preferably , the compounds of the present invention are those of formula i wherein : r 1 and r 2 are each , independently , lower alkyl , lower alkoxy , halogen , or together can form a 5 - 7 membered carbocyclic or heterocyclic ring ; most preferably , the compounds of the present invention are selected from the following : as used herein , the terms &# 34 ; lower alkyl &# 34 ; and &# 34 ; lower alkoxy &# 34 ; are meant to include both straight and branched carbon chains containing 1 to 6 carbon atoms . the term &# 34 ; halogen &# 34 ; is meant to include fluorine , chlorine , bromine , and iodine . the compounds of this formula i may advantageously be used in the form of the pharmaceutically acceptable acid addition salts thereof . such salts , prepared by methods well known to those skilled in the art , are formed with both inorganic or organic acids , for example : fumaric , maleic , benzoic , ascorbic , pamoic , succinic , bismethylenesalicylic , methanesulfonic , ethanedisulfonic , acetic , oxalic , propionic , tartaric , salicyclic , citric , gluconic , lactic , malic , mandelic , cinnamic , citraconic , aspartic , stearic , palmitic , itaconic , glycolic , p - aminobenzoic , glutamic , benzenesulfonic , hydrochloric hydrobromic , sulfuric , cyclohexylsulfamic , phosphoric and nitric acids . the compounds of the present invention may be prepared by any suitable method which will be recognized by those skilled in the art . however , the present compounds may be advantageously prepared according to any one of schemes 1 - 12 set forth below . in the schemes , the intermediate compounds exemplified hereinafter are identified in parenthesis . the compound produced in each of schemes 1 - 12 is identified with reference to the appropriate example set forth below . ## str7 ## the present invention will now be illustrated reference to the following , non - limiting examples : 5 - fluoroindole ( 4 . 96 , 0 . 036 mol ), 1 , 4 - cyclohexanedione monoethylene ketal ( 7 . 17 g , 0 . 046 mol ) and potassium hydroxide ( 6 g , 0 . 043 mol ) were heated to reflux in 70 ml methanol for 6 hours . the reaction was cooled and the product was isolated by filtration and washed with water to give 8 . 59 g ( 86 %) of product as a white solid : mp 153 - 155 ° c . this compound was prepared in the manner as described above for ( 1a ) by replacing 5 - fluoroindole with 6 - fluoroindole ( 5 . 14 g , 38 mmol ) and obtained in 96 . 3 % yield ( 10 g ) as a white solid : mp 196 - 197 ° c . elemental analysis for c 16 h 16 fno 2 calc &# 39 ; d : c , 70 . 32 ; h , 5 . 90 ; n , 5 . 13 found : c , 70 . 62 ; h , 5 . 91 ; n , 5 . 08 this compound was prepared in the manner as described above for ( 1a ) by replacing 5 - fluoroindole with 5 - cyanoindole ( 29 . 98 g , 0 . 21 mol ), and obtained in 50 % yield ( 29 . 32 g ) as a white solid : mp 158 - 160 ° c . indole ( 4 . 69 , 40 mmol ), 1 , 4 - cyclohexanedione monoethylene ketal ( 6 . 3 g , 40 mmol ) and potassium hydroxide ( 13 . 2 g , 60 mmol ) were heated to reflux in 70 ml methanol for 6 hours . the reaction was cooled and the product was isolated by filtration and washed with water to give 9 . 1 g ( 89 %) of product : ms m / e ( m +). a mixture of 4 -( 5 - fluoro - 1h - 3 - indolyl )- cyclohex - 3 - en - ethylene ketal ( 8 . 5 g ) and 10 % palladium on carbon ( 2 . 72 g ) in ethanol ( 200 ml ) was hydrogenated for 5 hours . the catalyst was filtered off and the solvent removed under vacuum . chromatography ( methanol - methylene chloride ) afforded 7 . 55 g ( 82 %) of product as a white solid : mp 183 - 185 ° c . this compound was prepared in the manner as described above for ( 2a ) by replacing 4 -( 5 - fluoro - 1h - 3 - indolyl )- cyclohex - 3 - en - ethylene ketal with 4 -( 6 - fluoro - 1h - 3 - indolyl )- cyclohex - 3 - en - isomer ethylene ketal ( 9 . 54 g ) in 60 % yield ( 5 . 83 g ) as a white solid : mp 158 - 159 ° c . elemental analysis for c 16 h 18 fno 2 calc &# 39 ; d : c , 69 . 80 ; h , 6 . 59 ; n , 5 . 09 found : c , 69 . 74 ; h , 6 . 48 ; n , 5 . 13 this compound was prepared in the manner as described above for ( 2a ) by replacing 4 -( 5 - fluoro - 1h - 3 - indolyl )- cyclohex - 3 - en - isomer ethylene ketal with 4 -( 5 - cyano - 1h - 3 - indolyl )- cyclohex - 3 - en - ethylene ketal ( 54 . 6 g ) in 95 % ( 52 . 12 g ) yield as a white solid : mp 153 - 155 ° c . a mixture of 4 -( 1h - 3 - indolyl )- cyclohex - 3 - en - ethylene ketal ( 8 . 0 g , 31 . 3 mmol ) and 10 % palladium on carbon ( 1 . 3 g ) in ethanol ( 700 ml ) was hydrogenated overnight . the catalyst was filtered off and the solvent removed under vacuum to afford 8 . 01 g ( 99 %) of product as a white solid : ms m / e ( m +). a solution of 4 -( 5 - fluoro - 1h - 3 - indolyl )- cyclohexanone ethylene ketal ( 2 . 8 g , 10 mmol ) in 2 l ( 1 : 1 ) tetrahydrofuran - hydrochloric acid ( 1n ) was allowed to stir at room temperature for 16 hours . the solvent was evaporated under vacuum . the crude product was dissolved in ethyl acetate , and washed with 1n sodium hydroxide ( 3 × 150 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( 40 % ethyl acetate - hexanes ) afforded 2 . 1 g ( 91 %) of product as yellow solid : mp 112 - 114 ° c . this compound was prepared in the manner as described above for ( 3a ) by replacing 4 -( 5 - fluoro - 1h - 3 - indolyl )- cyclohexanone ethylene ketal with 4 -( 6 - fluoro - 1h - 3 - indolyl )- cyclohexanone ethylene ketal ( 5 . 4 g ) in 99 % ( 19 . 3 g ) yield as a white solid : mp 102 - 105 ° c . elemental analysis for c 14 h 14 nof calc &# 39 ; d : c , 72 . 71 ; h , 6 . 10 ; n , 6 . 06 found : c , 72 . 77 ; h , 5 . 98 ; n , 5 . 96 this compound was prepared in the manner as described above for ( 3a ) by replacing 4 -( 5 - fluoro - 1h - 3 - indolyl )- cyclohexanone ethylene ketal with 4 -( 5 - cyano - 1h - 3 - indolyl )- cyclohexanone ethylene ketal ( 6 g ) in 81 % ( 4 . 0 g ) of product as a white solid : mp 162 . 5 - 164 ° c . elemental analysis for c 15 h 14 n 2 o calc &# 39 ; d : c , 75 . 61 ; h , 5 . 92 ; n , 11 . 76 found : c , 75 . 82 ; h , 6 . 06 ; n , 11 . 72 a solution of 4 -( 1h - 3 - indolyl )- cyclohexanone ethylene ketal ( 2 . 57 g , 10 mmol ) in 200 ml ( 1 : 1 ) tetrahydrofuran - hydrochloric acid ( 1n ) was allowed to stir at room temperature for 16 hours . the solvent was evaporated under vacuum . the crude product was dissolved in ethyl acetate , and washed with 1n sodium hydroxide ( 3 × 150 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( 40 % ethyl acetate - hexanes ) afforded 1 . 9 g ( 89 %) of product . to a suspension of sodium hydride ( 60 %, 1 . 74 , 0 . 073 mol ) in anhydrous n , n - dimethylformamide ( 100 ml ) was added 4 -( 5 - cyano - 1h - 3 - indolyl )- cyclohex - 3 - en - isomer ethylene ketal ( 9 . 9 g , 0 . 035 mol ) at room temperature . the mixture was stirred for 30 minutes at room temperature , then methyl iodide ( 9 ml , 0 . 14 mol ) was added at room temperature . the reaction was allowed to stir for 1 hour , then was quenched with water ( 50 ml ). the mixture was extracted with methylene chloride ( 3 × 150 ml ) and water ( 3 × 150 ml ). the organic layer was dried over magnesium sulfate and filtered . the solvent was removed under vacuum . chromatography ( 5 % methanol - methylene chloride ) afforded 2 . 54 g of product as a light yellow solid : mp 65 - 67 ° c . elemental analysis for c 18 h 18 n 2 o 2 calc &# 39 ; d : c , 73 . 45 ; h , 6 . 16 ; n , 9 . 52 found : c , 73 . 17 ; h , 6 . 24 ; n , 9 . 43 a mixture of 4 -( 5 - cyano - 1 - methyl - 3 - indolyl )- cyclohex - 3 - en - isomer ethylene ketal ( 3 . 77 g ) and 10 % palladium on carbon ( 0 . 99 g ) in ethanol - tetrahydrofuran ( 200 : 80 ml ) was hydrogenated for 5 hours . the catalyst was filtered off and the solvent was removed under vacuum to afford a white powder which was washed with ethanol - hexanes ( 1 : 1 ) and dried under vacuum for 4 hours ( 2 . 75 g ): mp 170 - 172 ° c . elemental analysis for c 18 h 20 n 2 o 2 calc &# 39 ; d : c , 72 . 95 ; h , 6 . 80 ; n , 9 . 45 found : c , 72 . 79 ; h , 6 . 82 ; n , 9 . 35 a solution of 4 -( 5 - cyano - 1 - methyl - 3 - indolyl )- cyclohexanone ethylene ketal ( 5 . 5 g ) in 150 ml ( 1 : 1 ) tetrahydrofuran - hydrochloric acid ( 1n ) was allowed to stir at room temperature for 16 hours , then to above solution sodium bicarbonate ( 4 . 49 g ) was added . the mixture was extracted with methylene chloride ( 3 × 100 ml ) and washed with brine ( 3 × 150 ml ). the organic layer was dried over anhydrous magnesium sulfate and filtered . the solvent was removed to afford a light brown solid which was boiled in ethyl acetate - hexanes ( 1 : 1 ). the mixture was cooled to room temperature and solid was collected and dried under vacuum ( 2 . 06 g ): mp 150 - 152 ° c . elemental analysis for c 15 h 15 n 2 o calc &# 39 ; d : c , 76 . 16 ; h , 6 . 39 ; n , 11 . 10 found : c , 75 . 84 ; h , 6 . 34 ; n , 10 . 92 to a suspension of sodium hydride ( 2 . 4 g , 60 mmol ) in n , n - dimethylformamide ( 100 ml ) was added guaiacol ( 6 . 3 g , 50 mmol ) at room temperature . the mixture was allowed to stir for 40 minutes at room temperature . to above reaction mixture was added bromoacetonitrile ( 7 ml , 100 mmol ). the reaction mixture was stirred for 3 hours and then quenched with water . the mixture was extracted with ethyl ether ( 3 × 150 ml ), washed with water ( 3 × 150 ml ) and brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( 20 % ethyl acetate - hexanes ) afforded 7 . 0 g ( 86 %) of product as a clear oil : ms m / e ( m +). to a solution of 2 -( 2 - methoxy - phenoxy ) acetonitrile ( 5 g , 31 mmol ) in anhydrous ethyl ether ( 100 ml ) was added lithium aluminum hydride ( 1 . 