Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:4]=1[CH:5]=O.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:4]=1[CH:5]=[N:14][OH:15]
Reactant: COc1ccc(F)c(F)c1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(F)c1C=NO
Reaction time: 16 h
Yield: 88.5 %

Procedure:
At 20-25° C., a solution of 29.4 g of 2-methoxy-5,6-difluoro-benzaldehyde (according to Ex. 27 of WO 97/03071) was added dropwise with stirring to a mixture of 16.0 g of hydroxylamine hydrochloride, 18.9 g of sodium acetate and 110 ml of 90% strength aqueous methanol. The mixture was stirred for 16 hours, the methanol was evaporated, the mixture was made into a paste using 250 ml of water and then washed and dried, giving 28.3 g of the desired product of m.p. 199-201° C.
Reaction SMILES: [C:1](NCCCl)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:12][CH2:13][N:14](CC)CC.C(Cl)Cl>CN(C=O)C>[C:1]([CH2:12][CH2:13][NH2:14])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCl
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCN

Procedure:
Compounds of formula IX may be prepared according to Scheme V. Alkylation of the secondary amine in a compound of formula VII or formula VIIa with 2-(N-Boc amino)ethyl chloride (prepared according to the procedure of Tanaka (Chem. Pharm. Bull. 1988, 36, 3125) in the presence of Et3N in a solvent such as CH2Cl2 or DMF gives the N-Boc ethylamine derivative of formula XI. Removal of the Boc group is accomplished by treatment with TFA in a solvent such as CH2Cl2 to give naphthyl-8-azabicyclo[3.2.1]octene/naphthyl-8-azabicyclo[3.2.1]octane of formula IX.
Reaction SMILES: [CH:1]1([C:7]2[CH:28]=[CH:27][C:10]([CH2:11]OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:29]([Si](C)(C)C)[CH:30]=[CH2:31].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(=O)(O)[O-]>COC(OC)C>[CH2:11]([C:10]1[CH:9]=[CH:8][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:28][CH:27]=1)[CH2:31][CH:30]=[CH2:29]
Reactant: O=P(OCc1ccc(C2CCCCC2)cc1)(c1ccccc1)c1ccccc1
Reactant: C=CC[Si](C)(C)C
Agent: COC(C)OC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Product: C=CCCc1ccc(C2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a stirred mixture of diphenyl-phosphinic acid 4-cyclohexyl-benzyl ester (1 g, 2.56 mmol) and 1.22 ml (7.69 mmol) of allyltrimethylsilane in 12 ml of dry dimethoxy-ethane at 0° C. was added 0.46 ml of trimethylsilyltriflate. The mixture was stirred at 0° C. for 1 h, poured into saturated bicarbonate, extracted with ethyl acetate, washed with water, dried (sodium sulfate) filtered and concentrated. The material was purified by chromatography on silica gel, eluting with ethyl acetate/heptane to provide 0.45 g of the title compound.
Reaction SMILES: [CH2:1]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23]C)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCc1ccccc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCc1ccccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
A solution of about 14.94 g of 1-hexadecyl-2-methoxybenzene in methylene chloride, under argon, was cooled to about -78° C. and about 3.76 g of boron tribromide was added. The mixture was allowed to warm to room temperature, was then stirred for about 24 hours and quenched by the dropwise addition of ice-cold water. The mixture was then washed with sodium bicarbonate solution, dried and evaporated, giving about 14 g of the desired reagent, mp 54°-55° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3]1>C(O)C.[Pd]>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]([CH3:1])([CH3:16])[CH2:3][CH:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5]1
Reactant: CCOC(=O)C=C1CC(C)(C)CC(C)(C)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CC(C)(C)CC(C)(C)C1
Yield: 94.5 %

Procedure:
Ethyl 3,3,5,5-tetramethylcyclohexylideneacetate (7) (4.48 g, 20 mmol) in ethanol (100 ml) was hydrogenated over 10% Pd/C (0.22 g, 5 wt. %) at 10 atm for 18 h. Filtration through Celite™ and evaporation afforded 4.28 g (95%) of 8 as an oil.
