Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:66][C:65](=[O:67])[N:64]([CH3:68])[C:63]2=[O:69])[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=4)=[O:50])[C@H:46]([CH:62]4[CH2:66][C:65](=[O:67])[N:64]([CH3:68])[C:63]4=[O:69])[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: CN1C(=O)CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(=O)N(C)C4=O)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 50.1 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate-(500 mg, 0.84 mmol) and (2S,4S)-4-mercapto-2-(N-methyl-2,5-dioxopyrrolidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer A (330 mg, 0.84 mmol, compound of Reference Example 8) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(N-methyl-2,5-dioxopyrrolidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate diastereomer A (311 mg, yield: 50.1%).
Reaction SMILES: C[Si](Cl)(C)C.[F:6][C:7]([F:17])([F:16])[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[CH:18]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)=O.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:31]=[C:32]([NH:36][C:37]([NH2:39])=[O:38])[CH:33]=[CH:34][CH:35]=1>CN(C)C=O.C(#N)C.O>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([CH:18]([C:11]2[C:12](=[O:14])[CH2:13][CH:8]([C:7]([F:16])([F:17])[F:6])[CH2:9][C:10]=2[OH:15])[NH:39][C:37]([NH:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:40])([F:41])[F:28])[CH:31]=2)=[O:38])=[CH:21][CH:22]=1)#[N:25]
Reactant: O=C1CC(=O)CC(C(F)(F)F)C1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(C(F)(F)F)CC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylsilyl chloride (775 μL, 6.11 mmol) is added to a solution of 5-(trifluoromethyl)-cyclohexane-1,3-dione (1.00 g, 5.55 mmol), 4-formylbenzonitrile (728 mg, 5.55 mmol) and 1-(3-(trifluoromethyl)phenyl)urea (1.13 g, 5.55 mmol) in a mixture of N,N-dimethylform-amide (4.3 mL) and acetonitrile (8.3 mL), and the mixture is stirred at room temperature for 1 h. The reaction mixture is cooled to room temperature and poured into a mixture of water and ice. The precipitate is filtered and dried under reduced pressure. Yield: 2.38 g; ESI mass spectrum [M+H]+=498, Retention time HPLC: 0.75 min (V011_S01).
Reaction SMILES: O[C@H](C(C)C)[C@@H](N([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)C(OC)=O)C(O)=O.O[C@@H:28]([CH:50]([CH3:52])[CH3:51])[C@@H:29]([N:33]([C:38]1C=CC(C2C=CC=CC=2)=CC=1)[C:34]([O:36]C)=[O:35])[C:30]([OH:32])=[O:31].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:36][C:34](=[O:35])[N:33]([CH3:38])[C@H:29]3[C:30](=[O:32])[O:31][C@@H:28]3[CH:50]([CH3:52])[CH3:51])=[CH:17][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)N(c1ccc(-c2ccccc2)cc1)[C@@H](C(=O)O)[C@@H](O)C(C)C
Reactant: COC(=O)N(c1ccc(-c2ccccc2)cc1)[C@@H](C(=O)O)[C@H](O)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H]1OC(=O)[C@@H]1N(C)C(=O)Oc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 17 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-3-hydroxy-4-methyl-2-[(4-phenylphenyl)-methoxy-carbonylamino]-pentanoic acid and (2R*,3S*)-3-hydroxy-4-methyl-2-[(4-phenylphenyl)-methoxy-carbonylamino]-pentanoic acid (0.059 g, 0.17 mmol) in dry CH2Cl2 (7.0 mL), at 0° C., Et3N (0.07 mL, 0.5 mmol) and subsequently TBTU (0.065 g, 0.2 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 90:10 to 80:20) to afford the pure title compound (0.01 g, 17%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 357 [M−NH4]+; (ESI) m/z: 338 [M−H]−. 