General isotopic labeling of bioactive carboxylic acids enabled by organic photoredox catalysis and use thereof

Abstract

Positron emission tomography and magnetic resonance imaging are among the most widely used modalities, requiring isotopic labeling of bioactive molecules to generate the desired imaging probes. This method was applied to a wide range of aliphatic carboxylic acids, including complex and functionalized drug molecules, amino acids and short peptides. For non-stabilized radicals derived from benzylic and non-benzylic carboxylic acids, a copper co-catalyst was introduced to obtain the labeled nitriles, whereas metal-free conditions were applied to nitrogen-stabilized radical derived from a-amino acids and peptides to form the radiolabeled a-amino nitriles. These radiolabeled nitriles were then easily converted back to radiolabeled carboxylic acids.

Description

[0001] GENERAL ISOTOPIC LABELING OF BIOACTIVE CARBOXYLIC ACIDS ENABLED BY ORGANIC PHOTOREDOX CATALYSIS AND USE THEREOF

[0002] RELATED APPLICATION DATA

[0003] The present application claims priority pursuant to Article 8 of the Patent Cooperation Treaty to United States Provisional Patent Application Number 63 / 570,587, filed March 27, 2024, which is incorporated herein by reference in its entirety.

[0004] FIELD OF INVENTION

[0005] The disclosure relates to organic photoredox-catalyzed cyanation methods to efficiently introduce a cyano functional group via decarboxylation of aliphatic carboxylic acid substrates. Furthermore, this method can be extended to include photoredox-catalyzed cyanation of aliphatic carboxylic acid substrates for introducing carbon isotopes such as [11 / I2 / 13 / 14C] and / or [13 / 14 / 15N] nitriles, which can be further diversified to other functional groups such as [11 / l2 / 13 / 14C]carboxylic acids, [11 / 12 / 13 / 14C] and / or [13 / 14 / 15N] amides, and [11 / 12 / 13 / 14C] and / or [13 / 14 / 15N] alkyl amines.

[0006] GOVERNMENTAL SUPPORT

[0007] This invention was made with government support under Grant No. EB029451 awarded by National Institutes of Health. The government has certain rights in the invention.

[0008] BACKGROUND

[0009] Precision medicine is transforming healthcare by customizing medical decisions and treatments based on individual characteristics.1-3Molecular imaging, especially with positron emission tomography (PET) and magnetic resonance imaging (MRI), is becoming increasingly important in precision medicine. It enables the collection of in vivo data for individuals and plays a vital role in early diagnosis, patient selection, and treatment monitoring.(Fig. lb).1,4The demand for innovative PET imaging technologies and the development of novel PET agents are driving progress in this field. Advancements in radiochemistry have facilitated the creation of high-quality PET agents of better imaging quality and easier synthesis, addressing the short half-lives of most PET isotopes. Notably, isotopes like18F (ti / 2 = 109.8 min) and11C (ti / 2 = 20.3 min) are ideal for PET, providing opportunities for precise and tailored medicine, while ensuring patient safety.5PET also holds promise in drug development, enabling the in vivo study of pharmaceutical kinetics and dynamics (PK and PD).4However, the introduction of18F may involve functional group modifications6"11that could potentially alter biological or pharmacological properties, making it challenging to preserve the drug molecule structure during18F-fluorination.8’12-14Conversely, carbon is fundamental within an organic drug molecule. Incorporating labeled carbon atoms, such as11C (formal neutron loss from12C) and13C (formal neutron gain from12C), preserves the molecular structure and warrants the accurate investigation of specific pharmaceuticals.15 14C is widely used beta emitter in pharmaceutical research.13N is a PET isotope that allows for multi scans in same day. 15N is an interesting MRI agent or MRS agent. Unfortunately, methods for isotopically labeling organic drug molecules with carbon isotopes remain limited. Thus, there is an urgent need to develop new and efficient radiolabeling methodologies that are able to label a wide variety of organic labeling substrates.

[0010] SUMMARY

[0011] Carboxylic acids and their (bio)isosteres are frequently encountered as key functional groups in drug molecules. Herein, a general method to11 / 13 / 14C-label carboxylic acid via decarboxylative cyanation enabled by organic photoredox catalysis is disclosed. Specifically, an organic photoredox-catalyzed radiocyanation method is disclosed herein, which introduces a [11 / 13 / 14C][13 / 15N]nitrile quickly with high radiochemical conversion (RCC) into drug molecules, which can then be further diversified to other functional groups such as [11 / ,3 / ,4C]carboxylic acids, [11 / 13 / 14C][13 / 15N]amides, and [11 / 13 / 14C][13 / 15N]alkyl amines. This strategy can be applied to a wide range of carboxylic acids, including amino acids and small peptides, thereby providing easy access to new PET agents that were previously difficult to synthesize from readily available precursors.

[0012] As such, one aspect of the disclosure relates to a photoredox-catalyzed cyanation method comprising of a) obtaining a reaction mixture comprised of a photocatalyst and a solvent; b) contacting the reaction mixture with an aliphatic carboxylic acid substrate, a base additive, an oxidant and a cyanide source to afford a photocyanation reaction mixture; and c)az exposing the photocyanation reaction mixture to blue-violet light to form a cyano aliphatic product This cyano aliphatic product can then be hydrolyzed to obtain a labeled carboxylic acid- containing substrate. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Fig. 1a shows select examples of (isotopically-labeled) carboxylic acids and nitriles in drug molecules.

[0014] Fig. 1b shows the concept of carbon labeling to generate PET / MRI agents for Precision Medicine.

[0015] Fig. 1c shows the general labeling of carboxylic acids via organic photoredox catalysis as disclosed herein.

[0016] Fig. 2a. shows the substrate scope of decarboxylative radiocyanation of bioactive carboxylic acids. “Without TBHP.b2 min.cWith DIPEA (8.7 μL), RCC was obtained with Radio- TLC.dReaction was performed with EtOH / TFE / EA (550 / 100 / 100 μL), K2S2O8(5.4 mg), pH 8 buffer (4M, 100 μL). Reaction was performed with L11 instead of phen,gYield in the parentheses was obtained with EtOH / H2O (500 / 25 μL), K2S2O8(5.4 mg), pH 8 buffer (4M, 125 μL).

[0017] Fig. 2b shows the substrate scope of hydrolysis of11C-nitrile products.hRCY obtained from [12C]la in a 2-step one-pot protocol.

[0018] Fig. 2c shows images of a small animal PET imaging study of [11C]17a. 45 min p.i. PET / CT static imaging.

[0019] Fig. 3a shows the substrate scope for amino acids and peptides undergoing copper catalyzed decarboxylative radiocyanation.

[0020] Fig. 3b shows the substrate scope for amino acids and peptides undergoing copper-free radiocyanation of amino acids and peptides with 450 run LED in an LED radiolabeling device.

[0021] Fig. 4a shows the substrate scope for13C-labeled bioactive carboxylic acids such as decarboxylative13C-cyanation of bioactive acids. “InTFE / MeCN (1:1, 0.1M).

[0022] Fig. 4b shows the substrate scope for13C-labeled bioactive carboxylic acids such as decarboxylative13C-cyanation of amino acids and peptides.bYields in the parentheses were obtained with K2S2O8(10 equiv) and TMSCN (10 equiv).

[0023] Fig. 4c shows the substrate scope for13C-labeled bioactive carboxylic acids such as the hydrolysis of13C-nitrile product.

[0024] Fig. 5a shows additional substrate scope on primary acids.a24 h.

[0025] Fig. 5b shows additional substrate scope for secondary acids.bTFE / EA (1:1, 0.1 M).c5 °C. Fig. 5c shows additional substrate scope on enantioselective transformation. ‘‘With L11 as ligand in TFE / DCE (1 : 1 , 0.1 M) under 5 °C.eUsing RFTA instead of Acridinium as photocatalyst.fC-H functionalization,gUsing L9 instead of L11.

[0026] Fig. 5d shows additional substrate scope for tertiary acids.c5 °C.

[0027] Fig. 5e shows additional substrate scope with a commercial drug.hYield obtained from pure ibuprofen.

[0028] Fig. 6a shows additional substrate scope for amino acids and peptides such as a one-step strategy under aqueous buffer and high dilution conditions.

[0029] Fig. 6b shows additional substrate scope for amino acids and peptides such as the synthetic scale scope of amino acids and peptides. “In TFE / EA (1:1, 0.1 M) at 35-45 °C.b3 h.cIn TFE / EA / DCE (1:1:1, 0.067 M) at 35-45 °C.d6 h. 'Reaction was performed with 4CzIPN, TBHP, KCN in DMF.

[0030] Fig. 6c shows additional substrate scope for amino acids and peptides such as the divergent functionalization of glutamic acid.

[0031] Fig. 7a shows the substrate scope for “C and13C such as the general scope with “CN. a “aWithout TBHP.b2 min. 'With 450 nm LED.

[0032] Fig. 7b shows the substrate scope for11C and13C such as the C-H radiocyanation.

[0033] Fig. 7c shows the substrate scope for “C and13C such as the hydrolysis of “C-nitrile product. ‘‘With TMSC1 and KI.

[0034] Fig. 7d shows the substrate scope for “C and13C such as the scope with K12 / 13CN.eReaction was performed with HC1 (conc)ZAcOH (4:1).

[0035] Fig. 7e shows the substrate scope for “C and13C such as the hydrolysis of12C and13C- nitrile products.

[0036] Fig. 7f shows the substrate scope for “C and13C such as the hydrolysis of additional12C and13C-nitrile products.

[0037] Fig. 8 shows a representative in vivo head 3D PET / CT Image at 15 min p.i. at the scale of 5% ID / g (Right Ear, TPA-Treated Ear; Left Ear, Normal Ear).

[0038] Fig. 9 shows an image of a PRoBox LED reactor for full scale synthesis reactions.

[0039] Fig. 10a shows a schematic representation of photoredox [11C] cyanation for full scale synthesis reactions.

[0040] Fig. 10b shows a schematic representation of hydrolysis for full scale synthesis reactions. Fig. 11 shows a graphical representation of Radio-HPLC traces for full scale synthesis of [11C]17.

[0041] Fig. 12 shows a graphical representation of Radio-HPLC traces for full scale synthesis of [11C]17a.

[0042] DETAILED DESCRIPTION

[0043] The presently disclosed subject matter will now be described more fully hereinafter. However, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains, having the benefit of the teachings presented in the foregoing descriptions. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein covers all alternatives, modifications, and equivalents. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including, but not limited to, defined terms, term usage, described techniques, or the like, this application controls. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in this field. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0044] Molecular imaging is transforming healthcare into personalized medicine by tailoring medical decisions and treatments to an individual's unique characteristics.1-3Among the commonly used imaging modalities, positron emission tomography (PET) and magnetic resonance imaging (MRI) are undergoing rapid development and play an important role in early disease diagnosis, patient selection, and treatment monitoring.1,4Advances in these fields can depend heavily on the development of novel imaging agents, a process that can be accomplished through the isotopic labeling of bioactive ligands, but often constrained by the availability of chemistry methods. Clearly, there is a strong desire to develop general methods applicable to the labeling of commonly observed functional groups. For PET isotopes,18F (ti / 2 = 109.8 min) and11C (ti / 2 = 20.3 min) are extensively utilized,5and direct radiofluorination methods through the commonly encountered arene C-H bond functionalization have been reported.4However, the incorporation of an additional18F can induce changes in the polarity and electron density of bioligands,6-11potentially leading to changes in their biological or pharmacological properties, as the structure of the parent drug molecule is not preserved after18F fluorination.8,12-14Conversely, carbon atoms constitute the backbone of organic drug molecules. The development of general methods to substitute one or more carbons in the drug skeleton with11C (formal neutron loss from12C) would preserve the molecular structure and allow accurate investigation of specific pharmaceuticals via PET imaging.15,16Furthermore,11C PET can be performed on the same day as18F PET, which greatly simplifies patient management.

[0045] To develop a broadly applicable method, the11C labeling should be executed on a commonly encountered functional group. Carboxylic acids and their (bio)isosteres are highly represented in pharmaceuticals (Fig. la), including most marketed nonsteroidal anti-inflammatory drugs (NSAIDs), a variety of endogenous substances, and some isotopically-labeled molecular probes.17-21In fact, more than 40 of the 200 top-selling drugs in 2022 contain at least one carboxylic acid functional group.22-23In addition, the FDA has approved more than 30 nitrile drugs over the past few decades to manage various clinical conditions.24Clearly, the installation of carbon (radio)isotopes onto carboxyl groups presents a remarkable opportunity to investigate the in vivo drug / target activities of the acid or its (bio)isosteres. Considering the short half-life of11C, a practical toolbox for carboxylic acid radiolabeling should be simple, fast, starting from readily available precursors, and has high molar activity and broad substrate scope. Unfortunately, achieving these criteria has posed a persistent challenge in the field of radiochemistry over the past decades. Previous notable discoveries in carboxylic acid (radio)labeling include the use of Ni complexes in combination with metal reductants to promote carboxylate exchange with redox- active esters as substrates.25,26The application of these methods is largely limited to primary and secondary carboxylic acids, with no examples of11C labeling. Direct carboxylic acid exchange with free carboxylic acids and carbon labeled CO2under thermal27,28or photoredox29,30conditions provides a convenient and cost-effective pathway to access labeled carboxylic acids. These reactions proceed through the intermediacy of carbanions via a thermal- or photo-initiated decarboxylative pathway. However, presumably due to the high reactivity of the carbanion intermediates, the direct carboxylic acid exchange with CO2is specific to ^-stabilized carboxylic acids. In this vein, the clever use of a biomimetic pyridoxyl phosphate-type mechanism reported by Rotstein and Lundgren allowed for12C / 11C exchange with11CO2for free a-amino acids, but proceeds with low radiochemical yields (4-24% RCYs) and low molar activities.31The low molar activities (0.029 GBq μmol-1 30or 0.0084 GBq μmol-1 31) underscore one of the challenges for direct12C / 11C exchange in PET applications, primarily due to inseparable [12C]carboxylic acid precursors. This activity level is below the required threshold (1-230 GBq μmol-1) for human PET studies to avoid potential toxicity or blocking effects, especially when receptor density is limited.32

[0046] For MRI, there is a similar urgent need to incorporate carbon- 13 (formal neutron gain from

[0047] 12C into organic drug molecules to provide new tools for utilizing MRI for precision medicine.33In particular, hyperpolarized (HP)13C MRI stands out as an emerging molecular imaging technique that enables rapid, noninvasive and pathway-specific exploration of dynamic metabolic and physiological processes that were previously beyond the reach of conventional imaging.17,34With the increased availability of PET / MRI scanners, physicians can attain a higher level of precision medicine by synergistically leveraging the strengths of11C PET and13C hyperpolarized magnetic resonance imaging (HP MRI) to gain comprehensive insight into individual patient needs and optimize medical care accordingly (Fig. lb).15-35-36In summary, from both the PET and MRI perspective, there is a critical need to develop general carbon isotope labeling methods broadly applicable to bioactive agents. In this disclosure a general organic photoredox method for11C / 13C labeling through decarboxylative cyanation reactions (Fig. 1c) is presented.

[0048] The approach disclosed herein incorporates several unique features; 1) the utilization of carboxylic acids for introducing isotopic carbons ensures the ready availability of precursors. This allows for the direct use of carboxylic acid-containing natural products or drugs for labeling, which can significantly expedite the research and development process of PET and MRI probes. 2) The selection of mild photoredox reactions ensures both high efficiency and excellent tolerance of functional groups within the complex bioactive ligands. 3) The choice of a decarboxylative cyanation reaction enables easy access to nitriles from carboxylic acids with increased functional group compatibility compared to current protocols that proceed via dehydration of primary amides.37When12C cyanide sources are used, the resulting nitriles can frequently be found as key elements in drug molecules (Fig. la) and in some cases, their efficacy can be dramatically improved compared to the corresponding acids.24When11C / 13C cyanide sources are used, the resulting radiolabeled nitriles can serve as novel imaging agents on their own, or can be easily converted back to radiolabeled carboxylic acids after simple hydrolysis. Unlike direct carboxylic acid exchange reactions, the11C-nitrile can be easily separated from unlabeled carboxylic acid starting material (Fig. lb), leading to required high molar activity of the labeled carboxylic acid for PET imaging applications. This strategy would also provide a new route to access isotopically- labeled amino nitriles - valuable materials in peptide chemistry38, directly from amino acids or peptides (Fig. 1c). 4) The copper-catalyzed decarboxylative cyanation transformation could potentially provide a pathway to access enantioenriched isotopically labeled carboxylic acids, which remains relatively underdeveloped in the context of carbon isotope labeling (Fig. 1c).

[0049] In order to develop a general methodology to label bioactive carboxylic acids, flurbiprofen, a common NS AID, was used as a model substrate. Exposure of flurbiprofen under the decarboxylative conditions disclosed herein39combined with copper-catalyzed radical cyanation conditions,4082% of the desired cyanation product was obtained after systematic exploration. Further investigation of the solvents revealed that using a mixture of trifluoroethanol (TFE) and ethyl acetate (EA) provided the desired product in 95% yield. This chemistry could also be applied to achieve highly enantioenriched cyanation products. After screening various ligands, the serine- based bisoxazoline ligand (sBox) L1141,42was found to provide good enantioselectivity. Further optimization led to formation of the alkyl cyanide in 92% ee after 8h (Table 1). This methodology proved to be general for a range of bioactive carboxylic acids (Figs. 5a-e) The robustness of this process was further demonstrated by exploring the optimal conditions with multiscale synthesis (microgram to gram scale) as well as with an over the counter (OTC) tablet, Ibuprofen, without decreasing performance.

[0050] The most challenging and appealing development of this photoredox-catalyzed decarboxylative cyanation is the access to a general method for11C-labeled carboxylic acids. Although12C-cyanation methods were carefully optimized, translating these conditions to11C radiolabeling remains a significant challenge owing to 1) the rapid decay of11C requiring a highly efficient reaction; 2) the limited availability of11C starting material / reagent; 3) the extremely low concentration (generally in nanomolar quantities) of11C-cyanide. These obstacles placed additional screening requirements of the reaction conditions for the11C-nitrile construction. Recently a11C-labeling photochemical apparatus was disclosed43,44that we sought to apply to the decarboxylative radiocyanation by photoirradiation (450 nm). Through extensive screening, conditions (Table 8) for radiolabeling fenbufen (la) were identified, which afforded the11C-nitrile ([11C] 1) in high radiochemical conversion (RCC, 47.4%). Aiming to examine the generality of the disclosed methodology, we next explored said conditions (Fig. 2a, 450 nm laser irradiation for 5 mins) to obtain radiolabeled bioactive carboxylic acids (Fig. 2a). Benzylic (1a-5a) and non-benzylic primary carboxylic acids (6a-10a) were well suited to the radio decarboxylative cyanation conditions. Upon further decreasing the reaction time (2 mins) and simplifying the light source (LED), benzylic acid 2a could still undergo11C-cyanation. Good to excellent radiochemical conversions (RCCs) were obtained from selected NSAIDs, such as fenbufen (la), felbinac (3a), isoxepac (4a), and indomethacin (5a). Gamma-aminobutyric acid (GABA) (6a), gabapentin (7a) and mycophenoic acid (8a) also proved to be suitable substrates for the radio cyanation transformation. Complex primary carboxylic acids, such as mupirocin (9a), a typical antibiotic drug, and ursodeoxycarboxylic acid (10a), an off-patent drug that could prevent SARS-CoV-2 infection,45were smoothly converted to the desired11C-nitriles, indicating excellent functional group tolerance. Secondary carboxylic acids were also accommodated, providing the desired products in appreciable RCCs. Like primary carboxylic acids, these conditions could also be utilized to obtain radiolabeled nitriles from various complex secondary carboxylic acids, likeβ-amino proline analogues, including azetidine-3-carboxylic acid (11a) and nipecotic acid (12a), in very good RCCs. Other secondary carboxylic acids such as the cyclic (13a) and acyclic (14a) saccharide derivatives, as well as terpenoid-based carboxylic acids (15a, 16a) could also be11C- labeled in good RCCs. For secondary benzylic carboxylic acids, using flurbiprofen as an example, high radiochemical yields and enantioselectivities could be achieved in the presence of a chiral ligand. This represents an example of an enantioselective11C-radiolabeling method. Benzylic (18a) and non-benzylic tertiary carboxylic acids (19a-21a) could also be converted to the desired11C-labeled nitriles. It is worth noting that [11C]1 and [11C]17 can be hydrolyzed back to11C- labeled acids [11C]la and [11C]17a with excellent RCY and high molar activity (209.1 GBq / μmol for [11C]17a, Fig. 2b), demonstrating the complete12C / 11C isotope exchange sequence. These radiolabeled bioactive carboxylic acids with high molar activity could potentially serve as clinically relevant PET tracers without altering their structure. As a working example, the possibility of turning the anti-inflammatory NSAID flurbiprofen (17a) into a PET agent using the disclosed12C / 11C isotope exchange approach was explored. While flurbiprofen is known for its anti-inflammatory properties46, previous studies had only focused on the18F-fluorinated analog of the NSAID such as [18F]fenoprofen,6which alters the molecule's structure. Herein [11C]- flurbiprofen was successfully synthesized, as shown in Fig. 2b, and used to detect inflammation induced by 12-o-tetradecanoylphorbol-13-acetate (TP A) in mouse ears.6Preliminary ex vivo and in vivo PET studies (Fig. 2c and Fig. 8) indicated a higher uptake of [11C]flurbiprofen in the inflamed ear tissue compared to the control group, 45 minutes after intravenous injection of the PET tracer. These findings suggest that [11C]17a has the potential to serve as a PET agent, with a clear preference for accumulating in inflamed tissues. The feasibility of this transformation was further confirmed by a scaled-up (6.3-13.2 GBq) radiosynthesis of [11C] 17 and a two-step one-pot synthesis of [11C]17a (Fig. 2b). A strong-anion cartridge was used before hydrolysis to trap most of the carboxylic acids, facilitating the purification of the scaled-up radiolabelled product [’ *C]17a. a-Amino acids and peptides, basic building blocks of life, are frequently encountered as key components in small molecule pharmaceuticals and peptide-based therapeutics.47-50The preparation of isotope-labeled variants of these structures is essential to study and guide the design of new drugs. Current methods towards synthesis of11C-labeled amino acids are dominated by radiocyanation of the imine precursors or alkylation of the a-imino-ester.51These methods are frequently associated with low radiochemical yields and molar activity.

[0051] When the conditions depicted in Fig. 2a were explored with amino acid substrates (Fig. 3a), good RCCs were observed with glycine (22a) and side chain carboxylic acids (23a). These conditions proved to be suboptimal for other amino acids, such as Fmoc-Val (24a). After extensive screening (Table 5, 9), it was identified that by introducing an aqueous buffer as base, the desired product [11C]24 was obtained in 58.4% RCC under copper-free conditions with high molar activity (95.3 GBq / μmol). This method undergoes a pathway with a stabilized radical intermediate (Fig. 1c) and showed great compatibility with other Fmoc-protected natural amino acids (25a-30a) and small peptides (31a, 32a) with applicable RCCs (Fig. 3b). A commercial LED radiolabeling reactor also afforded good radiocyanation for Fmoc-Val (24a), under the same conditions except for the light source.

[0052] Next, this methodology extends beyond the11C chemistry applications. Other common isotopes of carbon (13C and14C) should be able to be adapted to this method as well. For example,13C is a readily available stable isotope that has various applications.52Considering the instability and high cost of TMS13CN, we investigated whether a more cost-effective cyanide source such as K13CN could be utilized in the decarboxylative cyanation reaction (Table 7). Although lower yields were observed in the absence of any additives, equivalent performance to TMS12CN was observed when a silyl Lewis acid additive (TMSOTf or TMSC1) was introduced (Fig. 4a). This procedure could also achieve dual labeling by incorporating both13C and15N isotopes into a nitrile molecule from a [13C15N]-cyanide source.53This principle was confirmed under similar conditions (Fig. 4a) during the synthesis of the doubly-labeled flurbiprofen, yielding [13C15N]17 with remarkable efficiency. Similar to the13C-labeled agents, the15N MRI agents can also undergo hyperpolarization, thereby extending the potential applications of MRI beyond the13C HP MRI.54By introducing K13CN to amino acid decarboxylative cyanation conditions (Fig. 6a-c, Table 5), modest to good yields were achieved for Fmoc-protected natural amino acids and peptides (Fig. 4b). Due to the prevalence of carboxylic acid functional groups in certain drug molecules, the development of a method for carbon labeling of carboxylic acids would be of high importance.16By exploring the hydrolysis of nitrile products under acidic ([13C]17a) or saponification conditions ([13C]10a), the corresponding labeled carboxylic acids were obtained in good yields (Fig. 4c). Stable isotopes like13C and15N can be incredibly useful and challenging in the field of structural biology, particularly in proteomics.55This novel Csp3-C cyanation method has been extended to the synthesis of13C analogues for pharmaceutical molecules and amino acids, which could be very useful in HP13C MRI.

[0053] I. Definitions

[0054] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0055] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an alkyl group” or “a phenyl” includes mixtures of two or more such alkyl groups or phenyls.

[0056] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another aspect includes fiom the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. Further, unless specified by the term “integer,” the number specified includes fractions or numbers with decimals. For example, the range of “from about 1 to about 5” includes numbers such as 1, 1.1, 1.5, 2.0, 2.2, and so on. As used herein, the term “integer” refers to a number that is a whole number, and not a fraction.

[0057] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denote the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5 and are present in such ratio regardless of whether additional components are contained in the compositions.

[0058] Throughout this specification and the claims, the words “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise. It is understood that embodiments described herein include “consisting of’ and / or “consisting essentially of’ embodiments.

[0059] As used therein, the term “a biologically active molecule or a portion thereof’ generally refers to compounds of Formula (II) or (III), with the same number of atoms for each element as disclosed in the compounds of Formula (I), the only difference being that Formula (II) or (III) contain a different carbon isotope (11 / 13 / 14C) and / or a nitrogen isotope (13 / 15N) than Formula (I). For Example, the following compound of Formula (II) represents the entire biologically active molecule, which can be modified to a compound of Formula (III), wherein R4is [11 / 13C]CONH2, which is attached to a portion of the biologically active molecule.

[0060] A skilled artisan would be able to apply the above definition to other biologically active molecules and would therefore have an understanding of the meaning of “a portion” of a biologically active molecule.

[0061] As used herein, the terms “increase,” “increases,” “increased,” “increasing”, “improve,” “enhance,” and similar terms indicate an elevation in the specified parameter of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, 500%, or more.

[0062] As used herein, the terms “reduce,” “reduces,” “reduced,” “reduction,” “inhibit,” and similar terms refer to a decrease in the specified parameter of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 100%.

[0063] As used herein, “contacting” refers to reagents in close proximity so that a reaction may occur.

[0064] As used herein, the term “stereoisomer” refers to compounds which are identical chemical constitutional isomers, but differ with regards to the arrangement of the atoms or groups in space. These “stereoisomers” have a “stereogenic center” which may be a chiral center.

[0065] As used herein, the term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.

[0066] As used herein, the term “diastereomers” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers may separate under high-resolution analytical procedures such as electrophoresis and chromatography.

[0067] As used herein, the term “enantiomers” refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wiley, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including, but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.

[0068] As used herein, the term “aliphatic” refers to open chain hydrocarbons, wherein each atom is connected by single, double, or triple bonds forming nonaromatic structures.

[0069] As used herein, the term “cyano aliphatic" refers to an aliphatic compound, which is substituted with one nitrile group (-CN). For example, propionitrile. However, the cyano aliphatic can further contain additional substituents. For example, 3-hydroxypropionitrile.

[0070] As used herein, the term “substituted” refers to a moiety (such as heteroaryl, aryl, cycloalkyl, alkyl, and / or alkenyl) wherein the moiety is bonded to one or more additional organic or inorganic substituent radicals. In some embodiments, the substituted moiety comprises 1, 2, 3, 4, or 5 additional substituent groups or radicals. Suitable organic and inorganic substituent radicals include, but are not limited to, halogen, hydroxyl, cycloalkyl, aryl, amino (including protected primary and / or secondary amine functional groups, e.g., -NHFmoc), ester, amide, substituted aryl, heteroaryl, heterocyclic ring, substituted heterocyclic ring, amino, mono-substituted amino, di- substituted amino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkyl carboxamide, substituted alkyl carboxamide, dialkyl carboxamide, substituted dialkyl carboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, alkoxy, substituted alkoxy or haloalkoxy radicals, wherein the terms are defined herein. Unless otherwise indicated herein, the organic substituents can comprise from 1 to 4 or from 5 to 8 carbon atoms. When a substituted moiety is bonded thereon with more than one substituent radical, then the substituent radicals may be the same or different. As used herein, the term “unsubstituted” refers to a moiety (such as heteroaryl, aryl, alkenyl, and / or alkyl) that is not bonded to one or more additional organic or inorganic substituent radicals as described above, meaning that such a moiety is only substituted with hydrogens.

[0071] As used herein, the term “alkyl” refers to a straight or branched chain hydrocarbon containing from 1 to 12 carbon atoms. Representative examples of alkyl include, but are not limited to: methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. These groups may be substituted with groups selected from halo (e.g., haloalky 1), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy (thereby creating a polyalkoxy such as polyethylene glycol), alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto carboxy, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, ester, amide, nitro, or cyano.

[0072] The term “cycloalkyl” refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system having at least one saturated ring or having at least one non-aromatic ring, wherein the non-aromatic ring may have some degree of unsaturation. Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be substituted by a substituent. Representative examples of cycloalkyl group include: cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

[0073] As used herein, the term “heterocycloalkyl” refers to a nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, S, B, P or Si, wherein the nonaromatic ring system is completely saturated. Heterocycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocycloalkyl group may be substituted by a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomoipholinyl, 1,3-dioxolanyl, tetrahydrofuryl, tetrahydrothienyl, thienyl, and the like.

[0074] As used herein, the terms “alkenyl” and “alkene” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decenyl), branched-chain alkenyl groups and cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl) groups. The term alkenyl further includes alkenyl groups that include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkenyl group with 10 or fewer carbon atoms in its backbone (e.g., C2-C10 for straight chain, C3-C10 for branched chain) is used. Likewise, cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The term C2-C10 includes alkenyl groups containing 2 to 10 carbon atoms. Certain alkene compounds of the invention may exist as a mixture of E and Z isomers, predominantly as E isomers, or predominantly Z isomers. In certain embodiments, compounds of the invention may be enriched in either the E or Z isomer. For example, a compound of the invention may have greater than 50%, 60%, 70%, 80%, 90%, or 95% or more of the E or Z isomer.

[0075] As used herein, the term “heteroaryl” or “heteroaromatic" refers to a monovalent aromatic radical of 5- or 6-membered rings and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example,

[0076] 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl (including, for example, 3-amino-l,2-4-triazole or

[0077] 3 -mercapto- 1, 2, 4-triazole), pyrazinyl (including, for example, aminopyrazine), tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, oxazol-2(3H)-onyl, and furopyridinyl. The heteroaryl groups are thus, in some embodiments, monocyclic or bicyclic. Heteroaryl groups are optionally substituted independently with one or more substituents described herein.

[0078] As used herein, the term “aryl” refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. Aryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

[0079] As used herein, the term “unsubstituted” refers to a moiety (such as an alkyl group) that is not bonded to one or more additional organic or inorganic substituent radical as described above, meaning that such a moiety is only substituted with hydrogens.

[0080] As used herein, the term “alkoxy”, used alone or as part of another group, means the radical -OR, where R is an alkyl group as defined herein.

[0081] As used herein, the terms “halo,” “halogen,” and “halide” refer to any suitable halogen, including -F, -Cl, -Br, and -I.

[0082] As used herein, the term “mercapto” refers to an -SH group.

[0083] As used herein, the term “cyano” refers to a -CN group.

[0084] As used herein, the term “carboxylic acid” refers to a -C(O)OH group.

[0085] As used herein, the term “hydroxyl” refers to an -OH group.

[0086] As used herein, the term “nitro” refers to an -NO2group.

[0087] As used herein, the term “sulfonyl” refers to the SO2" group. The “sulfonyl” may refer to a sulfonyl group, which is, for example, an alkylsulfonyloxy group such as a methylsulfonyloxy or ethylsulfonyloxy group and an aromatic sulfonyloxy group such as a benzenesulfonyloxy or tosyloxy group.

[0088] As used herein, the terms “ether” and “alkylether” are represented by the formula Ra-O- Rb, where Raand Rbcan be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyether” as used herein is represented by the formula -( Ra-O-Rb)x-, where Raand Rbcan be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “x” is from about 1 to about 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0089] As used herein, the term “acyl”, used alone or as part of another group, refers to a -C(O)R radical, where R is any suitable substituent such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl or other suitable substituent as described herein.

[0090] As used herein, the term “amino” means the radical -NH2.

[0091] As used herein, the term “alkylamino” or “mono-substituted amino”, used alone or as part of another group, means the radical -NHR, where R is an alkyl group.

[0092] As used herein, the term “disubstituted amino”, used alone or as part of another group, means the radical -NRaRb, where Raand Rbare independently selected from the groups alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, and heterocycloalkyl.

[0093] As used herein, the term “ester”, used alone or as part of another group, refers to a -C(O)OR radical, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

[0094] As used herein, the term “amide”, used alone or as part of another group, refers to a -C(O)NRaRbradical, where Raand Rbare any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

[0095] It will be understood that the structures provided herein and any recitation of “substitution” or “substituted with” includes the implicit proviso that such structures and substitution are in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0096] The phrase “pharmaceutically acceptable" indicates that the substance or composition is compatible chemically and / or toxicologically with the other ingredients comprising a formulation, and / or the subject being treated therewith.

[0097] The phrase “pharmaceutically acceptable salt” as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound disclosed herein. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., l,l'-methylene-bis-(2- hydroxy-3-naphthoate)) salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. In instances where multiple charged atoms are part of the pharmaceutically acceptable salt, the salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counter ions.

[0098] “Carriers” as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Non-limiting examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™. In certain embodiments, the pharmaceutically acceptable carrier is a non-naturally occurring pharmaceutically acceptable carrier.

[0099] As used herein, the term “pharmaceutical composition” refers to the active agent in combination with a pharmaceutically acceptable carrier, e.g., a carrier commonly used in the pharmaceutical industry. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. In some embodiments of any of the aspects, a pharmaceutically acceptable carrier can be a carrier other than water. In some embodiments of any of the aspects, a pharmaceutically acceptable carrier can be an emulsion, liposome, nanoparticle, and / or solution. In some embodiments of any of the aspects, a pharmaceutically acceptable carrier can be an artificial or engineered carrier, e.g., a carrier that the active ingredient would not be found to occur in nature.

[0100] The term “administration” or “administering” includes routes of introducing the compound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (including, but not limited to, subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), topical, oral, inhalation, rectal and transdermal.

[0101] The term “effective amount” includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. An effective amount of compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject (i.e., being able to conduct imaging studies).

[0102] The term “subject” refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.

[0103] As used herein, a subject is “in need of* a treatment if such subject would benefit biologically, medically or in quality of life from such treatment. n. Photoredox System

[0104] In light of the abundance of aliphatic nitriles and aliphatic carboxylic acids in therapeutics21, the current disclosure is directed towards organic photoredox catalysis mediating a decarboxylative11 / 13C-cyanation of aliphatic carboxylic acids via carbon radical intermediates

[0105] (Fig. lb).

[0106] Thus, one aspect of the current disclosure is a photoredox system comprising a photocatalyst, a cyanide source, a base additive, an oxidant, a blue- violet light, and a solvent. Such a photoredox system can then be used to introduce cyanide functional groups into a variety of aliphatic carboxylic acid substrates. As already mentioned above there is an abundance of therapeutics and natural products that contain nitriles. Another aspect of the current disclosure is to employ a radioactive cyanide source in the disclosed photoredox system. Cyanation of aliphatic carboxylic acid substrates with radioactive cyanide sources (which is also referred to as radiocyanation) render radioactive cyano aliphatic substrates, which can be used in a variety of application, e.g., PET, magnetic resonance spectroscopy (MRS) and HP MRI imaging modalities.

[0107] Therefore, each component of the disclosed photoredox system as well as the aliphatic carboxylic acid substrate is described in more detail below. It should be noted that any mention of a concentration (in M), catalyst loading amount (in mol%), or relative amounts of certain components of the photoredox system provided as equivalents (equiv.) are all based on the amount of aliphatic carboxylic acid substrate employed in methods using the disclosed photoredox system (and its components). A skilled artisan would be very familiar with this kind of expression of these units in this particular manner.

[0108] A. Photocatalyst

[0109] The photoredox system as disclosed herein requires a photocatalyst. As used herein, the term “photocatalyst” can be any material that exhibits photocatalytic properties, i.e., the ability to foster and accelerate specific chemical reactions upon stimulation by light of suitable wavelengths.

[0110] The photocatalyst can be any material as along as it exhibits a suitable excited state reduction potential. As used herein, the term “excited state reduction potential” refers to the likelihood of a chemical element to be reduced, wherein the chemical element temporarily occupies an energy state that is greater than die ground state. In some embodiments, the excited state reduction potential is up to about +2.5 V vs. SCE, about +2.2V vs. SCE, about +2.0V vs. SCE, about +1.8V vs. SCE, about +1.6V vs. SCE, about +1.4V vs. SCE, about +1.2V vs. SCE, about +1.0V vs. SCE, about +0.8V vs. SCE, about +0.6V vs. SCE, about +0.4V vs. SCE, or about +0.2V vs. SCE (saturated calomel electrode) in acetonitrile.

[0111] In some embodiments, the excited state reduction potential ranges from about +2.5V vs. SCE to about 0.1V vs. SCE, from about 2.2V vs. SCE to about 0.2V vs. SCE, from about 2.0V vs. SCE to about 0.5 V vs. SCE, from about 0.75 V vs. SCE to about 1.75V vs. SCE, or from about IV vs. SCE to about 1.5V vs. SCE (saturated calomel electrode) in acetonitrile. In some embodiments, the photocatalyst is selected from the group consisting of Mes-Acr- Ph+(also referred to as “Acridinium”), 4CzIPN, 4CzTPN, RFTA, EOSIN, Ir-11, and a combination thereof. The chemical structures of these photocatalysts are shown below:

[0112] In some embodiments, the photocatalyst is Mes-Acr-Ph+or RFTA. In some embodiments, the photocatalyst does not contain a metal, i.e., the photocatalyst is metal-free.

[0113] The amount of photocatalyst loading present in the photoredox system can vary. In some embodiments, the photocatalyst is present in an amount of from about 0.1 mol% to about 15 mol%,

[0114] 0.1 mol% to about 12 mol%, from about 1 mol% to about 10 mol%, from about 1 mol% to about

[0115] 8 mol%, from about 1.5 mol% to about 7 mol%, from about 2 mol% to about 6 mol%, from about

[0116] 2.5 mol% to about 6.5 mol%, from about 3 mol% to about 6 mol%, from about 4 mol% to about

[0117] 6 mol%, or from about 4.5 mol% to about 5.5 mol%. In some embodiments, the photocatalyst is present in an amount of from about 1 mol% to about 50 mol%, from about 5 mol% to about 50 mol%, from about 10 mol% to about 40 mol%, from about 15 %mol to about 40 mol%, from about

[0118] 20 %mol to about 35 mol%, from about 25 %mol to about 35 mol%, or from about 27 %mol to about 33 mol%. In some embodiments, the photocatalyst is present in an amount of from about 5 mol% to about 30 mol%.

