Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:32])[CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[CH:26]1([CH2:25][CH2:24][C:23]([NH:22][C:17]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:15]([NH:14][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[O:13])[CH:16]=2)=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1ccc(NC(=O)CCC2CCCCC2)cc1N
Reactant: O=C(O)c1ccc2ncccc2c1
Product: Cc1ccc(NC(=O)CCC2CCCCC2)cc1NC(=O)c1ccc2ncccc2c1

Procedure:
Using an analogous procedure to that described in Example 5, quinoline-6-carboxylic acid was reacted with N-(3-amino-4-methylphenyl)-3-cyclohexylpropionamide to give the title compound; NMR Spectrum: (DMSOd6) 0.76-1.28 (m, 6H), 1.42-1.78 (m, 7H), 2.2 (s, 3H), 2.28 (t, 2H), 7.17 (d, 1H), 7.39 (d, 1H), 7.6 (m, 1H), 7.69 (s, 1H), 8.12 (d, 1H), 8.24 (d, 1H), 8.49 (d, 1H), 8.63 (s, 1H), 9.0 (m, 9.0 (m, 1H), 9.82 (s, 1H), 10.09 (s, 1H); Mass Spectrum: M+H+ 437.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:7]([CH:28]=[O:29])=[C:8]([C:14]2[C:19]([CH:20]=[O:21])=[CH:18][C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[C:15]=2[O:26][CH3:27])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])(=[O:4])=[O:3].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[CH3:1][S:2]([O:5][C:6]1[C:7]([CH2:28][OH:29])=[C:8]([C:14]2[C:19]([CH2:20][OH:21])=[CH:18][C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[C:15]=2[O:26][CH3:27])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])(=[O:4])=[O:3]
Reactant: COc1ccc(-c2c(C=O)cc(OC)c(OC)c2OC)c(C=O)c1OS(C)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2c(CO)cc(OC)c(OC)c2OC)c(CO)c1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 2,6′-diformyl-4,2′,3′,4′-tetramethoxybiphenyl-3-yl methanesulfonate (170 mg, 0.40 mmol) in methanol (4 mL) was added sodium borohydride (45 mg, 1.20 mmol) and the solution was stirred at room temperature for 1 hour. Water (20 mL) and ethyl acetate (20 mL) were added to the reaction, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined extracts were dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (25 g), eluting with hexane-ethyl acetate (1:2), followed by crystallisation (ethyl acetate), which yielded 2,6′-bis(hydroxymethyl)-4,2′,3′,4′-tetramethoxybiphenyl-3-yl methanesulfonate as a white solid (164 mg, 96%); m.p. 124-126° C.; High Resolution Mass Spectrometry Found: M+Na+ 451.1041 (C18H20O7Na requires 451.1039); NMR Spectrum δH (300 MHz, CDCl3) 7.08 (1H, d, J 8.4 Hz, 6-H), 7.01 (1H, d, J 8.4 Hz, 5-H), 4.64 (1H, d, J 12.0 Hz, 2-CHAOH), 4.26 (1H, d, J 12.0 Hz, 2-CHBOH), 4.18 (2H, dd, J 2.9, 11.8 Hz, 6′-CH2OH), 3.94 (3H, s, OCH3), 3.92 (3H, s, OCH3), 3.88 (3H, s, OCH3), 3.56 (3H, s, OCH3), 3.40 (3H, s, SCH3); NMR Spectrum δC (75 MHz, CDCl3) 50.2, 56.5, 56.9, 61.2, 61.5, 106.2, 116.8, 127.5, 130.0, 130.7, 131.0, 132.1, 139.8, 147.6, 151.1, 152.6, 154.0, 189.3, 190.5; νmax/cm−1 (thin film) 3219, 2947, 1607, 1484, 1410, 1363, 1328, 1278, 1161, 1111, 1006, 889; m/z (ES) 447 (MNa2H2O+, 100%); Rf (hexane-ethyl acetate 1:2) 0.18.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][O:8][C:9]=1[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])=[O:4].[OH-].[Na+].[NH2:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28]([NH:30][C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)=[O:29])[CH:24]=[CH:25][CH:26]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.O.C1COCC1.CO>[CH3:38][O:37][C:35]1[CH:36]=[C:31]([NH:30][C:28](=[O:29])[CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][C:3]([C:5]3[N:6]=[CH:7][O:8][C:9]=3[C:10]3[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])=[O:4])[CH:22]=2)[CH:32]=[C:33]([O:41][CH3:42])[C:34]=1[O:39][CH3:40]
Reactant: COc1cc(NC(=O)Cc2cccc(N)c2)cc(OC)c1OC
Reactant: COC(=O)c1ncoc1-c1c(F)cccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(NC(=O)Cc2cccc(NC(=O)c3ncoc3-c3c(F)cccc3Cl)c2)cc(OC)c1OC
Temperature: 50 °C
Yield: 38.6 %

