Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C(O)(=O)C.[C:21]1([CH2:27][N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH4+].[OH-]>CCO>[C:21]1([CH2:27][N:28]2[CH2:33][CH2:32][C:31]3([C:16]4=[C:15]5[C:10](=[N:9][C:8]4=[C:3]4[C:2](=[CH:7][CH:6]=[CH:5][CH2:4]4)[NH:1]3)[CH:11]=[CH:12][CH:13]=[CH:14]5)[CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: C1=CCC2=C3N=c4ccccc4=C3C3(CCN(Cc4ccccc4)CC3)NC2=C1

Procedure:
To a mixture prepared from 7.6 g of 2-(2-aminophenyl)indole, 2.5 ml of acetic acid and 90 ml of ethanol was added 7.4 ml of 1-phenylmethyl-4-piperidone. The resultant solution was refluxed for 6 hours. Concentration gave a solid/gum mixture which was taken up in EtOH and treated with dilute NH4OH. Filtration gave 12.45 g of yellow solid. This was recrystallized from CH3OH/H2O to give 9.0 g of yellow solid. High vacuum drying (90°) gave 2.6 g of dark yellow solid, m.p. 155°-157° C.
Reaction SMILES: C1[O:15][C:4]([CH3:14])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12]Br)=[CH:8][CH:7]=2)OC1.[CH3:16][O-:17].[Na+].[I-].[Na+]>CO>[CH3:16][O:17][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:15])[CH3:14])=[CH:11][CH:10]=1
Reactant: C[O-]
Reactant: CC1(Cc2ccc(CBr)cc2)OCCO1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(CC(C)=O)cc1
Reaction time: 1 h

Procedure:
1-(4-Bromomethylphenyl)propan-2-one ethylene ketal (1.35 g) in methanol was added to sodium methoxide (from sodium (0.11 g)) in methanol containing a trace of sodium iodide. The mixture was refluxed for 1 hour. Methanol was removed, the residue partitioned between water and ether and the combined organic extracts dried. Removal of the solvent gave an oil which was dissolved in methanol-2 N hydrochloric acid and left for 1 hour at room temperature. Extraction with ether gave the title compound, bp 106°/0.7 mm. τ(CDCl3) 7.9 (3H, s), 7.63 (3H, s), 6.33 (2H, s), 5.54 (2H, s), 2.8 (2H, d, J=8 Hz), 2.6 (2H, d, J=8 Hz).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:25]=[CH:24][C:16]3[C:17]([CH3:23])([CH3:22])[O:18][C:19](=[O:21])[NH:20][C:15]=3[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:26]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:25]=[CH:24][C:16]3[C:17]([CH3:22])([CH3:23])[O:18][C:19](=[O:21])[NH:20][C:15]=3[CH:14]=2)=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCSc3ccccc3)ccc21
Product: CC1(C)OC(=O)Nc2cc(OCCCCS(=O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 2 from 7-(4-phenylmercapto-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[OH:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:35]5[CH:34]=[C:29]([CH:28]=[C:27]([OH:26])[CH:36]=5)[C:30]([O:32][CH3:33])=[O:31])[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COC(=O)c1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cc(O)cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c1
Temperature: 120 °C
Yield: 97.9 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (130 mg, 0.36 mmol) was dissolved in 1,2-dimethoxyethane (3.6 mL) in a reaction tube. Methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (150 mg, 0.55 mmol), aqueous 2 M sodium carbonate (0.37 mL), and (Ph3P)4Pd (21 mg, 0.018 mmol) were added and the reaction mixture was heated at 120° C. for 30 minutes in the microwave. The resulting material was cooled to room temperature, filtered, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield methyl 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclo-propanecarboxamido)-3-methylpyridin-2-yl)-5-hydroxybenzoate (170 mg, 99%) as a white solid. ESI-MS m/z calc. 482.1, found 483.53 (M+1)+. Retention time 1.83 minutes.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:11]1[CH:29]=[CH:28][C:14]([O:15][CH:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17](=O)[OH:18])=[C:13]([Cl:30])[CH:12]=1)([CH2:8][CH2:9][CH3:10])([CH3:7])[CH3:6]>C1(C)C=CC=CC=1>[C:5]([C:11]1[CH:29]=[CH:28][C:14]([O:15][CH:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17]([Cl:3])=[O:18])=[C:13]([Cl:30])[CH:12]=1)([CH2:8][CH2:9][CH3:10])([CH3:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCC(Oc1ccc(C(C)(C)CCC)cc1Cl)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCC(Oc1ccc(C(C)(C)CCC)cc1Cl)C(=O)Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
9.7 ml of thionyl chloride was added dropwise with stirring to 34.4 g of 2-(4-t-hexyl-2-chlorophenoxy)capric acid dissolved in 34 ml of toluene heated to 60° C. The reaction was carried out at 60° C. for 2 hours. Excess thionyl chloride and toluene were distilled off under reduced pressure. 40.1 g of 2-(4-t-hexyl-2-chlorophenoxy)capric acid chloride was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)(=[O:14])[CH3:13]
Reactant: OCCSCc1ccncc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCSCc1ccncc1
Reaction time: 8 h