[0119] In some embodiments, the photocatalyst can be present in an amount of at least about

[0120] 0.1 mol%, about 0.5 mol%, about 1 mol%, about 1.25 mol%, about 1.75 mol%, about 2.0 mol%, about 2.25 mol%, about 2.50 mol%, about 2.75 mol%, about 3.0 mol%, about 3.25 mol%, about 3.5 mol%, about 3.75 mol%, about 4.0 mol%, about 4.25 mol%, about 4.5 mol%, about 4.75 mol%, about 5 mol%, about 10 mol%, about 15 mol%, about 20 mol%, about 25 mol%, or at least about 30 mol%. In addition, or in the alternative, the photocatalyst can be present in an amount of less than about 50 mol%, about 45 mol%, about 40 mol%, about 35 mol%, about 30 mol%, about 25 mol%, about 20 mol%, about 10 mol%, about 9.5 mol%, about 9.0 mol%, about 8.5 mol%, about 8.0 mol%, about 7.75 mol%, about 7 mol%, about 6.5 mol%, about 6.0 mol%, about 5.5 mol%, about 5 mol%, about 4.5 mol%, about 4 mol%, about 3.5 mol%, about 3.0 mol%, or less than about 2.5 mol%.

[0121] In alternate embodiments, the photoredox system contains radioactivity. In such embodiments, the photocatalyst is present in an amount of from about 0.1 mg to about 5 mg, from about 0.25 mg to about 4.5 mg, from about 0.3 mg to about 4 mg, from about 0.4 mg to about 3.5 mg, from about 0.5 mg to about 3 mg, from about 0.5 mg to about 2.5 mg, from about 0.6 mg to about 2.0 mg or from about 0.6 mg to about 1.7 mg. In some embodiments, the photocatalyst is present in an amount of at least about 0.1 mg, at least about 0.25 mg, at least about 0.4 mg, at least about 0.5 mg, at least about 0.6 mg, at least about 1 mg, at least about 1.25 mg, at least about 1.50 mg, or at least about 1.70 mg. In addition, or in the alternative, the photocatalyst is present in an amount of less than about 3.5 mg, less than about 3.25 mg, less than about 3.0 mg, less than about

[0122] 2.75 mg, less than about 2.5 mg, less than about 2.25 mg, less than about 2.0 mg, less than about

[0123] 1.75 mg, less than about 1.5 mg, less than about 1.25 mg, less than about 1 mg, less than about 0.75 mg, or less than about 0.6 mg.

[0124] B. Cyanide source

[0125] The photoredox system disclosed herein requires a cyanide source. Exemplary cyanide sources include, but are not limited to, acetone cyanohydrin (ACH), tetrabutylammonium cyanide (TBACN or NBu4CN), trimethylsilyl cyanide (TMSCN), sodium cyanide (NaCN), triethylamine cyanide (TEACN), potassium cyanide (KCN), and combinations thereof. In some embodiments, the cyanide source is not radioactive. Non-radioactive carbon and / or nitrogen isotopes employed in the disclosed cyanide sources include, but are not limited to, [12C] carbon isotope, [13C] carbon isotope and / or [14N] nitrogen isotope and [15N] nitrogen isotope. For example, a nonradioactive cyanide source comprising [12C] and [13C] carbon isotopes includes, but is not limited to, [12 / 13C]TMSCN, [12 / 13C]KCN, [12 / 13C]NaCN, NBu4[12 / 13C]CN, TBA[12 / 13C]CN, TEA[12 / 13C]CN, and combinations thereof. In another example, a nonradioactive cyanide source comprising [14N] or [15N] nitrogen isotopes includes, but is not limited to, [14 / 15N]TMSCN, [14 / 15N]KCN, [14 / 15N]NaCN, [14 / 15N]NBu4CN and combinations thereof.

[0126] In some embodiments, the cyanide source is radioactive. Radioactive carbon and / or nitrogen isotopes employed in the disclosed cyanide sources include, but are not limited to, [11C] carbon isotope, [14C] carbon isotope and / or [13N] nitrogen isotope. For example, a radioactive cyanide source comprising [11C] and / or [14C] carbon isotope includes, but is not limited to, [11 / 14C]TMSCN, [11 / 14C]KCN, [11 / 14C]NaCN, NBu4[11 / 14C]CN, TBA[11 / 14C]CN, TEA[11 / 14C]CN, and combinations thereof. In another example, a radioactive cyanide source comprising [13N] nitrogen isotope includes, but is not limited to, [13N]TMSCN, [13N]KCN, [13N]NaCN, [13N]NBu4CN and combinations thereof.

[0127] The amount of (non-radioactive) cyanide source present in the photoredox system can vary. In some embodiments, the cyanide source does not contain a radioisotope and is present in the photoredox system in an amount that ranges from about 1 equiv. to about 10 equiv., from about 1 equiv. to about 8 equiv., from about 1 equiv. to about 6 equiv., from about 1 equiv. to about 5 equiv., from about 1.5 equiv. to about 5 equiv., from about 2 equiv. to about 5 equiv., from about 3 equiv. to about 5 equiv., or from about 3.5 equiv. to about 4.5 equiv. In some embodiments, the cyanide source is present in the photoredox system in an amount that ranges from about 1 equiv. to about 15 equiv. from about 2 equiv. to about 15 equiv., from about 5 equiv. to about 12 equiv., from about 7 equiv. to about 12 equiv., from about 8 equiv. to about 12 equiv., from about 9 equiv. to about 11 equiv., or from about 9.5 equiv. to about 10.5 equiv. In some embodiments, the cyanide source is present in the photoredox system in an amount of less than about 15 equiv., less than about 12 equiv., less than about 10 equiv., less than about 8 equiv., less than about 6 equiv., less than about 5 equiv., less than about 4.0 equiv., less than about 3.5 equiv., less than about 2 equiv., less than about 1.0 equiv., less than about 0.75 equiv., less than about 0.5 equiv., less than about 0.25 equiv., less than about 0.1 equiv., or less than about 0.01 equiv. In addition, or in the alternative, the cyanide source is present in the photoredox system in an amount of at least about 0.0001 equiv., at least about 0.001 equiv., at least about 0.01 equiv., at least about 0.1 equiv., at least about 1 equiv., at least about 1.5 equiv., at least about 1.75 equiv., at least about 2 equiv., or at least about 2.5 equiv. As already mentioned above, the cyanide source may contain a radioisotope. In some embodiments, the cyanide source containing the radioisotope (also referred to as radioligand) is dissolved in a solvent to form a solution (referred to herein as radioactive cyanide source) to promote ease of handling of the radioligand. The solvent used for such solution can vary but are selected to ensure that (a) the radioligand is fully soluble in the chosen solvent; and / or (b) that die radioligand is stable in the chosen solvent. In some embodiments, the solvent is a polar protic solvent or an aprotic polar solvent as is described in more detail below. In some embodiments, the solvent is ethanol.

[0128] The amount of cyanide source containing a radioisotope present in a photoredox system can vary. In some embodiments, the amount of the radioactive cyanide source used in the disclosed photoredox system is significantly smaller compared to the amount of non-radioactive cyanide source employed in the disclosed photoredox system. In such embodiments, the amount of radioactive cyanide source is provided as a function of radioactivity measured in becquerels (Bq). Thus, in some embodiments, the radioactivity of the cyanide sources ranges from about 0.001 GBq to about 2 GBq, from about 0.001 GBq to about 1.5 GBq, from about 0.01 GBq to about 1.5 GBq, from about 0.1 GBq to about 1.25 GBq, from about 0.1 GBq to about 1.20 GBq, from about 0.1 GBq to about 1.15 GBq, from about 0.11 GBq to about 1.10 GBq, from about 0.11 GBq to about 0.8 GBq, from about 0.11 GBq to about 0.6 GBq, from about 0.11 GBq to about 0.4 GBq, or from about 0.11 GBq to about 0.2 GBq. In some embodiments, the radioactivity of the cyanide source is at least about 0.001 GBq, about 0.005 GBq, about 0.008 GBq, about 0.01 GBq, about 0.08 GBq, about 0.06 GBq, about 0.04 GBq, about 0.02 GBq, about 0.1 GBq, about 0.12 GBq, about 0.14 GBq, about 0.16 GBq, about 0.18 GBq, about 0.2 GBq, about 0.25 GBq, about 0.3 GBq. In addition, or in the alternative, the radioactivity of the cyanide source is less than about 2.5 GBq, about 2.25 GBq, about 2.0 GBq, about 1.75 GBq, about 1.50 GBq, about 1.25 GBq, about 1.15 GBq, or less than about 1 GBq.

[0129] In some embodiments, the amount of radioactive cyanide source is provided as a function of radioactivity measured in curies (Ci). Thus, in some embodiments, the radioactivity of the cyanide source ranges from about 1 mCi to about 500 mCi, from about 2 mCi to about 400 mCi, from about 3 mCi to 300 mCi, from about 4 mCi to about 200 mCi, from about 5 mCi to about 100 mCi, or from about 10 mCi to about 50 mCi. C. Base additive

[0130] The photoredox system as disclosed herein requires a base additive. In some embodiments, the base additive is an organic base selected from the group consisting of ammonia, methylamine, tetrabutylammonium hydroxide (TBAOH), trimethylamine, ethylamine, di-isopropylethylamine (DIPEA), phenylamine, pyridine, imidazole, histidine, guanidine, benzimidazole, phosphazene, tetrabutylammonium hydrogen carbonate [(TBA)HCO3], tetrabutyl ammonium bicarbonate [(TBA)2CO3] and a combination thereof. In some embodiments, the base additive is DIPEA or TBAOH.

[0131] In some embodiments, the base additive is a buffer solution. Exemplary buffer solutions include, but are not limited to, a borate buffer, a phosphate buffer, and a combination thereof. In such embodiments the concentration of the buffer solution can vary. For example, in some embodiments, the concentration of the buffer solution ranges from about 0.1M to about 5M, from about IM to about 5M, from about 2M to about 5M, from about 3M to about 5M, from about 3.5M to about 4.5M, or from about 3.8M to about 4.2M. In some embodiments, the base additive is a phosphate buffer with a concentration of about 4M.

[0132] The pH of the base additive can vary. In some embodiments, the base additive is an organic base or an inorganic base with a pH neat or in solution ranging from about 7.5 to about 10.5, from about 7.5 to about 10.0, from about 7.8 to about 9.5, from about 7.8 to about 9.0, or from about 8 to about 9. In some embodiments, the pH of organic or inorganic base neat or in solution is at least about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, or at least about 8.9. In addition, or in the alternative, the pH of the organic or inorganic base neat or in solution is less than about 9.2, less than about 9.1, less than about 9.0, less than about 8.9, less than about 8.8, less than about 8.7, less than about 8.6, less than about 8.5, less than about 8.4, less than about 8.3, less than about 8.2, or less than about 8.1. In some embodiments, the base additive is a phosphate buffer with a pH of about 8.0.

[0133] The amount of base additive present in the photoredox system can vary. In some embodiments, the base additive is present in an amount that ranges from about 0.1 mol% to about 45 mol%, 1 mol% to about 40 mol%, from about 5 mol% to about 35 mol%, from about 10 mol% to about 30 mol%, from about 15 mol% to about 30 mol%, from about 20 mol% to about 28 mol%, from about 22 mol% to about 26 mol%, or from about 24 mol% to about 26 mol%. In some embodiments, the base additive is present in an amount of from about 0.001 mol% to about 0.1 mol%, from about 0.001 mol% to about 0.01 mol%, or from about 0.001 mol% to about 0.005 mol%.

[0134] In some embodiments, the base additive is present in the photoredox system in an amount of less than about 30 mol%, less than about 25 mol%, less than about 20 mol%, less than about 10 mol%, less than about 5.0 mol%, less than about 1 mol%, less than about 0.5 mol%, less than about 0.1 mol%, less than about 0.01 mol%, less than about 0.001 mol%, or less than about 0.0001 mol%. In addition, or in the alternative, the base additive is present in the photoredox system in an amount of at least about 0.0001 mol%, at least about 0.001 mol%, at least about 0.01 mol%, at least about 0.1 mol%, at least about 1 mol%, at least about 12 mol%, at least about 15 mol%. At least about 20 mol%, at least about 23 mol%, or at least about 25 mol%.

[0135] D. Co-catalyst

[0136] The photoredox system as disclosed herein can further comprise a co-catalyst. In some embodiments, such a co-catalyst is a metal-containing co-catalyst, e.g., a copper-containing co- catalyst and / or a nickel-containing co-catalyst . Exemplary copper-containing co-catalysts include, but are not limited to, copper (II) sulfate pentahydrate, copper (II) chloride, copper (II) iodide, copper (II) bromide, copper (I) chloride, copper (I) iodide, copper (I) bromide, copper (II) trifluouromethanesulfonate, copper (II) acetate, tetrakis (acetonitrile) copper (I) tetrafluoroborate and copper bromide. In some embodiments, the co-catalyst is copper (II) trifluouromethanesulfonate. Exemplary nickel-containing co-catalysts include, but are not limited to nickel (II) sulfate, nickel (II) chloride hexahydrate, nickel (II) bromide, nickel (II) iodide, nickel (II) fluoride tetrahydrate, nickel (II) tetrafluoroborate and nickel (II) acetate tetrahydrate

[0137] The amount of the co-catalyst present in the photoredox system can vary. In some embodiments, the co-catalyst is present in an amount that ranges from about 0.1 mol% to about 15 mol%, 1 mol% to about 12 mol%, from about 3 mol% to about 10 mol%, from about 4 mol% to about 10 mol%, from about 5 mol% to about 10 mol%, from about 8 mol% to about 12 mol%, from about 9 mol% to about 11 mol%, or from about 9.5 mol% to about 10.5 mol%. In some embodiments, the co-catalyst is present in an amount that ranges from about 0.1 mol% to about 10 mol%, 1 mol% to about 8 mol%, from about 2 mol% to about 6 mol%, from about 3 mol% to about 6 mol%, from about 3.5 mol% to about 5.5 mol%, or from about 4 mol% to about 5 mol%.

[0138] In some embodiments, the co-catalyst can be present in an amount of at least about 0.1 mol%, about 0.5 mol%, about 1 mol%, about 1.25 mol%, about 1.75 mol%, about 2.0 mol%, about 2.25 mol%, about 2.50 mol%, about 2.75 mol%, about 3.0 mol%, about 3.25 mol%, about 3.5 mol%, about 3.75 mol%, about 4.0 mol%, about 4.25 mol%, about 4.5 mol%, about 4.75 mol%, about 5 mol%, about 10 mol%, about 15 mol%, about 20 mol%, about 25 mol%, or at least about 30 mol%. In addition, or in the alternative, the co-catalyst can be present in an amount of less than about 50 mol%, about 45 mol%, about 40 mol%, about 35 mol%, about 30 mol%, about 25 mol%, about 20 mol%, about 10 mol%, about 9.5 mol%, about 9.0 mol%, about 8.5 mol%, about 8.0 mol%, about 7.75 mol%, about 7 mol%, about 6.5 mol%, about 6.0 mol%, about 5.5 mol%, about 5 mol%, about 4.5 mol%, about 4 mol%, about 3.5 mol%, about 3.0 mol%, or less than about 2.5 mol%.

[0139] In alternate embodiments, the photoredox system contains radioactivity. In such embodiments, the co-catalyst is present in an amount of from about 0.01 mg to about 5 mg, from about 0.1 mg to about 4.0 mg, from about 0.15 mg to about 3 mg, from about 0.20 mg to about 2.0 mg, from about 0.25 mg to about 1.0 mg, from about 0.25 mg to about 0.5 mg, from about 0.3 mg to about 0.4 mg or from about 0.35 mg to about 0.4 mg. In some embodiments, the photocatalyst is present in an amount of at least about 0.01 mg, at least about 0.1 mg, at least about 0.2 mg, at least about 0.25 mg, at least about 0.30 mg, or at least about 0.32 mg. In addition, or in the alternative, the photocatalyst is present in an amount of less than about 1.0 mg, less than about 0.75 mg, less than about 0.5 mg, less than about 0.4 mg, or less than about 0.38 mg.

[0140] E. Ligand

[0141] The photoredox system as disclosed herein can further comprise a ligand. The ligand is designed to provide an enantioselective product when used in the photoredox system disclosed herein. In some embodiments, the ligand is selected from the group consisting of phenanthroline (phen), 1,10-phenanthroline (LI), 2,2'-Isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (L2), 2,2'-Methylenebis[(4R,5S)-4,5-diphenyl-2-oxazoline] (L3), (4R,4'R)-2,2’-(propane-2,2- diyl)bis(4-isopropyl-4,5-dihydrooxazole) (L4), (+)-2,2'-Isopropylidenebis[(4R)-4-benzyl-2- oxazoline] (L5), (4S,4'S)-2,2'-(l ,3-Diphenylpropane-2,2-diyl)bis(4-benzyl-4,5-dihydrooxazole) (L6), (3aS,3'aS,8aR,8'aR)-2,2'-Methylenebis[3a,8a-dihydro-8H-indeno[l ,2-d]oxazole] (L7), (4S)-(+)-Phenyl-a-[(4S)-phenyloxazolidin-2-ylidene]-2-oxazoline-2-acetonitrile (L8),

[0142] (3aS,3a'S,8aR,8a’R)-2,2'-(cyclopropane-l , 1 -diyl)bis(3a,8a-dihydro-8H-indeno[ 1 ,2-d]oxazole) (L9), Di-tert-butyl 2,2'-(cyclopropane- 1 , 1 -diyl)(4S,4'S)-bis(4,5-dihydrooxazole-4-carboxylate) (L10), Di-isopropyl 2,2'-(cyclopropane-l,l-diyl)(4S,4’S)-bis(4,5-dihydrooxazole-4-carboxylate) (L11), and (S)-4-(Isopropyl)-2-(quinolin-2-yl)-4,5-dihydrooxazole (L12) (see Table 1).

[0143] In some embodiments, the ligand is di-isopropyl 2, 2 '-(cyclopropane- 1,1 -diyl)(4S, 4 'S)- bis(4,5-dihydrooxazole-4-carboxylate) (L11) or phenanthroline (phen).

[0144] The amount of the ligand present in the photoredox system can vary. In some embodiments, the ligand is present in an amount that ranges from about 0.1 mol% to about 20 mol%, 1 mol% to about 18 mol%, from about 3 mol% to about 15 mol%, from about 3 mol% to about 10 mol%, from about 5 mol% to about 10 mol%, from about 6 mol% to about 8 mol%, from about 7 mol% to about 8 mol%, or from about 7.2 mol% to about 7.8 mol%. In some embodiments, the ligand is present in an amount that ranges from about 7 mol% to about 11 mol% or from about 7.5 mol% to about 10 mol%.

[0145] In some embodiments, the ligand can be present in an amount of at least about 0.1 mol%, about 0.5 mol%, about 1 mol%, about 2.0 mol%, about 3.0 mol%, about 4.0 mol%, about 5.0 mol%, about 6.0 mol%, about 7.0 mol%, about 8.0 mol%, about 9.0 mol%, or at least about 9.5 mol%. In addition, or in the alternative, the ligand can be present in an amount of less than about 15 mol%, about 13 mol%, about 11 mol%, about 10 mol%, about 9 mol%, about 8 mol%, about 7 mol%, about 6 mol%, or less than about 5 mol%.

[0146] In alternate embodiments, the photoredox system contains radioactivity. In such embodiments, the ligand is present in an amount of from about 0.01 mg to about 3 mg, from about 0.1 mg to about 2 mg, from about 0.15 mg to about 0.75 mg, from about 0.20 mg to about 0.50 mg, or from about 0.25 mg to about 0.30 mg. In some embodiments, the ligand is present in an amount of at least about 0.01 mg, at least about 0.1 mg, at least about 0.15 mg, at least about 0.20 mg, at least about 0.23 mg, or at least about 0.26 mg. In addition, or in the alternative, the photocatalyst is present in an amount of less than about 0.30 mg, less than about 0.28 mg, or less than about 0.27 mg.

[0147] F. Oxidant The photoredox system as disclosed herein can further comprise an oxidant. Exemplary oxidants include, but are not limited to, tert-butyl hydroperoxide (TBHP), potassium persulfate, (diacetoxyiodo)benzene (PIDA), ammonium persulfate, tetrabutyl ammonium persulfate, OXONE and combinations thereof.

[0148] The amount of oxidant present in the photoredox system can vary. In some embodiments, the oxidant is present in an amount that ranges from about 1 equiv. to about 10 equiv., from about 1 equiv. to about 8 equiv., from about 1 equiv. to about 6 equiv., from about 1 equiv. to about 5 equiv., from about 1.5 equiv. to about 5 equiv., from about 1.5 equiv. to about 3 equiv., from about 1.5 equiv. to about 2.5 equiv., or from about 1.75 equiv. to about 2.25 equiv. In some embodiments, the oxidant is present in an amount that ranges from about 2 equiv. to about 10 equiv. In some embodiments, the oxidant is present in the photoredox system in an amount of less than about 15 equiv., less than about 12 equiv., less than about 10 equiv., less than about 8 equiv., less than about 6 equiv., less than about 5 equiv., less than about 4.0 equiv., less than about 3 equiv., less than about 2.5 equiv., less than about 2.25 equiv., less than about 2.0 equiv., less than about 1.5 equiv., less than about 1.0 equiv., less than about 0.5 equiv., less than about 0.25 equiv., less than about 0.1 equiv., or less than about 0.01 equiv. In addition, or in the alternative, the oxidant is present in the photoredox system in an amount of at least about 0.0001 equiv., at least about 0.001 equiv., at least about 0.01 equiv., at least about 0.1 equiv., at least about 1 equiv., at least about 1.5 equiv., at least about 1.75 equiv., or at least about 2 equiv.

[0149] G. Solvent

[0150] The photoredox system as disclosed herein requires a solvent. In some embodiments, the solvent is selected from the group consisting of a polar protic solvent, a poler aprotic solvent, and a combination thereof.

[0151] In some embodiments, the solvent is a polar protic solvent. Exemplary polar protic solvents include, but are not limited to, water, ammonia, acetic acid, dimethylacetamide (DMA), n- propanol (n-PrOH), t-butanol, methanol (MeOH), ethanol (EtOH), and isopropyl alcohol (iPr- OH).

[0152] In some embodiments, the solvent is a polar aprotic solvent. Exemplary aprotic solvents include, but are not limited to, acetonitrile (ACN), chloroform, dichloromethane (DCM), hexafluoro-2-propoanol (HFIP), dichloroethane (DCE), trifluoroethanol (TFE), tetrahydrofiiran (THE), ethyl acetate (EA), dimethyl formamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetone, diethyl ether, trifluorotoluene (PhCF3) and hexamethylphosphoric triamide (HMPT). In some embodiments, the polar aprotic solvent is dichloroethanol and / or trifluoroethanol. In some embodiments, the polar aprotic solvent is acetonitrile.

[0153] In some embodiments, the solvent is selected from the group consisting of water, acetonitrile, trifluoroethanol, t-butanol, ethanol, ethyl acetate, dimethyl formamide, dichloroethanol and a combination thereof.

[0154] In some embodiments, the solvent is selected from the group consisting of ethyl acetate, ethanol, hexafluoro-2-propanol, dichloromethane, trifluorotoluene, acetonitrile, dichloroethane, trifluoroethanol, water and a combination thereof.

[0155] The amount of solvent present in the photoredox system can vary. In some embodiments, the solvent is present in the photoredox system at a concentration of about 0.01M to about 1.0M, about 0.01M to about 0.5M, about 0.01M to about 0.25M, about 0.05M to about 0.25M, about 0.067M to about 0.20M, about 0.067M to about 0.15M, about 0.067M to about 0.12M, or of about 0.067M to about 0.10M. In some embodiments, the solvent present in the photoredox system is at least about 0.01M at least about 0.02M, at least about 0.03M, at least about 0.04M, at least about 0.05M, at least about 0.06M, at least about 0.065M, at least about 0.07M, at least about 0.08M, at least about 0.09M, least about 0.1M, least about 0.12M, at least about 0.14M, at least about 0.16M, at least about 0.18M, or at least about 0.2M. In addition, or in the alternative, the solvent present in the photoredox system is less than about 0.3M, less than about 0.25M, less than about 0.23M, less than about 0.22M, less than about 0.20M, less than about 0.18M, less than about 0.16M, less than about 0.14M, less than about 0.12M, less than about 0.10M, less than about 0.08M, less than about 0.070M, less than about 0.06M, less than about 0.04M, less than about 0.02M.

[0156] In some embodiments, the solvent is a combination of a first solvent and a second solvent. In some embodiments, such first and second solvents can individually be selected from any of the above mentioned polar protic solvents and polar aprotic solvents. In some embodiments, the solvent is a combination of ethanol as a first solvent and water as a second solvent. In some embodiments, the solvent is a combination of water as a first solvent and acetonitrile as a second solvent. In some embodiments, the solvent is a combination of trifluoroethanol as a first solvent and ethyl acetate as a second solvent. In some embodiments, the solvent is a combination of water as a first solvent and acetonitrile as a second solvent. In some embodiments, the solvent is a combination of water as a first solvent and ethanol as a second solvent.

[0157] The amount of each first and second solvent in the above solvent combinations can vary. In some embodiments, the first solvent and second solvent are present as a weight ratio ranging from about 1:20 to about 20:1, from about 1:15 to about 15:1, from about 1:12 to about 12:1, from about 1:10 to about 10:1, from about 1:8 to about 8:1, from about 1:6 to about 6:1, from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1, or about 1:1, first solvent to second solvent. In some embodiments, the first solvent and second solvent are present as a weight ratio ranging from about 1:12, about 1:11, about 1:10, about 1:9, about 1 :8, about 1 :7, about 1 :8, about 1 :6, about 1 :5, about 1 :4, about 1 :3, or about 1 :2, first solvent to second solvent.

[0158] In some embodiments, the solvent can also be a combination of more than two solvents, e.g., a first solvent, a second solvent, and a third solvent or more. For example, in some embodiments, the solvent comprises trifluoroethanol as a first solvent, ethyl acetate as a second solvent and tert-butanol as a third solvent.

[0159] In alternate embodiments, the photoredox system contains radioactivity. In such embodiments, the solvent is present in an amount of from about 100 μl to about 1000 μl, from about 100 μl to about 800 μl, from about 150 μl to about 750 μl, from about 200 μl to about 700 μl, from about 250 μl to about 650 μl, from about 300 μl to about 600 μl, from about 350 μl to about 575 μl, from about 400 μl to about 550 μl, from about 450 μl to about 550 μl, or from about 475 μl to about 525 μl. In some embodiments, the solvent is present in an amount of at least about 125 μl, about 225 μl, about 325 μl, about 425 μl, about 450 μl, about 475 μl, or at least about 500 μl. In addition, or in the alternative, the solvent is present in an amount of less than about 725 μl, about 700, μl about 675 μl, about 650 μl, about 625 μl, less about 600 μl, about 575 μl, about 550 μl, about 525 μl, or less than about 500 μl. In some embodiments, the solvent is present in an amount of about 500 μl.

[0160] H. Blue-Violet Light

[0161] The photoredox system as disclosed herein requires a blue-violet light. Blue-violet light refers to blue light rays with the shortest wavelengths (and highest energy), wherein the wavelengths range from about 390 nm to about 465 nm. In some embodiments, the blue-violet light has a wavelength ranging from about 420 nm to about 465 nm, from about 430 nm to about 465 nm, from about 440 nm to about 465 nm, or from about 450 nm to about 465 nm. Not to be bound by theory, but it is believed that blue-violet light is required in the disclosed photoredox system to promote the formation a cation radical species, which can then subsequently react with the cyanide source as disclosed herein to generate the cyanated product, which can then be hydrolyzed to the corresponding carboxylic acid (see Scheme 1c).

[0162] Several sources of blue-violet light are available, such as sunlight, and various artificial sources such as, but not limited to, fluorescent light, LED light, CFL (compact fluorescent light), and / or lasers (e.g., neodymium-doped yttrium aluminum garnet (Nd-YAG) and / or krypton fluoride (KrF), Xenon monochloride (XeCl)). In some embodiments, the disclosed photoredox system comprises an LED light as a blue-violet light source. In some embodiments, the disclosed photoredox system comprises a laser as a blue-violet light source. m. Aliphatic Carboxylic Acid Substrate

[0163] The photoredox system disclosed herein can be used to label aliphatic carboxylic acid substrates with a different carbon isotope besides12C. In addition, the disclosed photoredox system can be used to introduce a cyano functional group into aliphatic carboxylic acid substrates, wherein the cyano group can also contain a nitrogen isotope other than14N.

[0164] In general, the aliphatic carboxylic acid substrate can be any molecule containing an alkyl moiety or an unsaturated moiety within the molecule to which a carboxylic acid group (-COOH) is attached to. In some embodiments, such a carboxylic acid group is a primary carboxylic acid. In some embodiments, such a carboxylic acid group can be a secondary carboxylic acid. In some embodiments, such a carboxylic acid group is a tertiary carboxylic acid. In some embodiments, aliphatic carboxylic acid substrate is chiral, e.g., the carbon atom to which the carboxylic acid group is attached to is designated as being (S) or (R).

[0165] In some embodiments, the aliphatic carboxylic acid substrate can be a biologically active molecule. Exemplary biologically active molecules include, but are not limited to, a natural product, a biomolecule, an amino acid, a peptide or a pharmaceutical agent.

[0166] In some embodiments, the biologically active molecules can be found in nature (e.g., a natural product) or can be present in the body of a mammal (e.g., a neurotransmitter). In some embodiments, the aliphatic carboxylic acid substrate is not derived from nature but is prepared synthetically, e.g., a pharmaceutical agent or a pharmacological agent. Exemplary pharmaceutical agents include, but are not limited to, fenbufen, felbinac, isoxepac, indomethacin, gabapentin, mycophenolic acid, ibuprofen, mupirocin, 3-keto-4-etiocholenic acid, nipecotic acid, flurbiprofen, enoxolone, pemetrexed, vildagliptin, ruxolitinib, and betulinic acid.

[0167] In some embodiments, the biologically active molecule is a biomolecule. Exemplary biomolecules include, but are not limited to, gamma-aminobutyric acid, ursodeoxycholic acid, gibberellic acid, gluconic acid, pyruvate, and D-glucuronic acid.

[0168] In some embodiments, the biologically active molecule is an amino acid. Exemplary amino acids include, but are not limited to, Glutamic acid, Glutamine, Valine, Alanine, Serine, Phenylalanine, Lysine and Phenylglycine.

[0169] In some embodiments, the biologically active molecule is a peptide. In such embodiments, the number of amino acid residues present in the peptide can vary. In some embodiments, the peptide comprises about 2 to about 1000, about 100 to about 1000, about 200 to about 1000, about 300 to about 1000, about 400 to about 1000, about 500 to about 1000, about 600 to about 1000, about 700 to about 1000, about 800 to about 1000, or more than 1000 amino acid residues. In such embodiments, the peptide can be a protein.

[0170] In some embodiments, the peptide comprises less than about 100 amino acid residues, less than about 90 amino acid residues, less than about 80 amino acid residues, less than about 70 amino acid residues, less than about 60 amino acid residues, less than about 50 amino acid residues, less than about 40 amino acid residues, less than about 30 amino acid residues, less than about 25 amino acid residues, less than about 20 amino acid residues, less than about 15 amino acid residues, less than about 14 amino acid residues, less than about 13 amino acid residues, less than about 12 amino acid residues, less than about 11 amino acid residues, less than about 10 amino acid residues, less than about 9 amino acid residues, less than about 8 amino acid residues, less than about 7 amino acid residues, less than about 6 amino acid residues, less than about 5 amino acid residues, less than about 4 amino acid residues, or less than about 3 amino acid residues. In some embodiments, the peptide comprises 2-100 amino acid residues, 2-75 amino acid residues, 2-50 amino acid residues, 2-25 amino acid residues, 2-15 amino acid residues, 2-10 amino acid residues, or 2-5 amino acid residues. In some embodiments, the peptide comprises 2 amino acid residues. In some embodiments, the peptide comprises 3 amino acid residues. Exemplary peptides are Gly- Gly, Pro-Val, and Gly-Gly-Phe.

[0171] Thus, in some embodiments, the aliphatic carboxylic acid substrate is a compound of Formula (I): and any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein

[0172] X is a carbon atom C or a bond;

[0173] R1is absent or selected from the group consisting of -H, substituted or unsubstituted -(C1-C12) alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and a bond connecting to an atom of a biologically active molecule or a portion thereof; and

[0174] R2, and R3are independently selected from the group consisting of being absent, -H, substituted or unsubstituted -(C1-C12) alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -NH(PG), -N[(C1-C12) alkyl][PG], -[(C1-C12)alkyl]NH[PG], -OH, - O(PG), and a bond connecting to an atom of the biologically active molecule, wherein PG, in each instance, is a protecting group.

[0175] In some embodiments, R2and R3form a covalent bond between each other thereby forming a cycloalkyl or heterocycloalkyl.

[0176] In some embodiments, R1is -H. In some embodiments, R2is -H. In some embodiments, R3is -H.

[0177] In some embodiments X is C. In some embodiments, X is a bond.

[0178] In some embodiments, R1is H and X is C. In some embodiments, R1and R2are -H, and X is C. In some embodiments, R1and R2are -H, X is C and R3is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, R1and R2are -H, X is C and R3is substituted or unsubstituted aryl (e.g., phenyl). In some embodiments, R1and R2are -H, X is C and R3is substituted or unsubstituted heteroaryl. In some embodiments, the substituted or unsubstituted aryl or heteroaryl is substituted with at least one substituent as described above, e.g., halogen and / or phenyl.

[0179] In some embodiments, R3is substituted or unsubstituted aryl or heteroaryl. In some embodiments, R3is an aryl or heteroaryl substituted with one or more substituents as described above, e.g., halogen and / or phenyl. In such embodiments, X is -C-.

[0180] In some embodiments, R1and R2are -H, X is C and R3is a (C1-C12) alkyl group. In some embodiments, R1and R2are -H, X is C and R3is a substituted or unsubstituted (C1-C6) alkyl group. In such embodiments, the substituted or unsubstituted (C1-C6) alkyl group is selected from the group consisting of -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, and CH2CH(CH3)2. In some embodiments, the (C1-C12) alkyl group is substituted with one or more substituents as described above, e.g., -NH(PG), -OH(PG), -NH2, -OH, -COOH, C=O, etc.

[0181] In some embodiments, R1and R2are -H, X is C and R3is a bond. In some embodiments,

[0182] R1and R2are -H, X is a bond and R3is a bond.

[0183] In some embodiments, R1is -H and R2is a substituted or unsubstituted (C1-C12) alkyl group. In some embodiments, R1is -H and R2is a substituted or unsubstituted (C1-C6) alkyl group (e.g., -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, and CH2CH(CH3)2). In some embodiments, R1is -H and R2is a substituted or unsubstituted (C1-C12) alkyl group, and R3is substituted or unsubstituted aryl or heteroaryl. In some embodiments, R1is -H and R2is a substituted or unsubstituted (C1-C6) alkyl group, and R3is substituted or unsubstituted aryl or heteroaryl. In some embodiments, R1is -H and R2is a substituted or unsubstituted (C1-C12) alkyl group, and R3is substituted or unsubstituted aryl. In some embodiments, R1is -H and R2is a substituted or unsubstituted (C1-C6) alkyl group, and R3is substituted or unsubstituted aryl (e.g., phenyl and / or naphthyl). In some embodiments, R1is -H and R2is a substituted or unsubstituted (C1-C12) alkyl group, and R3is substituted or unsubstituted heteroaryl (e.g., pyridinyl). In some embodiments, R1is -H and R2is a substituted or unsubstituted (C1-C6) alkyl group, and R3is substituted or unsubstituted heteroaryl.

[0184] In some embodiments, R2is a substituted or unsubstituted (C1-C12) alkyl group. In some embodiments, R2is a substituted or unsubstituted (C1-C6) alkyl group (e.g., -CH3, -CH2CH3, - CH(CH3)2, -CH2CH2CH3, and CH2CH(CH3)2). In some embodiments, R2is a substituted or unsubstituted (C1-C12) alkyl group, and R3is substituted or unsubstituted aryl or heteroaryl. In some embodiments, Ri is a substituted or unsubstituted (C1-C6) alkyl group, and R3is substituted or unsubstituted aryl or heteroaryl. In some embodiments, R2is a substituted or unsubstituted (C1- C12) alkyl group, and R3is substituted or unsubstituted aryl. In some embodiments, R2is a substituted or unsubstituted (C1-C6) alkyl group, and R3is substituted or unsubstituted aryl (e.g., phenyl and / or naphthyl). In some embodiments, R2is a substituted or unsubstituted (C1-C12) alkyl group, and R3is substituted or unsubstituted heteroaryl (e.g., pyridinyl). In some embodiments, R2is a substituted or unsubstituted (C1-C6) alkyl group, and R3is substituted or unsubstituted heteroaryl. In some embodiments, R2is -CH3.

[0185] In some embodiments, R1and R2are independently selected from a substituted or unsubstituted (C1-C12) alkyl group. In some embodiments, R1and R2are independently selected from a substituted or unsubstituted (C1-C6) alkyl group. In some embodiments, R1and R2are independently selected from a substituted or unsubstituted (C1-C12) alkyl group and R3is substituted or unsubstituted aryl or heteroaryl. In some embodiments, R1and R2are independently selected from a substituted or unsubstituted (C1-C6) alkyl group and R3is substituted or unsubstituted aryl or heteroaryl. In some embodiments, R1and R2are independently selected from a substituted or unsubstituted (C1-C12) alkyl group and R3is substituted or unsubstituted aryl (e.g., phenyl or naphthyl). In some embodiments, R1and R2are independently selected from a substituted or unsubstituted (C1-C6) alkyl group and R3is substituted or unsubstituted aryl. In some embodiments, R1and R2are independently selected from a substituted or unsubstituted (C1-C12) alkyl group and R3is substituted or unsubstituted heteroaryl. In some embodiments, R1and R2are independently selected from a substituted or unsubstituted (C1-C6) alkyl group and R3is substituted or unsubstituted heteroaryl. In some embodiments, R1and R2are independently selected from a substituted or unsubstituted (C1-C12) alkyl group, R3is substituted or unsubstituted aryl (e.g., phenyl or naphthyl) and X is -C-. In some embodiments, R1and R2are independently selected from a substituted or unsubstituted (C1-C6) alkyl group, R3is substituted or unsubstituted aryl and X is -C-. In some embodiments, R1and R2are independently selected from a substituted or unsubstituted (C1-C12) alkyl group, R3is substituted or unsubstituted heteroaryl and X is -C-. In some embodiments, R1and R2are independently selected from a substituted or unsubstituted (C1- C6) alkyl group, R3is substituted or unsubstituted heteroaryl and X is -C-. In some embodiments,

[0186] R1and R2are both -CH3. In some embodiments, R1, R2and R3are independently selected from a substituted or unsubstituted (C1-C12) alkyl group, wherein in each instance the (C1-C12) alkyl group can optionally be substituted with one or more substituents as described above. In some embodiments,

[0187] R1and R2are both -CH3.

[0188] In some embodiments, R2is absent. In some embodiments, R1is absent. In some embodiments, R2is absent and R1is -H or a substituted or unsubstituted (C1-C12) alkyl group. In some embodiments, R2is absent and R1is -H. In some embodiments, R2is absent and R1is a substituted or unsubstituted (C1-C12) alkyl group, wherein the substituted or unsubstituted (C1-C12) alkyl group can optionally be substituted with one or more substituents as described above. In some embodiments, R2is absent and R1is a substituted or unsubstituted (C1-C6) alkyl group. In some embodiments, R2is absent and R1is -CH3. In some embodiments, R2is absent, R1is a substituted or unsubstituted (C1-C12) alkyl group (e.g., -CH3) and X is -C-. In some embodiments,

[0189] R2is absent, R1is a substituted or unsubstituted (C1-C12) alkyl group and X is a bond. In some embodiments, R2is absent, R1is a substituted or unsubstituted (C1-C12) alkyl group, X is a bond and R3is a bond. In some embodiments, R2is absent, R1is a substituted or unsubstituted (C1-C6) alkyl group, X is a -C- and R3is a bond. In such embodiments, the (C1-C12) alkyl group or (C1-C6) alkyl group can optionally be substituted with one or more substituents as described above.

