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The residue obtained is taken up in ml of cold water and ml of ethyl acetate. The resulting organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give an orange residue.

This residue is purified by chromatography on silica eluent: The mixture obtained is brought to C for 75 minutes. The heterogeneous mixture thickens and becomes yellow, with a slight release of gas.

The residue obtained is triturated with ethyl ether. The solid formed is filtered off through a sintered glass funnel and then taken up with 20 ml of cold water.

The suspension obtained is filtered through a sintered glass funnel and the insoluble matter is rinsed with ethyl ether so as to give The resulting mixture is then filtered and the filtrate is concentrated under reduced pressure.

The residue obtained is oven-dried, in the presence of P, so as to give 27 g of 4R,4S trifluoromethyl -1,4,5,6-tetrahydropyrimidinylamine hydrochloride, in the form of a grey solid, the characteristics of which are the following: The dextrorotatory enantiomer is concentrated so as to obtain 3.

After stirring for 4 hours at a temperature of 65 C and returning to a temperature of about 20 C, the reaction mixture is concentrated to dryness under reduced pressure.

The residue is diluted in ml of ethyl acetate and 10 ml of ice-cold water. At a temperature between 0 C and 10 C, a concentrated sodium hydroxide solution is added until a pH between 6 and 7 is obtained.

The solid form is filtered off so as to give 3. The filtrate is separated by settling out, and the organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure.

After purification of the residue on a silica column eluent: The two solids Si and S2 are combined so as to give 6. After stirring the suspension for 3 hours at a temperature of C, the medium obtained is concentrated to dryness under reduced pressure.

The residue is taken up in diethyl ether and then dried with suction under vacuum. After 2 hours of stirring at a temperature of 0 C and then overnight at a temperature of about 20 C, the suspension is filtered and then the solid is dried with suction and dried under vacuum over P AS 20pm; mobile phase: The laevorotatory enantiomer is concentrated so as to give 2.

The dextrorotatory enantiomer is concentrated so as to obtain 2. The mixture obtained is then stirred at ambient temperature for one hour.

The reaction medium is cooled in an ice bath. The white solid formed is filtered off so as to give 7 g of the solid Si.

After separation of the filtrate by settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 0.

The solid Si is taken up with water and ethyl acetate. After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 3.

The two solids S2 and S3 are combined for purification by chromatography on silica eluent: Mass spectrum method A: The residue obtained is taken up in 30 ml of cold water and ml of ethyl acetate.

The resulting organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica, eluents: Mass spectrum method B: The mixture obtained is then heated at reflux.

The residue obtained is taken up in 20 ml of cold water and ml of ethyl acetate. At the end of the addition, the mixture obtained is then heated at reflux for three hours in an oil bath preheated to C.

After cooling, the reaction mixture is evaporated to dryness under reduced pressure, so as to give At the end of the addition, the reaction medium, a suspension, is stirred at ambient temperature for 48 hours.

The reaction medium is cooled to 4 C in an ice bath, and then 11 ml of water, followed by 11 ml of 4N NaOH and then 22 ml of water are added dropwise.

The white precipitate formed is filtered off. The filtrate is dried over magnesium sulfate and then concentrated under reduced pressure, so as to give 9.

The reaction medium is cooled to 4 C in an ice bath, and then ml of water, followed by ml of ethyl acetate, are added dropwise.

The residue obtained is taken up with ml of methanol. The white solid formed is filtered off. The filtrate is concentrated under reduced pressure.

Alternatively, R chloro trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

The residue obtained is taken up in 50 ml of cold water and ml of ethyl acetate. The reaction medium is stirred at ambient temperature for 18 hours.

The reaction medium is concentrated to dryness under reduced pressure. The residue obtained is taken up with 10 ml of ice-cold water.

The mixture is concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on silica eluent: R hydroxy S 4-methoxyphenyl ethyl trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

At the end of the addition, the mixture obtained is then heated at reflux for two hours in an oil bath preheated to C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure, so as to give 11 g of a brown foam.

After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure, so as to give a residue of 11 g of a thick oil.

This residue is purified on a silica column, eluent: At the end of the addition, the reaction medium, a suspension, is stirred at ambient temperature for 72 hours.

The reaction medium is cooled to 4 C in an ice bath, and then 9. The filtrate is dried over MgSO4 and then concentrated under reduced pressure, so as to give HN F HN and R Chlorofluoro trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

FJL I CI -N N ml of trifluoroacetic acid are added, at ambient temperature and under an argon atmosphere, to a solution of 4 g of R chlorofluoro S 4-methoxyphenyl ethyl trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one in 30 ml of 1,2-dichloromethane.

The reaction medium turns a dark violet colour. The residue obtained is taken up with ml of dichloromethane and 50 ml of ice-cold water.

After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure.

The residue obtained is taken up with ethyl ether and the white solid formed is filtered off, so as to give 2. The filtrate is concentrated to dryness under reduced pressure and the residue obtained is purified by chromatography on silica eluent: The two solids Si and S2 are combined so as to give 2.

