Nitrification inhibiting mixtures

Abstract

Heterocyclic alkynes useful for nitrification inhibition, mixtures of heterocyclic alkynes with other active ingredients, and methods of using heterocyclic alkynes and mixtures of heterocyclic alkynes with other active ingredients for nitrification inhibition and crop yield enhancement are described.

Description

[0001] NITRIFICATION INHIBITING MIXTURES CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application Serial No.63 / 622614 filed January 19, 2024, the complete disclosure of which is expressly incorporated by reference herein. Background Nitrogen is an essential element for plant health. In growing media (e.g., soil), bound nitrogen for plant nutrition can be present in the form of ammonium compounds or nitrates. The ammonium form of nitrogen is preferred because it is readily incorporated into plants. In contrast, nitrate nitrogen must be reduced to ammonium by the plant before it can be used – an energetically costly process. Ammonium nitrogen, having a positive charge, is tightly bound to growing media. Nitrogen in the form of nitrate is negatively charged, water soluble, not tightly bound to growing media and is readily washed out. Ammonia-oxidizing bacteria of the genera Nitrosomonas and Nitrobacter oxidize ammonium nitrogen to nitrate nitrogen via nitrite nitrogen. This process is known as nitrification. The extent of nitrification is dependent on the temperature, type of growing medium, pH, moisture content and biological activity. The nitrification process leads to ammonium nitrogen loss and nitrate nitrogen creation. As much as half of applied nitrogen fertilizer is lost within a year, and an undesirable concentration of nitrate in the groundwater is promoted by this process. Therefore, the inhibition of nitrification is particularly important, and is generally considered to consist in selective inhibition of the growth of the above-mentioned bacteria strains. The incorporation of certain chemical compounds in critical quantities into growing media are known to have a pronounced effect on nitrification – the conversion of reduced nitrogen such as ammonia or ammonium ions into higher oxidized forms, particularly into the nitrate form. Prevention of such nitrification in growing media is known to be beneficial and desirable from the economic and agronomic points of view since it enhances plant health, enhances crop yields, and lessens nitrate runoff. A number of nitrification inhibitors are known including linoleic acid, α-linolenic acid, methyl- p-coumarate, methyl ferulate, MHPP, Karanjin, brachialacton, 2-chloro-6- trichloromethylpyridine (nitrapyrin), dicyandiamide (DCD), 3,4-dimethylpyrazole (DMP), 3,4- dimethylpyrazole phosphate (DMPP), 4-amino-1,2,4-triazole hydrochloride, 1-amido-2-thiourea, 2-amino-4-chloro-6-methylpyrimidine, 5-ethoxy-3-trichloromethyl-1,2,4-thiodiazole, 2- sulfanilamidethiazole, 3,5-dimethyltetrahydro-1,3,5-thiadiazine-2-thione (dazomet), N-(n- Butyl)thiophosphoric triamide (NBPT). Nitrification inhibition has been disclosed in the following publications: US 3,494,757 and US 3,635,690, German Laid Open Application DOS 2,745,833 and GB 1,592,516. See also U.S. 3,050,380 Goring; GB 970,663 Watkins; US 3,533,774 Nault; US 4,673,429 Rieber, et al; US 4,925,476 Wagner et al; US 2015 / 0052960 Makin et al; US 2017 / 0036969 Nave et al; US 2020 / 0352162 Cunningham et al; WO 2015 / 158853 Nave et al; WO 2020 / 002472 Cunningham et al; WO 2020 / 020765 Nesvadba et al; WO 2020 / 020777 Nesvadba et al. These references and other references cited in this application, the disclosures of which are hereby incorporated herein by reference in their entirety. Some conventional nitrification inhibitors lack traits that are beneficial to their users. For example, dazomet is known to have a very non-specific action and attack non-target bacteria in growing media, especially in soil. A need still exists for nitrification inhibitors which exhibit nitrification inhibition while lacking less beneficial traits. Summary It has been found that certain alkynyl-heterocycles are useful in controlling nitrification. Specifically, certain ethynyl-thiazoles, ethynyl-oxazoles, and ethynyl-isoxazoles have been found to inhibit nitrification. Such inhibition is useful because it promotes more efficient nitrogen uptake by plants – enhancing crop yields. Nitrification inhibition is also useful for lowering the production of nitrate in growing media – particularly in soil – thereby reducing the amount unwanted nitrate in groundwater. Methods of employing the compounds include applying to and / or incorporating into growing media (e.g., soil) an effective amount of nitrification-inhibiting alkynyl heterocycle. Preferred compounds include an ethynyl-thiazole, an ethynyl-oxazole, an ethynyl-isoxazole, or mixtures thereof. Detailed Description As used herein growing medium and growing media are defined as materials in which plants grow. Exemplary growing media include, but are not limited to, soil, perlite, pumice, vermiculite, zeolite, compost, peat moss, coconut coir, sand, silt, clay, water, bark, sawdust, water, and limestone. Exemplary growing media may be outdoor-soil-based or hydroponic. As used herein alkyl refers to a C1 – C6 branched or unbranched group consisting of carbon and hydrogen atoms. Alkyl groups include for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i- butyl, s-butyl, t-butyl and the like. As used herein alkoxy refers to a O-C1 – C6 group where the oxygen atom is connected to a C1 – C6 branched or unbranched alkyl group. Alkoxy groups include for example methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like. As used herein thioalkyl refers to a S-C1 – C6 group, branched or unbranched, where the sulfur atom is connected to a C1 – C6 alkyl group. Thioalkyl groups include for example thiomethyl, thioethyl, thiopropyl, thioisopropyl, thiobutyl, thioisobutyl, thiosecbutyl, thiotertbutyl, and the like. As used herein cycloalkyl refers to a C3 – C6 group where the carbon atoms form a carbocyclic ring. Cycloalkyl groups include for example cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like. As used herein alkenyl refers to a C2 – C6 to a branched or unbranched group consisting of carbon and hydrogen atoms and having one or more double bonds between carbon atoms. Alkenyl groups include for example ethylene, propene, 1-butene, 2-butene, isobutene and the like. As used herein cycloalkenyl refers to a C3 – C6 where the carbon atoms form a carbocyclic ring and contain one or two double bonds. Cycloalkenyl groups include for example cyclopropene, cyclobutene, cyclopentene, cyclohexene, cyclopentadiene, 1,4-cyclohexadiene and the like. As used herein halo refers to halogen atoms such as F, Cl, Br, and I. As used herein haloalkyl refers to a C1 – C6 branched or unbranched alkyl group where one or more hydrogen atoms has been replaced with a halogen atom. Haloalkyl groups include for example fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl, bromoethyl, iodobutyl, dichloroethyl, and the like. As used herein haloalkoxy refers to a C1 – C6 group where the oxygen atom is connected to a C1 – C6branched or unbranched alkyl group where one or more hydrogen atoms has been replaced with a halogen atom. Halolkoxy groups include for example trifluoromethoxy, difluoroethoxy, chloropropoxy, bromo-iso-propoxy, dibromobutoxy, and the like. As used herein haloalkenyl refers to a C2– C6to a branched or unbranched group consisting of carbon and hydrogen atoms where one or more hydrogen atoms has been replaced with a halogen atom and having one or more double bonds between carbon atoms. Haloalkenyl groups include for example 1-chloroethylene, 3,3-difluoropropene, 4-bromo-1-butene, and the like. The term N-oxide includes any compound which has at least one tertiary nitrogen atom that is oxidized to an N-oxide moiety. N-oxides may be formed for example through oxidation of tertiary amines, such as pyridine, by hydrogen peroxide. As used herein salts and agriculturally acceptable salts include hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, nitrates, hydrogensulfates, sulfates, dihydrogenphosphates, hydrogenphosphates, phosphates, carbonates, bicarbonates, oxalates, and C1 – C6 branched or unbranched alkanoates – such as formates, acetates, n-propionates, i-propionates, and the like. As used herein carrier includes a liquid or solid carrier. In some aspects, a carrier may include an organic or inorganic carrier. Exemplary liquid carriers include, but are not limited to: water; petroleum fractions or hydrocarbons, such as mineral oil, aromatic solvents, paraffinic oils, and the like; vegetable oils, such as soybean oil, rapeseed oil, olive oil, castor oil, sunflower seed oil, coconut oil, corn oil, cottonseed oil, linseed oil, palm oil, peanut oil, safflower oil, sesame oil, tung oil and the like; esters of the above vegetable oils; esters of monoalcohols or dihydric, trihydric, or other lower polyalcohols (4-6 hydroxy containing), such as 2-ethyl hexyl stearate, n- butyl oleate, isopropyl myristate, propylene glycol dioleate, di-octyl succinate, di-butyl adipate, di-octyl phthalate and the like; esters of mono, di and polycarboxylic acids and the like; toluene; xylene; petroleum naphtha; crop oil; acetone; methyl ethyl ketone; cyclohexanone; trichloroethylene; perchloroethylene; ethyl acetate; amyl acetate; butyl acetate; propylene glycol monomethyl ether and diethylene glycol monomethyl ether; methyl alcohol; ethyl alcohol; isopropyl alcohol; amyl alcohol; ethylene glycol; propylene glycol; glycerine; N-methyl-2- pyrrolidinone; N;N-dimethyl alkylamides; dimethyl sulfoxide; and liquid fertilizers, as well as mixtures thereof. Exemplary solid carriers include, but are not limited to: silicas, silica gels, silicates, talc, kaolin, limestone, lime, chalk, bole, loess, clay, dolomite, diatomaceous earth, calcium sulfate, magnesium sulfate, magnesium oxide, ground synthetic materials, pyrophyllite clay, attapulgus clay, kieselguhr, calcium carbonate, bentonite clay, Fuller's earth, cottonseed hulls, wheat flour, soybean flour, pumice, wood flour, walnut shell flour, lignin, ammonium sulfate, ammonium phosphate, ammonium nitrate, ureas, cereal meal, tree bark meal, wood meal, nutshell meal, cellulose powders, and mixtures thereof. Fertilizers, including but limited to, fertilizers comprising ammonia may be used as carriers. Exemplary fertilizers comprise, but are not limited to, anhydrous ammonium, ammonium salts such as ammonium nitrate, calcium ammonium nitrate, ammonium sulfate nitrate, ammonium sulfate or ammonium phosphate; organic ammonia sources, such as manure, biogas, worm castings, compost, seaweed or guano; urea-containing fertilizers such as, urea, formaldehyde urea, urea ammonium nitrate solution, urea sulfur, urea ammonium sulfate, or other urea-based fertilizers. As used herein surfactant or surfactants (e.g., wetting agents, tackifiers, dispersants, emulsifiers) include, but are not limited to: the alkali metal salts, alkaline earth metal salts and ammonium salts of fatty acids or of aromatic sulfonic acids (e.g., lignosulfonic acids, phenolsulfonic acids, naphthalenesulfonic acids, and dibutylnaphthalenesulfonic acid); alkyl- and alkylarylsulfonates; alkyl sulfates, lauryl ether sulfates and fatty alcohol sulfates; salts of sulfated hexa-, hepta- and octadecanols; salts of fatty alcohol glycol ethers; condensates of sulfonated naphthalene and its derivatives with formaldehyde; condensates of naphthalene or of the naphthalene sulfonic acids with phenol and formaldehyde; polyoxyethylene octylphenol ether; ethoxylated isooctyl-, octyl- or nonylphenol, alkylphenyl or tributylphenyl polyglycol ether; alkyl aryl polyether alcohols; isotridecyl alcohol; fatty alcohol / ethylene oxide condensates; ethoxylated castor oil; polyoxyethylene alkyl ethers or polyoxypropylene alkyl ethers; lauryl alcohol polyglycol ether acetate; sorbitol esters; lignosulfite waste liquors and proteins; denatured proteins, polysaccharides (e.g., methylcellulose); hydrophobically modified starches; and polyvinyl alcohol, polycarboxylates, polyalkoxylates, polyvinyl amine, polyethyleneimine, polyvinylpyrrolidone, and copolymers thereof. As used herein stabilizer includes compounds or ingredients that enhance the stability of active ingredients by decreasing undesirable reactions of active ingredients. Stabilizers