HERBICIDAL SUBSTITUTED ARYL ALKYLSULFONYL PYRAZOLES

FIELD Qf THE INVENTION The field of the invention contemplated herein pertains to herbicidal compounds generically defined by the above title, to compositions containing same and processes for preparing said compounds.

BACKGROUND OF THE INVENTION Various substituted 3- and 5-arylpyrazole- type compounds are known in the literature. Such compounds have various utilities, e.g., as chemical intermediates, pharmaceuticals and herbicides.

Among the substituted-arylpyrazole compounds in the prior art are those having a variety of substi- tuent radicals on the aryl and/or pyrazole moieties of the compound. For example, compounds of this type are known wherein the aryl moeity is a substituted or unsubstituted phenyl radical, in which the substituent radicals are alkyl, cycloalkyl, alkaryl, halogen, trifluoromethyl, heterocyclic or substituted hetero- cyclic, e.g., thienyl or alk l-substituted furanyl, pyridyl, pyri idinylurea, etc. and the pyrazolyl radical is substituted in various positions on the N or carbon atoms with alkyl, halogen, alkoxy, heterocycles, S(0) _n R members, wherein n is 0-2 and R may be a variety of radicals such as those substituted on the aryl or pyrazole moieties.

Prior compounds of the above type having utility as herbicides, typically require application rates as high as five or ten or more kilograms per hectare to achieve adequate weed control. Accordingly, it is an object of this invention to provide a novel class of arylpyrazole-type compounds having uniquely high phytotoxic unit activity against a spectrum of weeds, including narrovleaf and broadleaf weeds yet maintain a high degree of safety in a plurality of crops, especially small grains and/or row crops such as wheat, barley, corn, soybeans, peanuts, etc.

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SUMMARY OF THE INVENTION This invention relates to herbicidally-active compounds, compositions containing these compounds, processes for making them and herbicidal methods of using same.

wherein

R, is hydrogen, C,^ alkyl optionally substi¬ tuted with an R ₄ member; C _j . ₈ cycloalkyl or cycloalkenyl optionally substituted with C _1-t alkyl;

R ₂ is C _1-5 alkyl optionally substituted with an R ₄ member;

R ₃ is hydrogen or halogen and R ₄ is hydrogen, C,. _β alkyl, haloalkyl, alkyl- thio, alkoxyalkyl or polyalkoxyalkyl, C ₃ . ₈ cycloalkyl, cycloalkenyl, eyeloaIkyalkyl or cycloalkenylalk l; C ₂ _ _β alkenyl or alkynyl; carbamyl, halogen, amino, nitro, cyano, hydroxy, C ₄ . ₁₀ heterocycle containing 1-4 0, S(0) _B and/or N hetero atoms, C^^ aryl, aralkyl or alkaryl, -CXYR _g , -CXR,, -CH ₂ OCOR ₁₀ , -YR-,, -NR ₁₂ R ₁₃ , or any two R ₄ members may be combined through a saturated and/or X unsaturated carbon, -C- and/or hetero atom linkage to form a heterocyclic ring having up to 9 ring members, which may be substituted with any of said * members or where not self-inclusive said R^ or R ₈ . _1S members substituted vith any of said ) members; provided that when said two R ₄ members are combined through a -hetero

O atom -C-N- linkage, said heterocyclic ring has at least six ring members; X is O, S(0) _a , NR ₁₄ or CR ₁₅ R ₁₆ ;

Y is 0 or S(0) _a or NR ₁₇ ; g-R, _? are one of said R ₄ members;

■ is 0-2 and n is 0-5.

A preferred subgenus of substituted-arylpyra- zolyl compounds in this invention are those according to Formula II

-R ₂

wherein

R. , R ₂ and R ₃ are as defined for Formula I; Rς is independently one of said R ₃ members and

R ₆ and R ₇ are independently one of said R ₄ members or are combined to form a heterocyclic ring having up to 9 members and containing 0, N and/or S atoms, which ring may be substituted with alkyl, haloalkyl, alkoxy, alkenyl or alkynyl radicals each having up to 4 carbon atoms; provided that when said two R ₆ and R ₇ members are combined through a -hetero atom

-C-N- linkage, said heterocyclic ring has at least six ring members.

Particularly preferred compounds of this invention are those according to Formula III

-R ₂

wherein

R, and R _j are C,. ₅ alkyl;

R ₃ and R _j are hydrogen, bromo, chloro or fluoro;

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R ₆ is an R, member or nitro;

R ₇ is an R ₄ member or

R ₆ and R ₇ are combined through an -OCH ₂ (C=0)- N-(R ₄ )-linkage to form a fused six-membered ring. Still more preferred compounds according to

Formula III are those wherein

R, and R ₂ are methyl;

R ₃ is hydrogen, bromo or chloro; , is chloro or fluoro; R ₆ is chloro, fluoro or nitro;

R ₇ is a YR^ member as defined in Formula I or

R ₆ and R ₇ are combined through an -OCH ₂ (C=0)- N-(propynyl)-linkage to form a fused six-membered ring.

Preferred species according to this invention include the following: 4-Chloro-3-(2-fluoro-4-chloro-5-(2-propynyloxy)phenyl)- l-methyl-5-(methylsulfonyl)-lH-pyrazole 4-Bromo-3-(2-fluoro-4-chloro-5-(2-propynyloxy)phenyl)- l-methyl-5-(methylsulfonyl)-lH-pyrazole

4-Chloro-3-(2-fluoro-4-chloro-5-(2-methoxyethoxy)- phenyl)-l-methyl-5-(methylsulfonyl)-lH-pyrazole 4-Bromo-3-(2-fluoro-4-chloro-5-(2-methoxyethoxy)- phenyl)-l-methyl-5-(methylsulfonyl)-lH-pyrazole 6-( -Chloro-l-methyl-5-(methylsulfonyl)-lH-pyrazol-3- yl)-7-fluoro-4-(2-propynyl)-2H-l,4-benzoxazin-3- (4H)-one (5-(4-Bromo-l-methyl-5-(methylsulfonyl)-lH-pyrazol-3- yl)-2-chloro-4-fluorophenoxy)acetic acid, 1- methylethyl ester

(5-(4-Chloro-l-methyl-5-(methylsulfonyl)-lH-pyrazol-3- yl)-2-chloro-4-fluorophenoxy)acetic acid, l- methylethyl ester 2-(5-(4-Bromo-l-methyl-5-(methylsulfonyl)-lH-pyrazol-3- yl)-2-chloro-4-fluorophenoxy)propanoic acid, ethyl ester and

2-(5-(4-Chloro-l-*ethyl-5-(methylsulfonyl)-lH-pyrazol- 3-yl)-2-chloro-4- luorophenoxy)propanoic acid, ethyl ester.

Another aspect of this invention relates to processes for preparing the compounds according to Formulae I-III and their precursors and intermediates starting materials. These process aspects will be discussed in more detail below.

Other aspects of this invention relate to herbicidal compositions containing the compounds of

Formulae I-III and to herbicidal methods of using those compositions to control undesirable weeds.

It is further within the purview of this invention that the substituted-arylpyrazole compounds of Formulae I-III be formulated in compositions containing other herbicidal compounds as co-herbicides, e.g., acetanilides, thiocarba ates, ureas, sulfonylureas, imidazolinones, benzoic acids and their derivatives, diphenyl ethers, salts of glyphosate, etc. Other additaments may be included in such herbicidal formulations as desired and appropriate, e.g., antidotes (safeners) for the herbicide(s) , plant disease control agents, such as fungicides, insecti¬ cides, nematicides and other pesticides. As used herein, the terms "alkyl", "alkenyl", alkynyl" when used either alone or in compound form, e.g., haloalkyl, haloalkenyl, alkoxy, alkoxyalkyl, etc., are intended to embrace linear or branched-ch in members. Preferred alkyl members are the lover alkyls having from 1 to 4 carbon atoms and preferred alkenyl and alkynyl members are those having from 2 to 4 carbon atoms.

The term "haloalkyl" is intended to mean alkyl radicals substituted vith one or more halogen (chloro, bromo, iodo or fluoro) atoms; preferred members of this class are those having from 1 to 4 carbon atoms, especially the halomethyl radicals, e.g., trifluoro-

UBSTITUTESHEET

methyl. In polyhaloalkyl members, the halogens can all be the same or mixed halogens.

Representative, non-limiting alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl and cycloalkenylalkyl members include the following:

Methyl, ethyl, the isomeric propyls, butyls, pentyls, hexyls, heptyls, octyls, nonyls, decyls, etc.; vinyl, allyl, crotyl, methallyl, the isomeric butenyls, pentyls, hexenyls, heptenyls, octenyls; ethynyl, the isomeric propynyls, butynyls, pentynyls, hexynyls, etc.; the alkoxy, polyalkoxy, alkoxyalkyl and polyalkoxyalkyl analogs of the foregoing alkyl groups, e.g., methoxy, ethoxy, propoxys, butoxys, pentoxys and hexoxys and corresponding polyalkoxys and alkoxyalkyls, e.g., methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxy- ethoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxymethyl, isopropoxymethyl, butoxy- ethyl, isobutoxymethyl, tertbutoxymethyl, pentoxy- ethyl, hexoxymethyl, etc., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, etc.; the isomeric cyclopentenes, cyclohexenes and cycloheptenes having mono-or di-unsaturation; representative aryl, aralkyl and alkaryl groups include phenyl, the isomeric tolyls and xylyls, benzyl, naphthyl, etc.

Representative mon-, di- and tri- haloalkyl members include: chloromethyl, chloroethyl, bromo- methyl, bromoethyl, iodo ethyl, iodoethyl, chloropropyl, bromopropyl, iodopropyl, 1,1-dichloromethyl, 1,1-di- bromomethyl, 1,1-dichloropropyl, 1,2-dibromopropyl, 2,3-dibromopropyl, l-chloro-2-bromoethyl, 2-chloro-3- bromopropyl, trifluoromethyl, trichloromethyl, etc.

Representative heterocyclic members include: alkylthiodiazolyl; piperidyl; piperidylalkyl; dioxo- lanylalkyl, thiazolyl; alkylthiazolyl; benzothiazolyl; halobenzothiazolyl; furyl; alkyl-substituted furyl; furylalkyl; pyridyl; alkylpyridyl; alkyloxazolyl; tetrahydrof rylalkyl; 3-cyanothienyl; thienylalkyl;

EET

alkyl-substituted thienyl; 4,5-polyalkylene-thienyl; piperidinyl; alkylpiperidinyl; pyridyl; di- or tetrahydropyridinyl; alkyltetrahydromorpholyl; alkylmorpholyl; azabicyclononyl; diazacycloalkanyl, benzoalkylpyrrolidinyl; oxazolidinyl; perhydro- oxazolidinyl; alkyloxazolidyl; furyloxazolidinyl, thienyloxazolidinyl, pyridyloxazolidinyl, pyrimi- dinyloxazolidinyl, benzooxazolidinyl, C ₃ . ₇ spiro- cycloalkyloxazolidinyl, alkylaminoalkenyl; alkyl- ideneimino; pyrrolidinyl; piperidonyl; perhydroazepinyl; perhydroazocinyl; pyrazolyl; dihydropyrazolyl; pipera- zinyl; perhydro-l,4-diazepinyl; quinolinyl, isoguino- linyl; di-, tetra- and perhydroquinolyl - or - iso- quinolyl; indolyl and di- and perhydroindolyl and said heterocyclic members substituted vith radicals such as the members defined in Formula I.

As used herein, the term "agriculturally- acceptable salts" (of the compounds defined by the above formulae) is meant a salt or salts which readily ionize in aqueous media to form a cation or anion of said compounds and the corresponding salt anion or cation, which salts have no deleterious effect on the herbicidal properties of a given herbicide and which permit formu¬ lation of the herbicide composition without undue problems of mixing, suspension, stability, applicator equipment use, packaging, etc.

By "herbicidally-effective" is meant the amount of herbicide required to effect a meaningful injury or destruction to a signi icant portion of affected undesirable plants or weeds. Although of no hard and fast rule, it is desirable from a commercial viewpoint that 80-85% or more of the weeds be destroyed, although commercially significant suppression of weed growth can occur at much lover levels, particularly vith some very noxious, herbicide-resistant plants.

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-β-

DETAILED DESCRIPTION OF THE INVENTION

The compounds according to this invention are suitably prepared by a variety of processes as will be described below. In broad aspect, the preferred overall process for preparing the compounds of Formulae I-III is best viewed in the separate process steps required to get the necessary intermediates, immediate precursors and end products of the above formulae. Viewed from this per- spective, there are at least thirteen main process steps involved and these will be described below. The pro¬ ducts according to Formulae I-III are prepared by the general "Processes I-XIII" scheme described below; it being expressly understood that various modification obvious to those skilled in the art are contemplated. Specific embodiments are described in Examples 1-27 below.

In the sequence of process steps described below, the various symbols defining radical substi- tuents, e.g., R.,-R ₁₇ , X, Y, etc. have the same meanings as defined for the compounds of Formulae I-III, unless otherwise qualified or limited.

PRQCES? I

This process describes the preparation of important intermediate compounds, vhich are useful in the overall process scheme for producing compounds of Formulae I-III. Such intermediate compounds of Formula B belov in vhich R ₃ is H are prepared by this process step.

1) dithioke l R,

B

HEET

The process for the preparation of compounds according to Formula B suitably proceeds from (un)sub¬ stituted acetophenones of Formula A vhich are known in the art. The process can be carried out in any anhy- drous solvent or mixture of such solvents; the preferred solvents are dimethylsulfoxide, toluene, benzene, etc. The (un)substituted acetophenones are treated vith a strong base such as an alkali hydride or alkali alkoxide vith alkali alkoxides such as potassium t-butoxide being preferred. The basic mixture is treated vith carbon disulfide. Reaction temperature is in the range of -100'C to 100'C, preferably -78"C to 50 ^* C. After addition of the carbon disulfide is complete, the reaction may be treated vith an lkylhalide, alkyldihalide, alkylsulfate, dialkylsulfonate or other suitable alkylating agent vith the preferred reagent being methyl iodide. The reaction period may be chosen from the range of a fev minutes to several veeks depending on the amounts of reagents, reaction tempera- ture, etc. After completion of the reaction the intermediate 1-(substituted)-3,3-bis(alkylthio)-2- propen-l-one is isolated by diluting the reaction mixture vith vater and the product is isolated by a method such as crystallization or solvent extraction. If necessary, the product is purified by standard methods. The cyclization of this intermediate to give compounds of Formula B can be carried out in any suitable solvent by treatment vith hydrazine or substituted hydrasines vith alkylhydrazines being preferred. Reaction temperature is in the range of

-78 ^* C to 150*C, preferably 10'C to lOO'C. The reaction period may be chosen from the range of a fev minutes to several veeks depending on the amounts of reagents, reaction temperature, etc. The product is isolated after completion of the reaction by filtration and/or concentration of the reaction mixture. If necessary, the product is purified by standard methods such as extraction, crystallization, column chromatography, etc.