R Chlorofluoro S 4-methoxyphenyl ethyl trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

R Fluorohydroxy S 4-methoxyphenyl ethyl trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

The residue obtained is taken up with ml of cold water. The solid formed is filtered off and then washed three times with ethyl ether. The solid is oven-dried under vacuum in the presence of P, so as to give 15 g of R fluorohydroxy S 4-methoxyphenyl ethyl trifl uoromethyl -3,4-d ihyd ro-1H-pyri m ido[1,2-a]pyrim id in-6 2H -one, which is used as it is in the next step.

The reaction medium is heated at 65 C for 7 h 15 min. It is then evaporated to dryness under reduced pressure 2. The aqueous phase is extracted with 20 ml of ethyl acetate.

The organic phases are combined, dried over magnesium sulfate and then filtered through a sintered glass funnel, and the filtrate is evaporated to dryness under reduced pressure 2.

The crude obtained is purified by flash chromatography on silica [eluent: After evaporation of the fractions under reduced pressure, mg of 2-chloromethyl trifluoromethyl -6,7,8,9-tetrahydro-4 H-pyrim ido[1,2-a]pyrim id inone are obtained, in the form of a white solid mixture of enantiomers.

Prochrom Chiral stationary phase: UV nm After evaporation of the fractions under reduced pressure, 93 mg of 8R chloromethyl trifluoromethyl -6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinone are obtained, in the form of a white solid.

Gilson Chiral stationary phase: UV nm After evaporation of the fractions, mg of 8S chloromethyl trifluoromethyl -6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinone are also obtained, in the form of a white solid.

Retention time by chiral phase HPLC: UV nm 2-Hydroxymethyl trifluoromethyl -6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinone can be prepared in the following way.

The reaction medium is heated at reflux for 5 h 45 min. After cooling, the reaction medium is evaporated to dryness under reduced pressure.

The residue obtained is taken up in 0. The reaction medium is stirred in the cold bath for approximately 15 minutes and then, after having added approximately 3 ml of ethyl ether to the reaction medium, the latter is filtered through a sintered glass funnel.

After drying under vacuum, 92 mg of 2-hydroxymethyl trifl uoromethyl -6,7,8,9-tetrahydro-4 H-pyrim ido[1,2-a]pyrimidinone are obtained, in the form of a beige solid.

After evaporation to dryness under reduced pressure, mg of 4-methyl trifluoromethyl tetrahydropyrimidin-2 1H -imine hydrobromide are obtained in the form of a yellow solid.

The reaction medium is then filtered through celite and the filtrate is then evaporated to dryness. Toluene is added to the residue obtained and then the resulting product is evaporated to dryness, so as to give 1.

The aqueous phase is extracted with ethyl ether, then the organic phases are combined, dried over magnesium sulfate and then filtered through a sintered glass funnel, and the filtrate is evaporated in a rotary evaporator under reduced pressure the bath temperature is maintained below 25 C and the pump vacuum is maintained above mbar.

N1-benzy,4,4-trifluoromethylbutane-1,3-diamine can be prepared in the following way. The reaction medium is stirred at ambient temperature for 72 hand is then diluted with 80 ml of ethyl ether and 15 ml of THF and cooled to approximately 0 C, and 2.

The filtrate is dried over magnesium sulfate and then, after filtration through a sintered glass funnel, the filtrate obtained is evaporated to dryness under reduced pressure 2.

The crude is purified by flash chromatography on silica [eluent: After evaporation of the fractions under reduced pressure, 1.

The reaction medium is stirred at ambient temperature for 62 h and then 3. The reaction medium is stirred at ambient temperature for 27 h and then evaporated to dryness under reduced pressure 2.

After evaporation of the fractions under reduced pressure, 2. HCI A mixture of 4. The reaction medium is heated at 90 C for 4 h. A mixture of acetonitrile and toluene is added and then the mixture is evaporated to dryness under reduced pressure.

Ethyl 3-amino-4,4,4-trifluoromethylbutanoate and methyl 3-amino-4,4,4-trifluoromethylbutanoate can be prepared in the following way.

Jj 0 , F and F A solution of 1. The reaction medium is diluted with 20 ml of methylene chloride and then evaporated to dryness under reduced pressure the bath temperature is maintained below 25 C and the pump vacuum is maintained above mbar.

A mixture of mg 4. Intermediate F6 2-Chloro-8,8-dimethy,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinone can be prepared in the following way. The medium is concentrated to dryness.

The residue is taken up in 50 ml of ethyl acetate and 10 ml of water and then cooled in an ice bath. The aqueous phase is extracted with ethyl acetate and then the organic phase is dried over magnesium sulfate.

After the solvent has been evaporated off, 0. After 4 h of heating, the reaction medium is concentrated to dryness.

The oil obtained is taken up in ethyl ether. The precipitate formed is filtered off, washed with ethyl ether and oven-dried under vacuum. The mixture is stirred at ambient temperature for 2 h.

