Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:20])[C:4]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1.O>CN(C)C=O>[CH3:19][N:18]1[C:14]([C:4]2[C:3](=[O:20])[C:2]([O:1][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:7][N:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:5]=2)=[CH:15][CH:16]=[N:17]1
Reactant: Cn1nccc1-c1nn(-c2ccccc2)cc(O)c1=O
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nccc1-c1nn(-c2ccccc2)cc(OCc2ccc3ccccc3n2)c1=O
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a solution of 5-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)-1-phenylpyridazin-4(1H)-one (268 mg) in dimethylformamide (10 mL) was added cesium carbonate (782 mg), 2-(chloromethyl)quinoline hydrochloride (236 mg) was added with stirring under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 64 hr. Water was added to the reaction mixture and the mixture was stirred for 1 hr. The precipitated crystals were collected by filtration, washed successively with water, methanol and diisopropyl ether, and dried to give the title compound (226 mg) as a white solid.
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)=[CH:5][S:4][CH2:3][CH2:2]1.[NH2:14][CH:15]1[C:30](=[O:31])[N:17]2[C:18]([C:27]([OH:29])=[O:28])=[C:19]([CH2:22][O:23][C:24](=[O:26])[NH2:25])[CH2:20][S:21][C@H:16]12>>[O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:14][CH:15]2[C:30](=[O:31])[N:17]3[C:18]([C:27]([OH:29])=[O:28])=[C:19]([CH2:22][O:23][C:24](=[O:26])[NH2:25])[CH2:20][S:21][C@H:16]23)=[O:10])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)C1=CSCCO1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)C1=CSCCO1

Procedure:
2-(2,3-Dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetic acid (syn isomer, 0.508 g.) was allowed to react with 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (0.82 g.) in a similar manner to that of Example 1 to give the captioned compound (0.85 g.), pale yellow powder, mp. 175° to 180° C. (dec.).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][CH:8]([OH:24])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[OH:23])[CH:10]=1)=O.N.CO>ClCCl>[NH2:5][CH2:6][CH2:7][CH:8]([C:9]1[CH:10]=[C:11]([C:15]#[C:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[OH:23])[CH:12]=[CH:13][CH:14]=1)[OH:24]
Reactant: O=C(NCCC(O)c1cccc(C#CC2CCCCC2O)c1)C(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NCCC(O)c1cccc(C#CC2CCCCC2O)c1

Procedure:
Deprotection of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((2-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamide followed by flash chromatography (10% (7N NH3/MeOH)/dichloromethane) gave 2-((3-(3-amino-1-hydroxypropyl)phenyl)ethynyl)cyclohexanol as a light yellow glassy solid. Yield (0.402 g, 29%): 1H NMR (400 MHz, CDCl3) δ 7.44-7.46 (m, 1H), 7.21-7.31 (m, 3H), 4.92 (dd, J=8.8, 3.2 Hz, 1H), 3.47-3.56 (m, 1H), 3.05-3.12 (m, 1H), 3.01 (brs, 4H), 2.90-2.99 (m, 1H), 2.37-2.44 (m, 1H), 2.00-2.09 (m, 2H), 1.81-1.90 (m, 1H), 1.64-1.81 (m, 3H), 1.40-1.52 (m, 1H), 1.14-1.40 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[O:13][C:12]2[CH:14]=[C:15]([F:22])[C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:17][C:11]=2[O:10]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>C(OCC)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[O:13][C:12]2[CH:14]=[C:15]([F:22])[C:16]([S:18]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)(=[O:20])=[O:19])=[CH:17][C:11]=2[O:10]1
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1cc2c(cc1F)OC(c1ccc(F)cc1F)(c1ccc(F)cc1F)O2
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=S(=O)(c1cc2c(cc1F)OC(c1ccc(F)cc1F)(c1ccc(F)cc1F)O2)N1CCCC1
Yield: 73.7 %