may be employed to enhance storage stability of formulated or unformulated active ingredients. For example, stabilizers may decrease undesirable oxidation, reduction, condensation, addition, elimination, ionic, or free radical reactions. Exemplary stabilizers include, but are not limited to, oxygen scavengers, free radical scavengers, free radical inhibitors, ion scavengers, polymerization inhibitors, and the like. As used herein adjuvant includes agriculturally acceptable adjuvants. Exemplary agriculturally acceptable adjuvants include, but are not limited to, antifreeze agents, antifoam agents, compatibilizing agents, sequestering agents, neutralizing agents and buffers, corrosion inhibitors, colorants, odorants, penetration aids, wetting agents, spreading agents, dispersing agents, thickening agents, freeze point depressants, antimicrobial agents, crop oil (concentrates), adhesives (for instance, for use in seed treatment formulations), surfactants, protective colloids, emulsifiers, tackifiers, and mixtures thereof. Exemplary agriculturally acceptable adjuvants include, but are not limited to, crop oil concentrates (e.g., 85% mineral oil + 15% emulsifiers); nonylphenol ethoxylates; benzylcocoalkyldimethyl quaternary ammonium salts; blends of petroleum hydrocarbon, alkyl esters, organic acids, and anionic surfactants; C9-C11alkylpolyglycoside; phosphate alcohol ethoxylates; natural primary alcohol (C12-C16) ethoxylate; di-sec-butylphenol EO-PO block copolymers; polysiloxane-methyl cap; nonylphenol ethoxylate+urea ammonium nitrates; emulsified methylated seed oils; tridecyl alcohol (synthetic) ethoxylates (e.g., 8 EO); tallow amine ethoxylates (e.g., 15 EO); and PEG(400) dioleate-99. Exemplary agriculturally acceptable adjuvants include, but are not limited to, thickening agents (i.e., thickeners). Exemplary thickeners include, but are not limited to, polysaccharides (e.g., xanthan gum), organic and inorganic sheet minerals, and mixtures thereof. Exemplary agriculturally acceptable adjuvants include, but are not limited to, antifoam agents. Exemplary antifoam agents include, but are not limited to, silicone emulsions, long-chain alcohols, fatty acids, fatty acid salts, organofluorine compounds, and mixtures thereof. Exemplary agriculturally acceptable adjuvants include, but are not limited to, antifreeze agents. Exemplary antifreeze agents, include, but are not limited to ethylene glycol, propylene glycol, urea, glycerol, and mixtures thereof. Exemplary agriculturally acceptable adjuvants include, but are not limited to, colorants. Exemplary colorants include, but are not limited to, the dyes known under the names Rhodamine B, pigment blue 15:4, pigment blue 15:3, pigment blue 15:2, pigment blue 15:1, pigment blue 80, pigment yellow 1, pigment yellow 13, pigment red 112, pigment red 48:2, pigment red 48:1, pigment red 57:1, pigment red 53:1, pigment orange 43, pigment orange 34, pigment orange 5, pigment green 36, pigment green 7, pigment white 6, pigment brown 25, basic violet 10, basic violet 49, acid red 51, acid red 52, acid red 14, acid blue 9, acid yellow 23, basic red 10, basic red 108, and mixtures thereof. Exemplary agriculturally acceptable adjuvants include, but are not limited to, adhesives. Exemplary adhesives include, but are not limited to, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, tylose, and mixtures thereof. Compounds and compositions described herein may be formulated for use. Exemplary formulations include, but are not limited to, emulsifiable concentrates, oil dispersions, solution concentrates, suspension emulsions, micro-emulsions, granules, wettable powders, seed treatments, oil-in-water emulsions, water-dispersible granules. Such formulations are described in Chemistry and Technology of Agrochemical Formulations, D.A. Knowles Ed., Kluwer Academic Publishers, 2012. As used herein an agriculturally effective amount of nitrification inhibiting compound is an amount of compound that produces a measurable effect on one or more of: ammonium nitrogen, nitrification inhibition, nitrate formation, increased plant health, increased plant growth, increased plant or crop yield, bacteria of the genera Nitrosomonas and Nitrobacter. In general, an agriculturally effective amount of an active ingredient is from about 0.0001 grams per hectare to about 5000 grams per hectare, preferably from about 0.0001 grams per hectare to about 500 grams per hectare, and it is even more preferably from about 0.0001 grams per hectare to about 50 grams per hectare. Active ingredients include, but are not limited to, nitrification- inhibiting compounds described herein, as well as active ingredients of group AIG-1, defined below. As used herein “compound” or “compounds” comprise chemicals defined by molecular structure formulas and / or chemical names as well as their tautomers, salts, N-oxides, and stereoisomers. As used herein the term “locus” means a habitat, breeding ground, plant, seed, soil, material, or environment, in which a pest is growing, may grow, or may traverse. For example, a locus may be: where crops, trees, fruits, cereals, fodder species, vines, turf, and / or ornamental plants, are growing; where domesticated animals are residing; the interior or exterior surfaces of buildings (such as places where grains are stored); the materials of construction used in buildings (such as impregnated wood); and the soil around buildings. Examples provided herein are not exhaustive and should not be construed as limiting. It is understood that a substituent should comply with chemical bonding rules and steric compatibility constraints in relation to the particular molecule to which it is attached. These definitions are only to be used for the purposes of this disclosure. The term “Actives” or “Active ingredient” includes the compounds listed in the paragraph immediately below, each of which is considered as “active’ or an “active ingredient” These common names may be found in several locations, such as, the British Crop Production Council’s “Compendium of Pesticide Common Names” located at https: / / pesticidecompendium.bcpc.org / . These active ingredients may be used in mixtures with the molecules disclosed below for a variety of reasons. The term “Active Ingredient Group One” or “AIG-1” means the following preferred group of mixture partners that perform multiple agricultural functions selected from the group consisting of linoleic acid, α-linolenic acid, methyl-p-coumarate, methyl ferulate, MHPP, Karanjin, brachialacton, 2-chloro-6-trichloromethylpyridine (nitrapyrin), dicyandiamide (DCD), 3,4- dimethylpyrazole (DMP), 3,4-dimethylpyrazole phosphate (DMPP), 4-amino-1,2,4-triazole hydrochloride, 1-amido-2-thiourea, 2-amino-4-chloro-6-methylpyrimidine, 5-ethoxy-3- trichloromethyl-1,2,4-thiodiazole, 2-sulfanilamidethiazole, 3,5-dimethyltetrahydro-1,3,5- thiadiazine-2-thione (dazomet), N-(n-Butyl)thiophosphoric triamide (NBPT). The terms “Active Ingredient Group Two” or “AIG-2” and the term “Active ingredient Group Three” or “AIG-3” refer to groups of novel nitrification inhibiting compounds which are described in more detail below. Compounds described herein are nitrification inhibitors. One or more compounds described herein may be incorporated into a composition comprising other ingredients such as one or more compounds of AIG-1, carriers, surfactants, and adjuvants. A composition optionally may include a source of ammonia. To enhance plant health and / or improve crop yields, a compound or composition may be applied to a growing medium with or without a source of ammonia. Sources of ammonia include anhydrous ammonia, urea, urea-ammonium nitrate, and manure. A compound or composition may be mixed directly with the ammonia source. A mixture of compound or composition and ammonia source may be applied directly to a growing medium, such as soil. A compound or composition and the ammonia source may be applied separately to the growing medium, such as soil. A compound or composition and the ammonia source may be applied separately and simultaneously. A compound or composition and the ammonia source may be applied separately and sequentially. Sequential application of a compound or composition and a source of ammonia may take place within 24 hours, within 1 to 3 days, within 1 to 5 days, within one week, within two weeks, within three weeks, or within four weeks; between one week and two weeks, between one week and three weeks, or between one week and four weeks; between two weeks and three weeks, or between two weeks and four weeks. A compound or composition may be applied before planting or after planting. A compound or composition may be applied pre- emergence or post-emergence. In certain aspects a nitrification inhibiting composition or method provided herein comprises one or more of the following compounds and agriculturally acceptable salts, tautomers, stereoisomers, and N-oxides thereof: where R1-R4 are independently H, ethynyl, trimethylsilyl-ethynyl, C1 – C6 alkoxy, C1 – C6 thioalkyl, C1 – C6 alkyl, C3 – C6 cycloalkyl, C1 – C6 alkenyl, C3 – C6 cycloalkenyl, C1 – C6 haloalkyl, C1 – C6 haloalkenyl, C1– C6haloalkyl, C1– C6haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, wherein at least one of R1 – R4 is C≡C or C≡C-TMS. where R1 – R4 are independently H, C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, vinyl, wherein at least one of R1 – R4 is C≡C or C≡C-TMS. Formula IV, where dependently H, ethynyl, trimethylsilyl-ethynyl, C1 – C6 alkoxy, C1 – C6 thioalkyl, C1– C6alkyl, C3– C6cycloalkyl, C1– C6alkenyl, C3– C6cycloalkenyl, C1– C6haloalkyl, C1– C6haloalkenyl, C1– C6haloalkyl, C1– C6haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, wherein at least one of R11– R14is C≡C or C≡C-TMS. IVa, where C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, vinyl, wherein at least one of R11 and R14 is C≡C or C≡C-TMS. R12– R13are H. Formula V, where - are H, ethynyl, trimethylsilyl-ethynyl, C1 – C6 alkoxy, C1 – C6 thioalkyl, C1 – C6 alkyl, C3 – C6 cycloalkyl, C1 – C6 alkenyl, C3 – C6 cycloalkenyl, C1 – C6 haloalkyl, C1 – C6haloalkenyl, C1– C6haloalkyl, C1– C6haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, wherein at least one of R21 – R24 is C≡C or C≡C-TMS. Formula Va, where independently C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, vinyl, wherein at least one of R21 and R24 is C≡C or C≡C-TMS. R22, R23, and R25 are H. Formula VI, where H, ethynyl, trimethylsilyl-ethynyl, C1– C6alkoxy, C1– C6thioalkyl, C1 – C6 alkyl, C3 – C6 cycloalkyl, C1 – C6 alkenyl, C3 – C6 cycloalkenyl, C1 – C6 haloalkyl, C1 – C6 haloalkenyl, C1 – C6 haloalkyl, C1 – C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, wherein at least one of R31 – R34 is C≡C or C≡C-TMS. Formula VIa, where are independently C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, vinyl, wherein at least one of R31and R33is C≡C or C≡C-TMS. R32, and R34are H. Formula VII, where dependently H, ethynyl, trimethylsilyl-ethynyl, C1 – C6 alkoxy, C1 – C6 thioalkyl, C1– C6alkyl, C3– C6cycloalkyl, C1– C6alkenyl, C3– C6cycloalkenyl, C1– C6haloalkyl, C1– C6haloalkenyl, C1– C6haloalkyl, C1– C6haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, wherein at least one of R41– R44is C≡C or C≡C-TMS. Formula VIIa, where independently C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, vinyl, wherein at least one of R41 and R43 is C≡C or C≡C-TMS. R42and R44are H. Formula VIII, where are independently H, ethynyl, trimethylsilyl-ethynyl, C1 – C6 alkoxy, C1 – C6 thioalkyl, C1 – C6 alkyl, C3 – C6 cycloalkyl, C1 – C6 alkenyl, C3 – C6 cycloalkenyl, C1 – C6 haloalkyl, C1– C6haloalkenyl, C1– C6haloalkyl, C1– C6haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, wherein at least one of R51, R52, or R53 is C≡C or C≡C-TMS. Formula VIIIa, where 53 are independently H, C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, vinyl, wherein at least one of R51, R52, or R53is C≡C or C≡C-TMS. Formula IX, where are independently H, ethynyl, trimethylsilyl-ethynyl, C1 – C6 alkoxy, C1 – C6 thioalkyl, C1– C6alkyl, C3– C6cycloalkyl, C1– C6alkenyl, C3– C6cycloalkenyl, C1– C6haloalkyl, C1– C6haloalkenyl, C1– C6haloalkyl, C1– C6haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, wherein at least one of R61, R62, or R63is C≡C or C≡C-TMS. Formula IXa, where are independently H, C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, vinyl, wherein at least one of R61, R62, or R63is C≡C or C≡C-TMS.