The mixture is filtered and then evaporated to dryness. The reaction crude is solubilised in 20 ml of water, cooled with an ice bath.

After a return to ambient temperature, the product is precipitated with ethyl ether and filtration is carried out. The powder obtained is oven-dried at 70 C.

After a return to ambient temperature, the reaction medium is filtered and then the solvent is evaporated off. Et20 are added and the mixture is heated for 1 h 30 min at 70 C.

The organic phase is separated by settling out, washed with a saturated NaCI solution and then dried over magnesium sulfate. After a return to ambient temperature, the reaction medium is filtered and then taken up with a saturated aqueous NH4CI solution.

The aqueous phase is extracted with ethyl acetate, washed with an NaCI solution, then dried over magnesium sulfate and evaporated to dryness.

The solid obtained is placed in suspension in ml of water and stirred. The precipitated product is filtered off, rinsed with ether and then oven-dried under vacuum at 65 C.

The residue is taken up in ml of ethyl acetate and 10 ml of water and then cooled in an ice bath. Concentrated NaOH is added to pH After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure.

The residue obtained is triturated from ethyl ether and the solid is filtered and then dried, so as to give 2. HO N N H A suspension of 5 g of 4,4-dimethy,4,5,6-tetrahydropyrimidinamine, 29 g of dimethyl fluoromalonate and 3.

The residue obtained is taken up with ethyl ether. The solid formed is filtered off and then dried. The suspension is filtered and then the solid is washed with 5 ml of water and then dried under vacuum over P, so as to give 3.

S chloromethyl trifluoromethyl -2,3-dihydroimidazo [1,2-a]pyrimidin-5 1H -one can be prepared in the following way.

Y F CI N N F 11 ml of phosphorus oxychloride are added, at ambient temperature and under an argon atmosphere, to a suspension of 5. The resulting mixture is then heated to 70 C.

The residue obtained is taken up in 5 ml of cold water and ml of ethyl acetate. The organic phase is then separated and then dried over magnesium sulfate, filtered and concentrated under reduced pressure, so as to give 6 g of S chloromethyl trifluoromethyl -2,3-dihydroimidazo [1,2-a]pyrimidin-5 1H -one, the characteristics of which are the following: The resulting mixture is refluxed for 18 hours.

After cooling, the mixture obtained is concentrated to dryness under reduced pressure. The resulting suspension is stirred in an ice bath for two hours and then filtered through a sintered glass funnel.

The insoluble matter obtained is rinsed with water twice 4 ml and then dried so as to give 5. At the end of the addition, the reaction mixture is stirred at 5 C for 30 minutes.

The ice bath is then withdrawn and the mixture obtained is stirred at ambient temperature for 3 hours. The resulting mixture is then concentrated under reduced pressure.

The residue obtained is taken up twice with ml of ethanol and then twice with ml of toluene, and evaporated to dryness each time. The solid obtained is triturated with ethyl ether and then filtered off, so as to give 4.

The aqueous phase is subsequently separated by settling out and then extracted with 4 times ml of ethyl ether. The mixture obtained is then filtered and the filtrate is evaporated to dryness.

The oil obtained is taken up with a 3N hydrochloric acid solution 50 ml. The mixture obtained is extracted with diethyl ether 3 x 50 ml.

The aqueous phase is then evaporated to dryness, taken up with methanol, and then again evaporated to dryness.

The yellowish solid obtained is dried under vacuum, so as to give 5. Substantial evolution of gas and a temperature rise to 8 C are observed.

At the end of the addition, the temperature is left to come back up to ambient temperature, and then the reaction mixture is left stirring for 18 h.

The mixture obtained is cooled to 4 C, followed by very slow dropwise addition of 2 ml of water. Substantial evolution of gas and a temperature rise to 12 C are observed.

The white precipitate formed is filtered off and the filtrate obtained is dried over magnesium sulfate and then concentrated under reduced pressure, so as to give 2.

The cold bath is then withdrawn to allow the mixture to warm up to ambient temperature. The organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure.

The mixture obtained is then heated at reflux for 18 hours, during which time 0. After cooling, the reaction mixture is concentrated under reduced pressure.

The residue obtained is purified by filtration on silica eluent: S - 6-Fluorochloromethyl trifluoromethyl -2,3-dihydroimidazo[1,2-a]pyrimidin-5 1H -one can be obtained in the following way.

The organic phase is then separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure.

The residue obtained is purified by silica column chromatography eluent: The resulting mixture is refluxed for 3 hours.

The reaction mixture is evaporated to dryness under reduced pressure. The filtrate is concentrated under reduced pressure and the residue obtained is purified by chromatography on silica eluent: Starting intermediates of type F Intermediate:: Chiral S R Methyl- o m morpholinyI I K methylmorpholinyI -.

N undetermined co absolute configuration on the asymmetric carbon of the 2-fluoromethylbutyl chain o S R Methyl- Chiral.

Synthesis routes, number of steps used in the preparation of the examples claimed above.: Description of the reaction sequences: YO- tetrahydro-coo ethanone pyrimido[1,2-a]pyrimidinone m S R Methyl-morpholinyI R --o trifluoromethy,7,8,9-r Methyl- 3 Method-1 None m tetrahydro-.