Procedure:
To a solution of 2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl chloride (250 mg, 0.54 mmol) in diethylether (3 mL) was added pyrrolidine (0.11 mL, 1.35 mmol, 2.5 eq.). The reaction mixture was diluted with ethyl acetate (50 mL), washed with an aqueous solution of hydrochloric acid (IN), brine and water. The organic layer was dried over sodium sulfate and the volatiles were removed in vacuo. Purification by flash chromatography afforded the title compound (198 mg, 74%) as a white foam.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=O)[OH:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:46][C:47]1[CH:48]=[C:49]([CH:55]=[CH:56][CH:57]=1)[C:50]([O:52]CC)=[O:51].O.[OH-].[Li+].[OH-].[Li+].Cl>CN(C=O)C.O.C(O)C.C(N(CC)CC)C>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([NH:46][C:47]1[CH:48]=[C:49]([CH:55]=[CH:56][CH:57]=1)[C:50]([OH:52])=[O:51])=[O:6]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: N[C@@H](CCC(=O)Nc1cccc(C(=O)O)c1)C(=O)O
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Boc-Glu-OtBu (100 mg, 0.33 mmol) and HATU (150.4 mg, 0.40 mmol) were dissolved in 2 mL of DMF. Triethylamine (68.5 μL) was added thereto and stirred for 10 minutes. Ethyl 3-aminobenzoate (49.2 mg, 0.33 mmol) was added thereto and stirred overnight. After liquid separation was conducted with an ethyl acetate and an aqueous solution of 1M sodium hydroxide, the organic layer was washed with an aqueous solution of 1M sodium hydroxide, 1M hydrochloric acid and a saturated saline solution, successively, and dried with sodium sulfate to remove a solvent. The obtained residue was dissolved in 2 mL of THF, 1 mL of ethanol and 1 mL of water, and lithium hydroxide monohydrate (13.5 mg, 0.32 mmol) was added thereto. After stirring the mixture for 5 hours, 4.5 mg of lithium hydroxide was added thereto and stirred overnight. After confirming the completion of the reaction, pH of the reaction solution was adjusted to 2 with 1M hydrochloric acid, and a solvent was removed therefrom. 3 mL of TFA was added to the obtained residue and stirred at room temperature for 5 hours. After removing a solvent, purification was conducted in accordance with the purification process A to obtain a title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[S:33][C:32]([C:34]([OH:36])=O)=[CH:31][CH:30]=1)[CH:7]=[CH:6]2.ClCCl.C(Cl)(=O)C(Cl)=O.[NH3:46]>O1CCCC1.CCOCC.CO.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[S:33][C:32]([C:34]([NH2:46])=[O:36])=[CH:31][CH:30]=1)[CH:7]=[CH:6]2
Reactant: N
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C(=O)O)s3)ccc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C(N)=O)s3)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Add 5-(6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalene-2-yl)thiophene-2-carboxylic acid (86 mg, 0.2 mmol) and dichloromethane (2.4 mL) to a round bottom flask under nitrogen. Cool the suspension to 0° C. and add sequentially oxalyl chloride (22.2 μL, 0.3 mmol) and dimethylformamide (30.0 μL). Warm the resulting mixture to room temperature and stir for 30 minutes. Concentrate in vacuo to give a yellow solid. Add tetrahydrofuran (2.5 mL) to the solid. To the resulting suspension add a solution of ammonia (12.1M in water; 3 mL, 36.4 mmol) in tetrahydrofuran (5.7 mL). Stir the resulting solution for 30 minutes; then dilute with ether. Separate the layers and dry the organic layer (Na2SO4), filter and concentrate in vacuo to give a tan solid. Dissolve the resulting solid in methanol and load onto an SCX acidic ion exchange column. Flush the column with methanol then elute desired material with 2M ammonia in methanol. Concentrate the ammonia containing eluent to obtain the title compound (79 mg, 0.16 mmol) 1H NMR (d6-DMSO) δ 1.32-1.27 (m, 2H), 1.44-1.38 (m, 4H), 2.33 (s, 4H), 2.53 (t, J=5.9 Hz, 2H), 3.27 (s, 2H), 3.83 (s, 3H), 3.89 (t, J=5.9 Hz, 2H), 6.66-6.61 (m, 3H), 6.79-6.76 (m, 2H), 7.09 (dd, J=2.6, 9.2 Hz, 1H), 7.39 (d, J=2.6 Hz, 1H), 7.65-7.61 (m, 3H), 7.79 (d, J=8.8 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1.[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].CC(O)=O>C1(C)C=CC=CC=1>[C:13]([C:15](=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)C1CCCC(=O)C1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1CCCC(C(=O)OCC)C1
Yield: 73.3 %

