Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12](C(OCC3C=CC=CC=3)=O)[CH2:13][CH:14]2[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]2[NH:12][CH2:13][CH:14]([CH2:16][O:17][S:38]([CH3:37])(=[O:40])=[O:39])[CH:15]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(CO)CN2C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2NCC(COS(C)(=O)=O)C21
Reaction time: 1 h

Procedure:
A solution of alcohol 77 (0.78 g, 2.1 mmol) in DCM (12 mL) was cooled to 0° C. and treated with DIPEA (0.55 mL, 3.2 mmol) followed by methanesulfonyl chloride (0.22 mL, 2.8 mmol). After 1 h, the solution was diluted with DCM, washed successively with 1M HCl, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford mesylate 79 as a light yellow-colored foam which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.36-7.31 (m, 5H), 5.19-5.09 (m, 2H), 4.45 (m, 1H), 4.29-4.04 (m, 3H), 3.71-3.44 (m, 4H), 3.22-3.12 (m, 1H), 2.96 (s, 3H), 2.85-2.70 (m, 1H), 2.21-1.99 (m, 2H), 1.49 (s, 9H) ppm.
Reaction SMILES: C(O)(=O)CC1C(=CC=CC=1)C(O)=O.O.[O:15]=[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](C(O)=O)=[C:18]([C:29]([F:32])([F:31])[F:30])O1.[OH-].[NH4+:34]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[F:30][C:29]([F:32])([F:31])[C:18]1[NH:34][C:16](=[O:15])[C:25]2[C:20]([CH:19]=1)=[CH:21][CH:22]=[CH:23][CH:24]=2
Reactant: O=C(O)c1c(C(F)(F)F)oc(=O)c2ccccc12
Reactant: [NH4+]
Agent: O=C(O)Cc1ccccc1C(=O)O
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)cc2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
Homophthalic acid (1.00 g, 5.55 mmol) dissolved in trifluoroacetic anhydride (7.8 ml) was heated in a sealed tube for 24 h at 110° followed by a further 24 h at 140°. The reaction was poured into water (100 ml), left for 1 h and the resulting precipitate extracted into EtOAc (3×50 ml). The EtOAc solution was dried (MgSO4) and the solvent removed under reduced pressure to give a pale brown solid. LCMS showed these to be a 9:1 mixture of −1-oxo-3-(trifluoromethyl)-1H-isochromene-4-carboxylic acid. m/z (ES+, 70V) 259 (MH+) and 3-Trifluoromethyl)-1H-isochrom-1-one m/z (ES+, 70V) 215 (MH+). The solids were dissolved in concentrated ammonium hydroxide (70 ml) and heated for 4 days at 100°, an additional 10 ml of concentrated ammonium hydroxide added after 24 h. The solution was allowed to cool to room temperature, the precipitate removed by filtration and the filtrate extracted with EtOAc (1×50 ml). The EtOAc was dried (MgSO4). the solvent removed under reduced pressure, and the resulting yellow solids combined with the precipitated material, to give the title compound 825 mg, 70%. δH (CDCl3) 8.48 (1H, d, J 7.5 Hz), 7.77 (1H, t), 7.68 (2H, m), 6.95 (1H, s); m/z (ES+, 70V), 215 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[NH2:28][C@@H:29]([CH2:32][CH3:33])[CH2:30][OH:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([NH:28][CH:29]([CH2:30][OH:31])[CH2:32][CH3:33])[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(CO)c1cccc(Cl)c1)C1CCN(c2nc(Cl)ncc2Cl)CC1
Reactant: CC[C@H](N)CO
Solvent: CCO
Product: CCC(CO)Nc1ncc(Cl)c(N2CCC(C(=O)NC(CO)c3cccc(Cl)c3)CC2)n1