Synthesis steps 2 optionally 3 and 4 starting from the intermediates isolated after step 1 see Table 4: Lu morpholinyI Chloro-ct 8-trifluoromethyl- Method-methyl- 1.

Lu morpholinyI - 2-ChloroE2 8-trifluoromethyl- chloro R methyl-Lu morpholinyI - 3-BromoE2 8-trifluoromethyl- cyclo LL morpholinyI - 4-Bromo-E2 8-trifluoromethyl- methyl LL morpholinyI Chloro-ct 8-trifluoromethyl-methyl - Method-6thiazole 1.

CO azabicyclo- 3-Oxa [3. Methods used Method-1 to Method mentioned in Tables 4 and 5 In a suitable reactor, the chosen intermediate of type F is reacted with the selected reagent see Tables 1 to 5 in the presence or absence of solvent or of cosolvent.

The mixture is treated under the conditions specified below. In a 25 ml three-necked reactor, under static argon pressure, equipped with an internal thermometer, the intermediate obtained in the previous step amount and number of equivalents indicated in the table of the examples is introduced into THF 5 m1.

Ethylmagnesium bromide amount Method-and number of equivalents indicated in the table of the Examples is 46 added.

After 10 minutes of stirring at C, the cooling bath is withdrawn and the reaction mixture is stirred at ambient temperature for 3 hours.

After separation by settling out, the organic phase is dried over MgSO4, filtered, and then concentrated under reduced pressure. The expected compound is isolated.

In a dry 10 ml round-bottomed flask, under static argon pressure, the halogenated derivative amount and number of equivalents indicated in the table of the Examples is introduced into 2 ml of dry THF and the mixture is cooled to C, then isopropylmagnesium bromide amount and number of equivalents indicated in the table of the examples at 2.

The mixture is left to stir at this temperature for 30 min and then the intermediate see Table 5 is added, portionwise, and the mixture is left to warm up to AT over a period of 18 h.

The fractions containing the product are concentrated under reduced pressure. The expected compounds are isolated see table of the Examples.

THF 2 ml and the isopropyl magnesium chloride-lithium chloride complex number of equivalents, see table of the Examples are introduced into a 10 ml round-bottomed flask, under static argon pressure, and then the mixture is cooled to C and the halogenated derivative number of equivalents, see table of the Examples is added dropwise.

The reaction mixture is stirred for 30 minutes at C. The intermediate Method- obtained in the previous step number of equivalents, see table of the examples is then added portionwise and the mixture is left to warm up to AT over a period of 18 h.

Where appropriate, the compound is purified on chiral phase Example, Chiral Purif ref. The expected compounds are isolated see table of the Examples Example, 63, 67, The alkyl carboxylate derivative is placed in solution in methanol and then Method-treated with a sodium hydroxide solution until the ester has disappeared.

The intermediate obtained via the previous reaction 1 eq is placed in solution in dioxane and a solution of hydrochloric acid in dioxane 4M, eq is added to the reaction mixture.

The reaction mixture is stirred at Method-C until the protective group has been eliminated. The reaction mixture 49 is poured into water, separated by settling out, and extracted with ethyl acetate.

The organic extracts are combined, washed with a saturated sodium chloride solution, dried over magnesium sulphate, filtered, and evaporated under reduced pressure.

Diethylaminosulphur trifluoro 1 eq is added to a solution of the intermediate obtained during the previous reaction mg, 1 eq in dichloromethane at C.

After returning to 20 C, the reaction mixture is poured into a solution of NaHCO3, extracted with dichloromethane, dried over magnesium sulphate, and then evaporated to dryness.

The fractions containing the fluorination compound Example and also the elimination compound Example are brought to dryness in a rotary evaporator.

Method-The intermediate obtained by the previous reaction 1 eq, mg is 51 treated with hydrazine hydrate number of equivalents, see table of the Methods used for carrying out the conversions required for obtaining the examples from the intermediates of type I Examples in the presence of acetic acid at 90 C for 2 h.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,4-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,5-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3,5-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-propylbenzoic acid for 1-methylcyclopropanecarboxylic acid. The title compound was prepared according to the procedure for EXAMPLE , substituting 4-isopropylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-ethoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-isopropoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- diethylamino benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-butoxybenzoic acid for 1-methylcyclopropanecarboxylic acid. The title compound was prepared according to the procedure for EXAMPLE , substituting 2-fluoro trifluoromethyl benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-chloro trifluoromethyl benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting furancarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,5-dimethylfurancarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting thiophenecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-methylthiophenecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-methylthiophenecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting pyrrolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-methyl-1H-pyrrolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,5-dimethyl-1H-pyrrolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting thiazolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting isoxazolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3,5-dimethylisoxazolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting nicotinic acid for 1-methylcyclopropanecarboxylic acid. The title compound was prepared according to the procedure for EXAMPLE , substituting isonicotinic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-hydroxypicolinic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-hydroxynicotinic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 6-hydroxynicotinic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- pyridinyl acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-methylpyrazinecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1H-indolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-methylphenyl-1H-pyrazolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 6-chloro-2H-chromenecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

N 3 ,N 3 -dimethyl-N 1 - 3- 4-oxo-3,4,5,6,7,8-hexahydrophthalazinyl methyl phenyl -beta-alaninamide. The title compound was prepared according to the procedure for EXAMPLE , substituting 3- dimethylamino propanoic acid for 1-methylcyclopropanecarboxylic acid.