Procedure:
Into a 500-mL round-bottom flask, was placed ethyl 3-oxocyclohexane-1-carboxylate (7 g, 41.13 mmol, 1.00 equiv), ethyl 2-cyanoacetate (6.5 g, 57.46 mmol, 1.40 equiv), AcOH (0.8 mL) and NH4OAc (300 mg) in toluene (150 mL). The resulting solution was heated to reflux overnight in presence of a Dean-Stark. After the starting 4 was consumed completely, the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9) to give the corresponding ethyl 3-(1-cyano-2-ethoxy-2-oxoethylidene)cyclohexane-1-carboxylate (8.0 g, 73%) as yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.Cl.[CH3:15]O>>[CH3:15][O:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([OH:1])[CH:10]=2)=[O:13]
Reactant: CO
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Agent: Cl
Product: COC(=O)c1cc2ccc(O)cc2[nH]1
Temperature: 90 °C
Yield: 77 %

Procedure:
To a solution of 6-hydroxy-1H-indole-2-carboxylic acid (5.0 g, 28.2 mmol) in MeOH (250 mL) was added concentrated HCl (3 mL) and the reaction mixture was heated (90° C., 3 h). The reaction mixture was cooled (rt) and concentrated in vacuo. The resulting residue was partitioned between EtOAc (50 mL) and H2O (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×200 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound as a yellow solid (4.2 g, 77%). MS (ESI): mass calcd. for C10H9NO3, 191.1; m/z found, 192.1 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:52]=[CH:51][CH:50]=[CH:49][C:15]=1[C:16]([NH:18][C@H:19]([B:36]1[O:44]C2C(C)(C3CC(C2)C3(C)C)[O:37]1)[CH2:20][C:21]1[C:22](OC)=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([O:26]C(C)(C)C)=[O:25])=[O:17])=[O:13])=O)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:52]=[CH:51][CH:50]=[CH:49][C:15]=1[C:16]([NH:18][C@H:19]1[CH2:20][C:21]2[CH:33]=[CH:32][CH:31]=[C:23]([C:24]([OH:26])=[O:25])[C:22]=2[O:44][B:36]1[OH:37])=[O:17])=[O:13]
Reactant: COc1c(C[C@H](NC(=O)c2ccccc2C(=O)NCCNC(=O)OC(C)(C)C)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: NCCNC(=O)c1ccccc1C(=O)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from tert-butyl 3-((2R)-2-(2-(2-(tert-butoxycarbonylamino)ethylcarbamoyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate and BCl3 following the procedure described in Step 2 of Example 3. The product was then purified by reverse phase HPLC and dried using lyophilization. ESI-MS m/z 398 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:4]=1[C:5]([NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([F:17])([F:16])[F:15])[CH2:10][CH2:9]1)=[O:6].CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1.O>CO.[Pd].[H][H]>[NH2:22][C:19]1[CH:20]=[CH:21][C:3]([N:2]([CH3:25])[CH3:1])=[C:4]([CH:18]=1)[C:5]([NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([C:14]([F:16])([F:17])[F:15])[CH2:12][CH2:13]1)=[O:6]
Reactant: CN(C)c1ccc([N+](=O)[O-])cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Solvent: CO
Solvent: O
Product: CN(C)c1ccc(N)cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
Prepared analogously to example 4b with 2-dimethylamino-5-nitro-N-(trans-4-trifluoromethylcyclohexyl)-benzamide (50 mg; 0.14 mmol) with Pd/C/H2 (15 mg/50 psi) in 10 mL MeOH. Yield: quantitative; MS: [m+H]+=330; HPLC: Rt=1.14 min (Method MC-1)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([N+:27]([O-])=[O:28])[CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C)C=O.O.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[C:3]([C:12](=[N:27][OH:28])[CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:25])[F:23])=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: O=C(NCC(c1ncc(C(F)(F)F)cc1Cl)[N+](=O)[O-])c1ccccc1C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=NO)c1ncc(C(F)(F)F)cc1Cl)c1ccccc1C(F)(F)F
Temperature: 47.5 °C
Reaction time: 12 h
Yield: 58.2 %

