Technical field of the invention The present invention refers to the synthesis of chemical compounds, in particular to the efficient and practical one-pot synthesis of a great variety of squaramides, including some examples of biologically active derivatives.

Background of the invention

The development of one-pot syntheses, in which at least two sequential transformations are performed in a single reaction flask, has gained considerable attention during the last decade, especially when these processes can provide chemicals and drug candidates. This interest is due to the increasing concern about sustainable chemistry since it is related with saving resources and with the reduction of the produced waste compared with the traditional 'stop-and-go' approaches. In the 'stop-and-go' approach, after each chemical transformation the process is stopped previous to the subsequent reaction pathway in order to eliminate the reaction media and/or for the purification and isolation of the reaction intermediate. In this context, at industrial scale, one-pot approach could be the best solution to reduce time, costs, resources and waste generation, since these processes would avoid the purification of the intermediates between individual steps, where major efforts are invested. Moreover, by reducing the number of synthetic steps and avoiding the purification processes, it is possible to reduce the loss of material and thus to increase the overall yield of the reaction. Therefore, from a biological and pharmaceutical point of view, one-pot reactions are hugely attractive for the synthesis of active compounds.

On the other hand, nowadays novel strategies involving squaramides have received an increasing interest due to their interesting properties, becoming a fundamental motif in research. The squaramide moieties have unique an interesting characteristics that make them appealing for many different areas within chemistry such as organic synthesis and catalysis. In fact, after the pioneering work reported by Rawal and coworkers in 2008 using squaramides as excellent hydrogen bond donor catalysts, an impressive growth has been experimented in this area of research. However, although squaramides have been the focus of intensive studies (see: a) Aleman, J.; Parra, A.; Jiang, H.; Jgrgensen, K. A. Chem. Eur. J. 2011 , 17, 6890; b) Storer, R. I.; Aciro, C; Jones, L. H. Chem. Soc. Rev. 2011 , 40, 2330; c) Wurm, F. R.; Klokb, H.-A. Chem. Soc. Rev. 2013, 42, 8220; d) Alegre-Requena, J. V. Synlett 2014, 298) to the best of the knowledge of the authors of the present invention their syntheses have always been performed following at least two pathways, with purification of the first reaction intermediate as shown below.

purification

In this invention, the authors report for the first time the one-pot syntheses of squaramides (see Scheme 1 ).

Brief description of the invention The present invention refers to an improved process for the preparation of squaramides. In particular, the present invention refers to one-pot syntheses for the preparation of squaramides, in which all sequential transformations are performed in a single reactor in which the process is not stopped previous to the subsequent reaction pathway in order to eliminate the reaction media and/or for the purification and isolation of the reaction intermediate, which comprises the following steps:

1 . Adding to a mixture of 3-cyclobuten-1 ,2-dione derivative 1 in a polar solvent, an amine 2 solved or not in the same or another polar solvent, to obtain product 3;

2. Then adding a further amine 4 solved or not in a polar solvent, to the same reactor used to conduct the reaction of step 1 ) and without stopping the first reaction step, to obtain an adduct comprising squaramide product 5; and

3. optionally filtrating and/or purifying the adduct comprising squaramide product 5 of step 2) to obtain the substantially pure squaramide product 5.

In addition, the present invention further refers to a group of novel compounds, namely the compounds indicated in Table 1 (entries 1 -16) and Table I bis (entries 30-35 and 37-38) below, as well as to the use of these compounds as catalysts.

Brief description of the figures

Figure 1 shows the side-products generated in the first sequential transformation in a one-pot syntheses reaction, in which at least two sequential transformations are performed in a single reaction flask without evaporating the solvent after the first transformation or purifying the intermediate through other ways.

Figure 2 shows the side-products generated in the two sequential transformations in a one-pot syntheses reaction, in which at least two sequential transformations are performed in a single reaction flask without evaporating the solvent after the first transformation or purifying the intermediate through other ways.

Detailed description of the invention The present invention refers to the first one-pot synthesis of squaramides (see Scheme 1 ). The one-pot synthesis of squaramides described herein is an easy and straightforward procedure to obtain squaramide derivatives which saves energy, avoids time consuming purification steps, reduces costs and provides better yields as compared with those squaramides obtained through the traditional "stop-and-go" approach. Moreover, the authors of the present invention herein demonstrate the efficiency of this one-pot process with the synthesis of three biologically active structures, improving in most of the cases the results of the previous stepwise syntheses.

Scheme 1. One pot-synthesis of squaramides 5.

Since previous works using "stop-and-go" approaches required more efforts, the authors of the present invention envisioned the possibility of performing the synthesis of squaramides by a one-pot protocol, avoiding the purification of the intermediate in order to save time, costs and to reduce the generation of waste. Moreover, they performed the synthesis without excess of reactants as an attractive feature from an atom economy point of view, also in order to obtain the final product pure after a simple filtration - purification method used in many of the cases. For this purpose, they synthesized the only commercially available squaramide organocatalyst 5cg to date, following the synthetic route described in Scheme 2. In said Scheme, a comparison is made between the one-pot synthesis of the invention (see "our work") and known "stop-and-go" syntheses such as Rawal ^' s synthesis (Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem. Int. Ed. 2010, 49, 153) and Du ^' s synthesis (Yang, W.; Du, D.-M. Adv. Synth. Catal. 2011 , 353, 1241 ).

our work

Scheme 2. Syntheses of squaramide-based organocatalyst 5cg.

Surprisingly as illustrated in Scheme 2 above, commercially available squaramide 5cg was obtained with better yield than the one obtained with the reported syntheses for the same compound. This is remarkable for several reasons:

First, the intermediate product resultant from the reaction between the squarate 1a and the 4-(trifluoromethyl)aniline (3c) precipitates in the one-pot synthesis reaction pathway. Therefore, a priori, the expectation of obtaining a better yield in the one-pot synthesis than the one obtained with the reported syntheses for the same compound was greatly reduced. However, surprisingly by adding the second amine dissolved in methanol in the one-pot synthesis reaction, the intermediate product was re-dissolved favouring the formation, precipitation and, therefore, filtration of the final product in a high yield, in fact in a higher yield than the one obtained with the reported syntheses (see Scheme 2).

Secondly, a priori, the first sequential transformation in a one-pot syntheses reaction, in which at least two sequential transformations are performed in a single reaction flask without evaporating the solvent after the first transformation or purifying the intermediate through other ways, generates a great number of side products which could interfere with the second sequential transformation and, thus, affect (reduce) the overall yield of the final product. In this sense, some of these side-products are illustrated in Figure 1 . Moreover, the final reaction crude obtained in the one-pot syntheses reaction illustrated in Scheme 1 or in Scheme 2 above, should theoretically comprise the side-products illustrated in Figure 2, which could interfere with the sequential transformation reactions and thus affect (reduce) the overall yield of the final product. Yet, surprisingly the yield of the final product 5cg obtained with the one-pot synthesis is in fact higher than the one obtained with the reported prior art syntheses (see Scheme 2). In addition, it is remarkable that in the previous procedures illustrated in Scheme 2 the authors used an excess of amine 4g (1 .5 equiv) in their second reaction step, while the authors of the present invention performed the reaction under equimolar amounts of each reagent in order to reduce waste as well as the overall cost of the reaction. Moreover, the authors stopped the reaction after only 3 hours from the addition of amine 4g, which means a shorter reaction time as compared with previous procedures (24 h). Moreover, by scaling up the one-pot reaction the yield of the process increases avoiding a significant loss of material relative to the amount of product (For evidences of the latter see Table 1 , and compare entries 3 and 4, 19 and 20, and 25 and 26).

After this promising result, the authors of the present invention considered extending the applicability of the simple, cheap and direct methodology presented herein for the synthesis of squaramide compounds, in order to demonstrate the importance and applicability of the procedure.

In this sense, recently, Moreno, Costa and co-workers have discovered an effective anti-Chagasic drug, squaramide derivative 11 , which acts as a potent anti-parasitic agent (Scheme 3) that has shown to be a promising candidate in preliminary in vivo studies on the acute and chronic phases of the disease (Olmo, F.; Rotger, C; Ramirez- Macias, I.; Martinez, L; Marin, C; Carreras, L; Urbanova, K.; Vega, M.; Chaves- Lemaur, G.; Sampedro, A.; Rosales, M. J.; Sanchez-Moreno, M.; Costa, A. J. Med. Chem. 2014, 57, 987). Chagas disease is a tropical parasitic infection affecting rural areas of South America. Although there are treatments to this illness, further research efforts are required in order to find more efficient and cheaper drugs suitable for the treatment of Chagas disease. In this context, squaramide 11 , as a low-cost drug, could represent an interesting alternative to the current treatments since these have severe side-effects and low efficiency.

Moreno, Costa's work (67.5% overall yield, two steps) our work H, 2.5h H, 12.5h

Scheme 3. Synthesis of antiparasitic agent 11.

In this sense, the authors of the present invention synthesized derivative 11 by using the straightforward one-pot procedure illustrated in Scheme 1 , improving the methodology previously reported for the obtainment of this interesting compound as shown in Scheme 3 above. In the previous synthesis, the authors needed three reaction pathways with an overall yield for the last two steps of around 67.5%. In contrast, the authors of the present invention initiated the synthesis from squarate 1a (0.2 mmol) dissolved in MeOH (0.25 ml_), and then added amine 8 (0.2 mmol) (2.5 h). In the same vessel, then they added BuNH ₂ (10) (0.2 mmol) solved in MeOH (1 .75 ml_). After 12.5 hours, they evaporated the solvent and the product was purified by column chromatography, achieving the final product in 78% yield. Therefore, by applying the one-pot methodology illustrated in Scheme 1 the authors of the present invention were able to overcome the yield of the previous developed method where the authors used three steps. An interesting aspect of the present invention is that the authors repeated the same one-pot reaction illustrated in Scheme 3 in 0.25 ml_ MeOH by adding the 2nd amine without solvent surprisingly obtaining roughly the same yield, namely a 75% yield.

After this further promising result, the authors of the present invention foresaw the preparation of two other active compounds, namely of compounds 15 and 20 (see Schemes 4 and 5, products WAY-133537 and WAY-151616) which act as potent smooth muscle relaxants. These two bladder-selective KATP-channel openers exhibit remarkable oral efficacy in a rat hypertrophied bladder model of urge urinary incontinency disease which affects between 10 and 20% of the world population with the consequent health care costs. Consequently, these two drugs (WAY-133537 15 and WAY- 151616 20) seem to be promising candidates for the treatment of this disease. our work

But era's work (17.7% overall yield)

H, 73h

Scheme 4. Syntheses of bladder-selective agonist K _A TP channel 15.

Previous known in the art synthesis for compound 15 was prepared following the procedure described in Scheme 4 (a) Butera, John A.; Antane, Schuyler A. US Pat. 5,506,252 filed Oct. 2, 1994 and issued Ap. 9, 1996; b) Butera, J. A.; Antane, M. M.; Antane, S. A.; Argentieri, T. M.; Freeden, C; Graceffa, R. F.; Hirth, B. H.; Jenkins, D.; Lennox, J. R.; Matelan, E.; Norton, N. W.; Quagliato, D.; Sheldon, J. H.; Spinelli, W.; Warga, D.; Wojdan, A.; Woods, M. J. Med. Chem. 2000, 43, 1 187) with an overall yield of 17.7% (scale of 5.88 mmol). In contrast, the authors of the present invention tested the one-pot synthetic procedure described in Scheme 1 for the synthesis of this appealing drug and were able to obtain compound 15 in a 33% yield (scale of 0.2 mmol). In this case, due to the high insolubility of the intermediate product 13, the authors of the present invention slightly modified the initial amount of solvent and started the reaction from squarate 1 a dissolved in 1 ml_ of MeOH, and then amine 12 was added. After 73 h of reaction, they further added amine 14. Finally, 2 days later the authors filtered the precipitate under vacuum and washed the solid with cold MeOH (MeOH at -22°C, 0.5 ml_), achieving the final product in 33% yield. Thus, using the one-pot procedure the authors of the present invention were able to overcome the yield of the previous developed method in a ratio of 1 .8:1 . In addition, the authors of the present invention also prepared compound WAY-151616 (compound 20) by using the one-pot synthetic procedure illustrated in Scheme 5. our work

Scheme 5. Synthesis of anti-incontinent agent WAY-151616 (20).