[0190] In some embodiments, R2is absent and R1is -H. In some embodiments, R2is absent, R1is a -H and X is -C-. In some embodiments, R2is absent, R1is -H and X is a bond. In some embodiments, R2is absent, R1is -H, X is a bond and R3is a bond. In some embodiments, R2is absent, R1is -H, X is a -C- and R3is a bond.

[0191] In some embodiments, R2is substituted or unsubstituted -(C1-C12) alkyl or -[( C1-C12) alkyl] NH and R3is substituted or unsubstituted -( C1-C12) alkyl, wherein R2and R3are connected with a bond to form a saturated carbo- or heterocycle. In some embodiments, R2is substituted or unsubstituted -(C1-C6) alkyl or substituted or unsubstituted -[( C1-C6) alkyl] NH and R3is substituted or unsubstituted -( C1-C6) alkyl, wherein R2and R3are connected with a bond to form a saturated carbo- or heterocycle.

[0192] In some embodiments, R1is -H and R2is -NH(PG). In some embodiments, R1is -H, R2is -NH(PG) and R3is (C1-C12) alkyl optionally substituted with one or more substituents as described above. In some embodiments, R1is -H, R2is -NH(PG) and R3is substituted or unsubstituted aryl or heteroaryl. In such embodiments, PG is FMOC or BOC.

[0193] The aliphatic carboxylic acid substrates described herein may in some cases exist in stereoisomeric forms and / or pharmaceutically acceptable salt as will be described in more detail below.

[0194] IV. Methods of using the Photoredox System

[0195] The photoredox system described herein can be used in the cyanation of aliphatic carboxylic acid substrates. As already described above, the photoredox system contains the following components: a photocatalyst, a base additive, an oxidant, a cyanide source, a solvent, and blue-violet light. In some embodiments, the photoredox system can further comprise a co- catalyst and / or ligand. Disclosed herein is a photoredox-catalyzed cyanation method using the disclosed photoredox system to convert an aliphatic carboxylic acid substrate into a cyano aliphatic product, which can optionally be further modified to afford an amide-, amine-, or carboxylic acid- containing aliphatic product.

[0196] Thus, in some embodiments the photoredox-catalyzed cyanation method comprises: a) obtaining a reaction mixture comprising a photocatalyst and a solvent; b) contacting the reaction mixture with an aliphatic carboxylic acid substrate, a base additive, an oxidant and a cyanide source to afford a photocyanation reaction mixture; and c) exposing the photocyanation reaction mixture to blue-violet light to form a cyano aliphatic product.

[0197] In some embodiments, the photoredox-catalyzed cyanation method further comprises adding a co-catalyst and / or a ligand as described herein to the reaction mixture in step (a).

[0198] As already described above, in some instances the cyanide source is not radioactive and the disclosed photoredox-catalyzed cyanation method can provide non-radioactive cyano aliphatic products. However, in some instances, the cyanide source can be radioactive (meaning it contains a radioisotope) and then the disclosed photoredox-catalyzed cyanation method is able to provide radioactive cyano aliphatic products. Since die photoredox system and its components are already described in detail above, the method steps will be described in more detail below.

[0199] In some embodiments, the reaction mixture in step a) can be obtained by adding the photocatalyst and solvent (also referred to as “components”) into a container. For method comprising a co-catalyst and / or ligand these are added to the container as well. The order of addition of these reagents can vary and is not particularly relevant to obtains the photocyanation reaction mixture. In some embodiments, all of the agents in the container further underwent mixing, which can be carried out via stirring, rotating, shaking, or sonicating to obtain the reaction mixture in step a) or the photocyanation reaction mixture in step b).

[0200] In some embodiments, the container used in this cyanation method can be any suitable container that can hold all of the reagents, such as a flask, a vial, an Eppendorf vial, etc. In some embodiments, the container belongs to a reaction set-up used for execution of the cyanation method. For example, the reaction set-up can be located in a hot cell when the cyanide source is radioactive or the container belongs to a continuous flow chemistry set-up.

[0201] In some embodiments, the contacting step b) is carried out by addition of the aliphatic carboxylic acid substrate, the base additive, oxidant and cyanide source to the reaction mixture inside the container. Just like for step (a), the order of addition of these reagents to the reaction mixture obtained in step a) can vary and is not critical for the reaction to take place. In such embodiments, the cyanide source is in a liquid form (i.e., either neat or dissolved in a solvent). In some embodiments, the cyanide source is added rapidly to the container holding the reaction mixture (i.e., all at once) or added slowly over a certain time period. In some embodiments, this time period (also referred to as “addition time period”) ranges from one or more seconds to several minutes. In some embodiments, the addition time period ranges from about 1 minute to about 120 minutes, from about 2 minutes to about 100 minutes, from about 5 minutes to about 90 minutes, from about 8 minutes to about 80 minutes, from about 10 minutes to about 70 minutes, from about 15 minutes to about 60 minutes, from about 20 minutes to about 50 minutes, from about 25 minutes to about 40 minutes, or from about 30 minutes to about 40 minutes. In some embodiments, the addition period is less than about 60 seconds, less than about 55 seconds, less than about 50 seconds, less than about 45 seconds, less than about 40 seconds, less than about 35 seconds, less than about 30 seconds, less than about 25 seconds, less than about 20 seconds, less than about 15 seconds, less than about 10 seconds, less than about 5 seconds, or less than about 1 second.

[0202] In some embodiments, the reaction mixture continues mixing during the contacting step to ensure that the photocyanation reaction mixture is homogenous. In some embodiments, the exposing step c) comprises irradiating or shining the photocyanation reaction mixture with blue-violet light for a certain time period (referred to as “irradiation time”). During this irradiation time period blue-violet light is shining / irradiating onto the photocyanation reaction mixture located inside the container. In some embodiments, this irradiation time period ranges from several minutes to several hours. In some embodiment, the photocyanation reaction mixture is exposed to blue-violet light for an irradiation time period of at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes, at least about 7 minutes at least about 8 minutes, at least about 9 minutes, or at least about 10 minutes. In addition, or in the alternative, the photocyanation reaction mixture is exposed to blue-violet light for an irradiation time period of less than about 20 minutes, less than about 18 minutes, less than about 16 minutes, less than about 14 minutes, less than about 12 minutes, less than about 10 minutes, less than about 9 minutes, less than about 8 minutes, less than about 7 minutes, less than about 6 minutes, less than about 5 minutes, less than about 4 minutes, less than about 3 minutes, less than about 2 minute, or less than about 1 minute..

[0203] In some embodiments, the temperature at which each step of the disclosed cyanation method is carried out can vary. In some embodiments, the temperature of at least one step of the disclosed cyanation method is carried out at room temperature (i.e., about 20 °C). In some embodiments, the temperature of at least one step of the disclosed cyanation method is carried out at a temperature above room temperature (i.e., about 20 °C). In some embodiments, the temperature of at least one step of the disclosed cyanation method is carried out at a temperature of from about 20 °C to about 120 °C, from about 20 °C to about 100 °C, from about 20 °C to about 80 °C, from about 20 °C to about 60 °C, from about 20 °C to about 50 °C, from about 30 °C to about 50 °C, or from about 35 °C to about 45 °C. In some embodiments, the temperature of at least one step of the disclosed cyanation method is carried out at a temperature of at least about 20 °C, about 22 °C, about 25 °C, about 27 °C, about 30 °C, about 32 °C, about 34 °C, about 35 °C, about 36 °C, about 37 °C, about 38 °C, about 40 °C, about 45 °C, about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C, about 75 °C, about 80 °C, about 85 °C or at least about 90 °C. In addition to, or in the alternative, the temperature of at least one step of the disclosed cyanation method is carried out at a temperature of less than about 100 °C, about 95 °C, about 90 °C, about 85 °C, about 80 °C, about 75 °C, about 70 °C, about 65 °C, about 60 °C, about 55 °C, about 50 °C, about 45 °C, about 40 °C, less than about 38 °C, less than about 35 °C, less than about 30 °C. in some embodiments, the temperature of at least one step of the disclosed cyanation method is carried out at a temperature where the reaction mixture and / or the photocyanation mixture refluxes. In some embodiments, the at least one step of the disclosed cyanation is step a) and / or b) and / or c).

[0204] In some embodiments, the cyano aliphatic product obtained from the method disclosed herein is chiral, e.g., the carbon atom to which the cyano group is attached is designated as being either (R) or (S).

[0205] In some embodiments, the cyano aliphatic product obtained from the method disclosed herein can be further modified. Thus, the method disclosed herein can further comprise at least one additional step, which modifies one or more functional groups present in the cyano aliphatic product. Exemplary functional groups that can be modified include, but are not limited to, cyano (-CN) groups, hydroxyl (-OH) groups, amines (-NH2), carboxylic acids (-COOH), esters (- COCH3) and the like.

[0206] In some embodiments, the one or more functional groups being modified by at least one additional step further comprised in the disclosed method is a cyano (-CN) functional group. A skilled artisan would generally be aware of the possible modifications that can be made to such a functional group. For example, in some embodiments, the cyano (-CN) functional group present in the cyano aliphatic product can be modified to afford a carboxylic acid functional group, an amide group functionality, or an amine group functionality. A skilled artisan would generally be aware what reagents would be required to transform a cyano (-CN) functional group into any one of these.

[0207] Thus, the method disclosed herein further comprises chemically modifying the cyanate group (-CN) present in the cyano aliphatic product, wherein the cyano aliphatic product is a compound of Formula (II): Formula (II) and any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein

[0208] RI is selected from the group consisting of -H, substituted or unsubstituted -(C1-C12) alkyl, aryl, substituted or unsubstituted heteroaryl and a bond connecting to an atom of a biologically active molecule or portion thereof;

[0209] R2, and R3are independently selected from the group consisting of -H, substituted or unsubstituted -(C1-C12) alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -NH(PG), -N[(C1-C12) alkyl][PG], -OH,-O(PG), -[(C1-C12) alkyl]NH[PG] and a bond connecting to an atom of the biologically active molecule or a portion thereof, wherein PG, in each instance, is a protecting group, and the biologically active molecule is selected from the group consisting of a natural product, a biomolecule, an amino acid, a peptide and a pharmaceutical agent; and wherein C* is selected from the group consisting of [11C], [12C], [13C] and [14C], and N* is [13N], [14N] or [15N], to render an aliphatic product having a structure of Formula (III):

[0210] Formula (III) and any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein

[0211] R1is selected from the group consisting of -H, substituted or unsubstituted -(C1-C12) alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and a bond connecting to an atom of a biologically active molecule or a portion thereof;

[0212] R2, and R3are independently selected from the group consisting of -H, substituted or unsubstituted -(C1-C12) alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -NH2, -NH[(C1-C6) alkyl], -[(C1-C6) alkyl]NH(PG), -OH, and a bond connecting to an atom of the biologically active molecule or a portion thereof; and wherein R4is COOH, CONH2, CH2NH2, or an imaging moiety selected from the group consisting of [11C]COOH, [13C]COOH, [14C]COOH, [11C]CONH2, [13C]CONH2, [14C]CONH2, [11C]CH2NH2, [13C]CH2NH2[14C]CH2NH2, [13N]CH2NH2and [l5N]CH2NH2.

[0213] In some embodiments, the above-described method further comprises chemically modifying the cyano group present in the compound of Formula (II) by exposing the compound to an acid, e.g., sulfuric acid, followed by a base, e.g., sodium hydroxide, to obtain an amide- containing aliphatic product. In some embodiments, such an exposure occurs at elevated temperatures (e.g.,_>100 °C). In additional embodiments, the obtained amide-containing aliphatic product of Formula (III) can be further modified with a reducing agent to afford an alkyl amine- containing aliphatic product of Formula (III). Suitable reducing agents include, but are not limited to, aluminum-containing reducing agents (e.g., LiA1H4) or boron-containing reducing agents (e.g., NaBH4).

[0214] In another example, the method disclosed herein further comprises contacting the compound of Formula (II) with water and / or a base (e.g., an alkali hydroxide such as KOH) to hydrolyze the cyano (-CN) functional group into a carboxylic acid group (-COOH) to render a compound of Formula (III).

[0215] These are just examples of reagents and reaction conditions to modify the cyano (-CN) functional group present in the cyanated aliphatic product and the disclosed methods are meant to be exemplary and not limiting thereto.

[0216] In an alternate embodiment, the method disclosed herein is to resolve racemic aliphatic carboxylic acid substrates to obtain optically pure aliphatic carboxylic acid product of Formula (III). In such an embodiment, employing the methods disclosed herein using racemic aliphatic carboxylic acid substrates chiral cyano aliphatic products of compounds of Formula (II) can be obtained, which can be further hydrolyzed to obtain optically pure aliphatic carboxylic acid product of Formula (III).

[0217] In an alternate embodiment, the method further comprises at least one additional step, which modifies one or more functional groups present in the cyano aliphatic product of Formula (II) or the aliphatic carboxylic acid product of Formula (III) For example, in some embodiments, the method disclosed herein further comprises contacting the cyano aliphatic product of Formula (II) or the aliphatic carboxylic acid product of Formula (III) with suitable reagents, which are able to remove protecting groups (PG) from amine (e.g., BOC, FMOC) and / or hydroxy groups. A skilled artisan would generally be aware as to what such suitable reagents are, and no further elaboration is required. See, Peter G. M. Wuts, Theodora W. Greene “Greene’s Protective Groups in Organic Synthesis” 10 April, 2006, Copyright © 2007 John Wiley & Sons, Inc., which is hereby incorporated by reference in its entirety.

[0218] In some embodiments, the photoredox-catalyzed cyanation method further comprises isolation and / or purification of the cyano aliphatic product of the disclosed method and / or any aliphatic products resulting from further modifications of the cyano aliphatic product (i.e., compounds of Formula (III)). In some embodiments, one or more of such aliphatic product are isolated using chromatography techniques (e.g., HPLC, gravity), filtration, or distillation techniques. In some embodiments, one or more of these aliphatic products are isolated by simply removing any solvent and / or other volatile components present.

[0219] The yield by which the aliphatic products of Formula (II) and / or (III) can be obtained can vary. In some embodiments, the aliphatic product of Formula (II) and / or (III) is not radioactive and can be obtained with a yield of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98%. In addition, or in the alternative, the non-radioactive aliphatic product of Formula (II) and / or (III) can be obtained with a yield of less than about 99%, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 50%, less than about 45, or less than about 40%. In some embodiments, the non- radioactive aliphatic product of Formula (II) and / or (III) is not radioactive and can be obtained with a yield of about 50% to about 99%, from about 60% to about 99%, from about 70% to about 99%, from about 75% to about 99%, from about 80% to about 99%, from about 85% to about 99%, or from about 90% to about 99%. In some embodiments, the yield can be an isolated yield (yield taken post purification and / or isolation of desired aliphatic product) or a crude yield (yield taken of aliphatic product without any purification and / or isolation thereof). In some embodiments, the aliphatic products of Formula (II) and / or (III) is radioactive and can be obtained with a radiochemical yield (RCY) of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%. In addition, or in the alternative, the aliphatic products of Formula (II) and / or (III) can be obtained with a radiochemical yield (RCY) of less than about 99%, less than about 95%, less than about 90%, less than about 80%, less than about 75%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, or less than about 20%. In some embodiments, the aliphatic products of Formula (II) and / or (III) can be obtained with a radiochemical yield (RCY) of about 10% to about 80% from about 15% to about 70%, from about 18% to about 60%, from about 20% to about 50%, from about 20% to about 40%, or from about 25% to about 35%. In some embodiments, the RCY is decay corrected.

[0220] In some embodiments, the aliphatic products of Formula (II) and / or (III) are radioactive and can be obtained with a radiochemical conversion (RCC) of at least about 25%, at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 75%, at least about 85% or at least about 95%. In addition, or in the alternative, the aliphatic products of Formula (II) and / or (III) can be obtained with a radiochemical conversion (RCC) of less than about 99%, less than about 95%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, or less than about 40%. In some embodiments, the aliphatic products of Formula (II) and / or (III) can be obtained with a radiochemical conversion (RCC) of from about 30% to about 100%, from about 40% to about 100%, from about 45% to about 98%, from about 50% to about 95%, from about 55% to about 95%, from about 60% to about 95%, from about 65% to about 93%, from about 70% to about 93%, from about 75%, to about 93%, from about 80% to about 93%, or from about 85% to about 93%. In some embodiments, the RCC is decay corrected.

[0221] An exemplary photoredox system comprises photocatalyst Mes-Acr-BF4 present in an amount of from about 1 mol% to 8 mol%, base additive DIPEA present in an amount of from about 20 mol% to about 30 mol%, oxidant tert-butyl hydroperoxide (TBHP) present in an amount of from about 1 equiv. to about 10 equiv., Cu-containing co-catalyst copper (II) trifluouromethanesulfonate (Cu(OTf)2) present in an amount of from about 3 mol% to about 8 mol%, the ligand is 1,10-phenanthroline (phen) present in an amount of from about 5 mol% to about 10 mol%, and the cyanide source is KCN or TBACN present in an amount of from about 2 mol% to about 6 mol%. In some embodiments, the amount of cyanide source is in reference to the amount of carboxylic acid substrate.

[0222] Another exemplary photoredox system comprises Mes-Acr-BF4 present in an amount of from about 1 mol% to 8 mol%, the oxidant potassium persulfate present in an amount of from about 1 to about 5 equiv., the base additive being a phosphate buffer with a pH of about 8, and the cyanide source being KCN present in an amount of from about 1 mol% to about 5 mol%. This photoredox system is metal free and can be used for aliphatic carboxylic acid substrates such as amino acids and peptides. In some embodiments, the amount of cyanide source is in reference to the amount of carboxylic acid substrate.

[0223] Additional studies that further describe various aspects of the photoredox system and its use in methods for preparing cyano aliphatic products are discussed in more detail below.

[0224] Optimization of Carbon Labeling in Bioactive Carboxylic Adds using Decarboxylative Cyanation Methods

[0225] Disclosed herein is a general method to11 / 13C-label carboxylic acid via decarboxylative cyanation enabled by organic photoredox catalysis. This strategy was applied to a wide range of carboxylic acids, including amino acids and small peptides.

[0226] Among various carbon-containing functional groups, carboxylic acid and its (bio)isosteres play cardinal roles in isotopically labeled molecular probes17, 18, 19and pharmaceutical molecules (Fig. la), including most marketed nonsteroidal anti-inflammatory drugs (NSAIDs) as well as a variety of endogenous substances.20, 21Indeed, more than 40 drugs contain at least one carboxylic acid functional group in the top 200 small molecule drugs in 2022. And in the past few decades, the FDA has approved over 30 nitrile pharmaceuticals to manage various clinical conditions.24The installation of carbon (radio)isotopes on carboxyl groups provides a remarkable opportunity to study the in vivo drug activities of the acid or its (bio)isosteric structures. Hence, the development of a practical toolbox for their radiolabeling has always been both crucial and challenging in the field of radiochemistry over the decades.15, 35- 36Herein is offered a unique cyanation pathway for carboxylic acid11C / 13C labeling (Fig. lb).

[0227] Recently, noticeable discoveries in (radio)labeling carboxylic acid were reported. The combination of Ni complexes and metal reductants could successfully promote the carboxylate exchange with redox active esters as substrates.25,26The application of these methods is limited to primary and secondary carboxylic acids with few examples of11C labeling. Direct carboxylic acid exchange with free carboxylic acids and carbon labeled CO2under thermal27, 28or photoredox29130conditions provides a convenient and cost-effective pathway to achieve labeled carboxylic acid. These reactions proceed through the intermediacy of carbanion via a thermal or photo-initiated decarboxylative pathway. However, presumably due to the high reactivity of the carbanion intermediates, the direct carboxylic acid exchange with CO2is specific for β-stabilized carboxylic acids. A biomimetic aldehyde-catalyzed carboxylic acid exchange via the intermediacy of a-imine carboxylic acids was also reported only for free a-amino acids.31Another challenge in direct exchange for11C PET applications is the low molar activity (0.029 GBq μmol-1 30or 0.0084 GBq μmol-1 31), primarily due to inseparable [12C]carboxylic acid precursors. This activity level is below the required threshold (1-230 GBq μmol-1) for human PET studies32

[0228] To overcome these challenges, designing a general and convenient method to label carboxylic acids which would help to study the in vivo and in vitro behaviors of the small-molecule pharmaceuticals with the aim to expand the scope of acid radiotracers in PET imaging was considered. It was envisioned that a general method to convert carboxylic acids to carbon labeled derivatives, like nitriles, under mild conditions would provide a new avenue to obtain labeled acids. Nitriles, as carboxylic acid derivatives are frequently encountered as key elements in drug molecules (Fig. la), and the efficacy could be improved dramatically compared to the corresponding acids.24The introduction of isotope labeled nitrile via decarboxylative cyanation from carboxylic acid could benefit: i) the involvement of nitrile as the intermediate could help to achieve relative pure label acid after simple hydrolysis from the isolated11C -nitrile of high molar activity (Fig. lb), ii) Direct decarboxylative cyanation provides mild conditions to afford the nitriles from carboxylic acids, increasing the functional group compatibility compared to the current protocols to generate nitriles from acids, which is typified by amination followed by dehydration of primary amides.37This strategy provides a new route to generate amino nitriles, a valuable material in peptide chemistry38, directly from amino acids or peptides (Fig. 1c). iii) The copper-catalyzed decarboxylative cyanation transformation could also potentially access enantioenriched isotopically labeled carboxylic acids, which is still underdeveloped in carbon isotope labeling. Moreover, the introduction of a copper complex should trap the highly energetic free carbon radical generated via decarboxylative process, which could dramatically expand the scope to non-activated carboxylic acid substrates (Fig. 1c).

[0229] In order to develop a general methodology to label bioactive carboxylic acids, the investigation started with flurbiprofen, a common NSAID, as model substrate. Exposing flurbiprofen under the decarboxylative conditions developed by Nicewicz and co-workers39and copper catalyzed radical cyanation conditions40, 82% of the desired cyanation product was obtained after systematic exploration. Further investigation of the solvents revealed that using the mixture of trifluoroethanol (TFE) and ethyl acetate (EA) was optimal, providing the desired product in 95% yield.

[0230] This chemistry could also be applied to achieve highly enantioenriched cyanation products. After extensive screening, a serine-based bisoxazoline ligand (sBox) L1141, 42proved to be the best with high levels of enantioselectivity. Further optimization lead to 92% ee within 8 h (Table 1). Control experiments reveal that the photocatalyst, copper salt and light were all crucial for the title transformation.

[0231] Table 1: Optimization for Enantioselective Transformation of Flurbiprofen.

[0232]

[0233] The aim for testing the generality of this methodology was to explore the optimized conditions for bioactive carboxylic acids and the scope is outlined in Figs. 5a-d. Benzylic and non- benzylic primary carboxylic acids were well engaged in the decarboxylative cyanation transformation (1, 2). Good to excellent yields were obtained from selected NSAIDs (3-6), like Fenbufen, Felbinac, Isoxepac and Indomethacin. Gabapentin, gamma-aminobutyric acid (GABA) and oleic acid were also proved to be suitable substrates for decarboxylative cyanation transformation (7-9). Complex primary carboxylic acids, like mycophenoic acids, mupirocin and ursodeoxycarboxylic acid were also smoothly converted to the desired nitriles (10-13), indicating the excellent functional group tolerance. Secondary carboxylic acids were also accommodated, providing the desired product is modest to good yields (14-18). Carboxylic acids derived from cyclic 19 and acyclic 20 saccharides also engaged in the title transformation. These conditions could also be utilized to label terpenoid-based carboxylic acids 21, 22. Other than the flurbiprofen nitrile product 23, good to excellent enantioselectivities were obtained with other benzylic secondary carboxylic acids (24-28) (Fig. 5c, Table 2, 3).

[0234] Table S2: Optimization for Enantioselective Transformation of 2-(Naphthalen-l-yl)propanoic acid.

[0235] “10 mol% of Cu(OTf)2and 15 mol% of L11.b10 mol% of Cu(OTf)2and 15 mol% of L11 in TFE / DCE (1:1, 0.2 M) for 40 h.

[0236] Table 3: Optimization for Enantioselective Transformation of Zaltoprofen While good yields were obtained from non-benzylic tertiary carboxylic acids, only a small amount of cyanation product 30 was achieved with benzylic tertiary acid. We attribute the low yields to relative low oxidation potential of tertiary benzylic radical which could be readily form the corresponding carbocation under the presence of an oxidant (vide infra). Similar to secondary carboxylic acids, tertiary terpenoid based acids were also engaging in this transformation (31, 32). The robust of this process was also demonstrated by exploring the optimal condition to over the counter (OTC) tablet, Ibuprofen, the desired nitrile 33 was obtained in nearly identical yield with pure ibuprofen. It is worth noting that the nitrile product could also be obtained through C-H functionalization of alkyl arenes with pyridine jV-oxide as hydrogen atom abstracting reagent56. Indeed, 50% of the desired product 25 was obtained from 4-propylbiphenyl. (Fig. 5c, Table 5).

[0237] Table 4: Optimization for Transformation of Enoxolone

[0238] Table 5: Optimization for Decarboxylative Cyanation of Amino Acid under Aqueous Buffer, High Dilution Conditions. a-Amino acids and peptides, basic building blocks of life, are frequently encountered as key components in small molecular pharmaceuticals and peptide-based therapeutics.47-50The preparation of isotope labeled these structures is essential to study and guide the design of new drugs. While current methods towards synthesis of a-amino nitriles from natural a-amino acids are dominated by decarboxylative cyanation with electrophilic cyano sources57or dehydrogenative of the corresponding amide.37Incorporation of nucleophilic cyano source is still underdeveloped.58Investigation started with a bio-friendly condition (aqueous buffer and high dilution, 1 mM), the desired product 34 from Fmoc-Valine was obtained in 84% yield under the optimal condition. This method showed great compatibility to other Fmoc-protected natural amino acids (35-38) and small peptides (39, 40) (Fig.6a). When the concentration of the reaction media was increased, a decrease in yield was observed (Table 6).

[0239] Table 6: Optimization for Transformation of Fmoc-Val-OH

[0240] ‘HFIP addition product.bWithout TMSCN. 'Under dark.dWithout Mes-Acr-BF4.eWithout

[0241] Cu(OTf)2and phen

[0242] To achieve a synthetic applicable method to label amino acids, after extensive screening, a two-step strategy, photo-induced decarboxylation and Lewis acid-mediated cyanation, proved to be optimal providing the desired product 34 in 56% yield over two steps (67% and 87% respectively) (Fig. 6b, Table 7).

[0243] Table 7: Optimization for Transformation of KCN experiments

[0244] A range of natural amino acids were competent substrates in this transformation, providing the cyanation products in good to excellent yields over two steps (35-43). Di-, tri- and tetra- peptides also engaged in this methodology with only slightly diminished yields. It is worth noting that for Fmoc-Gly-Gly-OH, the direct decarboxylative cyanation condition in Figs. 5a-d could afford the desired product 44 in 33% yield. Benzylic tertiary carboxylic acid, which only provides 7% of cyanation product in direct decarboxylative condition, proved to be a suitable substrate for the stepwise strategy, yielding the desired product in 59% over 2 steps. For jV-benzyl proline, a slight change in conditions resulted in formation of the desired product in 41% with KCN as cyano source. By examining the conditions depicted in Figs. 5a-d and Fig. 6b for amino acids with a carboxylic acid side chain, such as glutamic acid, one successfully obtained two products: the side chain decarboxylative cyanation product 47 and the C-terminal selectivity product 48 (Fig. 6c). The practical nature of these processes was also exhibited by the gram-scale preparation of 23 (Fig. 5c) and 34 (Fig. 5b) through direct or stepwise processes with reduced photocatalyst loading (1 mol%), respectively. No decrease in performance was observed in both cases.

[0245] The most challenging and appealing development of this photoredox catalysis conversion is to generally11C-label the carboxylic acids efficiently. Though the12C-cyanation methods were well-explored, the establishment of successful11C-cyanation procedures was never straightforward due to the rapid decay of11C, less reactive11C-cyano source, and extremely low11C -cyanide concentration. These obstacles necessitated additional screening of the reaction conditions for the11C-nitrile construction. Based on a recent11C-labeling apparatus,59, 44the analogous method for radiocyanation under laser (450 run) irradiation of the model substrate, Fenbufen, was thoroughly explored. Condition A (Fig. 7a) afforded the11C-nitrile ([11C]3) with high radiochemical conversion (RCC, 50%). Then [11C]3 could also be hydrolyzed back to [11C]Fenbufen with an excellent RCC (Fig. 7c). Other primary acids, including a mycophenolic acid derivative (8) and a series of benzylic carboxylic acids were converted into11C-nitrile (1, 4, 5, and 6); oxidants became unnecessary for excellent RCCs. For secondary acids, the steroid structure (21, 31) survived in these mild conditions with good RCCs. Flurbiprofen 23 also achieved very good RCC and enantioselectivity under modified condition A with the chiral ligand, L11. Furthermore, the tertiary11C-nitrile products ([11C]29 and [11C]30) could be obtained using condition A through this photoredox-copper catalyzed pathway.11C-labeling on amino acids was also attempted with Fmoc-valine under condition A and the desired amino11C-nitrile ([11C]34) was collected and identified. Highly represented in the N -terminus of peptides and proteins, glycine is usually used as a labeling tag for peptides.38 11C could be installed onto the dipeptide Fmoc-Gly-Gly-OH with a high RCC (44), and the Fmoc-Glu-NH2was converted into the11C- nitrile ([11C]47) as a primary acid substrate. For other amino acids (35, 36, 38, 43) and peptides (39, 40) excellent decarboxylative11C-cyanation RCCs were achieved under a metal-free Condition B that was derived from the buffer condition in12C chemistry after continuous tests. The yield of tertiary nitrile [11C]30 was further enhanced with these conditions. Additionally, the Csp3-H radiocyanation product [11C]25 could be obtained in acceptable RCCs under pyridine N- oxide promoted copper co-catalyzed conditions (Fig. 7b).

[0246] The application of this conversion was not only be limited to11C chemistry but also includes other common isotopes of carbon (13C and14C). Considering the instability and higher cost of TMS12 / 13CN, the more inexpensive K12 / 13CN was chosen as the preferred cyanide source under the disclosed reaction conditions (Table 8).

[0247] Table 8: Optimization for Decarboxylative Radiocyanation of Fenbufen. Table 9: Optimization for Decarboxylative Radiocyanation of Fmoc-Val-OH.

[0248] Although lower yields were observed in the absence of any additives, equal performance with TMS12CN was observed when introducing a silyl Lewis acid additive (TMSOTf or TMSC1) (Fig. 7d). Due to the importance of carboxylic acid functional groups in certain drug molecules, it is essential to develop carbon labeled carboxylic acids. Exploring the nitrile products (1, [13C]23, 34) under acidic hydrolysis conditions, the corresponding carboxylic acids were formed in excellent yields (Fig. 7e). For nitriles, possessing acidic sensitive functional groups, the hydrolysis was conducted under basic conditions, providing the labeled carboxylic acid ([13C]13) in good yields (Fig. 7f). This novel Csp3-C cyanation method has expanded its application to synthesize 13C analogues for pharmaceutical molecules and amino acids, which could be very useful in HP 13C MRI.

[0249] As a side note, the incorporation of carbon- 13 labeling within organic drug molecules, imaged by MRI opens up another promising avenue for precision medicine33as emerging Hyperpolarized (HP)13C MRI is a molecular imaging technique that enables rapid, non-invasive, and pathway-specific exploration of dynamic metabolic and physiologic processes previously beyond the reach of imaging tecnologies.17, 34By synergistically harnessing the strengths of PET and HP13C MRI, physicians can attain a higher level of precision medicine, gaining comprehensive insights into individual patient requirements and optimizing medical care accordingly. This approach offers many opportunities for precise and tailored healthcare (Fig. lb).

[0250] In summary, the studies disclosed herein present a versatile method for isotopically labeling carboxylic acids, including natural amino acids and peptides, utilizing organic photoredox catalysis. Through this approach, we successfully obtained both11C and13C-carboxylic acids and derivatives from12C-carboxylic acids with moderate to excellent yields. The potential applications of these labeled compounds in PET and HP13C MRI are significant, offering a powerful combination of imaging modalities to advance healthcare. The synergy between PET and MRI holds promise for optimizing medical interventions and ultimately improving patient outcomes.

[0251] VI. Cyano and / or Carboxylic Acid Aliphatic Products

[0252] The cyano aliphatic products prepared from the photoredox-catalyzed cyanation method disclosed herein, comprises a cyano aliphatic product of Formula (II): and any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein

[0253] R1is selected from the group consisting of -H, substituted or unsubstituted -(C1-C12) alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and a bond connecting to an atom of a biologically active molecule or portion thereof;

[0254] R2, and R3are independently selected from the group consisting of -H, substituted or unsubstituted -(C1-C12) alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -NH(PG), -N[(C1-C12) alkyl][PG], -OH,-O(PG), -[(C1-C12) alkyl]NH[PG] and a bond connecting to an atom of the biologically active molecule or a portion thereof, wherein PG, in each instance, is a protecting group, and the biologically active molecule is selected from the group consisting of a natural product, a biomolecule, an amino acid, a peptide and a pharmaceutical agent; and wherein C* is selected from the group consisting of [11C], [12C], [13C] and [14C], and N* is [13N], [14N] or [15N].

[0255] As already mentioned above, the cyano aliphatic product can undergo additional chemical transformation to afford an aliphatic carboxylic acid product having a structure of Formula (III): and any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein

[0256] R1is selected from the group consisting of -H, substituted or unsubstituted -(C1-C12) alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and a bond connecting to an atom of a biologically active molecule;

[0257] R2, and R3are independently selected from the group consisting of -H, substituted or unsubstituted -(C1-C12) alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -NH2, -NH[(C1-C6) alkyl], -[(C1-C6) alkyl]NH(PG), -OH, and a bond connecting to an atom of the biologically active molecule or a portion thereof; and wherein R4is COOH, CONH2, CH2NH2, or an imaging moiety selected from the group consisting of [11C]COOH, [13C]COOH, [14C]COOH, [11C]CONH2, [13C]CONH2, [14C]CONH2, [11C]CH2NH2, [13C]CH2NH2[14C]CH2NH2, [13N]CH2NH2and [15N]CH2NH2.

[0258] In some embodiments, Ri and R3of Formula (II) and / or (III) form a covalent bond between each other thereby forming a cycloalkyl or heterocycloalkyl.

[0259] In some embodiments, R1of Formula (II) and / or (III) is -H. In some embodiments, R2of Formula (II) and / or (III) is -H. In some embodiments, R3of Formula (II) and / or (III) is -H.

[0260] In some embodiments X of Formula (II) and / or (III) is C. In some embodiments, X of Formula (II) and / or (III) is a bond. In some embodiments, in Formula (II) and / or (III) R1is H and X is C. In some embodiments, in Formula 01) and / or 011) R1and R2are -H, and X is C. In some embodiments, in Formula (II) and / or (III) R1and R2are -H, X is C and R3is substituted or unsubstituted aryl or heteroaryl. In some embodiments, in Formula (II) and / or (III) R1and R2are -H, X is C and R3is substituted or unsubstituted aryl (e.g., phenyl). In some embodiments, in Formula 01) and / or (III)

[0261] R1and R2are -H, X is C and R3is substituted or unsubstituted heteroaryl. In such embodiments, the aryl or heteroaryl can optionally be substituted with at least one substituent as described above, e.g., halogen and / or phenyl.

[0262] In some embodiments, R3of Formula (II) and / or (III) is unsubstituted aryl or heteroaryl. In some embodiments, in Formula 01) and / or (III) R3is an aryl or heteroaryl substituted with one or more substituents as described above, e.g., halogen and / or phenyl. In such embodiments, X is - C.

[0263] In some embodiments, in Formula (II) and / or (III) R1and R2are -H, X is C and R3is a substituted or unsubstituted (C1-C12) alkyl group. In some embodiments, in Formula (II) and / or (III) R1and R2are -H, X is C and R3is a substituted or unsubstituted (C1-C6) alkyl group. In some embodiments, in Formula (II) and / or (III) R1and R2are -H, X is C and R3is a substituted or unsubstituted (C1-C6) alkyl group. In such embodiments, in Formula (II) and / or (III) the substituted or unsubstituted (C1-C6) alkyl group is selected from the group consisting of -CH3, -CH2CH3, - CH(CH3)2, -CH2CH2CH3, and CH2CH(CH3)2. In some embodiments, in Formula (II) and / or (III) the (C1-C12) alkyl group is substituted with one or more substituents as described above, e.g., - NH(PG), -OH(PG), -NH2, -OH, -COOH, C=O, etc.

[0264] In some embodiments, in Formula (II) and / or (III) R1and R2are -H, X is C and R3is a bond. In some embodiments, in Formula 01) and / or 011) R1and R2are -H, X is a bond and R3is a bond.

[0265] In some embodiments, in Formula (II) and / or (III) R1is -H and R2is a substituted or unsubstituted (C1-C12) alkyl group. In some embodiments, in Formula (II) and / or (III) R1is -H and

[0266] R2is a substituted or unsubstituted (C1-C6) alkyl group (e.g., -CH3, -CH2CH3, -CH(CH3)2, - CH2CH2CH3, and CH2CH(CH3)2). In some embodiments, in Formula (II) and / or (III) R1is -H and

[0267] R2is a (C1-C12) alkyl group, and R3is aryl or heteroaryl. In some embodiments, in Formula (II) and / or (III) R1is -H and R2is a substituted or unsubstituted (C1-C6) alkyl group, and R3is substituted or unsubstituted aryl or heteroaryl. In some embodiments, in Formula (II) and / or (III)

[0268] R1is -H and R2is a substituted or unsubstituted (C1-C12) alkyl group, and R3is aryl. In some embodiments, in Formula (II) and / or (III) R1is -H and R2is a substituted or unsubstituted (C1-C6) alkyl group, and R3is substituted or unsubstituted aryl (e.g., phenyl and / or naphthyl). In some embodiments, in Formula (II) and / or (III) R1is -H and R2is a substituted or unsubstituted (C1-C12) alkyl group, and R3is substituted or unsubstituted heteroaryl (e.g., pyridinyl). In some embodiments, in Formula (II) and / or (III) R1is -H and R2is a (C1-C6) alkyl group, and R3is substituted or unsubstituted heteroaryl.

[0269] In some embodiments, in Formula (II) and / or (III) Ri is a substituted or unsubstituted (C1- C12) alkyl group. In some embodiments, in Formula (II) and / or (III) R2is a substituted or unsubstituted (C1-C6) alkyl group (e.g., -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, and CH2CH(CH3)2). In some embodiments, in Formula (II) and / or (III) R2is a substituted or unsubstituted (C1-C12) alkyl group, and R3is substituted or unsubstituted aryl or heteroaryl. In some embodiments, in Formula (II) and / or (III) R2is a substituted or unsubstituted (C1-C6) alkyl group, and R3is substituted or unsubstituted aryl or heteroaryl. In some embodiments, in Formula (II) and / or (III) R2is a substituted or unsubstituted (C1-C12) alkyl group, and R3is aryl. In some embodiments, in Formula (II) and / or (III) R2is a substituted or unsubstituted (C1-C6) alkyl group, and R3is substituted or unsubstituted aryl (e.g., phenyl and / or naphthyl). In some embodiments, in Formula (II) and / or (III) R2is a substituted or unsubstituted (C1-C12) alkyl group, and R3is substituted or unsubstituted heteroaryl (e.g., pyridinyl). In some embodiments, in Formula (II) and / or (III) R2is a substituted or unsubstituted (C1-C6) alkyl group, and R3is substituted or unsubstituted heteroaryl. In some embodiments, R2is -CH3.

