Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:12]=1.[F:24][C:25]([F:30])([F:29])[CH:26]1[O:28][CH2:27]1>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:22])([F:23])[CH:19]([F:20])[F:21])[CH:12]=1)[CH2:27][CH:26]([OH:28])[C:25]([F:30])([F:29])[F:24]
Reactant: FC(F)(F)C1CO1
Reactant: Fc1ccc(F)c(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cc(F)ccc1F)C(F)(F)F
Temperature: 50 °C
Yield: 83.5 %

Procedure:
EX-661B) The N-(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-amine (2.22 g, 6.67 mmol) product from EX-661A and 1,1,1-trifluoro-2,3-epoxypropane (1.12 g, 10 mmol) were dissolved in 1.5 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.21 g, 0.33 mmol) was added, and the stirred solution was warmed to 50° C. for 2 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over anhydrous MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:10) to give 2.49 g (84%) of the desired 3-[(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, 99% pure by HPLC analysis. HRMS calcd. for C18H14F9NO2: 448.0959 [M+H]+, found: 448.0940.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)#[CH:25]>>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)=[CH:27][CH:28]=1)(=[O:33])=[O:34]
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: CS(=O)(=O)c1ccc(-c2cn(C3CCc4c(CC(=O)O)c5ccccc5n4C3)nn2)cc1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and 1-ethynyl-4-(methylsulfonyl)benzene. MS (+ESI) m/z: 451.1.
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([O:14][CH3:15])[CH2:11][C@H:10]([C:16]([O:18][CH3:19])=[O:17])[C@H:9]1[C:20]([O:22]CC1C=CC=CC=1)=[O:21])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:15][O:14][C@@H:12]1[CH2:13][NH:8][C@H:9]([C:20]([OH:22])=[O:21])[C@@H:10]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1
Reactant: COC(=O)[C@H]1C[C@H](OC)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](OC)CN[C@@H]1C(=O)O

Procedure:
A solution of 2-benzyl 3-methyl(2S,3S,5S)-1-benzyl-5-methoxypiperidine-2,3-dicarboxylate (30.0 mg, 0.0000755 mol) in 2 mL of MeOH was hydrogenated in the presence of 10% Pd/C, under a balloon pressure of hydrogen, for 1 h. The catalyst was filtered off and the filtration was concentrated to dry. The residue was used directly in next step (16 mg, 97.6%). MS (ESI): (M+H)+=218.0.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)N)=[CH:6][CH:5]=1.CC[O:22][C:23]([CH2:25][CH:26]1[C:31](=O)[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:24]>>[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[C:27]3[CH:26]([CH2:25][C:23]([OH:24])=[O:22])[CH2:31][CH2:30][CH2:29][C:28]=3[C:16]3[C:11]2=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: COc1ccc(CN(N)c2ccc(F)cc2)cc1
Agent: Cl
Product: COc1ccc(Cn2c3c(c4cc(F)ccc42)CCCC3CC(=O)O)cc1

Procedure:
Following the procedure of Example 1, but using 1-(4-methoxybenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O.[NH2:21][C:22]([NH2:24])=[O:23].[H-].[Na+]>C(O)C>[F:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[C:10]1[C:11]([OH:13])=[N:21][C:22]([OH:23])=[N:24][C:16]=1[OH:18]
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Reactant: NC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(O)c(-c2c(F)cc(F)cc2F)c(O)n1
Temperature: 80 °C

Procedure:
To a mixture of diethyl 2-(2,4,6-trifluorophenyl)malonate (580 mg, 2.0 mmol, U.S. Pat. No. 6,156,925) and urea (360 mg, 6.0 mmol) in 10 mL of ethyl alcohol at room temperature is added sodium hydride (60% in mineral oil, 160 mg, 4.0 mmol). The mixture is then heated at 80° C. for 3 days, cooled to room temperature, and partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous layer is extracted with ethyl acetate, and the combined organic extracts are dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 10% methyl alcohol in ethyl acetate. Concentration provides 5-(2,4,6-trifluorophenyl)pyrimidine-2,4,6-triol as a light tan solid (148 mg). MS: m/z 257.0 (M−H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:7][N:6]=[CH:5]2.[CH2:16]([N:18]1[C:22]([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)=[CH:21][CH:20]=[N:19]1)[CH3:17]>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>[CH2:16]([N:18]1[C:22]([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:7][N:6]=[CH:5]4)[CH:26]=2)=[CH:21][CH:20]=[N:19]1)[CH3:17]
Reactant: CC(C)Nc1nncc2cc(Br)ccc12
Reactant: CCn1nccc1NC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCn1nccc1NC(=O)c1ccc(C)c(-c2ccc3c(NC(C)C)nncc3c2)c1