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In the case of the addition of hydrazine to the intermediate 1-(substituted)-3,3-bis(alkylthio)-2- propen-1-one, the resultant pyrazole may be treated vith an alkyl halide, alkyl sulfonate or other suitable alkylating agent to obtain compounds of Formula B. In this case, products of Formula B can be obtained by treatment of the above compound vith an alkylating agent such as methyl iodide, benzyl bromide, allyl bromide, dimethyl sulfate, etc. The preferred solvents are dimethylsulfoxide, acetone, dimethylformamide, dioxane, etc. Reaction temperature is in the range of -78"C to 150"C, preferably 10*C to 100 ^* C. The reaction period may be chosen from the range of a fev minutes to several veeks depending on the amounts of reagents, reaction temperature, etc. The product is isolated after com¬ pletion of the reaction by filtration and/or concen¬ tration of the reaction mixture. If necessary, the product is purified by standard methods such as extraction, crystallization, column chromatography, etc. The 2-fluoro-4-chloro-5-methoxyacetophenone, used to prepare compound Nos. 4, 9, 10 and 11 in Table 1 by the above process, vas prepared from 2-chloro-4- fluoroanisole, vhich can be obtained from 2-chloro-4- fluoro-phenol by methods known in the art (C. A. Buehler and D. E. Pearson, Survey of Organic Synthesis, pp. 285- 382, Wiley-Interscience, New York, 1970). Treatment of 2-chloro-4-fluoroanisole vith titanium tetrachloride and dichloromethylmethylether at room temperature gives 2- fluoro-4-chloro-5-methoxybenzaldehyde. The 2-fluoro- 4-chloro-5-methoxybenzaldehyde is converted to 2-fluoro- 4-chloro-5-methoxyacetophenone by treatment vith methyl Grignard folloved by oxidation using standard methods known in the art.

The above mentioned 2-fluoro-4-chloro-5- methoxyacetophenone and its analogous precursor, 2- fluoro-4-chloro-5-methoxybenzaldehyde and processes for preparing them are the discovery of other inventors

TITUTESHEET

(Bruce C. Hamper and Kindrick L. Leschinsky) employed by the assignee herein.

Table 1 shovs typical examples of compounds prepared by Process I. TABLE 1

PHYSICAL DATA FOR 3-ARYL-5-METHYLTHIOPYRAZOLES

Compounds such as those Formula B species shown in Table I are useful as starting materials to prepare various other compounds which, in turn, are useful as intermediates in the preparation of compounds according to Formula II. For example, the compounds in Table I may be halogenated at the pyrazole 3-position to

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prepare novel compounds typified by those shown in Table

II .

TABLE II

PHYSICAL DATA FOR 3-ARYL-4-HALO-5-METHYLTHIOPYRAZOLES 5

This process describes an important step involving oxidation of compounds according to Formula B to prepare compounds according to Formula I. The impor¬ tant feature of this process step is the conversion of sulfide derivatives of Formula B to obtain the S,S- dioxide derivatives of Formula I compounds. Accord¬ ingly, it will be understood that the oxidation system described below is merely representative, but concep¬ tually any suitable means of accomplishing the intended conversion of sulfide derivatives of Formula B to S,S- dioxide derivatives of Formula I is contemplated herein. Oxidation of substituted thiopyrazoles of Formula B can give the corresponding sulfonylpyrazoles of Formula I. Any inert solvent may be used in this reaction that does not markedly hinder the reaction from proceeding. Such solvents include, but are not limited to, organic acids, inorganic acids, hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, ethers or sulfones. Suitable oxidants include, but are not limited to molecular oxygen, organic and inorganic peroxides, organic peracids, inorganic oxides; the preferred reagents being hydrogen peroxide, perbenzoic acids, alkali periodates, alkali permanganates, etc. Reaction temperature is in the range of -78*C to 150'C, preferably 10"C to 100"C. The reaction period may be chosen from the range of a fev minutes to several weeks depending on the amounts of reagents, reaction temperature, etc. After completion of the reaction the product is isolated by diluting the reaction mixture vith vater and the product is isolated by a method such

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as crystallization or solvent extraction. If necessary, the product is purified by standard methods. PROCESS III

In this process description, one class of products according to Formula D vherein R ₃ is halogen is prepared by the halogenation of the corresponding Formula C compound vherein 19*. is hydrogen and p is 0 or 2.

Any inert solvent may be used in this reaction that does not markedly hinder the reaction from pro¬ ceeding. Such solvents include, but are not limited to, organic acids, inorganic acids, hydrocarbons, halo¬ genated hydrocarbons, aromatic hydrocarbons, ethers and sulfides, sulfoxides or sulfones. Halogenating agents suitable for the above reaction include bromine, chlorine, N-bromosuccinimide, N-chlorosuccinimide, sul- furyl chloride, l,3-dichloro-5,5-dimethylhydantoin, etc. With some halogenating agents it is preferable to use an organic peroxide or light as a catalyst. The amount of halogenating agent can range from equivalent molar amounts to an excess. Reaction temperature is in the range of -100*C to 150 ^# C, preferably 10'C to 100'C. The reaction period may be chosen from the range of a fev minutes to several veeks or longer depending on the amounts of reagents, reaction temperature, etc. After completion of the reaction the product is isolated by diluting the reaction mixture vith vater and the product is isolated by a method such as crystallization or solvent extraction. If necessary, the product is purified by standard methods.

PROCESS IV

This section describes a process for the preparation of compounds according to Formula I in which one of the R ₄ residues is a nitro group (Formula E) starting with compounds according to Formula I.

nitration

Nitrating agents such as concentrated nitric acid, fuming nitric acid, mixtures of nitric acid with concentrated sulfuric acid, alkyl nitrates and acetyl nitrate are suitable for this reaction. Solvents such as mineral acids, organic solvents such as acetic anhydride or methylene chloride, and water or mixtures of these solvents may be used. The nitrating agent may be used in equimolar amounts or in excess. Reaction temperature is in the range of -100'C to 150*C, prefer¬ ably -10*C to 100"C. The reaction period may be chosen from the range of a few minutes to several days de¬ pending on the amounts of reagents, reaction temper- ature, etc. After completion of the reaction the product is isolated by diluting the reaction mixture with water and the product is isolated by a method such as crystallization or solvent extraction. If necessary, the product is purified by standard methods. PROCESS v

In this process description, one class of products according to Formula G (one species of Formula II compounds) is prepared by displacement of the Z radical of the corresponding compound of Formula F, wherein Z is any suitable leaving group of the previously defined R ₄ members.

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— , lo _Λ —

Formation of products of Formula G can be carried out by treatment of compounds of Formula F with an alkoxide, thioalkoxide, amine, etc., or an alcohol, mercaptan, amine, etc. in the presence of a base in any suitable solvent. The preferred solvents are dimethyl¬ sulfoxide, acetone, dimethylformamide, dioxane, water, etc. The base may be an organic base (such as a trial- kylamine or another organic amine) or an inorganic base (an alkali carbonate such as potassium carbonate or sodium carbonate) . Reaction temperature is in the range of -100*C to 150 ^* C, 'preferably -10 ^# C to 100'C. The reaction period may be chosen from the range of a few minutes to several veeks depending on the amounts of reagents, reaction temperature, etc. The product is isolated after completion of the reaction by filtration and/or concentration of the reaction mixture. If necessary, the product is purified by standard methods such as extraction, crystallization, column chromato¬ graphy, etc. PROCESS VI

In this process description, a variety of compounds of Formula I (exemplified by Formula J below are prepared from compounds of Formula H (Formula I compounds in which one of the R ₄ members is a nitro residue) .

SHEET

A. In the first step of this tvo step process, com¬ pounds according to Formula H are reduced to give an amine derivative according to Formula J vherein one of the R ₄ radicals is an amine group. Reducing agents suitable in an acidic medium include, but are not limited to, metals such as iron, zinc or tin. The reaction solvent can include either organic or inorganic acids, such as acetic acid or hydrochloric acid, and may be used as concentrated acid solutions or dilute aqueous solutions. Reaction temperature is in the range of O'C to 150"C, preferably 10*C to 100 ^* C. The reaction period may be chosen from the range of a fev minutes to several veeks depending on the amounts of reagents, reaction temperature, etc. After completion of the reaction the product is isolated by diluting the reaction mixture vith vater and the product is isolated by a method such as crystal¬ lization or solvent extraction. If necessary, the product is purified by standard methods. Alternatively, compounds of Formula H may be reduced by catalytic hydrogenation. For catalytic hydrogenation, vhich may be carried out at normal or elevated pressures, suitable catalysts include Raney nickel, palladium-carbon, palladium black, palladium on any suitable support, palladium oxide, platinum, plati¬ num black, etc. Solvents include any inert solvent vhich does not markedly hinder the reaction including alcohols, ethers, etc. The product is isolated after completion of the reaction by filtration and concen- tration of the reaction mixture. If necessary, the product is purified by standard methods such as extraction, crystallization, column chromatography, etc.

B. The amine radical of the product of step A can be converted to a variety of functional groups, e.g., a halogen (preferred), cyano, hydroxyl, etc., radical by the folloving step in the process. In this reaction any suitable solvent may be employed, although, anhydrous

SUBSTITUTESHEET

solvents such as anhydrous acetonitrile are preferred. A solution or slurry of the product of step A is treated vith copper salts including cupric halides, cuprous halides, mixtures of cupric and cuprous halides or other copper salts and their mixtures and vith an alkyl nitrite or other organic nitrites, such as t-butyl- nitrite. Reaction temperature is in the range of O'C to 150"C, preferably 10"C to 100*C. The reaction period may be chosen from the range of a fev minutes to several veeks depending on the amounts of reagents, reaction tempera- ture, etc. The product is isolated after completion of the reaction by filtration and/or concentration of the reaction mixture. If necessary, the product is purified by standard methods such as extraction, crystallization, column chromatography, etc. Alternative process operations for converting the amine radical to various functional groups, including those mentioned in the preceding paragraph include use of various conventional procedures, e.g., the Sand eyer, Meervein, etc. , reactions vhich employ diazonium salts as intermediates. PROCESS VII

In this process description, compounds according to Formula I, vherein one of the R ₄ members is YH, are prepared from compounds according to Formula I vherein one of the R ₄ members is YR-, and R is not hydrogen.

The reaction can be carried out as a solution or suspension in any suitable solvent or neat. A Levis acid such as, but not limited to, BBr ₃ , A1C1 ₃ , etc. or inorganic acids such as concentrated or aqueous hydro¬ chloric acid, sulfuric acid, hydrobromic acid, etc. can be employed. Reaction temperature is in the range of O'C to 150'C, preferably 10*C to 100*C. The reaction period may be chosen from the range of a fev minutes to several veeks depending on the amounts of reagents, reaction temperature, etc. The product is isolated after completion of the reaction by filtration and/or

T

concentration of the reaction mixture. If necessary, the product is purified by standard methods such as extraction, crystallization, column chromatography, etc. PROCESS VIII In this process description, compounds according to Formula I, vherein one of the R ₄ members is YR„ and is not hydrogen, are prepared from compounds according to Formula I vherein one of the R ₄ members is YH. In representative embodiments of this process, formation of products defined above can be carried out by treatment of the starting material vith an alkylating agent such as an alkyl halide or alkyl sulfonate, e.g., methyl iodide, allyl bromide, propargyl bromide, methyl phenylsulfonate, etc., or an acylating agent. The reaction may be carried out in any suitable solvent or mixture of solvents, vith or vithout a catalyst, in the presence or absence of a base. The preferred solvents are dimethylsulfoxide, acetone, dimethylformamide, dioxane, etc. The base may be an organic base (such as a trialkyla ine or another organic amine) or an inor¬ ganic base (an alkali carbonate such as potassium car¬ bonate or sodium carbonate) . Reaction temperature is in the range of O'C to 150*C. preferably 10"C to lOO'C. The reaction period may be chosen from the range of a fev minutes to several veeks depending on the amounts of reagents, reaction temperature, etc. the product is isolated after completion of the reaction by filtration and/or concentration of the reaction mixture. If necessary, the product is purified by standard methods such as extraction, crystallization, column chromato¬ graphy, etc. PROCESS IX

This process describes the preparation of compounds of Formula M (Formula II compounds vherein R ₇ is YCH ₂ . _n (R ₁₈ ) _n COYR ₂₀ ) from the corresponding compounds of Formula K. The radicals R^. _g , are as previously defined for the said R ₄ members.

SUBSTITUTESHEET

M

A. In the first step of this tvo step process, com¬ pounds of Formula K are converted to compounds of Formula L by hydrolysis of the YR ₁₉ radical. The reaction can be carried out in any suitable solvent or mixture of solvents, vith or vithout a catalyst, .in the presence of a base or acid. The preferred solvents are vater, alcohols, dioxane, dimethylsulfoxide, acetone, dimethylformamide, etc. In the case of base hydrolysis, inorganic bases such as alkali hydroxides are preferred. For acid hydrolysis, inorganic acids such as concen¬ trated hydrochloric acid or sulfuric acid, organic acids or mixtures of such acids may be employed. Reaction temperature is in the range of 0*C to 150"C, preferably 10'C to 100"C. The reaction period may be chosen from the range of a fev minutes to several veeks depending on the amounts of reagents, reaction temperature, etc. After completion of the reaction the product is isolated

EET

by diluting the reaction mixture vith vater and/or treating the solution vith acid (in the case of base hydrolysis) and the product is isolated by a method such as crystallization or solvent extraction. If necessary the product is purified by standard methods.

B. The product of step A is converted to compounds of Formula M by esterification or an amide-forming reac¬ tion. This may be accomplished directly from compound L or via an alkali metal salt of compound L. The esterification can be carried out by using an excess of the alcohol corresponding to the objective ester in the presence of a mineral acid (e.g., sulfuric acid). The amide derivatives can be prepared by treating compound L vith the desired amine either neat or in a suitable solvent. The esterification or amide-forming reactions can also be carried out in the presence of an inert solvent and a dehydrating agent.

Alternatively, the product of step A can be converted to an acid halide or anhydride and treated vith an alcohol or amine. Preparation of the acid halide is carried out in the presence of a halogenating agent such as, but not limited to, thionyl chloride, phosporus pentachloride, oxalyl chloride, etc., vith or vithout an inert solvent. Any inert solvent vhich does not interfere vith the reaction may be employed. A catalytic amount of an amine base such as triethylamine, pyridine or dimethylformamide or the like may be added for the purpose of promoting this reaction. The reac- tion temperature is in the range of -20*C to the boiling point of the solvent used, the reaction period ranges from several minutes to 48 hours depending upon the amounts of reactants used and the reaction temperature. After completion of the reaction, the excess halogen- ating reagent and solvent(s) are removed from the reaction product by evaporation or distillation. The resultant acid halide may be subjected to an amine or alcohol directly or purified by the usual means.

SUBSTITUTESHEET

The acid halide is treated vith an alcohol or amine to give a compound of Formula M. Any inert solvent may be employed and a catalytic amount of an amine base such as triethylamine, pyridine or dimethyl- formamide or the like may be added for the purpose of promoting this reaction. The reaction temperature is in the range of -20'C to the boiling point of the solvent used. The reaction period ranges from several minutes to 48 hours depending upon the amounts of reactants used and the reaction temperature. The product is isolated after completion of the reaction by filtration and/or concentration of the reaction mixture. If necessary, the product is purified by standard methods such as extraction, crystallization, column chromatography, etc. pp CE?? X

This process describes the preparation of compounds of Formulae 0, P, Q, R, S or T (Formula II compounds in vhich the R ₇ substituent is alkyl, sub¬ stituted alkyl, haloalkyl, carboxaldehyde, carboxylic acid or a carboxylic acid derivative such as the previously defined CXYR _j or CXR _? ) from compounds of Formula N. The radicals R ₂₁ and R ₂₂ are as previously defined for the R ₄ members and X, and X ₂ are halogens. Process schematics are shown below.