Procedure:
1-(2,5-Dichloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid [1-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide (20 mg, 0.05 mmol) was dissolved in absolute ethanol (1 mL) then (S)-2-amino-butanol (0.1 mL) was added. The mixture was heated in a sealed Teflon reaction vial at 80° C. overnight. The resulting mixture was purified by preparative TLC (1 mm silica; eluent ethyl acetate) to afford the title compound as a colorless oil (4 mg). LC/MS Rt=4.42 minutes; 483.0 (M+1); 1H NMR δ 7.88 (s, 1H) 7.26 (m, 4H) 5.21 (NH) 4.97 (m, 1H) 3.91 (dd, J=11.2, 3.8, 1H) 3.86 (dd, J=11.2, 5.8, 1H) 3.7 (m, 1H) 3.66 (m, 5H) 3.62 (m, 1H) 3.54 (m, 4H) 1.65 (m, 1H) 1.54 (m, 1H) 1.26 (OH) 0.99 (t, J=7.5, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]1[NH:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:12])=[CH:5]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:25]([CH2:24][NH:23][C@@H:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][C@H:14]1[NH:13][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:12])([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
tert-Butyl N-((1R,2R)-2-{[(5-chloro-1H-indol-2-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)glycinate (Method 8, 230 mg, 0.52 mmol) was dissolved in DCM (10 mL). TFA (1 mL) was added and the reaction stirred at ambient temperature for 3 hours. Evaporation under reduced pressure, co-evaporation with CHCl3 (2×10 mL) and crystallization from EtOAc gave the title compound (85 mg, 36%) as a powder.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:36]=[CH:35][C:9]2[C:10]3[C:27]4([O:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][O:28]4)[C:11]=3[C:12]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])=[CH:16][C:13]=3[CH2:14][CH2:15][C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.Cl[C:44]([O:46][C:47]1[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=1)=[O:45]>C(Cl)Cl>[C:44](=[O:45])([O:46][C:47]1[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=1)[O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:12]2[C:11]3[C:27]4([O:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][O:28]4)[C:10]=3[C:9]3[CH:35]=[CH:36][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=3[CH2:15][CH2:14][C:13]=2[CH:16]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCO)ccc1C1=C2C12OCC(C)(C)CO2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCOC(=O)Oc3ccc([N+](=O)[O-])cc3)ccc1C1=C2C12OCC(C)(C)CO2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of alcohol 11 (0.439 g, 0.89 mmol) and pyridine (0.25 g, 3.21 mmol) in CH2Cl2 (approximately 5 mL) was added to a solution of 4-nitrophenyl chloroformate (0.30 g, 1.49 mmol) in CH2Cl2 (25 mL) at room temperature, and the reaction mixture was stirred for 20 minutes at room temperature. Solvent was evaporated under reduced pressure, and the residue was separated by chromatography (Hex:ExOAc 4:1+1.5% of Et3N) to provide 0.317 g (0.48 mmol 80%) of 12 as and 0.113 g (0.23 mmol) of starting 11. 1H NMR: 8.25 (d, J=8.8 Hz, 2 H) 7.65 (dd, J=8.4, 2.0 Hz, 2 H), 7.35, (d, J=9.2, 2 H), 6.92-6.82 (m, 4 H), 4.43 (t, J=4.4 Hz, 2 H), 4.19 (t, J=6.4 Hz, 2 H), 3.98 (t, J=4.4 Hz, 2 H), 3.92 (m, 7 H), 3.22 (d, J=10.8 Hz, 2 H), 2.43 (d, J=10.8 Hz, 2 H), 1.75 (p, J=7.2 Hz, 2 H), 1.51 (six, J=7.6 Hz, 2 H), 1.21 (s, 3H), 1.19 (s, 3 H), 0.98 (t, J=−7.2 Hz, 3 H); 13C NMR: 159.9, 159.2, 155.7, 152.7, 150.0 147.4, 145.6, 131.77, 131.63, 125.5, 124.6, 123.4, 122.0, 119.8, 119.1, 116.25, 116.19, 112.2, 112, 15, 84.1, 79.4, 70.0, 69.1, 68.4, 70.0, 67.8, 37.1, 31.5, 30.8, 22.87, 22.79, 19.5, 14.1.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH:8]([CH2:14][CH2:15][CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])OCC[O:3]1.O.C(OCC)(=O)C>CCCCCC.ClCCl>[O:3]=[C:2]([CH3:1])[CH2:7][CH:8]([CH2:14][CH2:15][CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCCC(CC1(C)OCCO1)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CCCC(CC(C)=O)C(=O)OCC
Temperature: -20 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a solution of ethyl 2-((2-methyl-1,3-dioxolan-2-yl)methyl)pentanoate (9.8 g; 42.55 mmol) in hexane (106 mL) at −78° C. under nitrogen atmosphere was added borontribromide (55 mL; 55 mmol; 1M in dichloromethane) and the reaction mixture was stirred at −20° C. for 2 h. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulphatesulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (1-40%) in heptane furnished 6.41 g (81%) of ethyl 4-oxo-2-propylpentanoate as a light yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH:12]1([C:15]2[NH:19][N:18]=[C:17]([NH2:20])[CH:16]=2)[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:20][C:17]2[CH:16]=[C:15]([CH:12]3[CH2:14][CH2:13]3)[NH:19][N:18]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (5 g) and 5-cyclopropyl-1H-pyrazol-3-amine (5 g) in acetonitrile (40 mL) with diisopropylethylamine (6 mL) was stirred at room temperature for 24 hours, The resulting mixture was concentrated, and the resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to afford 5 g desired product. MS (electrospray): 280 (M+1) for C11H10ClN5O2. 1H NMR (300 MHz, CD3OD) δ ppm 8.5 (d, 1H) 6.9 (d, 1H) 6.5 (s, 1H) 1.9 (m, 1H) 1.0 (m, 2H) 0.70 (m, 2H).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)(=O)=O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC#N>[CH2:14]([NH:21][CH2:6][C@H:7]1[CH2:11][O:10][C:9]([CH3:12])([CH3:13])[O:8]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: CC1(C)OC[C@H](COS(C)(=O)=O)O1
Solvent: CC#N
Product: CC1(C)OC[C@H](CNCc2ccccc2)O1
Yield: 75.5 %