Procedure:
To 19.80 g of N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-nitroethyl]-2-(trifluoromethyl)benzamide in 100 ml of a mixture of N,N-dimethylformamide-water (7:1), 21.65 g of sodium nitrite was added, and the mixture was stirred at from 45 to 50° C. for 12 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, poured into 150 ml of water and extracted with ethyl acetate (100 ml×2). The resulting organic layers were combined, washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 3:7 to 1:1) as the eluent to obtain 11.10 g of the desired product as white crystals.
Reaction SMILES: C(Cl)CCl.C(N(CC)CC)C.[C:12]1([CH2:22][OH:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[C:24]([NH:31][C@H:32]([C:40](O)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C1C=CN=CC=1)C.ClCCl>[C:12]1([CH2:22][O:23][C:40](=[O:41])[C@H:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:31][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: OCc1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1cccc2ccccc12
Reaction time: 8 h

Procedure:
1192 mg (6.2 mmol) of EDC, 578 μl (4.1 mmol) of triethylamine, 345 mg (2.8 mmol) of DMAP, and 328 mg (2.1 mmol) of 1-naphthylmethanol were added at RT to a solution of 500 mg (1.89 mmol) of N-Boc-L-phenylalanine in 25 ml dichlormethane. The reaction composition was stirred overnight, then diluted with 50 ml Dichlormethane and successively washed in a solution of 10% of aqueous citric acid, water, and saturated saline. The organic phase was dried over magnesium sulphate and then evaporated, and the residue purified with preparative HPLC. The yield was 501 mg (66% o. th.) of the title compound.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH:27]=1>>[C:1]1([C@@H:7]([CH3:11])[C:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)=[N:18][C:17]=3[CH:27]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc2oc(-c3ccncc3)nc2c1
Reactant: C[C@@H](C(=O)O)c1ccccc1
Product: C[C@@H](C(=O)Nc1ccc2oc(-c3ccncc3)nc2c1)c1ccccc1

Procedure:
Similarly prepared as per compound 8 procedure, using starting materials (R)-2-phenylpropanoic acid and compound 4 (4-pyridine) to obtain title compound Q49 as white solid (78%). 1H NMR (CDCl3, 400 MHz) δ 1.59 (d, J=7.2 Hz, 3H), 3.76 (q, J=6.8 Hz, 1H), 7.21-7.29 (m, 1H), 7.32-7.41 (m, 6H), 7.90 (s, 1H), 7.97 (d, J=4.8 Hz, 3H), 8.74 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 18.9, 48.0, 110.8, 112.3, 119.8, 121.2, 127.7, 127.8, 129.2, 134.3, 135.6, 141.1, 142.1, 147.7, 150.7, 161.4, 172.9; ESI-HRMS for C21H18N3O2 (M+H)+ calcd. 344.1399. found 344.1393 (% ee 99, tR=11.29 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C:9]=2[CH2:24][CH:25]=[CH2:26])=[O:5])[CH3:2]>C(Cl)Cl.CC#N.CC#N.Cl[Pd]Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[C:9]=2[CH:24]=[CH:25][CH3:26])=[O:5])[CH3:2]
Reactant: C=CCc1c(NC(=O)C(F)(F)F)ccc2c(=O)cc(C(=O)OCC)oc12
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: ClCCl
Product: CC=Cc1c(NC(=O)C(F)(F)F)ccc2c(=O)cc(C(=O)OCC)oc12
Temperature: 25 °C
Yield: 88 %

Procedure:
To 8-allyl-4-oxo-7-(2,2,2-trifluoro-acetylamino)-4H-chromene-2-carboxylic acid ethyl ester (12.2 g, 32 mmole) in 500 mL of methylene chloride was added 1.5 g (5.8 mmole) of bis(acetonitrile)palladium (II) chloride. The mixture was refluxed under nitrogen for 24 hours. Upon cooling to room temperature, the mixture was filtered through 75 g of silica gel, with additional methylene chloride as needed to fully elute the product. Concentration in vacuum gave 10.4 g of the title compound as a yellow solid, m.p. 140–141° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12].[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.CCOCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=1)=[O:12]
Reactant: CC(C)C(C(=O)O)c1cc2ccccc2s1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)c1cc2ccccc2s1
Reaction time: 8 h

