.2 Hz, 2H); 13 13C NMR (151 MHz, CDCl 3 ) δ168.5, 133.3, 131.1, 128.7, 128.7, 111.2, 47.6, 44.6, 32.0, 27.0, 23.7; IR(ATR) 2923, 2232, 1703, 1273, 1067, 702 cm -1 ; HRMS (ESI / [M+H] + ) m / zcalcd. for C 13 H 16 ClN 2 O + : 251.0946, found [M+H] + : 251.0952.

[0088] Method A: Colorless oily liquid (15.2 mg, 69%). 1 1H NMR (600 MHz, CDCl 3 )δ 7.80 (dt, J = 8.4, 1.2 Hz, 2H), 7.66-7.55 (m, 1H), 7.49 (t, J = 7.7 Hz,2H), 4.56 (t, J = 5.9 Hz, 1H), 4.48 (t, J = 5.7 Hz, 1H), 3.84 (t, J = 7.3 Hz,2H), 1.97 (p, J = 7.5 Hz, 2H), 1.89-1.79 (m, 2H); 13 13C NMR (151 MHz, CDCl 3 ) δ168.5, 133.4, 131.0, 128.8, 128.7, 111.2, 83.3 (d, J C-F= 166.0 Hz), 47.5, 27.4 (d, J C-F = 20.2 Hz), 24.1 (d, J C-F = 4.6 Hz); 19 F NMR (565 MHz, CDCl 3 ) δ -218.9; IR (ATR) 2970, 2232, 1705, 1275, 1076, 702 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 12 H 14 FN 2 O + : 221.1085, found [M+H] + : 221.1080.

[0089] Method A: Colorless oily liquid (18.2 mg, 71%). 1 H NMR (600 MHz, CDCl 3 ) δ 7.84 - 7.79 (m, 2H), 7.65 - 7.59 (m, 1H), 7.54 - 7.48 (m, 2H), 3.86 (t, J = 7.3 Hz, 2H), 2.31 - 2.18 (m, 2H), 2.16 - 2.06 (m, 2H); 13 C NMR (151 MHz, CDCl 3 ) δ 168.4, 133.6, 130.7, 128.8(128.85), 128.8(128.78), 126.6 (q, J C-F = 276.3 Hz), 110.9, 46.8, 31.1 (q, J C-F = 29.8 Hz), 20.8 (q, J C-F = 3.0 Hz); 19 F NMR (565 MHz, CDCl 3 ) δ -66.2; IR (ATR) 2988, 2235, 1709, 1265, 1056, 735, 703 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C12 H 12 F 3 N 2 O + : 257.0896, found [M+H] + :257.0889.

[0090] Method B: Colorless oily liquid (18.0 mg, 69%). 1 H NMR (600 MHz,CDCl 3 ) δ 6.71 (d, J = 7.8 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H), 6.58 (dd, J =7.9, 1.7 Hz, 1H), 5.91 (s, 2H), 3.49 (dd, J = 13.5, 6.5 Hz, 1H), 3.38 (dd, J= 13.5, 8.1 Hz, 1H), 2.59 (dd, J = 13.8, 6.3 Hz, 1H), 2.41-2.32 (m, 4H),2.20-2.11 (m, 1H), 0.91 (d, J = 6.7 Hz, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 169.5,147.7, 146.1, 132.8, 121.9, 111.2, 109.3, 108.2, 100.9, 51.4, 40.2, 34.0,22.2, 17.0; IR (ATR) 2972, 2233, 1727, 1489, 1241, 1037, 805 cm -1 ; HRMS(ESI / [M+H] + ) m / z calcd. for C 14 H 17 N 2 O 3 + : 261.1234, found [M+H] + : 261.1227.

[0091] Method B: White solid (17.9 mg, 62%). M.P. 54 - 56 °C; 1 H NMR(600 MHz, CDCl 3) δ 6.72 (d, J = 7.8 Hz, 1H), 6.64 (d, J = 1.7 Hz, 1H), 6.59(dd, J = 7.8, 1.7 Hz, 1H), 5.92 (s, 2H), 3.51 (dd, J = 13.5, 6.5 Hz, 1H),3.40 (dd, J = 13.4, 8.1 Hz, 1H), 2.68-2.56 (m, 3H), 2.38 (dd, J = 13.8, 8.2Hz, 1H), 2.16 (tq, J = 8.2, 6.6 Hz, 1H), 1.72 (h, J = 7.4 Hz, 2H), 0.98 (t, J= 7.4 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 172.4,147.8, 146.1, 132.9, 122.0, 111.1, 109.4, 108.3, 101.0, 51.5, 40.3, 36.4,34.1, 18.2, 17.1, 13.6; IR (ATR) 2971, 2233, 1726, 1490, 1249, 1039,734, 703 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 16 H 21 N 2 O 3 + : 289.1547, found [M+H] + : 289.1553.