[0270] In some embodiments, in Formula (II) and / or (III) R1and R2are independently selected from a substituted or unsubstituted (C1-C12) alkyl group. In some embodiments, in Formula (II) and / or (III) R1and R2are independently selected from a substituted or unsubstituted (C1-C6) alkyl group. In some embodiments, in Formula (II) and / or (III) R1and R2are independently selected from a substituted or unsubstituted (C1-C12) alkyl group and R3is substituted or unsubstituted aryl or heteroaryl. In some embodiments, in Formula (II) and / or (III) R1and R2are independently selected from a substituted or unsubstituted (C1-C6) alkyl group and R3is substituted or unsubstituted aryl or heteroaryl. In some embodiments, in Formula (II) and / or (III) R1and R2are independently selected from a substituted or unsubstituted (C1-C12) alkyl group and R3is substituted or unsubstituted aryl (e.g., phenyl or naphthyl). In some embodiments, in Formula (II) and / or (III) R1and R2are independently selected from a substituted or unsubstituted (C1-C6) alkyl group and R3is substituted or unsubstituted aryl. In some embodiments, in Formula (II) and / or (III) R1and R2are independently selected from a substituted or unsubstituted (C1-C12) alkyl group and R3is substituted or unsubstituted heteroaryl. In some embodiments, in Formula (II) and / or (III) R1and R2are independently selected from a substituted or unsubstituted (C1-C6) alkyl group and R3is substituted or unsubstituted heteroaryl. In some embodiments, in Formula (II) and / or (III) R1and R2are independently selected from a substituted or unsubstituted (C1-C12) alkyl group, R3is substituted or unsubstituted aryl (e.g., phenyl or naphthyl) and X is -C-. In some embodiments, in Formula (II) and / or (III) R1and R2are independently selected from a substituted or unsubstituted (C1-C6) alkyl group, R3is substituted or unsubstituted aryl and X is -C-. In some embodiments, in Formula (II) and / or (III) R1and R2are independently selected from a substituted or unsubstituted (C1-C12) alkyl group, R3is substituted or unsubstituted heteroaryl and X is -C-. In some embodiments, in Formula (II) and / or (III) R1and R2are independently selected from a substituted or unsubstituted (C1-C6) alkyl group, R3is substituted or unsubstituted heteroaryl and X is -C-. In some embodiments, in Formula (II) and / or (III) R1and R2are both -CH3.

[0271] In some embodiments, in Formula (II) and / or (III) R1, R2and R3are independently selected from a substituted or unsubstituted (C1-C12) alkyl group, wherein in each instance the (C1-C12) alkyl group can optionally be substituted with one or more substituents as described above. In some embodiments, R1and R2are both -CH3.

[0272] In some embodiments, R2is absent in Formula (II) and / or (III). In some embodiments, R1is absent in Formula (II) and / or (III). In some embodiments, in Formula (II) and / or (III) R2is absent and R1is -H or a substituted or unsubstituted (C1-C12) alkyl group. In some embodiments, R2is absent and R1is -H in Formula (II) and / or (III). In some embodiments, in Formula (II) and / or (III)

[0273] R2is absent and R1is a substituted or unsubstituted (C1-C12) alkyl group, wherein the substituted or unsubstituted (C1-C12) alkyl group can optionally be substituted with one or more substituents as described above. In some embodiments, in Formula (II) and / or (III) R2is absent and R1is a substituted or unsubstituted (C1-C6) alkyl group. In some embodiments, in Formula (II) and / or (III)

[0274] R2is absent and R1is -CH3. In some embodiments, in Formula (II) and / or (III) R2is absent, R1is a substituted or unsubstituted (C1-C12) alkyl group (e.g., -CH3) and X is -C-. In some embodiments, in Formula (II) and / or (III) R2is absent, R1is a substituted or unsubstituted (C1-C12) alkyl group and X is a bond. In some embodiments, in Formula (II) and / or (III) R2is absent, R1is a substituted or unsubstituted (C1-C12) alkyl group, X is a bond and R3is a bond. In some embodiments, R2is absent, R1is a substituted or unsubstituted (C1-C6) alkyl group, X is a -C- and R3is a bond. In such embodiments, the (C1-C12) alkyl group or (C1-C6) alkyl group can optionally be substituted with one or more substituents as described above.

[0275] In some embodiments, R2is absent and R1is -H in Formula (II) and / or (III). In some embodiments, in Formula (II) and / or (III) R2is absent, R1is a -H and X is -C-. In some embodiments, in Formula (II) and / or (III) R2is absent, R1is -H and X is a bond. In some embodiments, in Formula (II) and / or (III) R2is absent, R1is -H, X is a bond and R3is a bond. In some embodiments, in Formula (II) and / or (III) R2is absent, RI is -H, X is a -C- and R3is a bond.

[0276] In some embodiments, in Formula (II) and / or (III) R2is -(C1-C12) alkyl or -[( C1-C12) alkyl] NH and R3is -( C1-C12)alkyl, wherein R2and R3are connected with a bond to form a saturated cycloalkyl or heterocycloalkyl. In some embodiments, in Formula (II) and / or (III)R2is - substituted or unsubstituted (C1-C6) alkyl or -[( C1-C6) alkyl] NH and R3is substituted or unsubstituted -( C1- C6) alkyl, wherein R2and R3are connected with a bond to form a saturated cycloalkyl or heterocycloalkyl

[0277] In some embodiments, in Formula (II) and / or (III) R1is -H and R2is -NH(PG). In some embodiments, R1is -H, R2is -NH(PG) and R3is (C1-C12) alkyl optionally substituted with one or more substituents as described above. In some embodiments, in Formula (II) and / or (III) R1is -H,

[0278] R2is -NH(PG) and R3is aryl or heteroaryl. In such embodiments, PG is FMOC or BOC.

[0279] The aliphatic products described herein may, in some cases, exist as diastereomers, enantiomers, or other stereoisomeric forms. The aliphatic substrates presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography and / or recrystallization or by the forming diastereomers and separation thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley & Sons, Inc., 1981). Stereoisomers may also be obtained by stereoselective synthesis using synthetic methods known in the art. In some embodiments, the aliphatic products disclosed herein are enantiomers having an enantiomeric excess (% ee) of at least about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99.5%. In some embodiments, the cyano aliphatic products disclosed herein are diastereomers having a diastereomeric excess (% de) of at least about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99.5%. In some embodiments, the aliphatic substrates disclosed herein are present as enantiomeric or diastereomeric mixtures. In such embodiments, the aliphatic products are a cyano aliphatic product. In an alternate embodiment, the aliphatic products are aliphatic carboxylic acid products.

[0280] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The cyano arene and heteroarene products described herein may be in the form of pharmaceutically acceptable salts.

[0281] In some embodiments, the cyano aliphatic products described herein may be formed as, and / or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the aliphatic substrates with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l- carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l -carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium, or calcium), or an aluminum ion. In some cases, aliphatic substrates described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, cyano aliphatic products described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with cyano aliphatic products that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0282] Exemplary cyano aliphatic products and aliphatic carboxylic acid substrates are shown in Figs, la, 2a-b, 3a-b, 4a-c, 5a-e, 6a-c and 7a-c.

[0283] VII. Method of using Cyano Aliphatic and / or Aliphatic Carboxylic Acid Products.

[0284] The disclosed cyano aliphatic and / or aliphatic carboxylic acid products of Formula (II) and / or (III) containing a radioisotope can be used in imaging modalities such as PET, MRS, MRI and HP MRI technologies. Typically, imaging modalities are employed to screen for and / or diagnose various disease states and / or follow treatment of various disease states in subjects.

[0285] Thus, one aspect of the current disclosure is to employ radioactive cyano aliphatic and / or aliphatic carboxylic acid products as disclosed herein in methods of imaging a subject for diagnosing a disease or assessing efficacy of treatment of a disease by a) administering to a subject in need thereof a radioactive cyano aliphatic and / or aliphatic carboxylic acid product as disclosed herein in an effective amount; and b) acquiring at least one image of at least a portion of the subject.

[0286] In some embodiments, the radioactive cyano aliphatic and / or aliphatic carboxylic acid product is formulated into a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and / or carriers. As will be apparent to those skilled in the art, that one or more pharmaceutically acceptable excipients or carriers will vary depending on the mode of administration of the cyano aliphatic and / or aliphatic carboxylic acid products to a subject in need thereof. In some embodiments, the pharmaceutical composition is in the form of a saline-based solution, a suspension, an emulsion, liposome-based preparation, microsphere-based preparation, or any other pharmaceutical formulations in liquid form suitable for injection.

[0287] The effective amount of the radioactive cyano aliphatic and / or aliphatic carboxylic acid products can vary and depends on the mode of administration; the patient’s age, weight, and health; as well as the area to be imaged. A skilled artisan would know how to best determine effective amounts of the disclosed radioactive cyano aliphatic and / or aliphatic carboxylic acid product.

[0288] In some embodiments, the imaging methods disclosed herein are employed for diagnosing a disease or assessing efficacy of treatment of a disease of the integumentary system, the skeletal system, the muscular system, the nervous system, the endocrine system, the cardiovascular system, the lymphatic system, the respiratory system, the digestive system, the urinary system, and tire reproductive system.

[0289] In some embodiments, the imaging methods disclosed herein are employed to identify ulcers, infections, ischemia, irritable bowel syndrome, heart failure, cirrhosis, inflammation, and cancer, but should not be limited thereto.

[0290] EXAMPLES

[0291] A. Materials and Methods

[0292] General Reagent and Analytical Information:

[0293] Reagents were purchased from Sigma-Aldrich, Acros, Alfa Aesar, TCI, Matrix Scientific, Combi-Blocks, Oakwood Chemical, Chem Impex International, Chemscene and Fisher Scientific and were used as received unless otherwise noted. Proton and carbon magnetic resonance spectra (1H NMR and13C NMR) were recorded on a Broker AVANCE III 600 CryoProbe (1H NMR at 600 MHz or 400 MHz,13C NMR at 151 MHz or 101 MHz,19F NMR at 565 MHz) spectrometer with solvent resonance as the internal standard (1H NMR: CDCb at 7.26 ppm;13C NMR: CDCh at 77.16 ppm). All spectra are reported as parts per million.1H,13C,19F NMR and31P NMR data are reported as follows: chemical shift (ppm), multiplicity (app = apparent, s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, dd = doublet of doublets, td = triplet of doublets, ddd = double of doublet of doublets, ddd = double of doublet of doublet of doublets, m = multiplet), coupling constants (Hz), and integration. Electrochemical potentials were obtained with a standard set of conditions to main internal consistency. High Resolution Mass Spectra (HRMS) were obtained using a Thermo LTqFT mass spectrometer with electrospray ionization in positive or negative mode. Flash chromatography was performed using SiliaFlash P60silica gel (40-63 μm or 10-30 μm) purchased from Silicycle. Thin layer chromatography (TLC) was performed using SiliaPlate 250 μm silica gel plates provided by Silicycle. Visualization was accomplished with UV light, and potassium permanganate, and Dragendorff-Munier stains, followed by heating. Chiral HPLC analysis was carried out on an Agilent 1100 series instrument with autosampler and multiple wavelength detectors. Ratios of diastereomeric products were determined by1H-NMR analysis of the crude reaction mixture.

[0294] Buffer Preparation: 4M pH 8 Phosphate Buffer: Potassium phosphate monobasic (KH2PO4) (888 mg, 6.5 mmol) and potassium phosphate dibasic (K2HPO4) (16.28 g, 93.5 mmol) were dissolved in 100 mL of milli-Q purified H2O. The buffer was stored for months at a time in an amber bottle. Measured buffer pH: 8.66.

[0295] General Information for Radiochemistry:

[0296] All chemicals are ACS reagent grade purity or above and used without further purification. Tetrabutylammonium hydroxide solution (54—56%, w / w) was purchased from sigma-Aldrich. Anhydrous ethanol was the Koptec's Pure Ethanol 200-Proof purchased from Fisher Scientific. tert-Butyl Alcohol (TCI, Purity: >99.0%, GC grade) was purchased from Fisher Scientific. The 450 nm blue diode laser (MDL-D-450, 450nm, the power rating was set to 3.5W after fiber coupling) used for the labeling reaction was purchased from Changchun New Industries Optoelectronics Tech. Co., Ltd. The blue LED lamp (Kessil A160WE TUNA BLUE, 40W) was purchased from Kessil with the major irradiation peak centered around 456 nm. The LED BOX radiolabeling device (450 nm, PR486-450) was made and provided by the LED Radiofluidics Corp.11C activity was counted using a CRC-25 PET detector from Capintec. The reaction was timed with a lab timer. High-performance liquid chromatography (HPLC) was acquired on a SHIMADZU chromatography system (Model CBM-20A) and analyzed using LabSolutions software. The λ absorbance detector and the model 2200 scaler ratemeter radiation detector was added to the HPLC system. The Radio TLC was acquired on a LabLogic’s radio-TLC scanner, the innovative Scan-RAM, and analyzed using Laura software.

[0297] The PET / CT imaging was acquired by Sedecal Super Argus 4R PET / CT instrument in Small Animal Imaging Facility of the Biomedical Research Imaging Center (BRIC) at the University of North Carolina at Chapel Hill.

[0298] B. Substrate Synthesis and Characterization

[0299] Example 1: Synthesis of 2-(l-(((Tert-butoxycarbonyl)amino)methyl)cyclohexyl)acetic acid (7a) The title compound was prepared from 2-(l-(aminomethyl)cyclohexyl)acetic acid according to an existing literature protocol.60Spectral data align with literature values.60

[0300] Example 2: Synthesis of (E)-6-(4-acetoxy-6-methoxy-7-methyl-3-oxo-l,3- dlhydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid (8a)

[0301] The title compound was prepared from mycophenolic acid according to an existing literature protocol.61Spectral data align with literature values.61

[0302] Example 3: Synthesis of (2S3S,4S',5 R,6S)-3,4,5,6-tetraacetoxytetrahydro-2H -pyran-2- carboxylic acid (13a)

[0303] The title compound was prepared from D-Glucuronic acid according to an existing literature protocol.62Spectral data align with literature values.62

[0304] Example 4: Synthesis of (2R3S,4R, 5R )-2,3,4,5,6-pentaacetoxyhexanoic acid (14a)

[0305] The title compound was prepared from Gluconic acid according to an existing literature protocol.4Spectral data align with literature values.

[0306] Example 5: Synthesis of 2,2-Dimethyl-3-phenylpropanoic acid (18a) The title compound was prepared from methyl isobutyrate and benzyl bromide according to an existing literature protocol.39Spectral data align with literature values.39

[0307] Example 6: Synthesis of 2-([l,l’-Biphenyl]-4-yl)-2-methylpropanoic acid (19a)

[0308] The title compound was prepared from felbinac and iodomethane according to an existing literature protocol.64Spectral data align with literature values.64

[0309] Example 7: Synthesis of 2-((((9H -fluoren-9-yl)methoxy)carbonyl)amino)-6-(lr3- dioxoisoindolin-2-yl)hexanoic acid (30a)

[0310] The title compound was prepared from Fmoc-Lys-OH and phthalic anhydride according to an existing literature protocol.1H NMR (600 MHz, CDCI3) 8 7.86-7.82 (m, 2H), 7.78 (app d, J = 7.6 Hz, 2H), 7.71-7.68 (m, 2H), 7.63 (dd, J= 7.6, 4.5 Hz, 2H), 7.42 (app t, J= 7.5 Hz, 2H), 7.35-7.30 (m, 2H), 5.44 (d, J= 8.1 Hz, 1H), 4.46-4.35 (m, 3H), 4.23 (app t, J= 6.9 Hz, 1H), 3.73 (app t, J= 7.1 Hz, 2H), 2.06-1.96 (m, 1H), 1.88-1.70 (m, 3H), 1.54-1.41 (m, 2H).13C NMR (151 MHz,CDCl3) δ 176.1, 168.7, 156.32 144.0, 143.9, 141.5, 134.1, 132.2, 127.9, 127.2, 125.3, 123.4, 120.1, 67.3, 53.6, 47.3, 37.4, 31.6, 28.2, 22.5. HRMS (ESI-TOF): Calculated for ©HzeMNaOe [M + Na]+: 521.1683, found 521.1683.

[0311] Example 8: Synthesis of (((9H -fluoren-9-yl)methoxy)carbonyl)-Z,-prolyl-L-valine (31a)

[0312] To a 100 mL round bottom flask charged with a Teflon-coated stir was added Fmoc-Pro- OSu (3.9 g, 9 mmol, 1 equiv), L-Val-OH (1.11 g, 9.45 mmol, 1.05 equiv), NaHCOa (794 mg, 9.45 mmol, 1.05 equiv), THE (40 mL) and H2O (10 mL). The resulting suspension was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was triturated with IM HC1 (100 mL). Following filtration, the remaining solid was washed with IM HC1 (100 mL), H2O (100 mL) and dried under high vacuum to provide the desired product as a white solid in 79% yield (3.1 g). Spectral data align with literature values.66

[0313] Example 9: Synthesis of (((9HMluoren-9-yl)methoxy)carbonyl)glycylglycyl-L-phenylalanine (32a)

[0314] The title compound was prepared from Fmoc-Gly-Gly-OH, NHS, EDCI and Z-Phe-OH according to an existing literature protocol.67Spectral data align with literature values.67

[0315] Example 10: Synthesis of (115)-ll-Benzyl-14-((S)-sec-butyl)-l-(9H-fluoren-9-yl)-3,6,9,12- tetraoxo-2-oxa-4,7,10,13-tetraazapentadecan-15-oic acid (48a)

[0316] To a 50 mL round bottom flask charged with a Teflon-coated stir was added Fmoc-Gly- Gly-Phe-OSu67(2.34 g, 3.9 mmol, 1 equiv.), Z-Ile-OH (537 mg, 4.1 mmol, 1.05 equiv.), NaHCOa (344 mg, 4.1 mmol, 1.05 equiv.), THF (20 mL) and H2O (5 mL). The resulting suspension was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was triturated with IM HC1 (100 mL). Following filtration, the remaining solid was washed with IM HC1 (100 mL), H2O (100 mL) and dried under high vacuum to provide the desired product as a white solid in 75% yield (1.8 g). NMR (600 MHz, CD3OD) 57.79 (app d, J = 7.5 Hz, 2H), 7.70-7.64 (m, 2H), 7.40-7.36 (m, 2H), 7.33-7.28 (m, 2H), 7.27-7.12 (m, 5H), 4.76-4.61 (m, 1H), 4.49-4.34 (m, 3H), 4.28-4.20 (m, 1H), 3.99-3.84 (m, 1H), 3.81-3.72 (m, 3H), 3.24-3.09 (m, 1H), 3.04-2.94 (m, 1H), 1.96-1.73 (m, 1H), 1.59-0.75 (m, 8H).13C NMR (151 MHz, CD3OD) 5 174.87, 174.40, 173.49, 173.25, 172.76, 172.70, 171.49, 159.36, 159.29, 145.34, 145.30, 145.25, 145.21, 142.61, 138.38, 130.36, 130.35, 130.33, 129.51, 129.49, 129.47, 129.43, 128.79, 128.16, 127.80, 127.73, 126.27, 126.24, 126.23, 120.92, 68.36, 68.33, 68.25, 61.53, 58.34, 58.25, 58.19, 56.07, 55.96, 55.18, 45.25, 45.16, 43.42, 43.28, 43.11, 39.03, 38.65, 38.41, 38.38, 38.34, 38.28, 38.16, 26.27, 26.22, 26.19, 20.85, 16.02, 16.01, 15.94, 14.46, 11.83, 11.81, 11.75. HRMS (ESI-TOF): Calculated for C34H38N4NaO7[M + Na]+: 637.2633, found 637.2633.

[0317] Example 11: Synthesis of Benzyl-L-proline (49a)

[0318] The title compound was prepared from L-Pro-OH and benzyl bromide according to an existing literature protocol.68Spectral data align with literature values.68

[0319] C. General Procedure for Decarboxylative Cyanation

[0320] Example 12: General Procedure A for Decarboxylative Cyanation of Carboxylic Acids:

[0321] To a flame dried 2-dram vial charged with a Teflon-coated stir was added Cu(OTf)2(3.6 mg, 0.01 mmol, 5 mol%), 1,10-Phenanthroline (2.7 mg, 0.015 mmol, 7.5 mol%), ethyl acetate (0.5 mL) and TFE (0.5 mL). The resulting mixture was stirred for 1.5 hours and then 3,6-di-tertbutyl- 9 -mesityl- 10 -phenylacridinium tetrafluoroborate (5.74 mg, 0.01 mmol, 5 mol%), aliphatic carboxylic acid (0.2 mmol, 1 equiv.), diisopropylethylamine (8.7 μL, 0.05 mmol, 25 mol%), tert- Butyl hydroperoxide solution (5-6 M in decane, 80 μL, 0.4 mmol, 2 equiv.) and TMSCN (100 μL, 0.8 mmol, 4 equiv.). The vial was then sealed with a Teflon coated septum cap and the mixture sparged with argon for 10 minutes. And then the reactions were stirred under irradiation with 465 nm SynLED for indicated time. After completion, the reaction mixture was concentrated in vacuo and purified using silica gel chromatography using hexane to 5% EtOAc in hexanes as the eluent unless otherwise noted.

[0322] Example 13: General Procedure B for Enantioselective Decarboxylative Cyanation of Secondary Benzylic Carboxylic Acids:

[0323] To a flame dried 2-dram vial charged with a Teflon-coated stir was added Cu(OTf)z (1.8 mg, 0.005 mmol, 5 mol%), sBox (rPr) (2.64 mg, 0.0075 mmol, 7.5 mol%), DCE (0.5 mL) and TFE (0.5 mL). The resulting mixture was stirred for 1.5 hours and then 3,6-di-tertbutyl-9-mesityl-10- phenylacridinium tetrafluoroborate (2.87 mg, 0.005 mmol, 5 mol%) or riboflavin tetraacetate (2.58 mg, 0.005 mmol, 5 mol%), benzylic secondary carboxylic acid (0.1 mmol, 1 equiv.), diisopropylethylamine (4.4 μL, 0.025 mmol, 25 mol%), tert-Butyl hydroperoxide solution (5-6 M in decane, 40 μL, 0.2 mmol, 2 equiv.) and TMSCN (50 μL, 0.4 mmol, 4 equiv.). The vial was then sealed with a Teflon coated septum cap and the mixture sparged with argon for 10 minutes. And then the reactions were stirred under irradiation with 465 nm SynLED under 5 °C for indicated time. After completion, the reaction mixture was concentrated in vacuo and purified using silica gel chromatography using hexane to 5% EtOAc in hexanes as the eluent unless otherwise noted. Racemic products (for HPLC assays) were synthesized same as General Procedure A.

[0324] Example 14: General Procedure C for Decarboxylative Cyanation of Amino Acids and Peptides:

[0325] To a flame dried 2-dram vial charged with a Teflon-coated stir was added amino acid or peptides (0.2 mmol, 1 equiv.), (Diacetoxyiodo)benzene (129 mg, 0.4 mmol, 2 equiv.), 3,6-di- tertbutyl-9-mesityl-10-phenylacridinium tetrafluoroborate (5.74 mg, 0.01 mmol, 5 mol%), diisopropylethylamine (8.7 μL, 0.05 mmol, 25 mol%) and TFE (1 mL). The vial was then sealed with a Teflon coated septum cap and the mixture sparged with argon for 10 minutes. And then the reactions were stirred under irradiation with 465 nm SynLED under 5 °C for 18 h. After completion, the reaction mixture was concentrated in vacuo and purified using silica gel chromatography to achieve the trifluoroethanol addition intermediates.

[0326] The trifluoroethanol addition intermediate (0.1 mmol, 1 equiv.) was then dissolved in dry MeCN (1 mL), and the solution was cooled to 0 °C. After 5 min, TMSCN (37.5 μL, 0.3 mmol, 3 equiv) was added dropwise, followed by addition of BF3.Et2O (75 μL, 0.6 mmol, 6 equiv.) dropwise. The reaction was stirred for 1 h at the same temperature. Aqueous NH4CI (3 drops) was added, and the resulting mixture was vigorously stirred at room temperature. The reaction mixture was concentrated in vacuo and purified using silica gel chromatography using hexane to 20% EtOAc in hexanes as the eluent unless otherwise noted.

[0327] Note: The trifluoroethanol addition intermediates are not stable and decomposition was observed after one month in refrigerator. The NMR solvent. CDCl3, was used after filtering through a short pad of neutral Al2O3to remove trace amount of acid. Alternatively, filtering through a silica plug with dichloromethane was used to remove the polar materials and directly used for the cyanation step, providing similar results with stepwise pathway.

[0328] Example 15: General Procedure D for Decarboxylative Cyanation of Carboxylic Acids with KCN and K13CN: To a flame dried 2-dram vial charged with a Teflon-coated stir was added Cu(OTf)2(3.6 mg, 0.01 mmol, 5 mol%), 1,10-Phenanthroline (2.7 mg, 0.015 mmol, 7.5 mol%), 3,6-di-tertbutyl- 9-mesityl-10-phenylacridinium tetrafluoroborate (5.74 mg, 0.01 mmol, 5 mol%) and TFE (1 mL). The resulting mixture was stirred for 1.5 hours before use (Solution A). To another frame dried 2- dram vial charged with a Teflon-coated stir was added KCN or K13CN (52.1 mg, 0.8 mmol, 4 equiv) and dry MeCN (1 mL), followed by addition of TMSOTf (145 μL, 0.8 mmol, 4 equiv.). The resulting mixture was stirred for 1.5 hours before use (Solution B). Then solution A was transferred to Solution B, followed by addition of aliphatic carboxylic acid (0.2 mmol, 1 equiv.), diisopropylethylamine (8.7 μL, 0.05 mmol, 25 mol%) and tert-Butyl hydroperoxide solution (5-6 M in decane, 80 μL, 0.4 mmol, 2 equiv.). The vial was then sealed with a Teflon coated septum cap and the mixture sparged with argon for 10 minutes. And then the reactions were stirred under irradiation with 465 nm SynLED for indicated time. After completion, the reaction mixture was concentrated in vacuo and purified using silica gel chromatography.

[0329] When TMSC1 was used instead of TMSOTf, the solution B was prepared via the following procedure:

[0330] To a frame dried 2-dram vial charged with a Teflon-coated stir was added KCN or K13CN (52.1 mg, 0.8 mmol, 4 equiv.), KI (16.6 mg, 0.1 mmol, 0.5 equiv.) and dry MeCN (1 mL). The mixture was sparged with argon for 5 min followed by addition of TMSC1 (102 μL, 0.8 mmol, 4 equiv.). The resulting mixture was stirred for 20 hours and then filter through a celite plug to remove insoluble inorganic salt.

[0331] Example 16: General Photoreactor Configuration:

[0332] The SynLED Parallel Photoreactor (available for purchase from Millipore Sigma, Z742680) was placed on an IKA magnetic stirrer with round plate (#3810001) with stirring set between 550-700 rpm. The bottom-lit LEDS (465—470 nm) have a light intensity of 130-140 Im. The reactor contains a built-in cooling fan, the measured reaction temperature varied between 35- 45 °C with a parallel reactor lid.

[0333] For reactions run under 5 °C: Reactions were set up on a SynLED photoreactor inside a Neslab CB-80 cryobath chiller with temperature setting at -50 °C. The temperature was measured as 5 °C with thermometer. In case for -30 °C, dry ice was added to control the temperature.

[0334] D. Product Characterization:

[0335] Example 17: Synthesis of 2-Phenylacetonitrile (2).

[0336] The title compound was prepared using General Procedure A. The title compound was isolated using hexane to 5% ethyl acetate in hexane as eluent as a light yellow oil in 71% yield (16.6 mg) and spectral data align with commercially available source.

[0337] Example 18: Synthesis of 3-Phenylpropanenitrile (33).

[0338] The title compound was prepared using General Procedure A. The title compound was isolated using hexane to 5% ethyl acetate in hexane as eluent as a colorless oil in 53% yield (13.9 mg) and spectral data align with commercially available source.

[0339] Example 19: Synthesis of 4-([1,1'-Biphenyl]-4-yl)-4-oxobutanenitri]e (1).

[0340] The title compound was prepared using General Procedure A. The title compound was isolated using hexane to 20% ethyl acetate in hexane as eluent as a light yellow solid in 40% yield (19.0 mg).1H NMR (600 MHz, CDCl3) δ 8.05-8.01 (m, 2H), 7.74-7.70 (m, 2H), 7.65-7.62 (m, 2H), 7.50-7.46 (m, 2H), 7.44-7.40 (m, 1H), 3.45-3.40 (m, 2H), 2.83-2.78 (m, 2H).13C NMR (151 MHz, CDCl3) δ 195.0, 146.7, 139.7, 134.4, 129.2, 128.8, 128.6, 127.6, 127.4, 119.4, 34.4, 12.0. HRMS (ESI-TOF): Calculated for C16H13NNaO [M + Na]+: 258.0889, found 258.0890.

[0341] Example 20: Synthesis of 2-([l,l,-biphenyl]-4-yl)acetonitrile (3).

[0342] The title compound was prepared using General Procedure A. The title compound was isolated as eluent as a white solid in 60% yield (23.0 mg).1H NMR (600 MHz, CDCl3) δ 7.63- 7.57 (m, 4H), 7.46 (app t, J= 7.6 Hz, 2H), 7.41 (app d, J= 8.0 Hz, 2H), 7.38 (app t, J= 7.2 Hz, 1H), 3.80 (s, 2H).13C NMR (151 MHz, CDCl3) δ 141.3, 140.3, 129.01, 128.95, 128.5, 128.0, 127.8, 127.2, 118.0, 23.5. HRMS (ESI-TOF): Calculated for C14H11NNa [M + Na]+: 216.0784, found 216.0787.

[0343] Example 21: Synthesis of 2-([l,l’-Biphenyl]-4-yl)acetonitrile-l-13C ([,3C]3).

[0344] The title compound was prepared using General Procedure D with TMSOTf as the Lewis acid. The title compound was isolated as eluent as a white solid in 70% yield (27.0 mg).1H NMR (600 MHz, CDCl3) δ 7.64-7.57 (m, 4H), 7.46 (app t, J= 7.6 Hz, 2H), 7.41 (app d, J= 8.0 Hz, 2H), 7.38 (app t, J= 7.4 Hz, 1H), 3.80 (d, J= 10.6 Hz, 2H)13C NMR (151 MHz, CDCl3) δ 141.2, 140.3, 129.01, 128.95 (d, J= 3.4 Hz), 128.5 (d, J= 3.6 Hz), 128.0, 127.8, 127.2, 118.0, 23.4 (d, J = 57.8 Hz). HRMS (ESI-TOF): Calculated for (C1313CH11NNa [M + Na]+: 217.0817, found 217.0819.

[0345] Example 22: Synthesis of.2-(ll-Oxo-6,ll-dihydrodibenzo[b,e]oxepin-2-yl)acetonitrile (4) was prepared using General Procedure A.

[0346] The title compound was isolated as a light yellow solid in 94% yield (47.0 mg). NMR (600 MHz, CDCl3) δ 8.16 (d, J = 2.3 Hz, 1H), 7.89 (dd, J= 7.7, 1.4 Hz, 1H), 7.58 (app td, J= 7.5, 1.4 Hz, 1H), 7.50-7.46 (m, 2H), 7.38 (dd, J= 7.5, 1.2 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 5.20 (s, 2H), 3.76 (s, 2H)?3C NMR (151 MHz, CDCl3) δ 190.5, 161.1, 140.3, 135.5, 134.7, 133.2, 131.7, 129.7, 129.6, 128.1, 125.6, 123.8, 122.1, 117.8, 73.8, 23.0. HRMS (ESI-TOF): Calculated for C16H11NNaO2[M + Na]+: 272.0682, found 272.0685.

[0347] Example 23: Synthesis of 2-(ll-Oxo-6,ll-dihydrodibenzo[b,e]oxepin-2-yl)acetonitrile-l-13C ([13C]4). The title compound was prepared using General Procedure D with TMSOTf as the Lewis acid. The title compound was isolated as eluent as a light-yellow solid in 66% yield (33.0 mg). (For KCN: The title compound was isolated as a light-yellow solid in 87% yield (43.2 mg)).1H NMR (600 MHz, CDCl3) δ 8.16 (d, J= 2.5 Hz, 1H), 7.89 (dd, J= 7.7, 1.4 Hz, 1H), 7.58 (app td, J= 7.5, 1.4 Hz, 1H), 7.51-7.45 (m, 2H), 7.38 (dd, J= 7.5, 1.2 Hz, 1H), 7.09 (d, J= 8.4 Hz, 1H), 5.20 (s, 2H), 3.75 (d, J= 10.6 Hz, 2H / ?C NMR (151 MHz, CDCl3) δ 190.5, 161.1, 140.3, 135.5, 134.7 (d, J= 2.7 Hz), 133.2, 131.6 (d, J= 3.7 Hz), 129.7, 129.6, 128.1, 125.6, 123.8 (d, J= 3.8 Hz), 122.0, 117.8, 73.8, 22.9 (d, J = 58.0 Hz). HRMS (ESI-TOF): Calculated for G1513CH11NNaO2[M + Na]+: 273.0716, found 273.0718.

[0348] Example 24: Synthesis of 2-(l-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H -indol-3- yl)acetonitrile (5).

[0349] The title compound was prepared using General Procedure A. The title compound was isolated using hexane to 20% ethyl acetate in hexane as eluent and repurified with second column with hexane to 40% CH2CI2in hexane as eluent as a light white solid in 40% yield (27.0 mg).

[0350] 1H NMR (600 MHz, CDCl3) δ 7.69-7.63 (m, 2H), 7.51-7.46 (m, 2H), 6.98 (d, J= 2.5 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 6.71 (dd, J= 9.0, 2.5 Hz, 1H), 3.86 (s, 3H), 3.73 (s, 2H), 2.44 (s, 3H).

[0351] 13C NMR (151 MHz, CDCl3) δ 168.3, 156.4, 139.9, 136.1, 133.5, 131.4, 130.8, 129.4, 129.2, 117.1, 115.3, 112.6, 108.1, 100.6, 55.9, 13.3, 13.2. HRMS (ESI-TOF): Calculated for C19H1535ClN2NaO2[M + Na]+: 361.0714, found 361.0719; Calculated for C1151537ClN2NaO2[M

[0352] + Na]+: 363.0685, found 363.0689.

[0353] Example 25: Synthesis of Tert-butyl (3-cyanopropyl)carbamate (6) was prepared using General Procedure A.

[0354] The title compound was isolated using hexane to 20% ethyl acetate in hexane as eluent and repurified with second column with CH2CI2to 5% ethyl acetate in CH2CI2as eluent as a colorless oil in 45% yield (16.5 mg).1H NMR (600 MHz, CDCl3) δ 4.68 (br s, 1H), 3.24 (app q, J= 6.5 Hz, 2H), 2.39 (t, J= 12 Hz, 2H), 1.87 (app p, J= 6.9 Hz, 2H), 1.44 (s, 9H).13C NMR (151 MHz, CDCh) 8 156.1, 119.4, 79.9, 39.4, 28.5, 26.2, 14.8. HRMS (ESI-TOF): Calculated for

[0355] C9H16N2NaO2[M + Na]+: 207.1104, found 207.1106.

[0356] Example 26: Synthesis of tert-butyl ((l-(cyanomethyl)cyclohexyl)methyl)carbamate (7).

[0357] The title compound was prepared using General Procedure A. The title compound was isolated as eluent as a light yellow solid in 37% yield (18.5 mg). 'H NMR (600 MHz, CDCl3) δ 4.64 (t, J= 7.0 Hz, 1H), 3.18 (d, J = 6.9 Hz, 2H), 2.33 (s, 2H), 1.58-1.53 (m, 2H), 1.50-1.38 (m, 17H).13C NMR (151 MHz, CDCl3) δ 156.4, 118.3, 79.8, 47.2, 37.3, 32.9, 28.5, 25.7, 21.5. HRMS (ESI-TOF): Calculated for (C14H24N2NaO2[M + Na]+: 275.1730, found 275.1732.

[0358] Example 27: Synthesis of Oleonitrile (33).

[0359] The title compound was prepared using General Procedure A. The title compound was isolated as a light yellow oil in 40% yield (21.0 mg). NMR (600 MHz, CDCl3) δ 5.44-5.30 (m, 2H), 2.36-2.27 (m, 2H), 2.08-1.94 (m, 4H), 1.70-1.60 (m, 2H), 1.49-1.41 (m, 2H), 1.36-1.24 (m, 18H), 0.88 (t, .7= 6.9 Hz, 3H)?3C NMR (151 MHz, CDCl3) δ 130.3, 129.7, 120.0, 32.1, 29.9, 29.73, 29.67, 29.5, 29.1, 28.82, 28.80, 27.4, 27.2, 25.5, 22.8, 17.3, 14.3. HRMS (ESI-TOF): Calculated for C18H33NNa [M + Na]+: 286.2505, found 286.2508.

[0360] Example 28: Synthesis of (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-l,3- dihydroisobenzofuran-5-yl)-4-methylhex-4-enenitrile (34). The title compound was prepared using General Procedure A. The title compound was isolated using hexane to 20% ethyl acetate in hexane as eluent as a light-yellow solid in 31% yield (19.0 mg).1H NMR (600 MHz, CDCl3) δ 7.69 (s, 1H), 5.35 (tq, J= 7.0, 1.3 Hz, 1H), 5.20 (s, 2H), 3.78 (s, 3H), 3.42 (d, J= 7.0 Hz, 2H), 2.43 (td, J= 7.4, 0.8 Hz, 2H), 2.32 (t, J= 7.4 Hz, 2H)2.15 (s, 3H), 1.83 (d, J= 1.4 Hz, 3H)13C NMR (151 MHz, CDCl3) δ 173.1, 163.8, 153.8, 144.4, 132.1, 125.1, 121.7, 119.6, 117.0, 106.6, 70.2, 61.3, 35.1, 22.8, 16.3, 16.0, 11.7. HRMS (ESI-TOF): Calculated for C17H16NNaO4[M + Na]+: 324.1206, found 324.1210.

[0361] Me

[0362] •Me

[0363] :N

[0364] •Ac Me

[0365] Example 29: Synthesis of (E)-5-(5-cyano-3-methylpent-2-en-l-yl)-6-methoxy-7-methyl-3- oxo-l,3-dihydroiso-benzofuran-4-yl acetate (8).

[0366] The title compound was prepared using General Procedure A. The title compound was isolated using hexane to 20% ethyl acetate in hexane as eluent as a light-yellow solid in 12% yield (8.0 mg).1H NMR (600 MHz, CDCl3) δ 5.24-5.20 (m, 1H), 5.15 (s, 2H), 3.81 (s, 3H), 3.39 (app d, J = 6.8 Hz, 2H), 2.44-2.39 (m, 5H), 2.31 (t, J= 7.3 Hz, 2H), 2.23 (s, 3H), 1.82 (s, 3H)13C NMR (151 MHz, CDCl3) δ 169.2, 168.4, 162.8, 146.5, 146.1, 132.5, 128.8, 124.7, 123.2, 119.4, 113.7, 68.5, 61.4, 34.9, 23.7, 20.7, 16.3, 16.1, 12.0. HRMS (ESI-TOF): Calculated for C17H19NNaO4[M + Na]+: 366.1312, found 366.1311.