[0002] R71, R72, R73, and R74 are independently H, ethynyl, trimethylsilyl-ethynyl, C1 – C6 alkoxy, C1 – C6 thioalkyl, C1 – C6 alkyl, C3 – C6 cycloalkyl, C1 – C6 alkenyl, C3 – C6 cycloalkenyl, C1 – C6 haloalkyl, C1– C6haloalkenyl, C1– C6haloalkyl, C1– C6haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, wherein at least one of R71, R72, R73, or R74is C≡C or C≡C-TMS. Formula Xa, where and R74 are independently H, C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, vinyl, wherein at least one of R71, R72, R73, or R74is C≡C or C≡C-TMS. In certain aspects a nitrification inhibiting compound, composition, or method provided herein comprises a compound selected from the group (AIG-2) consisting of

[0003] ,MS5

[0004] ,a In certain aspects a nitrification inhibiting compound, composition, or method provided herein comprises a compound selected from the group (AIG-3) consisting of OO. and agriculturally acceptable salts, N-oxides, stereoisomers, and tautomers thereof. In certain aspects a nitrification inhibiting compound is selected from the group consisting of compounds in Table 1, and agriculturally acceptable salts, N-oxides, stereoisomers, and tautomers thereof. A nitrification composition may be mixed with active ingredients and other mixture partners to enhance the usefulness of the composition. Such active ingredients may have, for example, acaricidal, insecticidal, fungicidal, herbicidal, nematicidal activity, as well as other materials, compounds, and compositions. In light of the above, the following details are additionally provided. 1. A composition comprising a compound of Formula I combined with a mixture partner selected from AIG-1. 2. A composition comprising a compound of Formula Ia combined with a mixture partner selected from AIG-1. 3. A composition comprising a compound of Formula II combined with a mixture partner selected from AIG-1. 4. A composition comprising a compound of Formula IIa combined with a mixture partner selected from AIG-1. 5. A composition comprising a compound of Formula III combined with a mixture partner selected from AIG-1. 6. A composition comprising a compound of Formula IIIa combined with a mixture partner selected from AIG-1. 7. A composition comprising a compound of Formula IV combined with a mixture partner selected from AIG-1. 8. A composition comprising a compound of Formula IVa combined with a mixture partner selected from AIG-1. 9. A composition comprising a compound of Formula V combined with a mixture partner selected from AIG-1. 10. A composition comprising a compound of Formula Va combined with a mixture partner selected from AIG-1. 11. A composition comprising a compound of Formula VI combined with a mixture partner selected from AIG-1. 12. A composition comprising a compound of Formula VIa combined with a mixture partner selected from AIG-1. 13. A composition comprising a compound of Formula VII combined with a mixture partner selected from AIG-1. 14. A composition comprising a compound of Formula VIIa combined with a mixture partner selected from AIG-1. 15. A composition comprising a compound of Formula VIII combined with a mixture partner selected from AIG-1. 16. A composition comprising a compound of Formula VIIIa combined with a mixture partner selected from AIG-1. 17. A composition comprising a compound of Formula IX combined with a mixture partner selected from AIG-1. 18. A composition comprising a compound of Formula IXa combined with a mixture partner selected from AIG-1. 19. A composition comprising a compound of Formula X combined with a mixture partner selected from AIG-1. 20. A composition comprising a compound of Formula Xa combined with a mixture partner selected from AIG-1. 21. A composition comprising one or more active ingredients selected from AIG-2 combined with a mixture partner selected from AIG-1. 22. A composition comprising one or more active ingredients selected from the group consisting NO N O. 23. A composition comprising AIG-3.1 combined with mixture partner linoleic acid. 24. A composition comprising AIG-3.1 combined with mixture partner α-linolenic acid. 25. A composition comprising AIG-3.1 combined with mixture partner methyl-p-coumarate. 26. A composition comprising AIG-3.1 combined with mixture partner methyl ferulate. 27. A composition comprising AIG-3.1 combined with mixture partner MHPP. 28. A composition comprising AIG-3.1 combined with mixture partner Karanjin. 29. A composition comprising AIG-3.1 combined with mixture partner brachialacton. 30. A composition comprising AIG-3.1 combined with mixture partner nitrapyrin. 31. A composition comprising AIG-3.1 combined with mixture partner DCD. 32. A composition comprising AIG-3.1 combined with mixture partner DMP. 33. A composition comprising AIG-3.1 combined with mixture partner DMPP. 34. A composition comprising AIG-3.1 combined with mixture partner 4-amino-1,2,4-triazole hydrochloride. 35. A composition comprising AIG-3.1 combined with mixture partner 1-amido-2-thiourea. 36. A composition comprising AIG-3.1 combined with mixture partner 2-amino-4-chloro-6- methylpyrimidine. 37. A composition comprising AIG-3.1 combined with mixture partner 5-ethoxy-3- trichloromethyl-1,2,4-thiodiazole. 38. A composition comprising AIG-3.1 combined with mixture partner 2-sulfanilamidethiazole. 39. A composition comprising AIG-3.1 combined with mixture partner 3,5-dimethyltetrahydro- 1,3,5-thiadiazine-2-thione. 40. A composition comprising AIG-3.1 combined with mixture partner NBPT. 41. A composition comprising AIG-3.2 combined with mixture partner linoleic acid. 42. A composition comprising AIG-3.2 combined with mixture partner α-linolenic acid. 43. A composition comprising AIG-3.2 combined with mixture partner methyl-p-coumarate. 44. A composition comprising AIG-3.2 combined with mixture partner methyl ferulate. 45. A composition comprising AIG-3.2 combined with mixture partner MHPP. 46. A composition comprising AIG-3.2 combined with mixture partner Karanjin. 47. A composition comprising AIG-3.2 combined with mixture partner brachialacton. 48. A composition comprising AIG-3.2 combined with mixture partner nitrapyrin. 49. A composition comprising AIG-3.2 combined with mixture partner DCD. 50. A composition comprising AIG-3.2 combined with mixture partner DMP. 51. A composition comprising AIG-3.2 combined with mixture partner DMPP. 52. A composition comprising AIG-3.2 combined with mixture partner 4-amino-1,2,4-triazole hydrochloride. 53. A composition comprising AIG-3.2 combined with mixture partner 1-amido-2-thiourea. 54. A composition comprising AIG-3.2 combined with mixture partner 2-amino-4-chloro-6- methylpyrimidine. 55. A composition comprising AIG-3.2 combined with mixture partner 5-ethoxy-3- trichloromethyl-1,2,4-thiodiazole. 56. A composition comprising AIG-3.2 combined with mixture partner 2-sulfanilamidethiazole. 57. A composition comprising AIG-3.2 combined with mixture partner 3,5-dimethyltetrahydro- 1,3,5-thiadiazine-2-thione. 58. A composition comprising AIG-3.2 combined with mixture partner NBPT. 59. A composition comprising AIG-3.3 combined with mixture partner linoleic acid. 60. A composition comprising AIG-3.3 combined with mixture partner α-linolenic acid. 61. A composition comprising AIG-3.3 combined with mixture partner methyl-p-coumarate. 62. A composition comprising AIG-3.3 combined with mixture partner methyl ferulate. 63. A composition comprising AIG-3.3 combined with mixture partner MHPP. 64. A composition comprising AIG-3.3 combined with mixture partner Karanjin. 65. A composition comprising AIG-3.3 combined with mixture partner brachialacton. 66. A composition comprising AIG-3.3 combined with mixture partner nitrapyrin. 67. A composition comprising AIG-3.3 combined with mixture partner DCD. 68. A composition comprising AIG-3.3 combined with mixture partner DMP. 69. A composition comprising AIG-3.3 combined with mixture partner DMPP. 70. A composition comprising AIG-3.3 combined with mixture partner 4-amino-1,2,4-triazole hydrochloride. 71. A composition comprising AIG-3.3 combined with mixture partner 1-amido-2-thiourea. 72. A composition comprising AIG-3.3 combined with mixture partner 2-amino-4-chloro-6- methylpyrimidine. 73. A composition comprising AIG-3.3 combined with mixture partner 5-ethoxy-3- trichloromethyl-1,2,4-thiodiazole. 74. A composition comprising AIG-3.3 combined with mixture partner 2-sulfanilamidethiazole. 75. A composition comprising AIG-3.3 combined with mixture partner 3,5-dimethyltetrahydro- 1,3,5-thiadiazine-2-thione. 76. A composition comprising AIG-3.3 combined with mixture partner NBPT. 77. A composition comprising AIG-3.4 combined with mixture partner linoleic acid. 78. A composition comprising AIG-3.4 combined with mixture partner α-linolenic acid. 79. A composition comprising AIG-3.4 combined with mixture partner methyl-p-coumarate. 80. A composition comprising AIG-3.4 combined with mixture partner methyl ferulate. 81. A composition comprising AIG-3.4 combined with mixture partner MHPP. 82. A composition comprising AIG-3.4 combined with mixture partner Karanjin. 83. A composition comprising AIG-3.4 combined with mixture partner brachialacton. 84. A composition comprising AIG-3.4 combined with mixture partner nitrapyrin. 85. A composition comprising AIG-3.4 combined with mixture partner DCD. 86. A composition comprising AIG-3.4 combined with mixture partner DMP. 87. A composition comprising AIG-3.4 combined with mixture partner DMPP. 88. A composition comprising AIG-3.4 combined with mixture partner 4-amino-1,2,4-triazole hydrochloride. 89. A composition comprising AIG-3.4 combined with mixture partner 1-amido-2-thiourea. 90. A composition comprising AIG-3.4 combined with mixture partner 2-amino-4-chloro-6- methylpyrimidine. 91. A composition comprising AIG-3.4 combined with mixture partner 5-ethoxy-3- trichloromethyl-1,2,4-thiodiazole. 92. A composition comprising AIG-3.4 combined with mixture partner 2-sulfanilamidethiazole. 93. A composition comprising AIG-3.4 combined with mixture partner 3,5-dimethyltetrahydro- 1,3,5-thiadiazine-2-thione. 94. A composition comprising AIG-3.4 combined with mixture partner NBPT. 95. A composition comprising AIG-3.5 combined with mixture partner linoleic acid. 96. A composition comprising AIG-3.5 combined with mixture partner α-linolenic acid. 97. A composition comprising AIG-3.5 combined with mixture partner methyl-p-coumarate. 98. A composition comprising AIG-3.5 combined with mixture partner methyl ferulate. 99. A composition comprising AIG-3.5 combined with mixture partner MHPP. 100. A composition comprising AIG-3.5 combined with mixture partner Karanjin. 101. A composition comprising AIG-3.5 combined with mixture partner brachialacton. 102. A composition comprising AIG-3.5 combined with mixture partner nitrapyrin. 103. A composition comprising AIG-3.5 combined with mixture partner DCD. 104. A composition comprising AIG-3.5 combined with mixture partner DMP. 105. A composition comprising AIG-3.5 combined with mixture partner DMPP. 106. A composition comprising AIG-3.5 combined with mixture partner 4-amino-1,2,4-triazole hydrochloride. 107. A composition comprising AIG-3.5 combined with mixture partner 1-amido-2-thiourea. 108. A composition comprising AIG-3.5 combined with mixture partner 2-amino-4-chloro-6- methylpyrimidine. 109. A composition comprising AIG-3.5 combined with mixture partner 5-ethoxy-3- trichloromethyl-1,2,4-thiodiazole. 110. A composition comprising AIG-3.5 combined with mixture partner 2-sulfanilamidethiazole. 111. A composition comprising AIG-3.5 combined with mixture partner 3,5-dimethyltetrahydro- 1,3,5-thiadiazine-2-thione. 112. A composition comprising AIG-3.5 combined with mixture partner NBPT. 113. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is about 50000:1 to about 1:50000. 114. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is about 40000:1 to about 1:40000. 115. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is about 10256:1 to about 1:10256. 116. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is about 10000:1 to about 1:10000. 117. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is about 2564:1 to about 1:2564. 118. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is 1000:1 to about 1:1000. 119. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is about 640:1 to about 1:640. 120. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is 500:1 to about 1:500. 121. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is 100:1 to about 1:100. 122. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is 50:1 to about 1:50. 123. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is 20:1 to about 1:20. 124. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is about 16:1 to about 1:16. 125. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is 10:1 to about 1:10. 126. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is 5:1 to about 1:5. 127. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is 3:1 to about 1:3. 128. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is 2:1 to about 1:2. 129. A composition according to any of the previous details from 1 through 112 wherein the weight ratio of said compound to said mixture partner is 1:1. 