[0092] Method A: White solid (0.1 mmol scale: 29.1 mg, 81%; 5mmol scale: 1.35 g, 75%). M.P. 76 - 78 °C; 1 H NMR (600 MHz, CDCl 3) δ 9.46 (s, 1H), 8.88 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.78 (d, J = 6.9 Hz, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.9 Hz, 2H), 4.58 (t, J = 6.0 Hz, 2H), 4.03 (t, J = 6.9 Hz, 2H), 2.37 (p, J = 6.5 Hz, 2H); 13 C NMR (151 MHz, CDCl 3 ) δ 168.4, 165.0, 149.6, 139.6, 133.4, 132.5, 130.7, 129.4, 129.1, 128.7(128.74), 128.7(128.73), 127.9, 126.9, 122.8, 111.1, 62.2, 45.2, 27.1; IR (ATR) 2969, 2232, 1713, 1284, 789, 701 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 21 H 18 N 3 O 3 + : 360.1343, found [M+H] + : 360.1344.

[0093] Method A: Pale yellow liquid (16.3 mg, 54%). 11H NMR (600 MHz, CDCl3) δ 7.82 - 7.77 (m, 2H), 7.63 - 7.56 (m, 1H), 7.52 - 7.45 (m, 2H), 4.47 (dd, J = 8.4, 5.5 Hz, 1H), 4.28 (t, J = 6.0 Hz, 2H), 4.00 (dt, J = 8.2, 6.9 Hz, 1H), 3.94 - 3.83 (m, 3H), 2.24 (dtd, J = 12.5, 8.4, 6.4 Hz, 1H), 2.18 (dq, J = 7.6, 6.4 Hz, 2H), 2.07 - 2.01 (m, 1H), 2.00 - 1.85 (m, 2H); 13 13C NMR (151 MHz, CDCl3) δ 173.4, 168.4, 133.4, 130.8, 128.8, 128.7, 111.0, 76.7, 69.5, 61.3, 45.0, 30.3, 26.9, 25.4; IR (neat) 2234, 1712, 1706, 1274, 1086, 907, 725 cm -1 ; HRMS (ESI / [M + H] + ) m / z calcd. for C16H19N2O 4 + : 303.1339, found [M + H] + : 303.1339.

[0094] Method A: Colorless oily liquid (18.7 mg, 73%). 1 1H NMR (600 MHz, CDCl 3 ) δ 7.74 (dd, J = 8.4, 1.2 Hz, 2H), 7.59 (ddt, J = 8.8, 7.2, 1.3 Hz, 1H), 7.51 - 7.44 (m, 2H), 7.23 (dd, J = 5.1, 1.2 Hz, 1H), 7.04 - 6.92 (m, 2H), 4.03 (t, J = 7.1 Hz, 2H), 3.34 (t, J = 7.1 Hz, 2H); 13 13C NMR (151 MHz, CDCl 3) δ 168.4, 138.8, 133.3, 131.0, 128.7, 128.6, 127.3, 126.4, 124.9, 110.9, 49.0, 28.0; IR(ATR) 2972, 2233, 1703, 1270, 1076, 97 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd.for C 14 H 13 N 2 OS + : 257.0743, found [M+H] + : 257.0740.

[0095] Method A: Colorless oily liquid (30.0 mg, 73%). 1 H NMR (600 MHz, CDCl 3 ) δ 7.84 - 7.79 (m, 2H), 7.76 - 7.71 (m, 2H), 7.59 (td, J = 7.5, 1.3 Hz, 1H), 7.48(td, J = 7.8, 1.3 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 4.20 (dt, J = 10.3, 5.0Hz, 1H), 3.89 - 3.77 (m, 3H), 3.12 - 3.04 (m, 1H), 2.42 (s, 3H), 2.33 - 2.24 (m,1H), 1.83 (dddd, J = 14.3, 9.3, 6.8, 5.2 Hz, 1H), 1.55 - 1.40 (m, 5H), 1.20 - 1.10 (m, 1H); 13 C NMR (151 MHz, CDCl 3 ) δ 168.5, 143.3, 138.6, 133.3, 131.1,130.0, 128.8, 128.7, 127.1, 111.2, 50.4, 45.9, 40.8, 27.8, 27.7, 24.0, 21.6,18.6; IR (ATR) 2924, 2232, 1705, 1336, 1267, 1154, 734, 703 cm -1 ; HRMS(ESI / [M+H]+ ) m / z calculated for C 22 H 26 N 3 O 3 S + : 412.1689, found [M+H] + : 412.1688.