Reaction SMILES: [CH2:1]([CH:9]([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:10][C:11]1[C:12]([CH2:36][CH:37]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[C:13]([CH2:16][CH:17]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N#N.C([Li])CCC.CCCCCC.Br[CH2:80][CH2:81][C:82]#[N:83]>C(=O)=O.CC(C)=O.C1COCC1>[CH2:1]([CH:9]([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:10][C:11]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:80][CH2:81][C:82]#[N:83])[C:12]=1[CH2:36][CH:37]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCC(CCCCCCCC)CC1=CCC(CC(CCCCCCCC)CCCCCCCCCC)=C1CC(CCCCCCCC)CCCCCCCCCC
Reactant: N#CCCBr
Agent: N#N
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCC(CCCCCCCC)CC1=C(CC(CCCCCCCC)CCCCCCCCCC)C(CCC#N)(CC(CCCCCCCC)CCCCCCCCCC)C=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
Tris(2-octyldodecyl)cyclopentadiene (18.12 grams, 20 mmol) was placed in a 3-necked round bottom flask equipped with an additional funnel, a gas inlet adapter, and a septum. After flashing with dried N2 for 2 minutes, 50 ml of dried THF (distilled over K) was added. The solution was cooled in dry ice/acetone bath, followed injected 8.4 M n-butyl lithium in hexane solution (2.40 ml; 20 mmol). The dry ice/acetone bath was removed, and the resulting dark red solution was stirred at room temperature for 1 hour, followed by cooling in dry ice/acetone bath. 3-Bromopropionitrile (2.70 grams, 20 mmol) in 10 ml dried THF solution was then dropwise added from the additional funnel. After the addition, the reaction solution was stirred at room temperature for another 3 hours. The reaction was slowly quenched with 10 ml water. The organic layer was separated, and the aqueous layer was extracted with 50 ml hexane. The organic layers were combined, dried over MgSO4, filtered, and rota-vaporized to give 19.6 grams of yellow liquid. The crude reaction product was purified by column chromatography on SiO2 eluting with 5% ethyl acetate/hexane. The unreacted tris(2-octyldodecyl)cyclopentadiene (3.66 grams) was recovered and the title compound (12.83 grams) was isolated. FTIR: 2248 cm−1 (C≡N); 13C NMR (4 isomers): 152.5-129.1 ppm (C═C), 120.8-119.6 ppm (4 peaks; C≡N), 59.5 ppm, 56.9 ppm, 51.3 ppm, 41.1 ppm, 39.5-26.4 ppm, 22.7 ppm, 14.1 ppm
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:12]=1)[N:9]=[C:8]([C:20]([OH:22])=O)[CH:7]=[C:6]2[O:23][CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[N:28]1([C:31]2[CH:32]=[CH:33][C:34]([NH:35][C:20]([C:8]3[CH:7]=[C:6]([O:23][CH3:24])[C:5]4[C:10](=[C:11]([N:13]5[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]5)[CH:12]=[C:3]([F:2])[CH:4]=4)[N:9]=3)=[O:22])=[CH:36][CH:37]=2)[CH2:27][CH2:26][O:25][CH2:30][CH2:29]1
Reactant: COc1cc(C(=O)O)nc2c(N3CCN(C)CC3)cc(F)cc12
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2ccc(N3CCOCC3)cc2)nc2c(N3CCN(C)CC3)cc(F)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
Into a 250 mL round bottom flask equipped with a nitrogen inlet and magnetic stirrer is added 2.01 g (6.3 mmol, 1.0 equiv.) of 6-Fluoro-4-methoxy-8-(4-methyl-piperazin-1-yl)-quinoline-2-carboxylic acid hydrochloride salt. This material is dissolved in 20 mL of DMF and then 1.35 g (7.56 mmol, 1.2 equiv.) of 4-morpholinoaniline is added. To the stirred solution is quickly added simultaneously added 4.05 g (12.6 mmol, 2.0 equiv.) of TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3tetramethyluroniumtetrafluoroborate) and 1.7 g (12.6 mmol, 2.0 equiv.) of HOBT (1-hydroxybenzotriaole hydrate). At this point 3.25 