130. A composition according to any of the previous details from 1 through 129 wherein the composition further comprises a source of ammonia selected from the group consisting of anhydrous ammonia, ammonium nitrate, ammonium sulfate, urea ammonium nitrate, urea, manure, and mixtures thereof. In some aspects, compositions disclosed herein may exhibit enhanced efficacy may be expected when a compound is combined with a mixture partner at particular weight ratios within the ranges defined above. “Enhanced efficacy” in this context means an efficacy greater than the expected efficacy as calculated by the Colby equation. Application of Nitrification Inhibitor Compounds to Soil In certain aspects provided herein one or more nitrification inhibitor compounds or compositions are mixed with a source of ammonia. Sources of ammonia include, but are not limited to, anhydrous ammonium, ammonium salts, such as ammonium nitrate, calcium ammonium nitrate, ammonium sulfate nitrate, ammonium sulfate or ammonium phosphate; organic ammonia sources, such as manure, biogas, worm castings, compost, seaweed or guano; urea-containing fertilizers such as, urea, formaldehyde urea, urea ammonium nitrate solution, urea sulfur, urea ammonium sulfate, or other urea-based fertilizers. In certain aspects provided herein, one or more of the nitrification inhibitor compounds or compositions are mixed with anhydrous ammonia, which is then injected into the soil. In other aspects, the compound or composition is injected separately into the growing medium at the time of anhydrous ammonia application. The amount of compound or composition present in the anhydrous ammonia mixture, or directly injected, may be adjusted so that an agriculturally effective amount of the nitrification-inhibiting compound or composition is spread. In certain aspects provided herein, the nitrification inhibitor compound or composition is mixed with fertilizers such as urea-ammonium nitrate solution to form a urea-ammonium nitrate nitrification-inhibitor mixture. These mixtures may also include other ingredients such as herbicides, insecticides, fungicides, and safeners. Such mixtures may be applied at rates of from about 10 to about 70 gallons per acre depending on the fertilizer strength and concentration as well as the target amount of nitrogen per acre. For example, the amount of compound or composition present in the treated mixture may be adjusted so that an agriculturally effective amount of the compound or composition is spread. In certain aspects provided herein, the nitrification compound or composition is impregnated on dry urea. The amount of compound or composition impregnated will depend upon the application rate of the urea. For example, urea may be spread at a rate of from about 200 to about 700 pounds per acre. An amount of compound or composition may be impregnated on dry urea so that the compound or composition is spread at an agriculturally effective amount. In certain aspects provided herein, the compound or composition is spread as part of a manure slurry mixture. The compound or composition may be mixed with manure prior to application or may be separately applied. The amount of compound or composition present in a manure slurry may be adjusted so that an agriculturally effective amount of compound or composition is spread. A compound or composition may be applied to a growing medium at a rate of from about 50 grams per acre to about 4 kilograms per acre. A compound may be applied to a growing medium at the following rates: 50-60 grams / acre; 60-70 grams / acre; 70-80 grams / acre; 80-90 grams / acre; 90-100 grams / acre; 100-120 grams / acre; 120-140 grams / acre; 140-160 grams / acre; 160-180 grams / acre; 180-200 grams / acre; 200-225 grams / acre; 225-250 grams / acre; 250-275 grams / acre; 275-300 grams / acre; 300-350 grams / acre; 350-400 grams / acre; 400-450 grams / acre; 450-500 grams / acre; 500-550 grams / acre; 550-600 grams / acre; 600-650 grams / acre; 650-700 grams / acre; 700-750 grams / acre; 750-800 grams / acre; 800-850 grams / acre; 850-900 grams / acre; 900-950 grams / acre; 950-1000 grams / acre; 1.0-1.1 kilograms / acre; 1.1-1.2 kilograms / acre; 1.2-1.3 kilograms / acre; 1.3-1.4 kilograms / acre; 1.4-1.5 kilograms / acre; 1.5-1.6 kilograms / acre; 1.6-1.7 kilograms / acre; 1.7-1.8 kilograms / acre; 1.8-1.9 kilograms / acre; 1.9-2.0 kilograms / acre; 2.0-2.2 kilograms / acre; 2.2-2.4 kilograms / acre; 2.4-2.6 kilograms / acre; 2.6-2.8 kilograms / acre; 2.8-3.0 kilograms / acre; 3.0-3.2 kilograms / acre; 3.2-3.4 kilograms / acre; 3.4-3.6 kilograms / acre; 3.6-3.8 kilograms / acre; and 3.8-4.0 kilograms / acre. Experimental General Synthesis Procedures General Procedure 1 To a stirred solution of the heterocyclic (1 equiv) 0.7 g, 3.95 mmol, in EtOAc (0.2 mmolar ) were added Et3N(4 equiv.) and CuI (5 mol%) at RT (room temperature) and the reaction mixture was degassed with argon for 5 min, followed by addition of TMS-acetylene (4.5 equiv.) and bis(triphenylphosphine)palladium chloride (15 mol%). The reaction mixture was stirred at 50 °C for 16h. After completion of the reaction (monitor by TLC), the reaction mixture was filtered through celite pad, the filtrate was dried over Na2SO4and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 10 - 20% EtOAc in petroleum ether to afford the desired products. General Procedure 2 To a stirred solution of the ethynyl TMS heterocycle (1.0 eq) in methanol (0.2 mmolar) was added 1 equiv. potassium carbonate. The reaction was stirred at room temperature until completion of the reaction (monitor by TLC). The reaction mixture was filtered through celite pad, the filtrate was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 10 - 20% EtOAc in petroleum ether to afford the desired products. General Procedure 3 Aldehyde (1.0 equiv.) was a dissolved in anhydrous methanol (0.2-0.5 mM) and charged with cesium carbonate (1.0 equiv.) and cooled to 0-5 degrees C. Dimethyl (l-diazo-2-oxopropyl) phosphonate (1.0 equiv.) was added dropwise after which the reaction was allowed to stir for 1- 18h after which the crude mixture was concentrated onto silica gel and purified directly by flash silica gel chromatography to provide the desired alkyne. Synthesis Procedures 12780973 Trimethylsilylacetylene, (1.5 mL, 10.81 mmol), bis(triphenylphosphine)palladium(II) chloride (79 mg, 0.113 mmol) and copper(I) iodide (4.29 mg, 0.023 mmol) was added to a degassed solution of methyl 2-bromo-1,3-thiazole-5-carboxylate (500 mg, 2.252 mmol) and Et3N (1.4 mL, 9.68 mmol) in EtOAc (2.0 mL). The mixture was heated to 50 °C for 7h before cooling to 25 °C and filtering the reaction mixture through celite. The solvent was evaporated under reduced pressure to obtain the desired product. 12791843 To a solution of 1-(4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)thiazol-5-yl)ethan-1-one (0.4 g, 1.37 mmol) in MeOH (5 mL) was added NaBH4(0.025 g, 0.68 mmol) at 0 °C and stirred for 1h at same temperature. Water (10 mL) added to reaction mixture and extracted with DCM, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100 - 200 mesh) eluting with 20 - 25% EtOAc in petroleum ether to afford 0.2 g (65%) of target an off white solid; M P 73 – 77 °C;1H NMR (400 MHz, CDCl3) δ 5.48 – 5.45 (m, 1H), 3.50 (s, 1H), 2.44 – 2.43 (m, 1H), 1.60 – 1.58 (m, 3H);19F NMR (376 MHz, CDCl3) δ -60.41; ESIMS m / z 222.07 ([M+H]+). 12791845 To a solution of 4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide 0.2 g, 0.68 mmol) in THF-H2O mixture (3:1) (5 mL) was added LiOH.H2O (0.03 g, 0.68 mmol) and the reaction mixture was stirred for 2h at RT. The reaction mixture was acidified with 1N HCl and extracted with DCM. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100 - 200 mesh) eluting with 60 - 70% EtOAc in petroleum ether to afford 0.035 g (23%) of target, a pale brown solid; M P 134 - 138 °C;1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.14 (s, 1H), 5.24 (s, 1H);19F NMR (376 MHz, CDCl3) δ -60.27; ESIMS m / z 221.06 ([M+H]+). 12791847 To a solution of ethyl 2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide 0.1 g, 0.44 mmol) in THF-H2O mixture (3:1) (5 mL) was added LiOH.H2O (0.02 g, 0.44 mmol) and the reaction mixture was stirred for 2h at RT. The reaction mixture was acidified with 1N HCl and extracted with DCM. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 0.03 g (44%) of target, a pale brown solid; M P 178 - 182 °C;1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.26 (s, 1H), 7.80 (s, 1H), 5.08 (s, 1H); ESIMS m / z 153.01 ([M+H]+). 12791857 To a solution of 1-(2-ethynylthiazol-5-yl)ethan-1-one (0.1 g, 0.66 mmol) in MeOH (3 mL) was added NaBH4(0.013 g, 0.33 mmol) at 0 °C and stirred for 1h at same temperature. Water (10 mL) added to reaction mixture and extracted with DCM, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100 - 200 mesh) eluting with 20 - 25% EtOAc in petroleum ether to afford 0.09 g (89%) of target, a brown solid; M P 72 – 76 °C;1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 5.21 – 5.15 (m, 1H), 3.45 (s, 1H), 2.20 – 2.19 (m, 1H), 1.63 – 1.60 (m, 3H); ESIMS m / z 154.03 ([M+H]+). 12791863 To a solution ethyl 2-ethynylthiazole-5-carboxylate (1.4 g, 5.53 mmol) in THF:H2O mixture (3:1) (15 mL) was added LiOH.H2O (0.28 g, 6.64 mmol) and the reaction mixture was stirred at RT for 16h. The reaction mixture was acidified with 1N HCl (pH ~ 2) and was extracted with DCM. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 0.8 g (72%) of target, a black solid; M P 195 - 199 °C;1H NMR (400 MHz, DMSO-d6) δ 13.30 (brs, 1H), 8.54 (s, 1H), 5.02 (s, 1H); ESIMS m / z 153.99 ([M+H]+). 12791865 To a solution of 2-ethynylthiazole-5-carboxylic acid (0.25 g, 1.63 mmol) in DMF (5 mL) was added HATU (0.745 g, 1.96 mmol), DIPEA (0.315 g, 2.45 mmol), NH4Cl (0.1 g, 1.96 mmol) and the reaction mixture was stirred for 16h at RT. The reaction mixture was diluted with water (20 mL) and was extracted with EtOAc. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100 - 200 mesh) eluting with 50 - 60% EtOAc in petroleum ether to afford 0.17 g (66%) of target, an off white solid; M P 162 - 166 °C;1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.88 (s, 1H), 7.65 (s, 1H), 5.02 (s, 1H); ESIMS m / z 153.02 ([M+H]+). 12791867 To a solution of 2-ethynylthiazole-4-carboxylic acid (0.25 g, 1.63 mmol) in DMF (5 mL) was added HATU (0.93 g, 2.45 mmol), DIPEA (0.42 g, 3.26 mmol), 2-methylbut-3-yn-2-amine (0.16 g, 1.96 mmol) and the reaction mixture was stirred for 16h at RT. The reaction mixture was diluted with water (20 mL) and was extracted with EtOAc. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100 - 200 mesh) eluting with 30 - 40% EtOAc in petroleum ether to afford 0.16 g (45%) of target, an off white solid; M P 101 - 105 °C;1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.40 (brs, 1H), 3.53 (s, 1H), 2.38 (s, 1H), 1.76 (s, 3H), 1.75 (s, 3H); ESIMS m / z 219.07 ([M+H]+). 12791869 To a solution of 2-ethynylthiazole-4-carboxylic acid (0.25 g, 1.63 mmol) in DMF (5 mL) was added HATU (0.93 g, 2.45 mmol), DIPEA (0.42 g, 3.26 mmol), 2-methylbut-3-yn-2-amine (0.16 g, 1.96 mmol) and the reaction mixture was stirred for 16h at RT. The reaction mixture was diluted with water (20 mL) and was extracted with EtOAc. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100 - 200 mesh) eluting with 30 - 40% EtOAc in petroleum ether to afford the product, an off white solid (0.17 g, 54%); M P 121 - 125 °C;1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.47 (brs, 1H), 4.25 - 4.23 (m, 2H), 3.54 (s, 1H), 2.27 - 2.26 (m, 1H); ESIMS m / z 191.03 ([M+H]+). 12795389 To a solution of 2-bromo-N-(2-methylbut-3-yn-2-yl)thiazole-4-carboxamide (0.4 g, 1.46 mmol) in toluene (5 mL) was added CuI (0.03 g, 0.14 mmol) followed by the addition of DIPEA (0.37 g, 2.93 mmol), PdCl2(PPh3)2(0.05 g, 0.07 mmol), TMS acetylene (0.18 g, 1.75 mmol) under argon atmosphere and the reaction mixture was stirred at 70 °C for 16h. The reaction mixture was cooled to RT, EtOAc (30 mL) was added, filtered through a pad of celite, the filtrate was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100 - 200 mesh) eluting with 5 - 10% EtOAc in petroleum ether to afford 0.12 g (28%) of target, a brown liquid; FT-IR 1666.53 cm-1(C=O stretching present);1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.41 (brs, 1H), 2.38 (s, 1H), 1.74 - 1.73 (m, 6H), 0.30 (s, 9H); ESIMS m / z 291.01 ([M+H]+). 12795393 To a solution of 2-bromo-N-(prop-2-yn-1-yl)thiazole-4-carboxamide (0.4 g, 1.46 mmol) in toluene (5 mL) was added CuI (0.03 g, 0.14 mmol) followed by the addition of DIPEA (0.37 g, 2.93 mmol), PdCl2(PPh3)2 (0.05 g, 0.07 mmol), TMS acetylene (0.18 g, 1.75 mmol) under argon atmosphere and the reaction mixture was stirred at 70 °C for 16h. The reaction mixture was cooled to RT, EtOAc (30 mL) was added, filtered through a pad of celite, the filtrate was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100 - 200 mesh) eluting with 5 - 10% EtOAc in petroleum ether to afford 0.12 g (28%) of target, a pale brown solid (0.11 g, 25%); M P 79 - 83 °C;1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.48 (brs, 1H), 4.24 - 4.21 (m, 2H), 2.26 - 2.24 (m, 1H), 0.30 (s, 9H); ESIMS m / z 263.08 ([M+H]+). 12806737 To a stirred solution of 1-(2-((trimethylsilyl)ethynyl)thiazol-4-yl)prop-2-yn-1-one (0.2 g, 0.80 mmol) in MeOH (2 mL) was added K2CO3(1 mg, cat.) at RT. The reaction mixture was stirred at RT for 5 minutes. After completion of the reaction, the reaction mixture was poured in ice water (5 mL), acidified with 1N HCl (2 mL, pH ~4) and extracted with EtOAc. Combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 12 g) using 10 % EtOAc in petroleum ether eluent to afford the product, a pale brown solid (0.032 g, 27%); M P 126 - 130 °C;1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 3.56 (s, 1H), 3.50 (s, 1H); ESIMS m / z 162.08 ([M+H]+). 12806745 To a stirred solution of (E)-1-(2-((trimethylsilyl)ethynyl)thiazol-4-yl)but-2-en-1-one (0.2 g, 0.80 mmol) in MeOH (2 mL) was added K2CO3(1 mg, cat.) at RT. The reaction mixture was stirred at RT for 5 minutes. After completion of the reaction, the reaction mixture was poured in ice water (5 mL), acidified with 1N HCl (2 mL, pH ~4) and extracted with EtOAc. Combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 12 g) using 10 % EtOAc in petroleum ether eluent to afford a pale brown solid (0.025 g, 17%); M P 111 - 115 °C;1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.23 - 7.14 (m, 1H), 6.77 - 6.72 (m, 1H), 3.63 (s, 1H); 2.03 (t, J = 3.4 Hz, 3H); ESIMS m / z 178.09 ([M+H]+). 12806753 To a stirred solution of 1-(2-((trimethylsilyl)ethynyl)thiazol-5-yl)prop-2-yn-1-one (1.2 g, 5.76 mmol) in DCM (15 mL) was added DMP (3.17 g, 7.49 mmol) at 0 °C. The reaction mixture was stirred at RT for 3h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 24g) using 10 - 20% EtOAc in petroleum ether eluent to afford the product, a brown solid (0.2 g, 50%); M P 78 - 82 °C;1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 3.45 (s, 1H), 0.30 (s, 9H); ESIMS m / z 234.11 ([M+H]+). 