Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:1]([O:8][C@@H:9]([CH3:14])[CH2:10][C:11]([N:17]([O:18][CH3:19])[CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: C[C@@H](CC(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)C[C@H](C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of the above (3S)-3-(benzyloxy)butanoic acid (225 g) in DMF (1.5 L), N,O-dimethylhydroxylamine hydrochloride (111 g, 1.1 mol) and triethylamine (0.32 mL, 2.3 mol) were added, and the mixture was stirred at room temperature for 40 minutes. Subsequently, 1-hydroxybenzotriazole (112 g, 0.83 mol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (160 g, 0.83 mol) were successively added, and the mixture was stirred at room temperature for 5 hours. After the reaction, the reaction mixture was poured to ice-water, and it was extracted with diethyl ether. After it was successively washed with 1N hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, it was dried with sodium sulfate and the solvent was distilled off under reduced pressure to give (3S)-3-(benzyloxy)-N-methoxy-N-methylbutanamide (196 g) as a mixture. The present compound was used for the subsequent reaction without further purification.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6].Cl.[CH2:18](O)[CH3:19]>>[ClH:1].[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH2:4][C:5]([O:7][CH2:18][CH3:19])=[O:6]
Reactant: NC(CC(=O)O)c1cccc([N+](=O)[O-])c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CC(N)c1cccc([N+](=O)[O-])c1

Procedure:
60 g of (1a) were suspended in 660 ml of ethanol, and gaseous HCl was passed in for 1 h. The reaction mixture was then heated under reflux for 4 h and then cooled and concentrated. 62 g of a white solid were obtained.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH:3]([CH:5]1[C:11](=[O:12])[N:10]2[CH:6]1[CH2:7][C:8]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[C:9]2[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[OH:4].C.C(=O)(O)[O-].[Na+:36].O1CCOCC1>[Pd].O>[F:30][C:2]([F:1])([F:29])[CH:3]([CH:5]1[C:11](=[O:12])[N:10]2[CH:6]1[CH2:7][C:8]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[C:9]2[C:13]([O-:15])=[O:14])[OH:4].[Na+:36]
Reactant: O=C(OCc1ccccc1)C1=C(N2CCOCC2)CC2C(C(O)C(F)(F)F)C(=O)N12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C([O-])C1=C(N2CCOCC2)CC2C(C(O)C(F)(F)F)C(=O)N12
Reaction time: 0.5 h

Procedure:
A mixture of benzyl 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-morpholino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (25 mg), 10% palladium on powdered charcoal (25 mg), sodium bicarbonate (5 mg), dioxane (2 ml), and water (1 ml) is hydrogenated at 40 psi for 30 mins. The mixture is filtered to remove the catalyst which is washed with water (3×3 ml). The combined filtrate is extracted with ethyl acetate (2×2 ml), concentrated in vacuo, and lyophilized to give sodium 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-morpholino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][CH2:22][C:23]([N:25]3[CH:29]([CH3:30])[CH2:28][CH2:27][CH:26]3[CH3:31])=[O:24])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[C:10]3=[N:18][CH:19]=[CH:20][N:9]23)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:51][N:52]([CH3:56])[CH2:53][CH2:54]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][CH2:22][C:23]([N:25]3[CH:26]([CH3:31])[CH2:27][CH2:28][CH:29]3[CH3:30])=[O:24])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:54][CH2:53][N:52]([CH3:56])[CH3:51])[CH:15]=3)[C:10]3=[N:18][CH:19]=[CH:20][N:9]23)=[CH:4][CH:3]=1
Reactant: CC1CCC(C)N1C(=O)CCC1(c2ccc(Cl)cc2)c2cc(O)ccc2-c2nccn21
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CCC(C)N1C(=O)CCC1(c2ccc(Cl)cc2)c2cc(OCCN(C)C)ccc2-c2nccn21