To a solution of 2- 3-bromophenyl acetic acid 4. The reaction mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and brine.

The mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic phase was washed with water and concentrated.

The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 2,2,2-trifluorophenylethanone for 2-fluoroformylbenzonitrile.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-hydroxymethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-acetylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-methoxymethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-fluoromethoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-naphthoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-naphthoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-tert-butylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-acetamidobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-propoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-hydroxynaphthoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-chloro methylthio benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3,4-diethoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-benzoylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared as a trifluoroacetic acid salt according to the procedure for EXAMPLE , substituting 2- phenylamino benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared as according to the procedure for EXAMPLE , substituting 2-benzoylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-phenethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-bromochlorobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-methylbenzoyl benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-iodobenzoic acid for 1-methylcyclopropaneccarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-iodobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-iodobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared as a free base according to the procedure for EXAMPLE 39, substituting 3-acetamidophenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 3- methylsulfonyl phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 3- pyrrolidinecarbonyl phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 4- pyrrolidinecarbonyl phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 3-carbamoylphenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 4- dimethylcarbamoyl phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 1,1,1-trifluorophenylpropanone for 2-fluoroformylbenzonitrile.

The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The title compound was prepared according to the procedure for EXAMPLE A, substituting 4- benzyloxycarbonyl tert-butoxycarbonyl piperazinecarboxylic acid for 2- 3-bromophenyl acetic acid.

The catalyst was removed by filtration, and the filtrate was concentrated. The solid material was filtered off, and the filtrate was concentrated to give the title compound.

The mixture was stirred at room temperature overnight, and was concentrated. The residue was dissolved in absolute ethanol 5 mL , and was treated with sodium ethoxide 0.

A solution of 2-phenoxyacetic acid 28 mg, 0. The residue was re-dissolved in anhydrous dichloromethane 5 ml. The reaction mixture was stirred at room temperature overnight, and was concentrated.

After cooling, the reaction mixture was diluted with methanol 20 ml , and filtered. The title compound was prepared according to the procedure for EXAMPLE , substituting 4- morpholinecarbonyl phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE substituting 2- pyrrolidinecarbonyl phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- pyrrolidinecarbonyl phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- cyclopropylcarbamoyl phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- 2- dimethylamino ethylcarbamoyl phenylboronic acid for 3- morpholinecarbonyl -phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-carbamoylphenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- methylsulfonamido phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-acetamidophenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-chloronitrobenzaldehyde for 4-fluoronitrobenzaldehyde.

The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-methoxynitrobenzaldehyde for 4-fluoronitrobenzaldehyde.

The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-hydroxynitrobenzaldehyde for 4-fluoronitrobenzaldehyde.

The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-methylnitrobenzaldehyde for 4-fluoronitrobenzaldehyde. A solution of 3-bromoethyl benzene 2 g, 11 mmol.

After cooling, the reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and brine.

The organic layer was washed with brine, and was concentrated. After cooling to room temperature, the solid material was collected by filtration, washed with toluene, and dried to provide the title compound.

A solution of 4,5,6,7-tetrahydroisobenzofuran-1,3-dione 0. The reaction mixture was warmed up to room temperature, and stirred at room temperature for additional 4 hours.

After quenching with water, the reaction mixture was partitioned between ethyl acetate and brine. To a solution of 4- 4-methoxyphenyl oxobutanoic acid 29 mg, 0.

The reaction mixture was stirred at room temperature for 16 hours, and was concentrated. The reaction mixture was cooled and concentrated on a rotary evaporator.

The title compound was prepared according to the procedure for EXAMPLE A, substituting 2- 3-bromofluorophenyl acetic acid for 2- 3-bromophenyl acetic acid.

A mixture of 4-oxophenylbutanoic acid 50 mg, 0. The reaction mixture was stirred at room temperature for another 1 hour, and was diluted with 5 mL of methanol.

The solid material was collected by filtration, washed with methanol, and dried to provide the title compound.

The title compound was prepared according to the procedure for EXAMPLE , substituting hexahydroisobenzofuran-1,3-dione for oxabicyclo 3.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3,3-dimethyldihydrofuran-2,5-dione for oxabicyclo 3.

A mL round bottom flask was charged with 3-bromofluorobenzaldehyde 1. The mixture was purged with nitrogen, and anhydrous dioxane 15 mL , and 5-methylpyrrolidinone 0.