[0367] Example 30: Synthesis of 8-Cyanooctyl (E)-4-((2S,3 R,4R,5S)-3,4-dihydroxy-5-(((2S,3S)-3- ((2S,35)-3-hydroxybutan-2-yl)oxiran-2-yl)methyl)tetrahydro-2H-pyran-2-yl)-3-methylbut- 2-enoate (9).

[0368] The title compound was prepared using General Procedure A. The title compound was isolated using hexane to 20% ethyl acetate in hexane as eluent as a light-yellow solid in 35% yield (33.5 mg).1H NMR (600 MHz, CDCl3) δ 5.74 (s, 1H), 4.06 (t, J = 6.6 Hz, 2H), 3.95-3.91 (m, 1H), 3.86 (dd, J= 11.7, 2.9 Hz, 1H), 3.83-3.76 (m, 1H), 3.75 (app td, J = 8.9, 3.2 Hz, 1H), 3.53 (dd, J= 11.7, 2.6 Hz, 1H), 3.49-3.43 (m, 1H), 2.98 (br s, 1H), 2.86-2.78 (m, 2H), 2.70 (dd, J = 8.0, 2.3 Hz, 1H), 2.64 (br s, 1H), 2.62-2.56 (m, 1H), 2.31-2.24 (m, 1H), 2.20 (s, 3H), 2.03-1.96 (m, 1H), 1.76 (ddd, J= 14.6, 6.8, 4.7 Hz, 1H), 1.71-1.59 (m, 5H), 1.48-1.40 (m, 2H), 1.40-1.22 (m, 9H), 1.21 (d, J= 6.3 Hz, 3H), 0.93 (d, J= 7.0 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 166.9, 156.9, 120.0, 117.7, 74.9, 71.6, 70.4, 69.1, 65.5, 63.8, 61.6, 55.7, 43.0, 42.9, 39.6, 31.6, 29.0, 28.74, 28.67, 26.0, 25.4, 22.8, 21.1, 19.2, 17.3, 13.0. HRMS (ESI-TOF): Calculated for C26H43NNaO7[M + Na]+: 504.2932, found 504.2933.

[0369] Example 31: Synthesis of (4R)-4-((3S, 7S, 8R,9S,10S,13R,14S, 17R)-3,7-dihydroxy-10, 13- dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)pentanenitrile (10).

[0370] The title compound was prepared using General Procedure A for 24 h. The title compound was isolated using 20% ethyl acetate in hexane to 50% ethyl acetate in hexane as eluent as a light yellow solid in 35% yield (26.0 mg).1H NMR (600 MHz, CDCl3) δ 3.62-3.55 (m, 2H), 2.37 (ddd, J= 16.9, 8.6, 5.1 Hz, 1H), 2.27 (app dt, J= 16.8, 8.3 Hz, 1H), 1.99 (app dt, J= 12.5, 3.3 Hz, 1H), 1.93-1.76 (m, 5H), 1.69-1.64 (m, 2H), 1.63-1.21 (m, 17H), 1.15 (app td, J= 13.0, 4.0 Hz, 1H), 1.11-0.99 (m, 2H), 0.96 (d, J= 6.6 Hz, 3H), 0.95 (s, 3H), 0.69 (s, 3H).13C NMR (151 MHz, CDCl3) δ 120.3, 71.6, 71.5, 55.8, 54.8, 44.0, 43.9, 42.6, 40.2, 39.3, 37.4, 37.1, 35.2, 35.0, 34.2, 31.7, 30.5, 28.7, 27.0, 23.5, 21.3, 18.1, 14.4, 12.3. HRMS (ESI-TOF): Calculated for C24H39NNaO2[M + Na]+: 396.2873, found 396.2877. Example 32: Synthesis of (4R)-4-((3S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13- dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)pentanenitrile-l-13C ([13C]10).

[0371] The title compound was prepared using General Procedure D with TMSC1 as Lewis acid. The title compound was isolated as a white solid in 17% yield (12.8 mg). (For KCN: The title compound was isolated as a white solid in 18% yield (13.0 mg)).1H NMR (600 MHz, CDCl3) δ 3.63-3.55 (m, 2H), 2.37 (dddd, J= 16.8, 9.7, 8.5, 5.0 Hz, 1H), 2.27 (app ddt, J= 16.7, 9.6, 8.3 Hz, 1H), 1.99 (app dt, J= 12.4, 3.2 Hz, 1H), 1.92-1.75 (m, 5H), 1.70-1.64 (m, 2H), 1.62-1.21 (m, 17H), 1.15 (app td, J= 13.0, 3.9 Hz, 1H), 1.09-0.99 (m, 2H), 0.96 (d, J= 6.6 Hz, 3H), 0.95 (s, 3H), 0.69 (s, 3H),13C NMR (151 MHz, CDCl3) δ 120.3, 71.6, 71.5, 55.8, 54.8, 44.0, 43.9, 42.6,

[0372] 40.2, 39.3, 37.4, 37.1, 35.2 (d, J= 3.4 Hz), 35.0, 34.2, 31.7 (d, J = 2.6 Hz), 30.5, 28.7, 27.0, 23.5,

[0373] 21.3, 18.1, 14.4 (d, J= 56.1 Hz), 12.3. HRMS (ESI-TOF): Calculated for C2313CH39NNaO2[M + Na]+: 397.2907, found 397.2904.

[0374] Example 33: Synthesis of Cyclohexanecarbonitrile (35).

[0375] The title compound was prepared using General Procedure A. The title compound was isolated using hexane to 5% ethyl acetate in hexane as eluent as a colorless oil in 30% yield (6.6 mg) and spectral data align with commercially available source.

[0376] Example 34: Synthesis of l-Benzoylpiperidine-4-carbonitrile (36).

[0377] The title compound was prepared using General Procedure A. The title compound was isolated using 20% ethyl acetate in hexane as eluent as a white solid in 70% yield (30.0 mg).1H NMR (600 MHz, CDCl3) δ 7.45-7.39 (m, 3H), 7.39-7.36 (m, 2H), 4.03-3.32 (m, 4H), 2.92 (tt, J = 7.7, 4.3 Hz, 1H), 2.09-1.77 (m, 4H)13C NMR (151 MHz, CDCl3) δ 170.6, 135.4, 130.1, 128.8, 127.0, 120.8, 45.7, 40.2, 29.1, 28.4, 26.5. HRMS (ESI-TOF): Calculated for (C13H15N2O [M + H] *: 215.1179, found 215.1181.

[0378] Example 35: Synthesis of tert-butyl 3-cyanoazetidine-l-carboxylate (11).

[0379] The title compound was prepared using General Procedure A. The title compound was isolated using 20% ethyl acetate in hexane as eluent as a light yellow solid in 19% yield (7.0 mg). H NMR (600 MHz, CDCl3) δ 4.24-4.13 (m, 4H), 3.39 (tt, J= 8.9, 6.3 Hz, 1H), 1.44 (s, 9H)?3C NMR (151 MHz, CDCl3) δ 155.6, 119.6, 80.9, 52.6, 28.4, 17.2. HRMS (ESI-TOF): Calculated for C9H14N2NaO2[M + Na]+: 205.0948, found 205.0950.

[0380] Example 36: Synthesis of tert-butyl 3-cyanopiperidine-l-carboxylate (12).

[0381] The title compound was prepared using General Procedure A. The title compound was isolated, using 20% ethyl acetate in hexane as eluent, then repurified with 5% ethyl acetate in dichloromethane as eluent, as a colorless oil in 70% yield (30.0 mg).1H NMR (600 MHz, CDCb) 54.04-3.08 (m, 4H), 2.67 (app dq, J= 11.4, 4.0 Hz, 1H), 2.04-1.94 (m, 1H), 1.88-1.73 (m, 2H), 1.56-1.48 (m, 1H), 1.46 (s, 9H).13C NMR (151 MHz, CDCl3) δ 154.4, 120.2, 80.6, 46.4, 43.4, 28.4, 28.1, 27.5, 23.2. HRMS (ESI-TOF): Calculated for C11H18N2NaO2[M + Na]+: 233.1261, found 233.1263.

[0382] Example 37: Synthesis of 2-Hydroxy-2-phenylacetonitrile (37).

[0383] The title compound was prepared using General Procedure A. The title compound was isolated using hexane to 10% ethyl acetate in hexane as eluent as a colorless oil in 23% yield (6.0 mg) and spectral data align with commercially available source.

[0384] Example 38: Synthesis of (2S,3R,4S,5R,6R)-6-cyanotetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (13).

[0385] The title compound was prepared using General Procedure A under 5 °C for 18 h. The title compound was isolated using hexane to 50% ethyl acetate in hexane as eluent as a white solid in 47% yield (32.0 mg) with dr = 15:1.1H NMR (600 MHz, CDCl3) δ 6.36 (d, J = 3.7 Hz, 1H), 5.40 (app t, J= 9.7 Hz, 1H), 5.32 (app t, J= 9.8 Hz, 1H), 5.09 (dd, J= 10.0, 3.7 Hz, 1H), 4.73 (d, J = 10.2 Hz, 1H), 2.20 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H).13C NMR (151 MHz, CDCb) 6 170.1, 169.5, 168.8, 168.1, 114.3, 88.6, 68.9, 68.8, 68.4, 61.3, 20.8, 20.7, 20.48, 20.46.

[0386] HRMS (ESI-TOF): Calculated for C14H17NNaO9[M + Na]+: 366.0796, found 366.0799.

[0387] Example 39: Synthesis of Compounds 14 and 14’.

[0388] The title compound was prepared using General Procedure A. The title compound was isolated, using 20% ethyl acetate in hexane as eluent, then repurified with 5% ethyl acetate in dichloromethane to 10% ethyl acetate in dichloromethane as eluent, as a white solid for the major diastereomer in 25% yield (19.0 mg) and as a white solid for the minor diastereomer in 17% yield (13.0 mg). The stereochemistry was assigned according to literature reported data.69 1H NMR (600 MHz, CDCl3) δ 5.59 (dd, J = 6.3, 2.0 Hz, 1H), 5.48-5.43 (m, 2H), 5.10 (ddd, J= 9.6, 4.2, 2.5 Hz, 1H), 4.21 (dd, J= 12.7, 2.5 Hz, 1H), 4.13 (dd, J= 12.7, 4.2 Hz, 1H), 2.18 (s, 3H), 2.15 (s, 3H), 2.14 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H).13C NMR (151 MHz, CDCl3) δ 170.6, 170.1, 169.9, 169.6, 168.6, 114.3, 67.7, 67.6, 67.0, 61.5, 60.3, 20.9, 20.8, 20.7, 20.6, 20.3. 1H NMR (600 MHz, CDCl3) δ 5.59 (dd, J = 8.5, 2.5 Hz, 1H), 5.50 (d, J= 6.6 Hz, 1H), 5.38 (dd, J= 6.6, 2.4 Hz, 1H), 5.15 (ddd, J= 8.3, 5.1, 2.9 Hz, 1H), 4.27 (dd, J= 12.6, 2.9 Hz, 1H), 4.11 (dd, J= 12.6, 5.1 Hz, 1H), 2.19 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H), 2.07 (s, 6H).13C NMR (151 MHz, CDCl3) δ 170.7, 169.8, 169.64, 169.62, 168.4, 114.1, 68.2, 67.2, 67.0, 61.7, 58.8, 20.88, 20.86, 20.8, 20.5, 20.3. HRMS (ESI-TOF): Calculated for (C16H21NNaO10[M + Na]+: 410.1058, found 410.1063.

[0389] Example 40: Synthesis of (8S,9S,10R ,13S,14S,17S)-10,13-dimethyl-3-oxo-

[0390] 23,6,7,8, 9,10,11,12, 13,14, 15,16, 17-tetradecahydro-LH-cyclopenta[a]phenanthrene-17- carbonitrile (15).

[0391] The title compound was prepared using General Procedure A. The title compound was isolated using hexane to 20% ethyl acetate in hexane as eluent as a light-yellow solid in 39% yield (23.0 mg) with dr = 4.2:1.1H NMR (600 MHz, CDCl3) δ 5.74-5.71 (m, 1.28H), 2.60 (dd, J = 9.0, 2.1 Hz, 1H), 2.47-2.33 (m, 4.24H), 2.31-2.26 (m, 1.68H), 2.24-2.10 (m, 1.53H), 2.08-1.94 (m, 2.94H), 1.94-1.82 (m, 2.67H), 1.82-1.77 (m, 1.37H), 1.76-1.67 (m, 3.67H), 1.61-1.41 (m, 3.41H), 1.40-1.23 (m, 3.56H), 1.21-1.09 (m, 5.93H), 1.08-1.01 (m, 1.70H), 0.97 (s, 0.73H), 0.87 (s, 3H). For the major diastereomer13C NMR (151 MHz, CDCI3) 5 199.4, 170.5, 124.3, 122.1, 53.1, 51.7, 44.2, 40.0, 38.6, 36.1, 35.8, 34.9, 34.0, 32.8, 32.1, 27.4, 25.0, 20.9, 18.1, 17.5. For the minor diastereomer”C NMR (151 MHz, CDCl3) δ 199.5, 170.4, 124.1, 121.2, 53.9, 53.6, 44.4, 40.3, 38.7, 36.9, 36.1, 35.9, 34.0, 32.7, 31.9, 26.6, 24.7, 20.8, 17.5, 14.4. HRMS (ESI-TOF): Calculated for C20H28NO [M + H]+: 298.2165, found 298.2170. Example 41: Synthesis of (1S,2S,4aR,4bR,7S,9aR,10S,10aR )-2,7-dihydroxy-l-methyl-8- methylene-13-oxo-1,2,4b,5,6,7,8,9,10,10a-decahydro-4a,l-(epoxymethano)-7,9a- methanobenzo[a]azulene-10-carbonitrile (16).

[0392] The title compound was prepared using General Procedure A under 5 °C for 18 h. The title compound was isolated using hexane to 50% ethyl acetate in hexane as eluent as a white solid in 20% yield (13.0 mg) with dr = 13:1.1H NMR (600 MHz, CDCl3) δ 6.29 (d, J = 9.3 Hz, 1H), 5.93 (dd, J= 9.3, 3.8 Hz, 1H), 5.34 (dd, J= 3.2, 1.8 Hz, 1H), 5.05 (app t, J= 2.2 Hz, 1H), 4.26- 4.19 (m, 1H), 3.07 (d, J= 10.9 Hz, 1H), 2.86 (app dt, J= 15.6, 2.9 Hz, 1H), 2.82 (d, J= 11.4 Hz, 1H), 2.42-2.35 (m, 1H), 2.15-2.08 (m, 2H), 2.00 (dd, J= 10.8, 3.0 Hz, 1H), 1.96 (app dd, J= 11.9, 5.8 Hz, 1H), 1.91-1.80 (m, 2H), 1.73-1.69 (m, 2H), 1.68-1.65 (m, 1H), 1.47 (s, 3H).13C NMR (151 MHz, CDCl3) δ 177.2, 156.2, 132.8, 132.3, 118.7, 108.3, 90.0, 78.4, 69.7, 54.9, 53.7, 51.0, 49.7, 44.4, 44.3, 38.0, 36.7, 17.0, 14.7. HRMS (ESI-TOF): Calculated for C19H21NNaO4[M + Na]+: 350.1363, found 350.1362.

[0393] Example 42: Synthesis of (R)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propanenitrile (17)

[0394] To a flame dried 2-dram vial charged with a Teflon-coated stir was added Cu(OTf)2(1.8 mg, 0.005 mmol, 5 mol%), sBox (iPr) (2.64 mg, 0.0075 mmol, 7.5 mol%), DCE (0.5 mL) and TFE (0.5 mL). The resulting mixture was stirred for 1.5 hours and then 3,6-di-tertbutyl-9-mesityl-10- phenylacridinium tetrafluoroborate (2.87 mg, 0.005 mmol, 5 mol%), flurbiprofen (24.4 mg, 0.1 mmol, 1 equiv.), diisopropylethylamine (4.4 μL, 0.025 mmol, 25 mol%), tert-Butyl hydroperoxide solution (5-6 M in decane, 40 μL, 0.2 mmol, 2 equiv.) and TMSCN (50 μL, 0.4 mmol, 4 equiv.). The vial was then sealed with a Teflon coated septum cap and the mixture sparged with argon for 10 minutes. And then the reactions were stirred under irradiation with 465 nm SynLED under -30 °C for 8 h. After that, the reaction mixture was concentrated in vacuo and purified using silica gel chromatography using hexane to 10% EtOAc in hexanes as the eluent. Compound 17 was isolated as a white solid in 62% yield (14.0 mg), = +7.06 (c 0.5, CH2CI2, 92% ee).1H NMR (600 MHz, CDCl3) δ 7.56-7.52 (m, 2H), 7.50-7.43 (m, 3H), 7.42-7.37 (m, 1H), 7.23 (dd, J = 19, 1.9 Hz, 1H), 7.18 (dd, J = 11.0, 1.9 Hz, 1H), 3.95 (q, J= 13 Hz, 1H), 1.69 (d, J= 13 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 160.0 (d, d-F= 249.7 Hz), 138.3 (d, JC-F = 7.6 Hz), 135.1, 131.6 (d, JC-F= 4.2 HZ), 129.1 (d,J= 2.9 Hz), 128.7, 128.1, 122.8 (d, JC-F= 3.6 Hz), 121.1, 114.8 (d, JC-F= 24.5 Hz), 30.9 (d, JC-F = 1.9 Hz), 21.3.19F NMR (565 MHz, CDCfe) 8 -116.27. HPLC

[0395] Conditions: Daicel Chiralpak IC, n-hexane / i-PrOH = 99 / 1, Flow rate = 1 mL / min, UV = 254 run, tR= 20.3 min (major), tR= 22.1 min (minor). HRMS (ESI-TOF): Calculated for C15H12FNNa [M + Na]+: 248.0846, found 248.0849. The absolute configuration of 17 ( = +7.06 (c 0.5, CH2CI2, 92% ee)) was assigned by comparison with the compound reported in the literature42( = +7.411 (c 0.68, CH2CI2, 90% ee))

[0396] Example 43: Synthesis of 2-(2-Fluoro-[l,l’-biphenyl]-4-yl)propanenitrile-1-13C ([13C]17).

[0397] The test compound was prepared using General Procedure D with K12 / 13CN as cyano source and TMSOTf as promotor. The title compound was isolated as a white solid. For K12CN: the desired product was obtained in 92% yield (41.5 mg); For K13CN: the desired product was obtained in 87% yield (39.0 mg).1H NMR (600 MHz, CDCl3) δ 7.57-7.52 (m, 2H), 7.50-7.43 (m, 3H), 7.42-7.38 (m, 1H), 7.23 (dd, J= 7.9, 1.9 Hz, 1H), 7.18 (dd, J= 11.0, 1.9 Hz, 1H), 3.94 (dq, J = 10.2, 7.3 Hz, 1H), 1.69 (dd, J= 13, 6.1 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 160.0 (d, J = 249.7 Hz), 138.3 (dd, J= 7.8, 2.7 Hz), 135.1, 131.6 (d, J= 4.2 Hz), 129.1 (d, J= 3.0 Hz), 128.7, 128.1, 122.8 (app t, J= 3.3 Hz), 121.1, 114.8 (dd, .7= 24.5, 3.3 Hz), 30.9 (dd, J = 57.3, 1.7 Hz), 21.3 (d, J= 2.3 Hz).19F NMR (565 MHz, CDCl3) δ -116.27. HRMS (ESI-TOF): Calculated for C1413CH12FNNa [M + Na]+: 249.0880, found 249.0882. Example 44: Synthesis of 2-(2-Fluoro-[1,1’-biphenyl]-4-yl)propanenitrile-l-13C-15N ([13C15N]17).

[0398] The test compound was prepared using General Procedure D with K13C15N as cyano source and TMSC1 as promotor. The title compound was isolated as a white solid in 95% yield (43.0 mg).1H NMR (600 MHz, CDCl3) δ 7.56-7.51 (m, 2H), 7.50-7.43 (m, 3H), 7.42-7.37 (m, 1H), 7.23 (dd, J= 7.9, 1.9 Hz, 1H), 7.18 (dd, J= 11.1, 1.9 Hz, 1H), 3.95 (dddd, J= 14.7, 8.9, 7.3, 1.5 Hz, 1H), 1.69 (dd, J= 73, 6.1 Hz, 3H).,3C NMR (151 MHz, CDCl3) δ 160.0 (d, J= 249.7 Hz), 138.3 (dd, J= 7.7, 2.7 Hz), 135.1 (d, J= 1.2 Hz), 131.6 (d,J = 4.1 Hz), 129.1 (d, J= 3.1 Hz), 128.7, 128.1, 122.8 (app t, J= 3.3 Hz), 121.1 (d, J= 16.2 Hz), 114.8 (dd, J= 24.5, 3.3 Hz), 30.9 (ddd, J= 57.2, 2.7, 1.6 Hz), 21.3 (d, J= 2.4 Hz).19F NMR (565 MHz, CDCl3) δ -116.27.15N NMR (61 MHz, CDCl3) δ 247.56 (d, J = 15.7 Hz). HRMS (ESI-TOF): Calculated for C1413CH12FNNa [M + Na]+: 250.0850, found 250.0849.

[0399] Example 45: Synthesis of (R)-2-([1,1'-biphenyl]-4-yl)propanenitrile (38).

[0400] The test compound was prepared using General Procedure B with riboflavin tetraacetate as photocatalyst under 5 °C for 18 h. The title compound was isolated as a white solid in 68% yield (14.0 mg), = +8.67 (c 0.5, CH2CI2, 86% ee).1H NMR (600 MHz, CDCl3) δ 7.62 (app d, J = 8.0 Hz, 2H), 7.60-7.57 (m, 2H), 7.49-7.41 (m, 4H), 7.41-7.34 (m, 1H), 3.95 (q, J= 7.3 Hz, 1H), 1.69 (d, J= 7.3 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 141.3, 140.4, 136.1, 129.0, 128.0, 127.8, 127.3, 127.2, 121.7, 31.1, 21.6. HPLC Conditions: Daicel Chiralpak IB, n-hexane / i-PrOH = 99 / 1, Flow rate = 1 mL / min, UV = 254 nm,it = 12.6 min (major), tR= 15.1 min (minor). HRMS (ESI- TOF): Calculated for C15H13NNa [M + Na]+: 230.0940, found 230.0944. The absolute configuration of 38 ([ = +8.67 (c 0.5, CH2CI2, 86% ee)) was assigned by comparison with the compound reported in the literature42( = +11-95 (c 1.0, CH2CI2, 92% ee))

[0401] Example 46: Synthesis of (l?)-2-([l,l'-biphenyl]-4-yl)butanenitrile (39).

[0402] The test compound was prepared using General Procedure B with riboflavin tetraacetate as photocatalyst under 5 °C for 18 h. The title compound was isolated as a white solid in 68% yield (15.0 mg), [a] = +8.96 (c 0.5, CH2CI2, 76% ee).1H NMR (600 MHz, CDCI3) 57.63-7.57 (m, 4H), 7.49-7.43 (m, 2H), 7.42-7.39 (m, 2H), 7.39-7.35 (m, 1H), 3.79 (t, J= 7.2 Hz, 1H), 2.03- 1.94 (m, 2H), 1.12 (t, J= 7.4 Hz, 3H).13C NMR (151 MHz, CDCI3) 5 141.1, 140.4, 134.8, 129.0, 127.9, 127.8, 127.7, 127.2, 120.8, 38.7, 29.3, 11.6. HPLC Conditions: Daicel Chiralpak IA, n- hexane / i-PrOH = 95 / 5, Flow rate = 1 mL / min, UV = 254 nm,it = 6.8 min (minor), tR= 7.5 min (major). HRMS (ESI-TOF): Calculated for C16H15NNa [M + Na]+: 244.1097, found 244.1099. The absolute configuration was assigned by analogy.

[0403] Example 47: Synthesis of ( R)-2-(Naphthalen-l-yl)propanenitrile (40).

[0404] To a frame dried 2-dram vial charged with a Teflon-coated stir was added Cu(OTf)2(7.2 mg, 0.02 mmol, 10 mol%), sBox (zPr) (10.6 mg, 0.03 mmol, 15 mol%), DCE (0.5 mL) and TFE (0.5 mL). The resulting mixture was stirred for 1.5 hours and then riboflavin tetraacetate (5.16 mg, 0.005 mmol, 5 mol%), 2-(naphthalen-l-yl)propanoic acid (40.0 mg, 0.2 mmol, 1 equiv), diisopropylethylamine (8.7 μL, 0.05 mmol, 25 mol%), tert-Butyl hydroperoxide solution (5-6 M in decane, 80 μL, 0.4 mmol, 2 equiv) and TMSCN (100 μL, 0.8 mmol, 4 equiv). The vial was then sealed with a Teflon coated septum cap and the mixture sparged with argon for 10 minutes. And then the reactions were stirred under irradiation with 465 run SynLED under 5 °C for 40 h. After completion, the reaction mixture was concentrated in vacuo and purified using silica gel chromatography using hexane to 5% EtOAc in hexanes as the eluent.

[0405] The title compound was isolated as a white solid in 83% yield (30.0 mg). = +33.47 (c 0.5, CH2CI2, 91% ee).1H NMR (400 MHz, CDCI3) 5 7.97-7.89 (m, 2H), 7.85 (d, J= 8.2 Hz, 1H), 7.74-7.67 (m, 1H), 7.64-7.46 (m, 3H), 4.63 (q, J= 7.1 Hz, 1H), 1.80 (dd, J= 7.1, 1.1 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 134.2, 132.8, 129.9, 129.5, 129.1, 127.1, 126.3, 125.7, 124.8,

[0406] 122.2, 121.9, 28.4, 20.7. HPLC Conditions: Daicel Chiralpak IC, n-hexane / i-PrOH = 99 / 1, Flow rate = 1 mL / min, UV = 254 nm,it = 19.2 min (major), tx = 21.6 min (minor). HRMS (ESI-TOF): Calculated for C13H11NNa [M + Na]+: 204.0784, found 204.0788. The absolute configuration of 40 ( = +33.47 (c 0.5, CH2CI2, 91% ee)) was assigned by comparison with the compound reported in the literature42([ = +42.69 (c 1.0, CH2CI2, 94% ee)).

[0407] Example 48: Synthesis of (18)-2-(3-Phenoxyphenyl)propanenitrile (41).

[0408] The title compound was prepared using General Procedure B with riboflavin tetraacetate as photocatalyst, 10 mol% Cu(OTf)2and 15 mol% sBox (iPr) under 5 °C for 20 h. The title compound was isolated as a white solid in 81% yield (18.0 mg). = +5.22 (c 0.5, CH2CI2, 82% ee). NMR (600 MHz, CDCl3) δ 7.39-7.31 (m, 3H), 7.14 (app it, J= 7.5, 1.1 Hz, 1H), 7.10 (app ddt, J= 7.7, 1.6, 0.8 Hz, 1H), 7.04-6.99 (m, 3H), 6.94 (ddd, J= 8.2, 2.4, 1.0 Hz, 1H), 3.87 (q, J= 7.3 Hz, 1H), 1.64 (d, J= 7.3 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 158.2, 156.7, 139.1, 130.6, 130.1, 123.9, 121.4, 119.3, 118.2, 117.2, 31.2, 21.4. HPLC Conditions: Daicel Chiralpak IB, n-hexane / i-PrOH = 90 / 10, Flow rate = 1 mL / min, UV = 254 nm, tR= 7.2 min (major), tR= 8.4 min (minor). HRMS (ESI-TOF): Calculated for C15H13NNaO [M + Na]+: 246.0889, found 246.0894. The absolute configuration was assigned by analogy.

[0409] Example 49: Synthesis of (R)-2-(10-Oxo-10,ll-dihydrodibenzo[b,flthiepin-2- yl)propanenitrile (42).

[0410] To a frame dried 2-dram vial charged with a Teflon-coated stir was added Cu(OTf)z (1.8 mg, 0.005 mmol, 5 mol%), (3aR,3a'R,8aS,8a,S)-2,2'-(cyclopropane-l,l-diyl)bis(3a,8a-dihydro- 8H -indeno[l,2--d]oxazole) (2.67 mg, 0.0075 mmol, 7.5 mol%), DCE (0.5 mL) and TFE (0.5 mL). The resulting mixture was stirred for 1.5 hours and riboflavin tetraacetate (2.58 mg, 0.005 mmol, 5 mol%), Zaltoprofen (29.8 mg, 0.1 mmol, 1 equiv.), diisopropylethylamine (4.4 μL, 0.025 mmol, 25 mol%), tert-Butyl hydroperoxide solution (5-6 M in decane, 40 μL, 0.2 mmol, 2 equiv.) and TMSCN (50 μL, 0.4 mmol, 4 equiv.). The vial was then sealed with a Teflon coated septum cap and the mixture sparged with argon for 10 minutes. And then the reactions were stirred under irradiation with 465 nm SynLED under 5 °C for 18 h. After completion, the reaction mixture was concentrated in vacuo and purified using silica gel chromatography using hexane to 5% EtOAc in hexanes as the eluent. The title compound was isolated as a white solid in 82% yield (23.0 mg). = +10.21 (c 0.5, CH2CI2, 83% ee).1H NMR (600 MHz, CDCI3) 58.20 (dd, J = 8.0, 1.6 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.60 (dd, J = 7.9, 1.2 Hz, 1H), 7.46-7.41 (m, 2H), 7.33 (ddd, J =

[0411] 7.9, 7.2, 1.2 Hz, 1H), 7.22 (dd, J= 8.0, 2.1 Hz, 1H), 4.40 (d, J= 11.9 Hz, 1H), 4.37 (d, J= 11.9 Hz, 1H), 3.90 (q, J= 13 Hz, 1H), 1.63 (d, J= 13 Hz, 3H).13C NMR (151 MHz, CDCI3) 5 191.1,

[0412] 139.9, 139.2, 138.8, 136.2, 134.7, 132.8, 132.2, 131.7, 131.1, 127.8, 127.2, 125.7, 121.1, 51.1, 31.1, 21.5. HPLC Conditions: Daicel Chiralpak IC, n-hexane / i-PrOH = 80 / 20, Flow rate = 1 mL / min, UV = 254 nm, tR= 27.3 min (major), tR= 31.3 min (minor). HRMS (ESI-TOF):

[0413] Calculated for C17H14NOS [M + H]+: 280.0791, found 280.0794. The absolute configuration of = +10.21 (c 0.5, CH2CI2, 83% ee)) was assigned by comparison with the compound reported in the literature42 = +17.83 (c 0.7, CH2CI2, 86% ee))

[0414] Example 50: Synthesis of 4-(2-(2,2,2-Trifluoroethoxy)propan-2-yl)-l,l,-biphenyl (18b)

[0415] To a frame dried 2-dram vial charged with a Teflon-coated stir was added 2-([l,l'- biphenyl]-4-yl)-2-methylpropanoic acid (48.1 mg, 0.2 mmol, 1 equiv.), potassium persulfate (108 mg, 0.4 mmol, 2 equiv.), 3,6-di-tertbutyl-9-mesityl-10-phenylacridinium tetrafluoroborate (5.74 mg, 0.01 mmol, 5 mol%), diisopropylethylamine (8.7 μL, 0.05 mmol, 25 mol%), TFE (1 mL) and ethyl acetate (1 mL). The vial was then sealed with a Teflon coated septum cap and the mixture sparged with argon for 10 minutes. And then the reactions were stirred under irradiation with 465 nm SynLED under 35 °C for 18 h. After completion, the reaction mixture was concentrated in vacuo and purified using silica gel chromatography using hexane to 2% EtOAc in hexanes as the eluent. The product was obtained as colorless oil in 82% yield (48.0 mg).1H NMR (600 MHz, CDCl3) δ 7.64-7.59 (m, 4H), 7.53-7.48 (m, 2H), 7.48-7. 44 (m, 2H), 7.39-7.35 (m, 1H), 3.58 (q, J= 8.7 Hz, 2H), 1.64 (s, 6H).13C NMR (151 MHz, CDCl3) δ 143.4, 140.7, 140.6, 129.0, 127.6, 127.4, 127.2, 126.4, 124.4 (q, J = 277.6 Hz), 78.5, 61.7 (q, J = 34.2 Hz), 28.1.19F NMR (565 MHz, CDCl3) δ -74.04. HRMS (ESI-TOF): Calculated for C17H17F3NaO [M + Na]+: 317.1124, found 317.1123.

[0416] Example 51: Synthesis of 2-([l,l’-Biphenyl]-4-yl)-2-methylpropanenitrile (18)

[0417] To a frame dried 2-dram vial charged with a Teflon-coated stir was added 4-(2-(2,2,2- Trifluoroethoxy)propan-2-yl)- 1,1 '-biphenyl (29.4 mg, 0.1 mmol, 1 equiv.) and dry MeCN (1 mL). The resulting mixture was cooled to 0 °C. After 5 min, TMSCN (37.5 μL, 0.3 mmol, 3 equiv) was added dropwise, followed by addition of BF3.Et2O (75 μL, 0.6 mmol, 6 equiv.) dropwise. The reaction was stirred for 1 h at the same temperature. Aqueous NH4CI (3 drops) was added and the resulting mixture was vigorously stirred at room temperature for 5 min. The reaction mixture was concentrated in vacuo and purified using silica gel chromatography first using hexane to 5% EtOAc in hexanes as the eluent, followed by a second column with toluene as eluent. The product was obtained as white solid in 76% yield (16.9 mg).1H NMR (600 MHz, CDCl3) δ 7.63-7.60 (m, 2H), 7.60-7.57 (m, 2H), 7.56-7.53 (m, 2H), 7.47-7.44 (m, 2H), 7.39-7.34 (m, 1H), 1.77 (s, 6H).13C NMR (151 MHz, CDCl3) δ 141.0, 140.6, 140.4, 129.0, 127.8, 127.7, 127.2, 125.7, 124.7, 37.1, 29.3. HRMS (ESI-TOF): Calculated for C16H15NNa [M +Na]+: 244.1097, found 244.1095.

[0418] Example 52: Synthesis of 2,2-Dimethyl-3-phenyipropanenitrile (19).

[0419] The test compound was prepared using General Procedure A under 35 °C for 18 h. The title compound was isolated using hexane to 5% ethyl acetate in hexane as eluent as a colorless oil in 35% yield (11.0 mg).1H NMR (600 MHz, CDCl3) δ 7.36-7.32 (m, 2H), 7.32-7.29 (m, 1H), 7.30-7.26 (m, 2H), 2.82 (s, 2H), 1.35 (s, 6H)13C NMR (151 MHz, CDCl3) δ 135.8, 130.4, 128.5, 127.5, 124.9, 46.8, 33.6, 26.6. HRMS (ESI-TOF): Calculated for C11H13NNa [M + Na]+: 182.0940, found 182.0943.

[0420] Example 53: Synthesis of Compounds 20 and 20’.

[0421] The test compounds were prepared using General Procedure A under 5 °C for 18 h. The title compounds were isolated using 20% ethyl acetate in hexane as eluent as a white solid in 55% yield with dr = 2.3:1. The stereochemistry was assigned according to 2D NMR analysis (vide infra). 1H NMR (600 MHz, CDCl3) δ 5.58 (s, 1H), 3.23 (dd, J= 11.0, 5.3 Hz, 1H), 2.76 (app dt, J= 13.5, 3.6 Hz, 1H), 2.33 (s, 1H), 2.29 (app t, J= 13.7 Hz, 1H), 2.11-1.98 (m, 3H), 1.82 (app td, J= 13.8, 4.7 Hz, 1H), 1.71-1.65 (m, 2H), 1.65-1.59 (m, 3H), 1.56 (ddd, J= 13.7, 4.5, 2.4 Hz, 1H), 1.50-1.41 (m, 4H), 1.39 (s, 3H), 1.38 (s, 3H), 1.26-1.20 (m, 2H), 1.13 (s, 3H), 1.12 (s, 3H), 1.09- 1.02 (m, 1H), 1.00 (s, 3H), 0.97 (dd, J= 13.1, 4.7 Hz, 1H), 0.88 (s, 3H), 0.80 (s, 3H), 0.70 (dd, J = 11.9, 1.9 Hz, 1H)13C NMR (151 MHz, CDCl3) δ 200.0, 167.1, 129.2, 126.1, 78.8, 62.0, 55.0, 45.6, 45.3, 43.4, 39.9, 39.3, 39.2, 37.2, 34.2, 32.9, 32.2, 31.9, 30.6, 28.4, 28.2, 27.4, 26.4, 26.3, 23.6, 20.5, 18.8, 17.6, 16.5, 15.7.

[0422] 1H NMR (600 MHz, CDCl3) δ 5.69 (s, 1H), 3.22 (dd, J= 11.2, 5.1 Hz, 1H), 2.78 (app dt, J= 13.5, 3.6 Hz, 1H), 2.36 (ddd, J= 13.3, 5.3, 1.8 Hz, 1H), 2.31 (s, 1H), 1.94 (app td, J= 13.5, 4.2 Hz, 1H), 1.86 (app td, J= 13.5, 4.4 Hz, 1H), 1.80-1.69 (m, 3H), 1.69-1.59 (m, 5H), 1.54 (app dt, J= 14.5, 3.2 Hz, 1H), 1.49-1.45 (m, 2H), 1.44-1.39 (m, 2H), 1.36 (s, 3H), 1.33 (s, 3H), 1.27- 1.23 (m, 1H), 1.22-1.18 (m, 1H), 1.14 (s, 3H), 1.13 (s, 3H), 1.09-1.03 (m, 1H), 1.00 (s, 3H), 0.93 (s, 3H), 0.80 (s, 3H), 0.69 (dd, J= 11.9, 1.8 Hz, 1H)13C NMR (151 MHz, CDCl3) δ 199.9, 167.2, 129.2, 123.5, 78.9, 62.0, 55.1, 48.3, 45.5, 43.3, 42.5, 39.3, 37.5, 37.3, 35.3, 32.9, 32.8, 32.1, 28.23, 28.20, 27.5, 27.4, 26.5, 26.4, 23.5, 18.8, 17.6, 16.5, 15.7. HRMS (ESI-TOF): Calculated for G30H45NNaO2[M + Na]+: 474.3343, found 474.3351.

[0423] Example 54: Synthesis of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR) -9-Hydroxy- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-3aH-cyclopenta[«]chrysene-3a- carbonltrile (21).

[0424] The test compound was prepared using General Procedure A under 35 °C for 18 h. The title compounds were isolated using 10% ethyl acetate in hexane as eluent as a white solid in 26% yield (23.0 mg) with dr > 20: 1.1H NMR (600 MHz, CDCl3) δ 4.85 (dd, J = 1.7, 0.9 Hz, 1H), 4.74 (app t, J = 1.5 Hz, 1H), 3.20 (dd, J= 11.6, 4.7 Hz, 1H), 2.41 (app td, J= 8.7, 4.5 Hz, 1H), 2.06- 1.92 (m, 3H), 1.86-1.75 (m, 5H), 1.70-1.60 (m, 4H), 1.58-1.50 (m, 4H), 1.45-1.27 (m, 7H), 1.26- 1.17 (m, 3H), 0.98 (s, 3H), 0.97 (s, 3H), 0.95-0.90 (m, 4H), 0.83 (s, 3H), 0.76 (s, 3H), 0.71-0.67 (m, 1H).13C NMR (151 MHz, CDCl3) δ 148.0, 127.0, 110.5, 79.0, 55.6, 54.5, 51.1, 47.9, 42.1, 41.7, 40.8, 40.3, 39.0, 38.9, 37.3, 36.6, 33.8, 31.1, 29.4, 28.1, 27.5, 27.2, 26.3, 21.3, 21.0, 18.2, 16.5, 15.9, 15.7, 15.5. HRMS (ESI-TOF): Calculated for C30H48NO [M + H]+: 438.3730, found 438.3737.