Procedure:
To a solution of 5-(4-chlorophenyl)-5-[3-(2,5-dimethylpyrrolidin-1-yl)-3-oxopropyl]-5H-imidazo[2,1-a]isoindol-7-ol (30 mg) in dry THF (0.5 mL) was added triphenylphosphine (27 mg), 2-dimethylaminoethanol (11 μL), then DIAD (21 μL) at room temperature. After 3 h additional triphenylphosphine (27 mg), 2-dimethylaminoethanol (11 μL), and DIAD (21 μL) were added and stirring continued. After 24 h the mixture was concentrated. The crude material was purified by preparative reversed-phase HPLC (20×150 mm Waters Sunfire, 5-50% ACN/water containing 0.1% TFA over 20 min. at 20 mL/min). Fractions containing the product were pooled then passed through Dowex 1×2-400 ion exchange resin (prewashed with 1M NaOH, H2O, MeOH) washing with MeOH. The filtrate was concentrated to give a white solid (20 mg): 1H-NMR (500 MHz, CDCl3) δ 7.73 (dd, J=2.2 and 6.1 Hz, 1 H), 7.29-7.24 (m, 3 H), 7.12 (m, 2 H), 6.93 (m, 2 H), 6.78 (dd, J=2.2 and 3.9 Hz, 1 H), 4.04-3.90 (m, 3 H), 3.40 (m, 1 H), 3.11-2.79 (m, 2 H), 2.69 (t, J=5.37 Hz, 1 H), 2.32 (s, 6 H), 2.02-1.75 (m, 2 H), 1.66-1.49 (m, 5 H), 1.16 (dd, J=6.35 and 11.96 Hz, 3 H), 0.88 (dd, J=6.32 and 27.1 Hz, 3 H); HRMS (M+H)+ calculated 507.2521. found 507.2508.
Reaction SMILES: [C:1]1([S:7]([NH:10][C@H:11]([CH2:15][C:16]#[CH:17])[C:12]([OH:14])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:37][O:38][CH:39]([O:42][CH3:43])[CH2:40][NH2:41].CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:37][O:38][CH:39]([O:42][CH3:43])[CH2:40][NH:41][C:12](=[O:14])[C@H:11]([NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[CH2:15][C:16]#[CH:17]
Reactant: COC(CN)OC
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)NCC(OC)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-2-(benzenesulfonamido)pent-4-ynoic acid (11.66 g, 46.04 mmol), HOBt (7.46 g, 55.24 mmol), iPr2NEt (7.13 g, 55.24 mmol), (2,2-dimethoxyethyl)amine (5.81 g, 55.24 mmol), and EDCI (10.53 g, 55.24 mmol) in DMF (100 mL) was stirred for 24 h at RT. The reaction mixture was concentrated and taken up in H2O (100 mL). The aqueous layer was extracted with EtOAc (3×), dried over MgSO4, and concentrated to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 2.43 (m, 2H), 2.71 (s, 3H), 2.85 (s, 1H), 2.89 (s, 3H), 2.96 (m, 2H), 3.98 (t, 7.1 Hz, 3H), 4.15 (t, 5.5 Hz, 1H), 7.55 (m, 3H), 7.80 (d, 8.0 Hz, 2H), 7.97 (s, 1H), 8.11 (t, 5.5 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH:11](=[N:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: CCOP(=O)(CN)OCC
Solvent: CCO
Product: CCOP(=O)(CN=Cc1ccccc1)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.7 %

Procedure:
Diethyl aminomethylphosphonate (4.03 g., 24.1 mmole) is stirred in an ice bath while benzaldehyde (2.50 ml., 24.5 mMol) is added dropwise over a period of 5 minutes. After having been stirred an additional 15 minutes at 0°C., the mixture is diluted with absolute ethanol (20 ml.) and evaporated in vacuo. The residue is dissolved in dry benzene (20 ml.) and evaporated to give diethyl N-benzylidene-aminomethylphosphonate (6.073 g.) as a pale yellow oil: ir (CCl4) 1639, 1250, 1062, 1037, and 971 cm-1 ; nmr (CDCl3)τ8.68 (t, 6, J=7 Hz, CH3), 5.93 (d of d, 2, J=17.5 Hz and J=1 Hz, CH2), 5.85 (d of q, 4, J=8 Hz and J=7 Hz, CH2CH3), 2.65 (m, 3, ArH), 2.29 (m, 2, ArH), and 1.75 (t of d, 1, J=1 Hz and J=5 Hz, =CH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:16]([O:23][C:24](=[O:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:16]([O:23][C:24](=[O:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:12](=[O:14])[C@H:9]([CH2:10][OH:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 55.7 %