[0096] Method A: White solid (41.0 mg, 92%). M.P. 83 - 85 °C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.89 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 7.23 - 7.11 (m, 5H), 7.03 (d, J = 7.4 Hz, 1H), 4.72 - 4.64 (m, 2H), 4.60 (d, J = 16.6 Hz, 1H), 3.76 (dd, J = 14.1, 4.3 Hz, 1H), 3.66 (dd, J = 14.1, 10.2 Hz, 1H), 2.77 (dd, J = 16.2, 6.2 Hz, 1H), 2.61 (dd, J = 16.3, 2.3 Hz, 1H), 2.36 (s, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 168.7, 143.8, 136.5, 133.1, 131.2, 131.0, 130.8, 129.9, 129.1, 129.0, 128.6, 127.5, 127.2, 127.2, 126.6, 111.4, 50.0, 49.7, 44.0, 30.5, 21.6; IR (ATR) 2988, 2235, 1709, 1278, 1162, 1066, 737, 705 cm -1 ; HRMS (ESI / [M+H] + ) m / z calculated for C 25 H 24 N 3 O 3 S +: 446.1533, found [M+H] + : 446.1539.

[0097] Method A: White solid (29.0 mg, 73%). M.P. 105 - 107 °C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.79–7.72 (m, 2H), 7.63 (d, J = 7.8 Hz, 2H), 7.60 - 7.57 (m, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 3.83 (dt, J = 12.1, 3.1 Hz, 2H), 3.64 (d, J = 6.9 Hz, 2H), 2.42 (s, 3H), 2.27 (td, J = 12.0, 2.4 Hz, 2H), 1.86 - 1.77 (m, 3H), 1.47 (qd, J = 12.1, 4.2 Hz, 2H); 13 C NMR (151 MHz, CDCl 3 ) 168.4, 143.8, 133.4, 132.9, 130.7, 129.8, 128.8, 128.6, 127.8, 111.3, 52.4, 45.8, 34.5, 28.9, 21.6; IR (ATR) 2988, 2233, 1706, 1334, 1290, 1274, 1165, 728 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 21 H 24 N 3 O 3 S + : 398.1533, found [M+H] + : 398.1535.

[0098] Method A: White solid (19.8 mg, 81%). M.P. 96 - 97 °C; 1 H NMR (600 MHz, CDCl 3) δ 7.80 (dt, J = 8.4, 1.5 Hz, 2H), 7.60 (tt, J = 7.1, 1.4 Hz, 1H),7.49 (td, J = 7.9, 1.5 Hz, 2H), 4.02 (ddd, J = 11.8, 4.2, 2.0 Hz, 2H), 3.68(dd, J = 7.3, 1.4 Hz, 2H), 3.42 (tt, J = 11.7, 1.8 Hz, 2H), 2.14 (dtdd, J =8.7, 7.4, 5.5, 3.6 Hz, 1H), 1.72 (ddt, J = 12.9, 3.8, 1.9 Hz, 2H), 1.51–1.41(m, 2H); 13 C NMR (151 MHz, CDCl 3 ) δ 168.6, 133.4, 131.0, 128.8, 128.7, 111.5,67.4, 53.1, 34.2, 30.2; IR (ATR) 2969, 2232, 1704, 1273, 1094, 732, 705cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 14 H 17 N 2 O 2 + : 245.1285, found [M+H] + :245.1280.

[0099] Method A: Colorless oily liquid (35.0 mg, 79%). 1 H NMR (600 MHz,CDCl 3) δ 8.00 (dt, J = 8.4, 0.9 Hz, 1H), 7.77-7.72 (m, 2H), 7.70-7.65 (m,2H), 7.61-7.55 (m, 2H), 7.51 (s, 1H), 7.48-7.41 (m, 2H), 7.35 (ddd, J = 8.4,7.2, 1.2 Hz, 1H), 7.30-7.25 (m, 1H), 7.17-7.13 (m, 2H), 4.07-4.02 (m, 2H),3.20 (td, J = 7.3, 6.9, 1.0 Hz, 2H), 2.29 (s, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ168.6, 145.2, 135.5, 135.4, 133.5, 131.0, 130.6, 130.2, 128.9, 128.8, 127.1,125.4, 124.3, 123.7, 119.5, 117.7, 114.1, 111.2, 47.5, 23.6, 21.9; IR (ATR) 2988, 2234, 1706, 1266, 1172, 734 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. forC 25 H 22 N 3 O 3 S + : 444.1376, found [M+H] + : 444.1386.