[0425] Example 55: Synthesis of 2-(4-Isobutylphenyl)propanenitrile (43).

[0426] The test compound was prepared using General Procedure A under 35 °C for 18 h. The desired product 33 were isolated using 5% ethyl acetate in hexane as eluent as a colorless oil in 83% yield (31.0 mg).1H NMR (600 MHz, CDCl3) δ 7.29-7.27 (m, 2H), 7.20-7.17 (m, 2H), 3.90 (q, J= 13 Hz, 1 H), 2.50 (d, J= 7.2 Hz, 2H), 1.95-1.82 (m, 1 H), 1.66 (d, J= 13 Hz, 3H), 0.93 (d, J= 6.6 Hz, 6H).13C NMR (151 MHz, CDCl3) δ 141.8, 134.4, 129.9, 126.6, 122.0, 45.1, 31.0, 30.3, 22.5, 21.6. HRMS (ESI-TOF): Calculated for C13H17NNa [M + Na]+: 210.1253, found 210.1254.

[0427] Example 56: Synthesis of (9H-fluoren-9-yl)methyl (2-((cyanomethyl)amino)-2- oxoethyl)carbamate (22).

[0428] The test compound was prepared using General Procedure A under 35 °C for 18 h as solvent. The title compounds were isolated using hexane to 50% ethyl acetate in hexane as eluent, as a white solid in 33% yield (22.2 mg). (14:1 rotamer).!H NMR (600 MHz, (CD3)2SO) δ 8.60 (t, J= 5.7 Hz, 1H), 7.90 (app d, J= 7.5 Hz, 2H), 7.72 (app d, J= 7.5 Hz, 2H), 7.64 (t, J= 6.2 Hz, 1H), 7.42 (app t, J= 7.4 Hz, 2H), 7.37-7.30 (m, 2H), 4.30 (d, J= 7.1 Hz, 2H), 4.23 (t, J= 7.1 Hz, 1H), 4.14 (d, J= 5.7 Hz, 2H), 3.65 (d, J= 6.1 Hz, 2H).13C NMR (151 MHz, (CD3)2SO) δ 170.0, 156.5, 143.8, 140.7, 127.7, 127.1, 125.3, 120.1, 117.6, 65.8, 46.6, 43.3, 27.0. HRMS (ESI-TOF): Calculated for C19H17N3NaO3[M + Na]+: 358.1162, found 358.1157. Example 57: Synthesis of (9H-fluoren-9-yl)methyl (S)-(l-amlno-4-cyano-l-oxobutan-2-yl) (23).

[0429] The title compound was prepared using General Procedure A. and was isolated using 50% ethyl acetate in hexane to 80% ethyl acetate in hexane as eluent as a white solid in 33% yield (23.0 mg).1H NMR (600 MHz, CD3OD) 8 7.80 (app d, J = 7.6 Hz, 2H), 7.67 (app dd, J= 7.7, 4.3 Hz, 2H), 7.39 (app t, J= 7.5 Hz, 2H), 7.32 (app t, J= 7.5 Hz, 2H), 4.50 (dd, J= 10.6, 6.7 Hz, 1H), 4.42 (dd, J= 10.8, 6.4 Hz, 1H), 4.23 (app t, J= 6.5 Hz, 1H), 4.17 (dd, J= 9.7, 4.6 Hz, 1H), 2.44 (app t, J= 7.5 Hz, 2H), 2.18-2.10 (m, 1H), 1.95-1.86 (m, 1H)13C NMR (151 MHz, CD3OD) 8 175.9, 158.4, 145.3, 145.2, 142.69, 142.66, 128.81, 128.79, 128.2, 126.24, 126.15, 120.93, 120.91, 120.3, 67.8, 54.9, 29.2, 14.5. HRMS (ESI-TOF): Calculated for C20H19N3NaO3[M + Na]+: 372.1319, found 372.1316.

[0430] Example 58: Synthesis of (9H-fluoren-9-yl)methyl (2-methyl-l-(2,2,2- trifluoroethoxy)propyl)carbamate (24b).

[0431] The title compound was prepared using General Procedure C under 5 °C for 18 h. The title compounds were isolated using hexane to 5% ethyl acetate in hexane as eluent as a white solid in 67% yield (53.0 mg).1H NMR (600 MHz, CDCl3) δ 7.78 (ddd, J= 7.6, 2.3, 1.2 Hz, 2H), 7.59 (dd, J= 7.6, 3.4 Hz, 2H), 7.41 (app td, J= 7.5, 3.7 Hz, 2H), 7.33 (app tdd, J= 6.9, 5.7, 1.1 Hz, 2H), 5.05 (d, J= 10.5 Hz, 1H), 4.79 (dd, J= 10.4, 6.2 Hz, 1H), 4.60 (dd, J= 10.9, 6.5 Hz, 1H), 4.49 (dd, J= 10.9, 6.2 Hz, 1H), 4.22 (app t, J= 6.4 Hz, 1H), 3.89-3.76 (m, 2H), 1.85 (h, J= 6.7 Hz, 1H), 0.97 (d, J= 6.7 Hz, 3H), 0.92 (d, J= 6.9 Hz, 3H)13C NMR (151 MHz, CDCl3) δ 156.5, 143.8, 143.6, 141.58, 141.56, 127.98, 127.95, 127.24, 127.20, 125.1, 124.9, 124.0 (d, J= 278.3 Hz), 120.22, 120.18, 87.6, 66.7, 65.8 (q, J= 34.3 Hz), 47.5, 33.1, 17.8, 17.519F NMR (565 MHz, CDCI3) 8 -74.37, -77.14. HRMS (ESI-TOF): Calculated for C21H22F3NNaO3[M + Na]+: 416.1444, found 416.1444. Example 59: Synthesis of (9ZMluoren-9-yl)methyl (l-cyano-2-methylpropyl)carbamate (24).

[0432] The title compound was prepared using General Procedure C and was isolated using hexane to 10% ethyl acetate in hexane as eluent as a white solid in 84% yield (27.0 mg).1H NMR (600 MHz, CDCI3) 57.78 (app d, J= 7.5 Hz, 2H), 7.58 (app d, J= 7.5 Hz, 2H), 7.42 (app td, J= 73, 2.4 Hz, 2H), 7.36-7.31 (m, 2H), 5.05 (d, J= 9.4 Hz, 1H), 4.58-4.45 (m, 3H), 4.22 (app t, J= 6.5 Hz, 1H), 2.08-1.99 (m, 1H), 1.09 (d, J= 6.7 Hz, 3H), 1.06 (d, J= 6.8 Hz, 3H).13C NMR (151

[0433] MHz, CDCl3) δ 155.4, 143.64, 143.57, 141.5, 128.02, 128.00, 127.3, 125.03, 124.99, 120.23, 120.21, 117.8, 67.5, 49.1, 47.2, 32.0, 18.7, 18.1. HRMS (ESI-TOF): Calculated for C20H20N2NaO2[M + Na]+: 343.1417, found 343.1417.

[0434] Example 60: Synthesis of (9H -fluoren-9-yl)methyl (l-(cyano-13C)-2- methylpropyl)carbamate (I13C]24).

[0435] The title compound was prepared using General Procedure C with in situ generation of TMSCN from TMSC1, KI and K13CN based on the method in General Procedure D. The title compounds were isolated using hexane to 10% ethyl acetate in hexane as eluent as a white solid in 30% yield (8.7 mg).1H NMR (600 MHz, CDCl3) δ 7.78 (app d, J = 7.6 Hz, 2H), 7.58 (app d, J= 7.5 Hz, 2H), 7.42 (app td, J= 7.1, 2.0 Hz, 2H), 7.33 (app td, J= 7.4, 1.2 Hz, 2H), 5.03 (d, J= 9.4 Hz, 1H), 4.55-4.46 (m, 3H), 4.22 (app t, J= 6.6 Hz, 1H), 2.11-1.98 (m, 1H), 1.09 (d, J= 6.7 Hz, 3H), 1.06 (d, J= 6.8 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 155.4, 143.64, 143.57, 141.5, 128.02, 128.01, 127.3, 125.03, 124.99, 120.23, 120.21, 117.8, 67.6, 49.1 (d, J= 60.4 Hz), 47.2, 32.0, 18.7 (d, J= 2.1 Hz), 18.1. HRMS (ESI-TOF): Calculated for G1913CH20N2NaO2[M + Na]+: 344.1451, found 344.144. Example 61: Synthesis of (9H -fluoren-9-yl)methyl (l-(2,2,2-trifluoroethoxy)ethyl)carbamate (25b).

[0436] The title compound was prepared using General Procedure C under 5 °C for 18 h. The title compounds were isolated using hexane to 5% ethyl acetate in hexane as eluent as a white solid in 44% yield (32.0 mg). (9:1 rotamer) *H NMR (600 MHz, CDCl3) δ 7.78 (app dd, J= 7.6, 2.6 Hz, 2H), 7.58 (app dd, J= 7.6, 3.7 Hz, 2H), 7.41 (app tt, J= 8.3, 4.1 Hz, 2H), 7.36-7.31 (m, 2H), 5.25-5.15 (m, 2H), 4.59 (dd, J= 10.8, 6.6 Hz, 1H), 4.43 (dd, J= 10.8, 6.3 Hz, 1H), 4.24-419 (m, 1H), 3.90 (dq, J= 11.8, 8.6 Hz, 1H), 3.82 (dq, J= 12.1, 8.8 Hz, 1H), 1.40 (d, J= 5.7 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 156.0, 143.8, 143.5, 141.5, 127.98, 127.95, 127.24, 127.20, 125.1, 124.9, 124.0 (q, J= 278.3 Hz), 120.22, 120.18, 80.2, 66.8, 65.7 (q, J= 34.3 Hz), 47.3, 21.6.19F NMR (565 MHz, CDCl3) δ -74.30, -74.51. HRMS (ESI-TOF): Calculated for C19H18F3NNaO3[M + Na]+: 388.1131, found 388.1131.

[0437] Example 62: Synthesis of (9H -fluoren-9-yl)methyl (l-cyanoethyl)carbamate (25).

[0438] The title compound was prepared using General Procedure C. The title compounds were isolated using hexane to 10% ethyl acetate in hexane as eluent as a white solid in 68% yield (20.0 mg).1H NMR (600 MHz, CDCl3) δ 7.77 (app d, J= 7.5 Hz, 2H), 7.61-7.53 (m, 2H), 7.41 (app t, J= 7.5 Hz, 2H), 7.33 (app t, J= 6.9 Hz, 2H), 5.12-5.03 (m, 1H), 4.71-4.63 (m, 1H), 4.54-4.45 (m, 2H), 4.21 (app t, J= 6.6 Hz, 1H), 1.56 (d, J= 7.2 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 155.0, 143.6, 141.48, 141.46, 128.0, 127.3, 125.02, 125.00, 120.2, 119.2, 67.6, 47.2, 38.2, 19.7. HRMS (ESI-TOF): Calculated for C18H16N2NaO2[M + Na]+: 315.1104, found 315.1109.

[0439] Example 63: Synthesis of (9H-fluoren-9-yl)methyl (phenyl(2,2,2- trifluoroethoxy)methyl)carbamate (26b).

[0440] The title compound was prepared using General Procedure C under 5 °C for 18 h. The title compounds were isolated using hexane to 5% ethyl acetate in hexane as eluent as a white solid in 50% yield (42.3 mg). (8:1 rotamer).1H NMR (600 MHz, CDCl3) δ 7.80-7.75 (m, 2H), 7.64- 7.57 (m, 2H), 7.45-7.30 (m, 9H), 6.10 (d, J= 9.9 Hz, 1H), 5.42 (d, J= 10.0 Hz, 1H), 4.63 (dd, J = 10.7, 6.6 Hz, 1H), 4.52 (dd, J= 10.8, 6.4 Hz, 1H), 4.23 (app t, J= 6.5 Hz, 1H), 4.06-3.95 (m, 2H).13C NMR (151 MHz, CDCl3) δ 156.2, 143.7, 143.6, 141.6, 137.8, 129.1, 128.9, 128.8, 128.01, 127.98, 127.3, 127.2, 125.9, 125.1, 125.0, 123.9 (d, J= 277.7 Hz), 120.23, 120.21, 83.6, 67.0, 65.9 (q, J= 34.7 Hz), 47.4.19F NMR (565 MHz, CDCl3) δ -74.14. HRMS (ESI-TOF): Calculated for C24H20F3NNaO3[M + Na]+: 450.1288, found 450.1282.

[0441] Example 64: Synthesis of (9H -fluoren-9-yl)methyl (cyano(phenyl)methyl)carbamate (26).

[0442] The title compound was prepared using General Procedure C. The title compounds were isolated using hexane to 15% ethyl acetate in hexane as eluent as a white solid in 86% yield (30.6 mg).1H NMR (600 MHz, CDCl3) δ 7.77 (app d, J= 7.5 Hz, 2H), 7.60-7.54 (m, 2H), 7.48-7.39 (m, 7H), 7.35-7.30 (m, 2H), 5.84 (d, J= 8.7 Hz, 1H), 5.29 (d, J= 8.1 Hz, 1H), 4.55 (d, J= 6.6 Hz, 2H), 4.23 (app t, J= 6.6 Hz, 1H).13C NMR (151 MHz, CDCl3) δ 155.1, 143.6, 143.5, 141.51, 141.49, 133.1, 129.9, 129.6, 128.0, 127.3, 127.1, 125.03, 125.01, 120.24, 120.22, 117.5, 67.7,47.2, 46.7. HRMS (ESI-TOF): Calculated for C23H18N2NaO2[M + Na]+: 377.1266, found 377.1268.

[0443] Example 65: Synthesis of (9 / 7-fluoren-9-yl)methyl (2-phenyl-l-(2,2,2- trifluoroethoxy)ethyl)carbamate (27b).

[0444] The title compound was prepared using General Procedure C under 5 °C for 18 h with TFE / EA (1:1, 0.1 M) as solvent. The title compounds were isolated using hexane to 5% ethyl acetate in hexane as eluent as a white solid in 40% yield (35.0 mg). (7.22:1 rotamer)1H NMR (600 MHz, CDCl3) δ 7.77 (app dd, J= 7.7, 3.3 Hz, 2H), 7.51 (app dd, J= 17.0, 7.5 Hz, 2H), 7.41 (app q, J= 7.0 Hz, 2H), 7.34-7.27 (m, 5H), 7.23 (app d, J= 7.5 Hz, 2H), 5.33 (app dt, J= 11.0, 5.7 Hz, 1H), 5.15 (d, J= 10.2 Hz, 1H), 4.48 (dd, J= 10.8, 6.9 Hz, 1H), 4.42 (dd, J= 10.8, 6.4 Hz, 1H), 4.18 (app t, J= 6.7 Hz, 1H), 3.91-3.79 (m, 2H), 3.03 (dd, J= 14.1, 5.7 Hz, 1H), 2.96 (dd, J = 14.1, 5.6 Hz, 1H).13C NMR (151 MHz, CDCl3) δ 156.0, 143.8, 143.5, 141.49, 141.47, 135.1, 129.9, 129.8, 128.71, 128.67, 128.6, 128.0, 127.9, 127.3, 127.20, 127.18, 125.1, 125.0, 123.9 (q, J= 277.9 Hz), 120.20, 120.17, 83.3, 66.9, 65.8 (q, J= 34.5 Hz), 47.3, 41.4.19F NMR (565 MHz, CDCb) 5 -74.19, -74.32. HRMS (ESI-TOF): Calculated for C25H22F3NNaO3[M + Na]+: 464.1444, found 464.1443.

[0445] Example 66: Synthesis of (9H -fluoren-9-yl)methyl (l-cyano-2-phenylethyl)carbamate (27).

[0446] The title compound was prepared using General Procedure C. The title compounds were isolated using hexane to 10% ethyl acetate in hexane as eluent as a white solid in 82% yield (30.3 mg).1H NMR (600 MHz, CDCl3) δ 7.78 (app d, J= 7.6 Hz, 2H), 7.57-7.51 (m, 2H), 7.42 (app t, J= 7.5 Hz, 2H), 7.39-7.31 (m, 5H), 7.27-7.22 (m, 2H), 5.03 (d, J= 8.9 Hz, 1H), 4.88 (app q, J= 7.4 Hz, 1H), 4.55-4.40 (m, 2H), 4.20 (app t, J= 6.7 Hz, 1H), 3.16-3.00 (m, 2H)13C NMR (151 MHz, CDCl3) δ 155.0, 143.6, 143.5, 141.50, 141.48, 133.7, 129.7, 129.2, 128.2, 128.0, 127.3, 125.1, 125.0, 120.2, 118.0, 67.6, 47.2, 43.9, 39.2. HRMS (ESI-TOF): Calculated for C24H20N2NaO2[M + Na]+: 391.1417, found 391.1412.

[0447] Example 67: Synthesis of Benzyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2,2,2- trifluoroethoxy)butanoate (28b).

[0448] The title compound was prepared using General Procedure C under 5 °C for 18 h as solvent. The title compounds were isolated using hexane to 10% ethyl acetate in hexane as eluent, as a white solid in 57% yield (59 mg).1H NMR (600 MHz, CDCl3) δ 7.77 (app d, J = 7.6 Hz, 2H), 7.58 (dd, J= 7.5, 4.8 Hz, 2H), 7.44-7.39 (m, 2H), 7.38-7.29 (m, 7H), 5.40 (d, J= 10.1 Hz, 1H), 5.18-5.07 (m, 3H), 4.57 (dd, J= 10.8, 6.7 Hz, 1H), 4.43 (dd, J= 10.8, 6.4 Hz, 1H), 4.20 (app t, J= 6.3 Hz, 1H), 3.95-3.77 (m, 2H), 2.54 (app dt, J= 16.8, 7.1 Hz, 1H), 2.44 (app dt, J= 16.9, 7.2 Hz, 1H), 2.08-1.94 (m, 2H).13C NMR (151 MHz, CDCl3) δ 172.8, 156.2, 143.8, 143.6, 141.54, 141.51, 135.8, 128.7, 128.5, 128.4, 127.99, 127.97, 127.3, 127.2, 125.1, 125.0, 123.9 (d, J= 278.2 Hz), 120.22, 120.18, 82.6, 66.9, 66.8, 65.8 (q, J= 34.4 Hz), 47.4, 30.2, 29.7.19F NMR (565 MHz, CDCl3) δ -74.40. HRMS (ESI-TOF): Calculated for C28H26F3NNaO5[M + Na]+: 536.1655, found 536.1649.

[0449] Example 68: Synthesis of Benzyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4- cyanobutanoate (28).

[0450] The title compound was prepared using General Procedure C. The title compounds were isolated using hexane to 15% ethyl acetate in hexane as eluent, as a white solid in 98% yield (43 mg).1H NMR (600 MHz, CDCl3) δ 7.76 (app d, J= 7.7 Hz, 1H), 7.60-7.55 (m, 2H), 7.44-7.30 (m, 9H), 5.46 (d, J= 8.7 Hz, 1H), 5.14 (s, 2H), 4.74-4.66 (m, 1H), 4.54-4.41 (m, 2H), 4.26-4.16 (m, 1H), 2.66-2.48 (m, 2H), 2.20-2.13 (m, 2H).13C NMR (151 MHz, CDCl3) δ 172.1, 155.3, 143.6, 143.5, 141.5, 135.4, 128.8, 128.7, 128.6, 128.5, 128.0, 127.3, 125.1, 120.2, 118.0, 67.6, 67.2, 47.2, 42.3, 30.0, 28.2. HRMS (ESI-TOF): Calculated for C27H24N2NaO4[M + Na]+: 463.1634, found 463.1632.

[0451] Example 69; Synthesis of (9H -fluoren-9-yl)methyl (2-hydroxy-1 -(2,2,2- trifluoroethoxy)ethyl)carbamate (29b).

[0452] The title compound was prepared using General Procedure C under 5 °C for 18 h. The title compounds were isolated first using hexane to 20% ethyl acetate in hexane as eluent, then with 5% EA in DCM as eluent for the second column as a colorless oil in 52% yield (40.0 mg).1H NMR (600 MHz, CDCl3) δ 7.79-7.75 (m, 2H), 7.61-7.56 (m, 2H), 7.41 (app td, J = 7.5, 3.6 Hz, 2H), 7.35-7.29 (m, 2H), 5.72 (d, J= 10.1 Hz, 1H), 5.22-5.07 (m, 1H), 4.60 (dd, J= 10.7, 6.6 Hz, 1H), 4.46 (dd, J= 10.7, 6.3 Hz, 1H), 4.22 (app t, J= 6.3 Hz, 1H), 4.00-3.79 (m, 3H), 3.59 (ddd, J= 12.2, 8.3, 3.8 Hz, 1H), 2.04 (t, J= 6.9 Hz, 1H).13C NMR (151 MHz, CDCl3) δ 156.4, 143.8, 143.5, 141.54, 141.52, 128.01, 127.99, 127.3, 127.2, 125.1, 124.9, 123.8 (q, J= 278.5 Hz), 120.24, 120.20, 82.4, 67.0, 65.7 (q, J= 34.6 Hz), 64.3, 47.3.19F NMR (565 MHz, CDCl3) δ - 74.22, -74.39. HRMS (ESI-TOF): Calculated for (C19H18F3NNaO4[M + Na]+: 404.1080, found 404.1078.

[0453] Example 70: Synthesis of (9H-fluoren-9-yl)methyl (l-cyano-2-hydroxyethyl)carbamate (29).

[0454] The title compound was prepared using General Procedure C. The title compounds were isolated using hexane to 20% ethyl acetate in hexane as eluent as a white solid in 84% yield (26.0 mg).1H NMR (600 MHz, CDCl3) δ 7.77 (app d, J= 7.5 Hz, 2H), 7.60-7.54 (m, 2H), 7.42 (app t, J= 7.5 Hz, 2H), 7.33 (app td, J= 7.4, 1.1 Hz, 2H), 5.54 (d, J= 7.7 Hz, 1H), 4.75-4.68 (m, 1H), 4.55-4.44 (m, 2H), 4.28-4.18 (m, 1H), 3.96 (d, J= 11.3 Hz, 1H), 3.86-3.78 (m, 1H), 2.31 (br s, 1H).,3C NMR (151 MHz, CDCl3) δ 155.5, 143.6, 143.5, 141.50, 141.48, 128.1, 127.3, 125.1, 120.2, 117.3, 67.8, 62.8, 47.2, 45.1. HRMS (ESI-TOF): Calculated for C18H16N2NaO3[M + Na] *: 331.1053, found 331.1050.

[0455] Example 71: Synthesis of (9H-fluoren-9-yl)methyl (5-(l,3-dioxoisoindolin-2-yl)-l-(2,2,2- trifluoroethoxy)pentyl)carbamate (30b).

[0456] The title compound was prepared using General Procedure C under 5 °C for 18 h. The title compounds were isolated using hexane to 20% ethyl acetate in hexane as eluent as a white solid in 62% yield (68.0 mg).1H NMR (600 MHz, CDCl3) δ 7.82 (app dd, J = 5.4, 3.1 Hz, 2H), 7.76 (app dd, J= 7.6, 3.2 Hz, 2H), 7.58 (app dd, J= 5.5, 3.0 Hz, 2H), 7.58 (app t, J= 6.4 Hz, 2H), 7.40 (app q, J= 6.9 Hz, 2H), 7.33-7.28 (m, 2H), 5.29 (d, J= 10.1 Hz, 1H), 5.04 (app dt, J= 10.1, 6.3 Hz, 1H), 4.55 (dd, J= 10.8, 6.7 Hz, 1H), 4.41 (dd, J= 10.8, 6.4 Hz, 1H), 4.19 (app t, J= 6.6 Hz, 1H), 3.92-3.79 (m, 2H), 3.73-3.64 (m, 2H), 1.80-1.67 (m, 4H), 1.49-1.43 (m, 1H), 1.41-1.35 (m, 1H)13C NMR (151 MHz, CDCl3) δ 168.6, 156.3, 143.8, 143.6, 141.51, 141.49, 134.1, 132.2, 128.0, 127.9, 127.23, 127.19, 125.1, 125.0, 123.9 (q, J = 278.5 Hz), 123.4, 120.2, 120.1, 83.3, 66.8, 65.8 (q, J= 34.2 Hz), 47.4, 37.4, 34.5, 28.0, 21.9.”F NMR (565 MHz, CDCl3) δ -74.39, - 85.25. HRMS (ESI-TOF): Calculated for C30H27F3N2NaO5[M + Na]+: 575.1764, found 575.1760.

[0457] Example 72: Synthesis of (9 H-fluoren-9-yl)methyl (l-cyano-5-(l,3-dioxoisoindolin-2- yl)pentyl)carbamate (30).

[0458] The title compound was prepared using General Procedure C. The title compounds were isolated using hexane to 20% ethyl acetate in hexane as eluent as a white solid in 98% yield (47.0 mg).1H NMR (600 MHz, CDCl3) δ 7.87-7.79 (m, 2H), 7.75 (app d, J= 7.6 Hz, 2H), 7.72-7.66 (m, 2H), 7.57 (app d, J= 7.5 Hz, 2H), 7.39 (app t, J= 7.5 Hz, 2H), 7.32-7.28 (m, 2H), 5.43 (d, J = 8.6 Hz, 1H), 4.59 (app q, J= 7.6 Hz, 1H), 4.50-4.38 (m, 2H), 4.19 (app t, J= 6.9 Hz, 1H), 3.73- 3.65 (m, 2H), 1.94-1.86 (m, 2H), 1.77-1.67 (m, 2H), 1.54-1.45 (m, 2H).13C NMR (151 MHz, CDCl3) δ 168.7, 168.6, 155.3, 143.63, 143.59, 141.4, 134.2, 134.1, 132.10, 132.06, 128.0, 127.3, 125.1, 123.43, 123.39, 120.1, 118.5, 67.5, 61.1, 47.1, 42.7, 37.4, 37.1, 34.7, 32.5, 28.0, 27.8, 22.4, 21.9. HRMS (ESI-TOF): Calculated for C29H25N3NaO4[M + Na]+: 502.1737, found 502.1737.

[0459] Example 73: Synthesis of Tert-butyl 3-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2- cyanoethyl)-1H-indole-l-carboxylate (44).

[0460] To a 2 dram vial was added Fmoc-Trp(Boc)-OH (52.7 mg, 0.1 mmol, 1 equiv.), 3,6-di- tertbutyl-9-mesityl-10-phenylacridinium tetrafluoroborate (2.87 mg, 5 μmol, 5 mol%), K2S2O8(54.1 mg, 0.2 mmol, 2 equiv.), MeCN (1 mL), milli-Q purified water (0.9 mL) pH 8 phosphate buffer (4M, 0.1 mL) and TMSCN (25 μL, 0.2 mmol, 2 equiv.). The vial was then sealed with a Teflon coated septum cap and the mixture sparged with argon for 10 minutes. Then the reactions were stirred under irradiation with 465 nm SynLED for 18 h. After completion, the reaction mixture was diluted with ethyl acetate (20 mL) and Dl-water (20 mL). The layer was separated and the aqueous was washed with ethyl acetate (20 mL x 2). The combined organic layer was washed with water (20 mL) and brine (20 mL), and dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure and the residue was purified using silica gel chromatography using hexane to 20% EtOAc in hexanes as the eluent, followed by a second column using 60% dichloromethane in hexane. The desired product was obtained as a white solid in 12% yield (6.3 mg).1H NMR (600 MHz, CDCl3) δ 8.17 (d, J= 8.1 Hz, 1H), 7.76 (app d, J=

[0461] 7.6 Hz, 2H), 7.62 (s, 1H), 7.57-7.49 (m, 3H), 7.44-7.34 (m, 3H), 7.33-7.27 (m, 3H), 5.17 (d, J= 8.9 Hz, 1H), 5.03-4.95 (m, 1H), 4.51-4.42 (m, 2H), 4.20 (app t, J= 6.8 Hz, 1H), 3.24 (app d, J= 6.4 Hz, 2H), 1.67 (s, 9H)13C NMR(151 MHz, CDCl3) δ 155.1, 149.5, 143.6, 143.5, 141.5, 135.7,

[0462] 129.9, 128.0, 127.3, 125.21, 125.15, 125.07, 125.05, 123.2, 120.23, 120.22, 118.6, 118.3, 115.7,

[0463] 112.9, 84.3, 67.8, 47.1, 43.4, 29.4, 28.3.HRMS (ESI-TOF): Calculated for C31H29N3NaO4[M +

[0464] Na]+: 530.2050, found 530.2051.

[0465] Example 74: Synthesis of (9 / Z-fluoren-9-yl)methyl 4-(2-((((9H -fluoren-9- yl)methoxy)carbonyl)amino)-2-cyanoethyl)-1H-imidazole-l-carboxylate (45)

[0466] To a flame dried 2-dram vial charged with a Teflon-coated stir was added Fmoc- His(Fmoc)-OH (120 mg, 0.2 mmol, 1 equiv.), (Diacetoxyiodo)benzene (129 mg, 0.4 mmol, 2 equiv.), 3,6-di-tertbutyl-9-mesityl-10-phenylacridinium tetrafluoroborate (5.74 mg, 0.01 mmol, 5 mol%), diisopropylethylamine (8.7 μL, 0.05 mmol, 25 mol%), DCE (2 mL) and TFE (2 mL). The vial was then sealed with a Teflon coated septum cap and the mixture sparged with argon for 10 minutes. And then the reactions were stirred under irradiation with 465 nm SynLED under 35 °C for 18 h. After completion, the reaction mixture was concentrated in vacuo and filter through a silica gel using 20% ethyl acetate in hexane as the eluent. The solvent was then removed under reduced pressure to achieve the intermediate in 57% (75.0 mg). The resulting intermediate was then redissolved in dry MeCN (1 mL), and the solution was cooled to 0 °C. After 5 min, TMSCN (43 μL, 0.34 mmol, 3 equiv) was added dropwise, followed by addition of BFs.Et2O (85 μL, 0.69 mmol, 6 equiv.) dropwise. The reaction was stirred for 1 h at the same temperature. Aqueous NH4CI (3 drops) was added, and the resulting mixture was vigorously stirred at room temperature. The reaction mixture was concentrated in vacuo and purified using silica gel chromatography using hexane to 30% EtOAc in hexanes as the eluent. The desired product was obtained as a white solid in 65% yield (43.5 mg).1H NMR (600 MHz, CDCI3) 58.06 (s, 1H), 7.81 (app d, J= 7.6 Hz, 2H), 7.77 (app d, J= 7.5 Hz, 2H), 7.63-7.56 (m, 4H), 7.45 (app t, J= 7.5 Hz, 2H), 7.41 (app t, J= 7.5 Hz, 2H), 7.37-7.30 (m, 5H), 6.67 (d, J= 8.5 Hz, 1H), 5.05-4.95 (m, 1H), 4.75 (app d, J= 6.6 Hz, 2H), 4.44 (app d, J= 7.2 Hz, 2H), 4.36 (app t, J= 6.6 Hz, 1H), 4.25 (app t, J= 7.2 Hz, 1H), 3.09 (d, J= 5.1 Hz, 2H),13C NMR (151 MHz, CDCl3) δ 155.4, 148.2, 143.7, 142.70, 142.68, 141.5, 141.4, 137.8, 137.4, 128.4, 127.9, 127.6, 127.3, 127.2, 125.2, 124.9, 120.5, 120.2, 118.1, 115.6, 70.1, 67.8, 47.1, 46.7, 43.0, 30.7.HRMS (ESI-TOF): Calculated for C36H28N4NaO4[M + Na]+: 603.2003, found 603.2003.

[0467] Example 75: Synthesis of (9H-fluoren-9-yl)methyl 2-(2,2,2-trifluoroethoxy)pyrrolidine-l- carboxylate (46b).

[0468] The title compound was prepared using General Procedure C under 5 °C for 18 h. The title compounds were isolated using hexane to 5% ethyl acetate in hexane as eluent as a white solid in 77% yield (60.0 mg). (1.63:1 rotamer).1H NMR (600 MHz, CDCl3) δ 7.44-7.37 (m, 5.35H), 7.63-7.54 (m, 5.39H), 7.44-7.37 (m, 5.53H), 7.35-7.30 (m, 5.67H), 5.41 (d, J= 5.0 Hz, 1.60H), 4.81 (dd, J= 10.9, 4.3 Hz, 1.07H), 4.81 (dd, J= 10.9, 4.3 Hz, 1.01H), 4.55 (d, J = 4.9 Hz, 1.00H), 4.50 (dd, J= 10.6, 7.0 Hz, 1.67H), 4.39 (dd, J= 10.6, 7.0 Hz, 1.71H), 4.27-4.21 (m, 2.71H), 4.11 (dq, J= 12.6, 8.8 Hz, 1.64H), 4.00 (dq, J= 12.6, 8.9 Hz, 1.63H), 3.53 (ddd, J= 10.4, 8.7, 1.8 Hz, 1.64H), 3.42-3.32 (m, 2.84H), 3.27 (app td, J= 10.3, 7.3 Hz, 1.12H), 3.20 (dq, J= 13.6, 8.9 Hz, 1.10H), 2.88 (dq, J = 12.4, 8.6 Hz, 100H), 2.22-2.10 (m, 1.71H), 2.04 (dd, J = 13.1, 6.8 Hz, 1.71H), 1.98-1.90 (m, 2.83H), 1.88-1.73 (m, 3.88H).13C NMR (151 MHz, CDCl3) δ 156.14, 154.59, 143.88, 143.69, 141.53, 141.48, 141.47, 128.00, 127.92, 127.89, 127.49, 127.31, 127.19, 125.16, 125.08, 124.42, 124.37, 123.74 (d, J = 278.7 Hz), 120.22, 120.16, 89.54, 88.93, 67.55, 66.44 (q, J = 34.2 Hz), 66.26, 65.27 (q, J = 34.1 Hz), 47.41, 47.32, 46.15, 46.13, 33.25, 32.70, 22.76, 21.55. (Due to complexity of the CNMR, two decimals were reported).19F NMR (565 MHz, CDCl3) δ -74.43, -74.67. HRMS (ESI-TOF): Calculated for C21H20F3NNaO3[M + Na]+: 414.1288, found 414.1289.

[0469] Example 76: Synthesis of (9H-fluoren-9-yl)methyl 2-cyanopyrrolidine-l-carboxylate (46).

[0470] The title compound was prepared using General Procedure C. The title compounds were isolated using hexane to 10% ethyl acetate in hexane as eluent as a white solid in 91% yield (29.0 mg).1H NMR (600 MHz, CDCI3) 5 7.77 (app d, J = 7.6 Hz, 2H), 7.66 (app t, J= 8.7 Hz, 1H), 7.59 (app t, J= 8.7 Hz, 1H), 7.41 (app t, J= 7.5 Hz, 2H), 7.36-7.30 (m, 2H), 4.64-4.57 (m, 1H), 4.53-4.37 (m, 2H), 4.33-4.22 (m, 1H), 3.65-3.53 (m, 1H), 3.47-3.35 (m, 1H), 2.36-2.00 (m, 4H).13C NMR (151 MHz, CDCI3) 5 154.4, 153.9, 144.0, 143.9, 143.8, 143.6, 141.49, 141.45, 141.4, 127.9, 127.34, 127.28, 127.25, 127.2, 125.21, 125.17, 125.12, 125.06, 120.2, 120.1, 118.9, 118.7, 68.3, 68.0, 47.6, 47.3, 47.1, 46.5, 46.0, 32.0, 30.9, 24.8, 23.8. HRMS (ESI-TOF): Calculated for C20H18N2NaO2[M + Na]+: 341.1261, found 341.1260.

[0471] Example 77: Synthesis of Benzyl 2-(2,2,2-trifluoroethoxy)pyrrolidine-l-carboxylate (47b).

[0472] The title compound was prepared using General Procedure C under 5 °C for 18 h. The title compounds were isolated using hexane to 5% ethyl acetate in hexane as eluent as a white solid in 79% yield (48.0 mg). (2:1 rotamer).1H NMR (600 MHz, CDCl3) δ 7.40-7.31 (m, 15H), 5.42 (d, J= 5.1 Hz, 2H), 5.31 (d, J= 4.9 Hz, 1H), 5.23 (d, J= 12.1 Hz, 1H), 5.19-5.09 (m, 5H), 4.14 (dq, J= 12.6, 8.9 Hz, 2H), 4.05 (dq, J= 12.6, 9.0 Hz, 2H), 3.79 (app q, J= 8.8 Hz, 2H), 3.59-3.50 (m, 3H), 3.47-3.34 (m, 3H), 2.18-2.05 (m, 3H), 2.05-2.00 (m, 3H), 1.95-1.89 (m, 3H), 1.88-1.80 (m, 3H).,3C NMR (151 MHz, CDCl3) δ 156.2, 154.5, 136.5, 136.1, 135.4, 128.8, 128.7, 128.6, 128.3, 128.0, 124.2 (q,J= 278.2 Hz), 124.0 (d, J= 278.5 Hz), 89.7, 89.0, 67.7, 67.4, 66.5 (q, J= 34.2 Hz), 65.7 (q, J= 34.5 Hz), 46.4, 46.2, 33.3, 32.7, 22.7, 21.7.19F NMR (565 MHz, CDCI3) 5 -74.59, -74.72. HRMS (ESI-TOF): Calculated for (C14H16F3NNaO3[M + Na]+: 326.0975, found 326.0970. Example 78: Synthesis of Benzyl 2-cyanopyrrolidine-l-carboxylate (47).

[0473] The title compound was prepared using General Procedure C. The title compounds were isolated using hexane to 20% ethyl acetate in hexane as eluent as a white solid in 68% yield (15.8 mg).1H NMR (600 MHz, CDCl3) δ 7.44-7.30 (m, 5H), 5.26-5.13 (m, 2H), 4.65-4.52 (m, 1H), 3.64-3.55 (m, 1H), 3.48-3.37 (m, 1H), 2.32-2.02 (m, 4H)13C NMR (151 MHz, CDCI3) 5 154.4, 153.8, 136.2, 136.1, 128.7, 128.4, 128.3, 119.0, 118.8, 68.0, 67.8, 47.7, 47.1, 46.5, 46.1, 31.9, 30.9, 24.8, 23.9. HRMS (ESI-TOF): Calculated for C13H14N2NaO2[M + Na]+: 253.0948, found 253.0949.

[0474] Example 79: Synthesis of (9 / 7-fluoren-9-yl)methyl (25)-2-((2-methyl-l-(2,2,2- trifluoroethoxy)propyl)carbamoyl)-pyrrolidine-l-carboxylate (3 lb).

[0475] The title compound was prepared using General Procedure C under 5 °C for 18 h. The title compounds were isolated t using hexane to 20% ethyl acetate in hexane as eluent as a colorless oil in 31% yield (30.5 mg). (Due to the complexity of the NMR because of the existence of diastereomers and retainers, only major isomer was reported)1H NMR (600 MHz, CDCl3) δ 7.81-7.76 (m, 2H), 7.61-7.55 (m, 2H), 7.43-7.39 (m, 2H), 7.35-7.30 (m, 2H), 7.17-7.01 (m, 1H), 5.07-4.91 (m, 1H), 4.51-4.13 (m, 4H), 3.96-3.83 (m, 2H), 3.57-3.37 (m, 2H), 2.41-2.25 (m, 1H), 2.05-1.77 (m, 4H), 0.97-0.84 (m, 6H).13C NMR (151 MHz, CDCl3) δ 172.98, 172.69, 156.53, 143.84, 143.80, 141.50, 141.48, 127.97, 127.26, 125.08, 122.11 (q,J= 283.2 Hz), 120.21, 120.18, 85.18, 85.05, 67.99, 65.92 (q, J= 34.2 Hz), 60.88, 60.71, 47.30, 47.14, 32.92, 32.86, 28.18, 24.89, 24.79, 17.72, 17.33, 17.23?9F NMR (565 MHz, CDCl3) δ -74.36, -74.47, -85.36. HRMS (ESI- TOF): Calculated for C26H29F3N2NaO4[M + Na]+: 513.1972, found 513.1969. Example 80: Synthesis of (9H-fluoren-9-yl)methyi (25)-2-((l-cyano-2- methylpropyl)carbamoyl)pyrrolidine-l-carboxylate (31).

