9-methylidenefluorene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3.2 g (8.1 mmol) of N-[(9-fluorenyl)methoxycarbonyl]-3-(2-methylphenyl)-L-alanine and 2.17 g (6.75 mmol) of 2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 22 ml of dimethylformamide was added to the resin from paragraph viii) and subsequently 1.5 ml (13.5 mmol) of N-methylmorpholine were added. The mixture was agitated for 30 minutes andthen the resin was drained and washed five times with 30 ml of dimethylformamide, twice with 30 ml of dichloromethane, twice with 30 ml of ethyl acetate and twice with 30 ml of diethyl ether. After drying therewere obtained 8.95 g of 5-[4-[[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-N-[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propyl]amino]methyl]-3,5-dimethoxyphenoxy]-N-(4-methyl-α-(RS)-phenylbenzyl)valeramide-polystyrene conjugate as a pale brown solid (0.31 mmol/g loading estimated by quantitation of dibenzofulvene at 301 nm). were added washed five times with 30 ml of dimethylformamide After drying

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3.2 g (8.1 mmol) of N-[(9-fluorenyl)methoxycarbonyl]-3-(2-methylphenyl)-L-alanine and 2.17 g (6.75 mmol) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 22 ml of dimethylformamide was added to the resin from paragraph viii) and subsequently 1.5 ml (13.5 mmol) of N-methylmorpholine were added. The mixture was agitated for 30 minutes and then the resin was drained and washed five times with 30 ml of dimethylformamide, twice with 30 ml of dichloromethane, twice with 30 ml of ethyl acetate and twice with 30 ml of diethyl ether. After drying there were obtained 8.95 g of 5-[4-[[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-N-[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propyl]amino]methyl]-3,5-dimethoxyphenoxy]-N-(4-methyl-α-(RS)-phenylbenzyl)valeramide-polystyrene conjugate as a pale brown solid (0.31 mmol/g loading estimated by quantitation of dibenzofulvene at 301 nm). were added washed five times with 30 ml of dimethylformamide After drying there

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3.2 g (8.1 mmol) of N-[(9-fluorenyl)methoxycarbonyl]-3-(2-methylphenyl)-L-alanine and 2.17 g (6.75 mmol) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 22 ml of dimethylformamide was added to the resin from paragraph viii) and subsequently 1.5 ml (13.5 mmol) of N-methylmorpholine were added. The mixture was agitated for 30 minutes and then the resin was drained and washed five times with 30 ml of dimethylformamide, twice with 30 ml of dichloromethane, twice with 30 ml of ethyl acetate and twice with 30 ml of diethyl ether. After drying there were obtained 8.95 g of 5-[4-[[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-N-[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propyl]amino]methyl]-3,5-dimethoxyphenoxy]-N-(4-methyl-α-(RS)-phenylbenzyl)valeramide-polystyrene conjugate as a pale brown solid (0.31 mmol/g loading estimated by quantitation of dibenzofulvene at 301 nm). were added washed five times with 30 ml of dimethylformamide After drying there