6 g , 40 mmol ) portionwise . the reaction mixture was heated to reflux for 3 hours and then cooled to 0 ° c . the reaction was quenched with 1n hydrochloric acid and diluted with water ( ph = 1 , aqueous layer ). the mixture was extracted with ethyl acetate ( 3 × 150 ml ), neutralized with 50 % sodium hydroxide to ph & gt ; 10 , and extracted again with more ethyl acetate ( 3 × 100 ml ). the combined organic layers were washed with brine ( 3 × 150 ml ), dried over anhydrous sodium sulfate and filtered . the solvent was removed under vacuum to afford 2 . 85 g ( 56 %) of product as an oil ; ms ei m / e 167 ( m + ). a solution of 5 - fluoro - 2 - methoxy phenol ( 4 . 34 g , 31 mmol ) prepared according to the procedure set forth in mancini et al ., synth . comm ., 19 : 2001 ( 1989 ), 1 - bromo - 2 - chloroethane ( 8 . 9 ml , 107 mmol ) and potassium carbonate ( 14 . 8 g , 106 mmol ) in 2 - butanone ( 60 ml ) was refluxed for 24 hours . the mixture was poured into water ( 150 ml ), extracted with methylene chloride ( 3 × 150 ml ) and washed with brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate , filtered and the solvent was removed under vacuum . chromatography ( 20 % ethyl acetate - hexanes ) afforded 4 . 8 g ( 76 %) of product as a clear oil . elemental analysis for c 9 h 10 fclo 2 calc &# 39 ; d : c , 52 . 83 ; h , 4 . 93 found : c , 52 . 79 ; h , 4 . 75 a solution of 2 -( 5 - fluoro - 2 - methoxy - phenoxy ) ethylchloride ( 4 . 0 g , 19 mmol ) and sodium azide ( 2 . 6 g , 39 mmol ) in anhydrous n , n - dimethylformamide ( 60 ml ) was allowed to stir at 60 ° c . for 18 hours . the mixture was poured into water ( 150 ml ), extracted with methylene chloride ( 3 × 150 ml ) and washed with water ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate , filtered and the solvent was removed under vacuum . chromatography ( 20 % ethyl acetate - hexanes ) afforded 3 . 8 g ( 92 %) of product as a clear oil . elemental analysis for c 9 h 10 fn 3 o 2 calc &# 39 ; d : c , 51 . 18 ; h , 4 . 77 ; n , 19 . 90 found : c , 51 . 35 ; h , 4 . 71 ; n , 20 . 06 a solution of 2 -( 5 - fluoro - 2 - methoxy - phenoxy ) ethylazide ( 3 . 97 g , 0 . 019 mol ) and triphenylphosphine ( 5 . 95 g , 0 . 023 mol ) in tetrahydrofuran ( 80 ml ) and water ( 1 . 5 ml ) was allowed to stir for 18 hours at room temperature . the solvent was removed under vacuum . chromatography ( ethyl acetate followed by 25 - 50 % methanol - ethyl acetate plus ammonium hydroxide ) removed triphenylphosphine and triphenylphosphine oxide and afforded 3 . 14 g ( 90 %) of product as a clear oil . ms ei m / e 185 ( m + ) to a solution of 4 - hydroxyindole ( 3 g , 22 . 5 mmol ) in anhydrous n , n - dimethylformamide ( 20 ml ) was added sodium hydride ( 60 %, 1 . 08 g , 27 mmol ) at room temperature . after the reaction was allowed to stir for 40 minutes at room temperature , bromoacetonitrile ( 3 . 13 ml , 45 mmol ) was added thereto . the reaction was allowed to stir overnight at room temperature , was then quenched with water . the mixture was extracted with ethyl acetate ( 3 × 100 ml ) and washed with brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . the solvent was removed under vacuum . chromatography ( 30 % ethyl acetate - hexanes ) afforded 3 . 75 g ( 90 %) of product as a oil . to a solution of 2 -( 1h - indol - 4 - yloxy )- acetonitrile ( 0 . 9 g , 5 . 2 mmol ) in anhydrous ethyl ether ( 30 ml ) was added lithium aluminum hydride ( 95 %, 0 . 21 g , 5 . 2 mmol ) at room temperature . the reaction was allowed to reflux for 2 hours , another equivalent of lithium aluminum hydride ( 0 . 21 g , 5 . 2 mmol ) was added . the reaction was allowed to reflux for another 2 hours and then was quenched with 1n sodium hydroxide and water . the solid was removed by filtration and the filtrate was concentrated and dissolved in methanol and water . to a above mixture was added 2n hydrochloric acid until ph & lt ; 3 and then extracted with ethyl ether . to the above aqueous layer was added sodium hydroxide until ph & gt ; 9 , the mixture was extracted with isopropanol - methylene ( 1 : 3 ). the combined organic layers were washed with brine , and dried over anhydrous sodium sulfate . the solvent was removed under vacuum to afford 0 . 3 g ( 33 %) of product as a brown solid . mp : 123 - 125 ° c . ; ms ei m / e 177 ( m + ) pyrogallol ( 5 g , 0 . 04 mol ) was dissolved in 2 - butanone ( 600 ml ) and potassium carbonate ( 1 . 82 g , 0 . 013 mol ) was added to the resulting product . the mixture was stirred at reflux while 1 , 2 - dibromoethane ( 2 . 48 g , 1 . 14 ml , 0 . 013 mol ) was slowly added dropwise . the reaction was allowed to stir overnight and then was cooled to room temperature . the mixture was poured into water ( 100 ml ) and extracted with methylene chloride ( 200 ml ). the organic layer was dried over anhydrous sodium sulfate , filtered , and the solvent was removed under vacuum . chromatography ( 5 % methanol - methylene chloride ) afforded 2 . 74 g ( 45 %) of product as a clear oil ; ms ei m / e 152 ( m + ). to solution of 5 - hydroxybenzodioxin ( 1 . 0 g , 6 . 5 mmol ) and 2 - chloroethanol ( 0 . 79 g , 9 . 9 mmol ), triphenylphosphine ( 2 . 6 g , 9 . 9 nmol ) in tetrahydrofuran ( 50 ml ) was slowly added diisopropyl azodicarboxylate ( diad ) ( 2 . 0 g , 9 . 8 mmol ). after 2 hours , another 1 . 5 eq of triphenylphosphine , diad , and 2 - chloroethanol was added and the reaction stirred for another 2 hours . the reaction mixture was poured into water ( 100 ml ), and extracted with methylene chloride ( 100 ml ). the organic layer was separated and dried over anhydrous magnesium sulfate , filtered , and the solvent removed under vacuum . chromatography ( 20 % ethyl acetate - hexanes ) afforded 1 . 7 g ( 76 %) of product as a white solid : mp 70 . 5 - 72 . 5 ° c . elemental analysis for c 10 h 11 clo 3 calc &# 39 ; d c , 55 . 96 ; h , 5 . 17 found : c , 55 . 57 ; h , 5 . 20 a solution of 5 -( 2 - chloroethoxy )-( 2 , 3 )- dihydrobenzo [ 1 , 4 ] dioxin ( 4 . 6 g , 0 . 02 mol ) and sodium azide ( 2 . 78 g , 0 . 043 mol ) in anhydrous n , n - dimethyl - formamide ( 100 ml ) was allowed to stir for 18 hours at 60 ° c . the mixture was poured into water ( 200 ml ) and extracted with methylene chloride ( 3 × 100 ml ). the organic layer was washed with water ( 3 × 150 ml ), dried over anhydrous sodium sulfate , filtered , and the solvent removed under vacuum . chromatography ( 20 % ethyl acetate - hexanes ) afforded 3 . 43 g ( 72 %) of product as a clear oil . ms fab m / e 221 ( m + ) a solution of 2 -( 2 , 3 - dihydrobenzo [ 1 , 4 ] dioxin - 5 - yloxy ) ethylazide ( 3 . 43 g , 0 . 016 mol ) and triphenylphosphine ( 6 . 3 g , 0 . 023 mol ) in tetrahydrofuran ( 50 ml ) and water ( 2 ml ) was allowed to stir for 18 hours at room temperature . the solvent was removed under vacuum . chromatography ( 30 % methanol - methylene chloride plus ammonium hydroxide ) afford 1 . 93 g ( 62 %) of product as a yellow oil : ms fab m / e 196 ( m + h ) + a mixture of 6 - fluoro - 4 - oxo - chroman ( 2 g , 12 mmol ) and 10 % palladium on carbon ( 1 g ) in concentrated hydrochloric acid ( 20 ml ) and ethanol ( 30 ml ) was hydrogenated for 20 hours . the catalyst was filtered and the solvent removed under vacuum . the residue was dissolved in ethyl acetate ( 100 ml ), washed with 1n naoh ( 6 × 200 ml ) and water ( 3 × 150 ml ), dried over anhydrous sodium sulfate , filtered and the solvent was removed under vacuum . chromatography ( 20 % ethyl acetate - hexanes ) afforded 1 . 41 g ( 77 %) of product as a clear oil : ms ei m / e 152 ( m + ). to a solution of 6 - fluorochroman ( 0 . 7 g , 4 . 6 mmol ) in anhydrous methylene chloride ( 20 ml ) was slowly added ticl 4 ( 1 . 57 g , 8 . 3 mmol ) and α , α &# 39 ;- dichloromethyl methyl ether ( 0 . 53 g , 4 . 6 mmol ) at 0 ° c . the reaction was allowed to reach room temperature slowly and was stirred for 16 hours . the reaction mixture was poured into ice - water , extracted with methylene chloride ( 3 × 100 ml ), washed with saturated sodium carbonate ( 5 × 150 ml ) and brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate , filtered , and the solvent was removed under vacuum . the crude solid was collected and dried under the vacuum to afford 0 . 75 g ( 90 %) of product as a yellow solid : mp 55 - 57 ° c . elemental analysis for c 10 h 9 fo 2 calc &# 39 ; d : c , 66 . 66 ; h , 5 . 04 found : c , 66 . 64 ; h , 4 . 78 to a solution of 6 - fluorochroman - 8 - carbaldehyde ( 8 . 6 g , 48 mmol ), 3 - t - butyl - 4 - hydroxy - 5 - methylphenyl sulfide ( 100 mg ) in anhydrous methylene chloride ( 60 ml ) at 0 ° c . was added 3 - chloroperoxybenzoic acid ( mcpba ) ( 12 . 4 g , 70 mmol ) portionwise . the reaction mixture was allowed to reflux for 16 hours . the excess mcbpa was destroyed by adding 10 % sodium sulfite . the benzoic acid was filtered , and the filtrate was extracted with methylene chloride ( 3 × 150 ml ), and washed with water ( 3 × 150 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . the solvent was removed under vacuum and crude product ( 10 . 2 g , 52 mmol ) was dissolved in ethanol - water ( 200 ml , 1 : 1 ). sodium hydroxide ( 6 . 2 g , 160 mmol ) was added to above solution at 0 ° c . after 30 minutes the ice bath was removed , and the reaction mixture was allowed to stir for 3 hours at room temperature . ethanol was evaporated ,. the residue was neutralized with concentrated hydrochloric acid , extracted with methylene chloride ( 3 × 150 ml ) and washed with saturated sodium bicarbonate ( 2 × 100 ml ) and brine ( 2 × 100 ml ). the organic layer was dried over sodium sulfate , filtered and the solvent was removed under vacuum . chromatography ( 25 % ethyl acetate - hexanes ) afforded 6 . 