Procedure:
This compound was prepared according to the procedure described in Example 2c using the following starting materials: 6-Bromo-N-isopropylphthalazin-1-amine, tetrakis(triphenylphosphine)palladium and N-(1-ethyl-1H-pyrazol-5-yl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. MS (ESI, pos. ion) m/z: 415.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.O[NH:28][C:29]([C:31]1[S:32][C:33]([S:36](=[O:39])(=[O:38])[NH2:37])=[CH:34][CH:35]=1)=[NH:30]>>[F:26][C:2]([F:25])([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:14][N:30]=[C:29]([C:31]4[S:32][C:33]([S:36]([NH2:37])(=[O:39])=[O:38])=[CH:34][CH:35]=4)[N:28]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH:4]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) (188 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as an off-white solid (130 mg, 46%). MS (ISN) 558.0 [(M−H)−]; mp 276° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:10]([N:12]1[C@@H:20]([C:21]#[C:22][Si](C)(C)C)[CH2:19][CH2:18][C@H:13]1[C:14]([O:16]C)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>CO.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1)[C:10]([N:12]1[C@@H:20]([C:21]#[CH:22])[CH2:19][CH2:18][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCC1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: C#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl(5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-((trimethylsilyl)ethynyl)-L-prolinate (1.65 g, 3.66 mmol) in MeOH (10 mL) and H2O (10 mL) at room temperature was added LiOH.H2O (0.23 g, 5.49 mmol). The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was taken up in water and extracted with diethyl ether (2×). The aqueous layer was acidified to pH˜4 by adding 4% KHSO4 dropwise. The clear solution was extracted with ethyl acetate (3×) and the combined ethyl acetate layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound. MS (CI) m/e 365 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[N:3]1([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: CCOC(=O)CCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40.9 %

Procedure:
NaH (0.444 g, 11.1 mmol) was dissolved in anhydrous DMF (5 mL) under argon and cooled to 0° C. To it was added 1H-indole (1.00 g, 8.54 mmol) dissolved in anhydrous DMF (5 mL). The reaction was stirred for 15 min at 0° C. followed by the addition of ethyl 3-bromopropanoate (1.10 mL, 8.54 mmol). The reaction was then stirred for 3 h at 70° C. and then quenched by the addition of H2O (30 mL). The organic products were extracted with EtOAc (3×30 mL), washed with H2O (2×30 mL), brine (15 mL), dried with Na2SO4, filtered and concentrated in vacuo. The crude product was purified using automated column chromatography method 1 to yield ethyl 3-(1H-indol-1-yl)propanoate (0.759 g, 3.49 mmol). The title compound was then prepared from ethyl 3-(1H-indol-1-yl)propanoate (0.486 g, 5.52 mmol) according to General Procedure B (prep. HPLC method 1) and isolated as a white solid (0.104 g, 23%). 1H NMR (400 MHz, MeOD): δ 7.53 (d, J=7.83 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.16 (m, 2H), 7.02 (t, J=7.4 Hz, 1H), 6.41 (d, J=2.8 Hz, 1H), 4.48 (t, J=6.5 Hz, 2H), 2.56 (t, J=6.6 Hz, 2H). ESI-LRMS: [M+H]+=205.1 m/z. ESI-HRMS: calc. for C11H12N2O2: [M+H]+=205.0972 m/z, found: [M+H]+=205.0971 m/z.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[F:20][C:21]([F:30])([F:29])[C:22]1[S:26][CH:25]=[C:24]([CH2:27]O)[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:24]4[CH:23]=[C:22]([C:21]([F:30])([F:29])[F:20])[S:26][CH:25]=4)=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Reactant: OCc1csc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2cc(-n3ccc(OCc4csc(C(F)(F)F)c4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), [5-(trifluoromethyl)thiophen-3-yl]methanol (71 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (5 ml) was added bis(2-methoxyethyl)azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) and recrystallized from ethanol-hexane to give the title compound (35 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH2:17][CH2:16][CH2:15]2)=O)=[CH:5][C:4]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:14]1([C:12]2[C:7]3[C:6](=[CH:5][C:4]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[C:3]([O:2][CH3:1])[CH:8]=3)[CH2:9][CH2:10][N:11]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: COc1ccc(CCNC(=O)C2(c3ccccc3Cl)CCC2)cc1-c1ccccc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1-c1ccccc1)CCN=C2C1(c2ccccc2Cl)CCC1