Procedure:
A mixture of 2-(2-benzothienyl)-3-methylbutanoic acid (1 g, 4.3 mmol), 3-phenoxybenzyl bromide (1.1 g, 4.3 mmol) and K2CO3 (8.6 mmol) in 25 ml of THF/HMPA (1:1) is stirred overnight. The reaction is worked up by diluting with ether, washing with water, drying over Na2SO4, and solvent removed to yield 3-phenoxybenzyl 2-(2benzothienyl)-3-methylbutanoate which can be further purified by preparing thin layer chromatography eluting with 5 percent ether/hexane.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:19])([CH3:18])[CH:13]=[C:14]([F:17])[CH2:15][OH:16])=[CH:8][CH:7]=1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:16][CH2:15][C:14]([F:17])=[CH:13][C:12]([C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=1)([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(C)(C=C(F)CO)c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCC(F)=CC(C)(C)c1ccc(Cl)cc1
Yield: 87 %

Procedure:
The method of Example 11 was repeated using acetyl chloride (0.76 ml), 4-(4-chlorophenyl)-2-fluoro4-methylpent-2-enol (Example 8) (0.34 g), benzene (20 ml) and pyridine (0.15 ml) to yield the title compound (0.35 g, 87%).
Reaction SMILES: C([O:4][C:5]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C@@H:9]1[CH2:11][O:10]1)C=C.[C:24]1(C)[CH:29]=C(C)C=C(C)[CH:25]=1>>[CH2:29]([C:15]1[C:5]2[O:4][CH:9]([CH2:11][OH:10])[CH2:8][O:7][C:6]=2[CH:12]=[CH:13][C:14]=1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:24]=[CH2:25]
Reactant: C=CCOc1cc(OCc2ccccc2)ccc1OC[C@@H]1CO1
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1c(OCc2ccccc2)ccc2c1OC(CO)CO2
Reaction time: 15 h

Procedure:
A solution of (2S)-2-{[2-(allyloxy)-4-(benzyloxy)phenoxy]methyl}oxirane (28.5 g, 91.3 mmole) in 1 L of mesitylene was refluxed under nitrogen for 2 days. The solvent was then removed in vacuum and replaced with 500 mL of ethanol. Sodium bicarbonate (25.0 g) was added and the mixture was stirred under nitrogen for 15 hours. The mixture was filtered, the ethanol was removed in vacuum and 500 mL of methylene chloride added. This solution was washed with 500 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum to a dark oil. This was column chromatographed on silica gel with methylene chloride as eluant to give 15.6 g of the (S)-enantiomer of the title compound as a tan oil. 1H-NMR (CDCl3): multiplet 7.4 δ (5H); doublet 6.7 δ (1H); doublet 6.5 δ (1H); multiplet 6.0 δ (1H); singlet 5.05 δ (2H); multiplet 5.0 δ (2H); multiplet 4.3 δ (2H); doublet of doublets 4.1 δ (1H); doublet of doublets 3.8 δ (2H); multiplet 3.5 δ (2H), broad singlet 1.9 δ (1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:15])[CH3:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH:13]([OH:15])[CH3:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1c(C)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(C)O
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a solution of 1-(6-chloro-2-methyl-4-phenylquinolin-3-yl)ethanone (550 mg, 1.8 mmol) in methanol (10 ml) at room temperature was added portionwise sodium borohydride (315 mg, 8.3 mmol). After the addition the reaction was stirred for 3 hours. Most of the solvent was removed under reduced pressure, the residue diluted with ethyl acetate, and the mixture was poured into a separatory funnel. The organic layer was washed with water (2×), saturated sodium bicarbonate, then brine. The organic phase was separated and solvent removred under reduced pressure to provide 1-(6-chloro-2-methyl-4-phenylquinolin-3-yl)ethanol (460 mg, 83%) as a white powder. TLC Rf=0.4 using 1:1 ethyl acetate:hexanes as eluent. 1H NMR (CDCl3, 400 MHz) δ 7.88 (d, 1H, J=8.9 Hz); 7.54-7.42 (m, 4H); 7.18-7.08 (m, 3H); 5.05 (q, 1H, J=7.0 Hz); 2.95 (s, 3H); 1.0 (d, 3H, J=6.65 Hz). LCMS (CI) shows M+H 297.