After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was dried over MgSO 4 , filtered and concentrated.

The residue was dissolved in ethanol 5 mL and treated with hydrazine monohydrate 0. The mixture was allowed to cool and the precipitated solid was filtered and dried to provide the title compound.

The reaction mixture was concentrated, and the residual solid was dissolved in dioxane 3 mL. The residue was stirred with a mixture of ethyl acetate and water.

The precipitated solid was filtered, washed with water, and dried to provide the title compound. The combined organics were concentrated and dried under vacuum to provide the title compound.

After cooling to room temperature, the precipitated solid was filtered, and dried to provide the title compound. The reaction mixture was concentrated and dried to provide the title compound.

The reaction mixture was concentrated. The title compound was prepared according to the procedure for EXAMPLE , substituting thiophenylmethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting pyridinylmethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- pyrrolidinyl propanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- piperidinyl propanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 3-morpholinopropanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- benzyloxycarbonylamino acetic acid for 4-oxophenylbutanoic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-oxo 4-phenoxyphenyl butanoic acid for 4-oxophenylbutanoic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- benzyloxycarbonyl piperidinecarboxylic acid for 4-oxophenylbutanoic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- p-tolyloxy acetic acid for 4-oxophenylbutanoic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-methoxyphenoxy acetic acid for 4-oxophenylbutanoic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-tert-butylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-tert-butylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-fluoromethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-fluoromethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-fluoromethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-chloromethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-chloromethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-bromomethylaniline for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 4-bromomethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-fluoromethoxyaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-methoxy trifluoromethyl aniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-aminomethylphenol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-aminomethylphenol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-methoxymethylaniline for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 5-methoxymethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-aminomethoxyphenol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-tert-butylmethoxyaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting N- 3-aminomethoxyphenyl acetamide for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2,3-dihydrobenzo b 1,4 dioxinamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-chloro-2,4-dimethoxyaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- methylthio aniline for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 4- methylthio aniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- piperidinyl aniline for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 4-morpholinoaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting N 1 - 4-methoxyphenyl benzene-1,2-diamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-aminonaphthalenol for furanylmethanamine. To a solution of dimethylpyridine-2,3-dicarboxylate 1.

The reaction mixture was stirred at the same temperature for 30 minutes and was quenched with addition of water. After warming up to room temperature, the reaction mixture was partitioned between ethyl acetate and brine.

The reaction mixture was concentrated to about 5 mL. The solid was collected by filtration, washed with ethanol and dried to provide the title compound.

The title compound was prepared according to the procedure for EXAMPLE A, substituting 2-chlorofluorobenzyl magnesium chloride for 4-fluorobenzyl magnesium chloride.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-o-tolylethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-p-tolylethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- pyridinyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- pyridinyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- pyridinyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2-methoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- 2-methoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- 2-methoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2-fluorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3-fluorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-fluorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2-chlorophenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3-chlorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-chlorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3-bromophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-bromophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- biphenylyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3- trifluoromethyl phenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4- trifluoromethyl phenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-phenoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,4-dimethylphenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,4-dimethylphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,5-dimethylphenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3-ethoxymethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-ethoxymethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,3-dimethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,4-dimethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,5-dimethoxyphenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,4-dimethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,5-dimethoxyphenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- benzo d 1,3 dioxolyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,3-dichlorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,4-dichlorophenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,6-dichlorophenyl ethanamine for furanylmethanamine.

A solution of 1- 3-bromofluorophenyl ethanone After the addition, the ice bath was removed, and the mixture was stirred at room temperature for 30 minutes and at reflux overnight.

After cooling, 1N HCl 10 mL was slowly added and the reaction mixture was concentrated. The organic phase was washed with water, and concentrated.

After the addition, the reaction mixture was stirred at room temperature for additional 15 minutes, and partitioned between water ml and ethyl acetate ml.

The residue was purified by flash chromatography 2. The mixture was filtered, and the filtrate was concentrated. A mixture of magnesium turnings mg, 37 mmol and 2-bromo bromomethyl fluorobenzene 1.

The mixture was then heated to gentle reflux until the color of the mixture disappeared, after which the heating continued for additional hour.

The suspension was cooled to room temperature, and cannulated into a solution of dimethylpyridine-2,3-dicarboxylate 1. The reaction mixture was maintained at the same temperature for 30 minutes, and was quenched with addition of water.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- benzylamino ethanol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting N-methyl pyridinyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,4-dimethoxyphenyl -N-methylethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting piperidinecarboxamide for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting piperazinecarbaldehyde for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- piperazinyl ethanone for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- piperazinyl ethanol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- pyridinyl piperazine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- piperazinyl pyrimidine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2- piperazinyl ethoxy ethanol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- 2-fluorophenyl piperazine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- 4-fluorophenyl piperazine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- 2-chlorophenyl piperazine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-methyl piperazinyl azepane for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLEs 2, 3 and 4, substituting 3-nitrobenzaldehyde for 4-fluoronitrobenzaldehyde.