[0100] Method A: Colorless oily liquid (23.3 mg, 67%). 1 H NMR (600 MHz,CDCl 3 ) δ 7.85 (d, J = 8.3 Hz, 2H), 7.81 (d, J = 7.8 Hz, 2H), 7.73 (dd, J =5.1, 3.1 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 3.84(dt, J = 18.0, 7.0 Hz, 4H), 2.24 (p, J = 7.0 Hz, 2H);13 C NMR (151 MHz, CDCl 3 ) δ 168.5, 168.3, 134.3, 133.3, 132.0, 131.0, 128.8, 128.7, 123.6, 110.8, 45.2, 34.8, 26.8; IR (ATR) 2970, 2233, 1773, 1707, 1277, 1061, 719 cm -1 ; HRMS(ESI / [M+H] + ) m / z calcd. for C 19 H 16 N 3 O 3 + : 334.1186, found [M+H] + : 334.1187.

[0101] Method A: Colorless oily liquid (16.3 mg, 89%). 1 H NMR (600 MHz, CDCl 3 ) δ7.80 (d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H); 13 C NMR (151 MHz, CDCl 3 ) δ 168.7, 133.3, 130.8, 128.7(128.71), 128.7(128.70),111.8; IR (ATR) 2989, 2237, 1703, 1290, 736, 700 cm -1 ; HRMS (ESI / [M+H] + )m / z calcd. for C 9 H 6 D 3 N 2 O + : 164.0898, found [M+H] + : 164.0899.

[0102] Method A: Colorless oily liquid (7.1 mg, 38%). 1 H NMR (600 MHz, CDCl3 ) δ 7.81 - 7.76 (m, 2H), 7.63 - 7.56 (m, 1H), 7.51 - 7.46 (m, 2H), 4.69 (hept, J = 6.7 Hz, 1H), 1.42 (d, J = 6.7 Hz, 6H); IR (ATR) 2971, 2230, 1703, 1215, 1057, 752 cm -1 ; HRMS (ESI / [M + H] + ) m / z calcd. for C 11 H 13 N 2 O + : 189.1022, found [M + H] + : 189.1025.

[0103] Method B: White solid (10.8 mg, 47%). M.P. 92 - 93 °C; 1 1H NMR (600 MHz, CDCl 3 ) δ 7.82 - 7.78 (m, 2H), 7.60 (dt, J = 6.9, 3.7 Hz, 1H), 7.50 (dt, J = 7.8, 4.0 Hz, 2H), 4.53 (ddq, J = 13.1, 5.9, 3.9, 2.9 Hz, 1H), 4.12 (dd, J = 12.0, 4.5 Hz, 2H), 3.54 (tt, J = 11.8, 2.4 Hz, 2H), 2.06–1.90 (m, 4H); 13 13C NMR(151 MHz, CDCl 3 ) δ 168.4, 133.4, 131.3, 128.8, 109.4, 66.8, 52.6, 30.6; IR(ATR) 2923, 2229, 1705, 1279, 1087, 735 cm -1 ; HRMS (ESI / [M + H] + ) m / z calcd. for C 13 H 15 N 2 O 2 + : 231.1128, found [M + H] +: 231.1118.

[0104] Method A: White solid (19.3 mg, 70%). M.P. 80 - 82 °C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.81–7.78 (m, 2H), 7.59–7.55 (m, 1H), 7.49 - 7.45 (m, 2H), 7.36–7.32 (m, 2H), 7.29 (dd, J = 7.1, 1.6 Hz, 2H), 7.22 (tt, J = 7.0, 1.5 Hz, 1H), 5.02 - 4.93 (m, 1H), 3.68 (tt, J = 9.8, 4.7 Hz, 1H), 2.89 - 2.82 (m, 2H), 2.71–2.65 (m, 2H); 13 C NMR (151 MHz, CDCl 3 ) δ 168.3, 143.6, 133.3, 131.3, 128.8(128.77), 128.8(128.76), 128.7, 126.6, 126.5, 109.8, 49.5, 34.5, 33.4; IR(ATR) 2988, 2230, 1701, 1279, 697 cm -1 ; HRMS (ESI / [M + H] + ) m / z calcd. for C 18 H 17 N 2 O + : 277.1335, found [M + H] + : 277.1327.

