Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].[Cl:7][C:8]1[C:13]([CH2:14]Br)=[CH:12][C:11]([C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[C:10]([F:28])[CH:9]=1.O>CN(C=O)C>[Cl:7][C:8]1[C:13]([CH2:14][O:6][CH2:3][C:4]#[CH:5])=[CH:12][C:11]([C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[C:10]([F:28])[CH:9]=1
Reactant: C#CCO
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc(CBr)c(Cl)cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOCc1cc(-c2ccc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 0.5 h
Yield: 91 %

Procedure:
0.04 g (1.10 mmol) of sodium hydride was suspended in 5 ml of DMF, and 0.06 g (1.10 mmol) of propargyl alcohol was dropwise added thereto at room temperature, followed by stirring for 30 minutes. Then, 0.40 g (1.00 mmol) of 3-(4-chloro-2-fluoro-5-bromomethylphenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 5 ml of DMF, and dropwise added thereto, followed by stirring for 2 hours. The reaction mixture was poured into water and extracted with ethyl ether. The extract was dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.34 g (yield: 91%) of the desired product. Melting point: 99-101° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH:10]([C:14]2[N:15]=[CH:16][N:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:18]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[CH:25]1([O:31][C:32]([O:34][CH:35](Cl)[CH3:36])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH:10]([C:14]2[N:15]=[CH:16][N:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:18]=2)[C:11]([O:13][CH:35]([O:34][C:32]([O:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:33])[CH3:36])=[O:12])=[CH:5][CH:4]=1
Reactant: Nc1ccc(CC(C(=O)O)c2cn(C3CCCCC3)cn2)cn1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(OC(=O)OC1CCCCC1)OC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCCCC2)cn1
Yield: 41.3 %

Procedure:
A solution of 50.0 mg (0.16 mmol) of the compound from example 1i and 39 mg (0.19 mmol) of 1-cyclohexyloxycarbonyloxy-1-ethyl chloride, 13 mg (0.08 mmol) of KI and 26 mg (0.19 mmol) of K2CO3 in 2 ml of DMF was stirred at 60° C. for 12 h. Then 5 ml of water were added and the reaction solution was extracted several times with EA. The combined EA extracts were dried, filtered and concentrated to dryness. The resulting residue was purified on silica gel with CH2Cl2/methanol as mobile phase, resulting in 32 mg of the title compound in the form of an amorphous solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13]C)=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[OH2:15].[OH-].[Li+:17]>C1COCC1.O>[O:15]=[C:2]1[NH:6][C:5]2=[C:7]([C:11]([O-:13])=[O:12])[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1.[Li+:17]
Reactant: O
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])c1cccc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 149.5 %

