Nitrification inhibiting heterocycles

Abstract

Heterocyclic alkynes useful for nitrification inhibition and methods of using the heterocyclic alkynes to inhibit nitrification and increase crop yield are described.

Description

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 369,015, filed on July 21, 2022, which is hereby incorporated by reference in its entirety. Background Art

[0002] Nitrogen is an essential element for plant health. In a growth matrix (e.g., soil), the bound nitrogen used for plant nutrition can exist in the form of ammonium compounds or nitrates. Nitrogen in the form of ammonium is preferred because it is easily incorporated into plants. In contrast, nitrate nitrogen must be reduced to ammonium by plants before it can be used, which is a very expensive process. Ammonium nitrogen with a positive charge is tightly bound to the growth matrix. Nitrogen in the form of nitrates is negatively charged, water-soluble, not tightly bound to the growth matrix and easily washed off.

[0003] Ammonia oxidizing bacteria of the genus Nitrosomonas and Nitrobacter oxidize ammonium nitrogen to nitrate nitrogen via nitrite nitrogen. This process is called nitrification. The degree of nitrification depends on the temperature, the type of growth substrate, pH, moisture content and biological activity. The nitrification process causes ammonium nitrogen loss and nitrate nitrogen production. Up to half of the applied nitrogen fertilizer is lost within a year, and the process promotes undesirable nitrate concentrations in groundwater. Therefore, the inhibition of nitrification is particularly important and is generally considered to be selective inhibition of the growth of the above-mentioned bacterial strains.

[0004] It is known that the incorporation of certain compounds into the growth medium in critical amounts has a significant effect on nitrification - the conversion of reduced nitrogen (such as ammonia or ammonium ions) into higher oxidized forms, particularly into nitrate forms. Preventing such nitrification in the growth medium is known to be beneficial and desirable from an economic and agronomic standpoint, as it enhances plant health, increases crop yields and reduces nitrate loss.

[0005] Many nitrification inhibitors are known, including linoleic acid, α-linoleic acid, methyl p-coumarate, methyl ferulate, MHPP, pectin, brachialacton, 2-chloro-6-trichloromethylpyridine (chlorpyrifos), dicyandiamide, 3,4-dimethylpyrazole phosphate, 4-amino-1,2,4-triazole hydrochloride, 1-amido-2-thiourea, 2-amido-4-chloro-6-methylpyrimidine, 5-ethoxy-3-trichloromethyl-1,2,4-thiadiazole, 2-sulfathiazole, 3,5-dimethyltetrahydro-1,3,5-thiadiazine-2-thione (dazomethane).

[0006] Nitrification inhibition has been disclosed in the following publications: US 3,494,757 and US 3,635,690, German published application DOS 2,745,833 and GB 1,592,516. See also US3,050,380 Goring; GB 970,663 Watkins; US3,533,774 Nault; US 4,673,429 Rieber, et al.; US 4,925,476 Wagner et al.; US2015 / 0052960 Makin et al.; US2017 / 0036969 Nave et al.; US2020 / 0352162 Cunningham et al.; WO2015 / 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 by reference in their entirety.

[0007] Some conventional nitrification inhibitors lack properties that are beneficial to their users. For example, dazomethon is known to have very non-specific effects and attack non-target bacteria in the growth substrate, especially in soil.

[0008] There remains a need for nitrification inhibitors that exhibit nitrification inhibition while lacking less beneficial traits. Summary of the invention

[0009] It has been found that certain alkynyl-heterocycles can be used to control nitrification. Specifically, it has been found that certain ethynyl-thiazoles, ethynyl-oxazoles and ethynyl-isoxazoles inhibit nitrification. This inhibition is useful because it promotes more efficient nitrogen uptake by plants - increasing crop yields. Nitrification inhibition can also be used to reduce the production of nitrates in the growth medium - particularly in soil - thereby reducing the amount of unwanted nitrates in groundwater.

[0010] Methods employing the compounds include applying and / or incorporating into the growth medium (eg, soil) an effective amount of a nitrification inhibiting alkynyl heterocycle.Preferred compounds include ethynyl-thiazoles, ethynyl-oxazoles, ethynyl-isoxazoles, or mixtures thereof. DETAILED DESCRIPTION

[0011] As used herein, growth substrate (medium) and growth substrate (media) are defined as the material in which the plant grows. Exemplary growth substrates include, but are not limited to, soil, perlite, pumice, vermiculite, zeolite, compost, peat moss, coconut husk, sand, silt, clay, water, bark, sawdust, water, and limestone. Exemplary growth substrates can be outdoor soil-based or hydroponic.

[0012] As used herein, alkyl refers to a C1-C6 branched or unbranched group consisting of carbon and hydrogen atoms. Alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0013] As used herein, alkoxy refers to an O-C1-C6 group in which an oxygen atom is attached to a C1-C6 branched or unbranched alkyl group. Alkoxy includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0014] As used herein, thioalkyl refers to a branched or unbranched S-C1-C6 group in which the sulfur atom is attached to a C1-C6 alkyl group. Thioalkyl includes, for example, thiomethyl, thioethyl, thiopropyl, thioisopropyl, thiobutyl, thioisobutyl, thiosec-butyl, thiotert-butyl, etc.

[0015] As used herein, cycloalkyl refers to a C3-C6 group in which the carbon atoms form a carbocyclic ring. Cycloalkyl includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like.

[0016] As used herein, alkenyl refers to a C2-C6 branched or unbranched group consisting of carbon and hydrogen atoms and having one or more double bonds between carbon atoms. Alkenyl includes, for example, ethylene, propylene, 1-butene, 2-butene, isobutylene, etc.

[0017] As used herein, cycloalkenyl refers to C3-C6 wherein the carbon atoms form a carbon ring and contain one or two double bonds. Cycloalkenyl includes, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cyclopentadiene, 1,4-cyclohexadiene, and the like.

[0018] As used herein, halo refers to halogen atoms such as F, Cl, Br, and I.

[0019] As used herein, haloalkyl refers to a C1-C6 branched or unbranched alkyl group in which one or more hydrogen atoms have been replaced by a halogen atom. Haloalkyl includes, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl, bromoethyl, iodobutyl, dichloroethyl, etc.

[0020] As used herein, haloalkoxy refers to a C1-C6 group in which an oxygen atom is attached to a C1-C6 branched or unbranched alkyl group (in which one or more hydrogen atoms have been replaced by a halogen atom). Haloalkoxy includes, for example, trifluoromethoxy, difluoroethoxy, chloropropoxy, bromoisopropoxy, dibromobutoxy, etc.

[0021] As used herein, haloalkenyl refers to a C2-C6 branched or unbranched group consisting of carbon and hydrogen atoms, wherein one or more hydrogen atoms have been replaced by halogen atoms, and having one or more double bonds between carbon atoms. Haloalkenyl includes, for example, 1-chloroethylene, 3,3-difluoropropylene, 4-bromo-1-butene, etc.

[0022] The term N-oxide includes any compound having at least one tertiary nitrogen atom which is oxidized to form an N-oxide moiety. N-oxides can be formed, for example, by oxidation of a tertiary amine such as pyridine with hydrogen peroxide.

[0023] As used herein, salts and agriculturally acceptable salts include hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, nitrates, bisulfates, sulfates, dihydrogen phosphates, hydrogen phosphates, phosphates, carbonates, bicarbonates, oxalates, and C1-C6 branched or unbranched alkanoates - such as formates, acetates, n-propionates, isopropionates, and the like.

