Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:18][CH:19]([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][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[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].[NH2:39][C@H:40]([C:44]([NH:46][C@H:47]([C:51]([OH:53])=[O:52])[C@@H:48]([CH3:50])[OH:49])=[O:45])[C@@H:41]([CH3:43])[OH:42].C(N(CC)CC)C>O.O1CCCC1>[C:1]([O:18][CH:19]([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][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][C@H:40]([C:44]([NH:46][C@H:47]([C:51]([OH:53])=[O:52])[C@@H:48]([CH3:50])[OH:49])=[O:45])[C@@H:41]([CH3:43])[OH:42])=[O:23])(=[O:17])[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: C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@H](C(=O)O)[C@@H](C)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of N-hydroxysuccinimide ester of 3-hexadecanoyloxyoctadecanoic acid (1.5 g) prepared by the method of Example 8 (1), L-threonyl-L-threonine (0.7 g) and triethylamine (0.44 ml) in tetrahydrofuran water (100 ml-200 ml) was stirred at room temperature for 5 hours. After removal of tetrahydrofuran under reduced pressure, the residue was acidified with 1% hydrochloric acid (100 ml) and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated to give a residue which was purified by column chromatography on silica gel. Elution with a mixture of chloroform and methanol (20:1) afforded N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-threonyl]-L-threonine (1.2 ) as powder.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH2:13]([O:20][CH2:21][CH:22]1[CH2:25][C:24](=[O:26])[CH2:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)=O.CC(C)=O.[CH3:34][Si:35](Cl)([CH3:37])[CH3:36]>C1COCC1>[CH2:13]([O:20][CH2:21][CH:22]1[CH2:25][C:24]([O:26][Si:35]([CH3:37])([CH3:36])[CH3:34])=[CH:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CC(COCc2ccccc2)C1
Reactant: C[Si](C)(C)Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C[Si](C)(C)OC1=CC(COCc2ccccc2)C1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
In a 1 L flask charged with argon, dry THF 300 ml was added. This was cooled to −5° C., then n-BuLi (83 ml, 1.6M in hexane, 0.132 mol) was added. After mixing 5 min, diisopropylamine (18 ml, 0.132 mol) was added drop by drop. After stirring for 10 min, this solution was cooled to −78° C. Then a THF solution of 3-(benzyloxymethyl)-cyclobutanone (20 g, 0.11 mol) was added drop by drop at −78° C. After addition, replace the dry ice-acetone bath with ice-water bath. After stirring at 0° C. for 30 min, TMSCl (16 ml, 0.132 mol) was added dropwise, this was stirred at 0° C. for 1 hr and room temperature for 10 min. Then the solvents were removed and the residue was washed with dry pentane and filtered. The filtrate was concentrated to give crude product without further purification. 1H NMR (CDCl3, 600 MHz): δ 0.23 (s, 9H), 2.20 (dd, J=12.6, 1.2, 1H), 2.65 (m, 1H), 2.74 (dd, J=13.2, 4.2, 1H), 3.41 (m, 1H), 3.48 (m, 1H), 4.54 (s, 2H), 4.67 (s, 1H), 7.26-7.35 (m, 5H). 13C NMR (CDCl3, 150 MHz): δ 0.09, 32.70, 38.18, 73.26, 75.41, 93.69, 104.27, 127.70, 127.86, 128.55, 138.20.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:42])[CH2:10][C:11]1[CH:41]=[CH:40][C:14]2[CH:15]=[C:16]([C:18]([NH:20][C:21]3[C:25]([NH:26]C(=O)OC(C)(C)C)=[CH:24][N:23]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:22]=3)=[O:19])[S:17][C:13]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C.CO.O1CCOCC1>[NH2:26][C:25]1[C:21]([NH:20][C:18]([C:16]2[S:17][C:13]3[CH:12]=[C:11]([CH2:10][C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:42])[CH:41]=[CH:40][C:14]=3[CH:15]=2)=[O:19])=[N:22][N:23]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1cc2ccc(CC(=O)NCc3ccccc3)cc2s1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1cn(-c2ccccc2)nc1NC(=O)c1cc2ccc(CC(=O)NCc3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of crude tert-butyl {3-[({6-[2-(benzylamino)-2-oxoethyl]-1-benzothien-2-yl}carbonyl)amino]-1-phenyl-1H-pyrazol-4-yl}carbamate (from step A) in ethyl aceate (10 mL) and methanol (10 mL) was added 4M HCl in dioxane (10 mL) and the resulting solution was stirred for 16 hours at ambient temperature. The reaction was evaporated to dryness and purified by reverse phase LC to give 148 mg (40%, 2 steps) of N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-6-[2-(benzylamino)-2-oxoethyl]-1-benzothiophene-2-carboxamide as a white solid. 