Procedure:
To a solution of methyl 2-chlorobenzoxazole-4-carboxylate (100 mg, 0.47 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (29.7 mg, 0.71 mmol) in H2O (3 mL). The reaction mixture was stirred at room temperature for 18 h and then concentrated to dryness to afford lithium 2-oxo-2,3-dihydrobenzoxazole-4-carboxylate (130 mg, 100%) as a yellow solid that was directly used in the next step without purification. MS consistent
Reaction SMILES: [C-]#N.[Na+].[N:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28](=[O:43])/[CH:29]=[CH:30]/[C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[C:36](=[N:40][O:41][CH3:42])[CH2:35][CH2:34]3)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[CH2:12]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([C:28](=[O:43])[CH2:29][CH:30]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[C:36](=[N:40][O:41][CH3:42])[CH2:35][CH2:34]3)[C:10](=[O:11])[C:7]2[CH:8]=[CH:9][N:4]=[CH:5][CH:6]=2)[CH2:26][CH2:27]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CON=C1CCc2cc(/C=C/C(=O)C3CCN(C(=O)OCc4ccccc4)CC3)ccc21
Reactant: O=Cc1ccncc1
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON=C1CCc2cc(C(CC(=O)C3CCN(C(=O)OCc4ccccc4)CC3)C(=O)c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
A solution of sodium cyanide (240 mg, 4.8 mmol) in DMF (15 ml) was treated with a solution of pyridine-4-carbaldehyde (1.71 g, 16 mmol) in DMF (25 ml). After 15 minutes a solution of the product of Step 2 (6.92 g, 16 mmol) in DMF (20 ml) was added dropwise. After stirring at room temperature for 18 hours the mixture was diluted with saturated sodium bicarbonate solution and ethyl acetate. The organic phase was washed with water and brine, dried and concentrated in vacuo and the residue purified by silica gel chromatography to give the title compound (5.6 g, 65%); MS(ES+) m/e 540 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C@@H:13]([CH3:14])[C@H:12]([CH2:15][C:16]([O:18]C)=[O:17])[N:11]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]4[CH2:32][CH2:31][N:30]([C:33]5[CH:38]=[C:37]([O:39][CH2:40][CH3:41])[CH:36]=[CH:35][C:34]=5[F:42])[CH2:29][CH2:28]4)=[CH:22][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1)#[N:2].C(C[C@@H]1N(C2C=CC(OC3CCN(C4C=C(OCC)C=CC=4F)CC3)=CC=2)N=C(C2C=CC(C#N)=CC=2)[C@H]1C)#N.COC(C)=O.C(Cl)(C)=O>Cl.CO.C(Cl)Cl.CO.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C@@H:13]([CH3:14])[C@H:12]([CH2:15][C:16]([OH:18])=[O:17])[N:11]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33]5[CH:38]=[C:37]([O:39][CH2:40][CH3:41])[CH:36]=[CH:35][C:34]=5[F:42])[CH2:31][CH2:32]4)=[CH:24][CH:25]=3)[N:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOc1ccc(F)c(N2CCC(Oc3ccc(N4N=C(c5ccc(C#N)cc5)[C@@H](C)[C@@H]4CC(=O)OC)cc3)CC2)c1
Agent: CCOc1ccc(F)c(N2CCC(Oc3ccc(N4N=C(c5ccc(C#N)cc5)[C@@H](C)[C@@H]4CC#N)cc3)CC2)c1
Agent: Cl
Solvent: CO
Solvent: CC(=O)Cl
Solvent: COC(C)=O
Product: CCOc1ccc(F)c(N2CCC(Oc3ccc(N4N=C(c5ccc(C#N)cc5)[C@@H](C)[C@@H]4CC(=O)O)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
Methyl 2-((4S,5S)-3-(4-cyanophenyl)-1-(4-((1-(5-ethoxy-2-fluorophenyl)piperidin-4-yl)oxy)phenyl)-4-methyl-4,5-dihydro-1H-pyrazol-5-yl)acetate: 4-((4S,5S)-5-(Cyanomethyl)-1-(4-((1-(5-ethoxy-2-fluorophenyl)piperidin-4-yl)oxy)phenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (389 mg, 0.716 mmol) was dissolved in ˜2.5M HCl/MeOH, MeOAc, CH2Cl2 solution [36.6 mL, prepared by addition of AcCl (6.6 mL) to 3/2 CH2Cl2/MeOH (30.0 mL) at 0° C. and then stirring at rt for 30 min]. The resulting solution was stirred at rt for 6.5 h and then evaporated to a volume of about 5 mL. The oily remnant was stripped from MeOH (2×20 mL), taken up in EtOAc (100 mL) and, washed with 5% NaHCO3 (2×50 mL) and sat'd NaCl (40 mL). The organic layer was dried (Na2SO4) and concentrated. Purification via silica gel chromatography provided the desired (75 mg, 18% yield) as a yellow oil: LC-MS [M+H] 571.
Reaction SMILES: [NH2:1][C:2]1[C:23]([NH2:24])=[CH:22][C:5]2[CH2:6][C@@H:7]3[C:12]([CH3:14])([CH3:13])[C@:11]([CH3:15])([C:4]=2[CH:3]=1)[CH2:10][CH2:9][N:8]3[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].[C:25](O)(=O)[CH3:26]>>[F:19][C:17]([F:20])([F:18])[C:16]([N:8]1[CH2:9][CH2:10][C@:11]2([CH3:15])[C:12]([CH3:13])([CH3:14])[C@H:7]1[CH2:6][C:5]1[CH:22]=[C:23]3[N:24]=[C:25]([CH3:26])[NH:1][C:2]3=[CH:3][C:4]=12)=[O:21]
Reactant: CC1(C)[C@H]2Cc3cc(N)c(N)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Reactant: CC(=O)O
Product: Cc1nc2cc3c(cc2[nH]1)[C@]1(C)CCN(C(=O)C(F)(F)F)[C@H](C3)C1(C)C
Temperature: 130 °C
Reaction time: 3 h