[0024] As used herein, carriers include liquid or solid carriers. In some aspects, carriers may include organic or inorganic carriers. Exemplary liquid carriers include, but are not limited to: water; petroleum fractions or hydrocarbons, such as mineral oil, aromatic solvents, paraffin oil, etc.; vegetable oils, such as soybean oil, rapeseed oil, olive oil, castor oil, sunflower oil, coconut oil, corn oil, cottonseed oil, linseed oil, palm oil, peanut oil, safflower oil, sesame oil, tung oil, etc.; esters of the above vegetable oils; esters of monohydric alcohols or dihydric alcohols, trihydric alcohols or other low polyols (containing 4-6 hydroxyl groups), such as 2-ethylhexyl stearate, n-butyl oleate, isopropyl myristate, propylene glycol dioleate, Dioctyl succinate, dibutyl adipate, dioctyl phthalate, etc.; esters of monocarboxylic acids, dicarboxylic acids and polycarboxylic acids, etc.; toluene; xylene; 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; methanol; ethanol; isopropanol; amyl alcohol; ethylene glycol; propylene glycol; glycerol; N-methyl-2-pyrrolidone; N; N-dimethylalkylamide; dimethyl sulfoxide; and liquid fertilizers, and mixtures thereof. Exemplary solid carriers include, but are not limited to, silicon dioxide, silica gel, silicates, talc, kaolin, limestone, lime, chalk, red basalt, loess, clay, dolomite, diatomaceous earth, calcium sulfate, magnesium sulfate, magnesium oxide, ground synthetic materials, pyrophyllite clay, attapulgite clay, phytolith, calcium carbonate, bentonite, fuller's earth, cottonseed hulls, wheat flour, soybean flour, pumice, wood flour, walnut shell flour, lignin, ammonium sulfate, ammonium phosphate, ammonium nitrate, urea, cereal flour, bark flour, wood flour, nut shell flour, cellulose flour, and mixtures thereof. Fertilizers, including but not limited to fertilizers containing ammonia, can be used as carriers. Exemplary fertilizers include, but are not limited to, anhydrous ammonium, ammonium salts such as ammonium nitrate, calcium ammonium nitrate, ammonium nitrate sulfate, ammonium sulfate, or ammonium phosphate; organic ammonia sources such as manure, biogas, vermicompost, compost, seaweed, or guano; urea-containing fertilizers such as urea, urea formaldehyde, urea ammonium nitrate solution, urea sulfur, urea ammonium sulfate, or other urea-based fertilizers.

[0025] As used herein, one or more surfactants (e.g., wetting agents, tackifiers, dispersants, emulsifiers) include, but are not limited to: alkali metal salts, alkaline earth metal salts, and ammonium salts of fatty acids or aromatic sulfonic acids (e.g., lignin sulfonic acid, phenol sulfonic acid, naphthalene sulfonic acid, and dibutylnaphthalene sulfonic acid); alkyl- and alkylaryl sulfonates; alkyl sulfates, lauryl ether sulfates, and fatty alcohol sulfates; sulfated salts of hexadecanol, heptadecanol, and stearyl alcohol; salts of fatty alcohol glycol ethers; condensates of sulfonated naphthalene and its derivatives with formaldehyde; condensates of naphthalene or naphthalenesulfonic acid with phenol and formaldehyde; polyoxyethylene Octylphenol ethers; ethoxylated isooctyl-, octyl- or nonylphenol, alkylphenyl or tributylphenyl polyglycol ethers; alkylaryl polyether alcohols; isotridecanol; fatty alcohol / ethylene oxide condensates; ethoxylated castor oil; polyoxyethylene alkyl ethers or polyoxypropylene alkyl ethers; lauryl alcohol polyglycol ether acetates; sorbitan esters; lignin sulfite waste liquors and proteins; denatured proteins, polysaccharides (e.g., methylcellulose); hydrophobically modified starches; and polyvinyl alcohols, polycarboxylates, polyalkoxylates, polyvinylamines, polyethyleneimines, polyvinylpyrrolidones, and copolymers thereof.

[0026] As used herein, adjuvants include agriculturally acceptable adjuvants. Exemplary agriculturally acceptable adjuvants include, but are not limited to, antifreeze agents, defoamers, compatibilizers, sequestrants, neutralizers and buffers, corrosion inhibitors, colorants, flavor enhancers, penetration aids, wetting agents, spreaders, dispersants, thickeners, freezing point depressants, biocides, crop oils (concentrates), adhesives (e.g., for seed treatment formulations), surfactants, protective colloids, emulsifiers, tackifiers, and mixtures thereof.

[0027] Exemplary agriculturally acceptable adjuvants include, but are not limited to, crop oil concentrates (e.g., 85% mineral oil + 15% emulsifier); nonylphenol ethoxylate; benzyl cocoalkyl dimethyl quaternary ammonium salt; blends of petroleum hydrocarbons, alkyl esters, organic acids, and anionic surfactants; C9-C 11 Alkyl polyglycoside; Phosphate alcohol ethoxylate; Natural primary alcohol (C 12 -C 16 ) ethoxylate; di-sec-butylphenol EO-PO block copolymer; methyl terminated polysiloxane; nonylphenol ethoxylate + urea ammonium nitrate; emulsified methylated seed oil; tridecanol (synthetic) ethoxylate (e.g., 8EO); tallow amine ethoxylate (e.g., 15EO); and PEG (400) dioleate-99.

[0028] Exemplary agriculturally acceptable adjuvants include, but are not limited to, thickening agents (ie, thickeners). Exemplary thickeners include, but are not limited to, polysaccharides (eg, xanthan gum), organic and inorganic platelet minerals, and mixtures thereof.

[0029] Exemplary agriculturally acceptable adjuvants include, but are not limited to, defoamers. Exemplary defoamers include, but are not limited to, silicone emulsions, long chain alcohols, fatty acids, fatty acid salts, organic fluorine compounds, and mixtures thereof.

[0030] 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.

[0031] Exemplary agriculturally acceptable adjuvants include, but are not limited to, colorants. Exemplary colorants include, but are not limited to, dyes known by the name 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.

[0032] Exemplary agriculturally acceptable adjuvants include, but are not limited to, adhesives. Exemplary adhesives include, but are not limited to, polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl alcohol, tylose, and mixtures thereof.

[0033] As used herein, an agriculturally effective amount of a compound is an amount of the compound that produces a measurable effect on one or more of the following: ammonium nitrogen, nitrification inhibition, nitrate formation, increased plant health, increased plant growth, increased plant or crop yield, bacteria of the genera Nitrosomonas and Nitrobacter.

[0034] As used herein, "compound" or "compounds" include chemicals defined by molecular formula and / or chemical name, as well as their tautomers, salts, N-oxides and stereoisomers.

[0035] Compounds as described herein are nitrification inhibitors. One or more compounds as described herein can be incorporated into compositions comprising other ingredients such as carriers, surfactants and adjuvants. Compositions can optionally include ammonia sources. In order to enhance plant health and / or increase crop yield, compounds or compositions can be applied to a growth substrate containing or not containing ammonia sources. Ammonia sources include anhydrous ammonia, urea, urea-ammonium nitrate and manure. Compounds or compositions can be directly mixed with ammonia sources. A mixture of a compound or composition and ammonia source can be directly applied to a growth substrate (such as soil). Compounds or compositions and ammonia sources can be applied separately to a growth substrate (such as soil). Compounds or compositions and ammonia sources can be applied separately and simultaneously.

[0036] Compound or composition and ammonia source can be applied individually and sequentially. The sequential application of compound or composition and ammonia source can be within 24 hours, within 1 to 3 days, within 1 to 5 days, within a 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. Compound or composition can be applied before planting or after planting. Compound or composition can be applied before emergence or after emergence.

[0037] In certain aspects, the nitrification inhibition compositions or methods provided herein comprise one or more of the following compounds and agriculturally acceptable salts, tautomers, stereoisomers, and N-oxides thereof:

[0038]

[0039] R1-R4 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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 R1-R4 is C≡C or C≡C-TMS.

[0040]

[0041] 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.

[0042] in

[0043] R 11 -R 14are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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(CH2C H3)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 R 11 -R 14 At least one of them is C≡C or C≡C-TMS.

[0044] in

[0045] R 11 and R 14 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 R 11 and R 14 At least one of is C≡C or C≡C-TMS. 12 -R 13 It's H.

[0046] in

[0047] R 21 -R 24are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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(CH2C H3)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 R 21 -R 24 At least one of them is C≡C or C≡C-TMS.

[0048] in

[0049] R 21 and R 24 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 R 21 and R 24 At least one of is C≡C or C≡C-TMS. 22 , R 23 and R 25 It's H.

[0050] in

[0051] R 31 -R 34are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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(CH2C H3)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 R 31 -R 34 At least one of them is C≡C or C≡C-TMS.

[0052] in

[0053] R 31 and R 33 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 R 31 and R 33 At least one of is C≡C or C≡C-TMS. 32 and R 34 It's H.

[0054] in

[0055] R 41 -R 44are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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(CH2C H3)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 R 41 -R 44 At least one of them is C≡C or C≡C-TMS.

[0056] in

[0057] R 41 and R 43 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 R 41 and R 43 At least one of is C≡C or C≡C-TMS. 42 and R 44 It's H.