12806761 To a stirred solution of (E)-1-(2-((trimethylsilyl)ethynyl)thiazol-4-yl)but-2-en-1-one (0.2 g, 0.80 mmol) in MeOH (2 mL) was added K2CO3 (1 mg, cat.) at RT. The reaction mixture was stirred at RT for 5 minutes. After completion of the reaction, the reaction mixture was poured in ice water (5 mL), acidified with 1N HCl (2 mL, pH ~4) and extracted with EtOAc. Combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 12 g) using 10 % EtOAc in petroleum ether eluent to afford target (0.025 g, 21%), a pale brown solid (0.025 g, 17%); M P 111 - 115 °C;1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.23 - 7.14 (m, 1H), 6.77 - 6.72 (m, 1H), 3.63 (s, 1H); 2.03 (t, J = 3.4 Hz, 3H); ESIMS m / z 178.09 ([M+H]+). 12811457 1 mL MeOH was added to N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol) in 3 mL of THF at 0 °C and the reaction was stirred at 0 °C for 30 min. After the reaction was completed, the mixture was filtered and washed with THF, the filtrate was concentrated under low temperature to get product (40 mg, 86%), a yellow solid. 12811461 1 mL MeOH was added to N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol) in 3 mL of THF at 0 °C and the reaction was stirred at 0 °C for 30 min. After the reaction was completed, the mixture was filtered and washed with THF, the filtrate was concentrated under low temperature to get product (40 mg, 83%), a brown solid. 12811465 Under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidephenyl)benzamide (150 mg, 0.54mmol) was added to trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), NEt3 (1.5 ml) in 4.5 mL of THF. The reaction was stirred at 50 °C for 2h. After the reaction was completed, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give the product, a yellow solid. 12811467 Under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidephenyl)benzamide (150 mg, 0.54mmol) was added to trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), NEt3(1.5 ml) in 4.5 mL of THF. The reaction was stirred at 50 °C for 2h. After the reaction was completed, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give the product, a yellow solid. 12811469 Under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidephenyl)benzamide (150 mg, 0.54mmol) was added to trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4(62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), NEt3 (1.5 ml) in 4.5 mL of THF. The reaction was stirred at 50 °C for 2h. After the reaction was completed, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give the product, a yellow solid. 12811471 Under N2, 2-bromo-N-methylthiazole-5-carboxamide (0.54mmol) was added to trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), NEt3(1.5 ml) in 4.5 mL of THF. The reaction was stirred at 50 °C for 2h. After the reaction was completed, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give the product N-methyl-2- ((trimethylsilyl)ethynyl)thiazole-5-carboxamide, a brown solid (63%).1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 6.14 (s, 1H), 3.01 (d, J = 4.8 Hz, 3H), 0.29 (s, 9H).13C NMR (101 MHz, 155-156 °C. 12811481 1 mL MeOH was added to N-methyl-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (0.21 mmol), K2CO3(58 mg, 0.42 mmol) in 3 mL of THF at 0 °C and the reaction was stirred at 0 °C for 30 min. After the reaction was completed, the mixture was filtered and washed with THF, the filtrate was concentrated under low temperature to get product provide the desired product, a brown solid (55 mg, 98%)1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 6.25 (s, 1H), 3.57 (s, 1H), 3.01 (d, J = 4.9 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 160.22, 150.49, 142.97, 136.16, 84.05, 75.97, 26.90. ESIMS m / z 167 ([M+H]+). Mp, 118-119 °C. 12811473 1 mL MeOH was added to N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol) in 3 mL of THF at 0 °C and the reaction was stirred at 0 °C for 30 min. After the reaction was completed, the mixture was filtered and washed with THF, the filtrate was concentrated under low temperature to get product (40 mg, 86%), a brown solid. 12811475 1 mL MeOH was added to N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol) in 3 mL of THF at 0 °C and the reaction was stirred at 0 °C for 30 min. After the reaction was completed, the mixture was filtered and washed with THF, the filtrate was concentrated under low temperature to get product (40 mg, 86%), a brown solid. 12811477 1 mL MeOH was added to N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), K2CO3(58 mg, 0.42 mmol) in 3 mL of THF at 0 °C and the reaction was stirred at 0 °C for 30 min. After the reaction was completed, the mixture was filtered and washed with THF, the filtrate was concentrated under low temperature to get product (40 mg, 86%), a brown solid.1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 5.70 (s, 1H), 4.01 - 3.92 (m, 1H), 3.56 (s, 1H), 1.70 - 1.61 (m, 2H), 1.54 - 1.45 (m, 2H), 0.95 (t, J = 7.4 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 159.30, 150.41, 142.57, 136.71, 83.90, 76.03, 67.98, 53.11, 27.48, 10.29. ESIMS m / z 223 ([M+H]+). Mp, 81-82 °C. 12811479 Under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidephenyl)benzamide (150 mg, 0.54mmol) was added to trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), NEt3(1.5 ml) in 4.5 mL of THF. The reaction was stirred at 50 °C for 2h. After the reaction was completed, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give the product 1 (161mg, 64%), a brown solid. 12811481 Under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidephenyl)benzamide (150 mg, 0.54mmol) was added to trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4(62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), NEt3 (1.5 ml) in 4.5 mL of THF. The reaction was stirred at 50 °C for 2h. After the reaction was completed, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give the product 1 (114 mg, 72%), a brown solid. 12811485 Under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidephenyl)benzamide (150 mg, 0.54mmol) was added to trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), NEt3(1.5 ml) in 4.5 mL of THF. The reaction was stirred at 50 °C for 2h. After the reaction was completed, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give the product 1 (150 mg, 49%), a white solid. 12776911 To a solution of ethyl 2-bromooxazole-4-carboxylate L-a (1.5 g, 6.81 mmol) in toluene (10 mL) was added CuI (0.13 g, 0.0.68 mmol), DIPEA (1.75 g, 13.62 mmol), PdCl2(PPh3)2 (0.24 g, 0.34 mmol) and trimethylsilylacetylene (1 g, 10.21 mmol) under argon atmosphere and the reaction mixture was stirred at 50 °C for 16h. The reaction mixture was cooled to RT, EtOAc (150 mL) was added and filtered through pad of celite and filtrate was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100 - 200 mesh) eluting with 5 - 10% EtOAc in petroleum ether to afford 0.8 g (50%) of target, a brown liquid; FT-IR 1737.89 cm-1(C=O stretching present);1H NMR (400 MHz, CDCl3) δ 8.16 (s, 3H), 4.39 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H), 0.27 (s, 9H); ESIMS m / z 238.22 ([M+H]+). 12776913 To a solution of 2-ethynyloxazole-4-carboxylic acid (0.8 g, 3.37 mmol) in THF-H2O mixture (3:1) (10 mL) was added LiOH.H2O (0.14 g, 3.37 mmol) and the reaction mixture was stirred for 2h at RT. The reaction mixture was acidified with 1N HCl and extracted with DCM. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 0.6 g (86%) of target, a brown solid; M P 161 – 165 °C;1H NMR (400 MHz, DMSO-d6) δ 13.35 (bs, 1H), 8.83 (s, 1H), 4.95 (s, 1H); ESIMS m / z 138.16 ([M+H]+). 12776915 To a solution of 2-ethynyloxazole-4-carboxylic acid (0.1 g, 0.72 mmol) and amine input (0.073 g, 0.87 mmol) in DMF (3 mL), was added HATU (0.42 g, 1.09 mmol) and DIPEA (0.19 g, 1.44 mmol) at 0 °C and the reaction mixture was stirred for 16h at RT. The reaction mixture diluted with water (20 mL), was extracted with EtOAc. The organic layer was washed with ice water, brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100 - 200 mesh) eluting with 30 - 35% EtOAc in petroleum ether to afford 0.08 g (54%) of target, a brown solid. 12776921 To a solution of 2-ethynyloxazole-5-carboxylic acid (0.35 g, 2.55 mmol) and amine input (0.318 g, 3.83 mmol) in DMF (5 mL), was added HATU (1.45 g, 3.82 mmol) and DIPEA (0.98 g, 7.66 mmol) at 0 °C and the reaction mixture was stirred for 16h at RT. The reaction mixture diluted with water (30 mL), was extracted with EtOAc. The organic layer was washed with ice water, brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100 - 200 mesh) eluting with 20 - 25% EtOAc in petroleum ether to afford 0.240 g (46%) of product, an off white solid; M P 133 – 137 °C;1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 6.30 (s, 1H), 3.33 (s, 1H), 2.41 (s, 1H), 1.75 (s, 6H); ESIMS m / z 203.13 ([M+H]+). 12776925 To a solution of ethyl ethyl 2-iodooxazole-5-carboxylate h1 (2.5 g, 9.36 mmol) in toluene (25 mL) was added CuI (0.178 g, 0.93 mmol), DIPEA (2.4 g, 18.72 mmol), PdCl2(PPh3)2(0.33 g, 0.468 mmol) and trimethylsilylacetylene (1.8 g, 18.72 mmol) under argon atmosphere and the reaction mixture was stirred at 50 °C for 16h. The reaction mixture was cooled to RT. EtOAc (100 mL) was added and filtered through pad of celite and filtrate was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100 - 200 mesh) eluting with 5 - 10% EtOAc in petroleum ether to afford 1 g (45%) of product, a brown liquid; FT-IR 1733.07 cm-1(C=O stretching present);1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 4.39 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H), 0.28 (s, 9H); ESIMS m / z 238.15 ([M+H]+). 12791853 To a solution of 2-ethynyloxazole-4-carboxamide (0.3 g, 2.18 mmol) and Aq. NH3(2 mL) in THF (5 mL), was added HATU (1 g, 2.62 mmol) and DIPEA (0.42 g, 3.28 mmol) at 0 °C and the reaction mixture was stirred for 16h at RT. The reaction mixture diluted with water (20 mL), was extracted with EtOAc. The organic layer was washed with ice water, brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100 - 200 mesh) eluting with 40 - 45% EtOAc in petroleum ether to afford 0.05 g (42%) of product, a pale brown solid; M P 176 – 180 °C;1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.79 (s, 1H), 7.58 (s, 1H), 4.95 (s, 1H); ESIMS m / z 137.12 ([M+H]+). 12797705 To a stirred solution of 2-((trimethylsilyl)ethynyl)oxazole-4-carbaldehyde (0.2 g, 0.80 mmol) in MeOH (2 mL) was added K2CO3 (1 mg, cat.) at RT. The reaction mixture was stirred at RT for 5 minutes. After completion of the reaction, the reaction mixture was poured in ice water (5 mL), acidified with 1N HCl (2 mL, pH ~4) and extracted with EtOAc. Combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 12 g) using 10 % EtOAc in petroleum ether eluent to afford the product, an off white solid (0.078 g, 43%); M P 110 - 114 °C;1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 8.24 (s, 1H), 3.33 (s, 1H); ESIMS m / z 122.12 ([M+H]+). 12806755 To a stirred solution of 1-(2-((trimethylsilyl)ethynyl)oxazol-4-yl)prop-2-yn-1-ol (0.27 g, 1.14 mmol) in dichloromethane (6 mL) was added DMP (0.63 g, 1.49 mmol) at 0 °C. The reaction mixture was stirred at RT for 3h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 24 g) using 10 % EtOAc in petroleum ether eluent to afford the product, a pale brown solid (0.12 g, 42%); M P 75 - 79 °C;1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 3.44 (s, 1H), 0.29 (s, 9H); ESIMS m / z 218.15 ([M+H]+). 12806763 To a stirred solution of 1-(2-((trimethylsilyl)ethynyl)oxazol-4-yl)prop-2-yn-1-one (0.2 g, 0.80 mmol) in MeOH (2 mL) was added K2CO3(1 mg, cat.) at RT. The reaction mixture was stirred at RT for 5 minutes. After completion of the reaction, the reaction mixture was poured in ice water (5 mL), acidified with 1N HCl (2 mL, pH ~4) and extracted with EtOAc. Combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 12 g) using 10 % EtOAc in petroleum ether eluent to afford a pale brown solid (0.024 g, 45%); M P 117 - 121 °C;1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 3.45 (s, 1H), 3.33 (s, 1H); ESIMS m / z 146.05 ([M+H]+). 12811459 1 mL MeOH was added to N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), K2CO3(58 mg, 0.42 mmol) in 3 mL of THF at 0 °C and the reaction was stirred at 0 °C for 30 min. After the reaction was completed, the mixture was filtered and washed with THF, the filtrate was concentrated under low temperature to get product (25 mg, 86%), a yellow solid. 12811483 1 mL MeOH was added to N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), K2CO3(58 mg, 0.42 mmol) in 3 mL of THF at 0 °C and the reaction was stirred at 0 °C for 30 min. After the reaction was completed, the mixture was filtered and washed with THF, the filtrate was concentrated under low temperature to the product, a brown solid (85%)1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 6.45 (s, 1H), 4.24 (dd, J = 5.4, 2.6 Hz, 2H), 3.35 (s, 1H), 2.31 (t, J = 2.6 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 155.57, 145.61, 145.06, 132.07, 81.61, 78.37, 72.49, 70.68, 29.09. ESIMS m / z 175([M+H]+). Mp, 112-113 °C. 12811491 Under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidePhenyl)benzamide (150 mg, 0.54mmol) was added to trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), NEt3 (1.5 ml) in 4.5 mL of THF. The reaction was stirred at 50 °C for 2h. After the reaction was completed, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give the product, a yellow oil. 12811493 Under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidePhenyl)benzamide (150 mg, 0.54mmol) was added to trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), NEt3 (1.5 ml) in 4.5 mL of THF. The reaction was stirred at 50 °C for 2h. After the reaction was completed, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give the product, a white solid (25%)1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 6.45 (s, 1H), 4.23 (dd, J = 5.4, 2.6 Hz, 2H), 2.30 (t, J = 2.5 Hz, 1H), 0.30 (s, 9H).13C NMR (101 MHz, CDCl3) δ 156.53, 147.07, 145.37, 132.91, 102.42, 91.08, 79.24, 73.24, 29.85. ESIMS m / z 247([M+H]+). Mp, 134-135 °C. 12771961 To a solution of N-(2-methylbut-3-yn-2-yl)-2-(trichloromethyl)-4-(trifluoromethyl)thiazole-5- carboxamide (273 mg, 0.719 mmol) in THF:H20 (5:1, 6 mL) was added Fe(s) in a single portion. The resulting reaction mixture was allowed to warm to 60°C. Maintained the temperature for 16h (start at 4:00 PM). The reaction was monitor by TLC (n-hexane: ethyl acetate 8:2) and LCMS. No SM was visible by TLC after 16h. The reaction mixture was concentrated (nitrogen) and adsorbed onto celite pre-column and chromatographed over silica gel. 12799175 To a solution of 5-ethynylthiazole-2-carbaldehyde ( 40 mg, 0.292 mmol) in anhydrous THF at - 78C was slowly added methylmagnesium bromide (86 µl, 0.292 mmol)as a 3.4 molar solution in THF. After the addition was complete, the reaction was allowed to slowly warm to 25 °C over 30 minutes and then quenched with sat aq NH4Cl and diluted with 50 mL ether. The layers were partitioned and the ether layer was dried over magnesium sulfate and concentrated over a stream of nitrogen to afford a brown residue (42 mg, 85%). 