Procedure:
A mixture of 4-methoxycarbonyl-5-(2-chloro-6-fluorophenyl)oxazole (236 mg, 0.927 mmol), MeOH (5 ml), THF (1 ml), and 2N NaOH (1.5 ml, 3.00 mmol) was heated to 50° C. for 30 minutes. The mixture was cooled to room temperature and H2O and ice were added followed by acidification to pH 2 and extraction with EtOAc. The organic fraction was washed (brine), dried (Na2SO4), filtered, and concentrated to give the crude carboxylic acid. The crude carboxylic acid, 2-(3-aminophenyl)-N-(3,4,5-trimethoxyphenyl)acetamide (292 mg, 0.927 mmol), EDCI (354 mg, 1.85 mmol), and DMAP (11 mg, 0.093 mmol) were allowed to react in CH2Cl2 (5 ml) for 15 h at room temperature under N2. The mixture was applied directly to a silica gel column and elution with hexanes/EtOAc (gradient) gave the title compound (193 mg, 39%).
Reaction SMILES: Cl.Br[C:3]1[S:4][C:5](Br)=[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([CH3:19])[CH2:9][CH2:8][C:7]=12>C(O)(=O)C.[Zn]>[CH3:19][N:10]1[CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2=[CH:5][S:4][CH:3]=[C:7]2[CH2:8][CH2:9]1
Reactant: CN1CCc2c(Br)sc(Br)c2C(c2ccccc2)C1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CN1CCc2cscc2C(c2ccccc2)C1

Procedure:
Zinc powder (0.73 g) was added to a stirred solution of 1,3-dibromo-6-methyl-4-phenyl-5,6,7,8-tetrahydro-4H-thieno[3,4-d]azepine hydrochloride (0.98 g) in acetic acid (20 ml) under nitrogen and the mixture heated under reflux. Further portions of zinc powder (0.73 g) were added after 2 hours and 20 hours heating. After a total of 24 hours heating the mixture was evaporated, water (30 ml) 0.880 ammonia solution (10 ml) added, and extracted with dichloromethane (2×30 ml). The extracts were dried, filtered and evaporated to a yellow oil. Chromatography on silica (2% methanol in dichloromethane) gave the title product as a colourless oil. 1H NMR o(CDCl3) 7.24-7.39 (5H,m,ArH), 6.92 (lH,d,J=3.1 Hz, H1), 6.25 (lH,d,J=3.1 Hz, H3), 4.17 (lH,d,J=9.7 Hz, PhCH), 2.80-3.06 (5H,m,5-CH2 -CHeq 8-CH2), 2.45 (3H,s, NCH3), 2.30-2.50 (lH,m,7-CHax).
Reaction SMILES: [N:1]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[O:19]=[C:20]1[N:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C@@H:36]([C:47](O)=[O:48])[CH2:37][C:38]3[CH:43]=[C:42]([Br:44])[C:41]([OH:45])=[C:40]([Br:46])[CH:39]=3)=[O:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24][C:23]2[CH:50]=[CH:51][CH:52]=[CH:53][C:22]=2[NH:21]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:19]=[C:20]1[N:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C@H:36]([CH2:37][C:38]3[CH:39]=[C:40]([Br:46])[C:41]([OH:45])=[C:42]([Br:44])[CH:43]=3)[C:47]([N:10]3[CH2:11][CH2:12][CH:7]([CH:4]4[CH2:5][CH2:6][N:1]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:2][CH2:3]4)[CH2:8][CH2:9]3)=[O:48])=[O:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24][C:23]2[CH:50]=[CH:51][CH:52]=[CH:53][C:22]=2[NH:21]1
Reactant: CCOC(=O)CN1CCC(C2CCNCC2)CC1
Reactant: O=C(O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(O)c(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
208 mg (0.82 mmol) ethyl [4,4′]bipiperidinyl-1-yl-acetate were added to a solution of 500 mg (0.82 mmol) of (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 315 mg (0.98 mmol) TBTU and 150 μL (1.06 mmol) triethylamine in 5 mL DMF and the reaction mixture was stirred overnight at RT. To complete the reaction a further 315 mg (0.98 mmol) TBTU, 150 μL (1.06 mmol) triethylamine and 208 mg (0.82 mmol) ethyl [4,4′]bipiperidinyl-1-yl-acetate were added and the mixture was again stirred overnight at RT. The reaction mixture was purified directly by HPLC without any further working up. The fractions containing the product were combined, evaporated down i.vac., neutralised with saturated NaHCO3 solution, the aqueous phase was extracted twice with 100 mL DCM and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was triturated with DIPE, suction filtered and dried in the air.
Reaction SMILES: C(OC(=O)[N:7]([CH2:28][CH:29]1[CH2:31][CH2:30]1)[C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])=[CH:13][CH:12]=1)(C)(C)C.[ClH:33].COC1CCCC1>>[ClH:33].[CH:29]1([CH2:28][NH:7][C@@H:8]2[CH2:10][C@H:9]2[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:18](=[O:27])[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:25]3=[O:26])=[CH:13][CH:12]=2)[CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Solvent: COC1CCCC1
Product: O=C1c2ccccc2C(=O)N1c1ccc([C@@H]2C[C@H]2NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl(cyclopropylmethyl){trans-2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]cyclopropyl}carbamate (252.7 mg) was dissolved in 4N hydrochloric acid/cyclopentyl methyl ether solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (176.2 mg).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:15]#[N:16])[CH:6]([SiH:12]([CH3:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[OH-].[Li+].C(O)[C:20]1[CH:25]=[CH:24]C=[CH:22][CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([CH2:4][CH:5]([C:15]#[N:16])[CH:6]([SiH:12]([CH3:13])[CH3:14])[C:7]([O:9][CH2:10][C:11]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C(C#N)CC1CC1)[SiH](C)C
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[SiH](C)C(C(=O)OCc1ccccc1)C(C#N)CC1CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.2 %