9 g ( 79 %) of product as a white solid : mp 62 - 63 ° c . elemental analysis for c 9 h 9 fo 2 calc &# 39 ; d : c , 64 . 28 ; h , 5 . 39 found : c , 64 . 31 ; h , 5 . 27 a solution of 6 - fluorochroman - 8 - carbaldehyde ( 5 . 5 g , 33 mmol ), 1 - bromo - 2 - chloroethane ( 16 . 4 g , 114 mmol ) and potassium carbonate ( 16 g , 114 mmol ) in 2 - butanone ( 60 ml ) was refluxed for 24 hours . the mixture was poured into water ( 150 ml ), extracted with methylene chloride ( 3 × 150 ml ) and washed with brine ( 3 × 100 ml ). the organic layer was dried over sodium sulfate , filtered and the solvent was removed under vacuum . chromatography ( 20 % ethyl acetate - hexanes ) afforded 5 . 74 g of product as a white solid : mp 89 - 90 ° c . elemental analysis for c 11 h 12 fclo 2 calc &# 39 ; d : c , 57 . 28 ; h , 5 . 24 found : c , 57 . 15 ; h , 5 . 69 a solution of 2 -( 6 - fluorochroman - 8 - yloxy ) ethylchloride ( 4 . 13 g , 0 . 018 mol ) and sodium azide ( 2 . 33 g , 0 . 036 mol ) in anhydrous n , n - dimethylformamide ( 60 ml ) was allowed to stir at 60 ° c . for 18 hours . the mixture was poured into water ( 150 ml ), extracted with methylene chloride ( 3 × 150 ml ) and washed with water ( 3 × 100 ml ). the organic layer was dried over sodium sulfate , filtered and the solvent was removed under vacuum . chromatography ( 20 % ethyl acetate - hexanes ) afforded 4 . 12 g ( 97 %) of product as a clear oil . elemental analysis for c 11 h 12 fn 3 o 2 calc &# 39 ; d : c , 55 . 69 ; h , 5 . 10 ; n , 17 . 71 found : c , 55 . 44 ; h , 4 . 97 ; n , 17 . 88 a solution of 2 -( 6 - fluorochroman - 8 - yloxy ) ethylazide ( 4 . 12 g , 0 . 017 mol ) and triphenylphosphine ( 6 . 83 g , 0 . 026 mol ) in tetrahydrofuran ( 80 ml ) and water ( 1 . 5 ml ) was allowed to stir for 18 hours at room temperature . the solvent was removed under vacuum . chromatography ( ethyl acetate ) removed triphenylphosphine and triphenylphosphine oxide ( 40 % methanol - methylene chloride plus ammonium hydroxide ) to afford 3 . 45 g ( 94 %) of product as a white solid : mp 68 - 70 ° c . elemental analysis for c 11 h 14 fno 2 calc &# 39 ; d : c , 62 . 55 ; h , 6 . 68 ; n , 6 . 63 found : c , 62 . 18 ; h , 6 . 54 ; n , 6 . 63 to a suspension of sodium hydride ( 5 . 4 g , 0 . 134 mol ) in anhydrous n , n - dimethylformamide ( 100 ml ) was added 4 - fluorophenol ( 10 g , 0 . 089 mol ) at 0 ° c . after hydrogen evolution had ceased , bromo - acetaldehyde diethyl acetal ( 16 ml , 0 . 11 mol ) was added . the reaction was heated at 160 - 170 ° c . for 18 hours . the mixture was poured into ice - water , extracted with ethyl acetate ( 3 × 150 ml ) and washed with 1n sodium hydroxide ( 3 × 100 ml ) and brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate , filtered , and the solvent was removed under vacuum . chromatography ( 25 % ethyl acetate - hexanes ) afforded 16 . 36 g ( 80 %) of product as a clear oil : ms ei m / e 228 ( m + ). to a mixture of benzene ( 200 ml ) containing polyphosphoric acid ( 7 . 9 g , 0 . 035 mol ) was added 2 -( 4 - fluoro - phenoxy )- acetaldehyde diethyl acetal ( 8 g , 0 . 035 mol ). the mixture was stirred vigorously while being heated to reflux for 2 . 5 hours . the reaction mixture was cooled to room temperature and decanted from the polyphosphoric acid . the solvent was removed under vacuum . chromatography ( 5 % ethyl acetate - hexanes ) afforded 3 . 4 g ( 45 %) of product as a clear oil : 1 h nmr ( cdcl 3 or dmso - d 6 ) δ6 . 74 ( dd , 1h , j = 2 . 0 , 0 . 6 hz ), 7 . 01 ( td , 1h , j = 9 , 2 . 7 hz ), 7 . 25 ( dd , 1h , j = 8 . 4 , 2 . 7 hz ), 7 . 43 ( dd , 1h , j = 9 , 3 . 9 hz ), 7 . 65 ( d , 1h , j = 1 . 8 hz ). a solution of 5 - fluorobenzofuran and 10 % palladium on carbon in acetic acid ( 25 ml ) was hydrogenated under 50 psi for 12 hours . the catalyst was filtered through celite and the celite was washed with methylene chloride ( 200 ml ). the organic layer was washed with 1n naoh ( 3 × 100 ml ) and brine ( 3 × 100 ml ) and dried over anhydrous sodium sulfate and filtered . the solvent was removed under vacuum to afforded 2 . 59 g ( 85 %) of product as a clear oil : 1 h nmr ( 300 mhz , cdcl 3 ): δ3 . 12 ppm ( t , 2h , j = 8 . 7 hz ), 4 . 58 ( t , 2h , j = 8 . 7 hz ), 6 . 68 ( dd , 1h , j = 8 . 7 , 4 . 2 hz ), 6 . 79 ( tm , 1h , j = 8 . 7 hz ), 6 . 89 ( dm , 1h , j = 8 . 1 hz ). to a solution of 5 - fluoro - 2 , 3 - dihydrobenzofuran ( 7 g , 0 . 051 mol ) in anhydrous methylene chloride ( 40 ml ) was added titanium ( iv ) chloride ( 9 . 5 ml , 0 . 087 mol ) followed by α , α &# 39 ;- dichloromethyl methyl ether ( 4 . 6 ml , 0 . 051 mol ) at 0 ° c . the reaction was allowed to reach room temperature slowly and stirred overnight . the reaction mixture was poured into ice - water slowly , extracted with methylene chloride ( 3 × 100 ml ) and washed with saturated sodium carbonate ( 5 × 100 ml ) and brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( 25 % ethyl acetate - hexanes ) afforded 3 . 29 g ( 39 %) of product as a white solid : mp 103 - 104 ° c . elemental analysis for c 9 h 7 fo 2 calc &# 39 ; d : c , 65 . 06 ; h , 4 . 75 found : c , 65 . 01 ; h , 4 . 03 to a solution of 5 - fluoro - 2 , 3 - dihydrobenzofuran - 7 - carbaldehyde ( 3 . 29 g , 20 mmol ), 3 - t - butyl - 4 - hydroxy - 5 - methylphenyl sulfide ( 100 mg ) in anhydrous methylene chloride ( 40 ml ) at 0 ° c . was added 3 - chloroperoxybenzoic acid ( mcpba ) ( 8 . 5 g , 30 mmol ) portionwise . the reaction mixture was refluxed for 16 hours . the excess mcpba was destroyed by adding 10 % sodium sulfite . the benzoic acid was filtered off , and the filtrate was extracted with methylene chloride ( 3 × 100 ml ) and washed with water ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . the solvent was removed under vacuum and the crude product was dissolved in ethanol - water ( 100 ml , 1 : 1 ). to the above solution was added sodium hydroxide ( 2 . 11 g , 53 mmol ) at 0 ° c . after 30 minutes the ice bath was removed , and the reaction mixture was allowed to stir for 3 hours at room temperature . the ethanol was evaporated and the residue was neutralized with concentrated hydrochloric acid , extracted with methylene chloride ( 3 × 100 ml ) and washed sequentially with saturated sodium bicarbonate ( 2 × 100 ml ) and brine ( 2 × 100 ml ). the organic layer was dried over sodium sulfate , filtered and the solvent was removed under vacuum . chromatography ( 30 % ethyl acetate - hexanes ) afforded 1 . 62 g ( 50 %) of product as a white solid : mp 102 . 5 - 103 . 5 ° c . elemental analysis for c 8 h 7 fo 2 calc &# 39 ; d : c , 62 . 34 ; h , 4 . 58 found : c , 62 . 19 ; h , 4 . 59 a solution of 5 - fluoro - 7 - hydroxy - 2 , 3 - dihydro - benzofuran ( 1 . 6 g , 10 mmol ), 1 - bromo - 2 - chloroethane ( 7 . 8 g , 55 mmol ) and potassium carbonate ( 2 . 2 g , 16 mmol ) in 2 - butanone ( 40 ml ) was refluxed for 24 hours . the mixture was poured into water ( 150 ml ), extracted with methylene chloride ( 3 × 150 ml ) and washed with brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate , filtered and the solvent was removed under vacuum . chromatography ( 25 % ethyl acetate - hexanes ) afforded 2 . 10 g of product as a white solid : mp 72 . 5 - 74 . 5 ° c . elemental analysis for c 10 h 10 fclo 2 calc &# 39 ; d : c , 55 . 44 ; h , 4 . 65 found : c , 55 . 37 ; h , 4 . 58 a solution of 2 -( 5 - fluoro - 2 , 3 - dihydro - benzofuran - 7 - yloxy ) ethylchloride ( 2 . 05 g , 9 . 4 mmol ) and sodium azide ( 1 . 23 g , 19 mol ) in anhydrous n , n - dimethylformide ( 30 ml ) was allowed to stir at 60 ° c . for 24 hours . the mixture was poured into water ( 100 ml ), extracted with methylene chloride ( 3 × 150 ml ) and washed with water ( 3 × 100 ml ). the organic layer was dried over sodium sulfate , filtered and the solvent was removed under vacuum . chromatography ( 20 % ethyl acetate - hexanes ) afforded 2 . 0 g ( 95 %) of product as a clear oil : ms esi m / e 241 [ m + 1 ] + . a solution of 2 -( 5 - fluoro - 2 , 3 - dihydrobenzofuran - 7 - yloxy ) ethylazide ( 1 . 98 g , 89 mmol ) and triphenylphosphine ( 2 . 8 g , 10 . 6 mmol ) in tetrahydrofuran ( 50 ml ) and water ( 1 . 5 ml ) was allowed to stir for 18 hours at room temperature . the solvent was removed under vacuum . chromatography ( ethyl acetate ) removed triphenylphosphine and triphenylphosphine oxide and ( 40 % methanol - methylene chloride plus ammonium hydroxide ) afforded 2 . 0 g ( 100 %) of product as a clear oil : ms esi m / e 198 [ m + 1 ] + a solution of 4 - fluoro - 2 - hydroxyacetophenone ( 1 g , 6 . 5 mmol ), methyl iodide ( 0 . 4 ml ), potassium carbonate ( 1 . 34 g , 9 . 7 mmol ) in anhydrous dimethylsulfoxide ( 20 ml ) was allowed to stir at room temperature for 2 hours . the mixture was poured into water ( 100 ml ) and extracted with methylene chloride ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . the solvent was removed under vacuum to afford 1 . 1 g ( 100 %) of product as a light yellow solid : mp 50 - 51 . 5 ° c . elemental analysis for c 9 h 9 fo 2 calc &# 39 ; d : c , 64 . 28 ; h , 5 . 39 found : c , 64 . 22 ; h , 5 . 49 to a cooled ( 0 ° c .) solution of 4 - fluoro - 2 - methoxyacetophenone ( 16 . 8 g , 0 . 1 mol ) and 3 - tert - butyl - 4 - hydroxy - 5 - methylphenyl sulfide ( 200 mg ) in methylene chloride ( 300 ml ) was added 3 - chloroperoxybenzoic acid ( m - cpba ) ( 37 g , 0 . 