1H NMR (DMSO-d6) δ 0.89 (d, J=6.79 Hz, 3H), 0.97 (d, J=6.57 Hz, 3H), 1.81-2.12 (m, 1H), 4.26 (dd, J=4.38, 9.11 Hz, 1H), 4.80 (dd, J=4.39, 8.16 Hz, 1H), 5.12 (s, 2H), 7.29-7.54 (m, 5H), 7.63-7.77 (m, 4H), 8.26 (d, J=8.21 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1[C:39]([CH3:40])=[CH:38]C=CC=1C.C1(CN2C=CC(N)=N2)CC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH:38]3[CH2:39][CH2:40]3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cc1cccc(C)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: Nc1ccn(CC2CC2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC3CC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 410 mg, 1.23 mmol) was suspended in methylene chloride (7 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (615 μL, 1.23 mmol) was added and the reaction stirred at 25° C. for 15 min. The solution was chilled to 0° C. and 2,6-lutidine (293 μL, 2.46 mmol) was added dropwise. The reaction continued to stir at 0° C. for 15 min. 1-Cyclopropylmethyl-1H-pyrazol-3-ylamine (169 mg, 1.23 mmol) was added as a pre-dissolved reaction in methylene chloride (7 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride) followed by recrystallization from 10% methylene chloride/diethyl ether afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-propionamide (162 mg, 29%) as a white crystalline solid: ESI-LRMS m/e calcd for C22H28ClN3O3S [M+] 449.15, found 450.19 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.32-0.041 (m, 2H, CH2), 0.63-0.70 (m, 2H, CH2), 1.08-1.31 (m, 3H, CH2), 1.44-1.95 (m, 8H, 4×CH2), 2.13-2.37 (m, 1H, CH), 3.28 (s, 3H, SO2CH3), 3.55 (t, J=7.6 Hz, 1H, CH), 3.85 (d, J=7.0 Hz, 2H, NCH2), 6.67 (d, Jo=2.2 Hz, 1H, Ar), 7.38 (d, Jo=2.2 Hz, 1H, Ar), 7.46 (dd, Jo=8.1, Hz, Jm=1.7 Hz. 1H, Ar), 7.60 (d, Jm=1.7 Hz, 1H, Ar), 7.90 (s, 1H, NH), 8.09 (d, Jo=8.1 Hz, 1H, Ar).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[NH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](=O)[C:13]([O-:15])=[O:14])[N:7]=1.[K+]>CO>[NH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](=[N:4][O:3][CH3:2])[C:13]([OH:15])=[O:14])[N:7]=1
Reactant: CON
Reactant: Nc1ccnc(C(=O)C(=O)[O-])n1
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CON=C(C(=O)O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of O-methylhydroxylamine hydrochloride (0.25 g.) in methanol (6 ml.) was added a mixture of potassium 2-(4-aminopyrimidin-2-yl)glyoxylate and its monohydrate with stirring at ambient temperature, and the mixture was stirred for 4 hours. The reaction mixture was allowed to stand overnight at ambient temperature, filtered, and the filtered precipitates were washed with ethanol. After the filtrate and washings were combined together, the solvents were distilled off. The resultant oily substance was pulverized in acetone (15 ml.) and collected by filtration. Thus obtained powder was washed successively with acetone and diethyl ether and then dried to give a pale brown powder of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (290 mg.).
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:29]([CH2:30]C(O)=O)[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[N:22]=1>C1C=CC=CC=1>[CH3:14][C:11]([O:10][C:6](=[O:5])[CH2:30][N:29]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[N:22]=[C:21]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=1)([CH3:12])[CH3:13]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(O)Cn1c(-c2ccccn2)nc2cccnc21
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)Cn1c(-c2ccccn2)nc2cccnc21
Temperature: 25 °C
Yield: 45.1 %

Procedure:
Under a nitrogen atmosphere, N,N-dimethylformamide-ditert-butyl acetal (8.12 g, 0.040 mole) was added dropwise over a 20-minute period to a stirred, refluxing suspension of 2-(2-pyridyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.54 g, 0.010 mole) in anhydrous benzene (50 ml). The resulting solution was refluxed for 1 hour and allowed to cool to room temperature. The reaction mixture was washed with 10% potassium carbonate solution (2×25 ml), water (25 ml), dried over sodium sulfate and concentrated in vacuo. The residue (3.5 g) was dissolved in tetrahydrofuran and treated with excess ethereal hydrogen chloride. The crystalline solid was recrystallized from tetrahydrofuran, giving 1.5 g (43%). Drying in vacuo at 65° C. for 8 hours and then at 78° C. overnight gave 1.4 g of the compound as the free base, mp 124°-125.5° C.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][S:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1)(=[O:14])=[O:13])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.[NH4+].[OH-].O>C(Cl)(Cl)Cl>[NH:33]1[CH2:34][CH2:35][CH:30]([CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16][CH2:15][S:12]([NH:11][CH2:10][CH2:9][P:4]([OH:8])(=[O:3])[OH:5])(=[O:14])=[O:13])[CH2:31][CH2:32]1