Procedure:
The title compound was prepared in the same way as described by M. Lemaire, F. Posada, J.-G. Gourcy and G. Jeminet, Synlett, 1995, 627. A solution of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (3.9 g, 18.55 mmol) and benzylamine (8.10 ml, 74.2 mmol) was refluxed in CH3CN (50 ml) for 48 h. The solvent was evaporated and the residue dissolved in EtOAc and washed with aqueous sat. NaHCO3, dried and the solvent evaporated. The residue was chromatographed (EtOAc-hex, 6:4 then 8:2) to give (S)—N-benzyl-1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (3.1 g, 14.01 mmol, 76% yield) as a yellow oil. [α]D21 +4.3 (c, 0.69, CHCl3). The 1H NMR and 13C NMR were identical to that of compound 3.2.
Reaction SMILES: [CH:1]([O:4][P:5]([CH2:11][O:12][CH2:13][N:14]1[C:22]([CH2:23][CH2:24][CH2:25][N:26]=[N+]=[N-])=[N:21][C:20]2[C:15]1=[N:16][C:17]([C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[N:18][C:19]=2[NH:29][O:30][CH3:31])([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH:8]([O:7][P:5]([CH2:11][O:12][CH2:13][N:14]1[C:22]([CH2:23][CH2:24][CH2:25][NH2:26])=[N:21][C:20]2[C:15]1=[N:16][C:17]([C:32]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[N:18][C:19]=2[NH:29][O:30][CH3:31])([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])([CH3:9])[CH3:10]
Reactant: CONc1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1nc(CCCN=[N+]=[N-])n2COCP(=O)(OC(C)C)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CONc1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1nc(CCCN)n2COCP(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 38 (805 mg, 1.15 mmol) in THF (8 mL) and water (1.6 mL) is treated with triphenylphosphine (640 mg, 2.44 mmol) and stirred at room temperature for 14 h. The reaction mixture is concentrated and purified on silica gel column using chloroform:CMA-80 (1:0 to 1:1) as eluent to give 660 mg (85%) as a white solid: 1H NMR (DMSO-d6): δ 8.09 (s, 1H), 7.72 (s, 1H), 7.17-7.00 (m, 13H), 6.67 (d, J=9.0 Hz, 2H), 4.70-4.59 (m, 1H), 4.28-4.16 (m, 2H), 3.95 (t, J=9.2 Hz, 1H), 3.68-3.45 (m, 3H), 3.54 (s, 3H), 2.29-2.05 (m, 2H), 1.93-1.60 (m, 4H), 0.96-0.91 (m, 6H), 0.84 (d, J=6.1 Hz, 6H). IR (neat, cm−1) 3414, 3020, 1605, 1511 and 1216. Anal. Calcd for C36H45N6O5P.1.5 H2O: C, 61.79; H, 6.91; N, 12.01. Found: C, 61.70; H, 6.63; N, 12.07.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH2:16][CH3:17])[C:12]([OH:14])=O.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([CH2:19][NH:18][C:12](=[O:14])[CH:11]([C:3]2[C:4]([F:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:15][CH2:16][CH3:17])=[C:21]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(CN)c(Oc2ccccc2)c1
Reactant: CCOC(C(=O)O)c1c(F)cc(OC)cc1F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1Oc1ccccc1)c1c(F)cc(OC)cc1F