15 mol ) portionwise over a period of 5 minutes under an inert atmosphere . the mixture was refluxed for 14 hours . the solution was cooled to 0 ° c ., and the excess m - cpba was destroyed by vigorously stirring with 10 % aqueous sodium sulfite for 20 minutes . the organic layer was separated and then washed with equal volumes of water ( 3 × 150 ml ), 5 % sodium bicarbonate , water and brine . the organic layer was dried over anhydrous sodium sulfate , filtered and the solvent was removed under vacuum affording a yellow oil . the yellow oil was dissolved in 200 ml ethanol - water ( 1 : 1 ) and sodium hydroxide ( 0 . 3 mol ) was added at 0 ° c . under inert atmosphere . after 0 . 5 hour the ice - bath was removed and the reaction mixture stirred at room temperature for 2 hours . evaporation of the solvent under vacuum followed by neutralization with concentrated hydrochloric acid precipitated an oil which was extracted with methylene chloride ( 150 ml ). the organic layer was washed with equal volumes of water ( 3 × 150 ml ) and brine . the organic layer was dried over anhydrous sodium sulfate and filtered . the solvent was removed under vacuum . chromatography ( 25 % ethyl acetate - hexanes ) afforded 10 . 0 g ( 71 %) of product as a light - yellow oil ; ms ei m / e 142 ( m + ). to a suspension of sodium hydride ( 5 . 4 g , 0 . 13 mol ) in anhydrous n , n - dimethyl - formamide ( 100 ml ) was added 4 - fluoro - 2 - methoxyphenol ( 12 . 05 g , 0 . 085 mol ) at 0 ° c . after h 2 evolution had ceased , bromo - acetaldehyde diethyl acetal ( 14 . 66 ml , 0 . 1 mol ) was added . the reaction was heated at 160 - 170 ° c . for 18 hours . the mixture was poured into ice - water , extracted with ethyl acetate ( 3 × 150 ml ) and washed sequentially with 1n sodium hydroxide ( 3 × 100 ml ) and brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . the solvent was removed under vacuum . chromatography ( 25 % ethyl acetate - hexanes ) afforded 21 . 48 g ( 98 %) of product as a yellow oil : ms ei m / e 258 ( m + ). to a mixture of xylene ( 100 ml ) containing polyphosphoric acid ( 40 g ) was added 2 -( 2 - methoxy - 4 - fluoro - phenoxy )- acetaldehyde diethyl acetal ( 10 g ). the mixture was stirred while being heated to reflux for 0 . 5 hour . the reaction mixture was cooled to room temperature , and decanted from the polyphosphoric acid . the solvent was removed under vacuum . chromatography ( 25 % ethyl acetate - hexanes ) afforded 1 . 74 g ( 15 %) of product as a yellow oil : ms ei m / e 166 ( m + ) 5 - fluoro - 7 - methoxybenzofuran ( 2 . 16 g , 13 mmol ) was dissolved in anhydrous methylene chloride ( 25 ml ) in 100 ml round - bottom flask . the flask was placed in an acetone - ice bath at - 78 ° c . the flask was fitted with a air - condenser . a solution of boron tribromide in methylene chloride ( 1 m , 19 . 5 ml ) was added carefully to the stirred solution through the condenser . the reaction was kept at - 78 ° c . for 6 hours , then was allowed to stir at room temperature overnight . the reaction was quenched by adding water ( 20 ml ) and diluted with ethyl ether . the solvent was removed under vacuum . chromatography ( 25 % ethyl acetate - hexanes ) afforded 1 . 4 g ( 71 %) of product as a yellow oil . ms ei 152 m / e ( m + ) to a solution of 5 - fluoro - 7 - hydroxybenzofuran ( 1 . 4 g , 9 . 2 mmol ), triphenylphosphine ( 6 g , 23 mmol ), 2 - chloroethanol ( 1 . 53 ml , 23 mmol ) in tetrahydrofuran ( 50 ml ) was slowly added diisopropyl azodicarboxylate ( 4 . 5 ml , 23 mmol ). the reaction was stirred at room temperature for 2 hours , and the tetrahydrofuran was removed under vacuum . chromatography ( 25 % ethyl acetate - hexanes ) afforded 1 . 76 g ( 89 %) of product as a yellow oil : ms ei 214 m / e ( m + ). a solution 2 -( 5 - fluoro - benzofuran - 7 - yloxy )- ethylchloride ( 4 . 6 g , 0 . 02 mol ) and sodium azide ( 2 . 78 g , 0 . 043 mol ) in anhydrous n , n - dimethylformamide ( 100 ml ) was allowed to stir for 18 hours at 60 ° c . the mixture was poured into water ( 200 ml ), and extracted with methylene chloride ( 3 × 100 ml ). the organic layer was washed with water ( 3 × 150 ml ), dried over anhydrous sodium sulfate , filtered , and the solvent removed under vacuum . chromatography ( 20 % ethyl acetate - hexanes ) afforded 3 . 43 g ( 72 %) of product as a clear oil : ms fab m / e 221 ( m + ) a solution 2 -( 5 - fluoro - benzofuran - 7 - yloxy )- ethylazide ( 0 . 82 g , 3 . 7 mmol ) and triphenylphosphine ( 1 . 17 g , 4 . 4 mmol ) in tetrahydrofuran ( 50 ml ) and water ( 2 ml ) was allowed to stir for 18 hours at room temperature . the solvent was removed under vacuum . chromatography ( 30 % methanol - methylene chloride plus ammonium hydroxide ) afford 0 . 55 g ( 73 %) of product as a yellow oil : ms esi 196 m / e ( m + h ) + a slurry containing 2 - amino - 3 - nitrophenol ( 32 . 0 g , 0 . 208 mol ), 1 , 2 - dichloroethane ( 260 . 0 g , 2 . 65 mol ), potassium carbonate ( 35 . 0 g , 0 . 252 mol ) and 2 - butanone ( 750 ml ) was refluxed for 24 hours . the mixture was cooled , filtered and the solids were washed with ethyl acetate . the filtrate was concentrated to an oily residue that was dissolved in ethyl acetate ( 500 ml ). the organic layer was washed sequentially with 1n sodium hydroxide ( 250 ml ), water ( 500 ml ) and brine ( 2 × 500 ml ) and then dried over anhydrous magnesium sulfate . concentration of the filtered solution and trituration of the residue with hexanes afforded 37 . 8 g ( 84 . 6 %) of product as an orange solid : mp 71 - 73 ° c . ; ms ei m / e 216 ( m + ). elemental analysis for c 8 h 9 cin 2 o 3 calc &# 39 ; d : c , 44 . 36 ; h , 4 . 19 ; n , 12 . 93 found : c , 44 . 45 ; h , 4 . 02 ; n , 12 . 97 a solution of 2 -( 2 - chloro - ethoxy )- 6 - nitro - phenylamine ( 30 . 0 g , 0 . 14 mol ), n - chlorosuccinimide and acetonitrile ( 1 . 3 l ) was refluxed for 4 hours . the mixture was concentrated under vacuum and the residue was diluted with ethyl acetate ( 500 ml ). the organic layer was washed with water ( 2 × 250 ml ) and brine ( 250 ml ), dried over anhydrous magnesium sulfate , filtered , and the solvent removed under vacuum to give an orange solid residue . crystallization from ethyl acetate - hexanes gave 33 . 5 g ( 95 . 3 %) of product as an orange solid : mp 109 - 110 ° c . ; ms ( ei ) 250 / 252 / 254 m / e ( m + ). elemental analysis for c 8 h 8 cl 2 n 2 o 3 calc &# 39 ; d : c , 38 . 27 ; h , 3 . 21 ; n , 11 . 16 found : c , 38 . 15 ; h , 3 . 10 ; n , 10 . 96 a solution of 2 -( 2 - chloro - ethoxy )- 4 - chloro - 6 - nitro - phenylamine ( 3 . 07 g , 12 . 2 mmol ), sodium azide ( 1 . 59 g , 24 . 4 mmol ) in anhydrous n , n - dimethylformamide ( 30 ml ) was allowed to heat at 60 ° c . for 18 hours . the reaction was poured into water ( 150 ml ) and extracted with ethyl ether ( 2 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate , filtered and the solvent was removed under vacuum to afford an orange solid . the solid was washed with ethyl ether ( 5 ml ) to afford an orange crystalline solid : mp 113 - 114 ° c . elemental analysis for c 8 h 8 n 5 o 2 cl calc &# 39 ; d : c , 37 . 298 ; h , 3 . 13 , n , 27 . 19 found : c , 37 . 60 ; h , 2 . 94 ; n , 26 . 98 a solution of 2 -( 2 - azido - ethoxy )- 4 - chloro - 6 - nitro - phenylamine ( 1 . 9 g , 7 . 36 mmol ) and triphenylphosphine ( 2 . 27 g , 8 . 65 mmol ) in tetrahydrofuran ( 80 ml ) and water ( 2 ml ) was allowed to stir for 24 hours at room temperature . the solvent was removed under vacuum and the solid washed with methylene chloride ( 30 ml ) to afford an orange solid : mp 156 - 157 ° c . elemental analysis for c 8 h 10 n 3 o 3 calc &# 39 ; d : c , 41 . 48 ; h , 4 . 35 ; n , 18 . 19 found : c , 40 . 01 ; h , 4 . 05 ; n , 16 . 82 a solution of 2 -( 2 - amino - ethoxy )- 4 - chloro - 6 - nitro - phenylanmine ( 0 . 8 g , 3 . 45 mmol ), 4 -( 6 - fluoro - 1h - indol - 3 - yl )- cyclohexanone ( 0 . 82 g , 3 . 56 mmol ), sodium triacetoxyborohydride ( 1 . 05 g , 4 . 96 mmol ) and acetic acid ( 0 . 62 g ) in 1 , 2 - dichloroethane ( 80 ml ) was allowed to stir at room temperature for 24 hours . the reaction was quenched with 1n sodium hydroxide ( 20 ml ), extracted with methylene chloride ( 3 × 100 ml ) and washed with brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( 10 % methanol - ethyl acetate ) afforded 0 . 78 g ( 85 % pure ) of product : ms ( ei ) m / e ( m + ). to a mixture of 2 -{ 2 -[( 1 , 4 - trans )- 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexylamino ]- ethoxy }- 4 - chloro - 6 - nitro - phenylamine ( 0 . 78 g , 1 . 7 mmol ) and raney nickel ( 0 . 76 g ) in methanol ( 40 ml ) was slowly added hydrazine monohydrate ( 1 . 1 ml ). the reaction was allowed to reflux for 0 . 5 hour . the catalyst was filtered off and the solvent removed under vacuum . chromatography ( 10 % methanol - ethyl acetate ) afforded 0 . 56 g ( 90 %) of product as a light - yellow foam : ms esi m / e 417 ( m + h ) + . to a solution of 4 - fluorophenol ( 5 . 6 g , 50 mmol ), triphenylphosphine ( 19 . 7 g , 75 mmol ), 2 - chloroethanol ( 5 . 03 ml , 75 mmol ) in tetrahydrofuran ( 100 ml ) was slowly added diethyl azodicarboxylate ( 11 . 8 ml , 75 mmol ). the reaction was stirred at room temperature for 2 hours , and the tetrahydrofuran was removed under vacuum . chromatography ( 5 % ethyl acetate - hexanes ) afforded 6 . 5 g ( 75 %) of product as a oil : 1 h nmr ( 400 mhz , cdcl 3 ): δ3 . 80 ( 2h , t , j = 5 . 92 hz ); 4 . 19 ( 2h , t , j = 5 . 96 hz ); 6 . 85 - 6 . 88 ( 2h , m ); 6 . 95 - 7 . 00 ( 2h , m ). to a solution of 2 -( 4 - fluoro - phenoxy )- ethylchloride ( 5 . 23 g , 30 mmol ) in anhydrous methylene chloride ( 20 ml ) was slowly added ticl 4 ( 5 . 61 g , 51 mmol ) and α , α &# 39 ;- dichloromethyl methyl ether ( 2 . 