Procedure:
N-t-butyloxycarbonyl-L-serine (33.86 g, 165 mmole), L-proline benzylester hydrochloride (39.88 g, 165 mmole) and HOBT (22.29 g, 165 mmole) were dissolved in methylene chloride (500 ml), and triethylamine (16.70 g, 5 mmole) and WSC hydrochloride (31.63 g, 165 mmole) were added thereto at -30° C. The mixture was stirred for 2 hours at less than 0° C., and next overnight at room temperature. The solution was washed with 5% aqueous sodium bicarbonate (400 ml, twice), 5% aqueous citric acid (400 ml, twice) and water (400 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to produce oily residue. The residue was crystallized from ethyl acetate and n-hexane to obtain N-t-butyloxycarbonyl-L-seryl-L-proline benzylester (yield: 36.09 g, 55.7%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10](Cl)(=[O:20])[C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14](Cl)=[O:15])[CH:12]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:10](=[O:20])[C:11]2[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)=[O:15])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: NCc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(F)cc1)c1cccc(C(=O)NCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 27.4 %

Procedure:
4-Fluoro-benzylamine (1.25 g) is added to isophthaloyl dichloride (1.015 g) in toluene (100 mL). The reaction mixture is stirred at room temperature for 4 days. The product is filtered off and washed with toluene. Recrystallization from methanol gives the product (0.52 g), mp 190–191° C.
Reaction SMILES: [CH3:1][C:2]([SH:7])([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[C:14](Cl)(=[O:16])[CH3:15]>C(Cl)Cl>[C:14]([O:5][CH2:4][CH2:3][C:2]([CH3:6])([SH:7])[CH3:1])(=[O:16])[CH3:15]
Reactant: CC(C)(S)CCO
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCC(C)(C)S
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-Methyl-3-sulfanylbutan-1-ol (Sweetman et al, J. Med. Chem. 14:868 (1971), the disclosure of which is incorporated by reference herein in its entirety) (5 g, 42 mmol) and pyridine (3.6 mL, 43 mmol) were dissolved in methylene chloride (50 mL) and cooled to −78° C. Acetyl chloride (3.1 mL, 43 mmol) was added dropwise. The solution was kept cold for 30 min then allowed to warm to room temperature. Stirring was continued for 1.5 hours. The reaction mixture was diluted with methylene chloride, washed with 1 N HCl and brine, and dried over sodium sulfate. Evaporation of the solvent gave 6.6 g of the title compound which was used without further purification. 1H-NMR (CDCl3): δ1.41 (s, 3H), 1.92 (t, J=7.2 Hz, 2H), 2.03 (s, 3H), 2.21 (s, 1H), 4.25 (t, J=7.1 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([CH2:20][CH2:21][S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:19]=[CH:18][N:17]=[CH:16]1>>[N:15]1([CH2:20][CH2:21][S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[CH:4]=3)=[O:30])=[CH:27][CH:26]=2)(=[O:23])=[O:24])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)CCn2ccnc2)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCn2ccnc2)cc1