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5 g (5.25 mmol) of 4-methylbenzhydrylamine resin were swollen in dimethylformamide and excess solvent was drained from the resin. The resin was then resuspended in dimethylformamide containing 3.4 g (5.48 mmol) of 5-[2-[1(RS)-[[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]amino]propyl]-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvaleric acid and 3 g (8.2 mmol) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. Thereto were added 3.0 ml (16.5 mmol) of diisopropylamine. The resulting mixture was agitated for 100 minutes and the resin was then drained and washed three times with dimethylformamide. The resin was then resuspended in dimethylformamide containing 5 ml (54.8 mmol) of acetic anhydride and 11.5 ml (110 mmol) of N-methylmorpholine. The mixture was agitated for 30 minutes and the resin was then drained. The resin was then resuspended in dimethylformamide containing 5 ml (54.8 mmol) of acetic anhydride and 11.5 ml (110 mmol) of N-methylmorpholine. The mixture was agitated for 30 minutes and the resin was then drained and washed three times with dimethylformamide, twice with ethyl acetate, twice with dichloromethane and twice with diethyl ether and then dried under a vacuum. After drying there was obtained 6 g of 5-[2-[1(RS)-[[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]amino]propyl]-4-(RS),5,5-trimethyl-1,3 ,2-dioxoborolan-4-yl]-3(RS)-methyl-N-(RS)-(4-methylphenyl)-benzyl]valeramide-polystyrene conjugate as a pale brown solid (0.25 mmol/g loading estimated by quantitation of dibenzofulvene at 301 nM). washed three times with dimethylformamide The mixture was agitated for 30 minutes The mixture was agitated for 30 minutes washed three times with dimethylformamide twice with ethyl acetate, twice with dichloromethane and twice with diethyl ether and then dried under a vacuum After drying there

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3.2 g (8.1 mmol) of N-[(9-fluorenyl)methoxycarbonyl]-3-(2-methylphenyl)-L-alanine and 2.17 g (6.75 mmol) of 2-(lH-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 22 ml of dimethylformamide was added to the resin from paragraph viii) and subsequently 1.5 ml (13.5 mmol) of N-methylmorpholine were added. The mixture was agitated for 30 minutes and then the resin was drained and washed five times with 30 ml of dimethylformamide, twice with 30 ml of dichloromethane, twice with 30 ml of ethyl acetate and twice with 30 ml of diethyl ether. After drying there were obtained 8.95 g of 5-[4-[[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-N-[3,3 ,3-trifluoro-1(RS)-(dimethoxy-methyl)propyl]amino]methyl]-3,5-dimethoxyphenoxy]-N-(4-methyl-α-(RS)-phenylbenzyl)valeramide-polystyrene conjugate as a pale brown solid (0.31 mmol/g loading estimated by quantitation of dibenzofulvene at 301 nm). were added washed five times with 30 ml of dimethylformamide After drying there

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of methyl triphenylphosphonium bromide (31.22 g; 87.3 mmol) in 500 mL of ether was added at -30° C. 10M n-butyllithium in hexane (8.73 mL; 87.3 mmol) and the mixture was allowed to stir at room temperature for 1/2 h. To the above mixture was added 15 g (83.2 mmol) of 9-fluorenone in 50 mL of tetrahydrofuran and the mixture was refluxed for 1 h. The above mixture was cooled to 0° C., filtered, and concentrated to yield 11.3 g (76.3%) of 9-methylene-fluorene (Formula III: R3 =R4 =H; R5 =R6 together form a 9-fluorene ring). was added at -30° C the mixture was refluxed for 1 h The above mixture was cooled to 0° C. filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3.2 g (8.1 mmol) of N-[(9-fluorenyl)methoxycarbonyl]-3-(2-methylphenyl)-L-alanine and 2.17 g (6.75 mmol) of 2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 22 ml of dimethylformamide was added to the resin from paragraph viii) and subsequently 1.5 ml (13.5 mmol) of N-methylmorpholine were added. The mixture was agitated for 30 minutes andthen the resin was drained and washed five times with 30 ml of dimethylformamide, twice with 30 ml of dichloromethane, twice with 30 ml of ethyl acetate and twice with 30 ml of diethyl ether. After drying therewere obtained 8.95 g of 5-[4-[[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-N-[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propyl]amino]methyl]-3,5-dimethoxyphenoxy]-N-(4-methyl-α-(RS)-phenylbenzyl)valeramide-polystyrene conjugate as a pale brown solid (0.31 mmol/g loading estimated by quantitation of dibenzofulvene at 301 nm). were added washed five times with 30 ml of dimethylformamide After drying