Procedure:
4-(2-Hydroxyethylthiomethyl)pyridine (1.0 g.) was refluxed with 10 ml. of acetic anhydride for 3 hours. After standing overnight at room temperature, the acetic anhydride was evaporated in vacuo, the residue diluted with 10 ml. of water, made basic with sodium bicarbonate, and the product extracted into chloroform (four times 50 ml.). The chloroform was carbon treated, dried and concentrated to an oil (1.47 g.). The oil was chromatographed on 60 g. of silica gel with 5% methanol/chloroform as eluant. Fractions containing only product (Rf 0.6 on thin layer silica gel chromatography eluted with 18:1 chloroform:methanol) were combined and concentrated to yield 4-(2-acetoxyethylthiomethyl)pyridine [300 mg. of oil; pnmr/CDCl3 /TMS/delta: 7.9 (s, 3H), 7.3 (t, 2H), 6.3 (s, 2H), 5.8 (t, 2H), 2.7 (d, 2H), 1.4 (d, 2H)].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([O:15][N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 52.5 %

Procedure:
N-Benzyloxycarbonylglycine (10.9 g, 52.2 mmol) and N-hydroxysuccinimide (6.0 g, 52.2 mmol), were dissolved in dioxane (100 ml) and cooled in a cold water bath. N,N'-Dicyclohexylcarbodiimide (10.8 g, 52.2 mmol) was added and the mixture was stirred overnight. The white precipitate which formed was filtered, washed and air-dried (11.8 g, 100% of dicyclohexylurea). The filtrate was evaporated to dryness under reduced pressure, and the residual solid (16.2 g) was crystallized from ethyl acetate (50 ml) to give 8.4 g (53%) of crystalline N-(N-benzyloxycarbonylglycyloxy)succinimide, m.p. 110.5-112° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[CH3:2].P([O-])(O)(O)=[O:17].[Na+].Cl([O-])=O.[Na+].O>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:5]=1[C:6]([OH:17])=[O:7])[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: CCOc1cc(C(F)(F)F)ccc1C=O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 420.6 %

Procedure:
0.60 g of 2-ethoxy-4-(trifluoromethyl)benzaldehyde was dissolved in 5 ml dimethyl sulfoxide and an aqueous solution (1 ml) of 67 mg sodium dihydrogen phosphate, and an aqueous solution (3 ml) of 0.35 g sodium chlorite was added dropwise. After stirring at room temperature for 12 hours, water was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (2:1), 0.55 g of 2-ethoxy-4-(trifluoromethyl)benzoic acid was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([F:11])[C:5]([CH3:12])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:9])=[C:6]([F:11])[C:5]([CH3:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)c(C(=O)Cl)c1F
Reactant: Br[Mg]c1ccccc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(C(=O)c2ccccc2)c1F
Reaction time: 0.75 h