Biologically active squaramide 20 prepared by a well-known technique in the art, namely by the methodology used by Butera and co-workers, (a) Herbst, D. R.; Antane, M. M.; McFarlane, G. R.; Gundersen, E. G.; Hirth, B. H.; Quagliato, D. A.; Graceffa, R. F.; Butera, J . A. US Pat. 5,763,474 filed Jul. 7, 1997 and issued Jun. 9, 1998; b) Gilbert, A. M.; Antane, M. M.; Argentieri, T. M.; Butera, J. A.; Francisco, G. D.; Freeden, C; Gundersen, E. G.; Graceffa, R. F.; Herbst, D.; Hirth, B. H.; Lennox, J. R.; McFarlane, G.; Norton, N. W.; Quagliato, D.; Sheldon, J. H.; Warga, D.; Wojdan, A.; Woods, M. J. Med. Chem. 2000, 43, 1203) as illustrated in Scheme 5 provided an overall yield of 79%. In contrast, following the one-pot procedure, the authors of the present invention reached a 72% yield. However, it is noteworthy mentioning that the authors performed the known synthesis at a very low scale (0.4 mmol of product, 136 mg) in comparison to the scale used in the known method (28 g of compound 20), therefore, better yield should be expected following the one-pot procedure in a higher scale. In fact, to illustrate the latter, the authors of the present invention performed the one-pot reaction at 0.2 mmol obtaining the final product 20 at a yield of 62%, thus illustrating the importance of the scale and the possibility of improving the methodology by increasing the amounts of the synthesized final product. Additionally, to further illustrate the novel synthesis of the present invention, the authors synthesized novel squaramide structures (as illustrated in Table 1 below in entries 1 -16 and Table I bis entries 30-35 and 37-38 as well as previously reported ones (entries 17-29 and 36).

Table 1. Scope of one-pot synthesis of squaramides. ³

Entry NH ₂ R ¹ NH ₂ R ² ti (h) t ₂ (h) Product yield (%) ^b (2a-i)/ (4a-l)/

MeOH MeOH

(ml_) (ml_)

2a/0.2

1 4a/1 .75 80 20 75

5

2 2b/0.5 4a/1 .5 26 25 82 a Experimental conditions: To a mixture of squarate 1a (0.2 mmol) in MeOH (0.25-1 mL), amine 2a-i (0.2 mmol) was further added at room temperature. After the reaction time ti, amine 4a-l (0.2 mmol) was added solved in MeOH (4.5-1 mL). After t ₂ adducts 5 were filtrated under vacuum and the solid was washed with cold MeOH (1 mL). ^b Isolated yield. ^c Reaction performed for 1 mmol of reagents. ^d Reaction performed for 0.15 mmol of reagents. ^e Purified by column chromatography (SiO ₂ , using Hex:AcOEt 6:4 to AcOE MeOH 9:1 ). ^f Purified by column chromatography (SiO ₂ , using AcOEt to AcOE MeOH 7:3). ⁹ Reaction performed for 0.4 mmol of reagents. ^h Purified by column chromatography (SiO ₂ with Et ₃ N, using CH ₂ CI ₂ to CH ₂ CI ₂ :MeOH 98:2). ' Purified by column chromatography (SiO ₂ , using Hex:AcOEt 6:4 to AcOE MeOH 7:3).

Table I bis. Additional one-pot synthesis of squaramides. ²

Entry NH ₂ R ¹ NH ₂ R ² ti (h) t ₂ (h) Product yield (%) ^b (2a-m)/ (4a-n)/

MeOH MeOH (mL) (mL)

^a Experimental conditions: To a mixture of squarate 1 a (0.2 mmol) in MeOH (0.25-1 mL), amine 2a-m (0.2 mmol) was further added at room temperature. After the reaction time ti , amine 4a-n (0.2 mmol) was added solved in MeOH (4.5-1 mL). After t ₂ adducts 5 were filtrated under vacuum and the solid was washed with cold MeOH (1 mL). ^b Isolated yield. ^c Reaction performed for 1 mmol of reagents. ^d Reaction performed for 0.15 mmol of reagents. ^e Purified by column chromatography (SiO ₂ , using Hex:AcOEt 6:4 to AcOE MeOH 9:1 ). ^f Purified by column chromatography (SiO ₂ , using AcOEt to AcOE MeOH 7:3). ⁹ Reaction performed for 0.4 mmol of reagents. ^h Purified by column chromatography (SiO ₂ with Et ₃ N, using CH ₂ CI ₂ to CH ₂ CI ₂ :MeOH 98:2). ' Purified by column chromatography (SiO ₂ , using Hex:AcOEt 6:4 to AcOE MeOH 7:3). ^j Reaction performed for 3 mmol of reagents. ^k Reaction performed for 1 .2 mmol of reagents.

The method always requires a polar solvent. However, and exceptionally, preferably in case of both anilines are liquids as for compound 5an, the reaction can be performed in absence of solvent. These are really exceptional and rare conditions, since in all cases the anilines are preferably at least, one of them, solid.

Reference to 5ch is made in Zheng, B.; Hou, W.; Peng, Y. ChemCatChem 2014, 6, 2527-2530.

In most cases illustrated in Table 1 or Table I bis above, the final squaramide product 5 was obtained with moderate to very good yields (from 43% to >95%). Additionally, as already stated, the authors of the present invention have observed that it is possible to slightly increase the yield of the process by performing the reaction in a higher scale (see entries 4, 20 and 26 in Table 1 above), thus avoiding a loss of material which could represent an important percentage of the overall yield at lower scales (72% against 80% for entries 3 and 4, 45% against 52% in entries 19 and 20, and 43% against 53% for entries 25 and 26). Additionally, the authors performed a one-pot reaction in a gram- scale for compound 5da (81 %), showing that the scaling of the reaction is possible for diverse structures. This is certainly interesting from an industrial point of view since better yields will be expected by using a higher scale.

The concentration of the reaction has been studied and analysed for each single case due to the different solubility of the reagents and the final products, and the slight differences in the amount of MeOH employed in each optimized process are shown in Table 1 and Table I bis above.

Lastly, in entries 17 to 29 of Table 1 a comparison is given between the one-pot synthesis of the present invention and previously known syntheses. Citations of the previously known "stop and go" syntheses are herein provided:

¹ Konishi, H.; Lam, T. Y.; Malerich, J. P.; Rawal, V. H. Org. Lett. 2010, 12, 202.

² For the preparation of the opposite enantiomer, see: Yang, W.; Du, D.-M. Adv. Synth. Catal. 2011 , 353, 1241 .

³ Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem. Int. Ed. 2010, 49, 153.

⁴ Yang, W.; Du, D.-M. Org. Lett. 2010, 12, 5450.

⁵ Jiang, H.; Paixao, M. W.; Monge, D.; Jgrgensen, K. A. J. Am. Chem. Soc. 2010, 132, 2775.

6 Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416.

⁷ Baran, R.; Veverkova, E.; Skvorcova, A.; Sebesta, R. Org. Biomol. Chem. 2013, 11,

7705.

⁸ Yang, W.; Du, D.-M. Org. Biomol. Chem. 2012, 10, 6876. In summary, the authors of the present invention herein report the first one-pot synthesis of squaramides. This procedure provides a simpler and more efficient manner of obtaining appealing squaramide derivatives as compared to those previously obtained by the so called "stop-and-go" processes. By employing this novel methodology for the manufacture of squaramides, time consuming purification steps are avoided providing generally higher yields to those obtained through the traditional "stop- and-go" approach. In addition, the use of chlorinated solvents is avoided. Furthermore, the authors of the present invention have proved the utility of this novel process with the synthesis of a large number of squaramide structures (see Table 1 and Table I bis above). Moreover, the authors have been able to synthesize with better yields by a one- pot method the only commercially available squaramide that is largely employed as an organocatalyst today. The present invention could thus be a pivotal and crucial precedent in the field of squaramides due to the simple operational procedure reported herein.

Thus, a first aspect of the invention refers to one-pot syntheses for the preparation of squaramides, in which all sequential transformations are performed in a single reactor in which the process is not stopped previous to the subsequent reaction pathway in order to eliminate the reaction media and/or for the purification and isolation of the reaction intermediate, as represented in Scheme 6 below:

Scheme 6. One pot-synthesis of the invention.

In the context of the present invention the term "R" in 3-cyclobuten-1 ,2-dione derivative 1 is a leaving group that departs with a pair of electrons in a heterolytic bond cleavage. Leaving groups can be anions or neutral molecules with the premise that the leaving group must be able to stabilize the additional electron density that results from bond heterolysis. Leaving groups are known to the skilled person but can be preferably selected from the list consisting of alkoxides, halides, thiolates, sulfonates, hydroxides, carboxylates, amines, carbonates, sulfonamides, sulfones, amides, ethers, imides, carbamides, dinitrogen, nitrites, nitrates, phosphates and any combination thereof, preferably leaving groups are alkoxides, sulfonates, thiolates or halides or any combination thereof, more preferably the leaving groups are alkoxides, namely the conjugate base of an alcohol and, therefore, an organic group bonded to a negatively charged oxygen atom, still more preferably the leaving groups are selected from the list consisting of butoxi-, methoxi- and ethoxi-, chloro, and C1 to C5 alkyl alcohols such as etanol or methanol.

In the context of the present invention, reaction time ti is understood as the time needed for the maximum amount of starting reagents 1 and 2 to be consumed or when no significant progress of the reaction is observed, even when the starting reagents have not been fully consumed. In the context of the present invention, t ₂ is understood as the time needed for the maximum amount of intermediate reagent 3 to be consumed or when no significant progress of the reaction is observed, even when the intermediate reagent 3 has not been fully consumed.

As used herein "maximum amount" is when the amount of intermediate 3 is close to the same mmols added of 3-ciclobuten-1 ,2-dione derivative 1 .

In the context of the present invention, the progress of the reaction (reaction progress) can be easily determined by the skilled person by using well known techniques such as, but not limited to, thin layer chromatography (TLC) or nuclear magnetic resonance (NMR).

As used herein "no significant progress" is when by TLC or NMR we observe the same amount of product formed after two consecutive measures or when the reaction rate is close to cero. In particular, "No significant progress" is less of 5% of new product after two consecutive measures. An example of the use of the NMR technique to determine the progress of the reaction would be to take a small sample of the reaction diluted with DMSO-c/6 and put into a NMR tube with a known amount of an internal standard, such as dimethyl fumarate. Once placed in the NMR tube with the internal standard, it is measured with the NMR device and the amount of 3-ciclobuten-1 ,2-dione derivative 1/semi-squaramide /squaramide present in the reaction media is determined by comparing the significative peaks of each compound with the internal standard peaks. In particular, ti + t ₂ is any time interval from 1 hour to 144 hours, preferably from 4 hours to 120 hours, more preferably from 10 hours to 120 hours, more preferably from 24 hours to 120 hours, more preferably from 48 hours to 120 hours. Preferably, ti is from 0.5 hours to 94 hours and t ₂ is from 0.5 hour to 50 hours. The sequential transformations indicated in Scheme 6 are preferably performed at a temperature or temperature interval in which the skilled person can observe the higher reaction progress. In particular, preferred temperatures are from 0°C to 100°C, more preferably from 0°C to 70°C, more preferably from 10°C to 70°C, more preferably from 10°C to 50°C, still more preferably from 20°C to 50°C, still more preferably at room temperature (25°C at 1 atm); In the context of the present invention, the term "solvent" refers to any solvent, more preferably to a polar solvent having a value of relative polarity with respect to water greater than 0.1 , preferably from 0.1 to 1 , more preferably from 0.1 to 0.95, more preferably from 0.1 to 0.9. The values for relative polarity are normalized from measurements of solvent shifts of absorption spectra and were extracted from Christian Reichardt, Solvents and Solvent Effects in Organic Chemistry, Wiley-VCH Publishers, 3rd ed., 2003. We herein illustrate different solvents along with their relative polarity.