77 g , 30 mmol ) at 0 ° c . the reaction was allowed to reach room temperature slowly and was stirred for 2 hours . the reaction mixture was poured into ice - water , extracted with methylene chloride ( 3 × 100 ml ) and washed sequentially with saturated sodium carbonate ( 5 × 150 ml ) and brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate , filtered , and the solvent was removed under vacuum . chromatography ( 20 % ethyl acetate - hexanes ) afforded 5 . 5 g ( 59 %) of product as a oil : ms ( ei ) 202 / 204 m / e ( m + ). to a solution of 2 -( 2 - chloro - ethoxy )- 5 - fluoro - carbaldehyde ( 6 . 0 g , 29 . 6 mmol ), 3 - t - butyl - 4 - hydroxy - 5 - methylphenyl sulfide ( 100 mg ) in anhydrous methylene chloride ( 60 ml ) at 0 ° c . was added 3 - chloroperoxybenzoic acid ( mcpba ) ( 10 . 9 g ) portionwise . the reaction mixture was allowed to reflux for 16 hours . the excess mcbpa was destroyed by adding 10 % sodium sulfite . the benzoic acid was filtered and the filtrate was extracted with methylene chloride ( 3 × 150 ml ) and washed with water ( 3 × 150 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . the solvent was removed under vacuum to afford a crude product 4 . 8 g ( 22 mmol ) which was dissolved in anhydrous n , n - dimethylformamide ( 30 . ml ). to above solution was added sodium azide ( 4 . 3 g , 66 mmol ). the mixture was allowed to heat at 60 ° c . for 18 hours . the reaction was poured into water ( 150 ml ) and extracted with ethyl ether ( 2 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate , and the solvent was removed under vacuum . chromatography ( 20 % ethyl acetate - hexanes ) afforded 0 . 8 g of product as a oil . to a solution of 2 -( 4 - fluoro - 2 - hydroxy - phenoxy ) ethylazide ( 0 . 8 g , 4 . 06 mmol ), triphenylphosphine ( 3 . 2 g , 12 . 2 mmol ), methanol ( 0 . 5 ml , 12 . 2 mmol ) in dioxane ( 15 ml ) was slowly added diethyl azodicarboxylate ( 1 . 9 ml , 12 . 2 mmol ). the reaction was stirred at room temperature for 2 hours . the solvent was removed under vacuum . chromatography ( 20 % ethyl acetate - hexanes ) afforded 0 . 6 g ( 70 %) of product as a oil , which was dissolved in tetrahydrofuran ( 15 ml ) and water ( 0 . 06 ml ). to the above solution was added triphenylphosphine ( 1 . 04 g , 2 . 8 mmol ), and the mixture was allowed to stir for 18 hours at room temperature . the solvent was removed under vacuum . chromatography ( 90 % ethyl acetate - methanol plus ammonium hydroxide ) afforded 0 . 43 g ( 80 %) of product as a clear oil : ms ( ei ) 185 m / e ( m + ). to a suspension of ( methoxymethyl ) triphenylphosphonium chloride in tetrahydrofuran ( 26 ml ) was added n - butyllithium ( 5 . 2 ml , 13 mmol ) at - 78 ° c . the mixture was allowed to stir for 20 minutes at 78 ° c ., then a solution of 4 -( 5 - fluoro - 1h - 3 - indolyl )- cyclohexanone ( 1 . 5 g , 6 . 5 mmol ) was added . after addition , the reaction mixture was warmed to - 10 ° c ., and allowed to stir for 2 hours . the mixture was quenched with saturated ammonium chloride and diluted with ethyl acetate . the organic layer was separated , dried over anhydrous sodium sulfate and filtered . chromatography ( 25 % ethyl acetate - hexanes ) afforded 0 . 61 g ( 36 %) of product as a clear oil : ms ( ei ) 259 m / e ( m + ). the above compound was prepared in the manner described for ( 53a ) using 4 -( 5 - cyano - 1h - 3 - indolyl )- cyclohexanone ( 3c ) to obtain in 30 % yield ( 2 . 8 g ) of product as a white solid : ms (+ esi ) 267 m / e ( m + h ) + . to a solution of 3 -[ 4 -( methoxymethylene ) cyclohexyl ]- 5 - fluoro - 1h - indole in methanol ( 3 ml ) was added 1n hcl ( 40 ml ) at room temperature . the mixture was allowed to reflux for 30 minutes , whereby an oil precipitated . to the above mixture was added acetone ( 10 ml ), and the mixture was allowed to reflux for another 30 min and cooled to room temperature . the mixture was extracted with ethyl acetate , dried over anhydrous sodium sulfate and filtered . the solvent was removed under vacuum to afford 0 . 4 g of the title compound . the compound was prepared in the manner described for intermediate ( 54a ) using intermediate 53b to obtain the product in 6 % yield ( 0 . 15 g ). to a solution of 1 , 2 - difluoro - 4 , 5 - dimethoxybenzene ( 2 . 61 g , 15 mmol ) in n , n - dimethylformamide ( 20 ml ) was added sodium thiomethoxide ( 95 %, 1 . 11 g , 15 mmol ). the reaction was allowed to reflux for 3 hours and then was cooled to room temperature . the mixture was poured into 200 ml ice - water and neutralized with 2 n hcl . the aqueous layer was extracted with ethyl ether ( 2 × 100 ml ), washed with water , dried over anhydrous sodium sulfate and filtered . the solvent was removed under vacuum to afford a mixture of the two title products . to a solution of a mixture of 2 - methoxy - 4 , 5 - difluoro - phenol ( intermediate 55 ) and 2 - methoxy - 4 - methylthio - 5 - fluoro - phenol ( intermediate 56 ) ( 0 . 66 g ), triphenylphosphine ( 2 . 16 g ), 2 - chloroethanol ( 0 . 55 ml ) in tetrahydrofuran ( 15 ml ) was slowly added diethyl azodicarboxylate ( 1 . 3 ml ). the reaction was stirred at room temperature for 2 hours . tetrahydrofuran was removed under vacuum . chromatography ( 10 % ethyl acetate - hexanes ) afforded 0 . 31 g of 1 , 2 - difluoro - 4 -( 2 - chloroethoxy )- 5 - methoxy - benzene ( intermediate 57 ) as a white solid : mp 51 - 52 ° c . ; ms ei m / e 222 ( m + ), and 0 . 1 g of 1 - fluoro - 2 - methylthio - 4 -( 2 - chloroethoxy )- 5 - methoxy - benzene ( intermediate 62 ) as a white solid : mp 58 - 60 ° c . ; ms ei m / e 250 ( m + ). to a solution of 1 , 2 - difluoro - 4 -( 2 - chloroethoxy )- 5 - methoxy - benzene ( 0 . 77 g , 3 . 46 mmol ) in n , n - dimethylformamide ( 30 ml ) was added sodium azide ( 0 . 67 g , 10 . 4 mmol ). the mixture was allowed to heat at 60 ° c . for 18 hours . the reaction was poured into water ( 150 ml ) and extracted with ethyl ether ( 2 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate , filtered and the solvent was removed under vacuum . chromatography ( 20 % ethyl acetate - hexanes ) afforded 0 . 69 g of product as a oil . a solution of 2 -( 2 - methoxy - 4 , 5 - difluoro - phenoxy )- ethylazide ( 0 . 69 g , 3 . 46 mmol ) and triphenylphosphine ( 1 . 27 g , 4 . 84 mmol ) in tetrahydrofuran ( 15 ml ) containing water ( 0 . 08 ml ) was stirred at room temperature overnight . the solvent was removed under vacuum . chromatography with ethyl acetate removed triphenylphosphine oxide , followed elution with ethyl acetate - methanol - ammonium hydroxide 8 . 5 : 1 . 5 : 0 . 5 , afforded 0 . 53 g of product as a white solid : mp 44 - 46 ° c . ; ms ei m / e 203 ( m + ). a solution of 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexanone ( 2 . 31 g , mmol ), benzylamine ( 1 . 1 g , 10 mmol ), sodium triacetoxyborohydride ( 3 . 1 g , 14 mmol ) and acetic acid ( 0 . 57 ml ) in 1 , 2 - dichloroethane ( 30 ml ) was allowed to stir at room temperature for 4 hours . the reaction was quenched with 1n sodium hydroxide ( 10 ml ), extracted with methylene chloride ( 3 × 60 ml ) and washed with brine ( 3 × 60 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( ethyl acetate - hexanes - methanol - ammonium hydroxide : 50 : 50 : 5 : 0 . 5 ) afforded 0 . 51 g ( 16 %) of product as a white solid : mp 131 - 133 ° c . ms ei m / e 322 ( m + ) a mixture of ( trans )- 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexyl - benzyl amine ( 0 . 24 g , 0 . 74 mmol ) and 10 % palladium on carbon ( 0 . 1 g ) in ethanol ( 30 ml ) was hydrogenated overnight . the catalyst was filtered off and the solvent removed under vacuum . chromatography ( ethyl acetate - methanol - ammonium hydroxide : 9 : 1 : 0 . 1 ) afforded 0 . 17 g ( 100 %) of product as a white solid : mp 198 - 200 ° c . ; ms ei m / e 232 ( m + ). to a solution of 1 - fluoro - 2 - methylthio - 4 -( 2 - chloroethoxy )- 5 - methoxy - benzene in tetrahydrofuran ( 20 ml ) was added 3 - chloroperoxybenzoic acid ( mcpba ) ( 1 . 07 g ). the mixture was allowed to stir overnight at room temperature and quenched with na 2 s 2 o 5 . the mixture was diluted with ethyl acetate and washed with sodium bicarbonate and water . the organic layer was separated , dried over anhydrous sodium sulfate and filtered . chromatography ( 30 % ethyl acetate -- hexanes ) afforded 0 . 19 g of product as a white solid : mp 85 - 87 ° c . ; ms ei m / e 282 ( m + ). to a suspension of trimethylsulfoxonium iodide ( 1 . 3 g , 6 mmol ) in tetrahydrofuran ( 15 ml ) was added sodium hydride ( 60 %, 0 . 24 g , 6 mmol ) at room temperature . the reaction mixture was allowed to reflux for 1 hour . the mixture was cooled to room temperature , followed by addition of 4 -( 5 - fluoro - 1h - 3 - indolyl )- cyclohexanone in tetrahydrofuran ( 5 ml ) to above solution . after stirring for 2 hours at room temperature , the mixture was quenched with ammonium chloride and diluted with ethyl acetate . the organic layer was washed with water , dried over anhydrous sodium sulfate and filtered . chromatography ( 30 % ethyl acetate - hexanes ) afforded 0 . 45 g ( 92 %) of product as a white solid : mp 108 - 110 ° c . ; ms ei m / e 245 ( m + ). a solution of 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexanone ( 0 . 38 g , 1 . 6 mmol ), [ 2 -( 2 - methoxy - phenoxy )- ethyl ]- amine ( 0 . 27 g , 1 . 6 mmol ), sodium triacetoxyborohydride ( 0 . 5 g , 2 . 2 mmol ) and acetic acid ( 0 . 06 ml , 1 . 8 mmol ) in 1 , 2 - dichloroethane ( 8 ml ) was allowed to stir at room temperature for 4 hours . the reaction was quenched with 1n sodium hydroxide ( 10 ml ), extracted with methylene chloride ( 3 × 60 ml ) and washed with brine ( 3 × 60 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( 10 % methanol - ethyl acetate ) afforded 0 . 