[0476] The title compound was prepared using General Procedure C. The title compounds were isolated using hexane to 40% ethyl acetate in hexane as eluent as a white solid in 58% yield (24.0 mg).1H NMR (600 MHz, CDCl3) δ 7.82-7.76 (m, 2H), 7.69-7.54 (m, 3H), 7.46-7.39 (m, 2H), 7.37-7.29 (m, 2H), 4.72-4.66 (m, 1H), 4.52-4.01 (m, 4H), 3.57-3.34 (m, 2H), 2.56-2.44 (m, 1H), 2.12-1.80 (m, 4H), 1.16-0.92 (m, 6H)13C NMR (151 MHz, CDCI3) 5 171.1, 170.9, 157.2, 156.9,

[0477] 143.8, 143.7, 141.51, 141.48, 128.0, 127.33, 127.29, 127.26, 125.13, 125.08, 125.0, 120.24, 120.22, 117.9, 117.8, 68.2, 68.1, 60.4, 60.0, 47.3, 47.2, 46.8, 46.7, 31.7, 29.9, 27.5, 27.2, 25.0,

[0478] 24.8, 18.7, 18.6, 18.12, 18.08. HRMS (ESI-TOF): Calculated for C25H27N3NaO3[M + Na]+: 440.1945, found 440.1953.

[0479] Example 81: Synthesis of (9H-fluoren-9-yl)methyl (2-oxo-2-((2-oxo-2-((2-phenyl-l-(2,2,2- trifluoroethoxy)ethyl)-amino)ethyl)amino)ethyl)carbamate (32b).

[0480] The title compound was prepared using General Procedure C under 35 °C for 18 h using TFE / EA (1:1, 0.1 M) as solvent. The title compounds were isolated t using 50% ethyl acetate in hexane to 80% ethyl acetate in hexane as eluent as a light-yellow oil in 25% yield (28.0 mg).1H NMR (600 MHz, CDCI3) 57.75 (app d, J= 7.6 Hz, 2H), 7.60-7.54 (m, 2H), 7.43-7.37 (m, 2H), 7.30 (app d, J= 7.5 Hz, 2H), 7.27-7.24 (m, 2H), 7.23-7.21 (m, 1H), 7.18 (app d, J= 7.5 Hz, 2H), 7.00 (d, J= 9.3 Hz, 1H), 6.82-6.69 (m, 1H), 5.66-5.55 (m, 1H), 5.50 (app dt, J= 9.6, 5.9 Hz, 1H), 4.53-4.39 (m, 2H), 4.20 (app t, J= 6.7 Hz, 1H), 3.95-3.84 (m, 4H), 3.81-3.76 (m, 2H), 3.04 (dd, J= 14.1, 6.1 Hz, 1H), 2.93 (app dt, J= 14.0, 7.0 Hz, 1H).13C NMR (151 MHz, CDCI3) 5 169.90, 169.57, 157.15, 143.75, 143.74, 143.68, 141.47, 141.45, 129.77, 128.65, 127.95, 127.24, 127.17, 125.10, 125.06, 123.88 (d, J = 278.3 Hz), 120.20, 81.24, 67.42, 66.19 (q, J = 34.3 Hz), 47.21, 44.73, 43.21, 41.00.19F NMR (565 MHz, CDCb) 5 -74.32, -77.04. HRMS (ESI-TOF): Calculated for C29H28F3N3NaO5[M + Na]+: 578.1873, found 578.1873.

[0481] Example 82: Synthesis of (9H -fluoren-9-yl)methyl (2-((2-((l-cyano-2-phenylethyl)amino)-2- oxoethyl)amino)-2-oxoethyl)carbamate (32).

[0482] The title compound was prepared using General Procedure C. The title compounds were isolated using 80% ethyl acetate in hexane to 100% ethyl acetate as eluent as a light-yellow solid in 61% yield (29.5 mg).1H NMR (600 MHz, CDCl3) δ 7.73 (app d, J= 7.6 Hz, 2H), 7.55 (app t, J= 7.9 Hz, 2H), 7.37 (app td, J= 7.5, 2.5 Hz, 2H), 7.33-7.26 (m, 4H), 7.24-7.21 (m, 1H), 7.20- 7.17 (m, 2H), 6.73 (br s, 1H), 5.54 (app t, J= 5.8 Hz, 1H), 4.94 (app q, J= 7.5 Hz, 1H), 4.52-4.44 (m, 1H), 4.41 (dd, J= 10.7, 6.5 Hz, 1H), 4.16 (app t, J= 6.6 Hz, 1H), 3.96 (dd, J= 17.9, 5.8 Hz, 1H), 3.84-3.63 (m, 4H), 3.03 (app d, J = 7.3 Hz, 2H).13C NMR (151 MHz, CDCl3) δ 170.3, 169.0, 157.6, 143.7, 143.6, 141.50, 141.46, 134.1, 129.5, 129.1, 128.02, 128.00, 127.31, 127.27, 125.14, 125.07, 120.2, 118.3, 67.5, 47.2, 44.9, 42.9, 42.2, 38.5. HRMS (ESI-TOF): Calculated for C28H26N4NaO4[M + Na]+: 505.1846, found 505.1843.

[0483] Example 83: Synthesis of (9 H-fluoren-9-yl)methyl ((75)-7-benzyl-4-((5)-sec-butyl)-l,l,l- trifluoro-6,9,12-trioxo-3-oxa-5,8,ll-triazatridecan-13-yl)carbamate (48b).

[0484] The title compound was prepared using General Procedure C under 35 °C for 18 h using TFE / EA / DCE (1:1:1, 0.067 M) as solvent. The title compounds were isolated t using 50% ethyl acetate in hexane to 80% ethyl acetate in hexane as eluent as a light-yellow oil in 26% yield (35.0 mg). (Due to complexity of the HNMR and CNMR, only the major isomer was reported)1H NMR (600 MHz, CDCl3) δ 7.77-7.69 (m, 3H), 7.57 (app t, J= 6.9 Hz, 3H), 7.38 (app t, J= 7.6 Hz, 2H), 7.31-7.25 (m, 3H), 7.20-7.06 (m, 5H), 6.27-6.17 (m, 1H), 5.07-4.96 (m, 1H), 4.30 (app d, J= 7.3 Hz, 1H), 4.24-3.98 (m, 5H), 3.93-3.80 (m, 2H), 3.10-2.97 (m, 2H), 1.63-0.51 (m, 11H)13C NMR (151 MHz, CDCl3) δ 169.48, 168.62, 156.90, 143.75, 141.40, 136.21, 136.17, 129.77, 129.47, 128.69, 128.60, 127.93, 127.21, 125.18, 124.04 (q, J= 278.3 Hz), 120.15, 84.46, 67.57, 66.01 (q, J= 34.1 Hz), 54.93, 47.06, 44.38, 43.33, 39.47, 39.05, 38.89, 29.83, 24.42, 24.40, 13.75, 13.70, 11.30, 11.14, 11.04, 10.97.19F NMR (565 MHz, CDCl3) δ -74.13, -74.17, -74.18, -74.24, - 74.29. HRMS (ESI-TOF): Calculated for C35H39F3NaO6[M + Na]+: 691.2714, found 691.2718.

[0485] Example 84: Synthesis of (9 / 7-fhioren-9-yl)methyl (2-((2-(((25)-l-(((25)-l-cyano-2- methylbutyl)amino)-l-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2- oxoethyl)carbamate (48).

[0486] The title compound was prepared using General Procedure C. The title compounds were isolated using 80% ethyl acetate in hexane to 100% ethyl acetate as eluent as a light-yellow solid in 72% yield (43.0 mg) with dr = 1:1. Diastereomer 1 (4:1 rotamer)1H NMR (600 MHz, CDCb) 57.76 (app d, J= 7.5 Hz, 2H), 7.63-7.54 (m, 2H), 7.39 (app t, J= 7.4 Hz, 2H), 7.34-7.21 (m, 6H), 7.20-7.03 (m, 4H), 5.88 (d, J= 11.4 Hz, 1H), 4.91-4.83 (m, 1H), 4.77-4.68 (m, 1H), 4.45-4.31 (m, 2H), 4.2-4.13 (m, 1H), 4.10-3.75 (m, 4H), 3.14-2.97 (m, 2H), 1.77-1.57 (m, 2H), 1.02-0.71 (m, 7H).13C NMR (151 MHz, CDCl3) δ 170.7, 170.0, 168.7 (amide C), 157.1 (Fmoc carbamate C), 118.2, 117.7, 117.4 (CN peak) (Given the complexity of the CNMR, assignments are provided only for the key carbons). Diastereomer 2 (4:1 rotamerjH NMR (600 MHz, CDCl3) δ 7.76 (app d, J= 7.9 Hz, 2H), 7.58 (app dd, J= 13.7, 7.5 Hz, 1H), 7.42-7.36 (m, 3H), 7.32-7.23 (m, 6H), 7.19-7.12 (m, 3H), 6.99 (s, 1H), 5.76 (s, 1H), 4.83 (d, J= 7.7 Hz, 1H), 4.73 (app dt, J= 13.6, 6.9 Hz, 1H), 4.44-4.34 (m, 2H), 4.25-4.18 (m, 1H), 4.01-3.86 (m, 4H), 3.11-3.03 (m, 2H), 1.75-1.60 (m, 1H), 1.47-1.41 (m, 1H), 1.23-1.14 (m, 1H), 0.98-0.80 (m, 6H)?3C NMR (151 MHz, CDCb)

[0487] 8 170.7, 169.9, 168.7 (amide C), 157.0 (Fmoc carbamate C), 117.3 ( CN peak) (Given the complexity of the CNMR, assignments are provided only for the key carbons). HRMS (ESI- TOF): Calculated for C34H37N5NaO5[M + Na]+: 618.2687, found 618.2688.

[0488] Example 85: Synthesis of Compounds [12 / 13C] 49.

[0489] To a frame dried 2 -dram vial charged with a Teflon-coated stir was added N-benzylproline (41.1 mg, 0.2 mmol, 1 equiv.), K12 / 13CN (52.1 mg, 0.8 mmol, 4 equiv.), 4CzIPN (7.89 mg, 0.01 mmol, 5 mol%), THBP (80 μL, 0.4 mmol, 2 equiv.) and DMF (1 mL). The vial was then sealed with a Teflon coated septum cap and the mixture sparged with argon for 10 minutes. And then the reactions were stirred under irradiation with 465 nm SynLED under 5 °C for 18 h. After completion, the reaction mixture was diluted with ethyl acetate (2 mL) and DI water (2 mL), then transferred to a separatory funnel. The layer was separated, and the aqueous layer was extracted with ethyl acetate (2 mL) for 3 times. The organic layer was then washed with DI water and brine, and dried over anhydrous Na2SO4. Solvent was then removed under reduced pressure and the residue purified by silica gel chromatography (using 5% EtOAc in hexanes as eluent). For KCN, product 49 was obtained as a colorless oil in 41% yield (15.2 mg).1H NMR (400 MHz, CDCb) 57.39-7.27 (m, 5H), 3.92 (d, J= 12.9 Hz, 1H), 3.73-3.65 (m, 2H), 2.94 (ddd, J= 9.5, 8.1, 4.2 Hz, 1H), 2.59 (app q, J= 8.6 Hz, 1H), 2.23-2.07 (m, 2H), 2.02-1.84 (m, 2H).13C NMR (101 MHz, CDCl3) δ 137.7, 129.0, 128.7, 127.7, 118.1, 56.7, 53.4, 51.4, 29.7, 22.0. HRMS (ESI-TOF): Calculated for C12H15N2[M + H]+: 187.1230, found 187.1235. For K13CN, product [13C]49 was obtained as a light-yellow oil in 51% yield (19.0 mg).1H NMR (600 MHz, CDCl3) δ 7.38-7.31 (m, 4H), 7.30-7.27 (m, 1H), 3.92 (d, J= 12.9 Hz, 1H), 3.72-3.66 (m, 2H), 2.94 (app td, J= 8.9, 4.0 Hz, 1H), 2.63-2.55 (m, 1H), 2.22-2.08 (m, 2H), 2.01-1.86 (m, 2H).,3C NMR (151 MHz, CDCl3) δ 137.7, 129.0, 128.7, 127.7, 118.1, 56.7 (d, J= 2.0 Hz), 53.3 (d, J= 50.7 Hz), 51.4, 29.7, 22.0. HRMS (ESI-TOF): Calculated for C1113CH15N2[M + H]+: 188.1263, found 188.1268.

[0490] E. Synthetic Scale Experiments

[0491] Example 86: Gram Scale Synthesis for Flurbiprofen

[0492]

[0493] To a flame dried 100 mL round bottom flask charged with a Teflon-coated stir was added Cu(OTf)2(109 mg, 0.3 mmol, 5 mol%), 1,10-Phenanthroline (81.1 mg, 0.45 mmol, 7.5 mol%), ethyl acetate (15 mL) and TFE (15 mL). The resulting mixture was stirred for 1.5 hours and then 3,6-di-tertbutyl-9-mesityl-10-phenylacridinium tetrafluoroborate (34.4 mg, 0.06 mmol, 1 mol%), flurbiprofen (1.47 g, 6 mmol, 1 equiv.), diisopropylethylamine (261 μL, 1.5 mmol, 25 mol%), tert- Butyl hydroperoxide solution (5-6 M in decane, 2.4 mL, 12 mmol, 2 equiv.) and TMSCN (3 mL, 24 mmol, 4 equiv.). The flask was then sealed with a rubber septum and the mixture sparged with argon for 10 minutes. And then the reactions were stirred under irradiation with 450 nm Kessil LEDs for 18 h. After completion, the reaction mixture was concentrated in vacuo and purified using silica gel chromatography using hexane to 5% EtOAc in hexanes as the eluent The desired product was obtained as a white solid in 95% yield (1.28 g).

[0494] Example 87: Gram Scale Synthesis for Fmoc-Val-OH

[0495] To a flame dried 100 mL round bottom flask charged with a Teflon-coated stir was added Fmoc-Val-OH (2.0 g, 5.89 mmol, 1 equiv.), (Diacetoxyiodo)benzene (3.8 g, 11.8 mmol, 2 equiv.), 3,6-di-tertbutyl-9-mesityl-10-phenylacridinium tetrafluoroborate (33.8 mg, 0.059 mmol, 1 mol%), diisopropylethylamine (257 μL, 1.47 mmol, 25 mol%) and TFE (30 mL). The flask was then sealed with a rubber septum and the mixture sparged with argon for 10 minutes. And then the reactions were stirred under irradiation with 450 nm Kessil LEDs for 18 h. After completion, the reaction mixture was concentrated in vacuo and purified using silica gel chromatography using hexane to 5% EtOAc in hexanes as the eluent. The TFE addition intermediate was obtained as a white solid in 78% yield (1.8 g).

[0496] The TFE addition intermediate (1.8 g, 4.58 mmol, 1 equiv.) was then redissolved in dry MeCN (45 mL), and the solution was cooled to 0 °C. After 15 min, TMSCN (1.72 mL, 13.73 mmol, 3 equiv.) was added dropwise, followed by addition of BF3.Et2O (3.39 mL, 27.45 mmol, 6 equiv.) dropwise. The reaction was stirred for 1 h at the same temperature. Aqueous NH4CI (1 mK) was added, and the resulting mixture was vigorously stirred at room temperature for 5 min. The reaction mixture was concentrated in vacuo and purified using silica gel chromatography using hexane to 20% EtOAc in hexanes as the eluent. The desired product was obtained as a white solid in 72% yield (1.11 g).

[0497] Example 88: Microgram Scale Experiment with Flurbiprofen

[0498] Standard curve based on UV absorbance at 221 nm for product 17 (see Fig. X)

[0499] Example 89: Experiment with Over-the-Counter (OTC) Tablet, Ibuprofen

[0500]

[0501] To a flame dried 2-dram vial charged with a Teflon-coated stir was added Cu(OTf)2(3.6 mg, 0.01 mmol, 5 mol%), 1,10-Phenanthroline (2.7 mg, 0.015 mmol, 7.5 mol%), ethyl acetate (0.5 mL) and TFE (0.5 mL). The resulting mixture was stirred for 1.5 hours and then 3,6-di-tertbutyl- 9-mesityl-10-phenylacridinium tetrafluoroborate (5.74 mg, 0.01 mmol, 5 mol%), Ibuprofen tablet powder (59.7%, 69.1 mg, 0.2 mmol, 1 equiv.), diisopropylethylamine (8.7 μL, 0.05 mmol, 25 mol%), tert-Butyl hydroperoxide solution (5-6 M in decane, 80 μL, 0.4 mmol, 2 equiv.) and TMSCN (100 μL, 0.8 mmol, 4 equiv.). The vial was then sealed with a Teflon coated septum cap and the mixture sparged with argon for 10 minutes. And then the reactions were stirred under irradiation with 465 nm SynLED for 22 h. After completion, the reaction mixture was concentrated in vacuo and purified using silica gel chromatography using hexane to 5% EtOAc in hexanes as the eluent. The desired product 43 was obtained as a colorless oil in 80% yield (30.0 mg).

[0502] Example 90: Hydrolysis of nitrile products to corresponding acid

[0503] Phenylacetic acid (2a): Following a modified literature procedure70, to a 10 ml round bottom flask was added benzyl cyanide (11.7 mg, 0.1 mmol), H2O (0.33 mL), AcOH (0.33 mL) and concentrated H2SO4(0.33 mL). The mixture was heated to reflux for 3 h. The resulting mixture was allowed to cool to room temperature and diluted with H2O (5 mL). The aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were then washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography with 50% ethyl acetate in hexane. Product was obtained as a white solid in 98% yield (13.4 mg) and spectral data align with commercially available source.

[0504] 2-(2-Fluoro-[l,l’-biphenyl]-4-yl)propanoic-l-13C acid ([13C]17a): Following a modified literature procedure70, to a 10 ml round bottom flask was added product 17 (22.6 mg, 0.1 mmol), H2O (0.33 mL), AcOH (0.33 mL) and concentrated H2SO4 (0.33 mL). The mixture was heated to reflux for 3 h. The resulting mixture was allowed to cool to room temperature and diluted with H2O (5 mL). The aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were then washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography with 50% ethyl acetate in hexane. Product [13C]17a was obtained as a white solid in 98% yield (24.3 mg).1H NMR (600 MHz, CDCI3) 5 7.54 (app dt, J= 8.1, 1.4 Hz, 2H), 7.47-7.34 (m, 4H), 7.21-7.13 (m, 2H), 3.79 (app p, J= 13 Hz, 1H), 1.57 (dd, J= 7.2, 5.1 Hz, 3H)13C NMR (151 MHz, CDCI3)

[0505] 8 180.1, 159.8 (d, J = 248.5 Hz), 141.1 (dd, J= 7.8, 2.5 Hz), 135.5, 131.0 (d, J= 3.8 Hz), 129.1 (d, J= 2.8 Hz), 128.6, 128.3 (d, J= 13.6 Hz), 127.9, 123.8 (dd, J= 3.2, 2.1 Hz), 115.52 (dd, J= 23.8, 2.1 Hz), 44.9 (d, J= 54.6 Hz), 18.2.19F NMR (565 MHz, CDCI3) 5 -117.38 (d, J= 4.0 Hz) HRMS (ESI-TOF): Calculated for (C1413CH13FNaO2[M + Na]+: 268.0825, found 268.0826.

[0506] (((9H40-fluoren-9-yl)methoxy)carbonyl)valine (24a): Following a modified literature procedure71, to a 10 ml round bottom flask was added product 24 (20.0 mg, 0.063 mmol), AcOH (0.5 mL) and concentrated HC1 (2 mL). The mixture was heated to reflux for 16 h. The resulting mixture was allowed to cool to room temperature and diluted with H2O (5 mL). The aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were then washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography with ethyl acetate. Product was obtained as a white solid in 91% yield (19.3 mg) and spectral data align with commercially available source.

[0507] Example 91: Synthesis of (4R)-4-((3S,7S, 8R , 9S, 10S,13R , 14S,17R )-3,7-dihydroxy-10, 13- dimethylhexadecahydro-lZf-cyclopenta[a]phenanthren-17-yl)pentanoic acid (10a).

[0508] Following a modified literature procedure72, to a 10 ml round bottom flask was added12C- 10 (28.0 mg, 0.075 mmol) or13C-10 (20.0 mg, 0.053 mmol), KOH (42.0 mg for12C- or 30 mg for13C, 10 equiv.) and EtOCH3CH2OH (1.6 mL). The mixture was heated to reflux for 16 h. The resulting mixture was allowed to cool to room temperature and diluted with H2O (5 mL) and acidified with 3N HC1 until pH 2. The aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were then washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography with ethyl acetate. For12C-10a, Product was obtained as a white solid in 86% yield (19.3 mg) and spectral data align with commercially available source. For13C-10a, Product was obtained as a light-yellow solid in 76% yield (16 mg).1H NMR (600 MHz, CDCl3) δ 3.65-3.59 (m, 2H), 2.43 (dddd, J= 15.5, 10.1, 7.3, 5.1 Hz, 1H), 2.29 (app ddt, J= 16.4, 9.8, 6.8 Hz, 1H), 2.02 (app dt, J= 12.8, 3.3 Hz, 1H), 1.97-1.89 (m, 1H), 1.88-1.78 (m, 4H), 1.72-1.67 (m, 2H), 1.65-1.31 (m, 16H), 1.17 (app td, J= 12.9, 3.8 Hz, 1H), 1.13-1.02 (m, 2H), 1.00-0.89 (m, 6H), 0.70 (s, 3H)J3C NMR (151 MHz, CDCl3) δ 177.5, 71.7, 71.6, 55.8, 55.0, 43.9 (d, J= 0.8 Hz)„ 42.6, 40.3, 39.3, 37.4, 37.0, 35.4 (d, J = 3.8 Hz), 35.1, 34.2, 31.0, 30.8, 30.5, 29.9, 28.8, 27.0, 23.5, 21.3, 18.5, 12.3. HRMS (ESI-TOF): Calculated for C2313CH40NaO4[M + Na]+: 416.2852, found 416.2850.

[0509] Example 92: General Procedure E for the Decarboxylative Cyanation of Amino acids and Peptides

[0510] To a 2 dram vial was added amino acids or peptides (10 μmol), 3,6-di-tertbutyl-9-mesityl- 10-phenylacridinium tetrafluoroborate (1.72 mg, 3 μmol) and dichloromethane (2 mL). The mixture was stirred for 10 minutes until a homogeneous solution formed (solution A). To another 2 dram vial was added 400 μL of solution A and the dichloromethane was removed under reduced pressure. Then the vial was subsequently added a magnetic stir bar, K2S2O8(5.4 mg, 20 μmol, 10 equiv.) or K2S2O8(0.1 mL, 40 Mm in milli-Q purified water, 2 equiv.), MeCN (1 mL), milli-Q purified water (0.9 mL) or (0.7 mL for 2 equiv. of oxidant), pH 8 phosphate buffer (4M, 0.1 mL) and TMSCN (2.5 μL, 20 μmol, 10 equiv.) or K13CN (0.1 mL, 40 mM in milli-Q purified water, 2 equiv). The vial was then sealed with a Teflon coated septum cap and the mixture sparged with argon for 10 minutes. Then the reactions were stirred under irradiation with 465 nm SynLED for 18 h. After completion, the reaction mixture was concentrated in vacuo and diluted with ethanol (4 mL) (Solution B). To an Eppendorf tube was added EtOH (100 μL), Solution B (20 μL) and 5% AcOH in milli-Q purified water (350 μL). The resulting mixture was directly taken for HPLC analysis. The yields were detected by HPLC areas against the standard curve of the pure products.

[0511] Standard curve based on UV absorbance at 254 nm for product [ 12 / 13C]24 (see Fig. X) Standard curve based on UV absorbance at 254 nm for product [12 / 13C]25

[0512] (2 equiv. of K13CN and K2S2O8)

[0513] Standard curve based on UV absorbance at 212 nm for product [12 / 13C]26 (see Fig. X) (jig)

[0514] Standard curve based on UV absorbance at 212 nm for product [12 / 13C]27.

[0515] Standard curve based on UV absorbance at 254 nm for product [12 / 13C]31

[0516] Standard curve based on UV absorbance at 212 nm for product [12 / 13C]32.

[0517] Example 93: 2D NMR Analysis

[0518] 2D NMR Analysis of 20 (Selected Correlation):

[0519]

[0520] 2D NMR Analysis of 20 ’ ( Selected Correlation) Example 94; HPLC Profiles HPLC Profile of 17:

[0521] Conditions: Daicel Chiralpak IC, zz-hexane / z-PrOH = 99 / 1, Flow rate = 1 mL / min, UV = 254 nm, tR= 20.3 min (major), tR= 22.1 min (minor). HPLC Profile of 38:

[0522] Conditions: Daicel Chiralpak IB, zz-hexane / z-PrOH = 99 / 1, Flow rate = 1 mL / min, UV = 254 nm, tR= 12.6 min (major), tR= 15.1 min (minor); HPLC Profile of 39:

[0523] Conditions: Daicel Chiralpak IA, n-hexane / i-PrOH = 95 / 5, Flow rate = 1 mL / min, UV = 254 nm, tR= 6.8 min (minor), tR= 7.5 min (major) HPLC Profile of 40:

[0524] Conditions: Daicel Chiralpak IC, zz-hexane / z-PrOH = 99 / 1, Flow rate = 1 mL / min, UV = 254 nm, tR= 19.2 min (major), tR= 21.6 min (minor) HPLC Profile of 41:

[0525] Conditions: Daicel Chiralpak IB, zz-hexane / z-PrOH = 90 / 10, Flow rate = 1 mL / min, UV = 254 nm, tR= 7.2 min (major), tR= 8.4 min (minor). HPLC Profile of 42: Conditions: Daicel Chiralpak IC, n-hexane / z-PrOH = 80 / 20, Flow rate = 1 mL / min, UV = 254 nm, tR= 27.3 min (major), tR= 31.3 min (minor).

[0526] F. Experimental Procedures for Radiochemistry

[0527] Example 95: General procedure for the preparation of [11C]TBACN

[0528] [11C]CN" was first produced in form of [11C]HCN after cyclotron bombardment followed by aa two-step conversion.73,74[11C]TBACN(tetrabutylammonium11C-cyanide)- TBAOH(tetrabutylammonium hydroxide) solution was obtained at room temperature by delivering the gaseous [11C]HCN into the TBAOH aqueous ethanol solution (4.0-6.0μL 54-56% TBAOH aqueous solution in 600-800 μL pure ethanol or tBuOH) in a 5 mL V vial which sealed with an aluminum-rubber crimp cap and an outlet connected to the gaseous radio waste trap. The delivery gas flow usually lasted 10 mins before the obtained [11C]TBACN-TBAOH solution (typically 13.0 GBq to 18.5 GBq) which was finally aliquoted (20μL-80 μL) into 5 mL V vials for the labeling reactions.

[0529] Example 96: General Radio-HPLC Conditions for Crude Reaction Analysis (Radiochemical Conversion Calculation and Co-inj ection).

[0530] Column: Phenomenex, Kinetex® 5μm EVO C18 100 A, 250 X 4.6 mm LC Column.

[0531] Condition A: Solvent A: 0.1%TFA water; Solvent B: 0.1%TFA acetonitrile. Isocratic elution at x %solvent B. Flow rate: 1 ml / min. Injection volume: 1 mL (with 5% acetic acid solution)

[0532] Condition B: Column: Phenomenex, Kinetex® 5 μm F5 100 A, 250 X 4.6 mm LC Column. Solvent A: 0.1%TFA water; Solvent B: 0.1%TFA acetonitrile; Isocratic elution at x% solvent B. Flow rate: 1 ml / min. Injection volume: 1 mL (with 5% acetic acid solution)

[0533] Condition C: Column: DAICEL CHIRALPAK® IC column. Solvent A: Hexanes; Solvent B: Isopropanol; Isocratic elution at 1% solvent B. Flow rate: 1 ml / min. Injection volume: 0.1 mL (10% isopropanol and 90% hexanes)

[0534] Example 97: General HPLC Conditions for Quality Control Test and Co-inj ection Test

[0535] Condition D: Column: Phenomenex, Kinetex® 5 μm F5 100 A, 250 X 4.6 mm LC

[0536] Column. Solvent A: 0.1%TFA water; Solvent B: 0.1%TFA acetonitrile; Isocratic elution at x% solvent B. Flow rate: 1 ml / min. Injection volume: 1 mL (with 5% acetic acid solution) Condition E: Column: Phenomenex, Kinetex® 5μm EVO Cl 8 100 A, 250 X 4.6 mm LC Column. Solvent A: 0.1%TFA water; Solvent B: 0.1%TFA acetonitrile. Isocratic elution at x% solvent B. Flow rate: 1 ml / min. Injection volume: 1 mL (with 5% acetic acid solution)

[0537] Example 98: General Method of the Radio-HPLC Analysis

[0538] The activity injected into HPLC was measured (this activity was denoted by a) and the time was recorded. The fraction corresponding to radiolabeled product was collected and the activity was measured (this activity was denoted by β) and the time was recorded. The decay corrected β could be calculated from the recorded isolation time of each substrate. The radiochemical conversion (RCC) was obtained by dividing β by the decay corrected a. For most cases, the identity of the radiolabeled compound was confirmed by overlap the radio trace peak with the commercial or synthesized12C-nitrile standard UV peak via HPLC.

[0539] Due to the limited time and radio activity scales when running the11C-labelling reactions, it’s very difficult to run all the quality controls for every purified11C -nitrile product. For most of the labelling experiments we managed to use the same Cl 8 column on the same HPLC to conduct the isolation and analysis. Given the fact that the reaction works very well in normal12C cyanation, it would be very convincing if the radio peaks of the11C- labelled nitriles matched with the UV peaks of the authentic12C-nitrile product standards. Only in a few cases the products were isolated and confirmed with quality control. In a large portion of cases co-injection was carried out when doing the isolation and RCC analysis after reaction by mixing the corresponding12C nitrile product standard(s) into the aliquot from the crude reaction mixture. Consequently, we were able to confirm all the11C-labelled nitrile products that, similarly as the12C-nitriles, ranged from carboxylic acids([11C]1-[11C]21) to amino acids ([11C]22-[11C]32).

[0540] In some cases, co-injection of the reaction mixture above of the labeled compound with commercial or synthesized12C-nitrile standard via HPLC was also used to further confirm the identity of the radiolabeled compound.

[0541] In a few cases, co-injection of the purified11C-labeled compound with commercial or synthesized12C-nitrile standard via HPLC was also used to further confirm the identity of the radiolabeled compound.

[0542] RCC (decay corrected) was reported as (p / a) X 100% of one reaction or the average ± SD% of triplicated reactions unless otherwise noted. Example 99; General Procedure F for Radiocyanation of Bioactive Acids

[0543] Stock Solution: To a flame dried 2-dram vial charged with a Teflon-coated stir was added Cu(OTf)2(1.8 mg, 0.005 mmol, 5 mol%), 1,10-Phenanthroline (1.4 mg, 0.0075 mmol, 7.5 mol%), ethyl acetate (0.5 mL) and TFE (0.5 mL). The resulting mixture was stirred for 1.5 hours and then 3, 6-di-tertbutyl-9-mesityl-10-phenylacridinium tetrafluoroborate (2.87 mg, 0.005 mmol, 5 mol%) and aliphatic carboxylic acid (0.1 mmol, 1 equiv.) were added.

[0544] To a 5 mL V vial was charged 200 μL of the stock solution, TFE (150 μL), ethyl acetate (150 μL), and the TBHP (4 μL). Then a 20-80 μl aliquot of [11C]TBACN-TBAOH in tBuOH (typically 11 IMBq-l.l IGBq) was added to the reaction vial via pipette. The reaction V vial was then fixed on an aluminum block. A needle connected to an Ni filled balloon was inserted to the bottom of the V vial and the reaction medium was continuously sparged throughout the entire reaction time. The reaction was then irradiated top-down with a laser (MDL-D-450, 450 nm, 3.5W after fiber coupling) or an A160WE Tima Blue Kessil LED lamp for 5 min. The light source was turned off, the needle and balloon were removed and via pipette an aliquot of the reaction mixture (typically 2.0-37.0 MBq) was taken for radio HPLC analysis, or via a capillary an aliquot of reaction mixture (typically 1.0-2.0 MBq) was taken for radio-TLC analysis.

[0545] Example 100: General Procedure G for Radiocyanation of Amino Acids and Peptides

[0546] To a 5 mL V vial was charged amino acids or peptides (0.01 mmol), K2S2O8(5.4 mg, 2 equiv.), and 3,6-di-tertbutyl-9-mesityl-10-phenylacridinium tetrafluoroborate (1.7 mg, 30 mol%), EtOH (450 μL), Water (25 μL) and aqueous phosphate buffer (4M, pH=8, 125 μL). The reaction mixture was sonicated for 1 min. Then a 20-80 μl aliquot of [11C]TBACN-TBAOH in EtOH (typically 11 IMBq-l.l IGBq) was added to the reaction vial via pipette. The reaction V vial was then fixed on an aluminum block. A needle connected to an N2 filled balloon was inserted to the bottom of the V vial and the reaction medium was continuously sparged throughout the entire reaction time. The reaction was then irradiated top-down with a laser (MDL-D-450, 450 nm, 3.5W after fiber coupling) for 5 min. The light source was turned off, the needle and balloon were removed and via pipette an aliquot of the reaction mixture (typically 2.0-37.0 MBq) was taken for radio HPLC analysis.

[0547] F. Molar Activity Determination Example 101: Molar Activity of 17a (see Fig. X)

[0548] M.A. = 209.05 ± 43.2 GBq / μmol in average by Entry 1, 2, 3, and 4.

[0549] Example 102: Molar Activity of 24 (see Fig. X)

[0550] M.A. = 95.275 GBq / μmol in average by Entry 1 and 2 G. Radio-HPLC and Radio-TLC Data

[0551] Example 103: Synthesis of Compound [11C] 1

[0552] HPLC-isolated RCCs of [11C]1 from la

[0553] Example 104: Synthesis of Compound [11C]la

[0554] The previously isolated radiolabeled nitrile product [11C]1 in the mobile phase of water (55%, containing 0.1% TFA) and acetonitrile (45% containing 0.1% TFA) was transferred to a 5 mL V vial using a pipette. Subsequently, the V vial was then sealed with an aluminum-rubber crimp cap, before being fixed onto an aluminum heating block connected to a thermal couple within a hot cell. Two 20 G needles, one linked to an Ni stream line and the other serving as a vent, were employed. An azeotropic drying process was initiated by allowing a constant flow of N2 through the system. The V vial was then heated to 90 °C. To aid in the azeotropic drying process after the removal of acetonitrile, 1 mL of ethanol (EtOH) was introduced.

[0555] Upon nearly complete drying, the N2 flow was ceased, and the venting needle was removed. A syringe was utilized to introduce a mixture comprising sulfuric acid (50 μL), acetic acid (5Q1L), and water (50 μL) into the dried V vial. The resulting mixture was then subjected to °C fdre5tingputei3ffollowed by a cooling period of 5 minutes. To neutralize the reaction mixture, 200 μL of saturated aqueous sodium bicarbonate solution was si owly added after the venting needle was employed. Subsequently, (a portion of) the resultant mixture was taken for radio high-performance liquid chromatography (HPLC) analysis using an isocratic 40% HPLC condition B.

[0556] HPLC-isolated RCCs of*f C]la from [11C]l

[0557] Example 105: Synthesis of Compound [11C]la

[0558] One-pot Hydrolysis: The photoredox radiolabeling reaction mixture was passed through an activated SAX cartridge to a 5 mL V vial, and an aqueous EtOH solution (containing 5% ammonia water, 300 μL) was used to elute the SAX cartridge. Then the V vial was sealed with an aluminum-rubber crimp cap, before being fixed onto an aluminum heating block connected to a thermal couple within a hot cell. Two 20 G needles, one linked to an Ni streamline and the other serving as a vent, were employed. A drying process was initiated by allowing a constant flow of Ni through the system. The V vial was then heated to 80 °C. To aid in the azeotropic drying process after the removal of the organic solvents, 0.3 mL of ethanol (EtOH) was introduced.

[0559] Upon nearly complete drying, the N2 flow was ceased, and the venting needle was removed. A syringe was utilized to introduce a mixture comprising sulfuric acid (60 μL), acetic acid (60μL), and water (60 μL) into the dried V vial. The resulting mixture was then subjected to °C fdreStingpHtek36bllowed by a cooling period of 5 minutes. To neutralize the reaction mixture, 250 μL of saturated aqueous sodium bicarbonate solution was si owly added after the venting needle was employed. Subsequently, EtOH (20Q1L) was added to help dissolve the product before filtration with a syringe filter, and a portion of the resultant mixture was extracted for radio high-performance liquid chromatography (HPLC) analysis using an isocratic 40% HPLC condition B.

[0560] HPLC-isolated RCCs of*f C]la from la in a one-pot method

[0561] Example 106: Synthesis of Compound [11C]2

[0562] HPLC-isolated RCCs of [11C]2 from 2a

[0563] Example 107: Synthesis of Compound [11C]3

[0564] HPLC-isolated RCCs of [11C]3 from 3a

[0565] Example 108: Synthesis of Compound [11C]4

[0566] HPLC-isolated RCCs of [11C]4 from 4a

[0567] Example 109: Synthesis of Compound [11C]5

[0568] IPLC-isolated RCCs of [11C]5 from 5a

[0569] Example 110: Synthesis of Compound [11C]6

[0570] Radio TLC (40% ethyl acetate in hexane as eluent)

[0571] Example 111: Synthesis of Compound [11C]7

[0572] Radio TLC (40% ethyl acetate in hexane as eluent)

[0573] Example 112; Synthesis of Compound [11C]8

[0574] HPLC-isolated RCCs of [11C]8 from 8a

[0575] Example 113: Synthesis of Compound [11C]9

[0576] To a 5 mL V vial was charged stock solution prepared based on General Procedure F (200 μL), K2S2O8(5.4 mg, 2 equiv.), EtOH (440 μL) and aqueous phosphate buffer (4M, pH=8, 100 μL). The reaction mixture was sonicated for 1 min. Then a 60 μl aliquot of [11C]TBACN-TBAOH in EtOH (typically 40MBq-l.l IGBq) was added to the reaction vial via pipette. The reaction V vial was then fixed on an aluminum block. A needle connected to an N2 filled balloon was inserted to the bottom of the V vial and the reaction medium was continuously sparged throughout the entire reaction time. The reaction was then irradiated top-down with a laser (MDL-D-450, 450 nm,

[0577] 3.5W after fiber coupling) for 5 min. The light source was turned off, the needle and balloon were removed and via pipette an aliquot of the reaction mixture (typically 2.0-10.OMBq) was taken for radio HPLC analysis.