Solvent formula relative

polarity ²

acetic acid C2H ₄ O2 0.648

acetone C ₃ H ₆ O 0.355

acetonitrile C ₂ H ₃ N 0.460

acetyl acetone C5H8O2 0.571

2-aminoethanol C2H ₇ NO 0.651

aniline C ₆ H ₇ N 0.420

Anisole C ₇ H ₈ O 0.198

Benzene 0.1 1 1

Benzonitrile C ₇ H ₅ N 0.333

benzyl alcohol C ₇ H ₈ O 0.608

1 -butanol C ₄ HioO 0.586

2-butanol C ₄ HioO 0.506

/ ^' -butanol C ₄ HioO 0.552

2-butanone C ₄ H ₈ O 0.327

f-butyl alcohol C ₄ HioO 0.389

carbon disulfide CS ₂ 0.065

carbon tetrachloride CCI ₄ 0.052

Chlorobenzene CeHsCI 0.188

chloroform CHCI3 0.259

Cyclohexane C6H12 0.006 Cyclohexanol C6H12O 0.509

Cyclohexanone ΟβΗιοΟ 0.281 di-n-butylphthalate Ci6H22O ₄ 0.272

1 , 1 -d ich loroethane C2H ₄ Cl2 0.269 diethylene glycol C ₄ HioO3 0.713

Diglyme CeHi ₄ O3 0.244 dimethoxyethane C ₄ HioO2 0.231

(glyme)

N,N-dimethylaniline CeHi 1 N 0.179 dimethylformamide C3H ₇ NO 0.386

(DMF)

Dimethylphthalate CioHioO ₄ 0.309 dimethylsulfoxide C ₂ H ₆ OS 0.444

(DMSO)

dioxane C ₄ HsO2 0.164 ethanol C ₂ H ₆ O 0.654

Ether C ₄ HioO 0.117 ethyl acetate C ₄ HsO2 0.228 ethyl acetoacetate C6H10O3 0.577 ethyl benzoate C9H10O2 0.228 ethylene glycol C2H6O2 0.790

Glycerin C3H8O3 0.812

Heptane C7H16 0.012

1 -heptanol C ₇ H16O 0.549

Hexane ΟβΗι ₄ 0.009

1 -hexanol ΟβΗι ₄ Ο 0.559

Methanol CH ₄ O 0.762 methyl acetate C3H6O2 0.253 methyl f-butyl ether C ₅ H12O 0.124

(MTBE) methylene chloride CH2CI2 0.309

1 -octanol CsHisO 0.537

pentane C5H12 0.009

1 -pentanol C ₅ Hi ₂ O 0.568

2-pentanol C ₅ H12O 0.488

3-pentanol C ₅ H12O 0.463

2-pentanone C ₅ H10O 0.321

3-pentanone C ₅ H12O 0.265

1 -propanol C ₃ H ₈ O 0.617

2-propanol C ₃ H ₈ O 0.546

pyridine C ₅ H ₅ N 0.302

tetrahydrofuran(THF) C ₄ H ₈ O 0.207

toluene C7H8 0.099

water H ₂ O 1 .000

water, heavy D ₂ O 0.991

p-xylene CsHio 0.074

The sum of the interaction forces between the molecules of solvent and solute can be related to the so-called polarity of A and B. This depends on the action of all possible, specific and nonspecific, intermolecular forces between solvent and solute molecules. These intermolecular forces include Coulomb interactions between ions, directional interactions between dipoles, inductive, dispersion, hydrogen-bonding, and charge- transfer forces, as well as solvophobic interactions. For definitions and calculus see: Christian Reichardt, Solvents and Solvent Effects in Organic Chemistry, Wiley-VCH Publishers, 3rd ed., 2003, chapter 7, pp 389-469.

Preferably, the polar solvent is selected from the list consisting of a C1 to C18 (optionally substituted) alkyl or alkenyl alcohol or a C2 to C18 alkyl or alkenyl (optionally substituted) ester. More preferably, the polar solvent is selected from the list consisting of a C1 to C8 (optionally substituted) alky or alkenyl alcohol or a C2 to C8 alkyl or alkenyl (optionally substituted) ester. Still more preferably from the list consisting of a C1 to C5 (optionally substituted) alky or alkenyl alcohol and alkenyl esters. Still more preferably from the list consisting of chloroform, methanol, ethanol, acetonitrile and ethylacetate.

As understood herein amines 2 and 4 can be any type of primary or secondary amine. In particular, in the context of the present invention, radicals R1 , R2, R3 and R4 are independent of each other, hydrogen or a C5 to C7 aryl or a C5 to C7 heteroaryl or a C5 to C7 cydoalkane or an alkyl or alkylenyl or alkenyl or alkenylenyl or an alkynyl or an alkanesulfonyl or arylsulfonyl, or heteroarylsulfonyl or a cydoalkanesulfonyl or aroyl or an acyl or a perfluorinated aliphatic chain or a perfluorinated aryl or an imine or a guanidine or a hydroxide or a heteoatom as such or forming part of another functional group such as sulfones, hydrazines and hydrazides; where each of the groups or moieties mentioned herein can be optionally substituted.

"Alkyl" as used herein refers to an aliphatic hydrocarbon chain having 1 to 18 carbon atoms and includes straight or branched chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, f-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl . Lower alkyl refers to alkyl having 1 to 5, preferably from 1 -3 carbon atoms. In some embodiments of the invention, alkyl is preferably C1 to C8 and more preferably C1 to C6. Groups containing alkyl moieties may be optionally substituted as defined below or unsubstituted.

"Cycloalkyl" as used herein refers to monovalent or divalent groups of 3 to 10 carbon atoms derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Groups containing cycloalkyl moieties may be optionally substituted as defined below or unsubstituted.

"Alkylenyl" as used herein refers to alkyl linking (or bivalent alkyl group) a group, for example -CH ₂ - or -(CH ₂ )2-- "Alkenyl" as used herein refers to a linear or branched aliphatic hydrocarbon chain having 2 to 18 carbon atoms which contains 1 to 3 double bonds. Examples of alkenyl groups are mono-, di- or polyunsaturated linear or branched chains, such as vinyl, prop- 1 -enyl, allyl, methallyl, but-1 -enyl, but-2-enyl or but-3-enyl. Groups containing alkenyl moieties may be optionally substituted as defined below or unsubstituted.

"Alkenylenyl " as used herein refers to a linking alkenyl group (or a bivalent alkenyl group).

"Alkynyl" as used herein refers to an aliphatic straight or branched hydrocarbon chain having 2 to 18 carbon atoms, which may contain 1 to 3 triple bonds. Groups containing alkynyl moieties may be optionally substituted as defined below or unsubstituted.

"Acyl" as used herein refers to the group RC(=O)-, wherein R is an alkyl of 1 to 18 carbon atoms. For example, an acyl group of C2 to C7 refers to the group RC(=O)-, wherein R is an alkyl of 1 to 6 carbon atoms.

"Alkanesulfonyl" as used herein refers to the group RS(O)2-, wherein R is an alkyl of 1 to 6 carbon atoms.

"Arylsulfonyl" as used herein refers to an aryl group attached to the parent molecular moiety through a sulfonyl group.

"Aryl" as used herein refers to an aromatic mono or polycyclic of 5 to 18 members, such as a phenyl or a naphthyl ring. Preferably, groups containing aryl moieties are monocyclic having 5 to 7 carbon atoms in the ring. Heteroaryl means an aromatic mono- or polycyclic of 5 to 18 membered carbon-containing ring having one to five heteroatoms which may be selected, independently, from nitrogen, oxygen and sulfur. Preferably, groups containing heteroaryl moieties are monocyclic having 5 to 7 ring members, in which one or two of the ring members are independently selected from nitrogen, oxygen or sulfur. Groups containing aryl or heteroaryl moieties may be optionally substituted as defined below or unsubstituted.

"Aroyl " as used herein refers to the group Ar-C(=O)-, wherein Ar is aryl as defined above. For example, an aroyl moiety of C6 to C14 refers to the group Ar-C(=O)-, where Ar is an aromatic carbocyclic ring of 5 to 18 members.

"Halogen" as used herein means fluorine, chlorine, bromine or iodine.

"Substituted " as used herein refers to a moiety, such as an aryl or heteroaryl or cycloalkane or an alkyl or alkylenyl or alkenyl or alkynyl or alkenylenyl or alkanesulfonyl or aroyl or acyl having from 1 to about 5 substituents, and more preferably about 1 to 3 substituents independently selected from the group consisting of aryl or heteroaryl or cycloalkane or a hydrazide or an alkyl or alkylenyl or alkenyl or alkynyl or alkenylenyl or alkanesulfonyl or aroyl or acyl or halogen or nitro or sulfonamide or hydroxyl or alkoxy or nitrile, isocyanide, thiol, thioether, sulfoxide, sulfone, sulfonic acid, aromatic and non- aromatic heterocycles, amino, ammonium, amido, imino, imido, guanidino, urea, thiourea, isocyanate, isothiocyanate, hydrazine, hydroxylamino, phosphine, phosphorane, phosphate, phosphonate, phosphite, azide and silane, wherein these latter group can in turn also be optionally substituted.

The term "Substantially pure" is meant to refer to the compound where it is substantially free of biological or chemical constituents, e.g., isolated from a biological or chemical composition where biological or chemical components are co-isolated therewith, and wherein the analytical purity for the compound is preferably at least 70%. More preferred is where the analytical purity is at least 90%; even further preferred is where the analytical purity is at least 95% The term "about" as used herein means greater or lesser than the value or range of values stated by 1/10 of the stated values, but is not intended to limit any value or range of values to only this broader definition. For instance, a concentration value of about 30% means a concentration between 27% and 33%. Each value or range of values preceded by the term "about" is also intended to encompass the embodiment of the stated absolute value or range of values.

As used herein the term "Column chromatography" means a method used to purify individual chemical compounds from a mixture of compounds. The individual components are retained by the stationary phase differently and separate from each other while they are running at different speeds through the column with the eluent.

As used herein the term "crystallization" is the process of formation of solid crystals precipitating from a solution. It is also a chemical solid-liquid separation technique, in which mass transfer of a solute from the liquid solution to a pure solid crystalline phase occurs.

As used herein the term "filtration" is the common mechanical or physical operation which is used for the separation of solids from fluids (liquids or gases) by interposing a medium through which only the fluid can pass. This can be optionally done under vacuum conditions.

Other terms herein mentioned have the ordinary and customary meaning given to the term by those of ordinary skill in the art at the time of the invention.

It will be evident to a person skilled in the art that the precise one-pot method used herein for the preparation of a certain squaramide can vary depending on the chemical structure of the squaramide, being evident from the information disclose herein the methodology to be used for synthesizing the different chemical structures of squaramides. However, for merely illustrative purposes we herein incorporate a particularly optimized methodology for the one-pot synthesis reaction of the invention that can be generally used. - First, the required amount (x mmol) of 3-cyclobuten-1 ,2-dione derivative 1 should be added in a minimum amount of solvent so that the reaction can still be easily carried out after formation of the intermediate 3. NMR studies support that the higher the concentration of the reagents is in a solution the faster the reaction goes.

- The reaction should be carried out at a temperature T1 which provides a considerable improvement of the reaction at short times. NMR studies attest that at higher temperatures reactions proceed faster.

- The first amine should be added without dissolving it or dissolved in a minimum amount of solvent so that the sum of this amount and the amount of solvent already present in the reaction is the minimum amount of solvent so that the reaction can still be easily carried out after formation of the intermediate.

- Reaction time t1 should be sufficient to allow a significant progress of the reaction.

- The second amine should be added without dissolving it or dissolved in a minimum amount of solvent so that the sum of this amount and the amount of solvent already present in the reaction is the minimum amount of solvent so that the reaction can still be easily carried out after formation of the final squaramide 5.

- For the addition of the second amine, temperature T2 can be maintained or change to allow a significant progress of the reaction at short times.

- Reaction time t2 should be sufficient to allow a significant progress of the reaction. A preferred embodiment of the first aspect of the invention refers to one-pot syntheses for the preparation of squaramides, in which all sequential transformations are performed in a single reactor in which the process is not stopped previous to the subsequent reaction pathway in order to eliminate the reaction media and/or for the purification and isolation of the reaction intermediate, which comprises the following steps:

1 . Adding to a mixture of 3-cyclobuten-1 ,2-dione derivative 1 in a polar solvent, an amine 2 solved or not in the same or another polar solvent, to obtain product 3;

2. Then adding a further amine 4 solved or not in a polar solvent, to the same reactor used to conduct the reaction of step 1 ) and without stopping the first reaction step, to obtain an adduct comprising squaramide product 5; and

3. optionally filtrating and/or purifying the adduct comprising squaramide product 5 of step 2) to obtain the substantially pure squaramide product 5; wherein the term "R" in 3-cyclobuten-1 ,2-dione derivative 1 is a leaving group that departs with a pair of electrons in a heterolytic bond cleavage. Leaving groups can be anions or neutral molecules with the premise that the leaving group must be able to stabilize the additional electron density that results from bond heterolysis. Leaving groups are known to the skilled person but can be preferably selected from the list consisting of alkoxides, halides, thiolates, sulfonates, hydroxide, carboxylates, amines, carbonates, sulfonamides, sulfones, amides, ethers, imides, carbamides, dinitrogen, nitrites, nitrates, phosphates and any combination thereof, preferably leaving groups are alkoxides, sulfonates, thiolates or halides or any combination thereof, more preferably the leaving groups are alkoxides, namely the conjugate base of an alcohol and therefore an organic group bonded to a negatively charged oxygen atom, still more preferably the leaving groups are selected from the list consisting of butoxi-, methoxi- and ethoxi-, chloro, and C1 to C5 alkyl alcohols such as ethanol or methanol; wherein the term "polar solvent" refers to a solvent having a value of relative polarity with respect to water greater than 0.1 , preferably from 0.1 to 1 , more preferably from 0.1 to 0.95, more preferably from 0.1 to 0.9. Preferably the polar solvent is selected from the list consisting of a C1 to C18 (optionally substituted) alky or alkenyl alcohol or a C2 to C18 alkyl or alkenyl (optionally substituted) ester. More preferably, the polar solvent is selected from the list consisting of a C1 to C8 (optionally substituted) alky or alkenyl alcohol or a C2 to C8 alkyl or alkenyl (optionally substituted) ester. Still more preferably, the polar solvent is selected from the list consisting of a C1 to C5 (optionally substituted) alky or alkenyl alcohol. Still more preferably the polar solvent is selected from the list consisting of chloroform, methanol, ethanol, acetonitrile and ethylacetate; wherein amines 2 and 4 can be any type of primary or secondary amine. In particular, radicals R1 , R2, R3 and R4 in amines 2 and 4 are independently of each other, hydrogen or a C5 to C7 aryl or a C5 to C7 heteroaryl or a C5 to C7 cycloalkane or an alkyl or alkylenyl or alkenyl or alkenylenyl or an alkynyl or an alkanesulfonyl or arylsulfonyl, or heteroarylsulfonyl or a cycloalkanesulfonyl or aroyl or an acyl or a perfluorinated aliphatic chain a perfluorinated aryl or an imine or a guanidine or a hydroxide or a heteoatom as such or forming part of another functional group such as sulfones, hydrazines and hydrazides; where each of the groups or moieties mentioned herein can be optionally substituted.