Procedure:
(2R,6S)-1-(8,9-Diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]-azocin-3-yl)-2,2,2-trifluoro-ethanone (600 mg) dissolved in glacial acetic acid is stirred at 130° C. for 3 h. After cooling to ambient temperature, the solution is concentrated under reduced pressure and the residue is taken up in ethyl acetate. The organic solution is washed with aqueous K2CO3 solution and brine and dried (MgSO4). The solvent is removed under reduced pressure to give the crude title compound as a foam-like solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH2:9][OH:10])=[CH:5][CH:4]=1.[CH2:13](I)[CH3:14]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH2:9][O:10][CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CCO)cc1
Reactant: CCI
Product: CCOCC=Cc1ccc(OC)cc1
Yield: 80 %

Procedure:
Reaction of p-methoxycinnamyl alcohol with ethyl iodide in the same manner as described under Example III gave an 80% yield of ethyl p-methoxycinnamyl ether after molecular distillation (vacuum, 105° C): λmaxCCl4 6.1, 6.6, 6.75, 8.0, 8.55, 8.92, 9.55, 10.15, 10.8, and 12.05 μ.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])=[CH:16][C:17](Cl)=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1.[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])[CH3:37]>>[C:36]([N:39]1[CH2:44][CH2:43][N:42]([C:17]2[CH:16]=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:12]3[C:13](=[O:14])[N:7]([CH2:6][C:5]4[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[C:3]([C:2]([F:1])([F:35])[F:34])[CH:4]=4)[CH2:8][CH2:9][O:10][C:11]=3[N:18]=2)[CH2:41][CH2:40]1)(=[O:38])[CH3:37]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCO2
Product: CC(=O)N1CCN(c2cc(-c3ccccc3C)c3c(n2)OCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Yield: 9.9 %

Procedure:
In a similar manner to Example 1, 4-[3,5-bis(trifluoromethyl)benzyl]-8-chloro-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (compound of Reference Example 19; 51.5 mg) was reacted with 1-acetylpiperazine (38.5 mg) to obtain 8-(4-acetylpiperazine-1-yl)-4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (6.0 mg, 10%).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(Cl)Cl.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:10])=[CH:3][CH:4]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1
Yield: 25.3 %

Procedure:
p-Anisoyl chloride (10 g, 58.5 mmol) and methylene chloride (500 mL) were combined under Ar. Aniline (8.0 mL, 87.7 mmol) was added dropwise with stirring. Diisopropylethylamine (10.0 mL, 58.5 mmol) was added dropwise to give a white suspension. After 3 h the contents of the reaction flask were washed with 5% potassium bisulfate then sat. sodium bicarbonate. The organic portion was dried with sodium sulfate (anh.), filtered and evaporated in vacuo to give a solid. Trituration with ethyl acetate gave 108 as a white solid (3.37 g, 14.8 mmol, 25.4%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.C1C=CN=C(C2C=[CH:17][CH:18]=[CH:19]N=2)C=1.C1(B(O)O)CC1.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH:17]2[CH2:18][CH2:19]2)[CH:7]=1
Reactant: c1ccc(-c2ccccn2)nc1
Reactant: Oc1ccc(Br)cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Product: O=c1ccc(Br)cn1C1CC1
Temperature: 70 °C
Reaction time: 22 h
Yield: 57.3 %