[0058] in

[0059] R 51 , R 52 and R 53are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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(CH2C H3)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 R 51 , R 52 or R 53 At least one of them is C≡C or C≡C-TMS.

[0060] in

[0061] R 51 , R 52 and R 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 R 51 , R 52 or R 53 At least one of them is C≡C or C≡C-TMS.

[0062] in

[0063] R 61 , R 62 and R 63are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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(CH2C H3)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 R 61 , R 62 or R 63 At least one of them is C≡C or C≡C-TMS.

[0064] in

[0065] R 61 , R 62 and R 63 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 R 61 , R 62 or R 63 At least one of them is C≡C or C≡C-TMS.

[0066] in

[0067] R 71 , R 72 , R 73 and R 74are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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(CH2C H3)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 R 71 , R 72 , R 73 or R 74 At least one of them is C≡C or C≡C-TMS.

[0068] in

[0069] R 71 , R 72 , R 73 and R 74 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 R 71 , R 72 , R 73 or R 74 At least one of them is C≡C or C≡C-TMS.

[0070] In certain aspects, the nitrification inhibiting compounds, compositions, or methods provided herein comprise a compound selected from the group consisting of

[0071]

[0072]

[0073]

[0074] and agriculturally acceptable salts, N-oxides, stereoisomers and tautomers thereof.

[0075] In certain aspects, the nitrification inhibiting compounds, compositions, or methods provided herein comprise a compound selected from the group consisting of

[0076] and agriculturally acceptable salts, N-oxides, stereoisomers and tautomers thereof.

[0077] In certain aspects, the nitrification inhibiting compound is selected from the group consisting of compounds in Table 1 and agriculturally acceptable salts, N-oxides, stereoisomers and tautomers thereof.

[0078] Applying nitrification inhibitor compounds to the soil

[0079] In certain aspects provided herein, one or more nitrification inhibitor compounds or compositions are mixed with an ammonia source. Ammonia sources 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, vermicompost, compost, seaweed, or guano; urea-containing fertilizers such as urea, urea formaldehyde, urea ammonium nitrate solution, urea sulfur, urea ammonium sulfate, or other urea-based fertilizers.

[0080] In certain aspects provided herein, one or more of the nitrification inhibitor compounds or compositions are mixed with anhydrous ammonia and then injected into the soil. In other aspects, the compounds or compositions are injected separately into the growth substrate when anhydrous ammonia is applied. The amount of the compound or composition present in the anhydrous ammonia mixture or injected directly can be adjusted so that an agriculturally effective amount of the nitrification inhibitor compound or composition is broadcast.

[0081] In certain aspects provided herein, a nitrification inhibitor compound or composition is mixed with a fertilizer, such as a urea-ammonium nitrate solution, to form a urea-ammonium nitrate nitrification inhibitor mixture.

[0082] These mixtures may also include other ingredients, such as herbicides, insecticides, fungicides, and safeners. Such mixtures may be applied at a rate of about 10 to about 70 gallons per acre, depending on fertilizer strength and concentration and the target amount of nitrogen per acre. For example, the amount of the compound or composition present in the treated mixture may be adjusted so that an agriculturally effective amount of the compound or composition is broadcast.

[0083] In some aspects provided herein, the nitrifying compound or composition is impregnated on dry urea. The amount of the impregnated compound or composition will depend on the rate of application of urea. For example, urea can be broadcast at a rate of about 200 to about 700 pounds per acre. A certain amount of compound or composition can be impregnated on dry urea so that the compound or composition is broadcast in an agriculturally effective amount.

[0084] In some aspects provided herein, compound or composition is broadcast as a part of manure slurry mixture.Compound or composition can be mixed with manure before application or can be applied individually.The amount of compound or composition present in manure slurry can be regulated so that the compound or composition of agricultural effective amount is broadcast.

[0085] The compound or composition may be applied to the growth substrate at a rate of about 50 grams per acre to about 4 kilograms per acre. The compound may be applied to the growth substrate at the following rates: 50-60 grams per acre; 60-70 grams per acre; 70-80 grams per acre; 80-90 grams per acre; 90-100 grams per acre; 100-120 grams per acre; 120-140 grams per acre; 140-160 grams per acre; 160-180 grams per acre; 180-200 grams per acre; 200-225 grams per acre; 225-250 grams per acre. 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; 800-85 0 g / acre; 850-900 g / acre; 900-950 g / acre; 950-1000 g / acre; 1.0-1.1 kg / acre; 1.1-1.2 kg / acre; 1.2-1.3 kg / acre; 1.3-1.4 kg / acre; 1.4-1.5 kg / acre; 1.5-1.6 kg / acre; 1.6-1.7 kg / acre; 1.7-1.8 kg / acre; 1.8-1 .9 kg / acre; 1.9-2.0 kg / acre; 2.0-2.2 kg / acre; 2.2-2.4 kg / acre; 2.4-2.6 kg / acre; 2.6-2.8 kg / acre; 2.8-3.0 kg / acre; 3.0-3.2 kg / acre; 3.2-3.4 kg / acre; 3.4-3.6 kg / acre; 3.6-3.8 kg / acre; and 3.8-4.0 kg / acre.

[0086] experiment

[0087] General synthesis procedure

[0088] General Procedure 1

[0089] Under RT (room temperature), TEA (4 equivalents) and CuI (5mol%) are added to the stirring solution of heterocycle (1 equivalent, 0.7g, 3.95mmol) in EtOAc (0.2 millimole), and the reaction mixture is degassed with argon for 5min, TMS-acetylene (4.5 equivalents) and bis(triphenylphosphine)palladium chloride (15mol%) are added subsequently. The reaction mixture is stirred for 16h at 50 ℃. After the reaction is completed (monitored by TLC), the reaction mixture is filtered through a diatomaceous earth pad, and the filtrate is dried and concentrated under reduced pressure through Na2SO4. The crude product is purified by flash column chromatography using 10%-20%EtOAc in petroleum ether to obtain the desired product.

[0090] General Program 2

[0091] To the stirring solution of ethynyl TMS heterocycle (1.0 equivalent) in methanol (0.2 mmol), 1 equivalent of potassium carbonate is added. The reaction is stirred at room temperature until the reaction is completed (monitored by TLC). The reaction mixture is filtered through a diatomaceous earth pad, and the filtrate is dried and concentrated under reduced pressure through Na2SO4. The crude product is used in 10%-20% EtOAc purification in petroleum ether to obtain the desired product by flash column chromatography.

[0092] General Program 3

[0093] The aldehyde (1.0 eq) was dissolved in anhydrous methanol (0.2-0.5 mM) and charged with cesium carbonate (1.0 eq) and cooled to 0-5° C. Dimethyl (1-diazo-2-oxopropyl)phosphonate (1.0 eq) was added dropwise and the reaction was stirred for 1-18 h before the crude mixture was concentrated onto silica gel and purified directly by flash silica gel chromatography to provide the desired alkyne.

[0094] Synthesis Procedure 12780973

[0096] Trimethylsilyl acetylene (1.5mL, 10.81mmol), bis(triphenylphosphine)palladium chloride (II) (79mg, 0.113mmol) and copper iodide (I) (4.29mg, 0.023mmol) are added to 2-bromo-1,3-thiazole-5-methyl formate (500mg, 2.252mmol) and Et3N (1.4mL, 9.68mmol) in a degassed solution in EtOAc (2.0mL). The mixture is heated to 50°C for 7h, then cooled to 25°C and the reaction mixture is filtered through diatomite. The solvent is evaporated under reduced pressure to obtain the desired product. 12791843

[0098] 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 at the same temperature for 1 h. Water (10 mL) was added to the 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 give 0.2 g (65%) of the desired product as an off-white solid; MP 73°C-77°C; 1 H NMR (400MHz, CDCl3) δ5.48-5.45(m,1H),3.50(s,1H),2.44-2.43(m,1H),1.60-1.58(m,3H); 19 F NMR (376MHz, CDCl3) δ-60.41; ESIMS m / z 222.07 ([M+H]+). 12791845

[0100] 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 at room temperature for 2 h. 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 give 0.035 g (23%) of the target product as a light brown solid; MP 134°C-138°C; 1 H NMR (400MHz, DMSO-d6) δ8.39(s,1H),8.14(s,1H),5.24(s,1H); 19 FNMR (376MHz, CDCl3) δ-60.27; ESIMS m / z 221.06 ([M+H]+). 12791847