In another preferred embodiment of the first aspect of the invention or of any of its preferred embodiments, 3-cyclobuten-1 ,2-dione derivative 1 is present in the mixture of step 1 ) in a molar concentration (M) of from 4 M to 2x10 ^"4 M, preferably from 2 M to 2X10 ^"3 M, more preferably from 2 M to 2X10 ^"2 M, more preferably from 2 M to 4X10 ^"2 M, more preferably from 2 M to 0.1 M and still more preferably from 1 M to 0.1 M; and the concentration of amines 2 and 4 are present in an amount of from 0.5 to 10 molar equivalents with respect to the 3-ciclobuten-1 ,2-dione derivative 1 , preferably from 0.8 to 1 .5 molar equivalents with respect to the 3-ciclobuten-1 ,2-dione derivative 1 , more preferably from 0.8 to 1 .2 molar equivalents with respect to the 3-cyclobuten-1 ,2-dione derivative 1 and still more preferably about 1 molar equivalent with respect to 3- ciclobuten-1 ,2-dione derivative 1 .

As used herein the term "molar equivalents" refers, in reaction stoichiometry, to the relative amount of moles of one amine that is added to a reaction compared to one mole of the 3-ciclobuten-1 ,2-dione derivative 1 . Another preferred embodiment of the first aspect of the invention refers to one-pot syntheses for the preparation of squaramides, in which all sequential transformations are performed in a single reactor in which the process is not stopped previous to the subsequent reaction pathway in order to eliminate the reaction media and/or for the purification and isolation of the reaction intermediate, which comprises the following steps:

1 . Adding to a mixture of 3-cyclobuten-1 ,2-dione derivative 1 in a polar solvent, an amine 2 solved or not in the same or another polar solvent, to obtain product 3 after a reaction time ti ; 1 _D 2 Polar solvent

+ NHR 'R

R

R R R

1 2

R 2 3

Then adding a further amine 4 solved or not in the same or another polar solvent, to the same reactor used to conduct the reaction of step 1 ) and without stopping the first reaction step, to obtain an adduct comprising squaramide product 5 after a reaction time t ₂ ; and R

3. optionally filtrating and/or purifying the adduct comprising squaramide product 5 of step 2) to obtain the substantially pure squaramide product 5; wherein the term "R" in 3-cyclobuten-1 ,2-dione derivative 1 is a leaving group that departs with a pair of electrons in a heterolytic bond cleavage. Leaving groups can be anions or neutral molecules with the premise that the leaving group must be able to stabilize the additional electron density that results from bond heterolysis. Leaving groups are known to the skilled person but can be preferably selected from the list consisting of alkoxides, halides, thiolates, sulfonates, hydroxide, carboxylates, amines, carbonates, sulfonamides, sulfones, amides, ethers, imides, carbamides, dinitrogen, nitrites, nitrates, phosphates and any combination thereof, preferably leaving groups are alkoxides, sulfonates, thiolates or halides or any combination thereof, more preferably the leaving groups are alkoxides, namely the conjugate base of an alcohol and therefore an organic group bonded to a negatively charged oxygen atom, still more preferably the leaving groups are selected from the list consisting of butoxi-, methoxi- and ethoxi-, chloro, and C1 to C5 alkyl alcohols such as ethanol or methanol; wherein the term "polar solvent" refers to a solvent having a value of relative polarity with respect to water greater than 0.1 , preferably from 0.1 to 1 , more preferably from 0.1 to 0.95, more preferably from 0.1 to 0.9. Preferably the polar solvent is selected from the list consisting of a C1 to C18 (optionally substituted) alky or alkenyl alcohol or a C2 to C18 alkyl or alkenyl (optionally substituted) ester. More preferably, the polar solvent is selected from the list consisting of a C1 to C8 (optionally substituted) alky or alkenyl alcohol or a C2 to C8 alkyl or alkenyl (optionally substituted) ester. Still more preferably the polar solvent is selected from the list consisting of a C1 to C5 (optionally substituted) alky or alkenyl alcohol. Still more preferably from the list consisting of chloroform, methanol, ethanol, acetonitrile and ethylacetate; wherein amines 2 and 4 can be any type of primary or secondary amine. In particular, radicals R1 , R2, R3 and R4 in amines 2 and 4 are independently of each other, hydrogen or a C5 to C7 aryl or a C5 to C7 heteroaryl or a C5 to C7 cycloalkane or an alkyl or alkylenyl or alkenyl or alkenylenyl or an alkynyl or an alkanesulfonyl or arylsulfonyl, or heteroarylsulfonyl or a cycloalkanesulfonyl or aroyl or an acyl or a perfluorinated aliphatic chain or a perfluorinated aryl or an imine or a guanidine or a hydroxide or a heteoatom as such or forming part of another functional group such as sulfones, hydrazines and hydrazides; where each of the groups or moieties mentioned herein can be optionally substituted; wherein each the sequential transformations described above (step 1 and step 2) are conducted at a temperature of from 0°C to 100°C, preferably from 0°C to 70°C, more preferably from 10°C to 70°C, more preferably from 10°C to 50°C, more preferably from 20°C to 50°C and still more preferably at room temperature; wherein reaction time ti is understood as the time needed for the maximum amount of starting reagents 1 and 2 to be consumed or when no significant progress of the reaction is observed, even when the starting reagents have not been fully consumed; wherein reaction time t ₂ is understood as the time needed for the maximum amount of intermediate reagent 3 to be consumed or when no significant progress of the reaction is observed, even when the intermediate reagent 3 has not been fully consumed; wherein preferably reaction time ti + t ₂ is any time interval from 1 hour to 144 hours, preferably from 4 hours to 120 hours, more preferably from 10 hours to 120 hours, more preferably from 24 hours to 120 hours, more preferably from 48 hours to 120 hours. Preferably, t1 is from 0.5 hours to 94 hours and t2 is from 0.5 hour to 50 hours; and wherein 3-cyclobuten-1 ,2-dione derivative 1 is present in the mixture of step 1 ) in a molar concentration (M) of from 4 M to 2X10 ^"4 M, preferably from 2 M to 2X10 ^"3 M, more preferably from 2 M to 2X10 ^"2 M, more preferably from 2 M to 4X10 ^"2 M, more preferably from 2 M to 0.1 M and still more preferably from 1 M to 0.1 M; and the concentration of amines 2 and 4 are present in an amount of from 0.5 to 10 molar equivalents with respect to the 3-ciclobuten-1 ,2-dione derivative 1 , preferably from 0.8 to 1 .5 molar equivalents with respect to the 3-ciclobuten-1 ,2-dione derivative 1 , more preferably from 0.8 to 1 .2 molar equivalents with respect to the 3-cyclobuten-1 ,2-dione derivative 1 and still more preferably about 1 molar equivalent with respect to 3-ciclobuten-1 ,2-dione derivative 1.

Another preferred embodiment of the first aspect of the invention refers to one-pot syntheses for the preparation of squaramides, in which all sequential transformations are performed in a single reactor in which the process is not stopped previous to the subsequent reaction pathway in order to eliminate the reaction media and/or for the purification and isolation of the reaction intermediate, which comprises the following steps:

Adding to a mixture of 3-cyclobuten-1 ,2-dione derivative 1 in a polar solvent, an amine 2 solved or not in the same or another polar solvent, to obtain product 3 after a reaction time ti;

Then adding a further amine 4 solved or not in the same or another polar solvent, to the same reactor used to conduct the reaction of step 1 ) and without stopping the first reaction step, to obtain an adduct comprising squaramide product 5 after a reaction time t ₂ ; and

3. optionally filtrating and/or purifying the adduct comprising squaramide product 5 of step 2) to obtain the substantially pure squaramide product of 5; wherein the term "R" in 3-cyclobuten-1 ,2-dione derivative 1 is a leaving group that departs with a pair of electrons in a heterolytic bond cleavage. Leaving groups can be anions or neutral molecules with the premise that the leaving group must be able to stabilize the additional electron density that results from bond heterolysis. Leaving groups are known to the skilled person but can be preferably selected from the list consisting of alkoxides, halides, thiolates, sulfonates, hydroxide, carboxylates, amines, carbonates, sulfonamides, sulfones, amides, ethers, imides, carbamides, dinitrogen, nitrites, nitrates, phosphates and any combination thereof, preferably leaving groups are alkoxides, sulfonates, thiolates or halides or any combination thereof, more preferably the leaving groups are alkoxides, namely the conjugate base of an alcohol and therefore an organic group bonded to a negatively charged oxygen atom, still more preferably the leaving groups are selected from the list consisting of butoxi-, methoxi- and ethoxi-, chloro, and C1 to C5 alkyl alcohols such as ethanol or methanol; wherein the term "polar solvent" refers to a solvent having a value of relative polarity with respect to water greater than 0.1 , preferably from 0.1 to 1 , more preferably from 0.1 to 0.95, more preferably from 0.1 to 0.9. Preferably the polar solvent is selected from the list consisting of a C1 to C18 (optionally substituted) alky or alkenyl alcohol or a C2 to C18 alkyl or alkenyl (optionally substituted) ester. More preferably, the polar solvent is selected from the list consisting of a C1 to C8 (optionally substituted) alky or alkenyl alcohol or a C2 to C8 alkyl or alkenyl (optionally substituted) ester. Still more preferably the polar solvent is selected from the list consisting of a C1 to C5 (optionally substituted) alky or alkenyl alcohol. Still more preferably the polar solvent is selected from the list consisting of chloroform, methanol, ethanol, acetonitrile and ethylacetate; wherein each the sequential transformations described above (step 1 and step 2) are conducted at a temperature of from 0°C to 100°C, preferably from 0°C to 70°C, more preferably from 10°C to 70°C, more preferably from 10°C to 50°C, more preferably from 20°C to 50°C and still more preferably at room temperature; wherein reaction time ti is understood as the time needed for the maximum amount of starting reagents 1 and 2 to be consumed or when no significant progress of the reaction is observed, even when the starting reagents have not been fully consumed; wherein reaction time t ₂ is understood as the time needed for the maximum amount of intermediate reagent 3 to be consumed or when no significant progress of the reaction is observed, even when the intermediate reagent 3 has not been fully consumed; wherein preferably reaction time ti + t ₂ is any time interval from 1 hour to 144 hours, preferably from 4 hours to 120 hours, more preferably from 10 hours to 120 hours, more preferably from 24 hours to 120 hours, more preferably from 48 hours to 120 hours. Preferably, ti is from 0.5 hours to 94 hours and t ₂ is from 0.5 hour to 50 hours; and wherein 3-cyclobuten-1 ,2-dione derivative 1 is present in the mixture of step 1 ) in a molar concentration (M) of from 4 M to 2X10 ^"4 M, preferably from 2 M to 2X10 ^"3 M, more preferably from 2 M to 2X10 ^"2 M, more preferably from 2 M to 4X10 ^"2 M, more preferably from 2 M to 0.1 M and still more preferably from 1 M to 0.1 M; and the concentration of amines 2 and 4 are present in an amount of from 0.5 to 10 molar equivalents with respect to the 3-ciclobuten-1 ,2-dione derivative 1 , preferably from 0.8 to 1 .5 molar equivalents with respect to the 3-ciclobuten-1 ,2-dione derivative 1 , more preferably from 0.8 to 1 .2 molar equivalents with respect to the 3-cyclobuten-1 ,2-dione derivative 1 and still more preferably about 1 molar equivalent with respect to 3-ciclobuten-1 ,2-dione derivative 1 ; wherein R1 and R3 are hydrogen; wherein R2 is selected from the group consisting of:

and wherein R4 is selected from the group consisting of:

Another preferred embodiment of the first aspect of the invention refers to one-pot syntheses for the preparation of squaramides, in which all sequential transformations are performed in a single reactor in which the process is not stopped previous to the subsequent reaction pathway in order to eliminate the reaction media and/or for the purification and isolation of the reaction intermediate, which comprises the following steps:

1 . Adding to a mixture of 3-cyclobuten-1 ,2-dione derivative 1 in a polar solvent, an amine 2 solved or not in the same or another polar solvent, to obtain product 3 after a reaction time ti;

2. Then adding a further amine 4 solved or not in the same or another polar solvent, to the same reactor used to conduct the reaction of step 1 ) and without stopping the first reaction step, to obtain an adduct comprising squaramide product 5 after a reaction time t ₂ ; and

3. optionally filtrating and/or purifying the adduct comprising squaramide product 5 of step 2) to obtain the substantially pure squaramide product 5; wherein the term "R" in 3-cyclobuten-1 ,2-dione derivative 1 is a leaving group that departs with a pair of electrons in a heterolytic bond cleavage. Leaving groups can be anions or neutral molecules with the premise that the leaving group must be able to stabilize the additional electron density that results from bond heterolysis. Leaving groups are known to the skilled person but can be preferably selected from the list consisting of alkoxides, halides, thiolates, sulfonates, hydroxide, carboxylates, amines, carbonates, sulfonamides, sulfones, amides, ethers, imides, carbamides, dinitrogen, nitrites, nitrates, phosphates and any combination thereof, preferably leaving groups are alkoxides, sulfonates, thiolates or halides or any combination thereof, more preferably the leaving groups are alkoxides, namely the conjugate base of an alcohol and therefore an organic group bonded to a negatively charged oxygen atom, still more preferably the leaving groups are selected from the list consisting of butoxi-, methoxi- and ethoxi-, chloro, and C1 to C5 alkyl alcohols such as ethanol or methanol; wherein the term "polar solvent" is selected from the list consisting of a C1 to C18 (optionally substituted) alky or alkenyl alcohol or a C2 to C18 alkyl or alkenyl (optionally substituted) ester. More preferably, the polar solvent is selected from the list consisting of a C1 to C8 (optionally substituted) alky or alkenyl alcohol or a C2 to C8 alkyl or alkenyl (optionally substituted) ester. Still more preferably the polar solvent is selected from the list consisting of a C1 to C5 (optionally substituted) alky or alkenyl alcohol . Still more preferably the polar solvent is selected from the list consisting of chloroform, methanol, ethanol, acetonitrile and ethylacetate; wherein each the sequential transformations described above (step 1 and step 2) are conducted at a temperature of from 20°C to 50°C and still more preferably at room temperature; wherein reaction time t1 is from 0.5 hours to 94 hours and reaction time t ₂ is from 0.5 hour to 50 hours; wherein 3-cyclobuten-1 ,2-dione derivative 1 is present in the mixture of step 1 ) in a molar concentration (M) of from 4 M to 2X10 ^"4 M, preferably from 2 M to 2X10 ^"3 M, more preferably from 2 M to 2X10 ^"2 M, more preferably from 2 M to 4X10 ^"2 M, more preferably from 2 M to 0.1 M and still more preferably from 1 M to 0.1 M; and the concentration of amines 2 and 4 are present in an amount of from 0.5 to 10 molar equivalents with respect to the 3-ciclobuten-1 ,2-dione derivative 1 , preferably from 0.8 to 1 .5 molar equivalents with respect to the 3-ciclobuten-1 ,2-dione derivative 1 , more preferably from 0.8 to 1 .2 molar equivalents with respect to the 3-cyclobuten-1 ,2-dione derivative 1 and still more preferably about 1 molar equivalent with respect to 3-ciclobuten-1 ,2-dione derivative 1 ; wherein R1 and R3 are hydrogen; wherein R2 is selected from the group consisting of:

And wherein R4 is selected from the group consisting of:

A still further preferred embodiment of the first aspect of the invention refers to the one- pot syntheses for the preparation of squaramides represented in any of Schemes 2-5. A second aspect of the invention refers to compounds entries 1 -16 as indicated in Table 1 above as well as to entries 30-35 and 37-38 as indicated in Table I bis above. Any compound to which reference is made herein (in particular novel compositions entries 1 - 16 as indicated in Table 1 and entries 30-35 and 37-38 as indicated in Table I bis), seeks to represent such specific compound as well as certain variations or forms. Therefore the useful compounds in the present invention can be, for example, in neutral form, in the form of a base or acid, in the form of a salt, preferably a physiologically acceptable salt, in the form of a solvate or of a polymorph and/or in different isomeric forms. The term "salt" must be understood as any form of an active compound used according to this invention in which said compound is in ionic form or is charged and coupled to a counterion (a cation or anion) or is in solution. This definition also includes quaternary ammonium salts and active molecule complexes with other molecules and ions, particularly complexes formed by means of ionic interactions.

The compounds cited in the present invention can include optical isomers depending on the presence of chiral centers or geometric isomers depending on the presence of multiple bonds (for example Z, E). Individual isomers, enantiomers or diastereoisomers and mixtures thereof, such as a racemic mixture are within the scope of the present invention.

Furthermore, any compound to which reference is made herein can exist as tautomers. Specifically, the term tautomer refers to one of two or more structural isomers of a compound in equilibrium and converted from one isomeric form to another. Common tautomeric pairs are amine-imine, amide-imidic acid, keto-enol, lactam-lactim, etc.

Unless otherwise indicated, it also is understood that the compounds of the invention include isotopically labeled forms, i.e., compounds differing only by the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except the substitution of at least one hydrogen atom with a deuterium or tritium atom, or the substitution of at least one carbon with a 13C- or 14C-enriched carbon, or the substitution of at least one nitrogen with 15N enriched nitrogen, are within the scope of this invention.

A third aspect of the invention refers to a catalyst comprising or consisting of any of the compounds of the second aspect of the invention.

A fourth aspect of the invention refers to the use of any of the compounds of the second aspect of the invention as catalyst. For representative values for the Henry and Pudovik reactions using few of the new structures which demonstrate their capacity as organocatalysts see Schemes 7 and 8. L) ee

CH ₃ CN (0.1 mL) / MeN0 ₂ (0.4 mL) CH ₃ CN (0.15 mL) / MeN0 ₂ (0.6 mL)

5fg (10 mol%) 5hg (10 mol%)

T -22 °C, 62 h, 54% yield, 59% ee T -38 °C, 62 h, 48% yield, 84% ee

Scheme 7. Organocatalyzed Henry reaction.

Scheme 8. Organocatalyzed Pudovik reaction.

The invention is further described below by means of the following examples which must be considered as merely illustration and non-limiting thereof.

EXAMPLES Example 1. General Experimental Methods. - Purification of reaction products was carried out either by filtration or by flash chromatography using silical-gel (0.063-0.200 mm). Analytical thin layer chromatography was performed on 0.25 mm silical gel 60-F plates. ESI ionization method and mass analyzer type MicroTof-Q were used for the ESI measurements. ¹ H-NMR spectra were recorded at 400 MHz; ¹³ C-NMR spectra were recorded at 100 MHz; CDCI3 and DMSO-c/β as the solvents. Chemical shifts were reported in the δ scale relative to residual CDCI3 (7.26 ppm) and DMSO (2.50 ppm) for ¹ H-NMR and to the central line of CDCI ₃ (77 ppm) and DMSO (39.43 ppm) for ¹³ C-NMR.

- Materials. All commercially available solvents and reagents were used as received. The ¹ H and ¹³ C NMR spectra for compounds 5ag, 5cg, 5aj, 5cj, 5gj, 5ak, 5ck, 5gl, 5gg, 5ig, 5ai, 5ch, 11 , 15, and 20 are consistent with values previously reported in the literature.

Example 2. Representative procedure for the one-pot synthesis of squaramides 5

To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (1a) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the corresponding reaction time (t1 ) (see Table 1 ), the amine 4a-n (0.2 mmol) was then added with MeOH (1 .75-1 mL). After the corresponding reaction time (t2) (see Table 1 and Table I bis), the product was purified by filtration or by column chromatography. Yields are reported in Table 1 and Table I bis and pure compounds were obtained as stable solids. Example 3. One-pot synthesis for commercially available squaramide 5cg

To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (1a) (0.4 mmol) in MeOH (1 mL), 0.4 mmol of 4-(trifluoromethyl)aniline (2c) was firstly added at room temperature. After 48 h a precipitate was observed and 0.4 mmol of (1 R,2R)-frans-2-(1 - piperidinyl)cyclohexylamine (4g) was solved in MeOH (3 mL) and added to the reaction mixture. After 3 h the test tube was placed in a freezer (-22°C) for 30 minutes to facilitate the overall precipitation of final product 5cg. The product was filtered under vacuum and washed with cold MeOH (2 mL). Final squaramide 5cg was obtained as a white solid in 77% yield. Example 4. One-pot synthesis of antiparasitic agent 11

To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (1 a) (0.2 mmol) in MeOH (0.25 ml_), 0.2 mmol of /V,/V,/V'-trimethyl-1 ,3-propanediamine (8) was firstly added at room temperature. After 2.5 h n-butylamine (10) (0.2 mmol) was solved in MeOH (1 .75 ml_) and added to the reaction mixture. After 12.5 h the solvent was evaporated in vacuo and the product was purified by column chromatography (S1O2, AcOE MeOH 1 :1 to AcOEt:MeOH:Et ₃ N 5:5:0.1 ). Final anti-Chagasic drug 11 was obtained as a white solid in 78% yield.

Example 5. One-pot synthesis of WAY-133537 (15)

To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (1 a) (0.2 mmol) in MeOH (1 ml_), 0.2 mmol of 4-amino-3-ethylbenzonitrile (12) was firstly added at room temperature. After 3 days, 0.2 mmol of (R)-3,3-dimethyl-2-butylamine (14) was added to the reaction mixture. After 2 days the test tube was placed in a freezer (-22°C) for 30 minutes to facilitate the overall precipitation of final drug 15. The product was filtered under vacuum and washed with cold MeOH (1 ml_). Final bladder-selective agonist KATP channel 15 was obtained as a green solid in 33% yield.

Example 6. One-pot synthesis of WAY-151616 (20)

To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (1 a) (0.4 mmol) in MeOH (0.5 ml_), 0.4 mmol of 1 ,1 -dimethylpropylamine (17) were firstly added at room temperature. After 20 h, 0.4 mmol of 2,4-dichloro-6-methylbenzylamine (19) were solved in MeOH (3.5 ml_) and added to the reaction mixture. After 3 days, the test tube was placed in a freezer (-22°C) for 30 minutes to facilitate the overall precipitation of final drug 20. The product was purified by column chromatography (S1O2, hexane/EtOAc 6:4 to 0:1 and EtOAc/MeOH 9:1 . Final bladder-selective agonist KATP channel 20 was obtained as a white solid in 72% yield.

Example 7. Λ/-((1 R,2 ?)-2-(2-(3,5-bis(trifluoromethyl)phenylamino)-3,4- dioxocyclobut-1 - enylamino)cyclohexyl)-4-methylbenzenesulfonamide (5aa)

Following the general procedure, compound 5aa was obtained after 100 h of reaction at room temperature as a white solid in 75% yield. [a] _D ²⁵ = +34 (cO.55, DMSO). ¹ H NMR (400 MHz, DMSO-c/e) δ 10.02 (br s, 1 H), 8.06 (s, 2H), 7.74 (br d, J = 8.5 Hz, 1 H), 7.69 (s, 1H), 7.63 (br d, J = 8.9 Hz, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 3.62-3.52 (m, 1H), 3.18-3.05 (m, 1H), 2.13 (s, 3H), 1.92-1.89 (m, 1H), 1.72-1.37 (m, 4H), 1.35-1.10 (m, 3H). ¹³ C NMR (100 MHz, DMSO-c/ ₆ ) δ 183.8 (1C), 179.8 (1C), 169.5 (1C), 162.0 (1C), 141.7 (1C), 141.1 (1C), 139.3 (1C), 131.4 (q, J = 34.2 Hz, 2C), 130.9 (2C), 125.9 (2C), 123.1 (q, J = 271.7 Hz, 2C), 117.6 (2C), 114 (1C), 57.3 (1C), 56.8 (1 C), 32.7 (1 C), 32.6 (1 C), 24.0 (1 C), 24.0 (1 C), 20.5 (1 C). IR (KBr film) (cm ^"1 ) v 3284, 3177, 2924, 2854, 1793, 1659, 1582, 1559, 1457, 1379, 1277, 1191 , 1163, 1151 , 1129, 1093, 880, 754, 666. HRMS (ESI+) calcd C2 ₅ H ₂ F ₆ N3O ₄ S 576.1392; found 576.1360 [M+H].

Example 8.