Procedure:
A mixture of N-[2-(2-methoxy-5-biphenylyl)ethyl]-1-(2-chlorophenyl)cyclobutane carboxamide (12.5 g, prepared as described in Example E30), phosphorus oxychloride (25 ml) and acetonitrile (150 ml) was heated under reflux for 6 hours. The solvent was removed by distillation and the residue added to a mixture of ice and water. The mixture was extracted with dichloromethane to yield a solid which was recrystallised from propan-2-ol to give 1-[1-(2-chlorophenyl)cyclobutyl]-7-methoxy-6-phenyl-3,4-dihydroisoquinoline, m.p. 149°-152° C.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10](Cl)[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C=O)C.[CH2:25]([O:27][CH2:28][CH2:29][CH2:30][OH:31])[CH3:26]>>[NH2:2][C:3]1[N:11]=[C:10]([O:31][CH2:30][CH2:29][CH2:28][O:27][CH2:25][CH3:26])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOCCCO
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOCCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 120 °C
Yield: 76 %

Procedure:
To sodium (150 mg, 6.5 mmol) in 5 ml of 3-ethoxypropanol were added 6-amino-9-benzyl-2-chloropurine (500 mg, 1.93 mmol) and DMF (10 ml). The mixture was heated at 120° C. for 1 hour. The reaction mixture was concentrated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and the solvent was removed. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (481 mg, yield 76%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]=1[N+:20]([O-])=O)([CH3:3])[CH3:2].[H][H]>[C].[Pd].O1CCCC1>[CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]=1[NH2:20])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)Nc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)Nc1ccc(-c2nc3ccccc3o2)cc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.4 %

Procedure:
To a tetrahydrofuran solution (5 mL) of 2-(4-isopropylamino-3-nitrophenyl)benzoxazole (see Working Example 80-1) (224 mg, 0.753 mmol) was added 10% palladium-carbon (40 mg), a hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 15 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (184 mg, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[NH:14])=[CH:4][CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:15]([N:14]=[C:10]1[N:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][S:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N=C1SCCN1Cc1ccc(Cl)nc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(CN2CCSC2=NCc2ccccc2)cn1
Temperature: 90 °C
Yield: 68.3 %

Procedure:
Then, a mixture of 228 mg (1 mmol) of 3-(6-chloro-3-pyridyl)methyl-2-iminothiazolidine, 180 mg (1.05 mmol) of benzylbromide and 276 mg (2 mmol) of anhydrous potassium carbonate in 10 ml of acetonitrile was heated for 3 hours at 90° C. under refluxing. After the reaction mixture was cooled to the room temperature, the solvent was removed under reduced pressure. The resulting residue was mixed with dichloromethane and saturated sodium hydrogen carbonate aqueous solution, and the organic layer was separated. The water layer was extracted with dichloromethane, and combined organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by aminopropyl-coated silica gel (Chromatorex NH-type; Fuji Silysia Chemical Ltd.) column chromatography (eluent; hexane:ethyl acetate=2:1) to give 217 mg (yield; 68.3%) of 2-benzylimino-3-(6-chloro-3-pyridyl)methylthiazolidine as colorless oil. This product was dissolved in methanol and to this solution was added 79 mg (0.681 mmol) of fumaric acid, and the mixture was concentrated under reduced pressure. The resulting residue was treated with acetonitrile to give crystalline. The crystalline was collected by filtration and dried in vacuum to give 271 mg of fumarate of the title Compound 14.
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:8](=O)[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2.Cl.[NH2:13][OH:14].O.O.O.C([O-])(=O)C.[Na+]>CCO>[CH3:2][CH:3]1[C:8](=[N:13][OH:14])[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2
Reactant: CC1C(=O)C2CCN1CC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1C(=NO)C2CCN1CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
2-Methylquinuclidin-3-one hydrochloride from Step L (5.3 g, 30.2 mmol, 1 eq), hydroxylamine hydrochloride (2.5 g, 36.4 mmol, 1.2 eq) and sodium acetate trihydrate (12.4 g, 90.9 mmol, 3 eq) are suspended in 70 mL EtOH and stirred at room temperature. After 24 h, the mixture is concentrated in vacuo. The residue is suspended in CHCl3 and the solids are filtered. The solids are rinsed with excess CH3CN. The combined organic washes are concentrated in vacuo to give 4.65 g (100%) of 2-methyl-1-azabicyclo[2.2.2]octan-3-one oxime. MS (ESI) for C8H14N2O m/z 155.2 (M+H)30 .
Reaction SMILES: B(Br)(Br)Br.[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)=[C:18]([C:28]2[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=2)[N:17]=[C:16]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([OH:7])=[O:6].O>ClCCl>[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:18]([C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)[N:17]=[C:16]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([OH:7])=[O:6]
Reactant: COc1ccc(-c2nc(-c3ccccc3)n(CCCCCCCC(=O)O)c2-c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccc(O)cc2)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
Boron tribromide (0.7 ml) was added to a suspension of 1-(7-carboxyheptyl)-4,5-bis(4-methoxyphenyl)-2-phenylimidazole (0.7 g) in anhydrous dichloromethane (20 ml) and the reaction was stirred at room temperature for 1 h. Boron tribromide (0.3 ml) was added and the reaction was stirred at reflux for 2 h and at room temperature for 20 h. Water was carefully added to the cooled reaction mixture and the resulting yellow precipitate was collected. Column chromatography on silica gel eluted with a dichloromethane:methanol gradient and recrystallisation from ethanol and water gave 1-(7-carboxyheptyl)-4,5-bis-(4-hydroxyphenyl)-2-phenylimidazole (0.44 g, 67%) as a cream solid, m.p 135°-7°; Found C, 73.97; H, 6.38; N, 5.98%; C29H30N2O4 requires: C, 74.02; H, 6.42; N, 5.95%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[C:14]([CH3:20])[C:11]=1[CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:20][C:14]1[C:15]([CH3:19])=[CH:16][C:17]([CH3:18])=[C:10]([CH3:9])[C:11]=1[CH2:12][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1cc(C)c(C)c(CCl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(C)c(C)c(COc2ccc(Br)cc2)c1C
Yield: 79 %