[0102] 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 at room temperature for 2 h. 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 give 0.03 g (44%) of the target product as a light brown solid; MP 178°C-182°C; 1 H NMR (400MHz, DMSO-d6) δ8.40(s,1H),8.26(s,1H),7.80(s,1H),5.08(s,1H); ESIMS m / z 153.01([M+H]+). 12791857

[0104] 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 at the same temperature for 1 h. Water (10 mL) was added to the 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 give 0.09 g (89%) of the desired product as a brown solid; MP 72°C-76°C; 1 H NMR (400MHz, CDCl3) δ7.64(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 / z154.03([M+H]+). 12791863

[0106] To a solution of ethyl 2-ethynylthiazole-5-carboxylate (1.4 g, 5.53 mmol) in a mixture of THF:H2O (3:1) (15 mL) was added LiOH.H2O (0.28 g, 6.64 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was acidified with 1N HCl (pH about 2) and extracted with DCM. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 0.8 g (72%) of the target product as a black solid; MP 195°C-199°C; 1HNMR (400MHz, DMSO-d6) δ 13.30 (brs, 1H), 8.54 (s, 1H), 5.02 (s, 1H); ESIMS m / z 153.99 ([M+H]+). 12791865

[0108] 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 at room temperature for 16 h. The reaction mixture was diluted with water (20 mL) and 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 give 0.17 g (66%) of the target product as an off-white solid; MP 162°C-166°C; 1 H NMR (400MHz, DMSO-d6) δ8.36(s,1H),7.88(s,1H),7.65(s,1H),5.02(s,1H); ESIMS m / z 153.02([M+H]+). 12791867

[0110] 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 at room temperature for 16 h. The reaction mixture was diluted with water (20 mL) and 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 give 0.16 g (45%) of the target product as an off-white solid; MP 101°C-105°C; 1 H NMR (400MHz, CDCl3) δ8.13(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

[0112] 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 at room temperature for 16 h. The reaction mixture was diluted with water (20 mL) and 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 give the product as an off-white solid (0.17 g, 54%); MP 121°C-125°C; 1 H NMR (400MHz, CDCl3) δ8.16(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

[0114] 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) under argon atmosphere, followed by DIPEA (0.37 g, 2.93 mmol), PdCl2(PPh3)2 (0.05 g, 0.07 mmol), TMS acetylene (0.18 g, 1.75 mmol), and the reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was cooled to room temperature, EtOAc (30 mL) was added, filtered through a pad of celite, and 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 give 0.12 g (28%) of the desired product as a brown liquid; FT-IR 1666.53 cm -1 (C=O stretching exists); 1 H NMR (400MHz, 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

[0116] 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 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 16 h. The reaction mixture was cooled to room temperature, EtOAc (30 mL) was added, filtered through a pad of celite, and 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 give 0.12 g (28%) of the desired product as a light brown solid (0.11, 25%); MP 79° C.-83° C.; 1 H NMR (400MHz, CDCl3) δ8.11(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

[0118] 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 KCO (1 mg, catalyst) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. After the reaction was complete, the reaction mixture was poured into ice water (5 mL), acidified with 1N HCl (2 mL, pH about 4) and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using 10% EtOAc eluent in petroleum ether to give the product as a light brown solid (0.032 g, 27%); MP 126°C-130°C; 1 H NMR (400MHz, CDCl3) δ8.33(s,1H),3.56(s,1H),3.50(s,1H); ESIMS m / z 162.08([M+H]+). 12806745

[0120] 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 KCO (1 mg, catalyst) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. After the reaction was complete, the reaction mixture was poured into ice water (5 mL), acidified with 1N HCl (2 mL, pH about 4) and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using 10% EtOAc eluent in petroleum ether to give a light brown solid (0.025 g, 17%); MP 111° C.-115° C.; 1 H NMR (400MHz, 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 = 3.4Hz, 3H); ESIMS m / z 178.09 ([M+H]+). 12806753

[0122] 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) at 0°C was added DMP (3.17 g, 7.49 mmol). The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 24 g) using 10%-20% EtOAc eluent in petroleum ether to give the product as a brown solid (0.2 g, 50%); MP 78°C-82°C; 1 H NMR (400MHz, CDCl3) δ 8.50 (s, 1H), 3.45 (s, 1H), 0.30 (s, 9H); ESIMS m / z 234.11 ([M+H]+). 12806761

[0124] 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, catalyst) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. After the reaction was complete, the reaction mixture was poured into ice water (5 mL), acidified with 1N HCl (2 mL, pH about 4) 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% EtOAc eluent in petroleum ether to give the target (0.025 g, 21%) as a light brown solid (0.025 g, 17%); MP 111°C-115°C; 1 H NMR (400MHz, 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 = 3.4Hz, 3H); ESIMS m / z 178.09 ([M+H]+). 12811457

[0126] 1 mL of MeOH was added to N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), KCO (58 mg, 0.42 mmol) in 3 mL of THF at 0° C., and the reaction was stirred for 30 min at 0° C. After the reaction was complete, the mixture was filtered and washed with THF, and the filtrate was concentrated at low temperature to give the product (40 mg, 86%) as a yellow solid. 12811461

[0128] 1 mL of MeOH was added to N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), KCO (58 mg, 0.42 mmol) in 3 mL of THF at 0° C. and the reaction was stirred for 30 min at 0° C. After the reaction was complete, the mixture was filtered and washed with THF, and the filtrate was concentrated at low temperature to give the product (40 mg, 83%) as a brown solid. 12811465

[0130] Under N2, 2-bromo-N-(pentyl-3-yl)thiazole-5-formamide phenyl)benzamide (150mg, 0.54mmol) is added to trimethylsilyl acetylene (317mg, 3.23mmol), Pd(PPh3)4(62mg, 0.05mmol), Cul(21mg, 0.11mmol), NEt3(1.5ml) in 4.5mL THF. The reaction is stirred at 50°C for 2h. After the reaction is complete, the mixture is filtered and washed with THF. The filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel (petroleum ether / ethyl acetate=5:1) to obtain the product as a yellow solid. 12811467

[0132] Under N2, 2-bromo-N-(pentyl-3-yl)thiazole-5-formamide phenyl)benzamide (150mg, 0.54mmol) is added to trimethylsilyl acetylene (317mg, 3.23mmol), Pd(PPh3)4(62mg, 0.05mmol), Cul(21mg, 0.11mmol), NEt3(1.5ml) in 4.5mL THF. The reaction is stirred at 50°C for 2h. After the reaction is complete, the mixture is filtered and washed with THF. The filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel (petroleum ether / ethyl acetate=5:1) to obtain the product as a yellow solid. 12811469

[0134] Under N2, 2-bromo-N-(pentyl-3-yl)thiazole-5-formamide phenyl)benzamide (150mg, 0.54mmol) is added to trimethylsilyl acetylene (317mg, 3.23mmol), Pd(PPh3)4(62mg, 0.05mmol), Cul(21mg, 0.11mmol), NEt3(1.5ml) in 4.5mL THF. The reaction is stirred at 50°C for 2h. After the reaction is complete, the mixture is filtered and washed with THF. The filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel (petroleum ether / ethyl acetate=5:1) to obtain the product as a yellow solid. 12811471

[0136] Under N2, 2-bromo-N-methylthiazole-5-carboxamide (0.54mmol) is added to trimethylsilyl acetylene (317mg, 3.23mmol), Pd(PPh3)4 (62mg, 0.05mmol), Cul (21mg, 0.11mmol), NEt3 (1.5ml) in 4.5mL of THF. The reaction is stirred at 50°C for 2h. After the reaction is complete, the mixture is filtered and washed with THF. The filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel (petroleum ether / ethyl acetate=5:1) to obtain the product N-methyl-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide as a brown solid (63%). 1 HNMR (400MHz, CDCl3) δ8.10 (s, 1H), 6.14 (s, 1H), 3.01 (d, J = 4.8Hz, 3H), 0.29 (s, 9H). 13 C NMR (101 MHz, 155°C-156°C. 12811481