W-((1 ?,2?)-2-(2-(3,5-difluorophenylamino)-3,4-dioxocyclobut-1- enylamino)cyclohexyl)-4- methylbenzenesulfonamide (5ba)

Following the general procedure, compound 5ba was obtained after 51 h of reaction at room temperature as a white solid in 82% yield. [a] _D ²⁵ = +42 (cO.49, DMSO). ¹ H NMR (400 MHz, DMSO-c/e) δ 9.69 (br s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.59 (d, J= 7.9 Hz, 2H), 7.23-7.18 (m, 4H), 6.86 (t, J = 9.2 Hz, 1H), 3.60-3.53 (m, 1H), 3.16-3.09 (m, 1H), 2.17 (s, 3H), 1.92-1.89 (m, 1H), 1.64-1.11 (m, 7H). ¹³ C NMR (100 MHz, DMSO-c/e) δ 183.6 (1C), 179.6 (1C), 169.2 (1C), 163.0 (d, J = 242.7 Hz, 1C), 162.9 (d, J = 243.9 Hz, 1C), 162.4 (1C), 141.9 (1C), 141.8 (t, J = 13.8 Hz, 1C), 139.3 (1C), 129.2 (2C), 125.9 (2C), 100.9 (d, J = 29.6 Hz, 2C), 97.1 (t, J = 26.6 Hz, 1C), 57.2 (1C), 56.9 (1C), 32.8 (1C), 32.6 (1C), 24.0 (1C), 24.0 (1C), 20.6 (1C). IR (KBrfilm) (cnrT ¹ ) v 3369, 3289, 3189, 3044, 2924, 2854, 1797, 1664, 1616, 1575, 1536, 1461, 1377, 1319, 1205, 1158, 1118, 1089, 994, 854, 749, 670, 571. MS (ESI+) 476.2 [M+H].

Example 9.

W-((1 ?,2?)-2-(2-(4-tert-butylphenylamino)-3,4-dioxocyclobut-1- enylamino)cyclohexyl)-4- methylbenzenesulfonamide (5da)

Following the general procedure, compound 5da was obtained after 6.5 h of reaction at room temperature as a white solid in 80% yield. [a] _D ²⁴ = +48 (cO.52, DMSO). ¹ H NMR (400 MHz, DMSO-c/e) δ 9.40 (br s, 1 H), 7.65 (br d, J = 8.1 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 2H), 7.51 (br d, J = 7.1 Hz, 1H), 7.43-7.35 (m, 4H), 7.21 (d, J = 8.1 Hz, 2H), 3.60-3.43 (m, 1H), 3.12-3.07 (m, 1H), 2.13 (s, 3H), 1.94-1.87 (m, 1H), 1.69-1.11 (m, 7H), 1.28 (s, 9H). ¹³ C NMR (100 MHz, DMSO-c/ ₆ ) δ 183.0 (1C), 179.8 (1C), 168.6 (1C), 163.5 (1C), 144.9 (1 C), 142.0 (1 C), 139.2 (1 C), 136.5 (1 C), 129.2 (2C), 125.9 (4C), 117.5 (2C), 57.0 (1C), 56.9 (1C), 33.9 (1C), 32.9 (1C), 32.7 (1C), 31.1 (3C), 24.1 (1C), 24.0 (1C), 20.6 (1C). IR (KBr film) (cm ^"1 ) v 3343, 3195, 2924, 2854, 1795, 1660, 1604, 1568, 1535, 1460, 1375, 1322, 1268, 1162, 1143, 1094, 829, 723, 667. HRMS (ESI+) calcd C2 ₇ H ₃ N ₃ O ₄ S 469.2270; found 469.2233 [M+H].

Example 10.

W-((1R,2R)-2-(2-(4-methoxyphenylamino)-3,4-dioxocyclobut- 1- enylamino)cyclohexyl)-4- methylbenzenesulfonamide (5ea)

Following the general procedure, compound 5ea was obtained after 10 h of reaction at room temperature as a white solid in 85% yield. [a] _D ²⁴ = +40 (cO.58, DMSO). ¹ H NMR (400 MHz, DMSO-c/e) δ 9.35 (br s, 1 H), 7.64 (br d, J = 8.4Hz, 1 H), 7.59 (d, J = 8.2 Hz, 2H), 7.42 (br d, J = 7.1 Hz, 1 H), 7.37 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 3.74 (s, 3H), 3.59-3.50 (m, 1H), 3.16-3.06 (m, 1H), 2.16 (s, 3H), 1.91-1.88 (m, 1H), 1.67-1.17 (m, 7H). ¹³ C NMR (100 MHz, DMSO-c/ ₆ ) δ 182.6 (1C), 179.9 (1C), 168.3 (1C), 163.4 (1C), 155.0 (1C), 142.0 (1C), 139.2 (1C), 132.2 (1C), 129.2 (2C), 125.9 (2C), 119.2 (2C), 114.5 (2C), 56.9 (1C), 56.9 (1C), 55.2 (1C), 32.9 (1C), 32.8 (1C), 24.1 (1C), 24.0 (1C), 20.7 (1C). IR (KBr film) (cm ^"1 ) v 3348, 3266, 2922, 2853, 1790, 1646, 1613, 1564, 1538, 1515, 1477, 1368, 1323, 1251, 1160, 1094, 1077, 829, 810, 665. HRMS (ESI+) calcd C^sNsOsS 470.1750; found 470.1729 [M+H].

Example 11. Λ/-((1 R,2 ?)-2-(2-(3,5-bis(trifluoromethyl)benzylamino)-3,4- dioxocyclobut-1-enylamino)cyclohexyl)-4-methylbenzenesulfona mide (5ga)

Following the general procedure, compound 5ga was obtained after 23 h of reaction at room temperature as a white solid in 72% yield (85 mg). [a] _D ²⁴ = +33 (cO.49, DMSO). ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 8.09 (s, 2H), 8.05 (s, 1 H), 7.80 (br s, 1 H), 7.61 (d, J = 8.2 Hz, 2H), 7.57 (br s, 1H), 7.38 (br s, 1H), 7.27 (d, J = 8.1 Hz, 2H), 4.90 (br s, 2H), 3.60-3.45 (m, 1H), 3.04-2.94 (m, 1H), 2.33 (s, 3H), 1.86-1.80 (m, 1H), 1.60-1.01 (m, 7H). ¹³ C NMR (100 MHz, DMSO-c/ ₆ ) δ 182.1 (1C), 168.0 (1C), 142.5 (1C), 141.1 (2C), 139.3 (2C), 130.4 (q, J= 32.5 Hz, 2C), 129.3 (2C), 128.4 (2C), 126.0 (2C), 123.2 (q, J = 271.2 Hz, 2C), 121.1 (1C), 56.9 (1C), 56.7 (1C), 45.6 (1C), 32.8 (1C), 32.1 (1C), 24.0 (2C), 20.8 (1C). IR (KBr film) (cm ^"1 ) v 3373, 3166, 2924, 2854, 1798, 1650, 1569, 1496, 1456, 1377, 1321, 1268, 1237, 1203, 1186, 1171, 1095, 894, 729, 706, 682, 568. MS (ESI+) 590.2 [M+H].

Example 12.

(S)-3-(3,5-bis(trifluoromethyl)phenylamino)-4-(2-hydroxy- 1,2,2- triphenylethylamino)cyclobut-3-ene-1 ,2-dione (5ab)

Following the general procedure, compound 5ab was obtained after 92 h of reaction at room temperature as a white solid in 77% yield. [a] _D ²⁵ = -97 (c0.40, DMSO). ¹ H NMR (400 MHz, DMSO-c/e) δ 10.40 (br s, 1 H), 8.74 (br d, J = 9.6 Hz, 1 H), 8.00 (s, 2H), 7.67 (d, J = 7.5 Hz, 2H), 7.63 (s, 1H), 7.41-7.05 (m, 13H), 6.71 (br s, 1H), 6.22 (brd, J= 9.7 Hz, 1H). ¹³ C NMR (100 MHz, DMSO-c/ ₆ ) δ 184.6 (1C), 179.9 (1C), 168.3 (1C), 162.5 (1C), 145.5 (1C), 144.1 (1C), 140.8 (1C), 138.9 (1C), 131.2 (q, J = 31.6 Hz, 2C), 128.8 (2C), 128.0 (2C), 127.5 (1C) 127.4 (2C), 127.0 (1C), 126.7 (1C), 126.5 (1C), 126.3 (1C), 126.1 (2C), 126.0 (2C), 123.0 (q, J = 271.0 Hz, 2C), 118.0 (2C), 114.6 (1C), 80.4 (1C), 63.3 (1C). IR (KBr film) (cm ^"1 ) v 3506, 3220, 3135, 2923, 2854, 1804, 1660, 1604, 1575, 1546, 1506, 1469, 1380, 1280, 1184, 1128, 1062, 889, 752, 699. HRMS (ESI+) calcd C32H23F6N2O3597.1613; found 597.1599 [M+H].

Example 13. (S)-3-(3,5-difluorophenylamino)-4-(2-hydroxy-1,2,2-triphenyl ethylamino)cyclobut- 3-ene-1,2- dione (5bb)

Following the general procedure, compound 5bb was obtained after 62 h of reaction at room temperature as a white solid in >95% yield. [a] _D ²⁷ = -197 (c 0.65, DMSO). ¹ H NMR (400 MHz, DMSO-c/e) δ 10.12 (br s, 1 H), 8.73 (br d, J = 9.7 Hz, 1 H), 7.6 (d, J = 7.5 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.25-7.05 (m, 13H), 6.85-6.79 (m, 1H), 6.69 (br s, 1H), 6.23 (br d, J = 9.8 Hz, 1H). ¹³ C NMR (100 MHz, DMSO-c/ ₆ ) δ 184.5 (1C), 179.7 (1C), 168.1 (1C), 162.9 (d, J = 242.5 Hz, 1C), 162.8 (1C), 162.7 (d, J = 232.5 Hz, 1C), 145.6 (1C), 144.1 (1C), 141.5 (t, J= 13.7 Hz, 1C), 139.0 (1C), 128.9 (2C), 128.0 (2C), 127.4 (4C) 127.0 (1C), 126.7 (1C), 126.5 (1C), 126.2 (2C), 126.1 (2C), 101.2 (d, J= 29.5 Hz, 2C), 97.4 (t, J = 26.5 Hz, 1C) 80.4 (1C), 63.3 (1C). IR (KBr film) (cm ^"1 ) v 3483, 3446, 3227, 3122, 2924, 2853, 1800, 1656, 1608, 1565, 1493, 1465, 1377, 1188, 1166, 1119, 1065, 1004, 891 , 761 , 750, 728, 697. MS (ESI) 497.2 [M+H].

Example 14. (R)-3-(3,5^is(trifluoromethyl)phenyta

ene-1,2-dione (5ac)

Following the general procedure, compound 5ac was obtained after 85 h of reaction at room temperature as a white solid in 84% yield. [a] _D ²⁷ = -6 (c 0.87, DMSO). ¹ H NMR (400 MHz, DMSO-c/e) 510.06 (br s, 1 H), 8.15 (br s, 1H), 8.01 (s, 2H), 7.67 (s, 1H), 7.44- 7.30 (m, 5H), 5.36-5.27 (m, 1H), 1.61 (d, J = 6.9 Hz, 3H). ¹³ C NMR (100 MHz, DMSO- c/e) δ 184.3 (1C), 180.5 (1C), 168.8 (1C), 162.5 (1C), 142.7 (1C), 140.9 (1C), 131.2 (q, J = 34 Hz, 2C), 128.6 (2C), 127.5 (1C), 126.0 (2C), 123.0 (q, J = 271.2 Hz, 2C), 118.0 (2C), 114.7 (1C), 53.3 (1C), 22.7 (1C). IR (KBr film) (cm ^"1 ) v 3135, 2924, 1797, 1661, 1570, 1559, 1491, 1456, 1377, 1275, 1188, 1170, 1129, 944, 883, 750, 697, 683, 667. MS (ESI+)429.1 [M+H]. Example 15. (?)-3-(3,5-bis(trifluoromethyl)phenylamino)-4-(1-hydroxy-3- phenylpropan-2-ylamino)cyclobut- 3-ene-1,2-dione (5ad)

Following the general procedure, compound 5ad was obtained after 96 h of reaction at room temperature as a white solid in 60% yield. [a] _D ²⁴ = +125 (c 0.54, DMSO). ¹ H NMR (400 MHz, DMSO-c/e) δ 9.78 (br s, 1 H), 7.59 (s, 2H), 7.47 (br d, J = 9.0 Hz, 1 H), 7.19 (s, 1H), 6.85-6.73 (m, 5H), 4.78 (br s, 1H), 3.90-3.80 (m, 1H), 3.15-3.06 (m, 2H), 2.51 (dd, J= 6.6, 13.6 Hz, 1H), 2.38 (dd, J = 7.9, 13.4 Hz, 1H). ¹³ C NMR (100 MHz, DMSO-c/ ₆ ) δ 184.2 (1C), 180.1 (1C), 169.5 (1C), 162.0 (1C), 141.1 (1C), 137.8 (1C), 131.3 (q, J = 33.6 Hz, 2C), 129.2 (2C), 128.2 (2C), 126.2 (1C), 123.1 (q, J = 270.9 Hz, 2C), 117.7 (2C), 114.5 (1C), 62.2 (1C), 57.4 (1C), 38.0 (1C). IR (KBr film) (cm ^"1 ) v 3280, 3044, 2923, 2853, 1790, 1690, 1605, 1576, 1553, 1499, 1477, 1455, 1388, 1280, 1181, 1171, 1131, 1030, 899, 882, 701. HRMS (ESI+) calcd C21H17F6N2O3 459.1144; found 459.1130 [M+H].