12816775 To a stirred solution of (5-ethynylfuran-2-yl)methanol (0.1 g, 0.82 mmol) in THF (5 mL) were added NaH (60%, 0.078 g, 1.63 mmol) and CH3I (0.12 mL, 2.04 mmol) at 0 °C. The reaction mixture was stirred at RT for 2h. After completion of the reaction (monitor by TLC), the reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 12g) using 5 - 10% EtOAc in petroleum ether to afford product (0.026 g, 23%) a pale brown liquid; FT IR 2111.13 cm-1(C≡C Stretching present);1H NMR (400 MHz, CDCl3) δ 6.60 (d, J = 3.2 Hz, 1H), 6.31 (d, J = 3.6 Hz, 1H), 4.37 (s, 2H), 3.38 (s, 3H), 3.37 (s, 1H); ESIMS m / z 135.9 ([M]+). 12816797 To a stirred solution of 1-(5-ethynylfuran-2-yl)ethan-1-ol (0.1 g, 0.60 mmol) in DMF (5 mL) was added K2CO3 (0.1 g, 0.73 mmol) and methyl iodide (0.1 mL, 1.20 mmol) at RT. The reaction mixture was stirred at RT for 16h. After completion of the reaction (monitor by TLC), the reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 12 g) using 10 - 20% EtOAc in petroleum ether to afford the product, a brown liquid (0.026 g, 26%); FT IR 3288.69 cm-1(O-H Stretching present);1H NMR (400 MHz, CDCl3) δ 6.59 (d, J = 3.6 Hz, 1H), 6.22 (dd, J = 0.4, 3.2 Hz, 1H), 4.86 (q, J = 4.4 Hz, 1H), 3.39 (s, 1H), 1.92 (d, J = 4.4 Hz, 1H), 1.54 (d, J = 6.8 Hz, 3H); ESIMS m / z 135.9 ([M]+). 12830209 To a stirred solution of 1-(2-ethynyloxazol-4-yl)ethan-1-ol (0.1 g, 0.72 mmol) in THF (5 mL) was added NaH (48 mg, 0.72 mmol) at 0 °C and stirred for 15 minutes at 0 °C, followed by the addition of CH3I (0.091 mL, 1.45 mmol). The reaction mixture was slowly warmed to RT and stirred for 2h. After completion of the reaction (monitor by TLC), the reaction mixture was quenched with cold water (10 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 24 g) using 10-20% EtOAc in petroleum ether eluent to afford Product-A8 (0.036 g, 33%) a pale yellow liquid; FT IR 2121.70 cm-1(C≡C stretching present);1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 4.36 (q, J = 6.0 Hz, 1H), 3.36 (s, 3H), 3.23 (s, 1H), 1.48 (d, J = 6.4 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 145.58, 143.86, 135.94, 79.91, 72.18, 71.29, 56.66, 20.13; ESIMS m / z 152.07 ([M+H]+). 12830213 To a stirred solution of 1-(2-((trimethylsilyl)ethynyl)oxazol-4-yl)ethan-1-one (0.3 g, 1.55 mmol) in THF (10 mL) was added CH3MgI [3M in Diethyl ether (0.6 mL, 1.86 mmol)] at 0 °C. The reaction mixture was stirred at RT for 3h. After completion of the reaction (monitor by TLC), the reaction mixture was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 24 g) using 10-20% EtOAc in petroleum ether eluent to afford Int-A-1-5 (0.2 g, 59%) a pale yellow liquid; FT IR 2175.70 cm-1(C≡C stretching present);1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 4.83 (q, J = 6.8 Hz, 1H), 2.15 (d, J = 4.8 Hz, 1H), 1.52 (d, J = 6.4 Hz, 3H), 0.27 (d, 9H); ESIMS m / z 210.18 ([M+H]+). 12853673 To a stirred solution of thiazole-2-thiol (0.3 g, 2.56 mmol) in acetone (10 mL) were added K2CO3(0.35 g, 2.56 mmol) and propargyl bromide (0.2 mL, 2.56 mmol) at 0°C. The reaction mixture was stirred at RT for 3h. After completion (monitor by TLC) of the reaction, the reaction mixture was poured in water (10 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford product (0.15 g, 38%), a brown liquid; FT IR 2117.84 cm-1(C≡C stretching present);1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 3.2 Hz, 1H), 7.28 (d, J = 3.2 Hz, 1H), 3.95 (d, J = 2.8 Hz, 2H), 2.28 (t, J = 5.2 Hz, 1H); ESIMS m / z 156.12 ([M+H]+). 12853681 To a stirred solution of 2-bromothiazole (0.3 g, 1.82 mmol) in 1,4-dioxane (10 mL) were added LiCl (0.23 g, 5.48 mmol) and CuI (0.1 g, 0.55 mmol) at RT. The reaction mixture was degassed with argon for 5 minutes, then added input-1 (0.66 g, 2.01 mmol) and Pd(PPh3)4(0.1 g, 0.09 mmol) at RT. The reaction mixture was stirred at 100 °C for 16h. After completion (monitor by TLC) of the reaction, the reaction mixture was filtered through celite pad and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 12 g) using 5% - 10% EtOAc in petroleum ether to afford product (0.05 g, 22%), a brown liquid; FT IR 2235.50 cm-1(C≡C stretching present);1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 3.2 Hz, 1H), 7.77 (d, J = 3.6 Hz, 1H), 2.14 (s, 3H); ESIMS m / z 123.92 ([M+H]+). 12853683 To a stirred solution of 2-bromothiazole (1 g, 6.09 mmol) in EtOAc (20 mL) were added Et3N (3.6 mL, 26.21 mmol) and CuI (12 mg, 0.06 mmol) at RT. The reaction mixture was degassed with argon for 5 minutes, then added prop-2-yn-1-ol (input-2) (1.6 mL, 29.26 mmol) and bis(triphenylphosphine)palladium chloride (0.2 g, 0.30 mmol) at RT. The reaction mixture was stirred at 50-55 °C for 16h. After completion (monitor by TLC) of the reaction, the reaction mixture was filtered through celite pad and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 12 g) using 10% - 15% EtOAc in petroleum ether to afford product (0.25 g, 29%), a brown liquid; FT IR 2231.64 cm-1(C≡C stretching present);1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 3.6 Hz, 1H), 7.86 (d, J = 3.2 Hz, 1H), 5.53 (t, J = 6.2 Hz, 1H), 4.36 (d, J = 6.0 Hz, 2H); ESIMS m / z 139.94 ([M+H]+). 12853685 To a stirred solution of 2-bromothiazole (1 g, 6.09 mmol) in EtOAc (20 mL) were added Et3N (3.6 mL, 26.21 mmol) and CuI (12 mg, 0.06 mmol) at RT. The reaction mixture was degassed with argon for 5 minutes, then added the alkyne (1.6 mL, 29.26 mmol) and bis(triphenylphosphine)palladium chloride (0.2 g, 0.30 mmol) at RT. The reaction mixture was stirred at 50-55 °C for 16h. After completion (monitor by TLC) of the reaction, the reaction mixture was filtered through celite pad and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 12 g) using 10% - 15% EtOAc in petroleum ether to afford the desired product, a brown liquid (0.4 g, 43%); FT IR 2231.64 cm-1(C≡C stretching present);1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 3.2 Hz, 1H), 7.78 (d, J = 3.2 Hz, 1H), 4.99 (t, J = 5.6 Hz, 1H), 3.60 (q, J = 5.6 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H); ESIMS m / z 153.95 ([M+H]+). 12853687 To a stirred solution of 2-bromothiazole (1 g, 6.09 mmol) in EtOAc (20 mL) were added Et3N (3.6 mL, 26.21 mmol) and CuI (12 mg, 0.06 mmol) at RT. The reaction mixture was degassed with argon for 5 minutes, then added prop-2-yn-1-ol (input-2) (1.6 mL, 29.26 mmol) and bis(triphenylphosphine)palladium chloride (0.2 g, 0.30 mmol) at RT. The reaction mixture was stirred at 50-55 °C for 16h. After completion (monitor by TLC) of the reaction, the reaction mixture was filtered through celite pad and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 12 g) using 10% - 15% EtOAc in petroleum ether to afford the product, a Brown liquid (0.1 g, 21%); FT IR 2231.64 cm-1(C≡C stretching present);1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 3.2 Hz, 1H), 7.36 (d, J = 3.6 Hz, 1H), 4.37 (s, 2H), 3.47 (s, 3H); ESIMS m / z 153.1 ([M]+). 12855341 To a stirred solution of 2 bromo thiazole (0.3 g, 2.56 mmol) in Acetone (10 mL) were added K2CO3(0.35 g, 2.56 mmol) and propargyl alcohol (0.2 mL, 2.56 mmol) at 0°C. The reaction mixture was stirred at RT for 3h. After completion (monitor by TLC) of the reaction, the reaction mixture was poured in water (10 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a colorless liquid (0.03 g, 17%); FT IR 2239.36 cm-1(C≡C stretching present);1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 3.6 Hz, 1H), 6.70 (d, J = 4.0 Hz, 1H), 5.00 (q, J = 2.4 Hz, 2H), 1.89 (t, J = 2.2 Hz, 3H); ESIMS m / z 153.83 ([M+H]+). 12855343 To a stirred solution of 2,4-dibromothiazole (0.5 g, 2.07 mmol) in 1,4-Dioxane (10 mL) were added CsF (0.47 g, 3.11 mmol) at RT. The reaction mixture was degassed with argon for 5 minutes, then added input-1 (0.82 g, 2.48 mmol) and Pd(tBu3P)2(53 mg, 0.11 mmol) at RT. The reaction mixture was stirred at 100 °C for 16h. After completion (monitor by TLC) of the reaction, the reaction mixture was filtered through celite pad and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 12 g) using 5% - 10% EtOAc in petroleum ether to afford product (0.2 g, 41%), a yellow semi solid (0.15 g, 45%); FT IR 2235.50 cm-1(C≡C stretching present);1H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 2.10 (s, 3H), 2.04 (s, 3H); ESIMS m / z 161.88 ([M+H]+). 12856621 3-ethynyl-5-methylisothiazole (1.0 equiv) was a dissolved in anhydrous methanol (0.2-0.5 mM) and charged with cesium carbonate (1.0 equiv) and cooled to 0-5 degrees C. Dimethyl (l-diazo-2- oxopropyl)phosphonate (1.0 equiv) was added dropwise after which the reaction was allowed to stir for 1-18h after which the crude mixture was concentrated onto silica gel and purified directly by flash silica gel chromatography to provide the desired alkyne 12858893 To a stirred solution of TMS acetylene (0.9 mL, 8.01 mmol) in THF (15 mL) was added n-BuLi (2.5M) (3.2 mL, 7.69 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 30 minutes. Furan-2-carbaldehyde SM-C (0.5 g, 6.41 mmol) was then added into the reaction mixture at -78 °C and stirred for 5h at RT. After completion of the reaction, the reaction mixture was quenched with aq. NH4Cl (10 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 40 g) using 15% - 20% EtOAc in petroleum ether eluent to afford Int-C1 (0.2 g, 16%), a yellow solid; FT IR 2177.63 cm-1(C≡C stretching present);1H NMR (400 MHz, CDCl3) δ 7.41 (m, 1H), 6.45 (m, 1H), 6.35 (m, 1H), 5.45 (d, J = 6.8 Hz, 1H), 2.22 (d, J = 7.2 Hz, 1H), 0.21 (s, 9H); ESIMS m / z 194.94 ([M+H]+). Synthesis of 1-(furan-2-yl)-3-(trimethylsilyl)prop-2-yn-1-one: To a stirred solution of 1-(furan-2-yl)-3-(trimethylsilyl)prop-2-yn-1-ol (0.1 g, 0.51 mmol) in DCM (5 mL) was added pyridinium chlorochromate (0.16 g, 0.77 mmol) at RT. The reaction mixture stirred at RT for 16h. After completion (monitor by TLC) of the reaction, the reaction mixture was filtered through celite pad and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 24 g) using 2% - 5% EtOAc in petroleum ether to afford product (0.03 g, 30%), a brown liquid; FT IR 2158.35 cm-1(C≡C stretching present);1H NMR (400 MHz, CDCl3) δ 7.66 (m, 1H), 7.36 (m, 1H), 6.57 (dd, J = 1.6, 3.6 Hz, 1H), 0.29 (s, 9H); ESIMS m / z 192.90 ([M+H]+). General Procedure A Under air, to a 20 mL vial, aryl halide (1 equiv.), triethylamine (3 equiv.) and copper(I) iodide (0.1 equiv.) were charged and diluted with Dioxane (0.3 M concentration of substrate). The reaction was degassed for 5 min, then ethynyltrimethylsilane (4.0 equiv.) and bis(triphenylphosphine)palladium (II) chloride (0.1 equiv.) were added under an inert atmosphere. The vial was placed in a heating block that was warmed to 80 ºC and the solution was stirred for 20 h. The reaction was cooled and passed through a pad of celite. The filtrate was concentrated, and the resulting residue was purified by flash chromatography on silica gel. General Procedure B To a 50 mL RBF charged with TMS-Alkyne (1.0 equiv.), MeOH (0.25 M concentration of substrate) and potassium carbonate (0.2 equiv.) were added. The reaction was stirred at ambient temperature for 30 min. After reaction completion, the reaction was diluted with H2O and extracted with DCM. The combined organics were passed through a phase separator and concentrated. The resulting residue was purified by flash chromatography on silica gel. General Procedure C Aldehyde (1.0 equiv.) was a dissolved in anhydrous methanol (0.2-0.5 mM) and charged with cesium carbonate (1.0 equiv.) and cooled to 0-5 degrees C. Dimethyl (l-diazo-2-oxopropyl) phosphonate (1.0 equiv.) was added dropwise after which the reaction was allowed to stir for 1- 18h after which the crude mixture was concentrated onto silica gel and purified directly by flash silica gel chromatography to provide the desired alkyne. General Procedure D To a 20 mL vial, sodium hydride (60% Wt., 1.0 Equiv.) was charged and diluted with THF (1.0 M concentration of substrate) under an inert atmosphere. Then alcohol (1.0 equiv.) was added at ambient temperature and the reaction was allowed to stir for 30 min. Then aryl halide (1.0 equiv.) in THF (0.5 M concentration of substrate) was added. The vial was placed in a heating block that was warmed to 50 ºC and the solution was stirred for 20 h. The reaction was quenched with Sat NH4Cl and extracted with Et2O. The combined organics were dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel General Procedure E Under air, a 20 mL vial equipped with a magnetic stirring bar was charged with P(tBu)3Pd G2 (0.03 equiv.) and the aryl halide (1 equiv. if solid). The vial was capped, and the air was purged by evacuating the vial and backfilling with nitrogen three times. Dry DMF was added (0.4 M concentration of substrate) to the vial followed by the aryl halide (1 equiv. if liquid), the TMS- protected alkyne (1.5 equiv.) and TBAF (1.5 equiv., 1 M in THF). The vial was placed in a heating block that was warmed to 80 ºC and the solution was stirred for 20 h. After the reaction time, the vial was opened to air and aqueous Na2CO3 was added (4 mL). The crude product was extracted with CH2Cl2and purified by flash chromatography on silica gel. General Procedure F To a 20 mL vial, sodium alkoxide (1.0 equiv.) was charged. Then a solution of aryl halide (1.0 equiv.) in THF (0.2 M concentration of substrate) was added. The vial was