Procedure:
Step 1 To a solution of 6-chloro-2-fluoro-3-methyl-benzoyl chloride (2.07 g, 10.0 mmol) in anhydrous tetrahydrofuran (50 ml), stirred under nitrogen in an acetonitrile/CO2 bath, was added tributyl phosphine (2.75 ml, 11.0 mmol). The mixture was stirred for 15 minutes before phenylmagnesium bromide (3M in diethyl ether, 3.67 ml, 11.0 mmol) was added dropwise. After 45 minutes, the reaction was quenched by addition of hydrochloric acid (2N, 50 ml). The mixture was extracted with ethyl acetate. The organic liquors were washed with sodium bicarbonate solution and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica chromatography eluting with 0-10% diethyl ether/petroleum ether furnishing (6-chloro-2-fluoro-3-methyl-phenyl)-phenyl-methanone as a yellow oil that slowly crystallised (1.12 g, ca. 80% pure). Trituration with petroleum ether produced an analytically pure sample. MS: [M+H]+ 249
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)/[CH:5]=[CH:6]/[C:7]1[C:15]2[C:10](=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[CH3:30][O:31][C:32](=[O:43])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[C:35]([O:41][CH3:42])[CH:34]=1>CN(C)C=O>[O:3]=[C:4]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29]1)/[CH:5]=[CH:6]/[C:7]1[C:15]2[C:10](=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:19])=[CH:13][CH:14]=2)[N:9]([CH2:39][C:36]2[CH:37]=[CH:38][C:33]([C:32]([O:31][CH3:30])=[O:43])=[CH:34][C:35]=2[O:41][CH3:42])[CH:8]=1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=C(/C=C/c1ccc2c(/C=C/C(=O)N3CCCC3)c[nH]c2c1)N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cc(/C=C/C(=O)N3CCCC3)c3ccc(/C=C/C(=O)N4CCCC4)cc32)c(OC)c1
Yield: 76.1 %

Procedure:
Sodium hydride (0.15 g of a 60% dispersion in mineral oil) was added to a stirred solution of E,E-3,6-di(3-oxo-3-pyrrolidino-1-propenyl)indole (0.97 g) in N,N-dimethylformamide (30 ml) cooled in an ice bath. After approximately 1 hr a solution of methyl-4-bromomethyl-3-methoxybenzoate (0.74 g) in N,N-dimethylformamide (10 ml) was added dropwise, the cooling bath was removed, and the mixture stirred for hr. The mixture was added slowly to vigorously stirred 1M hydrochloric acid (300 ml); the precipitate was isolated by filtration, washed with water and dried. The solid obtained was recrystallized from ethyl acetate to give methyl E,E-4-[3,6-di(3-oxo-3-pyrrolidino-1-propenyl)indol-1-ylmethyl]-3-methoxybenzoate (1.1 g, 76%) as an off-white powder; mp 226°-228°; partial NMR (250 MHz, DMSO-d6): 1.70°-2.0(m, 8H, pyrrolidino H), 3.40(m, 4H, pyrrolidino H), 3.65(m, 4H, pyrrolidino H), 3.83(s, 3H, OCH3), 3.95(s, 3H, OCH3), 5.50(s, 2H, NCH2Ar), 6.75(d, J=15.5 Hz, 1H, olefinic H), 7.0(m, 2H, olefinic H, and ArH).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([CH:23]=O)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>N1CCCCC1.C(O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:23][C:19]1[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=1)[NH:14][CH:15]=[CH:16]3)[C:7](=[O:13])[NH:8]2
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: O=Cc1ccc2[nH]ccc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cccc(CCO)c2C1=Cc1ccc2[nH]ccc2c1
Temperature: 90 °C
Yield: 71.7 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (39 mg, 0.22 mmol), 1H-indole-5-carbaldehyde (32 mg, 0.22 mmol) and 1 drop of piperidine in ethanol was heated at 90° C. for overnight and cooled to room temperature. The reaction mixture was concentrated and the residue was purified on silica gel column to give 48 mg (72%) of 4-(2-hydroxy-ethyl)-3-(1H-indol-5-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][O:14]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:21]1[NH:20][CH:19]=[C:18]2[C:13](=[O:12])[O:14][CH2:15][CH2:16][C:17]=12
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Product: O=C1Nc2ccc(F)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-Fluoro-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH2:11][C:10]([CH3:12])=[C:9]([CH3:13])[C:8]=1[CH3:14].Cl[Si:16]([CH3:24])([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH3:23][Si:16]([CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:7]1([CH3:6])[CH:11]=[C:10]([CH3:12])[C:9]([CH3:13])=[C:8]1[CH3:14]
Reactant: C[Si](C)(Cl)c1ccccc1
Reactant: CC1=C(C)C(C)=C(C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=CC(C)([Si](C)(C)c2ccccc2)C(C)=C1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
30 ml (48 mmol) of n-butyllithium (1.6 M in hexane) were added dropwise at −78° C. to a solution of 5.4 g (44.2 mmol) of tetramethylcyclopentadiene in 90 ml of THF over the course of about 20 minutes. The mixture was then stirred at 25° C. for 24 hours. The solution was then cooled again to −78° C., 8.3 g (48.6 mmol) of chlorodimethylphenylsilane were added dropwise over the course of 15 minutes, and the mixture was stirred at 25° C. for 24 hours. The THF was then removed under reduced pressure, and the residue was taken up in 50 ml of pentane. The insoluble precipitate was filtered off and the pentane was removed under reduced pressure. The yellow liquid residue was distilled under a high vacuum. The product boils at 83 to 85° C. Characterization was carried out by means of 1H-NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33]C(=O)OC(C)(C)C)[C:10](=[O:32])[NH:11][C:12]2[CH:13]=[C:14]3[C:30](=[O:31])[NH:29][N:28]=[CH:27][C:16]4=[C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[NH:18][C:19]([CH:20]=2)=[C:15]34)=[CH:4][CH:3]=1.[ClH:41].C(N(CC)CC)C>O1CCOCC1>[ClH:41].[NH2:33][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:10]([NH:11][C:12]1[CH:13]=[C:14]2[C:30](=[O:31])[NH:29][N:28]=[CH:27][C:16]3=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[NH:18][C:19]([CH:20]=1)=[C:15]23)=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N[C@H](Cc1ccc(F)cc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 49 %