TESHEET

halogenation

N

SUBSTITUTE SHEET

In the first step of this process, compounds of Formulae N are converted to either compounds of Formula 0 or Q or a mixture of these products. Any inert solvent may be used in this reaction that does not markedly hinder the reaction from proceeding. Such solvents include, but are not limited to, organic acids, inorganic acids, hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, ethers and sulfides, sulfoxides or sulfones. Halogenating agents suitable for the above reaction include bromine, chlorine, N-bromosuccinimide, N-chlorosuccinimide, sulfuryl chloride, etc. With some halogenating agents it is preferable to use an organic peroxide or light as a catalyst. The amount of halo¬ genating agent can range from an equal molar amount to an excess. Reaction temperature is in the range of

-100"C to 150*C, preferably 10"C to 100"C. The reaction period may be chosen from the range of a few minutes to several weeks depending on the amounts of reagents, reaction temperature, etc. After completion of the reaction the product or products are isolated by diluting the reaction mix- ture with vater and the product(s) are isolated by a method such as crystal¬ lization or solvent extraction. If necessary the product(s) are purified by standard methods. Compounds of Formula 0 can be converted to compounds of Formula P by displacement of the halogen radical X ₁ by a suitable nucleophile. Formation of products of Formula P can be carried out by treatment of compounds of Formula O vith an alkoxide, thioalkoxide, amine, alkyl or aryl anion, etc., or an alcohol, mer¬ captan, amine, etc. in the presence of a base in any suitable solvent. The preferred solvents are dimethyl¬ sulfoxide, acetone, dimethylformamide, dioxane, etc. The base may be an organic base (such as a trialkylamine or another organic amine) or an inorganic base (an alkali carbonate such as potassium carbonate or sodium carbonate). Reaction temperature is in the range of 0*C to 150"C, preferably 10"C to 100"C. The reaction period

may be chosen from the range of a fev minutes to several veeks depending on the amounts of reagents, reaction temperature, etc. The product is isolated after com¬ pletion of the reaction by filtration and/or concen- tration of the reaction mixture. If necessary, the product is purified by standard methods such as extraction, crystallization, column chromatography, etc.

Formation of products of Formula R can be carried out by acid hydrolysis of compounds of Formula Q. To effect acid hydrolysis, compounds of Formula Q are subjected to an excess of a mineral acid such as hydrochloric acid or sulfuric acid, vith a large excess of sulfuric acid being preferred. Reaction temperature is in the range of o*C to the boiling point of the inert solvent, preferably 10"C to 100"C. The reaction period may be chosen from the range of a few minutes to several weeks depending on the amounts of reagents, reaction temperature, etc. After completion of the reaction the product or products are isolated by diluting the reac- tion mixture with vater and the product(s) are isolated by a method such as crystallization or solvent extrac¬ tion. If necessary, the product(s) are purified by standard methods.

Compounds of Formula S are obtained by oxidation of Formula R compounds. Any suitable inert solvent may be employed in this reaction including hydrocarbons, aromatic hydrocarbons, pyridine and its derivatives, vater, etc. Oxidizing agents employed include but are not limited to peroxides such as potassium permanganate or potassium dichromate.

Reaction temperature is in the range of 0*C to the boiling point of the inert solvent, preferably 10*C to 100'C. The reaction period may be chosen from the range of a fev minutes to several veeks depending on the amounts of reagents, reaction temperature, etc. After completion of the reaction the product or products are isolated by diluting the reaction mixture vith vater and the product(s) are isolated by a method such as crys-

SUBSTΪTUTESHEET

tallization or solvent extraction. If necessary, the product(s) are purified by standard methods.

The last step of this process is meant to include the transformation of compounds of Formula S to compounds of Formula T by any of the variety of standard techniques for preparation of derivatives of carboxylic acids. This process step is an esterification or an amide-forming reaction. This may be accomplished directly from a compound S or via an alkali metal salt of a compound S. The esterification can be carried out by using an excess of the alcohol corresponding to the objective ester in the presence of a mineral acid (e.g., sulfuric acid) . The amide derivatives can be prepared by treating a compound S vith the desired amine either neat or in a suitable solvent. The esterification or amide-forming reactions can also be carried out in the presence of an inert solvent and a dehydrating agent. Alternatively, compounds of Formula S can be nverted to an acid halide or anhydride and treated ,_th an alcohol or amine. Preparation of the acid halide is carried out in the presence of a halogenating agent such as, but not limited to, thionyl chloride, phosphorus pentachloride, oxalyl chloride, etc., vith or vithout an inert solvent. Any inert solvent vhich does not interfere vith the reaction may be employed. A catalytic amount of an amine base such as triethylamine, pyridine or dimethylformamide or the like may be added for the purpose of promoting this reaction. The reac¬ tion temperature is in the range of -20*C to the boiling point of the solvent used. The reaction period ranges from several minutes to 48 hours depending upon the amounts of reactants used and the reaction temperature. After completion of the reaction, the excess halogen¬ ating reagent and solvent(s) are removed from the reac- tion product by evaporation or distillation. The resultant acid halide may be subjected to an amine or alcohol directly and purified by the usual means.

TESHEET

_ _

The acid halide is treated vith an alcohol or amine to give a compound or Formula T. Any inert solvent may be employed and a catalytic amount of an amine base such as triethylamine, pyridine or dimethylformamide or the like may be added for the purpose of promoting this reaction. The reaction temperature is in the range of -20'C to the boiling point of the solvent used. The reaction period ranges from several minutes to 48 hours depending upon the amounts of reactants used and the reaction temperature. The product is isolated after completion of the reaction by filtration and/or concentration of the reaction mixture. If necessary, the product is purified by standard methods such as extraction, crystallization, column chromatography, etc. PROCESS XI

This section describes a process for the preparation of compounds according to Formula I in vhich one of the R ₄ residues is a thiol group (Formula U) starting vith compounds according to Formula I.

In this process, the desired compounds are obtained by preparation of a halosulfonyl intermediate folloved by reduction to give compounds of Formula U. Any solvent may be employed that does not hinder the progress of the reaction such as halogenated hydro¬ carbons, ethers, alkylnitriles, mineral acids, etc. An excess of chlorosulfonic acid is preferred as both the reagent and solvent for the formation of chlorosulfonyl intermediates. The reaction temperature is in the range of 25"C to the boiling point of the solvent employed. The reaction period may be chosen from the range of a

SUBSTITUTESHEET

fev minutes to several veeks depending on the amounts of reagents, reaction temperature, etc. After completion of the reaction the product or products are isolated by diluting the reaction mixture vith vater and the pro- duct(s) are isolated by a method such as crystallization or solvent extraction. If necessary, the product(s) are purified by standard methods.

Reduction of the halosulfonyl intermediate can be carried out in inert solvents including either organic or inorganic acids, such as acetic acid or hydrochloric acid, and may be used as concentrated acid solutions or dilute aqueous solutions. Reducing agents suitable in an acidic medium include, but are not limited to, metals such as iron, zinc or tin. The reaction solvent can include Reaction temperature is in the range of O'C to 150*C, preferably 10*c to 100*C. The reaction period may be chosen from the range of a fev minutes to several veeks depending on the amounts of reagents, reaction temperature, etc. After completion of the reaction the product is isolated by diluting the reaction mixture vith vater and the product is isolated by a method such as crystal¬ lization or solvent extraction. If necessary, the product is purified by standard methods. PROCESS XII

In this process step, compounds of Formula V (Formula I compounds in vhich R ₂ is CH _j R^ vhere R _a is one of the previously defined R ₄ members) are prepared from compounds of Formula I vhere R ₂ is methyl.

Any suitable solvent may be employed provided that it is anhydrous, does not react vith vater, and does not interfere vith the course of the reaction. Preferably, anhydrous ethers such as tetrahydrofuran, diethyl ether or polyethers are employed. The reaction temperature is usually -100 ^* C to the boiling point of the solvent employed vith -78"C to 25 ^* C being preferred. Initially, the compound of Formula I is treated vith a strong base such as an alkyl metal, metal hydride, metal amide, etc., folloved by treatment vith an alkylating agent such as an alkyl halide, an alkyl sulfonate, etc. The reaction period may be chosen from the range of a fev minutes to several veeks depending on the amounts of reagents, reaction temperature, etc. After completion of the reaction the product is isolated by diluting the reaction mixture vith vater and the product is isolated by a method such as crys¬ tallization or solvent extraction. If necessary, the product is purified by standard methods. PROCESS XIII

This process step describes the conversion of compounds of Formula W to either compounds of Formulae X or Y. The radical R ₂₄ is as previously defined for one of the R ₄ members and n is an integer of 0 or 1.

SUBSTITUTESHEET

In this process step, the nitro radical of compounds according to Formula W is reduced to give an amine derivative vhich can either be isolated or allowed to cyclize directly to give products of Formulae X or Y depending on the nature of the R ₂₄ radical. In some cases, it may be necessary to carry out the above reac¬ tions at elevated temperatures in order to facilitate cyclization of the amine intermediate. Reducing agents suitable in an acidic medium include, but are not limited to, metals such as iron, zinc or tin. The reaction solvent can include either organic or inorganic acids, such as acetic acid or hydrochloric acid, and may be used as concentrated acid solutions or dilute aqueous solutions. Reaction temperature is in the range of 0*0 to 150*0, preferably 10*C to 100 ^* C. The reaction period may be chosen from the range of a few minutes to several weeks depending on the amounts of reagents, reaction temperature, etc.

After completion of the reaction the product is isolated by diluting the reaction mixture with water and the product is isolated by a method such as crystallization or solvent extraction. If necessary, the product is purified by standard methods.

Alternatively, compounds of Formula W may be reduced by catalytic hydrogenation. For catalytic hydrogenation, vhich may be carried out at normal or elevated pressures, suitable catalysts include Raney nickel, palladium-carbon, palladium black, palladium on any suitable support, palladium oxide, platinum, plati- num black, etc. Solvents include any inert solvent which does not markedly hinder the reaction including alcohols, ethers, etc. The product is isolated after completion of the reaction by filtration and concentra¬ tion of the reaction mixture. If necessary, the product is purified by standard methods such as extraction, crystallization, column chromatography, etc.

TITUTESHEET

The following Examples 1-27 describe specific working embodiments for the preparation of representa¬ tive compounds according to this invention. In the examples which follow, where chromatographic purifi- cations were done the adsorbent material was silica. Examples 1-3 describe specific working embodiments of Process I, used to prepare intermediate compounds for preparing the final products of this invention. Example 1

(A.) All equipment vas flame dried under N ₂ . To a slurry of 5.4 g (0.18 mole) 80% oil dispersion NaH in 150 mL dry DMSO vas added 14.04 g (0.09 mole) 2,5-di- fluoroacetophenone (commercially available) over 10 min. A gas evolution vas noted. The reaction vas cooled to 15* and 5.4 mL (0.09 mole) CS ₂ vere added over 15 min. keeping the temperature at 15'C and the gas evolution under control. 11.1 mL (0.018 mole) methyl iodide was added immediately after the completion of the CS ₂ addition at 20*0. The reaction was stirred for 2 hr. at room temperature. The reaction mixture was poured into 500 mL ice and stirred for 1 hr. The solid was filtered, washed with water and air dried. The residue was purified chromatographically using 20% ethyl acetate in hexane as the eluent to give 19.8 g (85%) of l-(2,5- difluorophenyl)-3,3-bis(methylthio)-2-propen-l-one as a yellow solid, mp 105.5 ^* 0;

Alternatively, for the procedure described in step (A.) a mixture of anhydrous solvents can also be used, e.g., a mixture of DMSO and THF.

Anal. Calc. for C^H^F _j O^: 0,50.75; H,3.87; S,24.63.

Found: 0,50.85; H,3.86; S,24.75. (B.) To a slurry of 4.0 g (0.0154 mole) of the product of step (A.) in 50 mL acetonitrile was added 1.65 mL (0.031 mole) methylhydrazine over 15 min. at 24 ^* 0. The solution was refluxed for 6 hr. The solution was stripped in vacuo. The residue vas purified chromato-

SUBSTΪTUTESHEET

graphically using 10% ethyl acetate in hexane as the eluent to give 3.05 g (82%) of 3-(2,5-difluorophenyl)- l-methyl-5-(methylthio)-lH-pyrazole as a light yellow oil; Anal. Calc. for C^H^F^S,: C, 54.99; H,4.20; N,11.66;

S,13.34.

Found: 0,55.03; H,4.26; N,11.55; S.13.38.

Example 2 This example describes the preparation of an isomeric mixture of 3-(2,5-difluorophenyl)-l-methyl-5- methylthio-lH-pyrazole and 5-(2,5-difluorophenyl)-1- methyl-3-methylthio-lH-pyrazole.

A. To a solution of 5.2 g 1-(2,5-difluorophenyl)-3,3- bis(methylthio)-2-propen-l-one in 50 mL acetonitrile at

24*0 was added 1.3 mL of anhydrous hydrazine over a period of 3 minutes. The reaction was heated to 95*0 for l hour. The reaction was concentrated in vacuo. The residue was taken up in diethyl ether and washed with water, dried over anhydrous MgS0 ₄ , and concentrated in vacuo . The residue was recrystallized from hexane to give 4.14 g (94%) of 3-(2,5-difluorophenyl)-5-(methyl¬ thio)-lH-pyrazole as a white solid, mp 88*0. Anal. Calc. for C ₁₀ H ₈ F ₂ N ₂ S-: 0,53.09; H-3.56; N,12.38; S,14.17.

Found: 0,53.12; H,3.55; N,12.40; S,14.15.

B. A slurry of 3.44 g of the product of Step A, 2.2 g K ₂ C0 ₃ , and 1.0 mL methyl iodide in 75 mL acetone was stirred overnight at 25*0. The solution was diluted with 300 mL cold water and extracted three times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgS0 ₄ , and concentrated in vacuo. The residue was purified chromatographically using 10% ethyl acetate in hexane as the eluent to give 2.97 g (85%) of 3-(2,5-difluorophenyl)-l-methyl-5- methylthio-lH-pyrazole (analysis given in Example 1) and 0.35 g (10%) of 5-(2,5-difulorophenyl)-l-methyl-3-

(methylthio)-IH-pyrazole as a light yellow oil, n

1.5731.

Anal. Calc. for C^H^F _j N _j S,: 0,54.99; H,4.20; N,11.66.

Found: 0,54.83; H,4.19; N,11.85. Example 3

This example describes the preparation of 3- (2,4-difluorophenyl)-l-methyl-5-(methylthio)-1H- pyrazole. All glassware was flame dryed. To a mechanically stirred solution of potassium t-butoxide (43g 0.38mol) in anhydrous tetrahydrofuran (600ml) was added 2,4-di- fluoroacetophenone (30g, 0.192mol). The solution exothermed to 40*0 and was stirred at that temperature for 30 minutes. The solution was then cooled to 0*C and a solution of carbon disulfide (11.6 ml, 0.192 mol) was added at such a rate that the temperature of the reac¬ tion never exceeded 1*0. After the addition was complete, the reaction was stirred for 15 minutes at 0*0, followed by the addition of methyl iodide (23.6g, 0.38 mol) never letting the solution temperature rise above l*C. The solution was stirred using no cooling until it reached 10'C, at which time the reaction solution was poured onto 1L of ice water. Two crops of a filterable yellow solid were collected to give a total yield of 48.lg (96% yield) of the dithioketal. The dithioketal (47g, 0.180 mol) was dissolved in aceto¬ nitrile (500 ml) and methyl hydrazine (21g, 0.45 mol) was added all in one portion. The solution was brought to reflux for 24 hours and then most of the acetonitrile was stripped off under vacuum. The remaining liquid was poured onto ice water and extracted into diethyl ether. The organics were vashed vith brine three times and dried over anhydrous magnesium sulfate, and stripped of all volatiles to give 37.77g (87% yield) of 3-(2,4- difluorophenyl)-l-methyl-5-(methylthio)-lH-pyrazole as an amber oil. 'H (CDC1 ₃ ) ppm: 7.82 (q, J ^« 6.6, IH) , 6.78 (m, 2H), 6.55 (d, J=3.6, IH) , 3.83 (s, 3H) , 2.34 (s, 3H) .