[0105] Method A: White solid (22.8 mg, 68%). M.P. 88 - 90 °C; 1 H NMR (600 MHz, CDCl 3) δ 7.82 (dd, J = 5.7, 3.8 Hz, 2H), 7.66 - 7.60 (m, 1H), 7.50 (td, J = 7.9, 1.9 Hz, 2H), 7.44–7.27 (m, 5H), 5.13 (br s, 2H), 5.05 (ttd, J = 7.7, 5.4, 1.9 Hz, 1H), 4.44 (ddd, J = 9.9, 7.6, 1.8 Hz, 2H), 4.26 (ddt, J = 10.2, 4.8, 2.4 Hz, 2H); 13 C NMR (151 MHz, CDCl 3 ) δ 167.9, 156.0, 136.2, 133.8, 130.2, 128.9, 128.8, 128.6, 128.3, 128.2, 108.6, 67.2, 54.4, 45.6; IR (ATR) 2971, 2233, 1705, 1414, 1276, 1117, 697 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 19 H 18 N 3 O 3 + : 336.1343, found [M+H] + : 336.1347.

[0106] Method A: White solid (21.6 mg, 61%). M.P. 120 - 122 °C; 1 H NMR (600 MHz, CDCl 3 ) δ 8.17 (d, J = 2.3 Hz, 1H), 8.06 (dd, J = 8.8, 2.3 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 3.89 (d, J = 6.6 Hz, 2H), 3.38 (s, 3H), 2.69 (s, 3H), 2.19 (dt, J = 13.3, 6.6 Hz, 1H), 1.08 (d, J = 6.7 Hz, 6H); 13 C NMR(151 MHz, CDCl 3) δ 167.6, 162.8, 162.7, 161.5, 132.9, 132.4, 125.2, 119.6, 115.3, 112.8, 111.1, 103.1, 75.8, 35.6, 28.2, 19.1, 18.3; IR (ATR) max 2986, 2236, 1708, 1290, 1061, 796, 734 cm -1 ; IR (ATR) 2969, 2234, 1687, 1509, 1275, 1052, 735 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 18 H 19 N 4 O 2 S + : 355.1223, found [M+H] + : 355.1226.

[0107] Method A: Colorless oily liquid (16.1 mg, 56%). 1 H NMR (600 MHz, CDCl 3 ) δ 7.01 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 6.61 (s, 1H), 3.96 (t, J = 6.2 Hz, 2H), 3.20 (s, 3H), 2.32 (s, 3H), 2.21 (s, 3H), 2.05–2.01 (m, 2H), 1.79 - 1.73 (m, 2H), 1.44 (s, 6H); 13 C NMR (151 MHz, CDCl 3 ) δ 176.6, 156.8, 136.6, 130.5, 123.7, 120.9, 111.9, 67.3, 44.6, 36.5, 36.0, 25.2, 21.5, 15.9; IR (ATR) 2973, 2232, 1712, 1265, 1047, 807, 736 cm -1 ; HRMS (ESI / [M+H] +) m / z calcd. for C 17 H 25 N 2 O 2 + : 289.1911, found [M+H] + : 289.1919.

[0108] Method A: Colorless oily liquid (21.0 mg, 86%). 1 H NMR (600 MHz,CDCl 3 ) δ 7.24 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 4.26 (q, J = 6.8Hz, 1H), 3.14 (s, 3H), 2.45 (d, J = 7.2 Hz, 2H), 1.84 (dq, J = 13.6, 6.8 Hz,1H), 1.51 (d, J = 6.9 Hz, 3H), 0.90 (d, J = 6.6 Hz, 6H); 13 C NMR (151 MHz,CDCl 3 ) δ 173.8, 141.4, 135.8, 129.8, 127.5, 111.2, 45.1, 44.2, 34.1, 30.2,22.4, 19.4; IR (ATR) 2958, 2240, 1723, 1223, 1056, 850, 736 cm -1 ; HRMS(ESI / [M+H] + ) m / z calcd. for C 15 H 21 N 2 O + : 245.1648, found [M+H] + : 245.1651.