[0138] 1 mL of 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 complete, the mixture was filtered and washed with THF, the filtrate was concentrated at low temperature to give the product, affording the desired product as a brown solid (55 mg, 98%) 1 H NMR (400MHz, CDCl3) δ8.11 (s, 1H), 6.25 (s, 1H), 3.57 (s, 1H), 3.01 (d, J = 4.9Hz, 3H). 13 C NMR (101MHz, CDCl3) δ160.22,150.49,142.97,136.16,84.05,75.97,26.90. ESIMS m / z 167([M+H]+). MP, 118℃-119℃. 12811473

[0140] 1 mL of MeOH was added to N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), KCO (58 mg, 0.42 mmol) in 3 mL of THF at 0° C. and the reaction was stirred for 30 min at 0° C. After the reaction was complete, the mixture was filtered and washed with THF, and the filtrate was concentrated at low temperature to give the product (40 mg, 86%) as a brown solid. 12811475

[0142] 1 mL of MeOH was added to N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), KCO (58 mg, 0.42 mmol) in 3 mL of THF at 0° C. and the reaction was stirred for 30 min at 0° C. After the reaction was complete, the mixture was filtered and washed with THF, and the filtrate was concentrated at low temperature to give the product (40 mg, 86%) as a brown solid. 12811477

[0144] 1 mL of MeOH was added to N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), KCO (58 mg, 0.42 mmol) in 3 mL of THF at 0° C. and the reaction was stirred for 30 min at 0° C. After the reaction was complete, the mixture was filtered and washed with THF, and the filtrate was concentrated at low temperature to give the product (40 mg, 86%) as a brown solid. 1 H NMR (400MHz, CDCl3) δ8.09 (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 = 7.4Hz, 6H). 13 C NMR (101MHz, CDCl3) δ159.30,150.41,142.57,136.71,83.90,76.03,67.98,53.11,27.48,10.29. ESIMS m / z 223([M+H]+). MP, 81℃-82℃. 12811479

[0146] Under N2, 2-bromo-N-(pentyl-3-yl)thiazole-5-carboxamidephenyl)benzamide (150mg, 0.54mmol) was added to trimethylsilyl acetylene (317mg, 3.23mmol), Pd(PPh3)4(62mg, 0.05mmol), Cul(21mg, 0.11mmol), NEt3(1.5ml) in 4.5mL of THF. The reaction was stirred at 50°C for 2h. After the reaction was complete, 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 obtain product 1 (161mg, 64%) as a brown solid. 12811481

[0148] Under N2, 2-bromo-N-(pentyl-3-yl)thiazole-5-carboxamidephenyl)benzamide (150mg, 0.54mmol) was added to trimethylsilyl acetylene (317mg, 3.23mmol), Pd(PPh3)4(62mg, 0.05mmol), Cul(21mg, 0.11mmol), NEt3(1.5ml) in 4.5mL of THF. The reaction was stirred at 50°C for 2h. After the reaction was complete, 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 obtain product 1 (114mg, 72%) as a brown solid. 12811485

[0150] Under N2, 2-bromo-N-(pentyl-3-yl)thiazole-5-carboxamidephenyl)benzamide (150mg, 0.54mmol) was added to trimethylsilyl acetylene (317mg, 3.23mmol), Pd(PPh3)4(62mg, 0.05mmol), Cul(21mg, 0.11mmol), NEt3(1.5ml) in 4.5mL of THF. The reaction was stirred at 50°C for 2h. After the reaction was complete, 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 obtain product 1 (150mg, 49%), a white solid. 12776911

[0152] Under argon atmosphere, to a solution of ethyl 2-bromooxazole-4-carboxylate La (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), and the reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was cooled to room temperature, EtOAc (150 mL) was added and filtered through a celite pad, and 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 give 0.8 g (50%) of the desired product as a brown liquid; FT-IR 1737.89 cm -1 (C=O stretching exists); 1 H NMR (400MHz, CDCl3) δ 8.16 (s, 3H), 4.39 (q, J = 7.2Hz, 2H), 1.38 (t, J = 7.2Hz, 3H), 0.27 (s, 9H); ESIMS m / z 238.22 ([M+H]+). 12776913

[0154] 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 at room temperature for 2 h. 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 give 0.6 g (86%) of the target product as a brown solid; MP 161°C-165°C; 1 H NMR (400MHz, DMSO-d6) δ13.35(bs,1H),8.83(s,1H),4.95(s,1H); ESIMS m / z138.16([M+H]+). 12776915

[0156] 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) at 0°C was added HATU (0.42 g, 1.09 mmol) and DIPEA (0.19 g, 1.44 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (20 mL) and 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 give 0.08 g (54%) of the target product as a brown solid. 12776921

[0158] 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 at room temperature for 16 h. The reaction mixture was diluted with water (30 mL) and 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 give 0.240 g (46%) of the product as an off-white solid; MP 133°C-137°C; 1 H NMR (400MHz, CDCl3) δ7.70(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

[0160] Under argon atmosphere, to a solution of ethyl 2-iodooxazole-5-carboxylate hl (2.5 g, 9.36 mmol) in toluene (25 mL), CuI (0.178 g, 0.93 mmol), DIPEA (2.4 g, 18.72 mmol), PdCl(PPh) (0.33 g, 0.468 mmol) and trimethylsilyl acetylene (1.8 g, 18.72 mmol) were added, and the reaction mixture was stirred at 50 ° C for 16 h. The reaction mixture was cooled to room temperature. EtOAc (100 mL) was added and filtered through a celite pad, and the filtrate was washed with brine (30 mL), dried over anhydrous NaSO, 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 give 1 g (45%) of the product as a brown liquid; FT-IR 1733.07 cm -1 (C=O stretching exists); 1 H NMR (400MHz, CDCl3) δ7.73 (s, 1H), 4.39 (q, J = 7.2Hz, 2H), 1.38 (t, J = 7.2Hz, 3H), 0.28 (s, 9H); ESIMS m / z 238.15 ([M+H]+). 12791853

[0162] To a solution of 2-ethynyloxazole-4-carboxamide (0.3 g, 2.18 mmol) and NH3 aqueous solution (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 at room temperature for 16 h. The reaction mixture was diluted with water (20 mL) and 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 give 0.05 g (42%) of the product as a light brown solid; MP 176°C-180°C; 1 H NMR (400MHz, DMSO-d6) δ8.65(s,1H),7.79(s,1H),7.58(s,1H),4.95(s,1H); ESIMS m / z137.12([M+H]+). 12797705

[0164] To a stirred solution of 2-((trimethylsilyl)ethynyl)oxazole-4-carboxaldehyde (0.2 g, 0.80 mmol) in MeOH (2 mL) was added K2CO3 (1 mg, catalyst) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. After the reaction was complete, the reaction mixture was poured into ice water (5 mL), acidified with 1N HCl (2 mL, pH about 4) 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% EtOAc eluent in petroleum ether to give the product as an off-white solid (0.078 g, 43%); MP 110°C-114°C; 1 H NMR (400MHz, CDCl3) δ9.93(s,1H),8.24(s,1H),3.33(s,1H); ESIMS m / z 122.12([M+H]+). 12806755

[0166] 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 room temperature for 3 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 24 g) using 10% EtOAc eluent in petroleum ether to give the product as a light brown solid (0.12 g, 42%); MP 75°C-79°C; 1 H NMR (400MHz, CDCl3) δ 8.29 (s, 1H), 3.44 (s, 1H), 0.29 (s, 9H); ESIMS m / z 218.15 ([M+H]+). 12806763

[0168] 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 KCO (1 mg, catalyst) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. After the reaction was complete, the reaction mixture was poured into ice water (5 mL), acidified with 1N HCl (2 mL, pH about 4) and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using 10% EtOAc eluent in petroleum ether to give a light brown solid (0.024 g, 45%); MP 117°C-121°C; 1 H NMR (400MHz, CDCl3) δ8.32(s,1H),3.45(s,1H),3.33(s,1H); ESIMS m / z 146.05([M+H]+). 12811459

[0170] 1 mL of MeOH was added to N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), KCO (58 mg, 0.42 mmol) in 3 mL of THF at 0° C. and the reaction was stirred for 30 min at 0° C. After the reaction was complete, the mixture was filtered and washed with THF, and the filtrate was concentrated at low temperature to give the product (25 mg, 86%) as a yellow solid. 12811483