1H NMR (DMSO-d6) δ 11.01 (s, 1H), 8.59 (t, J=5.87 Hz, 1H), 8.35 (s, 1H), 7.89 (t, J=3.82 Hz, 2H), 7.80 (s, 1H), 7.67 (d, J=7.92 Hz, 2H), 7.42 (t, J=7.33 Hz, 2H), 7.36 (d, J=9.1 Hz, 1H), 7.28 (t, J=7.92 Hz, 2H), 7.19 (m, 4H), 4.25 (d, J=5.87 Hz, 2H), 3.61 (s, 2H). ESIMS calcd 482.2 (M++H), found 482.1 (M++H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[NH:15][C:16](=[O:24])[NH:17][C:18]=2[CH2:19][O:20][CH2:21][CH2:22]Cl)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:32]=[N+:33]=[N-:34].[Na+].[I-].[Na+]>CN(C=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[NH:15][C:16](=[O:24])[NH:17][C:18]=2[CH2:19][O:20][CH2:21][CH2:22][N:32]=[N+:33]=[N-:34])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1NC(COCCCl)=C(C(=O)NCCCc2ccccc2)C(c2cccc(Cl)c2)N1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCC1=C(C(=O)NCCCc2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
180 mg (0.389 mmol) of 6-(2-chloroethoxymethyl)-4-(3-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (3-phenylpropyl)amide was dissolved in 10 ml of DMF. 38.0 mg (0.584 mmol) of sodium azide and 58.3 mg (0.389 mmol) of sodium iodide were added to the obtained solution, and they were stirred at 60° C. for 2 days. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1) to obtain the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:24])=[O:4].O.[OH-].[Li+].CO>C1COCC1.O>[CH3:24][C:6]1[N:7]=[C:8]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(CCc2c(-c3ccccn3)noc2C)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(CCc2c(-c3ccccn3)noc2C)sc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
To a suspension of 4-methyl-2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (1.62 g, 5.0 mmol) in THF (16 mL) was added a solution of lithium hydroxide monohydrate (396 mg, 9.0 mmol) in water (16 mL) followed by methanol (6 mL) and the resulting mixture stirred at room temperature for 4 h. The mixture was then evaporated to half volume and then acidified to pH 4 with HCl (1N) and cooled to 0° C. for 30 min. A solid precipitated and was filtered off and dried to afford the title compound (1.45 g, 93%) which was obtained as an off white solid. MS: m/e=328.3 [M−H]−.
Reaction SMILES: CN(C=O)C.[SH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].[F:21][C:22](I)([F:45])[C:23]([F:44])([F:43])[C:24]([F:42])([F:41])[C:25]([F:40])([F:39])[C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30]>O>[F:45][C:22]([F:21])([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:23]([F:43])([F:44])[C:24]([F:41])([F:42])[C:25]([F:39])([F:40])[C:26]([F:37])([F:38])[C:27]([F:35])([F:36])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: Sc1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Sc1ccccc1-c1ccccc1
Yield: 63.5 %

Procedure:
To a solution composed of 40 ml of DMF and 4.66 g (25 mmol) of 2-mercaptobiphenyl was added 1.00 g (25 mmol) of sodium hydride (60% in oil) little by little under ice cooling and stirring. Then, 13.6 g (25 mmol) of perfluorooctyl iodide was added. The temperature of the mixture was slowly elevated to room temperature, and the mixture was stirred for 2 hours. Water was addd to the reaction mixture, and the mixture was extracted with hexane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a brown oil. It was purified by silica gel column chromatography using hexane as an eluent to give 9.60 g (64%) of 2-(perfluorooctylthio)biphenyl as a colorless oil. The properties of the product were as shown below.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([OH:20])[CH:14]([N+:17]([O-])=O)[CH2:15][CH3:16])[CH:10]=[CH:9][N:8]=1>[Pd].C1COCC1.CO>[NH2:17][CH:14]([CH2:15][CH3:16])[CH:13]([C:11]1[CH:10]=[CH:9][N:8]=[C:7]([O:6][CH3:5])[CH:12]=1)[OH:20]
Reactant: CCC(C(O)c1ccnc(OC)c1)[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(N)C(O)c1ccnc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ammonium formate (2.5 g, 40 mmol) and palladium on charcoal (10%, 390 mg) is added to a solution of 1-(2-methoxypyridin-4-yl)-2-nitrobutan-1-ol (1.7 g, 7.5 mmol) in 38 ml THF and 38 ml methanol. The reaction mixture is stirred overnight at room temperature, filtered through a path of cellites and concentrated. Yield 620 mg of a racemic mixture of two diastereomers, 42%.