SUBSTITUTESHEET

Anal. Calc. for C-^F^S, : C, 54.99 ; H, 4.20; N, 11.66

Found: 0,55.06; H,4.23; N,11.60. Examples 4, 5 and 6 describe specific vorking embodiments of Process II. Example 4

This example describes the preparation of 3- (2,5-difluorophenyl)-l-methyl-5-(methylsulfonyl)-1H- pyrazole.

A solution of 2.66 g (0.011 mole) of the product of step (B) , Example 1, in 50 mL methylene chloride vas cooled to -5*C. A solution of 7.6 g (0.022 mole) 50-60% m- chloro-perbenzoic acid in 100 mL methylene chloride vas added to the reaction mixture and allowed to stir over¬ night at room temperature. The solution was washed with a saturated sodium bicarbonate solution containing 5% sodium thiosulfate, followed by a vater vash, dried over anhydrous MgS0 ₄ , and concentrated in vacuo. The residue vas recrystallized from methylcyclohexane to give 2.8 g (93%) of 3-(2,5-difluorophenyl)-l-methyl-5-(methyl- sulfonyl)-lH-pyrazole as a vhite solid, mp 126-127*0; Anal. Calc. for C^H^F^S,: 0,48.53; H,3.70; N,10.29;

S,11.78. Found: 0,48.61; H,3.70; N,10.26; S,11.71. Exam le ?

This example describes the preparation of 5- (4-chloro-2-fluoro-5-methoxyphenyl)-3-(methylsulfonyl)- IH-pyrazole.

To a solution of 1.12 g of 5-(4-chloro-2- fluoro-5-methoxyphenyl)-3-(methylthio)-lH-pyrazole in a mixture of 30 mL of glacial acetic acid and 15 mL of ethanol vas added 3.2 g of Oxone*. The heterogeneous mixture vas heated to 85*0 and after 2 hours vas poured into ice vater. The resultant mixture vas extracted three times vith methylene chloride and the organic extracts concentrated to afford an oily residue. Solution of the oily residue in 10% aqueous NaOH folloved by neutralization vith concentrated HC1

SHEET

afforded a solid precipitate vhich vas collected and vashed vith vater to afford 0.60 g (48%) of 5-(4- chloro-2-fluoro-5-methoxyphenyl)-3-(methylsulfonyl)-1H- pyrazole. An analytical sample vas obtained by recrystallization from methanol/vater to give a yellow, crystalline solid; mp 213-216 (dec). Anal. Calc. for C^H^O _j F,: 0,43.36; H,3.31; N,9.19;

S, 10.52. Found: 0,43.51; H,3.33; N,9.10; S,10.44.

ExaffiPl? 6 This example describes the preparation of 4- chloro-3- (2-fluoro-4-methoxyphenyl) -l-methyl-5- (methyl¬ sulf onyl) -lH-pyrazole. To a 0 ^* 0 solution of 4-chloro-3- (2-fluoro-4- methoxyphenyl) -l-methyl-5- (methylthio) -lH-pyrazole ( 3. 5g , 0.0122 mol) in methylene chloride ( 150 mL) vas added m-chlorobenzoic acid in small portions . The reaction vas stirred for 20 hours at room temperature, then the organics vere extracted tvice vith a 50% solution of saturated sodium bicarbonate in saturated sodium thiosulfate solution. The organics vere dried over anhydrous magnesium sulfate and the volatiles removed under vacuum to give a yellow solid with mp * 75 * 0.

Anal. Calc. for ^F-^O^Cl, : C, 45.22 ; H, 3.79 ;

N,8.79. Found: 0,45.49; H,3.77; N,8.69. Examples 7 and 8 describe specific working embodiments of Process III.

ExfrffPl? 7 This example describes the preparation of 4- chloro-3-(2,5-difluorophenyl)-l-methyl-5-(methylsul- fonyl)-lH-pyrazole.

At 25*0, 2.25 g (8.2 mmole) of the product of Example 4 vas dissolved in 40 mL glacial acetic acid and 1.1 g (16.4 mmole) chlorine gas was bubbled in over a

SUBSTITUTESHEET

period of 50 minutes. The reaction vas a1loved to stir for 45 minutes. The reaction solution vas poured into 300 mL ice vater, and extracted vith diethyl ether. The ether vas vashed vith a saturated sodium bicarbonate solution, dried over anhydrous MgS0 ₄ , and concentrated in vacuo. The residue vas purified chromatographically using 30% ethyl acetate in hexane as the eluent to give 1.35 g (84%) of 4-chloro-3-(2,5-difluorophenyl)1-methyl- 5-(methylsulfonyl)lH-pyrazole as a vhite solid, mp 77 ^* 0; Anal. Calc. for C,43.08; H,2.96; N-9.13;

S,10.45; 01,11.56. Found: C,43.16;H,2.97;N,9.12; S,10.39; Cl,11.49. Example 8 This example describes the preparation of 4- chloro-3-(2-fluoro-4-methoxyphenyl)-l-methyl-5-(methyl¬ thio)-lH-pyrazole.

To a 0*C solution of 3-(2-fluoro-4-methoxy- phenyl)-l-methyl-5-(methylthio)-lH-pyrazole (4g, 0.015 mol) in diethyl ether (30 ml) and 1 drop of glacial acetic acid vas added l,3-dichloro-5,5-dimethylhydantoin (1.77 g, 0.009 mol). The reaction vas stirred for one hour at room temperature and then poured onto ice. The organics vere extracted into diethyl ether, vashed vith brine, dried over anhydrous magnesium sulfate and stripped in vacuo to give a yellov oil, n^ « 1.5943 at 25*0.

Anal. Calc. for C ₁₂ H ₁₂ F ₁ N ₂ 0 ₁ S ₁ C1 ₁ : 0,50.26; H,4.22; N-9.77.

Found: 0,49.84; H.4.13; N,9.61. Examples 9 and 10 describe specific vorking embodiments of Process IV.

Example 9 This example describes the preparation of 4- chloro-3-(2,5-difluoro-4-nitrophenyl)-l-methyl-5- (methylsulfonyl)-lH-pyrazole.

TUTESHEET

At 24'C, 1.5 g (4.9 mmole) 4-chloro-3-(2,5- difluorophenyl)-l-methyl-5-(methylsulfonyl)-lH-pyrazole, vas slowly added to 25 mL of fuming nitric acid. The reaction vas stirred at 30*C for 30 minutes. The reaction vas poured into 300 mL of ice. The slurry vas filtered and the cake vashed veil vith vater and air dried. The solid vas recrystallized from methylcyclo- hexane to give 1.13 g (66%) of 4-chloro-3-(2,5-difluoro- 4-nitrophenyl)-l-methyl-5-(methylsulfonyl)-lH-pyrazole as a beige solid, mp 147 ^* 0;

Anal. Calc. for C^H _g C^F _j N _j O^,: 0,37.56; H,2.29; N,11.95;

S.9.12. Found: C.37.60; H,2.29;N,11.98; S.9.10. EXMPl-? IQ

This example describes the preparation of 4- chloro-3-(4-chloro-2-fluoro-5-nitrophenyl)-l-methyl-5- (methylsulfonyl)-lH-pyrazole.

To a solution of 3g (0.0093 mol) of 4-chloro- 3-(4-chloro-2-fluorophenyl)-l-methyl-5-(methylsulfonyl)- lH-pyrazole in 3 L of concentrated sulfuric acid vas added a mixture of l mL of concentrated nitric acid in 3 mL concentrated sulfuric acid, dropvise. This mixture vas then stirred at 25 ^* 0 for 2 hours. The reaction mixture vas then poured into ice-vater and extracted vith ether. The organic extracts vere then vashed three times vith 100 L of aqueous NaCl, dried (MgS0 ₄ ), filtered and concentrated to afford 2.3g (67%) of 4- chloro-3-(4-chloro-2-fluoro-5-nitrophenyl)-l-methyl-5- (methylsul onyl)-IH-pyrazole as a yellov solid.

Chromatography (10% EtOAc/CH ₂ Cl ₂ ) afforded an analytical sample, mp 111-115*0.

Anal. Calc. for C ₁₁ H ₈ N ₃ 0 ₄ C1 ₂ F ₁ S ₁ + 1/4 EtOλc:

C,36.45; H,2.60; N,10.85. Found: 0,36.39; H,2.26; N,10.91.

Examples 11 and 12 describe specific vorking embodiments of Process V.

SUBSTITUTE SHEET

Examole 11 This example describes the preparation of 4- chloro-3-(2-fluoro-5-methoxy-4-nitrophenyl)-l-methyl-5- (methylsulfonyl)-lH-pyrazole. A mixture of 4.8 g (0.0137 mole) of the product of Example 9, 1.9 g (0.014 mole) K ₂ C0--, and 5 mL methanol vas slurried in 50 mL DMSO at 25*C. The reaction vas stirred at 45*C for 8 hours. The reaction vas cooled, diluted vith 100 mL cold vater, and extracted four times vith ethyl acetate. The ethyl acetate extracts vere vashed vith brine, dried over anhydrous MgS0 ₄ , and stripped in vacuo. The residue vas recrystallized from ethyl acetate/hexane to give 4.21 g (84%) of 4-chloro-3-(2- luoro-5-methoxy-4-nitrophenyl)- l-methyl-5-(methylsulfonyl)-lH-pyrazole as a yellov solid, mp 178.5-180*C;

Anal. Calc. for C^-Cl^N^S,: C,39.62; H,3.05;

N,11.55; S,8.81. Found: 0,39.58; H,2.98; N,11.54; S,8.59.

Example 12 This example describes the preparation of 5- [4-chloro-l-methyl-5-(methylsulfonyl)-lH-pyrazol-3-yl]- 4-fluoro-N-(1-methylethyl)-2-nitrobenzenamine. To a solution of 4-chloro-3-(2,5-difluoro-4- nitrophenyl)-l-methyl-5-(methylsulfonyl)-lH-pyrazole (7.6g, 0.0218 mol) in n-methyl pyrrolidinone (50 ml) vas added isopropyl amine (1.94g, 0.0328 mol), potassium carbonate (4.5g, 0.0328 mol) and a catalytic amount of copper (II) fluoride. The reaction vas heated to 60*0 for tvo hours and determined complete by TLC. The reaction vas diluted into ethyl acetate and the organics vere vashed three times vith brine, dried over anhydrous magnesium sulfate and the volatiles removed under vacuum to give 8.4g (98%) of 5-[4-chloro-l-methyl-5-(methyl¬ sulfonyl)-lH-pyrazol-3-yl]-4-fluoro-N-(l-methylethyl)- 2-nitrobenzenamine as an orange solid after recrys- talization from ethanol/methyl cyclohexane, mp 152*0.

SUBSTITUTESHEET

Anal. Calc. for C^Cl^N^S,: 0,43.03; H,4.13; N,14.34.

Found: 0,43.09; H-4.09; N,14.36.

Example 13 This example describes the preparation of 4- chloro-3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl- 5-(methylsulfonyl)-lH-pyrazole is a specific embodiment of Process VI.

(A.) A slurry of 3.3 g (9.1 mmole) of 4-chloro-3-(2- fluoro-5-methoxy-4-nitrophenyl)-l-methyl-5-( ethyl- sulfonyl)-lH-pyrazole in 100 mL of acetic acid vas heated to 80*0 under nitrogen and treated portionvise vith 1.5 g (27 mmole) of iron povder. After 20 minutes at 85*0, the mixture vas alloved to cool and filtered through Celitβe. The resultant solution vas diluted vith 250 mL of vater and extracted three times vith ethyl acetate. The organic extracts vere vashed vith vater, saturated aq. NaHCO _j , vater, dried vith MgS0 ₄ and concentrated to afford 3.1 g of a tan solid. (B.) A solution of 3.0 g (9.0 mmole) of the product of step (A.) in 70 L dry acetonitrile at 25*0 vas treated vith 0.9 g (9.0 mmole) CuCl and 1.8 g (13.1 mmole) CuCl ₂ . A solution of 2.4 L (18 mmole) 90% t-butyl nitrite vas added to the reaction mixture over 5 minutes. After 1 hour at 28'C the reaction mixture vas concentrated in vacuo. The reaction residue vas taken up in ethyl acetate and vashed three times vith a 10% HC1 solution, tvo times vith brine, dried over anhydrous MgS0 ₄ , and concentrated iii vacuo. The residue vas purified chromatographically using 50% ethyl acetate in hexane as the eluent to give 2.64 g (83%) of 4-chloro-3-(4-chloro- 2-fluoro-5-methoxyphenyl)-l-methyl-5-(methylsulfonyl)- lH-pyrazole as a vhite solid, mp 127.5*C Anal. Calc. for C^^Cl^N _j O _j S,: C,40.81; H,3.14;

N,7.93; S,9.08; Cl,10.08. Found: 0,40.94; H,3.14;

N, 7.88 ; S, 8.97 ; Cl, 19.95. Examples 14-16 describe specific vorking embodiments of Process VII .

TE SHEET

Examole 14 This example describes the preparation of 2- chloro-5-[ -chloro-l-methyl-5-(methylsulfonyl)-1H- pyrazol-3-yl]-4-fluoro-N-2-propenylbenzenamine. A solution of 1 g (0.0023 mol) of N-[2-chloro-

5-[4-chloro-l-methyl-5-(methylsulfonyl)-lH-pyrazol-3- yl]-4-fluorophenyl]-2,2,2-trifluoroacetamide, 0.97 g (0.007 mol) of potassium carbonate, 25 mL of anhydrous DMF and 0.85g (0.007 mol) of allyl bromide vas allowed to stir at 70*0 for 24 hours. This solution vas diluted vith EtOAc, vashed vith three times 100 mL of 5% HC1, dried (MgS0 ₄ ), filtered and concentrated to afford 0.9g of a red oil. This oil vas dissolved in 20 mL of methanol and 3 mL of 10% NaOH vas added. This mixture vas stirred at 25*C for 8 hours. The reaction mixture vas diluted vith EtOAc, vashed vith three times 100 mL of aqueous NaCl, dried (MgS0 ₄ ) , filtered and concentrated to afford 0.8g of a red oil. Chromatography (CH ₂ C1 ₂ ) afforded 0.6g (69%) of 2-chloro-5-[4-chloro-l-methyl-5- (methylsulfonyl)-lH-pyrazol-3-yl]-4-fluoro-N-2-propenyl- benzenamine as a yellov oil, n « 1.5956. Anal. Calc. for ^ ^Cl^S,: 0,44.46; H,3.73; 11,11.11.

Found: C,44.66; H,3.68; N,10.85.

Exanple 15 This example describes the preparation of N-

[2-chloro-5-[4-chloro-l-methyl-5-(methylsulfonylj-1H- pyrazol-3-y1]-4-fluorophenyl]-methanesulfonamide.

To a solution of 0.5g (0.001 mol) of N-[2- chloro-5-[4-chloro-l-methyl-5-(methylsulfonyl)-1H- pyrazol-3-yl]-4-fluorophenyl]-N-(methylsulfonyl)- methanesulfonamide in 20 mL of methanol vas added 2 mL of 10% NaOH. This mixture vas stirred at 25*0 for 4 hours. The reaction mixture vas diluted vith EtOAc, vashed vith three times 100 mL of 5% HC1, dried (MgS0 ₄ ) , filtered and concentrated to afford 0.2g (48%) of N-[2- chloro-5-[ -chloro-l-methyl-5-(methylsulfonyl)-1H- pyrazol-3-yl]-4-fluorophenyl]methanesulfonamide as a

yel low-tan solid. Chromatography (EtOAc) afforded an analytical sample, mp 165-166 *0. Anal . Calc. for ₂ H ₁₂ N ₃ 0 ₄ Cl ₂ P ₁ S ₂ + 1/4 EtOAc:

0, 35.18 ; H - 3.24 ; N, 9.65. Found: 0, 35.09 ; H, 2.97 ; N, 9.90.