Reactant: CCOP(=O)(CCNS(=O)(=O)CCCCc1ccccc1OCCCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC
Agent: C[Si](C)(C)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=P(O)(O)CCNS(=O)(=O)CCCCc1ccccc1OCCCCC1CCNCC1

Procedure:
A solution of 6-9 (0.63 g, 0.142 mmol) in CHCl3 (5 ml) at rt was treated with TMSBr (0.85 mmol) for 16 hrs. The solvent was removed and the residue was dissolved in 10% aqueous acetone and this stripped to dryness. The residue was mixed with toluene and the resulting gum was purified by flash chromatography on silica gel eluting with 4:1:1 EtOH/H2O/NH4OH to provide pure 6-11. Rf 0.38 (silica gel, 4:1:1EtOH/NH4OH/H2O. ##STR65##
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C(OOCC1C=CC=CC=1)C1C=CC=CC=1.[CH3:25][C:26]1[C:30]2[CH:31]=[CH:32][C:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[CH:34][C:29]=2[O:28][N:27]=1>C(Cl)(Cl)(Cl)Cl>[Br:8][CH2:25][C:26]1[C:30]2[CH:31]=[CH:32][C:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[CH:34][C:29]=2[O:28][N:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1noc2cc(O[Si](C)(C)C(C)(C)C)ccc12
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(CBr)noc2c1
Yield: 67.9 %

Procedure:
NBS (12.7 g, 71.5 mmoles) and benzyl peroxide (1.6 g, 6.5 mmoles) were added to a mixture of 3-methyl-6-[(tert-butyl(dimethyl)silyl)oxy]-1,2-benzisoxazole (17.1 g, 65 mmoles) and CCl4 (200 ml). The mixture was refluxed overnight and the precipitate was filtered, washed with CCl4 and purified by flash chromatography (AcOEt/Toluene 1/9 with 0.1% TEA) to give 3-(bromomethyl)-6-[(tert-butyl(dimethyl)silyl)oxy]-1,2-benzisoxazole (15.1 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Br)=[CH:4][C:3]=1[Br:19].[CH2:20]([C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C([O-])(=O)C.[K+]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:42][C:41]2[CH:43]=[CH:44][C:38]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:39][CH:40]=2)=[CH:4][C:3]=1[Br:19]
Reactant: Nc1c(Br)cc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: CCCCCCCCCCCCCCCCCCc1ccc(N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCc1ccc(Nc2cc(Br)c(N)c3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 24 h

Procedure:
A reactor was charged with 10 g of 1-amino-2,4-dibromoanthraquinone, 15 g of p-octadecyl-aniline, 20 g of pyridine, 0.2 g of copper acetate and 2.5 g of potassium acetate, and the reaction was effected at an elevated temperature of 115°-120° C. for 24 hours under stirring. A blue solid of 1-amino-2-bromo-4-p-octadecylanilinoanthraquinone was obtained by the reaction of the formula: ##STR9##
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=1.[S:16]([O:21]C)([O:19][CH3:20])(=[O:18])=[O:17]>C(OCC)C>[S:16]([O-:21])([OH:19])(=[O:18])=[O:17].[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4]([N:3]=1)=[C:5]1[C:10]([CH:9]=[CH:8][CH:7]=[N+:6]1[CH3:20])=[CH:11][CH:12]=2
Reactant: COS(=O)(=O)OC
Reactant: Brc1ccc2ccc3cccnc3c2n1
Solvent: CCOCC
Product: C[n+]1cccc2ccc3ccc(Br)nc3c21
Product: O=S(=O)([O-])O
Temperature: 120 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Under a stream of argon, to compound (7) (24.4 g; 94.2 mmol), dimethyl sulfate (77 g; 610 mmol) was added in an ice bath over 20 minutes. The reaction temperature was raised to 120° C. and the resulting reaction mixture was stirred for 1 hour. To the reaction mixture, diethyl ether was added in an ice bath, and solids which precipitated out were separated by filtration. The resulting solids were washed with a mixed solution of diethyl ether/ethanol (1/1 to 1/2) and dried under reduced pressure to give 33.6 g (yield: 96%) of the title compound (8).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C@@H:17]([NH:23][C:24]([C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]3)[CH2:27]2)=[O:25])[CH2:18][C:19]([O:21]C)=[O:20])[CH:14]=[N:15][CH:16]=1.CO.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C(O)(C)(C)C>[F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C@H:17]([NH:23][C:24]([C@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[CH2:27]2)=[O:25])[CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[N:15][CH:16]=1