Procedure:
In acetone (50 ml), a mixture of 4-bromophenol (7.8 g), 2,3,5,6-tetramethylbenzyl chloride (6.3 g) and potassium carbonate (6.5 g) was heated at reflux for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and successively washed with 3% aqueous sodium hydroxide solution, water and saturated brine. The solvent was evaporated under reduced pressure, thereby giving 8.7 g of the desired compound.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[O:23][C:22](=[O:24])[CH2:21][C:20]1([OH:29])[C:25]([O:27]C)=[O:26]>CO.O>[C:25]([C@:20]1([OH:29])[C@@H:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=2[Cl:3])[O:23][C:22](=[O:24])[CH2:21]1)([OH:27])=[O:26]
Reactant: COC(=O)C1(O)CC(=O)OC1CCCCCCCCc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1C[C@](O)(C(=O)O)[C@@H](CCCCCCCCc2ccc(Cl)cc2Cl)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
Aqueous NaOH (1M, 4 ml, 4.0 mmol) was added dropwise to a stirred solution of ±(4R*,5R*,) 5-[8-(2,4-dichlorophenyl)-octyl]-4-hydroxy-4 -methoxycarbonyltetrahydrofuran-2-one (198 mg, 0.474 mmol) in methanol (4 ml) at 0° C. The solution was stirred at room temperature for 24 h, diluted with water, and washed with ether. The aqueous phase was acidified (aqueous HCl), and extracted with ether. The extracts were washed with water, saturated aqueous NaCl, and dried (MgSO4). The solvent was removed under vacuum. The crude diacid was stirred with silica gel (3 g), impregnated with 2M aqueous H2SO4 (0.15 ml), in ether for 1 h. The mixture was filtered, and the solvent removed from the filtrate under vacuum to give the title compound (107 mg), (δ 200 MHz, CDCl3) 7.34-7.10 (3H, m), 4.66 (1H, dd), 3.25 (1H, d), 2.77 (1H, d), 2.67 (2H, t), 1.95-1.20 (14H, m), contaminated with a small amount of ±(E) (4R*,5R*) 4-carboxy-5-[8-(2,4-dichlorophenyl)-7-octenyl]-4-hydroxytetrahydrofuran-2-one.
Reaction SMILES: N1([C:6]([C:8]2[CH:9]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[NH:10][C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[O:7])C=CN=C1.[CH2:34]([OH:37])[CH2:35][OH:36]>>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[C:8]([C:6]([O:36][CH2:35][CH2:34][OH:37])=[O:7])=[C:13]([CH3:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=3)[C:11](=[O:25])[NH:10]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: CC1=C(C(=O)n2ccnc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCO
Product: CC1=C(C(=O)OCCO)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml ethylene glycol. The reaction mixture is stirred at approx. 100° C. for 1 hour. After cooling the reaction mixture is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% conc. ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 500 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.