43 g ( 71 %) of product as a white solid . the hcl salt was prepared in ethyl acetate : mp 186 - 188 ° c . elemental analysis for c 23 h 27 fn 2 o 2 . hcl . 0 . 06c 4 h 8 o 2 calc &# 39 ; d : c , 65 . 80 ; h , 6 . 77 ; n , 6 . 60 found : c , 65 . 59 ; h , 6 . 69 ; n , 6 . 44 the trans compound was isolated at same time as the cis isomer ( example 1a ) in 19 % yield ( 0 . 115 g ) as a white solid . elemental analysis for c 23 h 26 f 2 n 2 o 2 . 0 . 5c 4 h 4 o 4 calc &# 39 ; d : c , 67 . 47 ; h , 6 . 68 ; n , 6 . 29 found : c , 67 . 22 ; h , 6 . 53 ; n , 6 . 14 a solution of 4 -( 6 - fluoro - 1h - indol - 3 - yl )- cyclohexanone ( 0 . 62 g , 2 . 7 mmol ), [ 2 -( 5 - fluoro - 2 - methoxy - phenoxy )- ethyl ]- amine ( 0 . 5 g , 2 . 7 mmol ), sodium triacetoxyborohydride ( 0 . 86 g , 4 mmol ) and acetic acid ( 0 . 32 g , 5 . 4 mmol ) in 1 , 2 - dichloroethane ( 20 ml ) was allowed to stir at room temperature for 16 hours . the reaction was quenched with 1n sodium hydroxide ( 20 ml ), extracted with methylene chloride ( 3 × 100 ml ) and washed with brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( 10 % methanol - ethyl acetate ) afforded 0 . 75 g ( 73 %) of product as a clear oil . elemental analysis for c 23 h 26 f 2 n 2 o 2 . hcl . 0 . 5h 2 o calc &# 39 ; d : c , 61 . 95 ; h , 6 . 33 ; n , 6 . 28 found : c , 62 . 02 ; h , 6 . 28 ; n , 5 . 87 the trans compound was isolated at same time as the cis isomer in 14 % yield ( 0 . 15 g ) as a clear oil . elemental analysis for c 23 h 26 f 2 n 2 o 2 . 1 . 5c 2 h 2 o 4 calc &# 39 ; d : c , 58 . 31 ; h , 5 . 46 ; n , 5 . 23 found : c , 58 . 58 ; h , 5 . 27 ; n , 5 . 33 a solution of 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexanone ( 0 . 87 g , 3 . 75 mmol ), [ 2 -( 1h - indol - 4 - yloxy )- ethyl ]- amine ( 0 . 66 g , 3 . 75 mmol ), sodium triacetoxyborohydride ( 1 . 17 g , 5 . 25 mmol ) and acetic acid ( 0 . 22 ml , 3 . 75 mmol ) in 1 , 2 - dichloroethane ( 17 ml ) was allowed to stir at room temperature for 5 hours . the reaction was quenched with 1n sodium hydroxide ( 10 ml ), extracted with methylene chloride ( 3 × 60 ml ) and washed with brine ( 3 × 60 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( 2 % methanol - ethyl acetate plus 0 . 2 % ammonium hydroxide ) afforded 0 . 71 g ( 48 %) of product as a solid : mp 74 - 76 ° c . elemental analysis for c 24 h 26 fn 3 o . 0 . 5c 4 h 4 o 4 . 0 . 5c 3 h 8 o calc &# 39 ; d : c , 68 . 23 ; h , 6 . 77 ; n , 8 . 68 found : c , 68 . 07 ; h , 6 . 75 ; n , 8 . 43 the trans compound was isolated at same time as the cis isomer ( example 3a ) in 11 % yield ( 0 . 16 g ) as a white solid : mp 78 - 80 ° c . the fumarate salt was prepared in isopropanol : mp 245 ° c . ( decomposed ). elemental analysis for c 24 h 26 fn 3 o . 0 . 5c 4 h 4 o 4 calc &# 39 ; d : c , 68 . 78 ; h , 6 . 33 ; n , 9 . 25 found : c , 68 . 66 ; h , 6 . 31 ; n , 9 . 04 a solution of 4 -( 1h - indol - 3 - yl )- cyclohexanone ( 0 . 42 g , 1 . 99 mmol ), [ 2 -( 1h - indol - 4 - yloxy )- ethyl ]- amine ( 1 . 99 mmol ), sodium triacetoxyborohydride ( 0 . 62 g , 2 . 79 mmol ) and acetic acid ( 0 . 11 ml , 1 . 99 mmol ) in 1 , 2 - dichloroethane ( 10 ml ) was allowed to stir at room temperature for 5 hours . the reaction was quenched with 1n sodium hydroxide ( 10 ml ), extracted with methylene chloride ( 3 × 60 ml ) and washed with brine ( 3 × 60 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( methanol - ethyl acetate - hexanes - ammonium hydroxide 5 : 5 : 0 . 5 : 0 . 1 ) afforded 0 . 11 g of product . the hcl salt was prepared in ethyl acetate : mp 157 ° c . ( decomposed ). elemental analysis for c 24 h 27 n 3 ohcl calc &# 39 ; d : c , 66 . 65 ; h , 7 . 11 ; n , 9 . 72 found : c , 66 . 91 ; h , 6 . 89 ; n , 9 . 52 the trans compound was isolated at same time as the cis isomer ( example 3c ) in 14 % yield ( 0 . 12 g ). the hcl salt was prepared in ethyl acetate : mp 249 ° c . ( decomposed ). elemental analysis for c 24 h 27 n 3 o . hcl calc &# 39 ; d : c , 68 . 80 ; h , 6 . 98 ; n , 10 . 03 found : c , 68 . 74 ; h , 6 . 88 ; n , 10 . 03 a solution of 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexanone ( 0 . 78 g , 3 . 4 mmol ), [ 2 -( 2 , 3 )- dihydro - benzo [ 1 , 4 ] dioxin - 5 - yloxy )]- ethyl - amine ( 0 . 66 g , 3 . 4 mmol ), sodium triacetoxyborohydride ( 1 . 08 g , 5 mmol ) and acetic acid ( 0 . 3 g , 5 . 1 mmol ) in 1 , 2 - dichloroethane ( 50 ml ) was allowed to stir at room temperature for 4 hours . the reaction was quenched with 1n sodium hydroxide ( 20 ml ), extracted with methylene chloride ( 3 × 100 ml ), and washed with brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( 10 % methanol - ethyl acetate plus 0 . 2 % ammonium hydroxide ) afforded 0 . 67 g ( 48 %) of product as a clear oil . elemental analysis for c 24 h 27 fn 2 o 3 . c 2 h 2 o 4 calc &# 39 ; d : c , 62 . 35 ; h , 5 . 84 ; n , 5 . 59 found : c , 62 . 09 ; h , 5 . 86 ; n , 5 . 41 the trans compound was isolated at same time as the cis isomer ( example 4a ) in 12 % yield ( 0 . 16 g ) as a clear oil . elemental analysis for c 24 h 27 fn 2 o 3 . c 2 h 2 o 4 . 0 . 5h 2 o calc &# 39 ; d : c , 61 . 29 ; h , 5 . 94 ; n , 5 . 50 found : c , 61 . 47 ; h , 5 . 87 ; n , 5 . 22 a solution of 4 -( 6 - fluoro - 1h - indol - 3 - yl )- cyclohexanone ( 0 . 71 g , 3 . 1 mmol ), [ 2 -( 2 , 3 )- dihydro - benzo [ 1 , 4 ] dioxin - 5 - yloxy )]- ethyl - amine ( 0 . 6 g , 3 . 1 mmol ), sodium triacetoxyborohydride ( 0 . 98 g , 4 . 6 mmol ) and acetic acid ( 0 . 37 g , 6 . 1 mmol ) in 1 , 2 - dichloroethane ( 30 ml ) was allowed to stir at room temperature for 4 hours . the reaction was quenched with 1n sodium hydroxide ( 20 ml ), extracted with methylene chloride ( 3 × 100 ml ), and washed with brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( 10 % methanol - ethyl acetate plus 0 . 2 % ammonium hydroxide ) afforded 0 . 83 g ( 58 %) of product as a clear oil . elemental analysis for c 24 h 27 fn 2 o 3 . c 2 h 2 o 4 calc &# 39 ; d : c , 62 . 35 ; h , 5 . 84 ; n , 5 . 59 found : c , 62 . 22 ; h , 5 . 89 ; n , 5 . 46 the trans compound was isolated at same time as the cis isomer ( example 4c ) in 17 % yield ( 0 . 24 g ) as a clear oil . elemental analysis for c 24 h 27 fn 2 o 3 . c 2 h 2 o 4 . 0 . 25h 2 o calc &# 39 ; d : c , 61 . 34 ; h , 6 . 26 ; n , 5 . 26 found : c , 61 . 06 ; h , 6 . 31 ; n , 5 . 01 a solution of 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexanone ( 0 . 46 g , 2 . 4 mmol ), 2 -( 6 - fluorochroman - 8 - yloxy ) ethylamine ( 0 . 5 g , 2 . 4 mmol ), sodium triacetoxyborohydride ( 0 . 75 g , 3 . 6 mmol ) and acetic acid ( 0 . 28 g , 4 . 7 mmol ) in 1 , 2 - dichloroethane ( 20 ml ) was allowed to stir at room temperature for 16 hours . the reaction was quenched with 1n sodium hydroxide ( 20 ml ), extracted with methylene chloride ( 3 × 100 ml ) and washed with brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( 10 % methanol - ethyl acetate ) afforded 0 . 65 g ( 64 %) of product as a clear oil . elemental analysis for c 23 h 26 f 2 n 2 o 2 . hcl calc &# 39 ; d : c , 64 . 86 ; h , 6 . 31 ; n , 6 . 05 found : c , 65 . 32 ; h , 6 . 30 ; n , 6 . 06 the trans compound was isolated at same time as the cis isomer ( example 5a ) in 19 % yield ( 0 . 19 g ) as a clear oil . elemental analysis for c 25 h 28 f 2 n 2 o 2 . c 2 h 2 o 4 . 0 . 5h 2 o calc &# 39 ; d : c , 61 . 70 ; h , 5 . 95 ; n , 5 . 33 found : c , 61 . 38 ; h , 6 . 10 ; n , 5 . 15 this compound was prepared in the manner as described above for example 5a by replacing 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexanone with 4 -( 5 - cyano - 1 - methyl - 3 - indolyl )- cyclohexanone ( 0 . 6 g , 2 . 8 mmol ) to obtain 38 % ( 0 . 41 g ) of product as a clear oil . elemental analysis for c 27 h 30 fn 3 o 2 . c 2 h 2 o 4 calc &# 39 ; d : c , 64 . 79 ; h , 6 . 00 ; n , 7 . 82 found : c , 64 . 70 ; h , 6 . 02 ; n , 7 . 60 the trans compound was isolated at same time as the cis isomer ( example 5c ) in 13 % yield ( 0 . 14 g ) as a clear oil . elemental analysis for c 27 h 30 fn 3 o 2 . c 2 h 2 o 4 . 0 . 5h 2 o calc &# 39 ; d : c , 63 . 72 ; h , 6 . 09 ; n , 7 . 69 found : c , 63 . 72 ; h , 5 . 80 ; n , 8 . 24 this compound was prepared in the manner as described above for example 5a by replacing 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexanone with 4 -( 5 - cyano - 3 - indolyl )- cyclohexanone ( 0 . 32 g , 1 . 3 mmol ) to obtain 44 % ( 0 . 25 g ) of product . elemental analysis for c 26 h 28 fn 3 o 2 . c 2 h 2 o 4 calc &# 39 ; d : c , 64 . 20 ; h , 5 . 77 ; n , 8 . 02 found : c , 64 . 00 ; h , 6 . 17 ; n , 7 . 87 the trans compound was isolated at same time as the cis ( 5e ) isomer in 25 % yield ( 0 . 14 g ) as a white solid : mp 129 - 131 ° c . elemental analysis for c 26 h 28 fn 3 o 2 . c 2 h 2 o 4 . 0 . 25c 2 h 6 o . h 2 o calc &# 39 ; d : c , 61 . 89 ; h , 6 . 16 ; n , 7 . 60 found : c , 62 . 17 ; h , 6 . 19 ; n , 7 . 31 a solution of 4 -( 5 - cyano - 1h - indol - 3 - yl )- cyclohexanone ( 0 . 6 g , 2 . 5 mmol ), 2 -( 5 - fluoro - 2 , 3 - dihydrofuran - 7 - yloxy ) ethylamine ( 0 . 5 g , 2 . 5 mmol ), sodium triacetoxyborohydride ( 0 . 81 g , 3 . 8 mmol ) and acetic acid ( 0 . 30 g , 5 . 1 mmol ) in 1 , 2 - dichloroethane ( 20 ml ) was allowed to stir at room temperature for 16 hours . the reaction was quenched with 1n sodium hydroxide ( 20 ml ), extracted with methylene chloride ( 3 × 100 ml ) and washed with brine ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( 10 % methanol - ethyl acetate ) afforded 0 . 6 g ( 56 %) of product as a white solid : mp 152 . 5 - 154 ° c . elemental analysis for c 25 h 26 fn 3 o 2 . c 2 h 2 o 4 calc &# 39 ; d : c , 63 . 