Example 16 This example describes the preparation of 4- chloro-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-l-methyl- 5-(methylsulfonyl)-lH-pyrazole. A solution of 1.15 g (3.25 mmole) -chloro-3-

(4-chloro-2-fluoro-5-methoxyphenyl)-l-methyl-5-(methyl¬ sulfonyl)-lH-pyrazole in 30 mL methylene chloride vas chilled to 0*0 and treated vith 4 mL of a 1M methylene chloride solution of BBr ₃ (4.0 mmole) vas added slovly over 5 minutes. The solution vas alloved to stir over¬ night at room temperature. The solution vas vashed tvo times vith vater, dried over anhydrous MgS0 ₄ , and concentrated in vacuo. The residue vas recrystallized from hexane to give l.i g (100%) of 4-chloro-3-(4- chloro-2-fluoro-5-hydroxyphenyl)-l-methyl-5-(methyl¬ sulfonyl)-lH-pyrazole as a beige solid, mp 190.5*0; Anal. Calc. for C ₁₁ H ₉ C1 ₂ F ₁ N ₂ 0 ₃ S ₁ : C,38.95; H,2.67, N,8.26.

Found: 0,38.93; H,2.67; N,8.43. Examples 17, 18, 19 and 20 describe specific vorking embodiments of Process VIII.

Example 17 This example describes the preparation of 2- chloro-5-[4-chloro-l-methyl-5-(methylsulfonyl)-1H- pyrazol-3-yl]-4-fluoro-N-(1-methylethy1)-benzeneaaine. λ solution of 0.5g (0.0015 mol) of 2-chloro-

5-[4-chloro-l-methyl-5-(methylsulfonyl)-lH-pyrazol-3- yl]-4-fluorobenzenamine and 2 mL of 2-iodopropane in 5 L of anhydrous DMF vas stirred at 75*0 for 6 hours, then at 25'C for 2-1/2 days. The reaction mixture vas diluted vith EtOAc, vashed vith tvo times 50 mL of 5% HCl, dried (MgS0 ₄ ) , filtered and concentrated to afford 0.5g red oil. Chromatography (methylene chloride) afforded 0.25g (44%) of 2-chloro-5-[4-chloro-l-methyl

SUBSTITUTESHEET

5- (methy lsulf onyl ) -lH-pyrazol-3-y 1 ] -4 -f luoro-N- ( 1- methylethyl) -benzeneamine as a red solid, mp 118 *0- 121 * C.

Anal . Calc. for C _M H _1$ N ₃ 0 ₂ C1 ₂ P ₁ S ₁ + 1/2 H ₂ 0: C, 43.20 ; H, 4.40 ; N, 10.79.

Found: 0, 42.88 ; H, 4.02 ; N, 10.70.

Exam le 19

This example describes the preparation of N- [ 2-chloro-5-[4-chloro-l-methyl-5- (methylsulf onyl) -1H- pyrazol-3-yl] -4-f luorophenyl] -alanine, ethyl ester. A solution of alanine, N-[2-chloro-5-[4- chloro-2-methyl-5- (methylsulf onyl) -lH-pyrazol-3-yl] -4 - fluorophenyl] - in ethanol vith a catalytic amount of acetyl chloride vas al loved to stir at 25 *0 for 18 hours. This solution vas diluted vith EtOAc, vashed vith vater , tvo times vith 100 mL of aqueous potassium carbonate, dried (MgS0 ₄ ) , filtered and concentrated to afford 0.5g of a yellov oil. Chromatography (CH ₂ C1 ₂ ) afforded 0.17g (20%) of N-[2-chloro-5-[4-chloro-l- methyl-5- (methylsulf onyl) -lH-pyrazol-3-yl] -4-f luoro¬ phenyl] -alanine, ethyl ester as a yellov oil. ¹ HNMR (400 MHz , CDCl _j ) d 1.2 (5 , 3H) , 1.48 (d, 3H) , 3.23 (s , 3H) , 3.8 (q, IH) , 4.15 (q, 2H) , 4.18 (s, 3H) , 4.7 (bs, IH) , 6.6 (d, IH) , 7.1 (d, IH) ppm: ; ¹ FNMR(360MHz, CDC1 ₃ d - 128 (s, IF) ppm.

Anal. Calc. for C _M β ₁ A ⁰ ₄ ^cl ₂ ^F ι ^s ι ^: 0,43.85; H.4.14; N,9.59.

Found: C,43.90; H,4.11; N,9.52.

Exam e 19

This example describes the preparation of N- [2-chloro-5-[4-chloro-l-methyl-5-(methylsulfonyl)-1H- pyrazol-3-yl]-4-fluorophenyl]-N-(methylsulfonyl)methane¬ sulfonamide.

To a solution of 0.5g (0.0015 mol) of 2- chloro-5-[4-chloro-l-methyl-5-(methylsulfonyl)-1H- pyrazol-3-yl]-4-fluorobenzeneamine in 20 mL of methylene chloride vas added 0.33g (0.0033 mol) of triethylamine folloved by 0.37g (0.0033 mol) of methanesul onyl chloride. This mixture vas stirred at 25*0 for 18

EET

hourβ. The reaction mixture vas diluted vith EtOAc, vashed vith three times 100 mL of 5% HCl, dried (MgSO , filtered and concentrated to afford 0.7g (94%) of N-[2- chloro-5-[4-chloro-l-methyl-5-(methylsulfonyl)-1H- pyrazol-3-yl]-4-fluorophenyl]-N-(methylsulfonyl)- methanesulfonamide as an off-vhite solid. Chromato¬ graphy (EtOAc) afforded an analytical sample, mp 234- 237*C.

Anal. Calc. for C ₁₃ H ₁₄ N ₃ 0 _<i Cl ₂ F ₁ S ₃ + 1/4 EtOAc: C,32.17; H,3.14; N,8.18.

Found: C,32.05; H,2.86; N,8.48.

Example 20 This example describes the preparation of 4-chloro-3-(4-chloro-2-fluoro-5-(2-propynyloxy)- phenyl)-l-methyl-5-(methylsulfonyl)-lH-pyrazole

A mixture of 0.87 g (2.5 mmole) of 4-chloro- 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-l-methyl-5- (methylsulfonyl)-lH-pyrazole, 0.4 g (3.0 mmole) K^O _j , and 0.3 mL (3.0 mmole) propargyl bromide vere slurried in 10 mL DMSO at 25*C. The reaction vas stirred at 45*0 for 16 hours. The reaction vas cooled, diluted vith 100 L cold vater, and extracted four times vith ethyl acetate. The ethyl acetate extracts vere vashed vith brine, dried over anhydrous MgS0 ₄ , and stripped in vacuo. The residue vas purified chromatographically using 50% ethyl acetate in hexane as the eluent to give 0.93 g (96%) of 4-chloro-3-(4-chloro-2-fluoro-5-(2- propynyloxy)phenyl)-l-methyl-5-(methylsulfonyl)-1H- pyrazole as a tan solid, mp 135*0. Anal. Calc. for C^^Cl _j ^O _j S,: C44.58; H,2.94, N,7.43. Found: 0,44.75; H,3.08,*N,7.36 Examples 21 and 22 describe specific vorking embodiments of Process IX.

Example 21 This example describes the preparation of 2-

(2-chloro-5-(4-chloro-l-methyl-5- (methylsulf onyl) -1H- pyrazol-3-yl) -4-f luorophenoxy) -propanoic acid.

SUBSTITUTE SHEET

To a slurry of 3.77 g (8.6 mmole) 2-(2-chloro- 5-(4-chloro-l-methyl-5-(methylsulfonyl)-lH-pyrazol-3- yl)-4-fluorophenoxy)-propanoic acid, ethyl ester in 20 mL vater and 20 mL 1,4-dioxane vas added 3.5 mL (8.6 mmole) 10% aqueous NaOH. The reaction became clear after 30 min. and a TLC indicated that the reaction vas complete. The solution vas cooled and the pH adjusted to 3 vith concentrated HCl. The reaction vas extracted vith ethyl acetate. The extracts vere vashed vith vater, dried over anhydrous MgS0 ₄ , and concentrated in vacuo. The residue vas recrystallized from hexane to give 2.9g (83%) of 2-(2-chloro-5-(4-chloro-l-methyl-5- ( ethylsulfonyl)-lH-pyrazol-3-yl)-4-fluorophenoxy)- propanoic acid as a vhite solid, mp 56 ^* 0. Anal. Calc. for C ₁₄ H ₁₃ C1 ₂ F ₁ N ₂ 0 ₅ S ₁ :

C40.80; H,3.19; N,6.81. Found: 0,40.87; H,3.24; N,6.69.

Example 22

This example describes the preparation of 2- (2-chloro-5-(4-chloro-l-methyl-5-(methylsulfonyl)- l-pyrazol-3-yl)-4-fluorophenoxy)-N-methylpropanamide.

To a solution of 1.17g (5.9 mmole) 2-(2- chloro-5-(4-chloro-l-methyl-5-(methylsulfonyl)-1H- pyrazol-3-yl)-4-fluorophenoxy)-propanoic acid in 10 mL methylene chloride vas added 0.8 L (9.6 mmole) oxalyl chloride over 3 minutes, causing the evolution of gas. When this evolution ceased, one drop of DMF vas added and the solution stirred until the gas evolution ceased. The solution vas stripped to dryness in vacuo. The residue vas dissolved in 5 mL THF and at 0 ^* C added to 10 mL of a 40% aqueous solution of methyl amine over 5 minutes. The reaction mixture vas a1loved to stir for 30 minutes at room temperature. The solution vas poured into 150 mL cold vater and extracted vith ethyl acetate. The ethyl acetate extracts vere vashed times vith brine, dried over anhydrous MgS0 ₄ , and stripped in vacuo. The solid vas recrystallized from methylcyclohexane/ethyl acetate to give 0.96g (80%) of 2-(2-chloro-5-(4-chloro-

EET

1-methy1-5-(methylsulfonyl)-lH-pyrazol-3-yl)-4- luoro¬ phenoxy)-N-methylpropanamide as a vhite solid, mp 178*0; 'HNMR (CDC1 ₃ ) ppm: 1.55 (d, 3H) , 2.81 (d, 3H) , 3.23 (s, 3H), 4.17 (β, 3H), 4.64 (q, 3H) , 6.65 (br, IH) , 6.97 (d, IH), 7.22 (d, IH).

Anal. Calc. for C^H^Cl _j F-N _j O-S,: C-42.46; H.3.80; N,9.90.

Found: C 2.60; H,3.68; N.9.86. Examples 23 and 24 describe specific vorking embodiments of Process X. Example 23

This example describes the preparation of (((2-chloro-5-(4-chloro-l-methyl-5-(methylsulfonyl)-1H- pyrazol-3-yl)-4- luorophenyl)methyl)thio)acetic acid, ethyl ester. At 25'C, 1.25g (3.0 mmole) 3-(5-(bromomβthyl)-

4-chloro-2-fluorophenyl)-4-chloro-l-mβthyl-5-( ethyl¬ sulfonyl)-lH-pyrazole, 0.5g (3.3 mmole) K ₂ CO-,, and 0.4 mL (3.3 mmole) ethyl bromoacetate vere slurried in 15 mL acetone. The reaction vas stirred at 20*C for 8 hours. The reaction vas poured into 150 L vater, filtered and air dired. The solid vas recrystallized from methyl- cyclohexane to give l.2g (93%) of (((2-chloro-5-(4- chloro-l-mβthyl-5-(methylsulfonyl)-lH-pyrazol-3-yl)-4- fluorophenyl)methyl)thio)acetic acid, ethyl ester as a vhite solid, ap 110*0.

Anal. Calc. for C-^TCI^N^S-.: 0,42.20; H,3.76; 11,6.15.

Found: 0,42.25; H,3.72; N,6.18. Example 24 This example describes the preparation of 2- chloro-5-(4-chloro-l-methyl-5-(methylsulfonyl)-1H- pyrazol-3-yl)-4-fluoro-N-mβthylbβnzamide.

To a solution of 1.34g (3.7 mmole) 2-chloro- 5-(4-chloro-l-mβthy1-5-(methylsulfonyl)-lH-pyrazol-3- yl)-4-fluorobβnzoic acid in 25 L methylene chloride vas added 1.0 L (11.1 mmole) oxalyl chloride over 3 minutes, causing the evolution of gas. When this evolution ceased, one drop of DMF vas added and the solution stirred until the gas evolution ceased. The

SUBSTITUTESHEET

solution vas stripped to dryness in vacuo. The residue was dissolved in 5 mL THF and at 0 ^* 0 added to 10 L of a 40% aqueous solution of methyl amine over 5 minutes. The reaction mixture was allowed to stir for 30 minutes at room temperature. The solution was poured into 150 mL cold water, filtered, and air dried. The solid was recrystallized from methylcyclohexane/ethyl acetate to give 0.95g (69%) of 2-chloro-5-(4-chloro-l-methyl-5- ( ethylsulfonyl)-lH-pyrazol-3-yl)-4-fluoro-N-raeth l- benzamide as a white solid, mp 187*0.

Anal. Calc. for C^H^Cl^N _j O _j S-: C,41.07; H,3.18; N,11.05.

Found: 0,41.12; H,3.13; N,11.03.

Example ?

This example describes the preparation of 2- chloro-5-(4-chloro-l-methyl-5-(methylsulfonyl)-1H- pyrazol-3-yl)-4-fluorobenzenethiol and is a specific working embodiment of Process XI.

A slurry of 9.3g (0.022 mole) 2-chloro-5-(4- chloro-l-methyl-5-(methylsulfonyl)-lH-pyrazol-3-yl)-4- fluorobenzenesulfonyl chloride and 29g (0.44 mole) zinc powder in 125 mL glacial acetic acid was stirred at 90*0 for 4 hours. The slurry was cooled and filtered through Celite*. The filtrate was poured into 1 liter water and the slurry filtered and air dried. The solid vas recrystallized from ethanol/vater to give 5.8g (74%) of 2-chloro-5-(4-chloro-l-methyl-5-(methylsulfonyl)-1H- pyrazol-3-yl)-4-fluorobenzenethiol as a vhite solid, p lll*C.

Anal. Calc. for -ft-Cl _j F^O _j .S _j : C,37.19; H,2.55; N,7.86; S, 18.05.

Found: C,37.29; H,2.44; N,7.86; S,17.95. Example 26 This example describes the preparation of 4- chloro-3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl- 5-(ethylsulfonyl)-lH-pyrazole and is a specific vorking embodiment of Process XII.

All equipment was flame dried unαer nitrogen. To a solution of 4-chloro-3-(4-chloro-2-fluoro-5- ethoxyphenyl)-l-methyl-5-(methylsulfonyl)-lH-pyrazole (1.25g, 3.5 mmol) in 50 ml dry tetrahydrofuran at -78 ^* c was added a IM solution of n-butyl lithium (3.5 ml, 3.5 mmol) never letting the temperature rise above -60*C. The reaction was stirred for 30 minutes at -78*0 and then methyl iodide (0.49g, 3.5 mmol) was added to the reaction. The reaction was warmed to room temperature and then poured onto ice and extracted into ethyl acetate. The organics were washed twice with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified chromatographically in 1:1 hexane to ethyl acetate solvent system to give 0.5g (39% Yield) of a yellov solid, mp 65*C.