Procedure:
(RS)-(2,6-Difluoro-4-methoxy-phenyl)-ethoxy-acetic acid (example 101.3) was coupled with 4-aminomethyl-3-phenoxy-benzonitrile (example 106.3) according to general procedure C to give (RS)-N-(4-cyano-2-phenoxy-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-ethoxy-acetamide. Colorless foam. MS 453.1 ([M+H]+)
Reaction SMILES: [CH2:1]([C:8]([CH3:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11](Cl)[CH:12]=[CH:13][CH3:14].ClC(C)C=C>>[C:2]1([CH:1]([C:8](=[O:9])[CH3:10])[CH2:11][CH:12]=[CH:13][CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=CCCl
Reactant: CC(=O)Cc1ccccc1
Agent: C=CC(C)Cl
Product: CC=CCC(C(C)=O)c1ccccc1

Procedure:
Methyl benzyl ketone is reacted with crotyl chloride or 3-chloro-1-butene in accordance with the foregoing details and there is obtained 5-phenyl-hept-2-en-6-one of boiling point 88° C./3 mmHg; nD20 =1.5190. When 3-chloro-1-butene is used there is also obtained 3-methyl-5-phenyl-hex-1-en-5-one which is separated by distillation.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][CH:7]=1.[C:14](OC)(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[SH:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([C:12]2[S:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14](=[O:22])[N:13]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(-c2ccco2)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(-c3ccco3)n2)sc2ccccc12
Yield: 70 %

Procedure:
6-(2-Furyl)-2-pyridinecarbonitrile (0.60 g, 3.5 mmol) and methyl thiosalicylate (1.01 g, 6.0 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The reaction mixture was refluxed for 12 hrs. After cooling, the precipitates were collected by filtration and recrystallized from tetrahydrofuran-hexane to give the titled compound (0.75 g, 69%) as pale yellow crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[N:7]=1)=O)C.[CH3:21][NH:22][CH3:23]>>[CH3:21][N:22]([CH3:23])[C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[N:7]=1)=[O:3]
Reactant: CCOC(=O)c1nc(-c2cccc3ccccc23)no1
Reactant: CNC
Product: CN(C)C(=O)c1nc(-c2cccc3ccccc23)no1
Reaction time: 1 h