Procedure:
4 g of 4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure R to yield 4-(2-hydroxyethylsulfonyl)benzonitrile. 3.0 g of triphenylphosphine was added to a solution of 2 g of 4-(2-hydroxyethylsulfonyl)benzonitrile and 4.7 g of carbon tetrabromide in dichloromethane at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (0-70% ethyl acetate/hexane) to afford 4-(2-bromoethylsulfonyl)benzonitrile. 250 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with imidazole to give 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzonitrile. 300 mg of 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 467.1 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6]2.Cl.[CH2:22]([N:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)N)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.Cl>[CH2:22]([N:29]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:13]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NN(Cc1ccccc1)c1ccccc1
Reactant: CCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Agent: Cl
Solvent: CCO
Product: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)n(Cc2ccccc2)c2ccccc12
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
1-(6-methoxy-naphthalen-2-yl)heptan-1-one (0.176 kg, 0.651 moles) was dissolved in anhydrous ethanol (1.56 L), 1-benzyl-1-phenylhydrazine hydrochloride (BPH, 0.168 kg, 0.716 moles) was added, a 37% aqueous solution of hydrochloric acid (1.2 g, 12.2 mmoles) was added, and the reaction mixture was heated under reflux for 7 hours. Two portions of BPH (8.4 g, 71.6 mmoles each) were added to the mixture at one hour intervals at 70° C. The temperature of the mixture returned to the reflux temperature after the first BPH addition. Heating was terminated, the reaction mixture was diluted with heptane (1.65 L) followed by water (0.62 kg), and the mixture was stirred for 30 minutes while maintaining the temperature at 45° C. The addition of heptane resulted in the precipitation of solids from the homogeneous organic phase, while the addition of water brought the mixture to a biphasic state with layers in an approximate ratio of 1:1. The bottom layer was drained (pH 1) and the upper layer was washed with water (0.26 kg) while stirring the mixture for 30 minutes. The bottom layer was again drained (pH 3) and the upper layer was cooled to 12° C. in the reactor. All operations subsequent to the quenching step were conducted at 45° C. to prevent premature product crystallization. About 10 grams of the chilled solution were withdrawn from the reactor, subjected to low-temperature crystallization, and returned to the chilled solution as a seeding suspension. The mixture was kept at 12° C. for 30 minutes, cooled to −10° C. over two hours, and stirred at that temperature for 30 minutes. The suspension was filtered, the solids were dried in a nitrogen stream on a filter for 30 minutes, and the solids were vacuumed at 50° C./50 mm Hg to yield 221 g (78%) of the title compound as light-yellow prills with 99.45% ar. HPLC purity.
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:16][N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:19][C:18]2([CH3:30])[CH3:29])=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C1(C)C=CC=CC=1>[C:38]([N:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:8]([O:16][N:17]1[C:18]([CH3:30])([CH3:29])[CH2:19][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:21][C:22]1([CH3:24])[CH3:23])=[N:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC1CC(C)(C)N(OC(=NC2CCCCC2)NC2CCCCC2)C(C)(C)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)OC1CC(C)(C)N(OC(=NC2CCCCC2)N(C(C)=O)C2CCCCC2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 22.6 %

Procedure:
To a solution of compound 1 (4.21 g, 10 mmol) [prepared according to Example 1] in toluene (25 ml) is added triethylamine (1.55 ml, 11 mmol) and acetyl chloride (0.78 ml, 11 mmol). The mixture is stirred at room temperature for 7 hours, then washed with water (2×10 ml), dried over MgSO4 and evaporated. The residue is chromatographed over silica gel with hexane-ethyl acetate (4:1) and the pure fractions are recristallized from pentane to afford 1.05 g of the title compound as a white solid, mp. 125-130° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[C:16]([C:17]([NH:19][CH2:20][C:21]4[CH:32]=[CH:31][C:24]([O:25][C@H:26]([CH3:30])[C:27](O)=[O:28])=[CH:23][C:22]=4[F:33])=[O:18])=[CH:15][C:14]([F:34])=[CH:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.O1C2C=CC(OC3C(C(NCC4C=CC(O[C@H](C)C(O)=O)=CC=4F)=O)=CC=C[N:46]=3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:12]=[CH:13][C:14]([F:34])=[CH:15][C:16]=3[C:17]([NH:19][CH2:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][C@@H:26]([C:27](=[O:28])[NH2:46])[CH3:30])=[CH:23][C:22]=3[F:33])=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O
Product: C[C@@H](Oc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(N)=O