[0172] 1 mL of 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 complete, the mixture was filtered and washed with THF, and the filtrate was concentrated at low temperature to give the product as a brown solid (85%) 1 H NMR (400MHz, CDCl3) δ7.75 (s, 1H), 6.45 (s, 1H), 4.24 (dd, J = 5.4, 2.6Hz, 2H), 3.35 (s, 1H), 2.31 (t, J = 2.6Hz, 1H). 13C NMR (101MHz, CDCl3) δ155.57,145.61,145.06,132.07,81.61,78.37,72.49,70.68,29.09. ESIMS m / z 175([M+H]+). MP, 112℃-113℃. 12811491

[0174] Under N2, 2-bromo-N-(pentyl-3-yl)thiazole-5-formamide phenyl)benzamide (150mg, 0.54mmol) is added to trimethylsilyl acetylene (317mg, 3.23mmol), Pd(PPh3)4(62mg, 0.05mmol), Cul(21mg, 0.11mmol), NEt3(1.5ml) in 4.5mL THF. The reaction is stirred at 50°C for 2h. After the reaction is complete, the mixture is filtered and washed with THF. The filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel (petroleum ether / ethyl acetate=5:1) to obtain the product as a yellow oil. 12811493

[0176] Under N2, 2-bromo-N-(pentyl-3-yl)thiazole-5-carboxamidephenyl)benzamide (150mg, 0.54mmol) was added to trimethylsilylacetylene (317mg, 3.23mmol), Pd(PPh3)4 (62mg, 0.05mmol), Cul (21mg, 0.11mmol), NEt3 (1.5ml) in 4.5mL of THF. The reaction was stirred at 50°C for 2h. After the reaction was complete, 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 as a white solid (25%) 1 H NMR (400MHz, CDCl3) δ7.73 (s, 1H), 6.45 (s, 1H), 4.23 (dd, J = 5.4, 2.6Hz, 2H), 2.30 (t, J = 2.5Hz, 1H), 0.30 (s, 9H). 13 CNMR (101MHz, CDCl3) δ156.53,147.07,145.37,132.91,102.42,91.08,79.24,73.24,29.85. ESIMS m / z247([M+H]+). MP, 134-135℃. 12771961

[0178] To N-(2-methylbut-3-yn-2-yl)-2-(trichloromethyl)-4-(trifluoromethyl)thiazole-5-carboxamide (273mg, 0.719mmol) in THF:H2O (5:1, 6mL) in a disposable addition of Fe (s). The resulting reaction mixture was warmed to 60 ° C. The temperature was maintained for 16h (starting at 4:00PM). The reaction was monitored by TLC (n-hexane: ethyl acetate 8:2) and LCMS. After 16h, there was no visible SM by TLC. The reaction mixture was concentrated (nitrogen) and adsorbed on a diatomaceous earth pre-column and chromatographically analyzed on silica gel. 12799175

[0180] At -78°C, methylmagnesium bromide (86 μl, 0.292 mmol) was slowly added to a solution of 5-ethynylthiazole-2-carboxaldehyde (40 mg, 0.292 mmol) in anhydrous THF as a 3.4 molar solution in THF. After the addition was complete, the reaction was slowly warmed to 25°C over 30 minutes and then quenched with saturated NH4Cl aqueous solution and diluted with 50 mL of ether. The layers were distributed and the ether layer was dried over magnesium sulfate and concentrated on a stream of nitrogen to give a brown residue (42 mg, 85%). 12816775

[0182] At 0 ° C, NaH (60%, 0.078g, 1.63mmol) and CH3I (0.12mL, 2.04mmol) were added to a stirred solution of (5-ethynylfuran-2-yl)methanol (0.1g, 0.82mmol) in THF (5mL). The reaction mixture was stirred at room temperature for 2h. After the reaction was completed (monitored by TLC), the reaction mixture was poured into water (10mL) 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 give the product (0.026g, 23%) as a light brown liquid; FT IR 2111.13cm -1 (There is C≡C scaling); 1 H NMR (400MHz, CDCl3) δ6.60 (d, J = 3.2Hz, 1H), 6.31 (d, J = 3.6Hz, 1H), 4.37 (s, 2H), 3.38 (s, 3H), 3.37 (s, 1H); ESIMS m / z 135.9 ([M]+). 12816797

[0184] 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 KCO (0.1 g, 0.73 mmol) and iodomethane (0.1 mL, 1.20 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were dried over NaSO, 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 obtain the product as a brown liquid (0.026 g, 26%); FT IR 3288.69 cm -1 (OH stretching exists); 1 H NMR (400MHz, CDCl3) δ6.59 (d, J=3.6Hz, 1H), 6.22 (dd, J=0.4, 3.2Hz, 1H), 4.86 (q ,J=4.4Hz,1H),3.39(s,1H),1.92(d,J=4.4Hz,1H),1.54(d,J=6.8Hz,3H); ESIMS m / z 135.9([M]+). 12830209

[0186] At 0 ° C, NaH (48 mg, 0.72 mmol) was added to a stirred solution of 1- (2-ethynyl oxazol-4-yl) ethane-1-ol (0.1 g, 0.72 mmol) in THF (5 mL) and stirred for 15 minutes at 0 ° C, followed by CH3I (0.091 mL, 1.45 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 2 h. After the reaction was completed (monitored 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 eluent in petroleum ether to obtain product-A8 (0.036 g, 33%), which was a light yellow liquid; FT IR 2121.70 cm -1 (There is C≡C scaling); 1 H NMR (400MHz, CDCl3) δ7.54 (s, 1H), 4.36 (q, J = 6.0Hz, 1H), 3.36 (s, 3H), 3.23 (s, 1H), 1.48 (d, J = 6.4Hz, 3H); 13C NMR (101MHz, 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

[0188] 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 [3 M in ether (0.6 mL, 1.86 mmol)] at 0°C. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete (monitored 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 eluent in petroleum ether to give Intermediate-A-1-5 (0.2 g, 59%) as a light yellow liquid; FT IR 2175.70 cm -1 (There is C≡C scaling); 1 HNMR (400MHz, CDCl3) δ7.49 (s, 1H), 4.83 (q, J = 6.8Hz, 1H), 2.15 (d, J = 4.8Hz, 1H), 1.52 (d, J = 6.4Hz, 3H), 0.27 (d, 9H); ESIMS m / z 210.18 ([M+H]+). 12853673

[0190] To a stirred solution of thiazole-2-thiol (0.3 g, 2.56 mmol) in acetone (10 mL) was added KCO (0.35 g, 2.56 mmol) and propargyl bromide (0.2 mL, 2.56 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 3 h. After the reaction was completed (monitored by TLC), the reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the product (0.15 g, 38%) as a brown liquid; FT IR 2117.84 cm -1 (There is C≡C scaling); 1H NMR (400MHz, CDCl3) δ7.73 (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

[0192] At room temperature, LiCl (0.23 g, 5.48 mmol) and CuI (0.1 g, 0.55 mmol) were added to a stirred solution of 2-bromothiazole (0.3 g, 1.82 mmol) in 1,4-dioxane (10 mL). The reaction mixture was degassed with argon for 5 minutes, and then input-1 (0.66 g, 2.01 mmol) and Pd (PPh 3 ) 4 (0.1 g, 0.09 mmol) were added at room temperature. The reaction mixture was stirred at 100 ° C for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth 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 obtain the product (0.05 g, 22%), which was a brown liquid; FT IR 2235.50 cm -1 (There is C≡C scaling); 1 HNMR (400MHz, DMSO-d6) δ7.84 (d, J = 3.2Hz, 1H), 7.77 (d, J = 3.6Hz, 1H), 2.14 (s, 3H); ESIMS m / z 123.92 ([M+H]+). 12853683

[0194] At room temperature, Et3N (3.6mL, 26.21mmol) and CuI (12mg, 0.06mmol) were added to a stirred solution of 2-bromothiazole (1g, 6.09mmol) in EtOAc (20mL). The reaction mixture was degassed with argon for 5 minutes, and then prop-2-yn-1-ol (input-2) (1.6mL, 29.26mmol) and bis(triphenylphosphine)palladium chloride (0.2g, 0.30mmol) were added at room temperature. The reaction mixture was stirred at 50°C-55°C for 16h. After the reaction was completed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12g) using 10%-15% EtOAc in petroleum ether to obtain the product (0.25g, 29%), which was a brown liquid; FTIR 2231.64cm -1 (There is C≡C scaling); 1H NMR (400MHz, 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