Example 16. 3-(3,5-bis(trifluoromethyl)phenylamino)-4-((1 S,2R)-2-hydroxy-2,3- dihydro-1H-inden-1-ylamino)cyclobut-3-ene-1,2-dione (5ae)

Following the general procedure, compound 5ae was obtained after 52 h of reaction at room temperature as a white solid in 61% yield. [a] _D ²⁷ = +81 (cO.48, DMSO). ¹ H NMR (400 MHz, DMSO-c/e) δ 10.46 (br s, 1H), 8.16 (br d, J = 9.0 Hz, 1H), 8.10 (s, 2H), 7.65 (s, 1 H), 7.32-7.22 (m, 4H), 5.62 (br s, 1 H), 5.53 (dd, J = 5.0, 8.7 Hz, 1 H), 4.65-4.55 (m, 1H), 3.16 (dd, J = 4.8, 16.4 Hz, 1H), 2.89 (d, J = 16.2 Hz, 1H). ¹³ C NMR (100 MHz, DMSO-c/e) δ 184.6 (1C), 180.4 (1C), 169.5 (1C), 162.6 (1C), 141.2 (1C), 141.2 (1C), 140.5 (1C), 131.3 (q, J = 32.7 Hz, 2C), 128.0 (2C), 126.6 (1C), 125.1 (1C), 124.2 (1C), 123.1 (q, J= 271.1 Hz, 2C), 117.8 (2C), 114.5 (1C), 72.2 (1C), 62.2 (1C). IR (KBr film) (cm ^"1 ) v 3278, 2958, 2927, 2854, 1792, 1691, 1597, 1552, 1482, 1465, 1442, 1383, 1334, 1300, 1190, 1128, 1043, 933, 897, 742, 685. MS (ESI+) 457.1 [M+H]. Example 17. 3-(3,5-difluorophenylamino)-4-((1S,2R)-2-hydroxy-2,3-dihydro -1H- inden-1-ylamino)cyclobut-3- ene-1,2-dione (5be)

Following the general procedure, compound 5be was obtained after 40 h of reaction at room temperature as a white solid in 88% yield. [a] _D ²⁷ = +48 (cO.47, DMSO). ¹ H NMR (400 MHz, DMSO-c/e) δ 10.16 (br s, 1H), 8.17 (brd, J= 9.4 Hz, 1H), 7.32-7.23 (m, 6H), 6.85 (t, J = 9.5 Hz, 1H), 5.58 (br s, 1H), 5.52 (dd, J = 5.0, 9.0 Hz, 1H), 4.60-4.56 (m, 1H), 3.14 (dd, J = 4.0, 15.7 Hz, 1H), 2.87 (d, J = 16.3 Hz, 1H). ¹³ C NMR (100 MHz, DMSO-c/e) δ 184.4 (1C), 180.2 (1C), 169.3 (1C), 163.0 (d, J = 238.2 Hz, 1C), 162.8 (1C), 162.9 (d, J = 242.5 Hz, 1C), 141.9 (t, J = 13.7 Hz, 1C), 141.1 (1C), 140.5 (1C), 128.0 (1C), 126.6 (1C), 125.1 (1C), 124.2 (1C), 101.0 (d, J = 29.4 Hz, 2C), 97.2 (d, J = 26.1 Hz, 1C), 72.3 (1C), 61.2 (1C), 39.4 (1C). IR (KBr film) (cm ^"1 ) v 3460, 3261, 2922, 2852, 1794, 1662, 1613, 1576, 1559, 1541 , 1446, 1416, 1377, 1208, 1149, 1119, 1090, 1022, 995, 977, 854, 752, 727, 686, 646. MS (ESI+) 357.1 [M+H].

Example 18. (S)-3-(3,5-difluorophenylamino)-4-(1 -(naphthalen-1 -yl)ethylamino)cyclobut-3-ene- 1,2-dione (5bf)

Following the general procedure, compound 5bf was obtained after 33 h of reaction at room temperature as a white solid in 82% yield. [a] _D ²⁷ = +184 (cO.44, DMSO). ¹ H NMR (400 MHz, DMSO-c/e) δ 9.80 (br s, 1 H), 8.28 (br d, J = 6.9 Hz, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 7.8 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.67-7.55 (m, 4H), 7.16 (br d, J = 7.6 Hz, 2H), 6.84 (t, J= 9.3 Hz, 1H), 6.17-6.08 (m, 1H), 1.75 (d, J= 6.7 Hz, 3H). NMR (100 MHz, DMSO-c/e) δ 184.1 (1C), 180.1 (1C), 168.4 (1C), 162.9 (d, J = 242.5 Hz, 1C), 162.8 (1C), 162.8 (d, J = 242.5 Hz, 1C), 141.6 (t, J = 13.7 Hz, 1C), 138.1 (1C), 133.4 (1C), 129.9 (1C), 128.7 (1C), 128.2 (1C), 126.7 (1C), 125.9 (1C), 125.4 (1C), 122.7 (1C), 122.6 (1C), 101.1 (d, J = 29.4 Hz, 2C), 97.4 (t, J = 26.2 Hz, 1C), 49.4 (1C), 22.7 (1C). IR (KBr film) (cm ^"1 ) v 3165, 3080, 3017, 2924, 2854, 1793, 1664, 1631, 1609, 1460, 1375, 1307, 1153, 1116, 993, 854, 835, 804, 782, 754. MS (ESI+) 379.2 [M+H].

Example 19.

3-((1 R,2?)-2-(piperidin-1 -yl)cyclohexylamino)-4-(3 ,4,5- trifluorophenylamino)cyclobut-3-ene-1,2-dione (5fg)

Following the general procedure, compound 5fg was obtained after 69 h of reaction at room temperature as a white solid in 82% yield. [a] _D ²⁵ = -54 (c0.40, DMSO). ¹ H NMR (400 MHz, DMSO-c/e) δ 9.92 (br s, 1 H), 7.52 (br s, 1 H), 7.33 (d, J = 9.7 Hz, 1 H), 7.31 (d, J= 9.5 Hz, 1H), 4.02-3.85 (m, 1H), 2.76-2.56 (m, 2H), 2.39-2.17 (m, 3H), 2.10-1.97 (m, 1H), 1.91-1.80 (m, 1H), 1.79-1.60 (m, 2H), 1.51-1.00 (m, 10H). ¹³ C NMR (100 MHz, DMSO-c/e) δ 184.5 (1 C), 180.1 (1 C), 169.6 (1 C), 161.7 (2C), 150.6 (dd, J = 245.8, 10.0 Hz, 1 C), 150.5 (dd, J = 244.7, 10.0 Hz, 1 C), 134.3 (dt, J = 243.0, 15.6 Hz, 1 C), 102.5 (d, J = 23.7 Hz, 2C), 68.3 (1C), 54.3 (1C), 49.2 (1C), 33.6 (1C), 26.2 (1C), 24.6 (1C), 24.4 (1C), 24.3 (1C), 23.2 (1C). IR (KBr film) (cm ^"1 ) v 3194, 3084, 2924, 2853, 1796, 1657, 1631, 1575, 1480, 1450, 1377, 1241, 1154, 1098, 1044, 980, 856, 799, 744, 462. MS (ESI+) 408.2 [M+H].

Example 20. S-^Ri^'-hydroxy-l.l'-binaphthyl^-ylaminoi^-^IR^Ri^-ipiperidi n-l- yl)cyclohexylamino)cyclobut-3-ene-1 ,2-dione (5hg)

Following the general procedure, compound 5hg was obtained after 88 h of reaction at room temperature as a white solid in 68% yield. [a] _D ²⁴ = +85 (cO.44, CHCI ₃ ). ¹ H NMR (300 MHz, CDCIs) δ 8.01 (d, J = 8.8 Hz, 1H), 7.92-7.79 (m, 3H), 7.62 (br d, J = 6.7 Hz, 1 H), 7.40 (dt, J = 8.0, 1.1 Hz, 1 H), 7.34-7.11 (m, 5H), 6.96 (d, J = 8.3 Hz, 1 H), 6.00 (br s, 2H), 3.85 (br s, 1H), 2.77-2.10 (m, 6H), 1.91-1.51 (m, 3H), 1.49-0.99 (m, 11 H). NMR (75 MHz, CDCI3) δ 184.1 (1C), 182.1 (1C), 168.4 (1C), 163.8 (1C), 152.7 (1C), 134.5 (1C), 133.5 (1C), 133.4 (1C), 131.53 (1C), 130.7 (1C), 130.1 (1C), 129.0 (2C), 128.2 (2C), 127.4 (1C), 127.1 (1C), 125.7 (1C), 125.5 (1C), 124.1 (1C), 123.5 (1C), 120.7 (1 C), 118.8 (1 C), 113.2 (1 C), 67.9 (1 C), 54.2 (1 C), 49.5 (2C), 34.8 (1 C), 25.2 (1 C), 24.9 (2C), 24.2 (2C), 23.8 (1C), 23.2 (1C). IR (KBr film) (cm ^"1 ) v 3251, 2924, 2854, 1792, 1683, 1595, 1505, 1463, 1377, 1338, 1261, 1095, 1021, 801. MS (ESI+) 546.3 [M+H].

Example 21. a-^Ri^'-hydroxy-l.l'^inaphthyl^-ylaminoi-^IR^RJ^-ipyrrolidin - 1-yl)cyclohexylamino)cyclobut-3-ene-1,2-dione (5hh)

Following the general procedure, compound 5hh was obtained after 92 h of reaction at room temperature as a white solid in 50% yield. [a] _D ²⁴ = +227 (c 0.48, CHCI3). ¹ H NMR (400 MHz, CDCI3) 7.96 (d, J = 8.8 Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1 H), 7.81 (app. dd, J = 6.7, 7.5 Hz, 2H), 7.70-7.53 (m, 1H), 7.40 (t, J= 7.4 Hz, 1H), 7.33-7.09 (m, 5H), 6.94 (d, J = 8.4 Hz, 1H), 6.32 (br s, 2H), 3.72 (br s, 1H), 2.75-2.45 (m, 4H), 2.12-1.87 (m, 1H), 1.80-1.40 (m, 4H), 1.39-0.73 (m, 9H). ¹³ C NMR (100 MHz, CDCI ₃ ) δ 183.7 (1C), 181.9 (1C), 168.5 (1C), 164.8 (1C), 153.1 (1C), 134.5 (1C), 133.6 (1C), 133.3 (1C), 131.5 (1C), 130.4 (1C), 129.5 (1C), 128.8 (2C), 128.2 (1C), 128.1 (1C), 127.1 (1C), 126.9 (1C), 125.9 (1C), 125.5 (1C), 124.2 (1C), 123.3 (1C), 121.7 (1C), 119.2 (1C), 114.1 (1C), 63.1 (1C), 55.8 (1C), 48.0 (2C), 34.3 (1C), 29.7 (1C), 24.2 (1C), 24.0 (1C), 23.5 (2C). IR (KBr film) (cm ^"1 ) v 3240, 2924, 2854, 1792, 1683, 1596, 1505, 1462, 1428, 1377, 1336, 1271 , 815, 748. MS (ESI+) 532.3 [M+H]. Example 22. 3-(((1 S,2R)-2-hydroxy-2,3-dihydro-1 H-inden-1 -yl)amino)-4- (phenylamino)cyclobut-3-ene-1 ,2-dione (5je)

Following the general procedure, compound 5je was obtained after 9 h of reaction at room temperature as a white solid in 86% yield. [a] _D ³⁰ = +39.6 (c 0.61, DMSO). ¹ H NMR (300 MHz, DMSO-c/6) δ 9.90 (s, 1 H), 8.07 (d, J = 9.1 Hz, 1 H), 7.49 (d, J = 7.8 Hz, 2H), 7.42-7.21 (m, 6H), 7.07-6.96 (m, 1H), 5.54 (br s, 1H), 5.54 (dd, J = 8.8, 5.0 Hz, 1H), 4.58 (dt, J = 4.9, 1.6 Hz, 1H), 3.14 (dd, J= 15.7, 4.4 Hz, 1H), 2.88 (dd, J= 16.3, 1.4 Hz, 1H). ¹³ C NMR (75 MHz, DMSO-c/6) δ 184.5 (1C), 180.9 (1C), 169.6 (1C), 164.3 (1C), 141.9 (1C), 141.1 (1C), 139.7 (1C), 129.8 (2C), 128.5 (1C), 127.1 (1C), 125.6 (1C), 124.8 (1C), 123.0 (1C), 118.3 (2C), 72.9 (1C), 61.7 (1C), 39.9 (1C). IR (KBrfilm) (cm ^"1 ) v 3426, 3283, 2923, 2853, 1797, 1661, 1606, 1567, 1543, 1455, 1423, 1377, 1092, 760, 751 , 744, 430. MS (ESI+) 343.1 [M+Na].