Anal. Calc. for C^H^N _j O _j S^l _j : 0,42.52; H,3.57; N,7.63.

Found: 0,42.53; H,3.80; N,7.71. Example 27 This example describes the preparation of 7- [4-chloro-l-methyl-5-(methylsulfonyl)-lH-pyrazol-3-yl]- 6-fluoro-2H-l,4-benzothiazin-4(3H)-one and is a specific vorking embodiment of Process XIII.

A solution of ((5-(4-chloro-l-methyl-5- (methylsul onyl)-lH-pyrazol-3-yl)-4- luoro-2-nitro- phenyl)thio)acetic acid, ethyl ester (3.0g, 6.6 mmol) in glacial acetic acid (150 ml) vas heated to 80'C and iron (l.5g, 0.0268 mol) vas added all in one portion. The solution vas heated betveen 80*C-100*C for one hour and then cooled, filtered through Celite* and vashed vith vater until a solid falls out of solution. The solid vas filtered off to give l.7g (68%) of the compound named in the first paragraph of this example as a vhite solid, mp 245'C; ¹ HNMR (CDC1 ₃ ) ppm: 7.28 (d, J - 7.2, IH), 6.79 (d, J - 10.8, IH) , 4.1 (S, 3H) , 3.27 (s, 2H) , 3.22 (S, 3H).

Anal. Calc. for C- ₃ H _n Cl ₁ F ₁ N _j 0 ₃ S ₁ : C,41.55; H,2.95; N,11.18.

Found: 0,41.72; H,3.09; N,10.81.

SUBSTITUTESHEET

Tables 3 and 4 shov examples of compounds prepared by Processes II-XIII and/or any combination of these processes as exemplified in Examples 1-27.

TESHEET

Tablt 3. Ffcyafcal DMa for l-Meihyl-3 ι_>l S mcihyliulfonylpyruoles.

IibkJ. (co* 0

No. *s R« 7 phyiical data »(*C)o nD(25*C)

0) c ro

H G -H ω x

=1

Iafafci. (cαa-i)

0) c ro

c

x m

51

Tffbk3. (cool)

ConpowdNo. Rj --S "• ^R7 πφf*)ϊnD ₍ 25*C)

0) c ro

■me

H G H πi

0 ⁾

X m

21

IiblfcJ. (coot)

No. R ] "S R* R physical

CO c ro

Ά c m ω x m

=1

Tf Me 3. (cool) physical data

Compound No. R s Rj e R? >( ^i, V ^, -)ornD(25 ^, C)

147.0 ω I4S.0 c ro 116.0

175.0

% KM

H 152.0

G nD 1.5507 rπ 157.0 ω 124.0-125.0 X m 117.0-118.0

90.0

155.0

171 5 1800

164.0 nD 1.5846 155.0

Ttimmmm («

tn c ro

c

H m

X in

Ittfci. (OMt)

No. R3 Rj R4 R7 physical da mp(*C)ornD(25'C)

tn

G 136 α F α

S 137 α F F

H 131 α F F

H

G 139 Q F NO2

H 140 α F NO2 m i4i α F α

X 142 Q F NO2 in 14 α F α

SUBSTITUTE SHEET

SUBSTITUTE SHEET

SUBSTITUTE SHEET

BSTITUTE SHEET

PRE-EMERCEHCE HERBICIDE TESTS λs noted above, the compounds of this invention have been found to be surprisingly effective as herbicides. The tests for pre-emergence herbicide activity are conducted as follows:

Topsoil is placed in an aluminum pan and compacted to a depth of 0.95 to 1.27 cm from the top of the pan. On the top of the soil is placed a predetermined number of seeds of each of several monocotyledonous and dicotyledonous annual plant species and/or vegetative propagules of various perennial plant species, λ known amount of the active ingredient dissolved or suspended in an organic solvent, e.g., acetone, or water as a carrier is then applied directly to the seed bed, which is then covered with a layer of untreated topsoil to level fill the pan. After treat¬ ment, the pans are moved to a greenhouse bench where they are watered from below as needed to give adequate moisture for germination and growth.

Approximately 10/14 days (usually 11 days) after seeding and treating, the pans are observed and the results (% inhibition) are recorded.

Table 5 below summarizes the results of the pre-emergence herbicidal activity tests of compounds of this invention against weeds. The herbicidal rating shown in Table 5 is the percent inhibition of each plant species.

The plant species usually regarded as weeds which are utilized in one set of tests, the data for which are shown in Table 5, are identified by letter headings above the columns in accordnace with the following legend:

SUBSTITUTE SHEET

Yens- Yellow nutsedge

Anbg - Annual bluegrass

Sejg - Seedling johnsongrass

Dobr - Downy Bro e Bygr - Barnyardgrass

Mogl - Morningglory

Cobu - Cocklebur

Vele - Velvetleaf

In u - Indian Bustard i v - ild buckwheat

Where noted in the tables below, the symbol "C" represents 100% control and the symbol "N" indicates that the species was planted, but no data obtained for one reason or another.

SUBSTITUTESHEET

PREElttRCBMCg TESTS

^■ > PjWtffT IWHIBITIW

Ϊ A S D B M C V I W

• n o o y o o β n i cp . R*t* n b j b ς g b l a b No. kg/h* i g g r r l u β u w

22 1.12 80 C C C C C 70 C C C

23 1.12 30 20 80 30 20 C 80 90 90 C

24 11.21 70 C 90 70 C 90 70 C C C

25 11.21 0 80 80 70 80 70 30 C C 90

26 11.21 0 0 0 0 0 0 0 80 10 0

27 11.21 0 0 50 20 20 30 40 90 70 10

28 11.21 C C 70 80 C C C C C C

29 11.21 20 C 80 40 C C 0 C C 90

30 1.12 80 40 40 10 80 C C C C C

31 11.21 40 10 70 0 C 80 80808080

32 11.21 C C C C C C C C C C

33 11.21 90 C 90 C C C 70 C C C

34 11.21 90 C 90 60 C C 70 C C C

35 11.21 90 C C 50 C C 60 C C C

36 11.21 3030 60 C 9060 60 C C C

37 11.21 608090 30 C C C C C C

38 11.21 8080 80 50 C 90 7090 C C

39 11.21 90 C 90 80 C C C C C C

40 1.12 70 C 704080 C 60 C C 90

41 1.12 7050 30 10 80 C 20 C C C

42 11.21 80809080 C C C C C C

43 1.12 70 C C 50 90 C C C C C

SUBSTITUTE SHEET

TA8 B 5 .-.-.ntlnuod,

PRggMgRCBNCE TESTS

% PIANT INHIBITION

Y A S D B M C V I β n o o y o o β n i

Cpd. Rat* n b j b g g b l b

NO. Jg/ha s g g r r 1 u • u v 44 11.21 90 C C C C C 90 C C C 45 11.21 C C C C C C C C C C 46 1.12 0 0 30 10 0 10 20 7070 C 47 1.12 0 60 80 10 70 80 10 90 C C 48 1.12 0 30 60 20 C 40 20 8090 C 49 1.12 0 90 90 109090 30 C C C 50 11.21 20 80 70 6090 C 20 C 90 C 51 11.21 SO C C 80 C 80 C 90 C C 52 1.12 10 C C 90 90 80 60 C C C S3 1.12 0 10 0 90 4090 50 C C 60 54 1.12 40 10 30 20 0 70 30 C 9090 55 1.12 10 0 0 20 20 C 90 90 C C 56 1.12 109080 60 70 90 70 C C C 57 1.12 10 0 0 0 0 3020 708070 58 1.12 7040 70 10 C 90 C C C C 59 11.21 50 C C 80 C 90 90 C C C 60 1.12 3070 C 90806040 C 70 C 61 1.12 5090 60 5090 C 40 C C C 62 1.12 0 C 80 70 8090 C 80 C 80 63 1.12 40 5090 90 C 80 C C C C 64 1.12 3020 3080 C 70 C 90 C 90 65 1.12 4080 70 50 C C 60 C C C

TITUTESHEET

TABLE 5 .contlnuod.

PRS5MSP<?SE?B TS8TS ^* - P&ΛNT IW«BITI9ff

Ϊ A S D B M C V I W β n o o y o o o n i Cpd. Rate n b j g g b l m b

No. kg/h« β g g r r l u a u w

66 1.12 60 C 90 40 C C 70 C C C

67 1.12 0 C 70 80 C C 80 C C C

68 * 1.12 20 90 60 20 90 90 70 C C 90

69 1.12 60 C 90 50 90 C 30 C C C

70 1.12 30 C 90 40 C C 30 C C C

71 1.12 30 C 90 40 C 80 30 C C 90

72 1.12 60 20 60 20 80 C C 90 90 90

73 1.12 50 10 60 30 50 90 80 80 90 80 # 1.12 40 0 80 10 20 90 60 80 90 80

74 1.12 70 20 70 0 80 C C C C C

75 1.12 50 0 70 20 80 C 40 C 90 C

76 1.12 60 20 30 20 70 C 90 90 90 80

77 1.12 20 0 20 20 80 C 70 C 80 80

78 1.12 60 C 90 50 C C C C C C

79 1.12 90 C 70 20 90 C C C C C

80 1.12 60 10 70 20 20 C 60 90 90 90

81 1.12 60 C C 90 C 90 80 C C C

82 1.12 50 50 80 20 90 C 90 C C 90

83 1.12 70 C C C C C 60 C C C

84 1.12 0 80 70 80 80 C 80 C C C

85 11.21 90 90 90 90 90 90 C C C C

86 1.12 0 20 30 20 20 40 20 40 80 90

SUBSTITUTE SHEET

TABLE 5 Icontlnuod> PREBMERCENCB TESTS

^* t PUPT IWiWTWE

Y A S D B M C V I

• n ^' « o y o o « n i

Cpd. Rat* n b j b g g b l a b NO. kg/ha i g g r r l u a u w

87 1.12 0 70 80 80 60 C 80 C C C

88 1.12 20 40 80 80 60 C 80 C C C

89 1.12 0 20 40 30 80 80 80 C C C

90 _ \2 0 0 0 20 30 60 30 C C C

91 1.12 20 10 10 50 70 60 60 C C C

92 1.12 0 80 40 60 50 C 60 C C 90

93 11.21 0 10 0 10 50 20 0 80 80 10

94 11.21 60 C C 70 C 90 30 C C C

95 11.21 70 C C 70 C C 80 C C C

96 11.21 70 C C C C C 20 C C C

97 11.21 20 20 40 20 80 40 20 C C 80

98 11.21 0 0 20 0 0 0 0 0 0 30

99 11.21 0 0 0 0 0 0 0 20 0 0

100 11.21 0 0 0 0 0 0 0 0 0 0

101 11.21 0 070 080 60 20 SO 70 0

102 11.21 403060 3080 SO 060 C 90

103 11.21 208C 80 20 8090 70908090

104 11.21 40 C 808090 7080 C C C

105 11.21 408090 70 908060 C C 70

106 11.21 06070 30 604070 C 9090

107 11.21 409070 60 C 70 C C C 50

108 11.21 30909070 80 9080 C C C

ESHEET

TABLE S fcanfclnuad. PREEMERCEBCE TESTS

} PLMT IlffilBITIWf

Y A S D B M C V I W

• n * o y o o * n i π b j b g g b l a b

• g g r r l u a u

70 C C 60908090 C C C 80 C 90 80909090 C C 80 40 C 70 70 C 20 C C C 70 80 C C 70 90 C 70 C C C 6080 90 50 C 306090 C 90 0 0 0 20207020303020 C 40 9080 C C C C C C 90 0 80 20 609060 C C C 70 8090 70 C 7090 C C C 0 0 0 0 0 0 0 80 20 10 0 0 0 0 0 0 O 302010 0 0 0 0 0 0 0 03020 0 0 0 0 0 0 O 20 0 0 0 0 0 0 0 0 O 10 1020 409090 20907040 809090 502040 20 70702090 C 50 0 0 0 0 020 0704040 306040 2080 7020 C 9080 80 C C C C C C C C C 80 C 90 709090 C C C C 4070 60908080 C C C C 40 C 808090 C 60 C C C

SUBSTITUTE SHEET

TM« 5 fggn nyrt)

PREEMEROBNCE TESTS % PLANT INHIBITION

Y A S D B M C V I W

• n * o y o o * n i Cpd. Rat* n b j b g g b l a b

No. kg/ha a g g r r l β u w

131 1.12 80 20 80 20 70 C 30 C 90 C

132 1.12 0 30 80 C 80 80 30 C C C

133 1.12 10209040 10 80 30 C 80 C

134 1.12 C C 9090 C 90 C C C C

135 1.12 C 1080 10 C C 60 C C C

136 1.12 109090 40 C C 20 C C C

137 11.21 90 C C C C C C C C C

138 11.21 0 0 0 0 0 0 0 80 20 70

139 11.21 20 90 80 90 80 90 90 C C C

140 11.21 80 60 C 20 C C C C C C

141 1.12 30907060808020 C 9090

142 11.21 60 C 90209090 60 C C C

143 1.12 04020 10202080 308070

144 11.21 020 020 0 0 0202020

145 11.21 0 10 1020 30 20 30302040

146 11.21 60 C C C C 80 30 C C C

147 11.21 60 C 9070 C 8020 C C 90

148 11.21 80 C C C C 9050 C C C

149 11.21 0 0 0 0 0 50 20 70 60 80

150 11.21 0 0 0 0 0 0 0 0 0 0

151 11.21 30 90 90 30 90 C 80 C C C

152 11.21 0 0 0 0 0 0 0 0 0 0

TE SHEET

TABLE 5 feontlnu*d. PREEMERGENCE TESTS

^* . PMNT It-HIBITIPt

Y A S D B M C V I W • n * o y o o * n i n b j b g g b l m b a g g r r l u β u w

30 60 C 70 90 80 40 C C C

70 C 80 80 90 C C C C C

80 C C 60 C C C C C C

0 C 90 30 90 90 90 C C 80 70 C 90 C C C C C C C 10 10 80 40 30 50 40 80 20 30

0 0 0 0 0 0 0 0 0 0

t Observation ea. 4-weeks

SUBSTITUTESHEET

POST-EMERGENCE HERBICIDE TESTS The post-emergence herbicidal activity of some of the various compounds of this invention vas demon- strated by greenhouse testing in the following manner. Topsoil is placed in aluminum pans having holes in the bottom and compacted to a depth of 0.95 to 1.27 cm from the top of the pan. A predetermined number of seeds of each of several dicotyledonous and monocotyledonous annual plant species and/or vegetative propagules for the perennial plant species are placed on the soil and pressed into the soil surface. The seeds and/or vegetative propagules are covered vith soil and leveled. The pans are then placed on a bench in the greenhouse aid vatered from belov as needed. After the plants reach the desired age (tvo to three veeks) , each pan, is removed individually to a spraying chamber and sprayed by means of an atomizer, operating at a spray pressure of 170.3 kPa (10 psig) at the application rates noted. In the spray solution is an amount of an emulsifying agent mixture to give a spray solution or suspension vhich contains about 0.4% by volume of the emulsifier. The spray solution or suspension contains a sufficient amount of the candidate chemical in order to give application rates of the active ingredient corresponding to those shown in Table 2, while applying a total amount of solution or suspension equivalent to 1870 L/Ha (200 gallons/acre) . The pans were returned to the greenhouse and watered as before and the injury to the plants as compared to the control is observed at approximately 10- 14 days (usually 11 days) and in some instances observed again at 24-28 days (usually 25 days) after spraying. The post-emergent herbicidal activity shown in Table 6 is the percent inhibition of each plant species.