Reaction SMILES: CCOCC.[CH:6]1([Mg]Br)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([OH:29])=[C:19]([CH:28]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>C1C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([OH:29])=[C:19]([C:20]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:21])[CH:28]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: Br[Mg]C1CCCCC1
Solvent: c1ccccc1
Solvent: CCOCC
Product: Oc1ccc(Cl)cc1C(O)(c1ccccc1)C1CCCCC1

Procedure:
295 ml of an ether solution titrating 1.23 M/liter of cyclohexyl magnesium bromide were added over 2 hours at 40°-45° C. to a solution of 5-chloro-2-hydroxy-benzophenone in 150 ml of anhydrous benzene and the ether was distilled while being replaced with benzene. The mixture was refluxed for 4 hours, was cooled and poured into a liter of ice and ammonium chloride. The mixture was extracted 3 times with 400 ml of ether and the combined ether phases were washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was taken up in 250 ml of cyclohexane to obtain 15.9 g of 5-chloro-2-hydroxy-α-cyclohexyl-α-phenyl-benzene-methanol melting at 170° C.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:24][C:25]([Cl:29])([Cl:28])[CH2:26]O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([O:16][CH2:26][C:25]([Cl:29])([Cl:28])[Cl:24])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCC(Cl)(Cl)Cl
Reaction time: 20 h

Procedure:
Synthesis of the peptide segment is started by making the trichloroethanol ester of Boc-Asp(OBzl)-OH (Shioiri et al., 1989). This is achieved by stirring 1 g (3 mmol) of Boc-Asp(OBzl)-OH (Sigma), 0.4 ml of (3 mmol) 2,2,2-trichloroethanol (Aldrich), 100 mg of DMAP (dimethylaminopyridine; Aldrich), and 576 mg (3 mmol) of EDC (Aldrich) in 50 ml of DCM for 3 h at 0° C. and for 20 h at room temperature. The precipitate is filtered out and the filtrate is diluted with 100 ml of ethyl acetate. The ethyl acetate solution is extracted with 10% aqueous citric acid, water, saturated NaHCO3, water and saturated brine. Then, the ethyl acetate layer is dried over anhydrous Na2 SO4, decanted, and concentrated to give an oil. The crude oily product is purified by washing with petroleum ether to give Boc-Asp(OBzl)-OTce (9). 1H-NMR (CDCl3): 1.45 (9H, s), 2.93 and 3.15 (2H, dd, J=17 Hz and 4.5 Hz), 4.67 and 4.75 (2H, dd, J=12.3 Hz), 4.7-4.75 (1H, m), 5.13 (2H, s), 5.56 (1H, d, J=9 Hz), 7.34 -7.38 (5H, m). FABMS: 454 (M+1)
Reaction SMILES: C[O-].[Na+].Cl.[CH:5](OC(C1N(CCN(CC)CC)C(C2C=CC=CC=2)=C2C=1C=CC(Cl)=C2)=O)(C)C.C(Cl)Cl.[CH2:37]([O:39][C:40]([CH:42]1[N:48]=[C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46]2[CH:55]=[C:56]([Cl:59])[CH:57]=[CH:58][C:45]=2[NH:44][C:43]1=[O:60])=[O:41])[CH3:38]>C(O)(=O)C>[CH:37]([O:39][C:40]([CH:42]1[N:48]=[C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46]2[CH:55]=[C:56]([Cl:59])[CH:57]=[CH:58][C:45]=2[NH:44][C:43]1=[O:60])=[O:41])([CH3:5])[CH3:38]
Reactant: CCOC(=O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Reactant: CCN(CC)CCn1c(C(=O)OC(C)C)c2ccc(Cl)cc2c1-c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)OC(=O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
500 Ml. of propanol-(2) are treated with 14 g. of sodium methylate; the methanol formed is removed by concentration in vacuo to half the volume and the suspension obtained is diluted with 250 ml. of methylene chloride. Then, 34.2 g. of 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid ethyl ester are added and the mixture is subsequently stirred at 25° C. for 40 minutes. The orange solution is made acidic with glacial acetic acid and evaporated to dryness under reduced pressure. The residue is partitioned between water and chloroform; the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The solid crude product is triturated with ether, removed by filtration, washed with ether and recrystallized from methylene chloride/ether, whereby there is obtained 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid isopropyl ester having a melting point of 234°-238° C. (decomposition).