Procedure:
A mixture of 5-bromo-2-hydroxypyridine (0.8300 g, 4.77 mmol, 1.0 equiv), Cu(OAc)2 (0.902 g, 4.96 mmol, 1.04 equiv), bipyridine (0.785 g, 5.03 mmol, 1.05 equiv), cyclopropylboronic acid (0.846 g, 9.85 mmol, 2.06 equiv) and Na2CO3 (1.110 g, 10.47 mmol, 2.20 equiv) in dichloroethane (30 mL) was stirred at 70° C. for 22 h under air. The reaction mixture was quenched with satd aq NH4Cl, diluted with CH2Cl2, dried over Na2SO4. After the solvent was removed under reduced pressure, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford 0.585 g (58%) of 5-bromo-1-cyclopropylpyridin-2(1H)-one. LC-MS Method 1 tR=1.05 min, m/z 214, 216 (MH+); 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.7 Hz, 1H), 7.31 (dd, J=9.7, 2.9 Hz, 1H), 6.47 (d, J=9.9 Hz, 1H), 3.33-3.27 (m, 1H), 1.17-1.12 (m, 2H), 0.89-0.84 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.58, 142.29, 137.00, 121.77, 97.92, 32.83, 6.93.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:21][CH3:22])([O:19][CH3:20])=[O:18])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CI.[C:26](=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:19][CH3:20])([O:21][CH3:22])=[O:18])[CH2:10][C:11]([O:13][CH3:26])=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COP(=O)(CC(=O)C[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: COC(=O)C[C@@H](CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Yield: 92.4 %

Procedure:
1.05 g of (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid prepared above was dissolved in 16 ml of acetone to prepare the solution. To the solution, 2.02 g of methyl iodide and 0.391 g of potassium carbonate were added with stirring, and then the solution was further stirred for 5 hours at room temperature. After 16 ml of water was added to the solution, the solution was extracted with two portions of 20 ml of ethyl acetate. The ethyl acetate portions were combined and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation in vacuo to give 1.0 g of methyl (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoate as an oil (optical purity: 98% ee; yield: 92% based on the amount of (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:17]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([C:26]3[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=[N:4][CH:5]=2)=[CH:9][CH:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccc(-c2cncc(Br)c2)cc1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1cccc(-c2cncc(-c3ccc(C(C)C)cc3)c2)c1
Temperature: 80 °C
Yield: 66.3 %

Procedure:
Part B. A solution of 3-bromo-5-(4-isopropyl-phenyl)-pyridine (300 mg, 1.1 mmol) and 3-carboethoxybenzeneboronic acid (180 mg, 1.1 mmol) in ethanol-toluene-water (10 mL/5 mL/3 mL) is treated with sodium carbonate (345 mg), degassed twice and treated with a catalytic quantity of tetrakis(triphenylphosphine)palladium. The mixture is heated to 80° C. with stirring until the starting material is consumed as determined by TLC. Then, the mixture is cooled, filtered and evaporated, and the residual material is partitioned between water and ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate, filtered and evaporated, and the residue is separated by column chromatography to afford ethyl 3-[5-(4-isopropyl-phenyl)-pyridin-3-yl]-benzoate (252 mg, 79%).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1([CH2:39][O:40][CH3:41])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[C:28]([Cl:38])[CH:27]=4)[O:23][N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])C>C(O)(=O)C>[Cl:38][C:28]1[CH:27]=[C:26]([C:24]2[O:23][N:22]=[C:21]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][C:8]([CH2:39][O:40][CH3:41])([C:6]([OH:7])=[O:5])[CH2:9][CH2:10]4)=[CH:20][CH:19]=3)[N:25]=2)[CH:31]=[CH:30][C:29]=1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)C1(COC)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(Cl)c4)n3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COCC1(C(=O)O)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(Cl)c4)n3)cc2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Potassium hydroxide powder (85% assay, 0.394 g, 0.0060 mol) and N-methyl-N,N-dioctyloctan-1-ammonium chloride (0.02 g) are added to a solution of 1-{4-[5-(2-chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4-methoxymethylpiperidine-4-carboxylic acid ethyl ester (0.38 g, 0.00069 mol) in N,N′-dimethyl formamide (5 mL). The reaction mixture is stirred at 80° C. temperature for 2 hrs. It is then cooled to room temperature and acidified with 20% aqueous acetic acid solution to pH˜5-6. The precipitated solid is filtered, dried and washed with (2×5 mL) acetone. The solid mass is purified by column chromatography (silica gel 230-400 mesh, methanol:dichloromethane:t-butylamine, 1:8.9:0.1) to give 1-{4-[5-(2-chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4-methoxymethyl-piperidine-4-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=[C:16]2[C:25]3[CH:24]=[CH:23][S:22][C:21]=3[C:20](=O)[CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)[CH2:12][CH2:11]1.Cl.[NH2:32][OH:33]>N1C=CC=CC=1>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][C:13](=[C:16]2[C:25]3[CH:24]=[CH:23][S:22][C:21]=3[C:20](=[N:32][OH:33])[CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)[CH2:14][CH2:15]1
Reactant: O=C1Cc2ccccc2C(=C2CCN(CCOCCOCCO)CC2)c2ccsc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: OCCOCCOCCN1CCC(=C2c3ccccc3CC(=NO)c3sccc32)CC1