g, 4.11 mL (25.2 mmol, 4.0 equiv.) is added via syringe over 5 minutes. The reaction is allowed to stir at room temperature for 18 hrs, then is concentrated on a rotary evaporator under high vacuum in order to remove the DMF. The residue is triturated with methanol and the crude solids are recovered by filtration. The material is then dissolved in methylene chloride and extracted with 10% sodium bicarbonate solution. The organic layer is dried and then concentrated. These residues are then purified by flash chromatography using a gradient of 5-10% methanol in methylene chloride as eluent. The material which is obtained from chromatography, is then crystallized from methanol to give the pure product as 2.83 g (93%) of a yellow solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][S:13][CH:14]=1>C(O)(=O)C>[Cl:1][C:12]1[S:13][CH:14]=[C:10]([CH3:9])[C:11]=1[NH:15][C:16](=[O:21])[C:17]([F:20])([F:18])[F:19]
Reactant: Cc1cscc1NC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Cc1csc(Cl)c1NC(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.2 g of N-chlorosuccinimide in 50 ml of glacial acetic acid was added dropwise to a mixture of 5 g of 4-methyl-3-trifluoroacetylaminothiophene in 70 ml of glacial acetic acid, and the mixture was then stirred at room temperature for 30 minutes and at 50° C. for a further hour. The solvent was distilled off, and the residue was admixed with water and adjusted to pH 10 using 2N NaOH. The mixture was extracted using ethyl acetate, and the organic phase was washed with water and dried over sodium sulfate. After the solvent had been distilled off, a dark-colored oily product was obtained and was chromatographically purified on silica gel using an elution mixture of 10 parts by volume of toluene and 2 parts by volume of n-heptane. After the solvent had been distilled off, the product was obtained as a light yellow-colored oil.
Reaction SMILES: Br[C:2]([F:9])([F:8])[CH:3](F)[CH2:4][CH2:5]Br.[SH:10][C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>>[F:8][C:2]([F:9])=[CH:3][CH2:4][CH2:5][S:10][C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: FC(CCBr)C(F)(F)Br
Reactant: Sc1nc2ccccc2o1
Product: FC(F)=CCCSc1nc2ccccc2o1

Procedure:
To the solution of 4-bromo-1,1-difluorobut-1-ene prepared in Example 6 was added potassium carbonate (10.76 g) and 2-mercaptobenzthiazole (9.18 g). The mixture was stirred at 55° C. for 6 hours and then at room temperature overnight. Gas-liquid chromatography of a sample of the reaction mixture showed that a small amount of 4-bromo-1,1-difluorobut-1-ene remained. More potassium carbonate (1.0 g) was added and the mixture heated for another two and a half hours at 55° C., when all of the bromo compound had been consumed. The mixture was cooled to room temperature and filtered. The residue was washed with acetone and the filtrate and washings combined and evaporated under reduced pressure to give the crude product (16.18 g). This was dissolved in dichloromethane. The solution was filtered and washed with dilute sodium hydroxide (2×25 ml) and with brine (2×25 ml), dried over magnesium sulphate, filtered, the filtrate evaporated to give 2-(4,4-difluorobut-3-enyl)thiobenzthiazole, having a gas chromatographic retention time identical with that of an authentic sample. The yield was 63% based on the quantity of 1,4-dibromo-1,1,2-trifluorobutane used in step (b) of Example 1. 2-(4,4-Difluorobut-3-enyl)thiobenzoxazole was prepared in the same way, but using 2-mercapto benzoxazole instead of 2-mercapto benzthiazole.