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCCOCCOCCF)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)C[C@@H](NC(=O)[C@H]1CCCN(C(=O)CCC2CCNCC2)C1)c1cncc(OCCOCCOCCF)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 12.8 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-1-(5-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}pyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (16.5 mg, 22 μmol) as solved in tert.-butanol (0.62 mL) and methanol (0.6 mL) and barium hydroxide octahydrate (34 mg, 315 μmol) was added. After stirring for 45 minutes room temperature the solvent was distilled off at 0° C. by high vacuum. The residue was solved in water (0.3 mL) and acidified by formic acid (0.9 mL). After 18 hours at 5° C. the solvent was distilled off at 0° C. by high vacuum and the residue was purified by preparative HPLC to yield 1.6 mg of (3R)-3-(5-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}pyridin-3-yl)-3-[({(3S)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid.
Reaction SMILES: [H-].[Na+].[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([OH:12])[CH2:6][C:5]1([CH3:14])[CH3:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[OH:3][N:4]1[C:9]([CH3:10])([CH3:11])[CH2:8][CH:7]([O:12][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6][C:5]1([CH3:14])[CH3:13]
Reactant: CCOC(=O)CBr
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1CC(C)(C)N(O)C(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.48 g (20 mmol) of sodium hydride is added to a solution of 3.0 g (17 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine in 25 mL of anhydrous tetrahydrofuran. The reaction mixture is stirred under a blanket of nitrogen for one hour. The mixture is chilled to 0° C. and 2.9 g (17 mmol) of ethyl bromoacetate is added dropwise. After the addition is complete, the reaction is stirred for an additional 30 minutes during which time a white precipitate forms. The mixture is filtered and the solvent is removed under reduced pressure. The title compound is isolated as an orange solid after column chromatography and melts at 41-43° C.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].[C:18]([C:21]1[O:25][C:24]2[C:26]([C:30]3[CH:35]=[C:34]([CH2:36][CH3:37])[CH:33]=[C:32]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:31]=3[O:42][CH2:43][CH2:44][CH3:45])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)(=O)[CH3:19].O>CN(C=O)C>[CH2:4]([O:5][C:6](=[O:7])[C:8]([F:9])=[C:18]([C:21]1[O:25][C:24]2[C:26]([C:30]3[CH:35]=[C:34]([CH2:36][CH3:37])[CH:33]=[C:32]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:31]=3[O:42][CH2:43][CH2:44][CH3:45])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)[CH3:19])[CH3:3]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCCOc1c(-c2cccc3cc(C(C)=O)oc23)cc(CC)cc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(-c2cccc3cc(C(C)=C(F)C(=O)OCC)oc23)cc(CC)cc1C(C)(C)C
Reaction time: 0.25 h

Procedure:
To a mixture of 43 mg (0.89 mmol) of NaH in 1 mL of dry DMF was added 216 mg (0.89 mmol, 0.15 mL) of triethyl 2-fluoro-2-phosphonoacetate diluted in 1 mL of dry DMP at 0° C. After the gas evolution ceased, the solution was stirred at this temperature for 15 minutes and 0.296 mmol of 2-acetyl-7-(2-propoxy-3-tert-butyl-5-ethylphenyl) benzo[b]furan diluted in 1 mL of dry DMF was added dropwise. The reddish solution was stirred to 0° C. until completion (TLC monitoring). After cooling, water was added and the mixture as extracted with ethyl acetate. The organic layer was washed with water and brine and dried over MgSO4. The solvents were evaporated under reduced pressure, and the residual