[0109] Method A: Colorless oily liquid (26.2 mg, 90%). 1 H NMR (600 MHz,CDCl 3) δ 7.81 (d, J = 8.2 Hz, 2H), 7.77–7.72 (m, 2H), 7.60–7.55 (m, 2H), 7.48(td, J = 7.9, 7.4, 1.5 Hz, 3H), 4.35 (q, J = 6.9 Hz, 1H), 3.17 (d, J = 1.2Hz, 3H), 1.55 (d, J = 6.9 Hz, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 196.2, 173.2,138.9, 138.4, 137.2, 132.7, 131.7, 130.2, 129.6, 129.4, 129.1, 128.4, 111.0,44.5, 34.2, 19.5; IR (ATR) 2988, 2239, 1722, 1659, 1281, 1221, 1057,718, 699 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 18 H 17 N 2 O 2 + : 293.1285, found [M+H] + : 293.1294.

[0110] Method A: Colorless oily liquid (17.7 mg, 66%). 1 H NMR (600 MHz,CDCl 3 ) δ 7.73 (dd, J = 8.9, 5.7 Hz, 3H), 7.42 (dd, J = 8.5, 1.9 Hz, 1H), 7.16(dd, J = 9.0, 2.6 Hz, 1H), 7.12 (d, J = 2.5 Hz, 1H), 4.42 (q, J = 6.9 Hz,1H), 3.91 (s, 3H), 3.15 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H); 13 C NMR (151 MHz,CDCl 3) δ 173.8, 158.0, 134.1, 133.7, 129.5, 129.0, 127.8, 126.8, 126.0, 119.4, 111.2, 105.6, 55.4, 44.6, 34.2, 19.5; IR (ATR) 2988, 2240, 1722, 1606, 1265, 1058, 855, 736 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 16 H 17 N 2 O 2 + : 269.1285, found [M+H] + : 269.1291.

[0111] Method A: White solid (16.5 mg, 51%). M.P. 51 - 52 °C; 1 H NMR(600 MHz, CDCl 3 ) δ 7.92 (s, 4H), 3.41 (s, 3H), 3.13 - 3.06 (m, 4H), 1.55 (dq, J = 15.0, 7.3 Hz, 4H), 0.86 (t, J = 7.4 Hz, 6H); 13 C NMR (151 MHz, CDCl 3 ) δ 167.4, 144.6, 134.0, 129.4, 127.3, 111.2, 50.1, 35.6, 22.1, 11.3; IR (ATR) 2970, 2240, 1711, 1284, 1153, 1056, 753, 734 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 15 H 22 N 3 O 3 S + : 324.1376, found [M+H] + : 324.1385.

[0112] Method A: White solid (36.5 mg, 81%). M.P. 219 - 221 °C; 1 H NMR (600 MHz, CDCl 3 ) δ 8.41 (d, J = 1.8 Hz, 1H), 8.06 - 7.92 (m, 3H), 7.88 - 7.81 (m, 2H), 7.60 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 8.4, 2.3 Hz, 1H), 7.00(d, J = 8.4 Hz, 1H), 3.91 (s, 3H), 3.46 (s, 3H), 2.18 (s, 6H), 2.11 (s, 3H),1.81 (s, 6H); 13 C NMR (151 MHz, CDCl 3 ) δ 168.8, 159.2, 142.1, 139.2, 135.9,132.4, 130.8, 130.0, 129.8, 128.8, 127.3, 127.2, 126.1, 125.9, 124.9, 124.8,112.2, 112.1, 55.3, 40.7, 37.3, 37.2, 35.7, 29.2; IR (ATR) 2919, 2234,1703, 1231, 1057, 812, 739 cm -1 ; HRMS (ESI / [M + H] + ) m / z calcd. for C 30 H 31 N 2 O 2 + :451.2380, found [M + H] + : 451.2388.

[0113] Method A: Colorless oily liquid (36.1 mg, 86%). 1 H NMR (600 MHz,CDCl 3 ) δ 7.39 (d, J = 2.1 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.31 - 7.28 (m,3H), 7.26 (s, 1H), 7.07 - 7.05 (m, 2H), 3.41 (s, 3H), 2.26 (s, 3H);13 C NMR (151MHz, CDCl 3 ) δ 162.3, 143.0, 142.4, 136.3, 135.6, 135.3, 132.6, 130.8, 130.5,130.4, 129.1, 128.2, 126.7, 119.2, 111.3, 35.6, 9.3; IR (ATR) 2988,2239, 1701, 1493, 1057, 817, 733 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. forC 19 H 14 Cl 3 N 4 O + : 419.0228, found [M+H] + : 419.0233.