Procedure:
5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole (618 mg.) was dissolved in an ethanolic solution of dimethylamine (10 ml., 33% v/v). After 1 hr. The solution was evaporated leaving a residue that was recrystallised from methanol (3.5 ml.) to give title compound (424 mg.,) m.p. 109°-110°, λmax. (EtOH) 302.5 nm (ε 9,400) νmax. (CHBr3) 1660 cm.-1 (CONMe2).
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:20][C:21]([O:23]CC)=[O:22])([O-:5])=[O:4]>CO>[N+:3]([C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:20][C:21]([OH:23])=[O:22])([O-:5])=[O:4]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2C)c1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1Oc1cccc(CC(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of potassium hydroxide (3 g) in methanol (30 ml) was added to a solution of ethyl 2-[2-nitro-3-(o-tolyloxy)phenyl]acetate (3.9 g) in methanol (30 ml), and the mixture was stirred at room temperature for an hour. The reaction mixture was evaporated in vacuo, and the residue was dissolved in water. The aqueous solution was washed with diethyl ether and acidified with conc. hydrochloric acid. The precipitating crystals were collected by filtration and recrystallized from ethanol to give 2-[2-nitro-3-(o-tolyloxy)phenyl]acetic acid (1.5 g). mp 158°-160° C.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH2:6][N:5]2[CH:8]([C:11]3[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=3)[CH2:9][O:10][CH:4]2[C:3]=1[C:18]([NH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:19].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1.CO>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:14]2[CH:15]=[CH:16][C:11]([CH:8]3[N:5]4[CH2:6][CH2:7][C:2]([OH:1])=[C:3]([C:18]([NH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:19])[CH:4]4[O:10][CH2:9]3)=[CH:12][CH:13]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)CNC(=O)C1=C(O)CCN2C1OCC2c1ccc(I)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CNC(=O)C1=C(O)CCN2C1OCC2c1ccc(-c2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 1.17 h
Yield: 107.5 %

Procedure:
A mixture of the compound (100 mg) obtained in step (3) above, 4-fluorophenylboronic acid (66 mg), palladium(II) acetate (6.6 mg), tri(2-methylphenyl)phosphine (26 mg), potassium carbonate (186 mg), methanol (4.4 mL) and toluene (2.2 mL) was stirred in a sealed tube at 90° C. for 70 minutes. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1-0:100, then chloroform:methanol=100:0-85:15) to give methyl N-{[3-(4′-fluoro-4-biphenylyl)-7-hydroxy-2,3,6,8a-tetrahydro-5H-[1,3]oxazolo[3,2-a]pyridin-8-yl]carbonyl}-glycinate as a pale brown solid (100 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11])[CH3:8].[Cl:19][C:20]1[CH:21]=[C:22]([C:32]2[O:36][N:35]=[C:34]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43]Cl)=[CH:39][CH:38]=3)[N:33]=2)[CH:23]=[CH:24][C:25]=1[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[CH2:7]([O:9][C:10]([C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([CH2:43][C:40]2[CH:39]=[CH:38][C:37]([C:34]3[N:33]=[C:32]([C:22]4[CH:23]=[CH:24][C:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[C:20]([Cl:19])[CH:21]=4)[O:36][N:35]=3)=[CH:42][CH:41]=2)[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: ClCc1ccc(-c2noc(-c3ccc(C4CCCCC4)c(Cl)c3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)CCN(Cc2ccc(-c3noc(-c4ccc(C5CCCCC5)c(Cl)c4)n3)cc2)CC1
Temperature: 67.5 °C

Procedure:
Potassium carbonate (0.16 g, 0.0012 mol) and 4-methylpiperidine-4-carboxylic acid ethyl ester (0.21 g, 0.0012 mol) are added to a solution of 5-(3-chloro-4-cyclohexylphenyl)-3-(4-chloromethylphenyl)-[1,2,4]-oxadiazole (0.3 g, 0.00077 mol) in N,N-dimethylformamide 15 mL). The reaction mixture is heated at 65-70° C. for 2 hrs. Removal of solvent gives a crude residue which is purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:toluene, 1:4) to give 4-methyl-1-{4-[5-(3-chloro-4-cyclohexylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}piperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [O-2].[Zn+2:2].[C:3]([OH:7])(=[O:6])[CH:4]=[CH2:5].[C:8]([O:12]CC)(=[O:11])[CH:9]=[CH2:10].C(OC1CCCCC1)(=O)C(C)=C>C1(C)C(C)=CC=CC=1.C(O)CCC.C1(C)C(C)=CC=CC=1.C(O)CCC.O>[C:3]([O-:7])(=[O:6])[CH:4]=[CH2:5].[Zn+2:2].[C:8]([O-:12])(=[O:11])[CH:9]=[CH2:10]
Reactant: C=CC(=O)O
Reactant: C=CC(=O)OCC
Agent: C=C(C)C(=O)OC1CCCCC1
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Solvent: CCCCO
Solvent: Cc1ccccc1C
Product: C=CC(=O)[O-]
Temperature: 95 °C