[0196] At room temperature, Et3N (3.6mL, 26.21mmol) and CuI (12mg, 0.06mmol) were added to a stirred solution of 2-bromothiazole (1g, 6.09mmol) in EtOAc (20mL). The reaction mixture was degassed with argon for 5 minutes, then alkynes (1.6mL, 29.26mmol) and bis(triphenylphosphine)palladium chloride (0.2g, 0.30mmol) were added at room temperature. The reaction mixture was stirred for 16h at 50°C-55°C. After the reaction was completed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12g) using 10%-15% EtOAc in petroleum ether to obtain the desired product, which was a brown liquid (0.4g, 43%); FT IR 2231.64cm -1 (There is C≡C scaling); 1 ESIMS m / z 153.95([M+H]+). 12853687

[0198] At room temperature, Et3N (3.6mL, 26.21mmol) and CuI (12mg, 0.06mmol) were added to a stirred solution of 2-bromothiazole (1g, 6.09mmol) in EtOAc (20mL). The reaction mixture was degassed with argon for 5 minutes, and then prop-2-yn-1-ol (input-2) (1.6mL, 29.26mmol) and bis(triphenylphosphine)palladium chloride (0.2g, 0.30mmol) were added at room temperature. The reaction mixture was stirred at 50°C-55°C for 16h. After the reaction was completed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12g) using 10%-15% EtOAc in petroleum ether to obtain the product, which was a brown liquid (0.1g, 21%); FT IR2231.64cm -1 (There is C≡C scaling); 1 H NMR (400MHz, CDCl3) δ7.83 (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

[0200] To a stirred solution of 2-bromothiazole (0.3 g, 2.56 mmol) in acetone (10 mL) was added KCO (0.35 g, 2.56 mmol) and propargyl alcohol (0.2 mL, 2.56 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 3 h. After the reaction was completed (monitored by TLC), the reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a colorless liquid (0.03 g, 17%); FT IR 2239.36 cm -1 (There is C≡C scaling); 1 H NMR (400MHz, CDCl3) δ7.13 (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

[0202] At room temperature, CsF (0.47 g, 3.11 mmol) was added to a stirred solution of 2,4-dibromothiazole (0.5 g, 2.07 mmol) in 1,4-dioxane (10 mL). The reaction mixture was degassed with argon for 5 minutes, and then input-1 (0.82 g, 2.48 mmol) and Pd (tBu3P)2 (53 mg, 0.11 mmol) were added at room temperature. The reaction mixture was stirred at 100 ° C for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth 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 obtain the product (0.2 g, 41%), which was a yellow semi-solid (0.15 g, 45%); FT IR 2235.50 cm -1 (There is C≡C scaling); 1 H NMR (400MHz, CDCl3) δ7.22(s,1H),2.10(s,3H),2.04(s,3H); ESIMS m / z 161.88([M+H]+). 12856621

[0204] 3-Ethynyl-5-methylisothiazole (1.0 eq) was dissolved in anhydrous methanol (0.2-0.5 mM) and charged with cesium carbonate (1.0 eq) and cooled to 0-5° C. Dimethyl (1-diazo-2-oxopropyl)phosphonate (1.0 eq) was added dropwise and the reaction was stirred for 1-18 h, then the crude mixture was concentrated onto silica gel and purified directly by flash silica gel chromatography to afford the desired alkyne 12858893

[0205] At -78 ° C, n-BuLi (2.5M) (3.2 mL, 7.69 mmol) was added to a stirred solution of TMS acetylene (0.9 mL, 8.01 mmol) in THF (15 mL). The reaction mixture was stirred at -78 ° C for 30 minutes. Then furan-2-carboxaldehyde SM-C (0.5 g, 6.41 mmol) was added to the reaction mixture at -78 ° C and stirred at room temperature for 5 h. After the reaction was completed, the reaction mixture was quenched with NH4Cl aqueous solution (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 eluent in petroleum ether to obtain intermediate-C1 (0.2 g, 16%) as a yellow solid; FT IR 2177.63 cm -1 (There is C≡C scaling); 1H NMR (400MHz, CDCl3) δ7.41(m,1H),6.45(m,1H),6.35(m,1H),5.45(d,J=6.8Hz,1H),2.22(d,J=7.2Hz,1H),0.21(s,9H); ESIMS m / z 194.94([M+H]+).

[0206] Synthesis of 1-(furan-2-yl)-3-(trimethylsilyl)prop-2-yn-1-one:

[0207] 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 room temperature. The reaction mixture was stirred at room temperature for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through a pad of celite 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 give the product (0.03 g, 30%) as a brown liquid; FT IR 2158.35 cm -1 (There is C≡C scaling); 1 H NMR (400MHz, CDCl3) δ7.66 (m, 1H), 7.36 (m, 1H), 6.57 (dd, J = 1.6, 3.6Hz, 1H), 0.29 (s, 9H); ESIMS m / z 192.90 ([M+H]+).

[0208] General Procedure A

[0209] Under air, aryl halide (1 equivalent), triethylamine (3 equivalents) and copper iodide (I) (0.1 equivalent) are loaded into 20mL vials and diluted with dioxane (substrate of 0.3M concentration). The reaction is degassed for 5min, then ethynyl trimethylsilane (4.0 equivalents) and bis (triphenylphosphine) palladium chloride (II) (0.1 equivalent) are added under an inert atmosphere. The vial is placed in a heating block warming to 80°C, and the solution is stirred for 20h. The reaction is cooled and passed through a diatomaceous earth pad. The filtrate is concentrated, and the resulting residue is purified on silica gel by flash chromatography.

[0210] General Procedure B

[0211] In the 50mL RBF equipped with TMS-alkynes (1.0 equivalent), MeOH (0.25M concentration of substrate) and potassium carbonate (0.2 equivalent) are added. The reaction is stirred for 30min at ambient temperature. After the reaction is completed, the reaction H o is diluted and extracted with DCM. The organic matter merged is passed through a phase separator and concentrated. The gained residue is purified on silica gel by flash chromatography.

[0212] General Program C

[0213] The aldehyde (1.0 eq) was dissolved in anhydrous methanol (0.2-0.5 mM) and charged with cesium carbonate (1.0 eq) and cooled to 0-5° C. Dimethyl (1-diazo-2-oxopropyl)phosphonate (1.0 eq) was added dropwise and the reaction was stirred for 1-18 h before the crude mixture was concentrated onto silica gel and purified directly by flash silica gel chromatography to provide the desired alkyne.

[0214] General Program D

[0215] Under an inert atmosphere, sodium hydride (60% Wt., 1.0 eq.) was charged into a 20 mL vial and diluted with THF (1.0 M concentration of substrate). Alcohol (1.0 eq.) was then added and the reaction was stirred for 30 min at ambient temperature. Aryl halide (1.0 eq.) (0.5 M concentration of substrate) in THF was then added. The vial was placed in a heating block warmed to 50 ° C, 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 on silica gel by flash chromatography

[0216] General Program E

[0217] Under air, P(tBu)3PdG2(0.03 equivalent) and aryl halide (1 equivalent, if solid) are loaded into the 20mL bottle equipped with a magnetic stirring bar. The bottle is capped, and the air is purged by evacuating the bottle and backfilling with nitrogen three times. Dry DMF (0.4M concentration of substrate) is added to the bottle, followed by aryl halide (1 equivalent, if liquid), alkynes (1.5 equivalents) and TBAF (1.5 equivalents, 1M in THF) protected by TMS. The bottle is placed in a heating block warming up to 80°C, and the solution is stirred for 20h. After the reaction time, the bottle is opened to air and Na2CO3 aqueous solution (4mL) is added. The crude product is extracted with CH2Cl2 and purified on silica gel by flash chromatography.

[0218] General Program F

[0219] Load sodium alkoxide (1.0 equivalent) into 20mL vial. Then add solution of aryl halide (1.0 equivalent) in THF (substrate at 0.2M concentration). The vial is placed in a heating block warming to 50°C, and the solution is stirred for 20h. The reaction is quenched with saturated NH4Cl and extracted with Et2O. The combined organics are dried over MgSO4, filtered, and concentrated. The resulting residue is purified on silica gel by flash chromatography.