Reaction SMILES: O.[PH2]([O-])=O.[Na+].C=C.C([O-])([O-])=O.C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].C(N(C(=O)C)CCN(C(=O)C)C(=O)C)(=O)C.[Al:42].[Al+3].[CH2:44]([P:46](CC)(=[O:48])[O-:47])[CH3:45].[CH2:51]([P:53](CC)(=[O:55])[O-:54])[CH3:52].[CH2:58]([P:60](CC)(=[O:62])[O-:61])[CH3:59]>O>[Al+3:42].[CH2:44]([P:46]([O-:48])[O-:47])[CH3:45].[CH2:51]([P:53]([O-:55])[O-:54])[CH3:52].[CH2:58]([P:60]([O-:62])[O-:61])[CH3:59].[Al+3:42]
Reactant: CCP(=O)([O-])CC
Reactant: [Al]
Agent: C=C
Agent: CC(=O)N(CCN(C(C)=O)C(C)=O)C(C)=O
Agent: O=C([O-])[O-]
Solvent: O
Product: CCP([O-])[O-]
Temperature: 100 °C
Yield: 95.9 %

Procedure:
1500 g (14 mol) of sodium hypophosphite monohydrate are dissolved in 7.5 kg of water and initially charged in a 16 l steel-enamel jacketed pressure reactor. After heating the reaction mixture to 100° C., a reducing valve set to 6 bar is used to introduce ethylene into the reactor up to saturation. While stirring constantly at an ethylene pressure of 6 bar and a temperature of 100-110° C., a solution of 22 g (1 mol %) of sodium percarbonate and 16 g of tetraacetylethylenediamine in 300 g of water is metered in homogeneously. At a conversion of ethylene of 85%, the metered addition of sodium percarbonate and tetraacetylethylenediamine is stopped and the reactor is decompressed. After cooling to about 90° C., 3000 g (4.67 mol of aluminum) of a 46% aqueous solution of Al2(SO4)3.14 H2O is added within 60 minutes. Subsequently, the resulting solid was filtered off, washed with 2 l of hot water and dried at 130° C. under reduced pressure. The resulting mixture comprises diethylphosphinic acid aluminum(III) salt and ethylphosphonous acid aluminum(III) salt in a ratio of 79.5% by weight of diethylphosphinic acid aluminum(III) salt and 20.5% by weight of ethylphosphonous acid aluminum(III) salt (95.9% yield).
Reaction SMILES: [CH:1](=[C:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:18]O.[OH-].[Na+]>CO>[CH:1](=[C:8]1[CH2:16][C:15]23[O:18][CH:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:9]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: O=C1C(=Cc2ccccc2)Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2ccccc2)CC23OC2C=CC=C13
Yield: 90 %

Procedure:
2-Benzylidene-1-indanone [3.3 g (0.015 mole), prepared as described in U.S. Pat. No. 3,926,988] is dissolved in 160 ml of MeOH and converted to the epoxide using 3.5 g (0.031 mole) of 30% H2O2 and 3.5 ml (0.014 mole) of 16% NaOH as described in Example 1 to give 3.2 g (90%) of colorless solid; m.p. 115°-117°. A sample crystallized from i-PrOH melts at 118°-120°. Lit m.p. 121°-122° [JACS, 80, 900 (1958)].