Procedure:
A zinc acrylate polymer was prepared by the reaction of zinc oxide and naphthenic acid (acid value 200 mgKOH/g) with a carboxylic acid functional acrylic copolymer based on the monomers; Acrylic acid (25.0 mol %), Ethyl acrylate (62.9 mol %), Cyclohexyl methacrylate (9.6 mol %) and methoxy polyethyleneglycol methacrylate (MPEG350) (2.5 mol %). These components were mixed at a 1:1:1 molar ratio (zinc oxide:naphthenic acid:polymer carboxylic acid groups) in xylene/n-butanol (4:1 weight ratio) and heated and stirred at 95° C. until a clear solution was obtained resulting in a solution of zinc acrylate polymer of 45 wt % in xylene/n-butanol/water (41.7:12.3:1.0 wt %).
Reaction SMILES: C[N:2]1CCOCC1.[C:8]1([CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)Cl>C(#N)C>[CH2:14]([S:15]([NH2:2])(=[O:17])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCOCC1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: NS(=O)(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 118.1 %

Procedure:
To a solution of 5 (7.54 g, 0.0298 mole; see Example 5) and 4-methylmorpholine (9.04 g, 0.0894 mole, 9.83 mL) in 300 mL of anhydrous acetonitrile at 0° C. under N2 was added α-toluene-sulfonyl chloride (11.36 g, 0.0596 mole) in one portion. The solution was stirred at 0° C. for 1 hour and allowed to warm. to and stir at ambient temperature for 19 hours. The solution was filtered and evaporated. The crude residue was purified by flash chromatography on silica gel using a hexane, CH2Cl2: 4,1 to CH2Cl2 gradient system and afforded 12.05 g (99% yield) of product 6 as waxy reddish solid, mp 62-63° C. TLC (silica; CH2Cl2), Rf=0.45.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH:6]=[C:7]([O:12]C)[C:8]=1[CH2:9][CH2:10][CH3:11].Cl.N1C=CC=CC=1.CCOCC>C(OCC)(=O)C>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:15]=[CH:14][C:5]1[CH:6]=[C:7]([OH:12])[C:8]([CH2:9][CH2:10][CH3:11])=[C:3]([OH:2])[CH:4]=1
Reactant: CCCc1c(OC)cc(C=Cc2ccccc2F)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCc1c(O)cc(C=Cc2ccccc2F)cc1O
Temperature: 200 °C
Yield: 95.9 %

Procedure:
A mixture of 2-(3,5-dimethoxy-4-1-propylphenyl)-1-(2-fluorophenyl)ethene (27B) (0.308 g, 1.03 mmol) and pyridine hydrochloride (0.72 g, 6.2 mmol) was heated at 200° C. for 4 h under a stream of argon. The reaction mixture was cooled to room temperature. 2NHCl (10 mL) and ether (15 mL) was added. The organic layer was separated and the aqueous layer was extracted with ether (3×10 mL). The extract was dried over anhydrous Na2SO4. Evaporation of ether followed by flash chromatography using 15% ethyl acetate in hexane afforded pure 5-[2-(2-fluorophenyl)ethenyl]-2-1-propyl-1,3-benzenediol (37B) (0.269 g, 95% yield) as an off-white solid. 1HNMR (CDCl3, ppm): δ 1.41 (d, J=7.2 Hz, 6H), 3.51 (qint., J=7.2 Hz, 1H), 5.01 (b, 2H), 6.56 (s, 2H), 6.98 (d, J=17.6 Hz, 1H), 7.0-7.3 (m, 4H), 7.60 (ddd, J=7.5, 7.5, 2.2 Hz, 1H).