Procedure:
The compound of Formula (5.5.18) was prepared in a manner analogous to that described in Example 14, substituting (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-5-fluoro-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid for the corresponding (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid material.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=3)[O:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+:30]>C1COCC1.CCO>[Na+:30].[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=3)[O:17][CH2:18][CH2:19][CH2:20][C:21]([O-:23])=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCOc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C([O-])CCCOc1cccc(C#Cc2ccc3ccc(Br)cc3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the ethyl ester from Step 4 (380 mg) in THF (4 mL) and EtOH (2 mL) was added 2N NaOH (0.65 mL) and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and passed through a neutral XAD-8 resin, eluting with H2O and then with EtOH, to afford the title compound as a white solid: m.p. 250° C. (d).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:12]=[C:13]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:10])([CH3:9])[CH3:8].[CH2:27]([N:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>>[C:7]([C:11]1[CH:12]=[C:13]([CH:14]=[C:15]([C:18]([CH3:19])([CH3:20])[CH3:21])[C:16]=1[OH:17])[CH2:22][CH2:23][C:24]([O:26][N:34]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:25])([CH3:10])([CH3:8])[CH3:9]
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(CCC(=O)ON(Cc2ccccc2)Cc2ccccc2)cc(C(C)(C)C)c1O
Yield: 76.5 %

Procedure:
The procedure of Example II is followed using 3.17 g (25 mmol) of oxalyl chloride, 6.96 g (25 mmol) of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoic acid, 5.33 g (25 mmol) of N,N-dibenzylhydroxylamine, and 2.53 g (25 mmol) of triethylamine. The residue is recrystallized from petroleum ether to give 9.06 g (77%) of a white solid: mp 93°-95.5° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:23][CH2:22]2)[CH:4]=[CH:3][CH:2]=1.C1(CN)C=CC=CC=1>CO.[Pd]>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C(=O)CN1CCC(Nc2nc3ccccc3n2-c2cccc3cccnc23)CC1
Agent: [Pd]
Solvent: CO
Solvent: NCc1ccccc1
Product: CC(C)C(=O)CN1CCC(Nc2nc3ccccc3n2-c2cccc3c2NCCC3)CC1
Reaction time: 24 h
Yield: 27.1 %

Procedure:
A mixture of 1-[4-[[1-(8-quinolinyl)-1H-benzimidazol-2-yl]amino]1-piperidinyl]-3-methyl-2-butanone (0.0222 mol) and benzenemethanamine (0.0666 mol) in methanol (250 ml) was hydrogenated at 40° C. under a 3 bar pressure for 24 hours with palladium on activated carbon (1.5 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered through celite, washed with CH2Cl2 and CH3OH and the filtrate was evaporated. Palladium on activated carbon (1.5 g) and methanol (250 ml) were added again. Hydrogenation was continued at 40° C. under a 3 bar pressure for 24 hours. After uptake of hydrogen, the catalyst was filtered through celite, washed with CH2Cl2 and the filtrate was evaporated. The residue (22 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.1 and 85/15/1; 20–45 μm). Three pure fractions were collected and their solvents were evaporated, yielding 2.6 g 1-[4-[[1-(1,2,3,4-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-3-methyl-2-butanone (interm. 40) (fraction 1), 2.9 g of fraction 2 and 0.7 g of fraction 3. Fraction 2 and 3 were crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.82 g (±)-N-[1-[3-methyl-2-[(phenylmethyl)amino]butyl]4-piperidinyl]-1-(1,2,3,4-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-amine; mp. 126° C. and 0.55 g of N-(4-piperidinyl)-1-(1,2,3,4-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-amine; mp. 205° C. (comp. 48).
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11]([NH2:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH:9]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH2:23])[O:10][CH2:2][C@@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]1[OH:8]
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCN
Product: NCCCCCCCCCCCCC1OC[C@@H](O)[C@@H](O)[C@H]1O

Procedure:
The preparation is analogous to Example 1, starting from 15 g of D-ribose and 18 g of dodecylamine.