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[H-].[Na+].Cl[C:13]1[N:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1>C1COCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[N:15]=[N:14][C:13]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[CH:18][CH:17]=2)=[CH:24][CH:23]=1
Reactant: Fc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: OC1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(-c2ccc(OC3CN4CCC3CC4)nn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (rac.)-3-quinuclidinol (0.007 mole) in dry THF under nitrogen is treated with sodium hydride (60% in mineral oil; 1.1 equiv.). After 1 hr at room temperature, a solution of 3-chloro-6-(4-fluoro-phenyl)pyridazine (1.0 equiv.) in THF (30 ml) is added, and the reaction mixture heated to reflux for 6 hrs. After cooling to rt, the THF is evaporated and the residue dissolved in ethyl acetate (100 ml) and then washed with water (3×20 ml), followed by sodium chloride solution (20 ml). The ethyl acetate is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, and the residual oil purified by silica gel column chromatography (eluent: ethyl acetate-methanol-triethylamine (50:10:2) to afford (rac.)-3-[6-(4-fluorophenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane as a colourless solid. 1H-NMR (400 MHz, CDCl3): δ=8.00 (m, 2H), 7.75 (d, 1H), 7.17 (m, 2H), 7.1 (d, 1H), 5.35 (m, 1H), 3.5 (m, 1H), 2.99-2.83 (m, 5H), 2.32 (m, 1H), 1.98 (m, 1H), 1.76-1.68 (m, 2H), 1.46 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]([CH3:11])[CH2:9][O:10][C:6]=2[C:5]([CH:12]2[C@H:17]([O:18]CC3C=CC=CC=3)[C@@H:16]([O:26]CC3C=CC=CC=3)[C@H:15]([O:34]CC3C=CC=CC=3)[C@@H:14]([CH2:42][O:43]CC3C=CC=CC=3)[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=1>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:7]2[CH:8]([CH3:11])[CH2:9][O:10][C:6]=2[C:5]([CH:12]2[CH:17]([OH:18])[CH:16]([OH:26])[CH:15]([OH:34])[CH:14]([CH2:42][OH:43])[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:53]=[CH:54][C:55]([O:58][CH2:59][CH3:60])=[CH:56][CH:57]=1
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)C(C)CO3)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc(C3OC(CO)C(O)C(O)C3O)c3c(c2Cl)C(C)CO3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.6 %

Procedure:
To a solution of 4-chloro-5-(4-ethoxybenzyl)-3-methyl-7-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran (102 mg, 0.124 mmol) in THF/MeOH (4 mL/2 mL) was added 10% Pd/C (50 mg) at rt. The reaction mixture was stirred at r.t. for 15 hours under hydrogen and filtered off. The filtrate was concentrated in vacuo and the residue was purified using reverse phase preparative HPLC to provide the title compound (24 mg, 42%) as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:13])[CH2:11][NH2:12].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](=O)[CH3:30])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CO>ClCCl>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH:29]([NH:12][CH2:11][CH:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[OH:13])[CH3:30])=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: NCC(O)c1cc2ccccc2o1
Solvent: CO
Solvent: ClCCl
Product: CC(Cc1ccc(OCc2ccccc2)cc1)NCC(O)c1cc2ccccc2o1

Procedure:
This was prepared in an identical manner to the compound described in Example 2 using 2-(2-benzofuranyl)-2-hydroxyethanamine (3.51 g) and 1-(4-benzyloxyphenyl)propan-2-one (4.75 g). Chromatography of the residual oily solid on Kieselgel 60 (4% methanol in dichloromethane) gave the title compound, m.p. 111°-122°, as a 20:80 mixture of diastereoisomers.
Reaction SMILES: ClC1C=CC=C(F)C=1[C:9]1[N:10]=[C:11]([C:17]2[C:18]([CH3:26])=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=23)[S:12][C:13]=1[C:14]([OH:16])=[O:15].[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([O:35][CH3:36])[C:29]=1B(O)O>>[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([O:35][CH3:36])[C:29]=1[C:9]1[N:10]=[C:11]([C:17]2[C:18]([CH3:26])=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=23)[S:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: Cc1nn2ccccc2c1-c1nc(-c2c(F)cccc2Cl)c(C(=O)O)s1
Reactant: COc1ccc(F)c(F)c1B(O)O
Product: COc1ccc(F)c(F)c1-c1nc(-c2c(C)nn3ccccc23)sc1C(=O)O

Procedure:
According to the similar manner described in Example 97-B (i) and (ii), the title compound (237 mg, 78%) has been obtained as a brown solid by the Suzuki coupling reaction followed by standard ester hydrolysis reaction using methyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (339 mg, 0.805 mmol) obtained in Example 13-B (ii) and 2,3-difluoro-6-methoxyphenylboronic acid (303 mg, 1.61 mmol). The pure title compound has been obtained by washing with EtOAc (10 mL).