placed in a heating block that was warmed to 50 ºC and the solution was stirred for 20 h. The reaction was quenched with saturated NH4Cl and extracted with Et2O. The combined organics were dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel. General Procedure G A stock solution of [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.1 equiv) in dioxane (2 mL) and copper(I) iodide (0.1 equiv) in dioxane (1 mL) and triethylamine (3 equiv) were added to a vial containing a solution of Br / Cl-heterocycle (1 equiv) in dioxane (2 mL). The contents were sealed and degassed with nitrogen and the overall reaction concentration was 0.2M. With stirring, ethynyltrimethylsilane (2 equiv) was added neat and the contents were heated to 60oC overnight for 18 hours. The reaction was quenched with AcOH (10 equiv), the product mass was observed by LCMS. The contents were diluted with EtOAc and partitioned between 2.5 M KHCO3 (2 x) and brine then dried over MgSO4. The contents were condensed by rotoary evaporation and the residue was purified by silica-gel chromatography eluting with hexanes / EtOAc 10-100% over 10 minutes to yield the product. General Procedure H To a flask containing ((trimethylsilyl)ethynyl)-heterocycle was dissolved in a solution of potassium fluoride (0.1M, 2 equiv) in methanol and stirred at ambient temperature for 18 hours. The contents were condensed by rotary evaporation and purified over silica-gel eluting with DCM / MeOH 0-10% to obtain the product. General Procedure I To a stirring solution of aldehyde (1M, 1 equiv), potassium carbonate (2 equiv) in methanol was added dimethyl (1-diazo-2-oxopropyl)phosphonate (1.1 equiv) neat. Gas evolution was observed. The contents were stirred at ambient temperature for 2 - 5 hours. The contents were diluted with water and extracted with dichloromethane. The pooled organics were dried over MgSO4 and condensed by fractional distillation. The residue was purified over a silca-gel column eluting with DCM / MeOH 0-10% over 10 minutes. The fractions containing the product were pooled and evaporated to give the product. Procedure J A nitrogen containing heterocycle posing an alkyne was dissolved in diethyl ether (1M) and treated with an equal volume of 1M acid (HCl or anhydrous H3PO4) in diethyl ether. The volatile components were removed by evaporation using a stream of nitrogen gas to give the desired salt form of the heterocycle. General Procedure K To a stirred solution of 2-bromothiazole (1 g, 6.09 mmol) in EtOAc (20 mL) were added Et3N (3.6 mL, 26.21 mmol) and CuI (12 mg, 0.06 mmol) at RT. The reaction mixture was degassed with argon for 5 minutes, then added prop-2-yn-1-ol (1.6 mL, 29.26 mmol) and bis(triphenylphosphine)palladium chloride (0.2 g, 0.30 mmol) at RT. The reaction mixture was stirred at 50-55 °C for 16 h. After completion (monitor by TLC) of the reaction, the reaction mixture was filtered through celite pad and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 12 g) using 10% - 15% EtOAc in petroleum ether to afford the desired product. General Procedure L To a stirred solution of alkynyl alcohol (0.15 g, 1.07 mmol) in dichloromethane (10 mL) were added Et3N (0.2 mL, 1.60 mmol) and acetyl chloride (0.1 mL, 1.28 mmol) at 0°C. The reaction mixture was stirred at RT for 16 h. After completion (monitor by TLC) of the reaction, the reaction mixture was concentrated under reduced pressure, poured into water and extracted with DCM. The organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Column size: 24 g) using 10% - 15% EtOAc in petroleum ether to afford the desired product. Procedure M To a stirred solution of thiazole-2-thiol (0.3 g, 2.56 mmol) in Acetone (10 mL) were added K2CO3(0.35 g, 2.56 mmol) and methyl propargyl bromide (0.2 mL, 2.56 mmol) at 0°C. The reaction mixture was stirred at RT for 3 h. After completion (monitor by TLC) of the reaction, the reaction mixture was poured in water (10 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product. Procedure N To a stirred solution of 3-bromo pyrazole (0.5 g) in Et3N (5 mL) was added CuI (0.049 g). Then the reaction mixture was degassed with argon gas for 10 mins followed by addition of Pd(PPh3)4(0.148 g) and the acetylated alkyne input (5.14 mmol) at RT. The resultant reaction mixture was stirred at 80 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at 38 °C to get the crude compound, which was purified by prep-HPLC to give the desired product. Procedure O To a stirred solution of pyrazole (0.5 g) in dry THF (5V) was added NaH (2 eq) and followed by propargyl bromide (1.2 eq) at 0 °C. The resultant reaction mixture was stirred at 0 °C to RT for 3 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate and washed with aqueous NaCl solution and dried over with anhydrous Na2SO4. The resultant solution was concentrated under reduced pressure at 38 °C to get the crude compound, which was purified by combi flash chromatography to afford the desired product. Analytical Methods Synthesized compounds were characterized by the following methods: melting point, ESIMS – electrospray mass spec, HRMS – high resolution mass spec, EIMS – electron ionization mass spec, GCMS – gas chromatography mass spec, SIMS – secondary ion mass spec, Fourier Transform Infrared Spectroscopy – FTIR,1H,13C,19F, and31P Nuclear Magnetic resonance spectroscopy. Chiral structures in Table 1 are indicated by “&1” adjacent to the chiral center. Table 1 Nitrification Inhibiting Compounds Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Material ID Structure Preparation or Source Table 2 Analytical Data Mat. ID M.P. (°C) IR Mass NMR (H, C or F) FT-IR ), ; ), ) , , , ), ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) ESIMS m / z1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, ), ), s, = ), , ), ), ), 0 ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) ESIMS m / z1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), ), ), ), ), ), ), ), 5 , Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (500 MHz, Chloroform-d) δ 4.93 0, 3 R 3 2 9 R ), ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), R 6, ), 3) ), J t, ), 4. ), ), 4. ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 1, ), C 8, ), 9 ), ), ), ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) FT-IR ), , ), = 4, ), 9 ), ), ), ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), ) ), ), 1, 8, ), ) ), ), 7, 7 0. 0 ), 8 Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, Chloroform-d) δ 8.36 9 2 6 = ), ). Mat. ID M.P. (°C) IR Mass NMR (H, C or F) ESIMS m / z1H), = 0 ), = 8 5, 5 R 4 8 R - = 7 Mat. ID M.P. (°C) IR Mass NMR (H, C or F) FT IR = 0 = 6 = ), 2 ), 5 3 2 , ), C 3, 4, – – Mat. ID M.P. (°C) IR Mass NMR (H, C or F) FT - IR:1= 1 , = 0 , ), 3 R ), , = 6 = Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, CDCl3) δ 9.16 (t, J = ), ); = ), 9 – ) = 5 ), = 7 ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (500 MHz, CDCl3) δ 7.57 (s, 2H), ), 1 ), = 5 , , , = 7 Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, Chloroform-d) δ 7.46 0. 5 6 8 1 0 6 R = 0 ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, Chloroform-d) δ 7.69 , 6 7 8 ), 3 , 1, 0 = δ 7 Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (500 MHz, CDCl3) δ 7.39 (s, 1H), ), ), ), 5, ), 8 ), = 2. Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J = 2. 4 = 6, 8, 7 3 0. 1 4 Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, Chloroform-d) δ 8.16 , 2 ), 6, = 0 = 6, 7. 8, Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 3 ), ), = 5 = 1 ; = 6 0 , Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, Chloroform-d) δ 8.21 0 J 1 ), ), ), 6 J 3, Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = J s, δ z, ), 9, ), 9, ), 3, 2. ), 7, Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 0, ), 3) ), ), 2, 4, ), 6 = z, , Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, CDCl3) δ 9.05 (d, J = ), ), ), ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = ), ), 6. z, ), z, 7 6 Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (500 MHz, CDCl3) δ 8.26 (d, J = ), 8 0 1, ), J 0. ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 1, δ ), ), 0 z, ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 4, ), 7 ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (500 MHz, CDCl3) δ 9.20 (s, 2H), ), ), 4 ), ), ), ), 1 = Mat. ID M.P. (°C) IR Mass NMR (H, C or F) EIMS m / z ), δ ), ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) ESIMS m / z1H NMR (600 MHz, CDCl3) δ 8.51 (d, J = ), ), 7, 2, ), 9, Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 6, 8, ), , ), 8 ), 9, 9. Mat. ID M.P. (°C) IR Mass NMR (H, C or F) HRMS- = s, s, = 2 = ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (500 MHz, DMSO) δ 7.91 (s, 5 ), ), = 7 s, z ), 5, J , 0 ), C , = 4 Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (500 MHz, DMSO) δ 6.21 (s, ), J 1 7, = 9 = 9 – ), C 9, Mat. ID M.P. (°C) IR Mass NMR (H, C or F) ESIMS m / z1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), ), 5 ), C 3, 8, ), 7 ), ), ), 3 ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) ESIMS m / z1), J ), s, = 0 = 3 = 3 = 8 ), = 2 ), J ), ), Mat. ID M.P. (°C) IR Mass NMR (H, C or F) ESIMS m / z1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), ), ), 4 ), ), ), ), ), ), ), ), ), , Mat. ID M.P. (°C) IR Mass NMR (H, C or F) ESIMS m / z1H), ), ), ), ), J ), J s, ), s, ), , 6 ), - 2 ), , Mat. ID M.P. (°C) IR Mass NMR (H, C or F) ESIMS m / z1H NMR (400 MHz, CDCl3) δ 9.85 (brs, , = ), 1, ), 3 = Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (500 MHz, CDCl3) δ 9.22 (d, J = 4 3, ), = = = = ), ) Mat. ID M.P. (°C) IR Mass NMR (H, C or F) ESIMS m / z1= ), ). = = = = 0 Mat. ID M.P. (°C) IR Mass NMR (H, C or F) 1H NMR (500 MHz, CDCl3) δ 8.61 (s, 1H), z, s, = = Biological Testing Compound Preparation: Compounds were dissolved in DMSO at 0.1 mM concentrations. Soil Slurry Preparation: Two different soils were sourced from Kalamazoo, Michigan (loamy fine sand) and Windfall, Indiana (clay loam). After collection soils were sieved at 2 mm and stored at 4 °C for no more than 6 months. The slurry is prepared by weighing out 143 grams of field moist soil per liter of nitrification media with a chlorate block (0.8 µM K2HPO4; 0.1 µM KH2PO4; 0.5 µM(NH4)2SO4; 10 µM NaClO3) and stirring it in a Pyrex dish for 5 minutes. Experimental Approach: While stirring, 900 µL of slurry was pipetted into a 96 deep well plate. After slurry addition, 9 µL of 0.1 mM stock solution of a compound or solvent control (i.e., DMSO) was immediately added to the designated well to bring the final concentration to 0.1 µM. A sealing mat was placed on top of the plate and mixed by inverting the plates three times. Plates were incubated for 48 hours at 28°C while shaking sideways at 225 rpm. After 48 hours the plate was spun down at 3,000 rpm for 15 minutes and the supernatant was analyzed for nitrite concentrations using the colorimetric Griess assay. Nitrification rates were determined by the total amount of nitrite formed over the incubation period. Nitrification inhibition was determined by normalizing the nitrification rate by the DMSO control. The relative inhibition of tested compounds was additionally normalized to the reference nitrification inhibitor nitrapyrin. Results are shown in Table 3. Table 3 Inhibition of Soil Nitrification. Nitrification Nitrification Nitrification Nitrification Inhibition Inhibition Inhibition Inhibition Nitrification Nitrification Nitrification Nitrification Inhibition Inhibition Inhibition Inhibition Nitrification Nitrification Nitrification Nitrification Inhibition Inhibition Inhibition Inhibition Nitrification Nitrification Nitrification Nitrification Inhibition Inhibition Inhibition Inhibition Nitrification Nitrification Nitrification Nitrification Inhibition Inhibition Inhibition Inhibition Nitrification Nitrification Nitrification Nitrification Inhibition Inhibition Inhibition Inhibition Nitrification Nitrification Nitrification Nitrification Inhibition Inhibition Inhibition Inhibition We conducted soil incubations in the lab to determine nitrification inhibition activity of novel nitrification inhibitors (AIG-3.1, AIG-3.2, AIG-3.4) combined with fertilizers (No fertilizer, dry urea, urea-ammonium-nitrate, solubilized urea, ammonium nitrate, manure [composted manure], calcium potassium nitrate [CAN15], ammonium sulfate), and in combination with known nitrification and urease inhibiting mixture partners: nitrapyrin, NBPT [N-(n- Butyl)thiophosphoric triamide], DCD [Dicyandiamide], DMPP [3,4-dimethylpyrazole phosphate], and DMP [3,4-dimethylpyrazole]. Soil incubations were conducted in 15-mL conical centrifuge tubes in two soil types (clay loam and sandy loam) at 50% volumetric water content. Soil was added to the top 12 mL of the tube and the water content was maintained gravimetrically twice weekly. The mixtures (novel inhibitor, mixture partner, and fertilizer) were added by injecting 500 microliters of solution into the top 1-cm of the soil column with the exception of the solid fertilizers (dry urea and manure) in which case the fertilizer was applied first, and the remaining mixture components were applied afterwards by injecting 500 microliters of solution. The fertilization rate was equivalent to 169 US lbs. per acre [based on the surface area of the centrifuge tube]. The mixture partners were applied at the following rates [lbs. Per acre]: nitrapyrin: 0.5; DMPP: 1.0; DMP: 1.0; NBPT: 0.35; DCD: 2.5. The novel nitrification inhibitors (1.1, 1.2, 1.3) were applied at rates of 0.10 lbs. per acre. All compounds were dissolved in DMSO. DMSO was tested as the solvent control. All mixture combinations were replicated three times with destructive sampling occurring immediately after application, 7 days, and 14 days after application. After harvesting, soil was extracted with 2M KCl and analyzed for dissolved ammonium and nitrate concentrations. Ammonium retention was defined as the proportion of inorganic nitrogen in the ammonium form. The effect of a mixture partner was calculated by normalizing its performance to the novel- compound-only treatment of the same soil and fertilizer type. An effect <95% of activity may be defined as antagonism and >105% as synergy.