To a solution of 4-fluoronitrobenzoic acid 5 g, The reaction mixture was concentrated and partitioned between ethyl acetate mL and brine mL.

The catalyst was filtered off, and the filtrate was concentrated. The residue was used the subsequent step without further purification.

The residue was partitioned between ethyl acetate mL and brine 75 mL. The organic layer was washed with brine, and concentrated.

The reaction was quenched with water, and the mixture was partitioned between ethyl acetate and diluted HCl solution.

The organic layer was washed with brine, and concentrated on a rotary evaporator. To a solution of 2-bromofluoroiodobenzene The mixture was stirred for 2 hours, and a saturated aqueous ammonium chloride solution was added to the reaction mixture, which then was stirred at room temperature for 30 minutes.

Anhydrous magnesium sulfate was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated.

To the thionyl chloride solution was then added the residue from the filtrate in anhydrous methanol 15 mL. The residue was dissolved in methylene chloride 40 mL , and was treated with triethylamine 5.

Water was added, and the mixture was washed with sodium bicarbonate, brine and water. The organic phase was dried over magnesium sulfate, filtered and concentrated.

After cooling to room temperature, the solids were collected by filtration, washed with ethanol and dried to provide the title compound.

The solution was stirred at room temperature for 30 minutes, and benzyl chloromethylether 1. The reaction mixture was stirred at room temperature overnight.

After quenching with water, the reaction mixture was partitioned between water and ethyl acetate. Anhydrous dioxane 3 mL was added.

The suspension was purged with nitrogen, and was capped with a microwave septum. After cooling, the reaction mixture was partitioned between ethyl acetate and brine.

The residue was recrystallized from methanol 4 mL to provide the title compound. The solid was collected by filtration, washed with methanol and dried to provide the title compound.

A mixture of 1. After cooling, the mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated to about 10 mL.

The solid was collected by filtration, washed with methanol, and dried to provide the title compound. A solution of EXAMPLE 1 g, 3 mmol in anhydrous dimethylformamide ml was treated with potassium t-butoxide 1N solution in tetrahydrofuran, 3 mL, 3 mmol at room temperature for 30 minutes.

Piperazinyl pyrimidine dihydrochloride 78 mg, 0. The ice bath was removed and the mixture was stirred at room temperature for 30 minutes, and under reflux for 5 hours.

After cooling to room temperature, 1N HCl was added, and the reaction mixture concentrated. The organic layer was washed with brine, water and concentrated.

The reaction mixture was refluxed for 21 hours, and concentrated. The reaction mixture was stirred at ambient temperature for 18 hours, and concentrated.

The mixture was filtered and the solid was dried to provide the title compound. Solid material was filtered off, and the filtrate was concentrated.

The reaction mixture was acidified with 2 N HCl to a pH 3, and concentrated. The organics were concentrated and dried to provide the title compound.

The reaction mixture was stirred at ambient temperature for 16 hours and concentrated. Concentration of the mixture yielded the title compound as the HCl salt.

To a solution of 3-aminofluorobenzoic acid 30 g, mmol in a mixture of tetrahydrofuran mL and water mL was added cesium carbonate g, mmol and benzyl chloroformate This mixture was stirred at ambient temperature for 16 hours, and was concentrated to about mL.

The residue was acidified with 2N HCl to a pH 3, and was partitioned between ethyl acetate and brine. The precipitated solid was collected by filtration, washed with ethyl acetate and water, and dried to provide the title compound.

The reaction mixture stirred at room temperature for 16 hours and concentrated. The crude mixture was partitioned between ethyl acetate and water.

The mixture was partitioned between ethyl acetate and dilute aqueous HCl solution. The organics were washed with water and concentrated.

Ethyl acetate was added and the mixture washed with water and brine. The mixture was cooled and the precipitated solid was filtered and dried to provide the title compound.

The suspension was purged, and pressurized with hydrogen at 30 psi with stirring for 1 hour. The solid material was filtered off and the filtrate concentrated to provide the title compound.

The crude solid was triturated from methanol to provide the title compound. The mixture was stirred at room temperature for 16 hours and was concentrated.

The title compound was prepared, using the appropriate reagents, as the free base? To a mixture of magnesium turnings 1.

The slightly purple suspension was stirred at ambient temperature for minutes, and the color of the mixture disappeared.

The exothermic mixture was refluxed with stirring for an additional 1 hour, and cooled to room temperature. The formed Grignard reagent was directly used in the next step without further purification.

To a solution of dimethylpyridine-2,3-dicarboxylate 5. This mixture was partitioned between ethyl acetate and brine. Solid precipitated, and after cooling to room temperature, was collected by filtration, washed with ethanol, and dried to give the title compound.

Solid material was filtered off and the filtrate was concentrated. The solid was collected by filtration, washed with methanol, and dried to give the title compound.

This suspension was purged and pressurized with 30 psi of hydrogen, and stirred at ambient temperature for 32 hours. Solid material was filtered off and the filtrate concentrated.