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9-Hydroxymethylfluorene (10 g) and 1 g KOH were dissolved in 90 ml of methanol and reacted at 60° C. for 1 hour, and the methanol was evaporated. From the solid thus obtained, dibenzofulvene was extracted using hexane and water, and washed with water until the hexane phase containing dibenzofulvene was neutral. After separating off the hexane phase, the hexane was evaporated, and the solid obtained was recrystallized from a mixed solvent of hexane-diethyl ether (4/6 v/v) to obtain dibenzofulvene. The melting point of the dibenzofulvene was 50-52° C. reacted at 60° C. for 1 hour the methanol was evaporated From the solid thus obtained dibenzofulvene was extracted washed with water until the hexane phase containing dibenzofulvene After separating off the hexane phase the hexane was evaporated the solid obtained was recrystallized from a mixed solvent of hexane-diethyl ether (4/6 v/v)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9-Hydroxymethylfluorene (10 g) and 1 g KOH were dissolved in 90 ml of methanol and reacted at 60° C. for 1 hour, and the methanol was evaporated. From the solid thus obtained, dibenzofulvene was extracted using hexane and water, and washed with water until the hexane phase containing dibenzofulvene was neutral. After separating off the hexane phase, the hexane was evaporated, and the solid obtained was recrystallized from a mixed solvent of hexane-diethyl ether (4/6 v/v) to obtain dibenzofulvene. The melting point of the dibenzofulvene was 50-52° C. reacted at 60° C. for 1 hour the methanol was evaporated From the solid thus obtained dibenzofulvene was extracted washed with water until the hexane phase containing dibenzofulvene After separating off the hexane phase the hexane was evaporated the solid obtained was recrystallized from a mixed solvent of hexane-diethyl ether (4/6 v/v)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9-Hydroxymethylfluorene (10 g) and 1 g KOH were dissolved in 90 ml of methanol and reacted at 60° C. for 1 hour, and the methanol was evaporated. From the solid thus obtained, dibenzofulvene was extracted using hexane and water, and washed with water until the hexane phase containing dibenzofulvene was neutral. After separating off the hexane phase, the hexane was evaporated, and the solid obtained was recrystallized from a mixed solvent of hexane-diethyl ether (4/6 v/v) to obtain dibenzofulvene. The melting point of the dibenzofulvene was 50-52° C. reacted at 60° C. for 1 hour the methanol was evaporated From the solid thus obtained dibenzofulvene was extracted washed with water until the hexane phase containing dibenzofulvene After separating off the hexane phase the hexane was evaporated the solid obtained was recrystallized from a mixed solvent of hexane-diethyl ether (4/6 v/v)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of dibenzofulvene (1 g, 5.68 mmol), fluorene (0.93 g, 5.68 mmol) and EtONa (0.19 g, 2.79 mmol) in DMSO (20 mL) was heated at 90° C. for 16 hours, and was then cooled to room temperature. After carrying out the work-up, as reported in Example 8, 0.55 g of bis(9-fluorenyl)methane were obtained, with a yield of 28%. was then cooled to room temperature

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 1000 mL flask was charged with 9-acetoxymethylfluorene (30.0 g, 126 mmol) and anhydrous petroleum ether (bp 35-60° C., 400 mL, Aldrich) and it was cooled to 5° C. Solid potassium tert-butoxide (16.0 g, 142 mmol, Aldrich) was added in one portion. After stirring for 6 hours, the mixture was poured into dilute HCl (200 mL, 0.1 N). Et2O was added (100 mL); the layers were separated and the product extracted into Et2O (2×100 mL). Combined organic portions were dried over anhydrous MgSO4 and the solvent was removed via rotary evaporation. The crude product dibenzofulvene was isolated as a yellow solid (21.3 g, 94% yield, >99% pure by GC). Further purification was accomplished by recrystallization from petroleum ether, to yield dibenzofulvene in the form of white needles (Tm 51.5-53° C.). the layers were separated the product extracted into Et2O (2×100 mL) Combined organic portions were dried over anhydrous MgSO4 the solvent was removed via rotary evaporation