Procedure:
Ethyl 4-cyclopropyl(dimethyl)silyl-3-cyanobutanoate (6.39 g, 26.7 mmol) obtained in Example 3 mentioned above was hydrolyzed by using lithium hydroxide in the same manner as that of the aforementioned examples. The obtained reaction mixture (6.21 g) was dissolved in dichloromethane (85 ml), and the solution was added successively with benzyl alcohol (4.95 ml, 48.1 mmol), dicyclohexylcarbodiimide (8.81 g, 42.8 mmol) and 4-dimethylaminopyridine (163 mg, 1.34 mmol). The mixture was stirred for 30 minutes under ice cooling and for further 17 hours at room temperature. After the reaction vessel was cooled on ice, the reaction mixture was added with aqueous hydrochloric acid (1 N), and the mixture was stirred for 5 minutes, and further stirred for 30 minutes at room temperature. The deposited urea was removed by filtration under reduced pressure, and the filtrate was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, and treated in a conventional manner, and then the residue was purified by silica gel column chromatography [hexane/ethyl acetate (24:1 to 19:1)] to obtain benzyl 4-cyclopropyl(dimethyl)silyl-3-cyanobutanoate (7.50 g, 93%) mentioned in the title as colorless oil.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10]>>[C:2]1([C@H:1]([OH:8])[CH2:12][N+:9]([O-:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Product: O=[N+]([O-])C[C@@H](O)c1ccccc1
Yield: 84 %

Procedure:
Further, the present inventors has reported in Tetrahedron Letters (1993) Vol. 34, p. 2657 that the reaction between benzaldehyde and nitromethane under a catalyst of lanthanum-lithium-(R)-binaphthol complex at −50° C. gives (S)-1-phenyl-2 nitro ethanol in a yield of 84% (40% e.e.), and when carried out under a catalyst of samarium-lithium-(R)-binaphthol complex at −40° C., the reaction gives the same compound in a yield of 90% (62% e.e.) ((R) or (S) in the name of leach compound represents R or S isomer, respectively, showing the compound's configuration).
Reaction SMILES: [CH3:1][CH:2]([C:13]([O-:15])=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12].C[CH:17]([C:28]([OH:30])=[O:29])[CH2:18][CH2:19]CCC=CCCCC>>[CH3:1][CH:2]([C:13]([O-:15])=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:28]1(=[O:30])[O:29][C:19](=[O:14])[CH:18]=[CH:17]1
Reactant: CCCCC=CCCCCC(C)C(=O)O
Agent: CCCCC=CCCCCC(C)C(=O)[O-]
Product: O=C1C=CC(=O)O1