SUBSTITUTESHEET

POST-EMERGENCE TESTS % PLANT INHIBITION

Y A S D B M C V I W

• n - * o y o o * n i Cpd. Rat* n b j b g g b l m b

No. kg/ha s g g r r l u * u w

22 1.12 40 40 30 50 30 C C C 80 80

23 1.12 50 20 40 40 80 C C C 60 C

24 11.21 40 60 80 30 90 80 70 C 90 C

25 β 11.21 10 0 10 0 0 20 20 30 40 90

26 11.21 0 0 10 0 0 20 20 20 30 0

27 11.21 0 0 0 0 10 30 10 90 50 70

28 11.21 20 10 10 0 10 80 C C 90 C

29 11.21 20 10 60 10 0 20 20 C 70 60

30 1.12 0 10 30 20 30 90 90 90 80 80

31 9 11.21 0 20 20 0 20 80 80 C 50 60

32 11.21 40 90 90 C 90 C 90 C 90 C

33 11.21 30 90 C C C 90 C C C C

34 11.21 2040 70 10 70 8080 C 9080

35 11.21 30 10 70 0 C C 80 C 8070

36 β 11.21 2020 50 3040 6060 C 70 C

37 11.21 30809090 C C C C C C

38 t 11.21 206070 070 C 60 C 6060

39 11.21 308080 2090 C 50 C 9080

40 1.12 409090 C C 90 C C 9090

41 1.12 10107080 C C 60 C 9070

42 11.21 60909040 80 C C C C C

43 1.12 20 0 40 30309090 C 8070

SUBSTITUTE SHEET

TABLE 6 .continued. POST-EMERGENCE TESTS % PLANT INHIBITION

Y A S D B M C V I W β n e o y o o β n i n b j b g g b l m b ■ g g r r l u e u w

40 C C C C C C C C C

30 90 C 90 C C C C C C

20 0 0 0 0 30 30 30 30 60

20 0 20 20 0 30 30 50 40 80

10 20 20 20 20 C 60 C 40 80

0 10 0 0 0 40 30 50 40 60 20 30 90 SO SO 70 60 90 C C

0 20 40 20 50 90 C C 80 C 20 40 20 20 40 90 60 C 70 C 20 20 80 50 90 90 C C 80 90

0 20 40 20 10 30 40 70 60 60 30 10 40 20 80 C C C 70 C 20 50 20 20 0 90 90 C 70 90

0 0 0 0 0 20 20 60 50 80 20 10 20 0 30 C 90 C 70 C 20 60 80 20 80 C 90 90 80 C 20 20 60 20 60 C C C 50 80 30 60 90 C C 60 C C 80 90 20 50 80 SO 50 50 80 90 70 80 3080 C C C C C 90 90 C 30 90 C C 90 C C C C C 30 60 80 90 90 C C 90 C 90

TITUTE SHEET

TΛB1I S (ggn nutd)

POST-EMERGENCE TESTS % PLANT INHIBITION

Y A S D B M C V β n e o y o o e

Cpd. Rat* n b j b g g b l No. kg/ha a g g r r l u *

66 1.12 30 60 80 50 40 C 80 C

67 1.12 30 7070 80 709090 C

68 1.12 304090 50 30 60 6090

69 1.12 40 50 50 90 70 C C C

70 1.12 20 30 20 20 20 C C C

71 1.12 2090 90 90 80 C C 90

72 1.12 10 0 50 20 50908090

73 1.12 30 10 80 20 C 80 90 C

74 1.12 20 20 70 40 60 C C C

75 1.12 50 0 3020 40 C C C

76 1.12 20 20 80 50 70 C C 90

77 1.12 20 20 60 30 60 C C 90

78 1.12 20 30 30 50 30 C 8090

79 1.12 20 0 70 20 0 C 9090

80 1.12 30 10 70 20 60 C C 90

81 1.12 10 C C C C 90 C C

82 1.12 2020 30 0 08080 C

83 1.12 1090 C C C C C 90

84 1.12 20 70 C 90 90 90 70 C

85 11.21 30 60 90 6090 C 9090

86 1.12 103020 30 20 60 50 C

SUBSTITUTE SHEET

TABLE 6 .continu*d. POST-EMERGENCE TESTS % PLANT INHIBITION

Y A S D B M C V I W

• n e o y o o e n i

Cpd. Rat* n b j b g g b l m b

No. kg/ha β g g r r l u β u w

87 1.12 10 40 80 C C C C C 9090

88 1.12 20 70 80 C C C C C C 80

89 1.12 10 5060 704090909090 80

90 1.12 0 208090 909080 C 80 80

91 1.12 10 4090909080 C 909080

92 1.12 40 707080 30 C C C 9040

93 11.21 0 020 10 708080 C 90 70

94 11.21 10 20 0 0 020807060 40

95 11.21 10 20 20 0 020 30 C 90 C

96 11.21 10 2090 5090 6030 C 40 C

97 11.21 0 0 0 0 0 2030 6030 80

98 11.21 0 0 0 0 0 10 10 0 0 0

99 11.21 0 0 0 0 0 0 0 30 0 0

100 11.21 0 020 020 0 0301020

101 11.21 0 020 0 0302020 040

102 11.21 0 1020 10 3020 10302060

103 11.21 0 0 0 0 0 0 0 0 0 60 + 11.21 0 0 20 0 30 30 50 50 30 60

104 11.21 10 20 40 0 40 50 60 80 70 C

105 11.21 20 60 80 30 30 80 70 C 80 C

106 11.21 0 0 0 0 0 40 40 50 40 80

107 11.21 20 50 80 SO 60 C C C C C

TABLE 6 t continued , POST-EMERGENCE TESTS % PLANT INHIBITION

Y A S D B M C V I W e n e o y o o e n i

Cpd. Rate n b j b g g b l m b

No. kg/ha ■ g g r r l u e u v

108 11.21 30 30 60 20 30 60 50 90 50 C

109 11.21 30 30 40 20 40 30 30 90 50 C

110 11.21 30 70 80 40 50 50 70 C 70 C

111 11.21 0 40 20 0 10 20 10 70 80 50

112 11.21 20 60 90 40 50 40 70 C 80 C

113 1.12 0 0 10 0 10 10 10 20 0 90

114 11.21 0 0 0 0 0 0 30 20 0 40

115 11.21 30 30 C 90 90 90 C C C C

116 11.21 20 20 60 30 50 80 70 C 50 60

117 β 11-21 10 50 50 40 80 60 50 C 90 C

118 11.21 0 0 0 0 0 20 0 20 10 0

119 11.21 10 0 0 0 0 0 0 0 0 0

120 11.21 0 0 0 0 0 0 0 10 0 0

121 11.21 0 0 0 0 0 20 20 0 0 0

122 11.21 0 0 0 0 0 20 0 20 0 20

123 11.21 020 0 0 0 20 506020 C

124 11.21 0 0 0 0 0 0 0302020

125 11.21 0 0 0 0 0 0 0 20 0 0

126 11.21 0 0 0 0 020 2040 20 50

127 11.21 109090 70 C C 70 C C C

128 1.12 105040 80 80808080 60 C

129 11.21 1030 30 0 30 80 50 C 80 C

SUBSTITUTE SHEET

TABLE 6 t continue POST-EMERGENCE TESTS % PLANT INHIBITION

Y A S D B M C V I W β n -β o y o o β n i n b j b g g b l m b i g g r r l u e u w

30 60 40 50 20 C C C C C

40 20 60 20 70 C 90 C 40 80

30 30 40 80 80 C C C 80 80

10 40 40 80 90 90 90 C 40 40

0 90 80 C C C C C 80 50 20 10 80 0 60 C 80 C 50 50 10 20 60 30 20 80 80 C 90 90 20 C C C C C 90 C C C

0 0 20 0 0 40 30 40 20 C 10 30 80 30 20 50 40 C C C 20 10 80 10 70 60 50 C 70 70

0 90 90 80 70 80 70 C 70 70 10 20 80 20 10 40 30 80 30 70 20 90 90 C 70 C C C 90 50

0 20 0 20 0 20 20 30 20 50 10 0 0 0 10 20 20 40 40 20 10 70 80 90 90 60 60 C 80 C

0 60 80 30 80 80 70 C 90 C 10 40 40 0 20 20 30 C 90 C

0 0 0 0 0 10 10 10 0 40

0 0 0 0 0 20 0 0 0 20 10 0 0 0 0 60 60 80 60 C

TITUTE SHEET

TABLE 6 ( continued \ POST-EMERGENCE TESTS % PLANT INHIBITION

Y A S D B M C V I W e n e o y o o e n i Cpd. Rate n b j b g g b l m b

No. kg/ha t g g r r l u β u w

152 11.21 0 0 0 0 0 0 0 0 0 0

153 11.21 10 10 10 020 403080 80 C

154 1.12 20 C 80 80 70 7080 C C 80

155 1.12 10 90 80 70 90 70 C C 90 30

156 1.12 10 80 C 30 509040 C 90 70

157 1.12 20 90 90 90 90 C C C 90 80

158 1.12 10 70 70 60 40 C C C 70 50

159 11.21 0 0 0 0 0 20 10 10 0 0

9 Poor cocklebur response + Duplicate teat

SUBSTITUTESHEET

The herbicidal compositions of this invention, including concentrates which require dilution prior to application, may contain at least one active ingredient and an adjuvant in liquid or solid form. The compositions are prepared by admixing the active ingredient vith an adjuvant including diluents, extenders, carriers, and conditioning agents to provide compositions in the form of finely-divided particulate solids, granules, pellets, solutions, dispersions or emulsions. Thus, it is believed that the active ingredient could be used vith an adjuvant such as a finely-divided solid, a liquid of organic origin, vater, a vetting agent, a dispersing agent, an emulsifying agent or any suitable combination of these. Suitable vetting agents are believed to include alkyl benzene and alkyl naphthalene sulfonates, sulfated fatty alcohols, amines or acid amides, long chain acid esters of sodium isothionate, esters of sodium sulfosuccinate, sulfated or sulfonated fatty acid esters, petroleum sulfonates, sulfonated vegetable oils, ditertiary acetylenic glycols, polyoxyethylene derivatives of alkylphenols (particularly isooctylphenol and nonylphenol) and polyoxyethylene derivatives of the mono-higher fatty acid esters of hexitol anhydrides (e.g., sorbitan) . Preferred dispersants are methyl cellulose, polyvinyl alcohol, sodium lignin sulfonates, polymeric alkyl naphthalene sulfonates, sodium naphthalene sulfonate, and polymethylene bisnaphthalene sulfonate. Wettable povders are vater-dispersible compositions containing one or more active ingredients, an inert solid extender and one or more wetting and dispersing agents. The inert s iid extenders are usually of mineral origin such as the natural clays, diato aceous earth and synthetic minerals derived from silica and the like. Examples of such extenders include kaolinites, attapulgite clay and synthetic magnesium silicate. The vettable povders compositions of this invention usually contain from above 0.5 to 60 parts

T

(preferably from 5-20 parts) of active ingredient, from about 0.25 to 25 parts (preferably 1-15 parts) of vetting agent, from about 0.25 to 25 parts (preferably 1.0-15 parts) of dispersant and from 5 to about 95 parts (preferably 5-50 parts) of inert solid extender, all parts being by weight of the total composition. Where required, from about 0.1 to 2.0 parts of the solid inert extender can be replaced by a corrosion inhibitor or anti-foaming agent or both. Other formulations include dust concentrates comprising from 0.1 to 60% by weight of the active ingredient on a suitable extender; these dusts may be diluted for application at concentrations within the range of from about 0.1-10% by veight. Aqueous suspensions or emulsions may be prepared by stirring a nonaqueous solution of a water- insoluble active ingredient and an emulsification agent vith vater until uniform and then homogenizing to give stable emulsion of very finely divided particles. The resulting concentrated aqueous suspension is charac¬ terized by its extremely small particle size, so that vhen diluted and sprayed, coverage is very uniform. Suitable concentrations of these formulations contain from about 0.1-60%, preferably 5-50% by veight of active ingredient, the upper limit being determined by the solubility limit of active ingredient in the solvent. Concentrates are usually solutions of active ingredient in water-immiscible or partially water-immiscible solvents together with a surface active agent. Suitable solvents for the active ingredient of this invention include dimethylformamide, dimethylsulfoxide, N- methylpyrrolidone, hydrocarbons, and water-immiscible ethers, esters, or ketones. However, other high strength liquid concentrates may be formulated by dissolving the active ingredient in a solvent then diluting, e.g., with kerosene, to spray concentration.

SUBSTITUTESHEET

The concentrate compositions herein generally contain from about 0.1 to 95 parts (preferably 5-60 parts) active ingredient, about 0.25 to 50 parts (preferably 1-25 parts) surface active agent and where required about 5 to 94 parts solvent, all parts being by veight based on the total veight of emulsifiable oil. Granules are physically stable particulate compositions comprising active ingredient adhering to or distributed through a basic matrix of an inert, finely- divided particulate extender. In order to aid. leaching of the active ingredient from the particulate extender, a surface active agent such as those listed hereinbefore can be present in the composition. Natural clays, pyrophyllites, illite, and vermiculite are examples of operable classes of particulate mineral extenders. The preferred extenders are the porous, absorptive, preformed particles such as preformed and screened particulate attapulgite or heat expanded, particulate vermiculite and the finely-divided clays such as kaolin clays, hydrated attapulgite or bentonitic clays. These extenders are sprayed or blended vith the active ingredient to form the herbicidal granules.

The granular compositions of this invention may contain from about 0.1 to about 30 parts by weight of active ingredient per 100 parts by weight of clay and 0 to about 5 parts by weight of surface active agent per 100 parts by weight of particulate clay.