[0220] General Program G

[0221] A stock solution of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (0.1 equivalent) in dioxane (2 mL) and copper(I) iodide (0.1 equivalent) and triethylamine (3 equivalents) in dioxane (1 mL) were added to a vial containing a solution of Br / Cl-heterocycle (1 equivalent) in dioxane (2 mL). The contents were sealed and degassed with nitrogen, and the total reaction concentration was 0.2 M. Under stirring, pure ethynyltrimethylsilane (2 equivalents) was added, and the contents were heated to 60° C. overnight for 18 hours. The reaction was quenched with AcOH (10 equivalents), and the product mass was observed by LCMS. The contents were diluted with EtOAc and distributed between 2.5M KHCO (2x) and brine, then dried over MgSO. The contents were concentrated by rotary evaporation and the residue was purified by silica gel chromatography eluting with hexanes / EtOAc 10%-100% over 10 minutes to give the product.

[0222] General Procedure H

[0223] The flask was charged with ((trimethylsilyl)ethynyl)-heterocycle dissolved in a solution of potassium fluoride (0.1 M, 2 eq.) in methanol and stirred at ambient temperature for 18 hours. The contents were concentrated by rotary evaporation and purified on silica gel eluting with DCM / MeOH 0-10% to obtain the product.

[0224] General Program I

[0225] To a stirred solution of aldehyde (1M, 1 eq.), potassium carbonate (2 eq.) in methanol was added neat dimethyl (1-diazo-2-oxopropyl)phosphonate (1.1 eq.). 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 combined organics were dried over MgSO4 and concentrated by fractional distillation. The residue was purified on a silica gel column eluted with DCM / MeOH 0-10% for 10 minutes. The fractions containing the product were combined and evaporated to give the product.

[0226] Program J

[0227] The nitrogen-containing heterocycle forming the alkyne is dissolved in diethyl ether (1 M) and treated with an equal volume of 1 M acid (HCl or anhydrous H3PO4) in diethyl ether. The volatile components are removed by evaporation using a stream of nitrogen to give the desired heterocycle in salt form.

[0228] General Program K

[0229] At room temperature, Et is added to the stirring solution of 2-bromothiazole (1g, 6.09mmol) in EtOAc (20mL) N (3.6mL, 26.21mmol) and CuI (12mg, 0.06mmol). The reaction mixture is degassed with argon for 5 minutes, then propan-2-yn-1-ol (1.6mL, 29.26mmol) and bis(triphenylphosphine)palladium chloride (0.2g, 0.30mmol) are added at room temperature. The reaction mixture is stirred for 16h at 50 ℃-55 ℃. After the reaction is completed (monitored by TLC), the reaction mixture is filtered through a diatomaceous earth pad and the filtrate is concentrated under reduced pressure. The crude product is purified by flash column chromatography (column size: 12g) using 10%-15% EtOAc in petroleum ether to obtain the desired product.

[0230] General Program L

[0231] At 0 ℃, add Et to the stirring solution of alkynol (0.15g, 1.07mmol) in dichloromethane (10mL) N (0.2mL, 1.60mmol) and acetyl chloride (0.1mL, 1.28mmol).Reaction mixture is stirred to 16h at room temperature.After reaction is completed (monitored by TLC), reaction mixture is concentrated under reduced pressure, poured into water and extracted with DCM.Organic layer is through anhydrous Na SO Dry and concentrate under reduced pressure.The crude product is used in 10%-15% EtOAc purification in petroleum ether to obtain the desired product by flash column chromatography (column size: 24g).

[0232] Program M

[0233] At 0 ℃, add K to the stirring solution of thiazole-2-thiol (0.3g, 2.56mmol) in acetone (10mL) CO (0.35g, 2.56mmol) and methyl bromide propynyl (0.2mL, 2.56mmol).Reaction mixture is stirred at room temperature for 3h.After reaction is completed (monitored by TLC), reaction mixture is poured in water (10mL) and extracted with EtOAc.By the organic layer merged through Na SO Dry, filter, and under reduced pressure concentrate to obtain desired product.

[0234] Program N

[0235] To a stirred solution of 3-bromopyrazole (0.5 g) in TEA (5 mL) was added CuI (0.049 g). The reaction mixture was then degassed with argon for 10 minutes, followed by the addition of Pd(PPh ) (0.148 g) and acetylated alkyne input (5.14 mmol) at room temperature. The resulting reaction mixture was stirred at 80 ° C for 2 h. After the reaction was complete, the reaction mixture was concentrated at 38 ° C under reduced pressure to obtain a crude compound, which was purified by preparative HPLC to obtain the desired product.

[0236] Program O

[0237] To a stirred solution of pyrazole (0.5 g) in dry THF (5 V) was added NaH (2 eq.), and then bromopropyne (1.2 eq.) was added at 0 ° C. The resulting reaction mixture was stirred for 3 h at 0 ° C to room temperature. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate, and washed with a NaCl aqueous solution and dried over anhydrous Na2SO4. The resulting solution was concentrated under reduced pressure at 38 ° C to obtain a crude compound, which was purified by combi flash chromatography to obtain the desired product.

[0238] Analytical methods

[0239] The synthesized compounds were characterized by the following methods: melting point, ESIMS-electrospray mass spectrometry, HRMS-high resolution mass spectrometry, EIMS-electron ionization mass spectrometry, GCMS-gas chromatography mass spectrometry, SIMS-secondary ion mass spectrometry, Fourier transform infrared spectroscopy-FTIR, 1 H. 13 C. 19 F and 31 P NMR spectroscopy.

[0240] Chiral structures in Table 1 are indicated by "&1" adjacent to the chiral center.

[0241] Table 1 Nitrification inhibitory compounds

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346] Biological tests

[0347] Compound preparation: Compounds were dissolved in DMSO at 0.1 mM concentration.

[0348] Soil slurry preparation: Two different soils were sourced from Kalamazoo, Michigan (loamy fine sand) and Windfall, Indiana (clay loam). After collection, the soils were sieved at 2 mm and stored at 4°C for no longer than 6 months. Slurries were prepared by weighing out 143 grams of field wet soil / liter of nitrification matrix with 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.

[0349] Experimental method: While stirring, 900 μL of slurry was pipetted into a 96-deep well plate. Immediately after the slurry was added, 9 μL of a 0.1 mM stock solution of the compound or solvent control (i.e., DMSO) was added to the designated wells to bring the final concentration to 0.1 μM. The sealing pad was placed on the top of the plate and mixed by inverting the plate three times. The plate was incubated at 28°C for 48 hours while oscillating laterally at 225 rpm. After 48 hours, the plate was rotated at 3,000 rpm for 15 minutes, and the nitrite concentration of the supernatant was analyzed using a colorimetric Griess assay. The nitration rate was determined by the total amount of nitrite formed during the incubation period. Nitrification inhibition was determined by normalizing the nitration rate with a DMSO control. In addition, the relative inhibition of the test compound was normalized to the reference nitrification inhibitor chlorpyrifos.

[0350] The results are shown in Table 3.

[0351] Table 3 Inhibition of soil nitrification.

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

Claims

1. A nitrification inhibition composition comprising carrier; and A compound selected from the group consisting of wherein R1-R4 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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 Where R 11 -R 14 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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(CH2CH 3) 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 R 11 -R 14 At least one of is C≡C or C≡C-TMS; and Where R 21 -R 24 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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(CH2CH 3) 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 R 21 -R 24 At least one of is C≡C or C≡C-TMS; and Where R 31 -R 34 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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(CH2CH 3) 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 R 31 -R 34 At least one of is C≡C or C≡C-TMS; and Where R 41 -R 44 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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(CH2CH 3) 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 R 41 -R 44 At least one of is C≡C or C≡C-TMS; and Where R 51 , R 52 and R 53 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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(CH2CH 3) 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 R 51 , R 52 or R 53 At least one of is C≡C or C≡C-TMS; and and Where R 61 , R 62 and R 63 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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(CH2CH 3) 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 R 61 , R 62 or R 63 At least one of is C≡C or C≡C-TMS; and Where R 71 , R 72 , R 73 and R 74 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 alkylthio, 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(CH2CH 3) 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 R 71 , R 72 , R 73 or R 74 At least one of them is C≡C or C≡C-TMS.

2. The composition according to claim 1, wherein The compound is selected from the group consisting of:

3. The composition according to claim 1, wherein The compound is selected from the group consisting of:

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

5. The composition according to claims 1 to 4, wherein The ammonia source is selected from the group consisting of anhydrous ammonia, ammonium nitrate, urea ammonium nitrate, manure, and mixtures thereof.

6. The composition of claims 1 to 5, further comprising a second nitration inhibiting compound as claimed in claim 1.

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

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

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

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