Procedure:
Preparation of example 168 from the title compound of Example 152 (49 mg, 0.091 mmol) and 4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner, included freebasing with triethylamine and subsequent silica gel chromatography eluting with 3:1:1 hexane:ethyl acetate:ethanol. With ice bath cooling, the purified freebase in CH2Cl2 (10 mL) was treated with 4M HCl in dioxane (0.1 mL). After removal of the volatile components, the title compound (21 mg, 0.044 mmol) was obtained as an orange/yellow powder in 49% yield.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH:15]=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:21]([NH2:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][NH:27][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccccc2C=O)cc1
Reactant: CCCCCCN
Product: CCCCCCNCc1ccccc1C#Cc1ccc(CCCC)cc1
Yield: 11.7 %

Procedure:
The title compound was prepared following procedure described in example 19, step b) from 2-[(4-butylphenyl)ethynyl]benzaldehyde (1.12 g, 4.28 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) and n-hexylamine (Aldrich, 294 μl, 5.13 mmol). Purification of the crude product by flash chromatography on silicagel (DCM/MeOH/NH4OH 98/2/1) gave 174 mg (12%) of the title compound. HPLC, Rt: 4.39 min purity: 91.6%). LC/MS, M+(ESI): 348.4. 1HNMR (CDCl3) δ: 0.82 (t, J=6.8 Hz, 3H), 0.91 (t, J=7.3 Hz, 3H), 1.23-1.40 (m, 8H), 1.46-1.64 (m, 4H), 2.25 (m, 1H), 2.62 (t, J=7.5 Hz, 4H), 4.00 (s, 2H), 7.15 (d, J=8.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.39 (m, 1H), 7.42 (d, J=8.3 Hz, 2H), 7.50 (dd, J=7.3, 1.7 Hz, 1H).
Reaction SMILES: [N:1]1([CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:21][O:22][C:23](OC)(OC)OC.C(O)(=O)C>ClCCl>[N:1]1([CH:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]2[CH:12]=[CH:11][C:10]3[NH:13][C:21]([O:22][CH3:23])=[N:14][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(OC)(OC)OC
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1nc2cc(C(c3ccccc3)n3ccnc3)ccc2[nH]1
Temperature: 25 °C
Yield: 32.8 %