Example 23. 3-(((1 S,2R)-2-hydroxy-2,3-dihydro-1 H-inden-1 -yl)amino)-4-((4- methoxyphenyl)amino)cyclobut-3-ene-1 ,2-dione (5ee)

Following the general procedure, compound 5ee was obtained after 10 h of reaction at room temperature as a white solid in 88% yield. [a] _D ²⁹ = +41.8 (c 0.60, DMSO). ¹ H NMR (300 MHz, DMSO-c/6) δ 9.80 (s, 1H), 8.07 (br d, J = 8.9 Hz, 1H), 7.41 (d, J = 8.9 Hz, 2H), 7.46-7.19 (m, 4H), 6.93 (d, J = 9.0 Hz, 2H), 5.55 (br s, 1H), 5.53 (dd, J = 9.0, 4.8 Hz, 1 H), 4.57 (dt, J = 4.8, 1.6 Hz, 1 H), 3.73 (s, 3H), 3.14 (dd, J = 16.3, 4.9 Hz, 1 H), 2.87 (dd, J = 16.5, 1.3 Hz, 1H). ¹³ C NMR (75 MHz, DMSO-c/6) δ 183.4 (1C), 180.5 (1C), 168.7 (1C), 163.9 (1C), 155.2 (1C), 141.5 (1C), 140.6 (1C), 132.4 (1C), 128.0 (1C), 126.7 (1C), 125.1 (1C), 124.3 (1C), 119.4 (2C), 114.6 (2C), 72.5 (1C), 61.2 (1C), 55.3 (1 C), 39.5 (1 C). IR (KBr film) (cm ^"1 ) v 3413, 3278, 2923, 2853, 1795, 1656, 1605, 1565, 1541, 1517, 1496, 1459, 1426, 1419, 1377, 1351, 1321, 1257, 1209, 1183, 1157, 1140, 1116, 1099, 1032, 1001, 872, 861, 801, 773, 747, 637, 599, 439. MS (ESI+) 373.2 [M+Na].

Example 24. N-((1 R,2R)-2-((2-(hexylamino)-3,4-dioxocyclobut-1 -en-1 - yl)amino)cyclohexyl)-4-methylbenzenesulfonamide (5ka)

Following the general procedure, compound 5ka was obtained after 5 h of reaction at room temperature as a white solid in 74% yield. [a] _D ³⁰ = +18.2 (c 0.64, DMSO). ¹ H NMR (300 MHz, DMSO-c/6) δ 7.61 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 7.7 Hz, 1H), 7.32 (br s, 1H), 7.29 (d, J = 8.1, 2H), 7.18 (d, J = 7.9 Hz, 1H), 3.60-3.36 (m, 3H), 3.12-2.96 (m, 1H), 2.36 (s, 3H), 1.92-1.78 (m, 1H), 1.66-1.00 (m, 14H), 0.96-0.77 (m, 4H). ¹³ C NMR (75 MHz, DMSO-c/6) δ 182.1 (1C), 181.9 (1C), 167.8 (1C), 167.3 (1C), 142.1 (1C), 139.4 (1C), 129.3 (2C), 126.0 (2C), 56.8 (1C), 56.4 (1C), 43.2 (1C), 33.1 (1C), 32.6 (1C), 30.8 (1C), 30.6 (1C), 25.5 (1C), 24.0 (2C), 22.0 (1C), 20.9 (1C), 13.8 (1C). IR (KBr film) (cm ^"1 ) v 3197, 2956, 2923, 28569, 1798, 1656, 1650, 1572, 1521, 1465, 1342, 1162, 1094, 814, 665, 575, 549, 419. MS (ESI+) 470.3 [M+Na].

Example 25. 3-(3,5-bis(trifluoromethyl)phenylamino)-4-((1 S,2R)-2-(piperidin-1 - yl)-2,3-dihydro-1 H-inden-1 -ylamino)cyclobut-3-ene-1 ,2-dione (5am)

Following the general procedure, compound 5am was obtained after 88 h of reaction at room temperature as a brown solid in 87% yield. [a] _D ²⁸ = -183.9 (c0.51, CHCI ₃ ). ¹ H NMR (400 MHz, CDCI ₃ ) δ 10.29 (br s, 1 H), 8.02 (s, 2H), 7.40 (s, 1 H), 7.37-7.16 (m, 4H), 5.96 (br d, J = 5.2 Hz, 1 H), 4.03-3.85 (m, 1 H), 3.67-3.06 (m, 4H), 2.25-1.43 (m, 8H). ¹³ C NMR (100 MHz, CDCI ₃ ) δ 185.0 (1C), 181.3 (1C), 168.5 (1C), 165.7 (1C), 140.8 (1C), 139.7 (1C), 137.0 (1C), 132.8 (q, J = 33.5 Hz, 2C), 130.0 (1C), 128.8 (1C), 125.4 (1C), 125.2 (1C), 123.2 (q, J = 272.8 Hz, 2C), 118.1 (2C), 115.8 (1C), 67.0 (1C), 57.3 (1C), 32.7 (2C), 22.8 (2C), 21.9 (2C). IR (KBr film) (cm ^"1 ) v 2953, 2924, 2853, 1790, 1609, 1557, 1456, 1379, 1278, 1181, 1130. MS (ESI+) 524.3 [M+H].

Example 26. S-UiSi^'-hydroxy-tl.l'-binaphthalenl^-y amino)-^! ?^ ?)^- (piperidin-1 -yl)cyclohexyl)amino)cyclobut-3-ene-1 ,2-dione ((S)-5hg)

Following the general procedure, compound (S)-5hg was obtained after 75 h of reaction at room temperature as a pale yellow solid in 58% yield. [a] _D ²⁹ = -41.0 (c 0.19, DMSO). ¹ H NMR (400 MHz, DMSO-c/6) δ 9.58 (br s, 1H), 8.57 (br s, 1H), 8.11-7.83 (m, 4H), 7.74-7.58 (m, 1H), 7.56-7.43 (m, 1H), 7.43-7.33 (m, 2H), 7.26 (t, J= 7.4 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H), 3.90-3.72 (br m, 1 H), 2.29-2.05 (m, 3H), 1.96-1.50 (m, 5H), 1.48-0.98 (m, 11H). ¹³ C NMR (100 MHz, DMSO- c/6) δ 184.7 (1C), 180.4 (1C), 169.7 (1C), 163.8 (1C), 153.5 (1C), 135.1 (1C), 133.7 (1C), 132.7 (1C), 130.7 (1C), 129.9 (1C), 128.3 (1C), 128.2 (1C), 128.0 (2C), 126.4 (2C), 125.2 (1C), 124.6 (1C), 123.8 (1C), 122.7 (1C), 122.6 (1C), 118.7 (1C) 113.6 (1C), 68.3 (1C), 54.1 (1C), 49.3 (2C), 34.1 (1C), 26.3 (2C), 24.8 (1C), 24.5 (2C), 23.6 (2C). IR (KBr film) (cm ^"1 ) v 3249, 2924, 2853, 1794, 1655, 1594, 1524, 1506, 1465, 1448, 1434, 1377, 1339, 1270, 811, 751, 451. HRMS (ESI+) calcd C35H35N3O3545.2678; found 546.1961 [M+H].

Example 27. 3-(3,5-bis(trifluoromethyl)phenylamino)-4-(4-tert- butylphenylamino)cyclobut-3-ene-1 ,2-dione (5an)

Following the general procedure, compound 5an was obtained after 99 h of reaction at room temperature as a yellow solid in 61% yield. ¹ H NMR (300 MHz, DMSO-c/6) δ 10.33 (br s, 1 H), 10.02 (br s, 1 H), 8.00 (s, 2H), 7.68 (br s, 1 H), 7.45-7.20 (m, 4H), 1.26 (s, 9H). ¹³ C NMR (75 MHz, DMSO-c/6, 60°C) δ 182.8 (1C), 181.8 (1C), 166.6 (1C), 164.0 (1C), 146.1 (1C), 140.7(1C), 135.3 (1C), 131.0 (q, J= 33.1 Hz, 2C), 125.5 (2C), 122.7 (q, J = 273.0 Hz, 2C), 118.5 (2C), 118.3 (2C), 114.9 (m, 1C), 33.7(1C), 30.7 (3C). IR (KBrfilm) (cm ^"1 ) v 3561, 3193, 3064, 2923, 2853, 1787, 1695, 1620, 1576, 1557, 1508, 1471, 1447, 1383, 1288, 1278, 1180, 1169, 1140, 1032, 894, 885, 701. MS (ESI+) 479.3 [M+Na].

Example 28. 3-(((R)-2'-methoxy-[1 ,1 '-binaphthalen]-2-yl)amino)-4-(((1 R,2R)-2- (piperidin-1 -yl)cyclohexyl)amino)cyclobut-3-ene-1 ,2-dione (5lg)

Following the general procedure, compound 5lg was obtained after 85 h of reaction at room temperature as a pale yellow solid in 31% yield. [CI]D ²⁸ = -54.8 (cO.26, CH ₃ CN). ¹ H NMR (300 MHz, CD ₃ CN) δ 8.13 (d, J = 9.1 Hz, 1H), 8.04 (d, J = 8.9 Hz, 1H), 8.00-

7.93 (m, 2H), 7.89 (d, J = 8.9 Hz, 1H), 7.60 (d, J= 9.1 Hz, 1H), 7.44-7.19 (m, 5H), 7.04-

6.94 (m, 2H), 6.11 (br s, 1H), 3.76 (s, 3H), 3.75-3.50 (br m, 1H), 2.56-2.40 (br m, 2H), 2.35-2.25 (m, 1H), 2.22-2.05 (br m, 3H), 1.85-1.74 (br m, 1H), 1.74-1.66 (br m, 1H), 1.66-1.55 (br m, 1H), 1.40-1.02 (m, 10H). ¹³ C NMR (75 MHz, CD ₃ CN) δ 185.9 (1C), 182.3 (1C), 170.7 (1C), 164.9 (1C), 156.7 (1C), 135.9 (1C), 134.6 (1C), 134.2 (1C), 132.0 (1C), 131.9 (1C), 130.5 (1C), 129.8 (1C), 129.3 (1C), 129.2 (1C), 128.1 (1C), 127.8 (1C), 126.2 (1C), 126.0 (1C), 125.1 (1C), 124.9 (1C) 122.4 (1C), 117.7 (2C), 115.0 (1C), 69.4 (1C), 57.1 (1C), 55.6 (1C), 50.3 (2C), 35.3 (1C), 27.3 (2C), 26.1 (1C), 25.5 (2C), 24.1 (1C). IR (KBrfilm) (cm ^"1 ) v 3253, 2930, 2854, 2780, 1792, 1678, 1593, 1545, 1504, 1463, 1427, 1339, 1270, 1259, 1086, 1055, 810, 748, 419. HRMS (ESI+) calcd C36H37N3O3559.2835; found 560.2242 [M+H].

Example 29. 3-(naphthalen-2-ylamino)-4-(((1 R,2R)-2-(piperidin-1 - yl)cyclohexyl)amino)cyclobut-3-ene-1,2-dione (5mg)

Following the general procedure, compound 5mg was obtained after 30 h of reaction at room temperature as a pale yellow solid in 81% yield. [a] _D ²⁹ = -47.4 (c 0.20, DMSO). ¹ H NMR (300 MHz, DMSO-c/6) δ 9.89 (br s, 1H), 8.00-7.75 (m, 4H), 7.65 (d, J = 8.3 Hz, 1H), 7.51 (br s, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), 4.08-3.84 (br m, 1H), 2.70-2.55 (br m, 2H), 2.37-2.20 (br m, 3H), 2.15-2.02 (br m, 1H), 1.90-1.80 (br m, 1 H), 1.80-1.60 (br m, 2H), 1.50-1.05 (br m, 10H). ¹³ C NMR (75 MHz, DMSO-c/6) δ 184.2 (1C), 180.2 (1C), 169.8 (1C), 162.9 (1C), 136.9 (1C), 133.7 (1C), 129.3 (1C), 129.2 (1C), 127.7 (1C), 127.0 (1C), 126.8 (1C), 124.4 (1C), 119.0 (1C), 113.5 (1C), 68.4 (1C), 54.4 (1C), 49.4 (2C), 34.1 (1C), 26.4 (2C), 24.8 (1C) 24.6 (1C), 24.5 (1C), 23.4 (1C). IR (KBrfilm) (cm ^"1 ) v 3178, 2924, 2853, 1791, 1657, 1634, 1605, 1588, 1567, 1512, 1453, 1380, 1272, 1138, 872, 740, 470.