Reaction SMILES: [CH:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][NH:9][C:10]([C@@H:12]2[N:17]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:16][CH2:15][N:14]([C:31]3[S:32][C:33]([C:37](O)=[O:38])=[C:34]([CH3:36])[N:35]=3)[CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH3:42]>O1CCCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:13][N:14]([C:31]3[S:32][C:33]([C:37](=[O:38])[NH2:42])=[C:34]([CH3:36])[N:35]=3)[CH2:15][CH2:16][N:17]2[S:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[O:11])=[CH:40][CH:41]=1)([CH3:2])[CH3:3]
Reactant: N
Reactant: Cc1nc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)cc3)C2)sc1C(=O)O
Solvent: C1CCOC1
Product: Cc1nc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)cc3)C2)sc1C(N)=O
Temperature: 25 °C

Procedure:
To a solution of the compound (30 mg) obtained in Example 6 in tetrahydrofuran (0.3 ml) was added, with stirring at room temperature, N,N′-carbonyldiimidazole (10 mg). After stirring at room temperature for 3 hr, 28% aqueous ammonia solution (10 μl) was added. After stirring at room temperature for 2.5 hr, 28% aqueous ammonia solution (10 μl) was added. After stirring at room temperature for 2.5 hr, 28% aqueous ammonia solution (10 μl) was added. After stirring overnight at room temperature, the reaction mixture was partitioned by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer chromatography (10% methanol/chloroform) to give the title compound (20 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([N:18](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[K+]>C(#N)C.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:16]#[N:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (9.0 g, 42 mmol) in acetonitril (125 mL) was added triethylamine (5.5 g, 54 mmol) followed by dropwise addition of methanesulfonyl chloride (5.7 g, 50 mmol). When addition was complete the mixture was stirred overnight. The mixture was filtered and the solvent was evaporated. The residue was dissolved in ethyl acetate (100 mL) and the organic solution was washed with water (2×10 mL) and brine. The organic phase was dried (MgSO4) and the solvent was evaporated to give a residue that was dissolved in absolute ethanol (250 mL). Potassium cyanide (8.2 g, 125 mmol) was added and the mixture was heated at reflux overnight. The reaction mixture was allowed to cool to ambient temperature, filtered and the solvent was evaporated. The residue was dissolved in diethyl ether (200 mL) and the organic solution was washed with water (2×20 mL) and then dried (MgSO4) in the presence of activated carbon. The mixture was filtered and the solvent was evaporated to give 9.2 g of 4-(cyanomethyl)piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, CDCl3) δ 1.20-1.33 (m, 2H), 1.46 (s, 9H), 1.77-1.88 (m, 3H), 2.32 (d, 2H), 2.66-2.78 (m, 2H), 4.10-4.23 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
Periodinane (18.2 g, 42.9 mmol) was added to 3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (7.10 g, 33.0 mmol) in CH2Cl2 (230 mL) and stirred for 90 min. Diethyl ether (230 mL) was added and precipitates were removed by extraction with 10% Na2S2O3/saturated NaHCO3 (1:1, 230 mL). The organic layer was washed with 0.5 M NaOH solution and brine. The organic phase was dried and concentrated under reduced pressure to yield 3-Formyl-piperidine-1-carboxylic acid tert-butyl ester (6.50 g, 93%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@@H:15]([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)(=[O:13])=[O:12].C(N1CCOCC1)C.[S:37]([OH:40])([OH:39])=[O:38].[NH2:41][CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][N:45]([C:49](=[NH:51])[NH2:50])[CH2:44]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[S:37](=[O:38])([OH:40])[OH:39].[C:49]([N:45]1[CH2:46][CH2:47][CH2:48][CH:43]([CH2:42][NH:41][C:26](=[O:27])[C@H:15]([NH:14][S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:13])=[O:12])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH2:44]1)(=[NH:50])[NH2:51]
Reactant: N=C(N)N1CCCC(CN)C1
Reactant: O=C(O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc2ccccc2c1
Agent: CCN1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: N=C(N)N1CCCC(CNC(=O)[C@@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccc3ccccc3c2)C1
Reaction time: 15 h
Yield: 44.3 %

Procedure:
A solution of 1.5 g of N-(2-naphthylsulfonyl)-D-tryptophan in 30 ml of DMF is treated with 1.5 ml of ethylmorpholine. After the addition of 0.7 g of rac-3-aminomethyl-1-amidinopiperidine sulphite (Example 1)and 1.7 g of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate the reaction mixture is stirred for 15 hours. The solvent is evaporated and the residue is taken up in 50 ml of water and extracted with 100 ml of ethyl acetate. The ethyl acetate phase is washed with water, dried and evaporated. The crude material is purified on a RP-18 column with water/acetonitrile (0-30%). There is obtained 0.8 g of (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α(2-naphthylsulfonamido)indole-3-propionamide bisulfite, FAB-MS: 533 (M+H)+.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-])=O.[Cl:13][CH2:14][CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O>O>[Cl:13][CH2:14][CH2:15][O:12][C:9]1[CH:10]=[CH:11][C:6]([NH2:3])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(OCCCl)cc1
Temperature: 100 °C

Procedure:
42 grams (1.05 mole) of sodium hydroxide were dissolved in 75 milliliters of water, and 139 grams (1 mole) of 4-nitrophenol and 235 grams (1 mole) of β-chloroethyl-p-toluene sulfonate were added, while stirring. Subsequently the reaction mixture was heated at 100°C for 4 hours. After cooling, the mixture was made alkaline by means of a solution of sodium hydroxide of 33 % strength and was diluted with about 5 liters of water. The precipitated crystalline product was filtered off with suction, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])C(F)(F)F)=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38]([F:41])([F:40])[F:39])[CH:30]=2)[C:3]1=[O:42].CC1(C)N(CCCCCCCCCSCCCC(F)(F)[F:64])C(=O)N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O>>[CH3:43][C:2]1([CH3:1])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:64])[F:26])=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38]([F:40])([F:41])[F:39])[CH:30]=2)[C:3]1=[O:42]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)F
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)F
Yield: 73 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, the compound of Example 12 replacing the compound of Example 1. A pale yellow oil is obtained with a yield of 73% (140 mg).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([CH3:13])=[C:11]([S:14](=[O:20])(=[O:19])[NH:15][CH:16]3[CH2:18][CH2:17]3)[CH:10]=[C:9]2C(O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CCO>[CH:1]1([CH2:7][N:8]2[CH:9]=[CH:10][C:11]([S:14]([NH:15][CH:16]3[CH2:18][CH2:17]3)(=[O:20])=[O:19])=[C:12]2[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(S(=O)(=O)NC2CC2)cc(C(=O)O)n1CC1CCCCC1
Agent: Cl
Solvent: CCO
Product: Cc1c(S(=O)(=O)NC2CC2)ccn1CC1CCCCC1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
To a solution of compound 3b (6.0 g, 17.6 mmol) in EtOH (100 mL) was added 4N aq. HCl (50 mL) and the solution was refluxed for 5 h, cooled to rt and concentrated. The residue was diluted with EA, washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (EA/PE=1/5) to give compound 3c (3.2 g, 61%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:21]=[N:22][N:23]([CH3:37])[C:24]=4[NH:25][C:26]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:30])=[O:27])=[C:16]([F:38])[CH:15]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].O1CCCC1.[Li+].[OH-]>CO>[F:38][C:16]1[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]3)=[CH:13][CH:12]=2)[CH:19]=[CH:18][C:17]=1[C:20]1[N:21]=[N:22][N:23]([CH3:37])[C:24]=1[NH:25][C:26]([O:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27]
Reactant: COC(=O)C1(c2ccc(-c3ccc(-c4nnn(C)c4NC(=O)O[C@H](C)c4ccccc4)c(F)c3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](OC(=O)Nc1c(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2F)nnn1C)c1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 91.8 %

Procedure:
In a 250 ml, round-bottomed flask, 1-{3′-fluoro-4′-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazole-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid methyl ester (95 mg, 185 μmol) was combined with tetrahydrofuran (5 mL) and methanol (1.5 mL) to give a light yellow solution. 1M LiOH (1.85 mL, 1.85 mmol, Eq: 10) was added and the reaction was stirred at 25° C. for 22 h. The crude reaction mixture was concentrated in vacuo, acidified with 1M HCl and extracted with dichloromethane. The aqueous layer was back-extracted with dichloromethane (1×15 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 10% methanol in dichloromethane) to afford 85 mg (92%) of the desired product as a white powder. (M+H)′=501.1 (m/e). 1H NMR (DMSO-d6) δ ppm 12.39 (br. s., 1H), 9.92 (br. s., 1H), 7.64-7.78 (m, 3H), 7.59 (d, J=7.8 Hz, 2H), 7.37-7.50 (m, 5H), 7.02-7.37 (m, 2H), 5.74 (br. s., 1H), 3.89 (s, 3H), 1.41-1.60 (m, 4H), 1.09-1.32 (m, 3H).