[0114] Method A: Pale yellow liquid (38.6 mg, 85%). 1 H NMR (600 MHz,CDCl 3 ) δ 8.12 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 7.7, 1.4 Hz, 1H), 7.82-7.75(m, 2H), 7.62-7.55 (m, 1H), 7.54 (td, J = 7.5, 1.4 Hz, 1H), 7.50-7.40 (m,4H), 7.34 (dd, J = 7.5, 1.2 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 5.17 (s, 2H),4.25 (t, J = 6.0 Hz, 2H), 3.85 (t, J = 7.1 Hz, 2H), 3.67 (s, 2H), 2.19-2.12(m, 2H); 13 C NMR (151 MHz, CDCl 3) δ 190.8, 171.3, 168.3, 160.6, 140.5, 136.4, 135.6, 133.3, 132.8, 132.5, 130.9, 129.6, 129.3, 128.7(128.71), 128.7(128.67), 127.9, 127.6, 125.2, 121.2, 111.0, 73.7, 61.4, 45.1, 40.1, 26.9; IR(ATR) 2988, 2235, 1735, 1709, 1265, 1121, 732, 702 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 27 H 23 N 2 O 5 + : 455.1601, found [M+H] + : 455.1609.

[0115] Method A: Pale yellow liquid (36.3 mg, 90%). 1 H NMR (600 MHz, CDCl 3 ) δ 7.82 (dt, J = 5.6, 2.9 Hz, 2H), 7.75 (dd, J = 7.8, 2.1 Hz, 2H), 7.69 (dt, J = 5.6, 2.9 Hz, 2H), 7.59 - 7.51 (m, 1H), 7.45 (td, J = 7.7, 2.3 Hz, 2H), 3.86 (tq, J = 7.4, 4.6, 3.5 Hz, 2H), 3.68 (ddd, J = 13.9, 5.8, 2.2 Hz, 1H), 3.62 (ddd, J = 13.8, 7.8, 2.2 Hz, 1H), 2.09 (p, J = 6.6 Hz, 1H), 1.83 - 1.71 (m, 3H), 1.37 - 1.11 (m, 2H), 0.94 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H); 13 C NMR (151 MHz, CDCl 3) δ 168.8, 168.4, 134.1, 133.1, 132.0, 131.1, 128.6(128.63), 128.6(128.61), 123.4, 110.9, 45.2, 41.6, 41.4, 32.8, 29.8, 25.4, 22.8, 22.6; IR (ATR) 2959, 2232, 1772, 1708, 1399, 1271, 1066, 723, 703 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 24 H 26 N 3 O 3 + : 404.1969, found [M+H] + : 404.1970.

[0116] Method A: White solid (27.9 mg, 61%). M.P. 127 - 129 °C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.79 (d, J = 7.3 Hz, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 1H), 6.72 (dd, J = 8.6, 2.7 Hz, 1H), 6.65 (d, J = 2.7 Hz, 1H), 4.09 (t, J = 5.6 Hz, 2H), 3.99 (t, J = 7.0 Hz, 2H), 2.96 - 2.82 (m, 2H), 2.50 (dd, J = 19.0, 8.8 Hz, 1H), 2.43 - 2.35 (m, 1H), 2.26 (ddt, J = 21.6, 10.9, 5.2 Hz, 3H), 2.21 - 2.11 (m, 1H), 2.08–1.98 (m, 2H), 1.98 - 1.91 (m, 1H), 1.70 - 1.39 (m, 6H), 0.91 (s, 3H); 13 C NMR (151 MHz, CDCl 3) δ 221.0, 168.5, 156.6, 137.9, 133.2, 132.6, 131.0, 128.7, 128.6, 126.5, 114.7, 112.2, 111.2, 64.7, 50.4, 48.0, 45.7, 44.0, 38.4, 35.9, 31.6, 29.7, 27.6, 26.6, 26.0, 21.6, 13.9; IR (ATR) 2970, 2232, 1736, 1704, 1276, 1057, 734, 702 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 29 H 33 N 2 O 3 + : 457.2486, found [M+H] + : 457.2488.