The formed solid was collected by filtration, washed with methanol and dried to give the title compound. After cooling to room temperature, the mixture was acidified with dilute HCl to pH 4, and concentrated to about 10 mL.

The solid material was collected by filtration, washed with water and dried to provide the title compound. The reaction mixture was warmed until homogeneous.

The solution was stirred at ambient temperature for 16 hours and concentrated. After cooling to room temperature the precipitate was collected by filtration, washed with methanol, and dried to give the title compound.

To a mixture of ice 30 g and solution of KOH 1. After cooling, the mixture was acidified with HCl to pH 7, and partitioned between brine and ethyl acetate.

The mixture was concentrated and the residue partitioned between ethyl acetate and brine. The organic phase was washed with brine, and was concentrated.

The reaction mixture was purged and pressurized with hydrogen 30 psi , and stirred at ambient temperature for 3 days. The reaction mixture was stirred at ambient temperature for 16 hours and was concentrated.

The residue was diluted with ethyl acetate and washed with brine. The title compound was prepared, using the appropriate reagents, as a TFA salt?

After cooling to room temperature, the white solid material was collected by filtration, washed with methanol, and dried to give the title compound.

To a mixture of ice 50 g and a solution of KOH 2 g, 36 mmol in 8 mL of water was added bromine 0. After cooling to room temperature, the mixture was partitioned between water mL and ethyl acetate mL.

The organic phase was washed with brine, water and concentrated to about 10 mL. The formed solid material was washed with methanol and dried to give the title compound.

After cooling, methyl 2-isocyanatomethylbutanoate 32 mg, 0. The mixture was concentrated and the residue dissolved in N,N-dimethylformamide 10 mL , 2N NaOH 1 mL was added, and the mixture stirred at room temperature overnight.

This suspension was purged with hydrogen, and stirred under hydrogen balloon for 1. The solution was stirred at room temperature for 16 hours and sodium hydroxide 15 mg, 0.

The residue was partitioned between ethyl acetate and brine and the organic layer was washed with brine and concentrated.

The suspension was purged with hydrogen, and stirred under hydrogen at room temperature for 18 hours. Solid material was filtered off, and the filtrate was concentrated to provide the title compound.

The mixture was stirred at room temperature for 16 hours, filtered, and concentrated. The residue was partitioned between ethyl acetate and water and the organic layer collected and concentrated.

The residue was partitioned between ethyl acetate and water and the organic layer concentrated. The mixture was stirred at ambient temperature for 5 minutes and washed with brine.

The mixture was stirred at ambient temperature overnight and was partitioned between ethyl acetate and brine. The organic phase was washed with brine and water and concentrated.

The residue was purified by flash chromatography ethyl acetate to give the title compound. The mixture was stirred at ambient temperature overnight, and was partitioned between ethyl acetate and brine.

Toluene 10 mL was added and the solution concentrated. The residue was dissolved in methylene chloride and methanol, and treated with an access of 2M HCl in ether.

Concentration provided the title compound as the HCl salt. The reaction mixture was stirred at ambient temperature overnight, and partitioned between methylene chloride and brine.

The organic phase was washed with brine, water, and concentrated. The mixture was heated until homogeneous and stirred at ambient temperature overnight.

The mixture was partitioned between methylene chloride and brine. N-hydroxybenzotriazole HOBt 38 mg, 0. This solution was stirred at ambient temperature overnight and concentrated.

The foregoing is meant to be illustrative of the invention and not meant to limit it to disclosed embodiments. Variations and changes obvious to one skilled in the art are intended to be within the scope and nature of the invention as defined in the appended claims.

A SumoBrain Solutions Company. Search Expert Search Quick Search. Inhibitors of poly ADP-ribose polymerase, ways to make them and methods of treating patients using them are disclosed.

Click for automatic bibliography generation. National Cancer Institute http: Smith, Molecular Cancer Therapeutics, 6, , N.

V North Chicago IL A method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of selected from the group consisting of 4- 3- 1,4-diazepanylcarbonyl fluorobenzyl -5,6,7,8-tetrahydrophthalazin-1 2h -one; 4- 2-fluoro 4-oxo-3,4,5,6,7,8-hexahydrophthalazinyl methyl phenyl amino oxobutanoic acid; and 1- 2-fluoro 4-oxo-3,4,5,6,7,8-hexahydrophthalazinyl methyl phenyl pyrrolidine-2,5-dione; or a pharmaceutically acceptable salt thereof.

A method according to claim 47 additionally comprising radiotherapy. Still another embodiment comprises methods for decreasing tumor volume in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I Still another embodiment comprises the use of a compound of Formula I for the preparation of a medicament for the treatment of cancer.

Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: Compounds having Formula I may be administered with or without an excipient.

Polo-like kinase inhibitors include BI and the like. In another embodiment of formula I, A 1 is R 1 , and R 1 is unsubstituted cyclohexane, as shown in formula Ia: In another embodiment of formula I, A 2 is R 5 , wherein R 5 is C 1 -alkyl, substituted with R 10 as described in Formula I and further unsubstituted as shown in formula Ib:

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