61 ; h , 5 . 54 ; n , 8 . 24 found : c , 63 . 38 ; h , 5 . 50 ; n , 8 . 26 the trans compound was isolated at same time as the cis isomer ( example 6a ) in 27 % yield ( 0 . 29 g ) as a white solid : mp 190 - 190 . 5 ° c . elemental analysis for c 25 h 26 fn 3 o 2 . c 2 h 2 o 4 . 0 . 5h 2 o calc &# 39 ; d : c , 62 . 54 ; h , 5 . 64 ; n , 8 . 01 found : c , 62 . 38 ; h , 5 . 65 ; n , 7 . 97 a solution of 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexanone ( 0 . 72 g , 3 . 1 mmol ), 2 -( 5 - fluoro - benzofuran - 7 - yloxy ) ethylamine ( 0 . 55 g , 2 . 82 mmol ), sodium triacetoxyboro - hydride ( 0 . 84 g , 3 . 94 mmol ) and acetic acid ( 0 . 18 g , 2 . 82 mmol ) in 1 , 2 - dichloroethane ( 20 ml ) was allowed to stir at room temperature for 16 hours . the reaction was quenched with 0 . 5 n sodium hydroxide ( 100 ml ), extracted with methylene chloride ( 2 × 100 ml ) and washed with brine ( 2 × 100 ml ). the organic layer was dried over anhydrous magnesium sulfate and filtered . the solvent was removed under vacuum and crystals appeared after 1 hour . the product was triturated with ethyl ether ( 80 ml ) to afford 0 . 27 g of product . the mother liquor was concentrated and diluted with ethyl ether to afford another 0 . 2 g of product . elemental analysis for c 24 h 24 f 2 n 2 o 2 . c 2 h 2 o 4 calc &# 39 ; d : c , 63 . 61 ; h , 5 . 54 ; n , 8 . 24 found : c , 63 . 38 ; h , 5 . 50 ; n , 8 . 26 the trans compound was isolated by chromatography from the residue remaining in example 7a ( 3 : 5 : 3 acetone - methanol - hexanes ) to afford 0 . 17 g of product as a glass . elemental analysis for c 24 h 24 f 2 n 2 o 2 . c 2 h 2 o 4 calc &# 39 ; d : c , 62 . 40 ; h , 5 . 24 ; n , 5 . 60 found : c , 62 . 98 ; h , 5 . 28 ; n , 5 . 36 a solution of [ 2 -( 2 , 3 - diamino - 5 - fluoro - phenoxy )- ethyl ]-[( 1 , 4 - trans )- 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexyl ]- amine ( 0 . 25 g ) in formic acid ( 15 ml ) was allowed to reflux for 3 hours . the mixture was poured into 1n sodium hydroxide , extracted with ethyl acetate ( 3 × 100 ml ) and washed with 1n sodium hydroxide ( 3 × 100 ml ). the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( 10 % methanol - methylene chloride plus ammonium hydroxide ) afforded 0 . 14 g ( 39 %) of product as a clear oil . elemental analysis for c 23 h 24 clfn 4 o . c 2 h 2 o 4 . 0 . 25h 2 o calc &# 39 ; d : c , 53 . 03 ; h , 4 . 70 ; n , 9 . 16 found : c , 52 . 87 ; h , 4 . 58 ; n , 9 . 54 a solution of [ 2 -( 2 , 3 - diamino - 5 - fluoro - phenoxy )- ethyl ]-[( 1 , 4 - trans )- 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexyl ]- amine ( 0 . 15 g ) in acetic acid ( 15 ml ) was allowed to reflux for 18 hours . the mixture was poured into saturated sodium bicarbonate and extracted with methylene chloride ( 2 × 150 ml ). the organic layer was dried over anhydrous magnesium sulfate and filtered . chromatography ( 7 % methanol - methylene chloride plus 1 % ammonium hydroxide ) afforded 0 . 10 g of product as a yellow solid : mp 185 - 187 ° c . elemental analysis for c 24 h 26 clfn 4 o . 2c 2 h 2 o 4 calc &# 39 ; d : c , 54 . 15 ; h , 4 . 87 ; n , 9 . 02 found : c , 53 . 94 ; h , 5 . 21 ; n , 8 . 87 a solution of 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexanone ( 0 . 41 g , 1 . 78 mmol ), 2 -( 4 - fluoro - 2 - methoxy - phenoxy ) ethylamine ( 0 . 33 g , 1 . 78 mmol ), sodium triacetoxyborohydride ( 0 . 56 g , 2 . 49 mmol ) and acetic acid ( 0 . 1 ml ) in 1 , 2 - dichloroethane ( 10 ml ) was allowed to stir at room temperature for 16 hours . the reaction was quenched with 0 . 5 n sodium hydroxide ( 100 ml ), extracted with methylene chloride ( 2 × 100 ml ) and washed with brine ( 2 × 100 ml ). the organic layer was dried over anhydrous magnesium sulfate and filtered . the solvent was removed under vacuum . chromatography ( 2 % methanol - ethyl acetate plus 0 . 2 % ammonium hydroxide ) afforded 0 . 4 g ( 56 %) of product as a white foam . the hcl salt was prepared in ethyl acetate : mp 150 - 152 ° c . elemental analysis for c 23 h 26 f 2 n 2 o 2 . hcl calc &# 39 ; d : c , 62 . 58 ; h , 6 . 28 ; n , 6 . 35 found : c , 62 . 72 ; h , 6 . 34 ; n , 6 . 27 the trans compound was isolated at same time as the cis isomer ( example 9a ) in 15 % yield ( 0 . 11 g ) as a white foam . the hcl salt was prepared in ethyl acetate : mp 188 - 190 ° c . elemental analysis for c 23 h 26 f 2 n 2 o2 . hcl calc &# 39 ; d : c , 62 . 58 ; h , 6 . 28 ; n , 6 . 35 found : c , 62 . 83 ; h , 6 . 18 ; n , 6 . 22 a solution of 4 -( 5 - fluoro - 1h - indol - 3 - yl ) cyclohexanecarbaldehyde ( 0 . 25 g , 1 . 02 mmol ), 2 -( 2 - methoxy - phenoxy ) ethylamine ( 0 . 17 g , 1 . 02 mmol ), sodium triacetoxyborohydride ( 0 . 32 g , 1 . 4 mmol ) and acetic acid ( 0 . 06 ml ) in 1 , 2 - dichloroethane ( 5 ml ) was allowed to stir at room temperature for 16 hours . the reaction was quenched with 0 . 5 n sodium hydroxide ( 100 ml ), extracted with methylene chloride ( 2 × 100 ml ) and washed with brine ( 2 × 100 ml ). the organic layer was dried over anhydrous magnesium sulfate and filtered . the solvent was removed under vacuum . chromatography ( 2 % methanol - ethyl acetate plus 0 . 2 % ammonium hydroxide ) afforded 0 . 1 g ( 25 %) of product . the hcl salt was prepared in ethyl acetate : mp 157 - 159 ° c . elemental analysis for c 24 h 29 fn 2 o 2 . hcl calc &# 39 ; d : c , 65 . 22 ; h , 7 . 07 ; n , 6 . 34 found : c , 65 . 10 ; h , 6 . 84 ; n , 6 . 25 the compound was prepared in a similar fashion described above using 4 -( 5 - cyano - 1h - indol - 3 - yl ) cyclohexanecarbaldehyde in 50 % yield ( 0 . 08 g ) of product . the hcl salt was prepared in ethyl acetate : mp 50 ° c . ( decomposed ). elemental analysis for c 25 h 29 n 3 o 2 . hcl calc &# 39 ; d : c , 63 . 68 ; h , 7 . 16 ; n , 8 . 91 found : c , 63 . 66 ; h , 6 . 80 ; n , 8 . 73 a solution of 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexanone ( 0 . 41 g , 1 . 78 mmol ), 2 -( 2 - methoxy -- 4 , 5 - difluoro - phenoxy )- ethylamine ( 0 . 36 g , 1 . 78 mmol ), sodium triacetoxy - borohydride ( 0 . 56 g , 2 . 49 mmol ) and acetic acid ( 0 . 1 ml ) in 1 , 2 - dichloroethane ( 10 ml ) was allowed to stir at room temperature for 16 hours . the reaction was quenched with 0 . 5 n sodium hydroxide ( 100 ml ), extracted with methylene chloride ( 2 × 100 ml ) and washed with brine ( 2 × 100 ml ). the organic layer was dried over anhydrous magnesium sulfate and filtered . the solvent was removed under vacuum . chromatography ( 2 % methanol - ethyl acetate plus 0 . 2 % ammonium hydroxide ) afforded 0 . 38 g ( 41 %) of product . the hcl salt was prepared in ethyl acetate : mp 98 - 100 ° c . elemental analysis for c 23 h 25 f 3 n 2 o 2 . hcl calc &# 39 ; d : c , 58 . 97 ; h , 5 . 92 ; n , 5 . 98 found : c , 58 . 76 ; h , 5 . 84 ; n , 5 . 79 the trans compound was isolated at same time as the cis isomer ( example 11a ) in 16 % yield ( 0 . 15 g ) of product . the hcl salt was prepared in ethyl acetate : mp 225 - 227 ° c . elemental analysis for c 23 h 25 f 3 n 2 o 2 . hcl calc &# 39 ; d : c , 57 . 32 ; h , 6 . 07 ; n , 5 . 81 found : c , 57 . 91 ; h , 55 . 94 ; n , 5 . 72 a solution of 1 - fluoro - 2 - methylsulfonyl - 4 - methoxy - 5 -( 2 - chloro - ethoxy )- benzene ( 0 . 14 g , 0 . 5 mmol ), ( trans )- 4 -( 5 - fluoro - 1h - indol - 3 - yl )- cyclohexyl - amine ( 0 . 11 g , 0 . 5 mmol ) and triethylamine ( 0 . 28 ml ) in anhydrous dimethylsulfoxide ( 10 ml ) was allowed to stir for 12 hours at 90 ° c . the mixture was poured into water ( 100 ml ) and extracted with methylene chloride ( 3 × 100 ml ). the organic layer was washed with water ( 3 × 100 ml ), dried over anhydrous sodium sulfate , filtered and the solvent was removed under vacuum . chromatography ( 7 % methanol - methylene chloride ) afforded 0 . 05 g of product as a oil . the hc salt was prepared in ethyl acetate : mp 128 - 130 ° c . elemental analysis for c 24 h 28 f 2 n 2 o 4 . hcl calc &# 39 ; d : c , 51 . 89 ; h , 6 . 08 ; n , 5 . 04 found : c , 51 . 66 ; h , 5 . 91 ; n , 4 . 82 a solution of 2 -( 1h - indol - 4 - yloxy )- ethylamine ( 0 . 17 g , 1 mmol ), 5 - fluoro - 3 -( 1 - oxa - sprio [ 2 , 5 ] oct - 6 - yl )- 1h - indole ( 0 . 245 g , 1 mmol ) in tetrahydrofuran ( 10 ml ) was allowed to reflux overnight and then 10 % p - toluenesulfonic acid in 10 ml methanol was added to a above mixture . the mixture was allowed to reflux for 24 hours and cooled to room temperature . the solvent was removed under vacuum , the residue was neutralized with 1 n sodium hydroxide ( ph = 9 ). the mixture was extracted with nethylene - isopropanol . the organic layer was dried over anhydrous sodium sulfate and filtered . chromatography ( ethanol - hexanes - ethanol - ammonium hydroxide : 7 : 3 : 0 . 1 : 0 . 01 ) afforded 0 . 19 g ( 44 %) of product as white solid . the hc salt was prepared in ethyl acetate : mp 160 ° c . ( decomposed ). elemental analysis for c 25 h 28 fn 3 o 2 . hcl calc &# 39 ; d : c , 60 . 23 ; h , 6 . 77 ; n , 8 . 43 found : c , 60 . 11 ; h , 6 . 38 ; n , 8 . 17 the activity of the present compounds is demonstrated by the following standard pharmacological test procedures . the pcr cloning of the human 5 - ht 1a receptor subtype from a human genomic library has been described previously chanda et al ., mol . pharmacol ., 43 : 516 ( 1993 ). a stable chinese hamster ovary cell line expressing the human 5 - ht 1a receptor subtype ( 5 - ht 1a . cho cells ) was employed throughout this study . cells were maintained in dmem supplemented with 10 % foetal calf serum , non - essential amino acids and penicillin / streptomycin . cells were grown to 95 - 100 % confluency as a monolayer before membranes were harvested for binding studies . cells were gently scraped from the culture plates , transferred to centrifuge tubes , and washed twice by centrifugation ( 2000 rpm for 10 min ., 4 ° c .) in buffer ( 50 mm tris ; ph 7 . 