Procedure:
The procedure according to Example 76 is repeated but using 3-hydroxypropyl 12-oxatetracyclo[4.4.0.1.1]dodec-7-ene-2-carboxylate as the second comonomer instead of 2-hydroxyethyl 12-oxatetracyclo[4.4.0.1.1]dodec-7-ene-2-carboxylate (0.15 mole), and methyl 12-oxatetracyclo[4.4.0.1.1]dodecne-2,3-dicarboxylic acid (0.15 mole) as the third comonomer instead of 12-oxatetracyclo[4.4.0.1.1]dodec-7-ene-2-carboxylic acid monomer, to obtain poly(1,1-dimethylethyl 12-oxatetracyclo[4.4.0.1.1]dodec-7-ene-2-carboxylate/methyl 12-oxatetracyclo[4.4.0.1.1]dodec-7-ene-2,3-dicarboxylic acid/3-hydroxypropyl 12-oxatetracyclo[4.4.0.1.1]dodec-7-ene-2-carboxylate/maleic anhydride) represented by the following Chemical Formula 196:
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.B(O)(O)[C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1>>[C:16]1([C:3]2[C:2]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(C)cc3)nc2c1
Yield: 74.7 %

Procedure:
The ester product was obtained via a Suzuki coupling reaction using the method previously shown in Example 13, Step 6. Methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (100 mg, 0.34 mmol, 1.00 equiv) and p-tolylboronic acid (54 mg, 0.4 mmol, 1.10 equiv) were used as starting materials and chromatography was performed with ethyl acetate/petroleum ether (1:20) as the eluent, affording 90 mg (76%) of methyl 2-phenyl-3-p-tolylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[NH:9][C:8]([CH3:10])=[C:7]([C:11]2[O:15][N:14]=[C:13]([CH2:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:18])[N:12]=2)[CH:6]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[C:5]=1[C:35]([O:37][CH3:38])=[O:36].Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH2:19]([N:17]([CH2:16][C:13]1[N:12]=[C:11]([C:7]2[CH:6]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)[C:5]([C:35]([O:37][CH3:38])=[O:36])=[C:4]([CH:3]=[O:2])[NH:9][C:8]=2[CH3:10])[O:15][N:14]=1)[CH3:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C1=C(C(OC)OC)NC(C)=C(c2nc(CN(C)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C1=C(C=O)NC(C)=C(c2nc(CN(C)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
To a solution of 1.0 g of methyl 1,4-dihydro-6-dimethoxymethyl-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-2-methyl-4-(3-nitrophenyl)pyridine-5-carboxylate in 15 ml of acetone was added 2 ml of 6N-hydrochloric acid. After stirring at room temperature for 3 hours, the reaction mixture was neutralized with sodium bicarbonate solution and then concentrated in vacuo. To the residue was added ethyl acetate and the resultant solution was washed with water, dried and evaporated in vacuo. The residue was chromatographed on silica gel using chloroform-methanol (50:1) as eluent to give 740 mg of methyl 1,4-dihydro-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-6-formyl-2-methyl-4-(3-nitrophenyl)pyridine-5-carboxylate, IR νmaxneat cm-1 : 3350, 1700, 1680, 1640, 1600, 1520.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([C:12]([NH:14][C:15]3[S:16][C:17]([CH3:33])=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:19]=3[C:20]([O:22]C(C)(C)C)=[O:21])=[O:13])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.FC(F)(F)C(O)=O.CCCCCC>C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([C:12]([NH:14][C:15]3[S:16][C:17]([CH3:33])=[C:18]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:19]=3[C:20]([OH:22])=[O:21])=[O:13])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1
Reactant: Cc1sc(NC(=O)c2cccc(-c3ccoc3)c2)c(C(=O)OC(C)(C)C)c1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1sc(NC(=O)c2cccc(-c3ccoc3)c2)c(C(=O)O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
0.5 g (1.2 mmol) of tert-butyl 2-({[3-(furan-3-yl)phenyl]carbonyl}amino)-5-methyl-4-phenylthiophene-3-carboxylate was dissolved in 2 mL of chloroform, and 5 mL of trifluoroacetic acid (TFA) was added thereto at 0° C. The mixture was stirred at room temperature for 5 hours. n-hexane was added to the reaction mixture, and solids were collected by filtration, followed by recrystallization using a mixed solvent of ethyl acetate and n-hexane, thereby giving 0.34 g of the target 2-({[3-(furan-3-yl)phenyl]carbonyl}amino)-5-methyl-4-phenylthiophene-3-carboxylic acid (yield: 70%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:6]([F:16])=[C:7]([CH:11]=[C:12]([F:15])[C:13]=1[F:14])[C:8](N)=[O:9].C(OCC)(=[O:19])C>O>[CH3:3][O:4][C:5]1[C:6]([F:16])=[C:7]([CH:11]=[C:12]([F:15])[C:13]=1[F:14])[C:8]([OH:19])=[O:9]
Reactant: COc1c(F)c(F)cc(C(N)=O)c1F
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
226 ml (0.226 mole) of a 1N aqueous solution of sodium hydroxide were added to a suspension of 46.4 g (0.226 mole) of 3-methoxy-2,4,5-trifluorobenzamide (XXV) [prepared as described in Step (E5) above] in 900 ml of water, and the mixture was heated under reflux with stirring for 2 hours. At the end of this time, the reaction mixture was cooled to room temperature and then shaken with ethyl acetate to remove unreacted material. The aqueous layer was separated and acidified with hydrochloric acid to precipitate a crystalline substance, which was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was removed by evaporation under reduced pressure to afford 37.1 g of 3-methoxy-2,4,5-trifluorobenzoic acid (XXVI) as colorless needles having the same properties as the product of Preparation 1.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[F:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[C:19]([F:21])[CH:18]=1
Reactant: COC1(c2cc(F)cc(F)c2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC1(c2cc(F)cc(F)c2)CCNC1
Yield: 79.8 %