The compositions of this invention can also contain other additaments, for example, fertilizers, other herbicides, other pesticides, safeners and the like used as adjuvants or in combination with any of the above-described adjuvants. Chemicals useful in combina¬ tion with the active ingredients of this invention included, for example, triazines, ureas, sulfonylureas, carbamates, acetamides, acetanilides, uracils, acetic acid or phenol derivatives, thiolcarbamates, triazoles, benzoic acid derivatives, nitriles, heterophenyl ethers,

TITUTESHEET

nitrophenyl ethers, diphenyl ethers, pyridines and the like such as:

Heterocyclic Nitroσen/Sulfur Derivatives 2-Chloro-4-ethylamino-6-isopropylamino-a-triazine 2-Chloro-4,6-bis(isopropylamino)-s_-triazine 2-Chloro-4,6-bis(ethylamino)-a-triazine 3-Isopropyl-lH-2,l,3-benzothiadiazin-4-(3H)-one 2 ,2- dioxide 3-Amino-l ,2, -triazole δ^-Dihydrodipyridofl^-^^l'-cJ-pyrazidiinium salt 5-Bromo-3-isopropyl-6-methyluracil 1,1'-Dimethyl-4 ,4•-bypyridinium

2-(4-Isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-3- quinolinecarboxylie acid Isopropylaminβ salt of 2-(4-isopropyl-4-methyl-5- oxo-2-imidazolin-2-yl)nicotinic acid Methyl 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2- yl)-m-toluate and methyl 2-(4-isopropyl-4-methyl- 5-oxo-2-imidazolin-2-yl)-p-toluatβ 5-(Trifluoromethyl)-4-chloro-3-(3'-[1-ethoxycarbonyl]- ethoxy-4'-nitrophenoxy)-1-methylpyrazol; 5-(Trifluoromethyl)-4-chloro-3-(3•-methoxy-4'-nitro¬ phenoxy)-1-methylpyrazole;

5-(Trifluoromethyl)-4-chloro-3-(3•-[l-butoxycarbonyl]- ethoxy- *-nitrophenoxy)-4-mβthylpyrazol;

5-(Trifluoromethyl)-4-chloro-3-(3•-methylsulfamoylcar- bony1 propoxy-4•-nitrophenoxy)-4-methylpyrazol; 5-(Trifluoromethyl)-4-chloro-3-(3'-propoxycarbonyl- methyloxime-4•-nitrophenoxy)-1-methylpyrazole; (+)-2-[4-[[5-(Trifluoromethyl)-2-pyridinyl]oxy]phenoxy]- propanoic acid (9CI) . S,S-dimethyl-2-(di luoromethyl)-4-isobutyl-6- trifluoromβthyl-3,5-pyridinβdicarbothioatβ; 3-Pyridinecarboxylic Acid, 2-(difluoromethyl)-5-(4,5- dihydro-2-thiazolyl)-4-(2-methylpropyl)-6-(tri- fluoromethyl)-, methyl ester;

3 ,5-Pyridinedicarboxylic acid, 2-(difluoromethyl)-4-(2- methylpropyl)-6-(trifluoromethyl)-, dimethyl ester;

SUBSTITUTE SHEET

3 , 5-Pyridinedicarbothioic acid, 4- (cyclopropylmethyl) -2- ( dif luoromethyl) -6- (trif luoromethyl) -, s, S-dimethyl ester; Sulf oximine,. N- (diethoxyphosphinyl) -S-methyl-S-phenyl-

Ureas and Sulfonvlureas N- ( 4 -Chlorophenoxy ) pheny 1-N , N-dimethylurea N, N-dimethyl-N ' - (3-chloro-4-methylphenyl) urea 3- ( 3 , 4-dichlorophenyl) -1 , l-dimethylurea ι , 3-Dimethyl-3- (2-benzothiazolyl) urea 3- (p-Chlorophenyl) -1 , l-dimethylurea l-Butyl-3- (3 , 4-dichlorophenyl) -1-methylurea 2-Chloro-N[ (4-methoxy-6-methyl-l , 3 , 5-triazin-2-yl) aminocarbonyl ] -benzenesulf onamide Methyl 2- ( ( ( ( (4 , 6-dimethyl-2-pyrimidinyl) amino) - car bony 1) amino) sulf onyl) benzoate Ethyl 1- [methyl 2- ( ( ( ( (4 , 6-dimethyl-2-pyrimidinyl) - amino) car bony 1) amino) sulf onyl) ] benzoate Methy 1-2 ( ( 4 , 6-dimethoxy pyrimidin-2-yl) aminocar- bonyl) amino sulf onyl methyl) benzoate

Methyl 2- ( ( ( ( (4-methoxy-6-methyl-l, 3 , 5-triazin-2-yl) - amino) car bonyl) amino) sulf onyl) benzoate N- [ 3- (N, N-dimethylcarbamoyl) -2-pyridin-2-yl] sulf onyl- N ' - ( 4 , 6-dimethoxypyr imidin-2-y 1 ) urea N-[ ( 3-ethy lsulf onyl) -2-pyridin-2-yl] -sulf onyl-N* - (4 , 6- dimethoxy-pyrimidin-2-yl) urea N- ( 2 -methoxy car bony lpheny 1 sulf onyl ) -N ' - ( 4 , 6-bis- dif luoromethoxypyrimidin-2-yl) urea

Carbamates /Thiolcarbamates 2-Chloroallyl diethyldithiocarbamate

S- ( 4 -chlorobenzy 1 ) N , N-diethy lthiolcarbamate Isopropyl N- (3-chlorophenyl) carbamate s-2 , 3-dichloroallyl N, N-diisopropy lthiolcarbamate S-N , N-dipropy lthiolcarbamate S-propyl N, N-dipropy lthiolcarbamate

S-2 , 3 , 3-trichloroallyl-N, N-diisopropy lthiolcarbamate

SUBSTITUTE SHEET

^etaaides/Acetanilldβs/Anilines/Aniidaa 2-Chloro-N,N-diallylacetamide N,N-dimethyl-2,2-diphenylacetamide

N-(2,4-dimethylthien-3-yl)-N-(l-methoxyprop-2-yl)-2- chloroacetamide

N-(lH-pyrazol-l-ylmethyl-N-(2,4-dimethylthien-3-yl)-2- chloroacetamide N-(l-pyrazol-l-ylmethyl)-N-(4,6-dimethoxypyrimidin-5- yl)-2-chloroacetamide N-(2,4-dimethyl-5-[[[ (trifluoromethyl)sulfonyl]amino]- phenyl]acetamide N-Isopropyl-2-chloroacetanilide N-Isopropyl-1-(3,5,5-trimethylcyclohexen-l-yl)-2- chloroacβtamide 2• ,6•-Diethyl-N-(butoxymethyl)-2-chloroacetanilide

2• ,6'-Diethyl-N-(2-n-propoxyethyl)-2-chloroacetanilide 2' ,6'-Dimethyl-N-(l-pyrazol-l-ylmethyl)-2-chloro- acetanilide 2 ^• ,6 ^• -Diβthyl-N-methoxymethyl-2-chloroacetanilide 2 ^, -Methyl-6'-βthyl-N-(2-methoxyprop-2-yl)-2-chloro- acetanilide 2•-Methy1-6•-ethyl-N-(ethoxymethyl)-2-chloroacet¬ anilide a , a ,c-Tri luoro-2,6-dinitro-N,N-dipropyl-p-toluidine N-(l ,l-dimethylpropynyl)-3,5-dichlorobenzaaιide

Acids/Esters/Alcohols 2,2-Dichloropropionic acid 2-Methy1-4-chlorophenoxy cetic acid 2,4-Dichlorophenoxyacetic acid Methy1-2-[ -(2, -dichlorophenoxy)phenoxy]propionate 3-Amino-2,5-dichlorobenzoic acid 2-Methoxy-3,6-dichlorobenzoic acid 2,3,6-Trichlorophenylacetic acid N-l-naphthylphthalamic acid Sodium 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2- nitrobenzoate 4,6-Dinitro-o-sβc-butylphenol N-(phosphonomethyl)glycine and its salts

SUBSTITUTESHEET

Butyl (R)-2-[4-[(5-(trifluoromethyl)-2-pyridinyl)oxy]- phenoxy] propanoate

Ether? 2, -Dichlorophenol-4-ni-trophenyl ether 2-Chloro-$, δ,5-trifluoro-p-tolyl-3-ethoxy-4-nitro- diphenyl ether 5-(2-chloro-4-trifluoromethylphenoxy)-N-methylsul- fonyl 2-nitrobenazmide l'-(Carboethoxy) ethyl 5-[2-chloro-4-(trifluoro- methyl)phenoxy]-2-nitrobenzoate

Miscellaneous 2,6-Dichlorobenzonitrile Monosodium acid methanearsonate Disodium methanearsonate 2-(2-chlorophenyl)methyl-4,4-dimethyl-3-isoxa- zolidinone 7-όxabicyclo (2.2.1) heptane, l-methyl-4-(l-methyl- ethy1)-2-(2-methylphenylmethoxy)-, exo- Glyphosate and salts thereof. Fertilizers useful in combination vith the active ingredients include, for example, ammonium nitrate, urea, potash and superphosphate. Other useful additaments include materials in vhich plant organisms take root and grow such as compost, manure, humus, sand and the like.

TITUTESHEET

Herbicidal formulations of the types described above are exemplified in several illustrative embodiments below.

I. E ulsifiable Concentrates eight Perςept

A. Compound No. 22 4.0 Free acid of complex organic phosphate or aromatic or aliphatic hydrophobe base (e.g., GAFAC RE-610, registered trademark of GAF Corp.) 3.5

Polyoxyethylene/polyoxypropylene block copolymer with butanol (e.g., Tergitol XH, registered trademark of Union Carbide

Corp.) 1.5 Xylene 5.34

Monochlorobenzene 85.66

100.00

B. Compound No. 36 3.0 Free acid of complex organic phosphate of aromatic or aliphatic hydrophobe base (e.g., GAFAC RE-610) 4.0 Polyoxyethylene/polyoxypropylene block copolymer with butanol (e.g., Tergitol XH) 1.60

Xylene 4.75 Monochlorobenzene 86.65

100.00

C. Compound No. 43 2.5 Free acid of complex organic phosphate or aromatic or aliphatic hydrophobe base (e.g., GAFAC RE-610, registered trademark of GAF Corp.) 4.0

Polyoxyethylene/polyoxypropylene block copolymer with butanol (e.g., Tergitol XH, registered trademark of Union Carbide Corp.) 1.5

Cyclohexanone 5.5

Aromatic 200 86.5

100.00

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Weiαht Percent

D. Compound of No. 52 5.0 Free acid of complex organic phosphate of aromatic or aliphatic hydrophobe base (e.g., GAFAC RE-610 3.00

Polyoxyethylene/polyoxypropylene block copolymer with butanol (e.g., Tergitol XH) Phenol Monochlorobenzene

E. Compound No. 53 Free acid of complex organic phosphate or aromatic or aliphatic hydrophobe base (e.g., GAFAC RE-610, registered -ademark of GAF Corp.) 4.50

-.lyoxyethylene/polyoxypropylene block copolymer with butanol (e.g., Tergitol XH, registered trademark of Union Carbide Corp.) 1.00 Isophorone 5.3

Emerset 2301 87.6$

100.00

F. compound No. 54 4.50 Free acid of complex organic phosphate of aromatic or aliphatic hydrophobe base (e.g., GAFAC RE-610 3.00 Polyoxyethylene/polyoxypropylene block

• copolymer with butanol (e.g., Tergitol XH) 2.00

Cyslohexanone 4.75 7-Butyrolactone 85.75

100.00

ITUTESHEET

A.

B.

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wejght ercen

III. Wettable Powders

A. Compound No. 83 25.0 Sodium lignosulfonate 5.0 Kaolin 60.0

Amorphous silica (synthetic) 10.0

100.0

B. Compound No. 85 80.0 Sodium dioctyl sulfosuccinate 1.5 Alkyl Aryl Sulfonate 3.5

Kaolin 5.0

Amorphous silica (synthetic) 10.0

100.0

C. Compound No. 93 10.0 Sodium lignosulfonate 3.0

Sodium N-methyl-N-oleyl-taurate l.o

Amorphous silica (synthetic) 10.0

Kaolinite clay 76.0

100.0 D. Compound No. 96 30.0

Sodium lignosulfonate 4.0

Sodium dioctyl sulfosuccinate 1.0

Attapulgite clay 60.0

Amorphous silica (synthetic) 5.0 100.0

E. Compoud No. 102 75.0 Sodium dioctyl sulfosuccinate 1.25 Sodium lignosulfonate 3.0 Kaolin 10.75 Amorphous silica synthetic 10.0

100.0

F. Compound No. 106 15.0 Sodium lignosulfonate 3.0 Sodium N-methyl-N-oleyl-taurate 1.0 Amorphous silica (synthetic 10.0

Kaolinite clay 71.0

100.0

ESHEET

TV. Granules

A. Compound No. 36 Dipropylene Glycol ' Granular attapulgite (24/48 mesh)

B. Compound No. 43

Ethylene Glycol (24/48 mesh) Granular Montmorillonite

c. compound No. 49 Ethylene glycol Granular Pyrophyllite (24/48 mesh)

D. Compound No. 52

Dipropylene Glycol

Granular Pyrophyllite (24/48 mesh)

E. Compound No. 53 Granular Bentonite (24/48 mesh)

F. Compound No. 54 Amorphous silica (synthetic) Granular Montmorillonite (24/48 mesh)

G. Compound No. 58 Ethylene glycol

Granular Montmorillonite (24/48 mesh)

H. Compound No. 59

Dipropylene Glycol

Granular Bentonite (30/60 mesh)

SUBSTITUTESHEET

Weiσht Percent V. Suspension Concentrates

A. Compound No. 66 32.5 Sodium Naphthalene-Formaldehyde Condensate (Morvet D-425) 3.0

Propylene Glycol 10.0 Sodium Diisopropyl Naphthalene Sulfonate

(Morvet IP) 1.0

Xanthan Gum (Kelzan S) 0.2 Water 52.3

100.0

B. Compound No. 81 37.0 Sodium Lignin Sulfonate (Polyfon H) 5.0 EO/PO Block Copolymer (Pluronic P-105) 2.0 Propylene Glycol 10.0

Xanthan Gum 0.2 water 45.8

100.0

C. Compound No. 83 25.0 Sodium Lignin Sulfonate (Polyfon H) 4.0

Sodium N-Methyl-N-oleyltaurate

(Igepon T-77) 1.0

Ethylene Glycol 10.0

Xanthan Gum (Rhodopol MD50) 0.2 Magnesium Aluminum Silicate (Van Gel-B) 0.2 ater 59.6

100.0

D. Compound No. 85 30.0 Sodium naphthalene sulfonate formaldehyde condensate 5.0

Glycerine 8.0

Methyl Cellulose (Methocel A15C) 0.3

Magnesium Aluminum Silicate (Van Gel B) 0.2

Water 56.5 100.0

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G.

A.

SUBSTITUTE SHEET

Weight Percent

B. Compound No. 81 0.5 Polyurea shell wall 6.82 Reax* C-21 (dispersant) 1.0 NaN0 ₃ (electrolyte) 5.0 Aromatic 200 (solvent) 45.0 Water 41 _* 68 100.00

C. Compound No. 130 1.0 Polyurea shell vail 7.0 Reaxe c-21 2.0

NaCl 10.0

Xylene 40.0

Water 40.0 100.0

D. Compound No. 63 48.0 Polyurea shell vail 4.8 Reax* 88B 3.0

NaCl 15.0 Kerosene 29>2

100.0

E. Compound No. 74 40.0 Polyurea shell vail 6.5 Reax* 88B 2.0

NaNO _j 10.5

Solvent 25.0

Water 16.0 100.0

F. Compound No. 157 10.0 Polyurea shell vail 8.5 Reax* c-21 1.5

NaCl 6.0

Solvent 20.0

Water 54,0

100.0

UTESHEET

When operating in accordance with the present invention, effective amounts of the compounds of this invention are applied to the soil containing the seeds, or vegetative propagules or may be incorporated into the soil media in any convenient fashion. The application of liquid and particulate solid compositions to the soil can be carried out by conventional methods, e.g., power dusters, boom and hand sprayers and spray dusters. The compositions can also be applied from airplanes as a dust or a spray because of their effectiveness at low dosages. The exact amount of active ingredient to be employed is dependent upon various factors, including the plant species and stage of development thereof, the type and condition of soil, the amount of rainfall and the specific compounds employed. In selective pre- emergence, post-emergence and soil applications a dosage of from about 0.0005 kg/ha (0.5 g/ha) to about 11.2 kg/ha is usually employed. A dosage of about 0.001 kg/ha (1.0 g/ha) to about 0.50 kg/ha (500 g/ha) is preferred. Lower or higher rates may be required in some instances. One skilled in the art can readily determine from this specification, including the above examples, the optimum rate to be applied in any particular case. The term "soil" is employed in its broadest sense to be inclusive of all conventional "soils" as defined in Webster's New International Dictionary. Second Edition, Unabridged (1961). Thus, the term refers to any substance or medium in which vegetation say take root and grow, and includes not only earth but also compost, manure, muck, humus, loam, silt, mire, clay, sand, and the like, adapted to support plant growth.

Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limits- tions. Various equivalents, changes and modifications may be made without departing from the spirit and scope of this

SUBSTITUTESHEET

invention, and it is understood that such equivalent em _b o _d iments are part of this invention.

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