5 ). the resulting pellets were aliquoted and placed at - 80 ° c . on the day of assay , the cells were thawed on ice , and resuspended in buffer . studies were conducted using [ 3 h ] 8 - oh - dpat as the radioligand . the binding assay was performed in 96 well microtiter plates in a final total volume of 250 μl of buffer . competition experiments were performed by using 7 concentrations of unlabelled drug and a final ligand concentration of 1 . 5 nm . non - specific binding was determined in the presence of 10 μm 5ht . saturation analysis was conducted by using [ 3 h ] 8 - oh - dpat at concentrations ranging from 0 . 3 - 30 nm . following a 30 minute incubation at room temperature , the reaction was terminated by the addition of ice cold buffer and rapid filtration using a m - 96 brandel cell harvester ( gaithersburg , md .) through a gf / b filter presoaked for 30 minutes in 0 . 5 % polyethyleneimine . a protocol similar to that used by cheetham et al ., neuropharmacol ., 32 : 737 ( 1993 ) was used to determine the affinity of compounds for the serotonin transporter . briefly , frontal cortical membranes prepared from male sprague - dawley rats were incubated with 3 h - paroxetine ( 0 . 1 nm ) for 60 min at 25 ° c . all tubes also contained either vehicle , test compound ( one to eight concentrations ), or a saturating concentration of fluoxetine ( 10 μm ) to define specific binding . all reactions are terminated by the addition of ice cold tris buffer followed by rapid filtration using a tom tech filtration device to separate bound from free 3 h - paroxetine . bound radioactivity was quantitated using a wallac 1205 beta plate ® counter . nonlinear regression analysis was used to determine ic 50 values which were converted to ki values using the method of cheng and prusoff , biochem . pharmacol ., 22 : 3099 ( 1973 ); ki = ic50 /(( radioligand conc . )/( 1 + kd )). the [ 35 s ]- gtpγs binding assay was similar to that used by lazareno and birdsall , br . j . pharmacol . 109 : 1120 ( 1993 ). briefly , 5 - ht 1a cloned receptor membrane fragments ( as used for 5 - ht 1a receptor binding assays ) were stored at - 70 ° c . until needed . when needed , membranes were rapidly thawed , centrifuged at 40 , 000 × g for 10 minutes and resuspended at 4 ° c . for 10 minutes in assay buffer ( 25 nm hepes , 3 mm mgcl 2 , 100 mm nacl , 1 mm edta , 10 um gdp , 500 mm dtt , ph 8 . 0 ). these membranes were then incubated for 30 min at 30 ° c . with [ 35 s ] gtpgs ( 1 nm ) in the presence of vehicle , test compound ( one to eight concentrations ), or excess 8 - oh - dpat to define maximum agonist response . all reactions are terminated by the addition of ice cold tris buffer followed by rapid filtration using a tom tech ® filtration device to separate bound from free [ 35 s ] gtpgs . agonists produce an increase in the amount of [ 35 s ] gtpgs bound whereas antagonists produce no increase in binding . bound radioactivity was counted and analyzed as above . the following assays were performed by incubating the cells with dmem containing 25 mm hepes , 5 mm theophylline and 10 μm pargyline for a period of 20 minutes at 37 ° c . functional activity was assessed by treating the cells with forskolin ( 1 um final concentration ) followed immediately by test compound ( 6 concentrations ) for an additional 10 min at 37 ° c . in separate experiments , 6 concentrations of antagonist were preincubated for 20 min prior to the addition of 10 nm 8 - oh - dpat and forskolin . the reaction was terminated by removal of the media and addition of 0 . 5 ml ice cold assay buffer . plates were stored at - 20 ° c . prior to assessment of camp formation by a camp spa assay ( amersham ). the compounds tested correspond to those prepared in examples 1 - 13 above . the results of the procedures are set forth in table 1 . table 1______________________________________example 5 - ht . sub . 1a st gtpγs ed50 camp ed50 no . ( ki , nm ) ( k . sub . i , nm ,) (% emax ) ( emax ) ______________________________________1a 306 . 9 6 . 76 -- -- 1b 22 . 4 6 . 48 43 . 0 ( 80 %) 9 . 8 ( 92 %) 2a 996 . 2 1 . 19 -- -- 2b 47 . 8 0 . 42 ( 0 %) ( 0 %) 3a 146 . 8 26 -- -- 3b 1 . 08 2 . 50 60 . 5 ( 62 %) 5 . 2 ( 90 %) 4a 484 . 4 18 . 0 -- -- 4b 18 . 9 1 . 12 -- ( 61 %) 4c 353 . 2 6 . 37 -- -- 4d 16 . 7 0 . 21 ( 74 . 8 %) -- 5a 49 % @ 1000 nm 13 . 0 -- -- 5b 19 . 4 1 . 52 137 ( 22 %) 0 % 5c 47 % @ 1000 nm 0 . 53 -- -- 5d 24 . 0 21 . 35 -- -- 5e 384 . 6 2 . 74 -- -- 5f 10 . 1 2 . 6 346 . 0 ( 30 %) 8 . 1 ( 0 %) 6a 49 % @ 1000 nm 1 . 07 -- -- 6b 23 . 52 1 . 53 -- -- 7a 145 . 8 -- -- -- 7b 18 . 80 -- -- -- 8a 12 . 7 1 . 6 ( 0 %) -- 8b 18 . 9 0 . 52 -- 0 % 9a 16 % @ 10 nm 1 . 76 ( 45 %) -- 9b 78 . 3 3 . 28 583 ( 39 . 5 %) -- 10a 26 . 8 7 . 33 92 . 7 ( 60 %) -- 10b 7 % @ 10 nm 1 . 53 -- -- 11a 0 % @ 10 nm 1 . 70 0 -- 11b 24 . 9 0 . 70 0 -- 12 0 % @ 10 nm 0 . 47 0 -- 13 257 . 3 21 31 ( 85 %) -- ______________________________________ as demonstrated by the results set forth above , the compounds of the present invention are active towards 5ht1a receptors and generally elevate serotonin levels by inhibiting 5 - ht transport . accordingly , the present compounds should be useful in treating disorders related to defects in serotonin concentration . the compounds of this invention may be administered orally or parenterally , neat or in combination with conventional pharmaceutical carriers . applicable solid carriers can include one or more substances which may also act as flavoring agents , lubricants , solubilizers , suspending agents , fillers , glidants , compression aids , binders or tablet - disintegrating agents or an encapsulating material . in powders , the carrier is a finely divided solid which is in admixture with the finely divided active ingredient . in tablets , the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired . the powders and tablets preferably contain up to 99 % of the active ingredient . any of the solid carriers known to those skilled in the art may be used with the compounds of this invention . particularly suitable solid carriers include , for example , calcium phosphate , magnesium stearate , talc , sugars , lactose , dextrin , starch , gelatin , cellulose , methyl cellulose , sodium carboxymethyl cellulose , polyvinylpyrrolidone , low melting waxes and ion exchange resins . liquid carriers may be used in preparing solutions , suspensions , emulsions , syrups and elixirs of the compounds of this invention . the compounds of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water , an organic solvent , a mixture of both or pharmaceutically acceptable oils or fat . the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers , emulsifiers , buffers , preservatives , sweeteners , flavoring agents , suspending agents , thickening agents , colors , viscosity regulators , stabilizers or osmo - regulators . suitable examples of liquid carriers for oral and parenteral administration include water ( particularly containing additives as above , e . g ., cellulose derivatives , preferably sodium carboxymethyl cellulose solution ), alcohols ( including monohydric alcohols and polyhydric alcohols , e . g ., glycols ) and their derivatives and oils ( e . g ., fractionated coconut oil and arachis oil ). for parenteral administration , the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate . sterile liquid carriers are used in sterile liquid form compositions for parenteral administration . liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by , for example , intramuscular , intraperitoneal or subcutaneous injection . sterile solutions can also be administered intravenously . compositions for oral administration may be either liquid or solid composition form . preferably , the pharmaceutical compositions containing the compounds of this invention are in unit dosage form , e . g ., tablets or capsules . in such form , the compositions may be sub - divided in unit doses containing appropriate quantities of the present compounds . the unit dosage forms can be packaged compositions , for example , packeted powders , vials , ampoules , prefilled syringes or sachets containing liquids . alternatively , the unit dosage form can be , for example , a capsule or tablet itself , or it can be the appropriate number of any such compositions in package form . the therapeutically effective amount of the compounds of this invention that is administered and the dosage regimen depends on a variety of factors , including the weight , age , sex , and medical condition of the subject , the severity of the disease , the route and frequency of administration , and the specific compound employed , and thus may vary widely . however , it is believed that the pharmaceutical compositions may contain the compounds of this invention in the range of about 0 . 1 to about 2000 mg , preferably in the range of about 0 . 5 to about 500 mg and more preferably between about 1 and about 100 mg . projected daily dosages of active compound are about 0 . 01 to about 100 mg / kg body weight . the daily dose can be conveniently administered two to four times per day . the present invention may be embodied in other specific forms without departing from the spirit and essential attributes thereof and accordingly , reference should be made to the appended claims , rather than to the foregoing specification , as indicating the scope of the invention .