oil was purified over silica gel (eluent: ethyl acetate/hexane: 5/95) to afford 2-fluoro-3-[7-(2-propoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid ethyl ester as a clear yellow oil. 1H NMR (CDCl3), δ: 7.52 (d, J=7.8 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.39 (d, J=3.4 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.22 (d, J=2.1 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 3.27 (t, J=6.2 Hz, 2H), 2.66 (dd, J=15.1, 7.5 Hz, 1H), 2.54 (d, J=3.4 Hz, 3H), 1.46 (s, 9H), 1.27 (t, J=7.7 Hz, 3H), 1.19 (m, 2H), 0.50 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:11][C:12](=[O:14])[CH3:13])(=O)[CH3:9].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:12]([O:11][CH:8]([CH3:9])[CH2:7][C:1]1[CH:6]=[CH:5][C:4]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:3][CH:2]=1)(=[O:14])[CH3:13]
Reactant: Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC(C)Cc1ccc(-c2ccccc2)cc1
Reaction time: 4 h
Yield: 98.5 %

Procedure:
In a four-necked flask equipped with a thermometer and stirrer, were placed 17.0 g (0.08 mole) of the compound (XII-1) obtained in Preparation Example 1, 50 ml of toluene and 20 ml of pyridine, thereafter 10.2 g (0.1 mole) of acetic anhydride and 0.1 g of 4-dimethylaminopyridine was added thereto, and the resulting mixture was stirred at 40°-50° C. for 4 hours. After completion of the reaction, the reaction mixture was poured into 50 ml of 4N hydrochloric acid to conduct extraction and layer separation. The organic layer obtained was washed successively with 1% hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water. The organic layer was then concentrated under reduced pressure to obtain 20.0 g of 4-(2-acetoxypropyl)biphenyl (XIII-1). Yield: 98.5%, nD20 1.3405
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([NH2:25])[C:18]([NH:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:32](OCC)(OCC)OCC>C(O)(=O)C>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[N:21]([CH2:22][CH2:23][CH3:24])[CH:32]=[N:25][C:17]=4[CH:16]=3)[CH2:12][CH2:13]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CCCn1cnc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21

Procedure:
A mixture of 5 parts of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1 -propyl-1,2-benzenediamine, 35 parts of 1,1',1"-[methylidynetris(oxy)]trisethane and 1.5 parts of acetic acid is stirred and refluxed for 2 hours. The reaction mixture is cooled and evaporated. The residue is taken up in 100 parts of water and a hydrochloric acid solution 10 N is added till all solid enters solution. This solution is treated with activated charcoal. The latter is filtered off and the filtrate is alkalized with a sodium hydroxide solution. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off, washed with a small amount of 4-methyl-2-pentanone and with 2,2'-oxybispropane, and dried, yielding 2.2 parts of 5-[4-(diphenylmethyl)- 1-piperazinylmethyl]-1-propyl-1H-benzimidazole; mp. 154.8° C.
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:7][C:6]2[CH:8]=[C:9]([F:20])[CH:10]=[C:11]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:5]=2[O:4]1.[CH3:21][NH:22][CH3:23]>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:11]1[C:5]2[O:4][C@@H:3]([CH2:2][N:22]([CH3:23])[CH3:21])[CH2:7][C:6]=2[CH:8]=[C:9]([F:20])[CH:10]=1
Reactant: CNC
Reactant: Fc1cc2c(c(-c3c(Cl)cccc3Cl)c1)O[C@@H](CBr)C2
Product: CN(C)C[C@H]1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Yield: 80 %

Procedure:
Treatment of (R)-2-bromomethyl-7-(2,6-dichloro-phenyl)-5-fluoro-2,3-dihydrobenzofuran (0.41 g, 1.1 mmol) and N,N-dimethylamine (2.0 M in tetrahydrofuran, 5.4 ml) generally according to the procedure described for Example 390 afforded 0.29 g (80%) of (R)-[7-(2,6-dichloro-phenyl)-5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl]-dimethyl-amine as a white solid, hydrochloride salt. mp 156-158° C.; [α]D25=−21.04 (c 7.71 in methanol); Anal. calcd. for C17H16Cl2FNOHCl: C, 54.21; H, 4.55; N, 3.72. Found: C, 53.98; H, 4.62; N, 3.56.