Procedure:
6.0 g 4-{1-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]piperidin-4-ylidene}-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)one and 0.95 g hydroxylaminehydrochlorid in 70 ml pyridine are refluxed for 12 hours. After elimination of the pyridine by distillation, ethanol and a little water are added to the residue and the title compound is crystallised out as the hydrochlorid (Mt. p. 240°-243°).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1>>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: c1ccoc1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3ccco3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and furane
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1.Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=[CH:19][C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 2-benzyloxy-5-bromobenzaldehyde (0.10 mol), malonic acid (15.0 g), and piperidine (2.0 ml) in 150 ml of pyridine was first heated at 90° C. for 90 min and subsequently refluxed for 0.5 hrs. After cooling to room temperature, the reaction was poured on a mixture of ice (1 kg) and concentrated aqueous hydrochloric acid (250 ml). The solid material that precipitated after stirring for 2 hrs. was collected by suction and recrystallized from a minimum of boiling methanol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:5]=[C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:3]=1.[C:34]1([C:40]2[CH:46]=[C:45]([OH:47])[CH:44]=[C:43]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:41]=2[OH:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[OH-].[Na+].Cl>O>[OH:42][C:41]1[C:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:46][C:45]([O:47][C:2]2[N:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:5]=[C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:3]=2)=[CH:44][C:43]=1[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: Oc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reactant: CCCCCCCCCCCCOc1nc(Cl)nc(OCCCCCCCCCCCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCOc1nc(OCCCCCCCCCCCC)nc(Oc2cc(-c3ccccc3)c(O)c(-c3ccccc3)c2)n1
Temperature: 0 °C

Procedure:
In a 500 ml-three-necked flask 4.8 g (0.01 mole) of the 2-chloro-4,6-dilauroxy-s-triazine prepared above, were mixed with 2.6 g (0.01 mole) of 2,6-diphenyl hydroquinone. After rinsing with nitrogen, 150 ml of acetone were added, followied by adding dropwise, with vigorous stilling, 0.4 g (0.01 mole) of NaOH dissolved in 7 ml of water, at 20° C. The solution then assumed an orange-yellow color, which largely disappeared upon heating the reaction mixture for a longth of time under reflux. After completion of the reaction, the contents of the flask were poured into 100 ml of ice water containing 2 ml of hydrochloric acid. The organic layer was extracted three times with methylene chloride, after which the combined extracts were washed and dried. After concentration of the organic layer by evaporation a product was obtained which crystallized out after a length of time (melting point 18°-20° C).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][NH2:32])[CH2:21]1.C(N(C(C)C)CC)(C)C>C(#N)C>[NH2:32][CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:22]1[CH2:23][CH2:24][N:20]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:21]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: NCc1ccccc1C1CCNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NCc1ccccc1C1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A suspension of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.13 g, 4.0 retool), 2-(3-pyrrolidinyl)benzenemethanamine (1.25 g, 5.0 mmol), and a diisopropylethylamine (2.07 g, 16.0 mmol) in acetonitrile (50 mL) was heated at gentle reflux for 24 hours. The suspension was allowed to cool to room temperature; the precipitated solids were filtered, washed successively with cold acetonitrile and ether, and dried in vacuo to give the title compound (0.73 g, 43%) as a white solid, after recrystallization from methanol, mp 226°-228° C.