[0005] Table 4: Mixture Ammonium Retention normalized to the compound activity (100% = equal to the corresponding compound [1.1, 1.2, 1.3] activity) after a seven-day incubation. Cmpd. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3.2 DMP 99% 101% 98% 94% 99% 98% 114% 116% 99% 97% 140% 202% 93% 83%

[0006] Table 5: Mixture Ammonium Retention normalized to the compound activity (100% = equal to the corresponding compound [1.1, 1.2, 1.3] activity) after a fourteen-day incubation. Cmpd. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3. AIG-3.2 DMP 97% 89% 86% 76% 97% 74% 78% 76% 94% 89% 133% 48% 91% 29%

[0007] Table 6: Distribution of ammonium retention data for the 14-day incubation for novel and commercial nitrification inhibitors across fertilizer and soil types (without novel compound-commercial compound interactions). Compounds Ammonium Retention (%NH4)1tQuartile Median 3rdQuartile O O OG : We conducted soil incubations in the lab to determine nitrification inhibition activity three novel nitrification inhibitors along different fertilizers (No fertilizer, urea-ammonium-nitrate, solubilized urea, ammonium sulfate), and in combination with different commercial product mixture partners containing nitrification or urease inhibitors [Limus (BASF), Piadin (SKW Stickstoffwerke Piesteritz), ANVOL (Koch Agronomic Services), CENTURO (Koch Agronomic Services), FunctioN (Rosen’s Inc.), Factor (Rosen’s Inc.)] which includes the following chemistries: N - ((3 (5) -methyl-1H-pyrazol-1-yl) methyl) acetamide, 3-methylpyrazole, N-(n- Butyl)thiophosphoric triamide), dicyandiamide, pronitridine, duromide, N-(n-butyl)- thiophosphoric triamide, and N-methyl-2-pyrrolidone. Soil incubations were conducted in 15-mL conical centrifuge tubes in two soil types (clay loam and sandy loam) at 50% volumetric water content. Soil was added to the top 12 mL of the tube and the water content was maintained gravimetrically twice weekly. The mixtures (commercial nitrification inhibitor, novel inhibitors, and fertilizer) were added by injecting 500 microliters of solution into the top 1-cm of the soil column with the exception of the solid fertilizers (dry urea and manure) in which case the fertilizer was applied first, and the remaining treatment was applied on afterwards by injecting it in 500 microliters of solution. The fertilization rate was kept consistent at the equivalent of 169 US lbs. per acre [based on the surface area of the centrifuge tube]. The commercial chemistries were applied at the following rates: Limus: 2.84 liter per 920 kg of urea-N; Piadin: 5 L per hectare; ANVOL: 1.55 liters per ton of UAN28, 0.8 liters per ton of urea; CENTURO: 2.5 gallon per ton of UAN28, 1.5 gallon per ton of urea; Function: 24 US fluid ounces per acre; Factor: 33 fluid ounces per acre. The novel nitrification inhibitors were applied at lower rates of 0.10 lbs per acre and were solubilized in DMSO. All mixture combinations were replicated three times with destructive sampling occurring immediately after applied, and 7, and 14 days after application. After harvesting soils were extracted with 2M KCl and analyzed for dissolved ammonium and nitrate concentrations. Ammonium retention was defined as the proportion of inorganic nitrogen in the ammonium form. The mixture effect of commercial inhibitor was calculated by normalized its performance in the novel compound only treatment of the same soil and fertilizer type. An effect <95% of activity may be defined as antagonism and >105% as synergy. RESULTS: The summarized data for the 7- and 14-day incubation can be found in Tables 7 and 8. Table 7: Ammonium Retention normalized to the compound’s activity (100% = equal to the corresponding compound’s activity) after a seven-day incubation. Cmpd. Mixture UAN Liquid Urea Ammonium Sulfate Partner Table 8: Ammonium Retention normalized to the compound activity (100% = equal to the corresponding compound’s activity) after a fourteen-day incubation. Cmpd. Mixture UAN Liquid Urea Ammonium Sulfate Partner Sandy Clay Sandy Clay Sandy Clay Table 9: Distribution of ammonium retention data for the 14-day incubation for novel and commercial nitrification inhibitors across fertilizer and soil types (without novel compound-commercial mixture partner interactions). Product / Compound Ammonium Retention (%NH4) Table 10. Distribution of ammonium retention data for the 14-day incubation for novel and commercial nitrification inhibitors across fertilizer and soil types (without novel compound-commercial mixture partner interactions). Nitrification Mean NH4 Soil Fertilizer Compound Inhibition Ammonium Windfall 12870263 87.44 87% Nitrate Liquid Kalamazoo DMSO 10.59 1% Urea Ammonium Windfall DMPP 45.15 1% Nitrate

Claims

We claim:

1. A nitrification inhibiting composition comprising a carrier; and a compound selected from the group consisting of. wherein R1-R4are independently H, ethynyl, trimethylsilyl-ethynyl, C1– C6alkoxy, C1– C6thioalkyl, C1 – C6 alkyl, C3 – C6 cycloalkyl, C1 – C6 alkenyl, C3 – C6 cycloalkenyl, C1 – C6 haloalkyl, C1 – C6 haloalkenyl, C1 – C6 haloalkyl, C1 – C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and wherein at least one of R1 – R4 is C≡C or C≡C-TMS; and Formula IV .– are independently H, ethynyl, trimethylsilyl-ethynyl, C1– C6alkoxy, C1– C6thioalkyl, C1– C6alkyl, C3– C6cycloalkyl, C1– C6alkenyl, C3– C6cycloalkenyl, C1– C6haloalkyl, C1 – C6 haloalkenyl, C1 – C6 haloalkyl, C1 – C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3,C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and wherein at least one of R11 – R14 is C≡C or C≡C-TMS; and Formula V .are independently H, ethynyl, trimethylsilyl-ethynyl, C1– C6alkoxy, C1– C6thioalkyl, C1 – C6 alkyl, C3 – C6 cycloalkyl, C1 – C6 alkenyl, C3 – C6 cycloalkenyl, C1 – C6 haloalkyl, C1 – C6 haloalkenyl, C1 – C6 haloalkyl, C1 – C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and wherein at least one of R21 – R24 is C≡C or C≡C-TMS; and Formula VI.– are independently H, ethynyl, trimethylsilyl-ethynyl, C1– C6alkoxy, C1– C6thioalkyl, C1– C6alkyl, C3– C6cycloalkyl, C1– C6alkenyl, C3– C6cycloalkenyl, C1– C6haloalkyl, C1 – C6 haloalkenyl, C1 – C6 haloalkyl, C1 – C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen,C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and wherein at least one of R31– R34is C≡C or C≡C-TMS; andwherein R41 – R44 are independently H, ethynyl, trimethylsilyl-ethynyl, C1 – C6 alkoxy, C1 – C6 thioalkyl, C1 – C6 alkyl, C3 – C6 cycloalkyl, C1 – C6 alkenyl, C3 – C6 cycloalkenyl, C1 – C6 haloalkyl, C1– C6haloalkenyl, C1– C6haloalkyl, C1– C6haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and wherein at least one of R41– R44is C≡C or C≡C-TMS; and Formula VIII.and R53 are independently H, ethynyl, trimethylsilyl-ethynyl, C1 – C6 alkoxy, C1 – C6 thioalkyl, C1 – C6 alkyl, C3 – C6 cycloalkyl, C1 – C6 alkenyl, C3 – C6 cycloalkenyl, C1 – C6haloalkyl, C1– C6haloalkenyl, C1– C6haloalkyl, C1– C6haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and wherein at least one of R51, R52, or R53 is C≡C or C≡C-TMS; and Formula IX, andand R63are independently H, ethynyl, trimethylsilyl-ethynyl, C1– C6alkoxy, C1 – C6 thioalkyl, C1 – C6 alkyl, C3 – C6 cycloalkyl, C1 – C6 alkenyl, C3 – C6 cycloalkenyl, C1 – C6 haloalkyl, C1 – C6 haloalkenyl, C1 – C6 haloalkyl, C1 – C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl,C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and wherein at least one of R61, R62, or R63is C≡C or C≡C-TMS; and Formula X.R73, and R74 are independently H, ethynyl, trimethylsilyl-ethynyl, C1 – C6 alkoxy, C1– C6thioalkyl, C1– C6alkyl, C3– C6cycloalkyl, C1– C6alkenyl, C3– C6cycloalkenyl, C1 – C6 haloalkyl, C1 – C6 haloalkenyl, C1 – C6 haloalkyl, C1 – C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH- cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and wherein at least one of R71, R72, R73, or R74is C≡C or C≡C-TMS; and a mixture partner selected from the group consisting of linoleic acid, α-linolenic acid, methyl-p-coumarate, methyl ferulate, MHPP, Karanjin, brachialacton, 2-chloro- 6-trichloromethylpyridine (nitrapyrin), dicyandiamide (DCD), 3,4-dimethylpyrazole (DMP), 3,4-dimethylpyrazole phosphate (DMPP), 4-amino-1,2,4-triazole hydrochloride, 1-amido-2- thiourea, 2-amino-4-chloro-6-methylpyrimidine, 5-ethoxy-3-trichloromethyl-1,2,4-thiodiazole, 2-sulfanilamidethiazole, 3,5-dimethyltetrahydro-1,3,5-thiadiazine-2-thione (dazomet), N-(n- Butyl)thiophosphoric triamide (NBPT).

2. The composition of claim 1 wherein the compound is selected from the group consisting ofN O N O,,,,,,,,nda l-p- coumarate, methyl ferulate, MHPP, Karanjin, brachialacton, 2-chloro-6-trichloromethylpyridine (nitrapyrin), dicyandiamide (DCD), 3,4-dimethylpyrazole (DMP), 3,4-dimethylpyrazole phosphate (DMPP), 4-amino-1,2,4-triazole hydrochloride, 1-amido-2-thiourea, 2-amino-4- chloro-6-methylpyrimidine, 5-ethoxy-3-trichloromethyl-1,2,4-thiodiazole, 2- sulfanilamidethiazole, 3,5-dimethyltetrahydro-1,3,5-thiadiazine-2-thione (dazomet), N-(n- Butyl)thiophosphoric triamide (NBPT).

3. The composition of claim 1, wherein the compound is selected from the group consisting of SN O N Omethyl-p- coumarate, methyl ferulate, MHPP, Karanjin, brachialacton, 2-chloro-6-trichloromethylpyridine (nitrapyrin), dicyandiamide (DCD), 3,4-dimethylpyrazole (DMP), 3,4-dimethylpyrazole phosphate (DMPP), 4-amino-1,2,4-triazole hydrochloride, 1-amido-2-thiourea, 2-amino-4- chloro-6-methylpyrimidine, 5-ethoxy-3-trichloromethyl-1,2,4-thiodiazole, 2- sulfanilamidethiazole, 3,5-dimethyltetrahydro-1,3,5-thiadiazine-2-thione (dazomet), N-(n- Butyl)thiophosphoric triamide (NBPT).

4. The composition of claims 1 to 3 further comprising a source of ammonia.

5. The composition of claims 1 to 4, wherein the source of ammonia is selected from the group consisting of anhydrous ammonia, urea, urea-ammonium-nitrate, urea, ammonium nitrate, ammonium sulfate, manure, calcium potassium nitrate [CAN15], ammonium sulfate and mixtures thereof.

6. The composition of claims 1 to 5 further comprising a second nitrification inhibiting compound of claim 1.

7. A method of reducing nitrification in soil comprising applying a composition of claims 1 to 6 to soil.

8. The method of claim 7, wherein the composition and source of ammonia are applied simultaneously.

9. The method of claim 7, wherein the composition and source of ammonia are applied sequentially.

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