Procedure:
A mixture of 2.6 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-1,2-benzenediamine, 10 parts of tetramethoxymethane, 0.6 parts of acetic acid and 6.5 parts of dichloromethane was stirred over weekend at room temperature. After evaporation, the residue was treated with ammonium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was dried in vacuo, yielding 1 part (32.8%) of 5-[(1H-imidazol-1-yl)phenylmethyl]-2-methoxy-1H-benzimidazole; mp. 109.5° C. (compound 115).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>O1CCCC1.O>[C:8]([C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:9]
Reactant: CCOC(=O)CBr
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(c1ccccc1)c1ccccc1

Procedure:
To a solution of diphenylacetonitrile (1 g) in tetrahydrofuran (10 ml) was added 60% sodium hydride (0.25 g) portionwise under ice-cooling and stirring. After completion of portionwise addition, the mixture was further stirred for 15 minutes. Then, ethyl bromoacetate (0.69 ml) was added dropwise and the mixture was further stirred for 30 minutes. The reaction mixture was then diluted with water and the organic layer was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to provide the title compound (1.2 g) as colorless powder.
Reaction SMILES: [CH:1]1[C:6]([N:7]=[C:8]=[O:9])=[CH:5][C:4]2[C:10]([F:17])([F:16])[O:11][C:12]([F:15])([F:14])[O:13][C:3]=2[CH:2]=1.[CH3:18][O:19][C:20]([C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=2)[CH:25]=[CH:24][N:23]=1)=[O:21]>C(Cl)Cl>[F:14][C:12]1([F:15])[O:13][C:3]2[CH:2]=[CH:1][C:6]([NH:7][C:8]([NH:35][C:31]3[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=3)[O:28][C:26]3[CH:25]=[CH:24][N:23]=[C:22]([C:20]([O:19][CH3:18])=[O:21])[CH:27]=3)=[O:9])=[CH:5][C:4]=2[C:10]([F:16])([F:17])[O:11]1
Reactant: COC(=O)c1cc(Oc2cccc(N)c2)ccn1
Reactant: O=C=Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2cccc(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)c2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirring solution of 2,2,4,4-tetrafluoro-6-isocyanato-1,3-benzodioxene (0.816 g, 3.28 mmol) was added 4-(3-aminophenoxy)pyridine-2-carboxylic acid methyl ester (0.800 g, 3.28 mmol) in DCM (13 mL) in portions. The homogenous contents turned white and opaque within 1 min. of addition, and were allowed to stir at room temperature for 12 h. The heterogenous mixture was filtered, and solid product repeatedly washed with DCM to remove residual starting material. The desired product was collected as a white powder, 1.36 g (83%). 1H-NMR (DMSO-d6) δ 9.08 (d, 2H), 8.59 (s, 1H), 8.07 (s, 1H), 7.60 (dd, 1H), 7.37 (m, 4H), 7.25 (d, 1H), 7.20 (dd, 1H), 6.80 (d, 1H), 3.82 (s, 3H); MS LC MS [M+H]+=494.1, RT=3.23 min.
Reaction SMILES: [NH2:1][C@H:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:20]([O:19][C:17]([C@@H:2]([NH:1][S:32]([C:29]1[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:36])[F:37])=[CH:31][CH:30]=1)(=[O:34])=[O:33])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCCCC(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
210.5 mg of 4-[4-((2S)-2-amino-2-tert-butoxycarbonyl-ethyl)-phenoxy]-butyric acid were dissolved in 2 ml of DMF and cooled to 0° C. 269 mg of 4-trifluoromethylbenzenesulfonyl chloride and 284 mg of diisopropylethylamine were added and the reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was cooled to −25° C. for 16 hours and then warmed to room temperature. The reaction was quenched by the addition of water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/water/acetic acid (9/1/0.1/0.1). Yield 66 mg. MS (ES+): m/e=532.2 (M+H)+; 476.1.