[0578] HPLC-isolated RCCs of [11C]9 from 9a

[0579] Example 114: Synthesis of Compound [11C]10

[0580]

[0581] Radio TLC (80% ethyl acetate in hexane as eluent) n = 3)

[0582] HPLC-isolated RCCs of [uC]10 from 10a

[0583] Example 115: Synthesis of Compound [11C]ll

[0584] Radio TLC (40% ethyl acetate in hexane as eluent)

[0585] Example 116: Synthesis of Compound [11C] 12

[0586] Radio TLC (40% ethyl acetate in hexane as eluent)

[0587] Example 117: Synthesis of Compound [11C]13 Radio TLC (40% ethyl acetate in hexane as eluent)

[0588] Example 118: Synthesis of Compound [11C]14

[0589] Radio TLC (40% ethyl acetate in hexane as eluent)

[0590] Example 119: Synthesis of Compound [11C] 15

[0591] HPLC-isolated RCCs of ['1C] 15 from 15a

[0592] Example 120: Synthesis of Compound [11C] 16

[0593] Radio TLC (ethyl acetate as eluent)

[0594] Example 121: Synthesis of Compound [11C] 17

[0595] Stock Solution: To a flame dried 2-dram vial charged with a Teflon-coated stir was added Cu(OTf)2(1.8 mg, 0.005 mmol, 5 mol%), L11 (2.6 mg, 0.0075 mmol, 7.5 mol%) 3,6-di-tertbutyl- 9-mesityl-10-phenylacridinium tetrafluoroborate (2.87 mg, 0.005 mmol, 5 mol%) and TEE (1 mL). The resulting mixture was stirred for 1.5 hours and then flurbiprofen 17a (24.4 mg, 0.1 mmol, 1 equiv.) was added.

[0596] Laser condition: To a 5 mL V vial was charged 400 μL of the above stock solution, TFE (200 μL), and the TBHP (16 μL). Then a 20-80 μl aliquot of [11C]TBACN-TBAOH in EtOH (typically 11 IMBq-l.l IGBq) was added to the reaction vial via pipette. The reaction V vial was then fixed on an aluminum block. A needle connected to an Ni filled balloon was inserted to the bottom of the V vial and the reaction medium was continuously sparged throughout the entire reaction time. The reaction was then irradiated top-down with an A160WE Tuna Blue Kessil LED lamp for 5 min. The light source was turned off, the needle and balloon were removed and via pipette an aliquot of the reaction mixture (typically 2.0-37.0MBq) was taken for radio HPLC analysis with isocratic 50%, HPLC condition B.

[0597] HPLC-isolated RCCs of [11C]17 from 17a

[0598] LED condition: To a 5 mL V vial was charged 400 μL of the above stock solution, TFE (200 μL), and the TBHP (16 μL). Then a 20-80 μl aliquot of [11C]TBACN-TBAOH in EtOH (typically 11 IMBq-l.l IGBq) was added to the reaction vial via pipette. The reaction V vial was then fixed on an aluminum block which was pre-fix in an ice bath. A needle connected to an Ni filled balloon was inserted to the bottom of the V vial and the reaction medium was continuously sparged throughout the entire reaction time. The reaction was then irradiated top-down with an A160WE Tima Blue Kessil LED lamp for 5 min. The light source was turned off, the needle and balloon were removed and via pipette an aliquot of the reaction mixture (typically 2.0-37.0MBq) was taken for radio HPLC analysis with isocratic 50%, HPLC condition B. The product was collected (tR= 7.7 - 8.1 min) and solvent was removed under reduced pressure. The product was redissolved in iPrOH / Hexane (10 / 90, 0.1 mL) for chiral analysis with iPrOH / Hexane (1 / 99), HPLC condition c.

[0599] HPLC-isolated RCCs of [11C]17 from 17a tadio ee = 86.0%

[0600] Example 122: Synthesis of Compound [11C] 17

[0601] 10 ii

[0602] Example 123: Synthesis of Compound [MC]17a

[0603]

[0604] The previously isolated radiolabeled nitrile product [11C]17 in the mobile phase of water (55%, containing 0.1% TEA) and acetonitrile (45% containing 0.1% TEA) was transferred to a 2- dram vial using a pipette. Subsequently, standard sodium hydroxide (IM, 20 μL) was added into the vial to basify the product mixture. Then the vial was dried by using a Biotage® V-10 Touch Evaporation System (Under HPLC fraction mode, 23C, 90 seconds).

[0605] After drying, water (~100 μL) remained inside the vial. A syringe was utilized to introduce a mixture comprising sulfuric acid (100μL) and acetic acid (100 μL) into the vial. The resulting mixture was then capped and sfi6j&)teii0tariHratB^pateilSieating block on a heating plate behind an L-block in the fume hood, followed by a cooling period of 5 minutes. To neutralize the reaction mixture, 400 μL of saturated aqueous sodium bicarbonate solution was slowly added after the capped was carefully removed. Subsequently, (a portion of) the resultant mixture was taken for radio high-performance liquid chromatography (HPLC) analysis using an isocratic 45% HPLC condition B. n

[0606] Example 124: Synthesis of Compound [11C] 18

[0607]

[0608] HPLC-isolated RCCs of [11C]19 from 19a

[0609] Example 125: Synthesis of Compound [11C]19

[0610] H

[0611] Example 126: Synthesis of Compound [MC]20

[0612]

[0613] IPLC-isolated RCCs of [11C]20 from 20a

[0614] Example 127: Synthesis of Compound [MC]21

[0615] Radio TLC (40% ethyl acetate in hexane as eluent)

[0616] Example 128: Synthesis of Compound [11C]22

[0617]

[0618] HPLC-isolated RCCs of [11C]22 from 22a

[0619] Example 129: Synthesis of Compound [11C]23 iPLC isolated RCCs of [“

[0620] Example 130: Synthesis of Compound [MC]24

[0621] IPLC-isolated RCCs of [11C]24 from 24a

[0622] Example 131: Synthesis of Compound [11C]24 dPLC-isolated RCCs of [11

[0623] Example 132; Synthesis of Compound [11C]25

[0624]

[0625] HPLC-isolated RCCs of [11C]25 from 25a

[0626] Example 133: Synthesis of Compound [11C]26

[0627] IPLC-isolated RCCs of [11C]26 from 26a

[0628] Example 134: Synthesis of Compound [11C]27

[0629]

[0630] 4PLC-isolated RCCs of [“

[0631] Example 135: Synthesis of Compound [11C]28

[0632] HPLC-isolated RCCs of [11C]28 from 28a

[0633] Example 136: Synthesis of Compound [11C]29

[0634] ii

[0635] Example 137: Synthesis of Compound [uC]30

[0636] IPLC-isolated RCCs of |*1C]30 from 30a

[0637] Example 138: Synthesis of Compound |11C]31

[0638]

[0639] HPLC-isolated RCCs of [11C]31 from 31a

[0640] Example 139: Synthesis of Compound [11C]32

[0641] IPLC-isolated RCCs of [11

[0642] G. Experimental Procedures for Radiochemistry

[0643] Example 140: Ex vivo PET / CT Imaging of Mouse Ear Inflammation Models

[0644] All animal procedures were in compliance to the protocol approved by the University of

[0645] North Carolina Institutional Animal Care and Use Committee. Female 6-8-week-old nude mice were used. Acute inflammation was induced by topical application of 10 μL 12-o- tetradecanoylphorbol-13-acetate (TPA) acetone solution (125 μg / ml) to the inner and outer surface of the right ear of each mouse as previously described.75,76Six hours after TPA exposure, mice received an intravenous bolus injection of [11C]flurbiprofen (-1.85 MBq). At 15 min post-injection (p.i.), the animals were scanned for a 15 -min static PET scan along with CT scan. Animals are euthanized right after the scan and the ears were harvested and subjected to a 15 -min static PET scan along with CT scan (SuperArgus-4R, SEDECAL, Madrid, Spain).

[0646] Results of Inflammation Experiments: [11C]Flurbiprofen rapid appearance in the heart and liver was observed in nude mouse (n = 1) following an intravenous bolus injection. Six hours after TPA application, the treated ear exhibited edema. Accumulation of [11C]flurbiprofen in TPA- treated ear was seen in both ex vivo and in vivo PET images (Fig. S55 and S56). Quantitative analysis of the ex vivo images showed that the TPA-treated inflamed ear has 0.23% ID / g while the control normal ear has 0.14% ID / g. The 3D in vivo PET / CT images showed the head area with the scale of 5% ID / g (Fig. S56).

[0647] H. Full Scale Synthesis

[0648] Example 141: Scale Synthesis

[0649] Stock Solution: To a flame dried 2-dram vial charged with a Teflon-coated stir bar was added Cu(OTf)2 (3.6 mg, 0.01 mmol, 5 mol%), Phen ligand (2.7 mg, 0.015 mmol, 7.5 mol%) 3,6- ditertbutyl-9-mesityl-10-phenylacridinium tetrafluoroborate (5.7 mg, 0.01 mmol, 5 mol%), diisopropylethylamine (DIPEA) (8.7 μL) and TFE (1 mL). The resulting mixture was stirred for 1.5 hours and then flurbiprofen 17a (48.8 mg, 0.2 mmol, 1 equiv) was added.

[0650] H11CN production in a module and [11C]TBACN production: [11C]CN- was first produced in form of [11C]HCN after cyclotron bombardment followed by a two-step conversion (7(5, 77) in a Synthra HCNplus module. [11C]TBACN (tetrabutylammonium l lC-cyanide)- TBAOH (tetrabutylammonium hydroxide) solution was obtained at room temperature by delivering the gaseous [11C]HCN into the TBAOH aqueous ethanol solution (0.8 μL 54-56% TBAOH aqueous solution in 200μL pure ethanol) in a 5 mL V vial which sealed with an aluminum-rubber crimp cap and an outlet connected to the gaseous radio waste trap. The whole sequence usually lasted 12 mins after the end of bombardment. The obtained *fC]TBACN-

[0651] TBAOH solution (typically 5 GBq to 13.0 GBq) was then transferred into a lead shielded pig and manually transferred into a different hot cell with manipulators on for further radiolabeling reaction.

[0652] PRoBox radiolabeling procedures: To a quartz reaction vessel was added 100 μL of the stock solution. The vessel wa before being transferred into the reaction vessel with a cannula under N2. The reaction mixture was irradiated in the PRoBox under N2 for 5 minutes. Then, the reaction mixture was passed through a pre-conditioned SAX cartridge (500 mg) and a pre-activated Al cartridge, and the reaction vessel and line were further rinsed with 20Q1L of EtOH (1% NH3) under reduced pressure. Additional EtOH (1% NH3 50Q1L) was added to elute both cartridges. All fractions were combined and measured. Finally, an aliquot of the reaction mixture (typically 55.0 MBq) was taken for radio HPLC analysis using 50% isocratic condition.

[0653] HPLC condition A. The product was collected at a retention time of 6.6-7 minutes.

[0654] The above full-scale reaction was carried out in a PRoBox LED reactor (provided by LED Radiofluidics Corp.) using the reaction setup of Fig. 9 and Fig. 10A-B. Radio-HPLC traces for full synthesis of*f C]17 are shown in FIG. 11.

[0655] HPLC-Isolated RCCs of [11C]17 from 17a Theoretically isolation amount of [11C]17 (decay corrected):

[0656] 95.2 mCi * 47.0% = 44.7 mCi

[0657] 87.0 mCi * 49.6% = 43.2 mCi

[0658] 178.0 mCi * 48.1% = 85.6 mCi isocratic 50%, HPLC condition A

[0659] Representative HPLC chromatograph

[0660] The major radio trace [11C]17

[0661] Example 142: One-pot Hydrolysis

[0662] After filtration, the V-vial containing the combined filtrate was heated to 60 °C with an aluminum heating block connected to a thermal couple within the hot cell to remove the solvents. Continuous N2 flow was employed to accelerate the dryness. Upon nearly complete drying, the N2 flow was ceased, and the venting needle was removed. A mixture containing sulfuric acid (150 p.L), acetic acid (200 μL), and water (150 μL) was introduced via a syringe. The resulting mixture was then heated to 145 °C and maintain the same temperature for 15 minutes. The reaction mixture was removed from heat and cooled for 5 minutes. 1000 μL of saturated aqueous sodium bicarbonate solution was slowly added with a venting needle to neutralize the reaction mixture.

[0663] Subsequently, EtOH (300 μL) was added to help to dissolve the product before filtration with a syringe filter, and an aliquot of the resultant mixture was subjected for radio HPLC analysis using an isocratic 45% HPLC condition A. Radio-HPLC traces for full scale synthesis of [11C]17a are shown in Fig. 12.

[0664] Theoretically amount of [uC]17a (decay corrected):

[0665] 15.26 mCi » 59.7% = 9.1 mCi isocratic 45%, HPLC condition A

[0666] Representative HPLC chromatograph

[0667] REFERENCES

[0668] 1. Ehlerding, E. B. & Cai, W. Harnessing the Power of Molecular Imaging for Precision Medicine. J. Nucl. Med. 57, 171-172 (2016).

[0669] 2. Ginsburg, G. S. & Phillips, K. A. Precision Medicine: From Science To Value. Health AjJ. (Millwood) 37, 694-701 (2018).

[0670] 3. Langbein, T., Weber, W. A. & Eiber, M. Future of Theranostics: An Outlook on Precision Oncology in Nuclear Medicine. J. Nucl. Med. 60, 13S-19S (2019).

[0671] 4. Ametamey, S. M., Honer, M. & Schubiger, P. A. Molecular Imaging with PET. Chem. Rev. 108, 1501-1516 (2008).

[0672] 5. Deng, X. et al. Chemistry for Positron Emission Tomography: Recent Advances in11C18p- ,13N-, and15O-Labeling Reactions. Angew. Chem. Int. Ed. 58, 2580-2605 (2019).

[0673] 6. Chen, W. et al. Direct arene C-H fluorination with18F via organic photoredox catalysis. Science 364, 1170-1174 (2019).

[0674] 7. Szpera, R., Moseley, D. F. J., Smith, L. B., Sterling, A. J. & Gouvemeur, V. The Fluorination of C-H Bonds: Developments and Perspectives. Angew. Chem. Int. Ed. 58, 14824-14848 (2019). 8. Zhou, Y. et al. Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II— III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas. Chem. Rev. 116, 422-518 (2016).

[0675] 9. Leibler, I. N.-M., Gandhi, S. S., Tekle-Smith, M. A. & Doyle, A. G. Strategies for Nucleophilic C(sp3)-(Radio)Fluorination. J. Am. Chem. Soc. 145, 9928-9950 (2023).

[0676] 10. Van Der Bom, D. et al. Fluorine- 18 labelled building blocks for PET tracer synthesis. Chem Soc Rev 46, 4709-4773 (2017).

[0677] 11. Jacobson, O., Kiesewetter, D. O. & Chen, X. Fluorine- 18 Radiochemistry, Labeling Strategies and Synthetic Routes. Bioconjug. Chem. 26, 1-18 (2015).

[0678] 12. Tay, N. E. S. et al. 19F- and 18F-arene deoxyfluorination via organic photoredox-catalysed polarity-reversed nucleophilic aromatic substitution. Nat. Catal. 3, 734-742 (2020).

[0679] 13. Chen, W. et al. Arene radiofluorination enabled by photoredox-mediated halide interconversion. Nat. Chem. 14, 216-223 (2022).

[0680] 14. Meanwell, N. A. Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drag Design. J. Med. Chem. 61, 5822-5880 (2018).

[0681] 15. Eriksson, J., Antoni, G., Langstrom, B. & Itsenko, O. The development of 1 IC-carbonylation chemistry: A systematic view. Nucl. Med. Biol. 92, 115-137 (2021).

[0682] 16. Labiche, A., Malandain, A., Molins, M., Taran, F. & Audisio, D. Modem Strategies for Carbon Isotope Exchange. Angew. Chem. Int. Ed. e202303535 (2023) doi:10.1002 / anie.202303535.

[0683] 17. Zaccagna, F. et al. Imaging Glioblastoma Metabolism by Using Hyperpolarized [1- 13 C]Pyravate Demonstrates Heterogeneity in Lactate Labeling: A Proof of Principle Study. Radiol. Imaging Cancer 4, e210076 (2022).

[0684] 18. Cai, H. et al. Radiosynthesis of11C-Levetiracetam: A Potential Marker for PET Imaging of SV2A Expression. A CSMed. Chem. Lett. 5, 1152-1155 (2014).

[0685] 19. Cohen, A. S. et al. First-in-Human PET Imaging and Estimated Radiation Dosimetry of l-[5-

[0686] 11C]-Glutamine in Patients with Metastatic Colorectal Cancer. J. Nucl. Med. 63, 36-43 (2022).

[0687] 20. Ballatore, C., Huryn, D. M. & Smith, A. B. Carboxylic Acid (Bio)Isosteres in Drug Design. ChemMedChem 8, 385-395 (2013). 21. Lassalas, P. et al. Structure Property Relationships of Carboxylic Acid Isosteres. J. Med. Chem. 59, 3183-3203 (2016).

[0688] 22. McGrath, N. A., Brichacek, M. & Njardarson, J. T. A Graphical Journey of Innovative Organic Architectures That Have Improved Our Lives. J. Chem. Educ. 87, 1348-1349 (2010).

[0689] 23. Top 200 SMALL Molecule Drugs by Sales in 2022.

[0690] 24. Fleming, F. F., Yao, L., Ravikumar, P. C., Funk, L. & Shook, B. C. Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore. J. Med. Chem. 53, 7902- 7917 (2010).

[0691] 25. Tortajada, A. et al. Catalytic Decarboxylation / Carboxylation Platform for Accessing Isotopically Labeled Carboxylic Acids. ACS Catal. 9, 5897-5901 (2019).

[0692] 26. Kingston, C. et al. Direct Carbon Isotope Exchange through Decarboxylative Carboxylation.

[0693] J. Am. Chem. Soc. 141, 774-779 (2019).

[0694] 27. Destro, G. et al. Transition-Metal-Free Carbon Isotope Exchange of Phenyl Acetic Acids. Angew. Chem. 132, 13592-13597 (2020).

[0695] 28. Kong, D., Moon, P. J., Lui, E. K. J., Bsharat, O. & Lundgren, R. J. Direct reversible decarboxylation from stable organic acids in dimethylformamide solution. Science 369, 557- 561 (2020).

[0696] 29. Babin, V. et al. Photochemical Strategy for Carbon Isotope Exchange with CO 2. ACS Catal. 11, 2968-2976 (2021).

[0697] 30. Kong, D. et al. Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis. J. Am. Chem. Soc. 143, 2200-2206 (2021).

[0698] 31. Bsharat, O. et al. Aldehyde-catalysed carboxylate exchange in a-amino acids with isotopically labelled CO2. Nat. Chem. 14, 1367-1374 (2022).

[0699] 32. Luurtsema, G. et al. EANM guideline for harmonisation on molar activity or specific activity of radiopharmaceuticals: impact on safety and imaging quality. EJNMMI Radiopharm. Chem. 6, 34 (2021).

[0700] 33. McMillan, C. T. MRI biomarkers — a precision medicine tool in neurology? Nat. Rev. Neurol.

[0701] 12, 323-324 (2016). 34. Chen, H.-Y. et al. Hyperpolarized 13C-pyruvate MRI detects real-time metabolic flux in prostate cancer metastases to bone and liver: a clinical feasibility study. Prostate Cancer Prostatic Dis. 23, 269-276 (2020).

[0702] 35. Xu, Y. & Qu, W. [11C]HCN Radiochemistry: Recent Progress and Future Perspectives. Eur.

[0703] J. Org. Chem. 2021, 4653-4682 (2021).

[0704] 36. Taddei, C. & Pike, V. W. [11C] Carbon monoxide: advances in production and application to PET radiotracer development over the past 15 years. EJNMMI Radiopharm. Chem. 4, 25 (2019).

[0705] 37. Ganesan, M. & Nagaraaj, P. Recent developments in dehydration of primary amides to nitriles.

[0706] Org. Chem. Front. 7, 3792-3814 (2020).

[0707] 38. Canavelli, P., Islam, S. & Powner, M. W. Peptide ligation by chemoselective aminonitrile coupling in water. Nature 571, 546-549 (2019).

[0708] 39. Griffin, J. D., Zeller, M. A. & Nicewicz, D. A. Hydrodecarboxylation of Carboxylic and Malonic Acid Derivatives via Organic Photoredox Catalysis: Substrate Scope and Mechanistic Insight. J. Am. Chem. Soo. 137, 11340-11348 (2015).

[0709] 40. Zhang, Z., Chen, P. & Liu, G. Copper-catalyzed radical relay in C(sp3)-H functionalization.

[0710] Chem. Soo. Rev. 51, 1640-1658 (2022).

[0711] 41. Song, L. et al. Dual electrocatalysis enables enantioselective hydrocyanation of conjugated alkenes. Nat. Chem. 12, 747-754 (2020).

[0712] 42. Lai, X.-L., Chen, M., Wang, Y., Song, J. & Xu, H.-C. Photoelectrochemical Asymmetric Catalysis Enables Direct and Enantioselective Decarboxylative Cyanation. J. Am. Chem. Soc. 144, 20201-20206 (2022).

[0713] 43. Wu, X. et al. 11C-, 12C-, and 13C-cyanation of electron-rich arenes via organic photoredox catalysis. Chem 9, 343-362 (2023).

[0714] 44. Chen, W. et al. Direct C-H Radiocyanation of Arenes via Organic Photoredox Catalysis. Org. Utt. 24, 9316-9321 (2022).

[0715] 45. Brevini, T. et al. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature 615, 134-142 (2023). 46. Brogden, R. N., Heel, R. C., Speight, T. M. & Avery, G. S. Flurbiprofen: A Review of its Pharmacological Properties and Therapeutic Use in Rheumatic Diseases. Drugs 18, 417—438 (1979).

[0716] 47. Conti, P. et al. Drug Discovery Targeting Amino Acid Racemases. Chem. Rev. Ill, 6919- 6946 (2011).

[0717] 48. Bongioanni, A., Bueno, M. S., Mezzano, B. A., Longhi, M. R. & Gamero, C. Amino acids and its pharmaceutical applications: A mini review. Int. J. Pharm. 613, 121375 (2022).

[0718] 49. Zhang, H. & Chen, S. Cyclic peptide drugs approved in the last two decades (2001-2021).

[0719] RSC Chem. Biol. 3, 18-31 (2022).

[0720] 50. Wang, L. et al. Therapeutic peptides: current applications and future directions. Signal Transduct. Target. Ther. 7, 48 (2022).

[0721] 51. Shegani, A. et al. Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon- 11 Labeled Endogenous and Natural Exogenous Compounds. Chem. Rev. 123, 105-229 (2023).

[0722] 52. Farrant, R. D. & Lindon, J. C. NMR Parameter Survey, 13C. in Encyclopedia of Spectroscopy and Spectrometry 181-186 (Elsevier, 2017). doi:10.1016 / B978-0-12-803224-4.00112-6.

[0723] 53. Wang, H. et al. Catalytic Cyanation Using CO2 and NH3. Chem 4, 2883-2893 (2018).

[0724] 54. Park, H. & Wang, Q. State-of-the-art accounts of hyperpolarized15N-labeled molecular imaging probes for magnetic resonance spectroscopy and imaging. Chem. Sci. 13, 7378-7391 (2022).

[0725] 55. Gevaert, K. et al. Stable isotopic labeling in proteomics. PROTEOMICS 8, 4873—4885 (2008).

[0726] 56. M. Schlegel, S. Qian, D. A. Nicewicz, Aliphatic C-H Functionalization Using Pyridine N - Oxides as H-Atom Abstraction Agents. ACS Catal. 12, 10499-10505 (2022).

[0727] 57. R. I. Patel, S. Sharma, A. Sharma, Cyanation: a photochemical approach and applications in organic synthesis. Org. Chem. Front. 8, 3166-3200 (2021).

[0728] 58. G. S. Kumar, P. S. Shinde, H. Chen, K. Muralirajan, R. Kancherla, M. Rueping, Paired Electrolysis for Decarboxylative Cyanation: 4-CN-Pyridine, a Versatile Nitrile Source. Org. Lett. 24, 6357-6363 (2022). 59. X. Wu, W. Chen, N. Holmberg-Douglas, G. T. Bida, X. Tu, X. Ma, Z. Wu, D. A. Nicewicz, Z. Li, 11C-, 12C-, and 13C-cyanation of electron-rich arenes via organic photoredox catalysis. Chem. 9, 343-362 (2023).

[0729] 60. Lebedyeva, I. O. et al. Gabapentin hybrid peptides and bioconjugates. Bioorg. Med. Chem. 22, 1479-1486 (2014).

[0730] 61. Wu, H., Pagadala, J., Yates, C. R., Miller, DuaneD. & Mahato, R. I. Synthesis and Characterization of an Anti-Apoptotic Immunosuppressive Compound for Improving the Outcome of Islet Transplantation. Bioconjug. Chem. 24, 2036-2044 (2013).

[0731] 62. Laurent, P. et al. Synthesis and Surface-Active Properties of Uronic Amide Derivatives, Surfactants from Renewable Organic Raw Materials. J. Surfactants Deterg. 14, 51-63 (2011).

[0732] 63. Fan, X. et al. Oxygenated Hydrocarbon Ionic Surfactants Exhibit CO 2 Solubility. J. Am. Chem. Soc. 127, 11754-11762 (2005).

[0733] 64. Baba, A. & Yoshioka, T. An Improved Chemo-Enzymatic Synthesis of 1-0- O -Acyl Glucuronides: Highly Chemoselective Enzymatic Removal of Protecting Groups from Corresponding Methyl Acetyl Derivatives. J. Org. Chem. 72, 9541-9549 (2007).

[0734] 65. La-Venia, A., Dzijak, R., Rampmaier, R. & Vrabel, M. An Optimized Protocol for the Synthesis of Peptides Containing trans -Cyclooctene and Bicyclononyne Dienophiles as Useful Multifunctional Bioorthogonal Probes. Chem. - Eur. J. 27, 13632-13641 (2021).

[0735] 66. Jugniot, N. et al. An elastase activity reporter for Electronic Paramagnetic Resonance (EPR) and Overhauser-enhanced Magnetic Resonance Imaging (OMRI) as a line-shifting nitroxide. Free Radic. Biol. Med. 126, 101-112 (2018).

[0736] 67. HUANG, J. et al. PREPARATION METHOD FOR DUAL-DRUG-LINKER OF ADC AND USE THEREOF. 121 (2022).

[0737] 68. Spiegel, J. et al. Direct Targeting of Rab-GTPase-Effector Interactions. Angew. Chem. Int. Ed. 53, 2498-2503 (2014).

[0738] 69. Velasco, D., Castells, J., Lopez-Calahorra, F. & Jaime, C. Stereochemical elucidation of aldoses from the proton NMR spectrum of its peracetylated aldononitrile derivatives with the aid of MM2 / 3JHH calculations. J. Org. Chem. 55, 3526-3530 (1990). 70. Shirvani, G., Shockravi, A., Amini, M. & Saemian, N. Synthesis of 2-(methylsulfonyl)-5-(4- (methylsulfonyl) phenyl)-4-phenyl-lH-[5- 14 C]imidazole, a selective COX-2 inhibitor, via asymmetrical benzoins: Synthesis of series of 4,5-diarylimidazole with carbon-14. J. Label. Compd. Radiopharm. 59, 153-156 (2016).

[0739] 71. Nasrallah, A. et al. Catalytic Enantioselective Intermolecular Benzylic C(sp 3 )— H Amination. Angew. Chem. Int Ed. 58, 8192-8196 (2019).

[0740] 72. Huang, G. T. & Fames, H. Synthesis of mycophenolate mofetil-[14C], RS-61443-14C. J. Label. Compd. Radiopharm. 36, 449-456 (1995).

[0741] 73. Iwata, R., Ido, T., Takahashi, T., Nakanishi, H. & lida, S. Optimization of [11C]HCN production and no-carrier-added [l-llC]amino acid synthesis. Int. J. Rad. Appl. Instrum. [A] 38, 97-102 (1987).

[0742] 74. Ellison, P. A. et al. Production of [llC]cyanide and the synthesis of indole-3-[l-l lC]acetic acid for PET im- aging of auxin transport in living plants.

[0743] 75. 18. Cao, Q. et al. PET imaging of acute and chronic inflammation in living mice. Eur. J. Nucl. Med. Mol. Imaging 34, 1832-1842 (2007).

[0744] 76. 19. Ahn, E. H. et al. Transduced PEP- 1 -ribosomal protein S3 (rpS3) ameliorates 12-0- tetradecanoylphorbol-13-acetate-induced inflammation in mice. Toxicology 276, 192-197 (2010).

Claims

CLAIMS1. A photoredox-catalyzed decarboxylative cyanation method of carboxylic acids comprising: a) obtaining a reaction mixture comprising a photocatalyst and a solvent; b) contacting the reaction mixture with an aliphatic carboxylic acid substrate, a base additive, an oxidant and a cyanide source to afford a photocyanation reaction mixture; and c) exposing the photocyanation reaction mixture to blue-violet light to form a cyano aliphatic product.

2. The method of claim 1, wherein the photocatalyst is Mes-Acr-Ph+, 4CzIPN, 4CzTPN, RFTA, EOSIN, Ir-11, and a combination thereof.

3. The method of any one of the preceding claims, wherein the cyanide source is selected from the group consisting of acetone cyanohydrin (ACH), tetrabutylammonium cyanide (TBACN or NBiuCN), trimethylsilyl cyanide (TMSCN), sodium cyanide (NaCN), potassium cyanide (KCN), and combinations thereof.

4. The method of any one of the preceding claims, wherein the aliphatic carboxylic acid substrate is a biologically active molecule selected from the group consisting of a natural product, a biomolecule, an amino acid, a peptide and a pharmaceutical agent.

5. The method of any one of the preceding claims, wherein the aliphatic carboxylic acid substrate is a compound of Formula (I):Formula (I) and any stereoisomer and / or pharmaceutically acceptable salt thereof, whereinX is a carbon atom C or a bond;R1is selected from the group consisting of -H, -(C1-C12) alkyl, aryl, heteroaryl, and a bond connecting to an atom of a biologically active molecule or a portion thereof; andR2, and R3are independently selected from the group consisting of -H, -(C1-C12) alkyl, heteroaryl, aryl, -NH(PG), -N[(C1-C6) alkyl][PG], -[(C1-C6) alkyl]NH[PG], -OH,-O(PG), and a bond connecting to an atom of the biologically active molecule, wherein PG, in each instance, is a protecting group.

6. The method of any one of the preceding claims, wherein the biologically active molecule is a pharmaceutical agent selected from the group consisting of fenbufen, felbinac, isoxepac, indomethacin, gabapentin, mycophenolic acid, ibuprofen, mupirocin, 3-keto-4-etiocholenic acid, nipecotic acid, flurbiprofen, enoxolone, pemetrexed, vildagliptin, ruxolitinib, and betulinic acid.

7. The method of any one of the preceding claims, wherein the biologically active molecule is a biomolecule selected from the group consisting of gamma-aminobutyric acid, ursodeoxycholic acid, gibberellic acid, gluconic acid, pyruvate, and D-glucuronic acid.

8. The method of any one of the preceding claims, wherein the biologically active molecule is an amino acid selected from the group consisting of Glutamic acid, Glutamine, Valine, Alanine, Serine, Phenylalanine, Lysine and Phenylglycine.

9. The method of any one of the preceding claims, wherein the biologically active molecule is a peptide.

10. The method of any one of the preceding claims, wherein the biologically active molecule is a peptide selected from the group consisting of Gly-Gly, Pro-Val, and Gly-Gly-Phe.

11. The method of any one of the preceding claims, wherein the oxidant is selected from the group consisting of tert-butyl hydroperoxide (TBHP), potassium persulfate, (diacetoxyiodo)benzene (PIDA), ammonium persulfate, tetrabutyl ammonium persulfate, OXONE and combinations thereof.

12. The method of any one of the preceding claims, wherein the base additive is DIPEA NaaCO3, NaOAc, KHCOa, NaHCOa, KOAc, TBAOH, [(TBA)HCOa], [(TBA)2COa], a phosphate buffer and a combination thereof.

13. The method of any one of the preceding claims, wherein the reaction mixture in step a) further comprises a copper-containing co-catalyst or a nickel-containing co-catalyst, wherein the copper- containing co-catalyst is selected from the group consisting of copper (II) sulfate pentahydrate, copper (II) chloride, copper (II) iodide, copper (II) bromide, copper (I) chloride, copper (I) iodide,copper (I) bromide, copper (II) trifluouromethanesulfonate, copper (II) acetate, tetrakis (acetonitrile) copper (I) tetrafluoroborate and copper bromide; and wherein the nickel-containing co-catalyst is selected from the group consisting of nickel (II) sulfate, nickel (II) chloride hexahydrate, nickel (II) bromide, nickel (II) iodide, nickel (II) fluoride tetrahydrate, nickel (II) tetrafluoroborate and nickel (II) acetate tetrahydrate.

14. The method of any one of the preceding claims, wherein the reaction mixture in step a) further comprises a ligand selected from the group consisting of 1,10-phenanthroline (LI), 2,2'- Isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (L2), 2,2'-Methylenebis[(4R,5S)-4,5-diphenyl- 2-oxazoline] (L3), 2,2-Bis((4S)-(-)-4-isopropyloxazoline)propane (L4), (+)-2,2'-Isopropylidenebis[(4R)-4-benzyl-2-oxazoline] (L5), (4S,4'S)-2,2'-( 1 ,3-Diphenylpropane-2,2- diyl)bis(4-benzyl-4,5-dihydrooxazole) (L6), (3aS,3 'aS,8aR,8'aR)-2,2'-Methylenebis[3a,8a- dihydro-8H-indeno[ 1 ,2-d]oxazole] (L7), (4S)-(+)-Phenyl-a-[(4S)-phenyloxazolidin-2-ylidene]-2- oxazoline-2-acetonitrile (L8), (3aR,3'aR,8aS,8'a'S)-2,2'-Cyclopropylidenebis[3a,8a-dihydro-8H- indeno[l,2-d]oxazole (L9), Di-tert-butyl 2,2'-(cyclopropane-l,l-diyl)(4S,4'S)-bis(4,5- dihydrooxazole-4-carboxylate) (L10), Di-isopropyl 2, 2 '-(cyclopropane- 1,1 -diyl)(4S,4'S)-b is(4, 5- dihydrooxazole-4-carboxylate) (LI 1), and (S)-4-(tert-Butyl)-2-(quinolin-2-yl)-4,5- dihydrooxazole (LI 2).

15. The method of any one of the preceding claims, wherein the photocatalyst is Mes-Acr-BF4 present in an amount of from about 1 mol% to 8 mol%, the base additive is DIPEA present in an amount of from about 20 mol% to about 30 mol%, the oxidant is tert-butyl hydroperoxide (TBHP) present in an amount of from about 1 equiv. to about 10 equiv., the Cu-containing cocatalyst is copper (II)trifluouromethanesulfonate (Cu(OTf)2) present in an amount of from about 3 mol% to about 8 mol%, the ligand is 1,10-phenanthroline present in an amount of from about 5 mol% to about 10 mol%, and the cyanide source is KCN or TBACN present in an amount of from about 2 mol% to about 6 mol%.

16. The method of any once of the preceding claims, wherein the aliphatic carboxylic acid substrate is an amino acid or peptide, the photocatalyst is Mes-Acr-BF4 present in an amount of from about 1 mol% to 8 mol%, the oxidant is potassium persulfate present in an amount of from about 1 to about 5 equiv., the base additive is phosphate buffer with a pH of about 8, and the cyanide source is KCN present in an amount of from about 1 mol% to about 5 mol%.

17. The method of any one of the preceding claims, wherein the solvent is selected from the group consisting of ethyl acetate, ethanol, hexafluoro-2-propanol, dichloroethane, trifluorotoluene, acetonitrile, dichloroethanol, trifluoroethanol, water and a combination thereof.

18. The method of any one of the preceding claims, wherein the concentration of the solvent is about 0.05M to about SOM.

19. The method of any one of the preceding claims, wherein the method is carried out at a temperature of from about 20 °C to about 60 °C.

20. The method of any one of the preceding claims, wherein the photocyanation mixture is exposed to the blue-violet light for at least 18 hours, wherein the blue-violet light has a wavelength of about 390 nm to about 465 nm.

21. The method of any one of the preceding claims, wherein the method further comprises isolating the cyano aliphatic product with a yield of at least 35%.

22. The method of any one of the preceding claims, wherein the method further comprises isolating the cyano aliphatic product with an enantiomeric excess of at least 80% ee.

23. The method of any one of the preceding claims, wherein the aliphatic carboxylic acid is a racemic mixture.

24. The method of any one of the preceding claims, wherein the cyanide source comprises a carbon and / or nitrogen isotope selected from the group consisting of11C,12C,13C,14C,13N,14N and15N.

25. The method of claim 24, wherein the cyanide source is selected from the group consisting of [11 / 13 / 14C]TMSCN, [11 / 13 / 14C]KCN, NBu4[11 / 13 / 14C]CN, TBA[11 / 13 / 14C]CN, [13 / 15N]TMSCN, [13 / 15N]KCN, and a combination thereof.

26. The method of claims 24 or 25, wherein the aliphatic carboxylic acid substrate is present at a loading ranging from about 0.001 to about 0.3 mmol.

27. The method of any one of claims 24-26, wherein the radioactive cyanide source comprises an activity of from about 0.1 to about 1.0 GBq.

28. The method of any one of claims 24-27, wherein the photocyanation reaction mixture is exposed to the blue-violet light for about 1 to about 10 minutes.

29. The method of any one of claims 24-28, wherein the radiochemical conversion (RCC) is at least 50%.

30. The method of any one of claims 24-29, wherein the radiochemical yield (RCY) is at least 5%.

31. The method of any one of the preceding claims, further comprising chemically modifying the cyanate group (-CN) present in the cyano aliphatic product, wherein the cyano aliphatic product is a compound of Formula (II):and any stereoisomer and / or pharmaceutically acceptable salt thereof, whereinR1is selected from the group consisting of -H, -(C1-C12) alkyl, aryl, heteroaryl and a bond connecting to an atom of a biologically active molecule or a portion thereof;R2, and R3are independently selected from the group consisting of -H, -(C1-C12) alkyl, aryl, heteroaryl, -NH(PG), -N[(C1-C6) alkyl][PG], -OH,-O(PG), and a bond connecting to an atom of the biologically active molecule, wherein PG, in each instance, is a protecting group, and the biologically active molecule is selected from the group consisting of a natural product, a biomolecule, an amino acid, a peptide and a pharmaceutical agent; and wherein C* is selected from the group consisting of [11]C, [12]C and [13]C, and N* is [l4]N or [15]N, to render an aliphatic product having a structure of Formula (III):and any stereoisomer and / or pharmaceutically acceptable salt thereof, whereinR1is selected from the group consisting of -H, -(C1-C12) alkyl, aryl, heteroaryl and a bond connecting to an atom of a biologically active molecule;R2, and R3are independently selected from the group consisting of -H, -(C1-C12) alkyl, aryl, heteroaryl -NH2, -NH[(CI-C6) alkyl], -OH, and a bond connecting to an atom of the biologically active molecule; and wherein R4is COOH, CONH2, CH2NH2, or an imaging moiety is selected from the group consisting of [11C]CN, [13C]CN, [15N]CN, [11C]COOH, [13C]COOH, [11C]CONH2, [13C]CONH2, [11C]CH2NH2, [13C]CH2NH2and [15N]CH2NH2.

32. A method of imaging a subject for diagnosing a disease or assessing efficacy of a treatment, the method comprising: a) administering to the subject in need thereof an effective amount of a compound of Formula(II) or (III); and b) acquiring at least one image of at least one portion of the subject.

33. The method of claim 32, wherein the disease is of the integumentary system, skeletal system, muscular system, nervous system, endocrine system, cardiovascular system, lymphatic system, respiratory system, digestive system, urinary system, and reproductive system.

34. The method of claims 32 or 33, wherein the subject is imaged using PET, MRS, MRI or HP MRI imaging technologies.

Images