[0117] Method A: Pale yellow liquid (21.6 mg, 45%). 1 H NMR (600 MHz, CDCl 3 ) δ 7.79 (d, J = 8.4 Hz, 4H), 7.60 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 4.04 (t, J = 6.3 Hz, 2H), 3.73 (t, J = 7.3 Hz, 2H), 2.45 (s, 3H), 1.77 (p, J = 7.3 Hz, 2H), 1.68 (p, J = 6.5 Hz, 2H), 1.43 - 1.36 (m, J = 4.9, 3.9 Hz, 4H); 13 C NMR (151 MHz, CDCl 3 ) δ 168.6, 144.9, 133.3, 133.2, 131.2, 130.0, 128.8, 128.7, 128.0, 111.2, 70.3, 47.7, 28.8, 27.5, 25.8, 25.1, 21.8; IR (ATR) 2970, 2232, 1705, 1357, 1275, 1176, 736, 704, 664 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 21 H 25 N 2 O 4 S + : 401.1530, found [M+H] + : 401.1528.

[0118] Method A: Pale yellow liquid (14.3 mg, 67%). 1 1H NMR (600 MHz, CDCl 3 ) δ7.83 - 7.75 (m, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 5.82 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.11 (dq, J = 17.1, 1.7 Hz, 1H), 5.06 (dt, J = 10.2, 1.4 Hz, 1H), 3.80 - 3.76 (m, 2H), 2.21 (q, J = 7.0 Hz, 2H), 1.92 (p, J = 7.3 Hz, 2H); 13 13C NMR (151 MHz, CDCl 3 ) 168.5, 136.6, 133.2, 131.2, 128.7(128.70), 128.7(128.66), 116.3, 111.2, 47.4, 30.5, 26.8; IR (ATR) 2972, 2232, 1703, 1275, 1058, 700 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 13 H 15 N 2 O + : 215.1179, found [M+H] + : 215.1171.

[0119] Method A: White solid (367 mg, 93%). 1 H NMR (600 MHz, CDCl 3 ) δ 7.25 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.31 (s, 1H), 3.80 (s, 3H), 3.19 (s, 3H), 3.12 (dd, J = 15.1, 6.0 Hz, 4H); 13 C NMR (151 MHz, CDCl 3 ) δ 172.0, 159.0, 150.7, 142.7, 134.2, 132.9, 129.9, 129.0, 128.8, 126.7, 114.3, 111.2, 106.5, 55.6, 33.8, 23.0; IR (ATR) 2971, 2236, 1729, 1516, 1249, 1091, 834, 734 cm -1 ; HRMS (ESI / [M+H] + ) m / z calcd. for C 21 H 20 ClN 4 O 2 + : 395.1269, found [M+H] + : 395.1271.

Claims

1. A method for synthesizing N-cyanamide compounds, characterized in that: In an organic solvent and in the presence of a base, the amide N-OTs compound a undergoes an N-cyanation reaction with TMSCN to generate the target compound b; The reaction route is as follows: ； in: R 1 Any one selected from substituted or unsubstituted C1~C13 hydrocarbon groups, substituted or unsubstituted aryl groups, substituted or unsubstituted cycloalkyl groups; the substituents include one or more of alkyl substitution, alkoxy substitution, halogen substitution, heteroatom substitution, cyano substitution, and ester substitution; R 2 The substituents are selected from substituted or unsubstituted C1~C18 hydrocarbon groups, substituted or unsubstituted cycloalkyl groups; the substituents include one or more of alkyl substitution, cycloalkyl substitution, alkoxy substitution, halogen substitution, heteroatom substitution, aryl substitution, sulfonyl substitution, and ester substitution.

2. The synthesis method according to claim 1, characterized in that: R 1 Selected from C1~C13 alkyl, phenyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , Any one of R 3 Any one selected from methyl, methoxy, tert-butyl, chlorine, bromine, fluorine, cyano, trifluoromethyl, methyl formate, and alkynyl.

3. The synthesis method according to claim 1, characterized in that: R 2 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Any one of .

4. The synthesis method according to claim 1, characterized in that The target compound b is selected from any one of the compounds with the following structures: ； ； ； ； ； ； 。 5. The synthesis method according to claim 1, characterized in that: In the N-cyanation reaction, the molar ratio of the amide N-OTs compound a to TMSCN is 1:1.5 to 1:2.5, and the molar ratio of the amide N-OTs compound a to the base is 1:2 to 1:

3.

6. The synthesis method according to claim 1, characterized in that: The base is selected from any one of CsF, KF and RbF.

7. The synthesis method according to claim 6, characterized in that: The base is CsF.

8. The synthesis method according to claim 1, characterized in that: The solvent is selected from any one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and acetonitrile.

9. The synthesis method according to claim 8, characterized in that: The solvent is acetonitrile.

10. The synthesis method according to claim 1, characterized in that: The reaction temperature of the N-cyanation reaction is 0°C~80°C, and the reaction time is 2~20 h.

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