Procedure:
A mixture of (−)-1-benzyl-3-(3,5-difluorophenyl)-3-methoxypyrrolidine (0.43 g, 1.41 mmol), mlammoniumformate (0.18 g, 2.83 mmol) and palladium on carbon (10%, 0.08 g) in ethanol (10 ml), was refluxed for 40 min. Additional ammoniumformate (0.18 g, 2.83 mmol) was added and after 90 min reflux all starting material was consumed. The reaction mixture was allowed to reach ambient temperature and filtrated over a pad of celite and the solvent was evaporated. The remaining oil was dissolved in methylen chloride and potassium carbonate (2 g), was added. The mixture was stirred over night, filtrated and evaporated to give the title compound (0.24 g, 79%). [a]D=−2.1° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether: M.p. 185-187° C. MS m/z (rel. intensity, 70 eV) 213 (M+, 1), 198 (58), 183 (bp), 171 (84), 141 (55).
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[C:10]([O:16]C)(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.C([Sn](=O)CCCC)CCC>>[C:10]([OH:16])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].[C:10]([OH:16])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].[C:10]([OH:16])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].[CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2]
Reactant: COC(=O)CC(C)=O
Agent: CCC(CO)(CO)CO
Agent: CCCC[Sn](=O)CCCC
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: CC(=O)CC(=O)O
Temperature: 25 °C

Procedure:
A 1000 ml. four-necked flask fitted with overhead stirrer, nitrogen sparge tube, thermometer and Barrett trap on top of a 6" steam jacketed Vigreux column was charged with 134.2 g. trimethylolpropane (1.0 mol), 580.6 g. methyl acetoacetate (5.0 mols), 0.8 g. triphenyl phosphite and 0.8 g. dibutyltin oxide. Steam was turned on in the jacketed Vigreux and the mixture was stirred with a nitrogen sparge and heated. When the pot temperature reached 142° C. methanol began distilling rapidly from the mixture. Heating was continued for a total of 50 minutes to a maximum pot temperature of 185° C. Vacuum was then applied and the excess methyl acetoacetate was removed first at 20 mm. Hg then at 1 mm. Hg with a maximum pot temperature of 180° C. Yield of orange liquid product was 372.4 g., 96% of theory. A small amount of white solid formed in the sides of the flask after cooling to room temperature. This was removed by gravity filtration. Proton NMR showed 100% conversion based on integration of methylene adjacent to esterified oxygen relative to methyl of trimethylolpropane.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=3[CH:15]=2)=[O:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O>[Pd].O1CCOCC1>[CH3:24][C:20]1([CH3:25])[CH2:19][CH2:18][C:17]([CH3:26])([CH3:27])[C:16]2[CH:15]=[C:14]([C:12](=[O:13])[CH2:11][O:10][C:8]3[CH:7]=[CH:6][C:3]([CH3:4])=[C:2]([OH:1])[CH:9]=3)[CH:23]=[CH:22][C:21]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)COc3ccc(C=O)c(O)c3)ccc21
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1ccc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O

Procedure:
1 g (2.7 mmol) of 2-hydroxy-4-(5,6,7,8-tetrahydro -5,5,8,8-tetramethyl-2-naphthoylmethyloxy)benzaldehyde, 100 mg of palladium on charcoal (5%) and 50 ml of dioxane are introduced into a reactor. The mixture is hydrogenated at room temperature and under a pressure of 3 bars, the catalyst is filtered off and the filtrate is evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of hexane and ethyl ether (70:30). After evaporation of the solvents, 600 mg of the expected product, melting point 144°-5° C., are collected.