Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([OH:12])=[C:9]([Br:11])[CH:10]=1)=[O:4].[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][CH2:19][C:15]2[N:14]([CH3:13])[CH:18]=[CH:17][N:16]=2)=[N:7][CH:6]=1
Reactant: Cn1ccnc1CO
Reactant: COC(=O)c1cnc(O)c(Br)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OCc2nccn2C)c(Br)c1
Reaction time: 1 h
Yield: 27.1 %

Procedure:
5-Bromo-6-hydroxy-3-pyridinecarboxylic acid methyl ester (1.0 g, 4.3 mmol) was suspended in tetrahydrofurane, 1-methyl-1H-imidazole-2-methanol (0.72 g, 6.5 mmol) and triphenylphosphine was added (1.70 g, 6.5 mmol). To this mixture was added with stirring diisopropyl-azodicarboxylate (1.35 mL, 6.5 mmol) at room temperature. Stirring was continued for 1 h at room temperature, solvent was removed and the residue was purified by chromatography with heptane/ethylacetate/methanol on silica gel to yield 0.38 g of the title compound as a colorless solid, MS (ISP) 326.0, 328.0 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9](Cl)=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:14]([NH2:16])=O)(=O)C.[OH-].[Na+].C([O-])(O)=O.[Na+]>Cl>[CH2:6]([C:5]1[N:4]=[C:14]([C@@H:5]2[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4]2)[NH:16][CH:14]=1)[CH2:7][CH3:8]
Reactant: CC(=O)N1c2ccc(Cl)cc2CC1C(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCc1c[nH]c([C@@H]2Cc3ccccc3N2)n1
Temperature: 100 °C

Procedure:
Compound (8) (0.00170 mol) was dissolved in HCl, 6N (20 ml), and immediately warmed in an oil bath at 100° C. under nitrogen for 200 minutes. The heat was turned off, and the sample was cooled to 0° C. 3 N NaOH (35 ml) was slowly added. Basification was completed with saturated NaHCO3. The sample was extracted with chloroform. The combined organic phases were dried, filtered, and the resulting solution was used without further purification in further synthesis, yielding (S)-2,3-dihydro-2-(4-propyl-1H-imidazol-2-yl)-1H-indole (intermediate 5).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH:3]=O.[CH2:9]([O:11][C:12](=[O:16])[CH2:13][C:14]#[N:15])[CH3:10].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:16])[C:13]([C:14]#[N:15])=[CH:1][C:2]([CH3:8])([CH3:3])[CH2:5][CH:6]=[CH2:7])[CH3:10]
Reactant: C=CCC(C)(C)C=O
Reactant: CCOC(=O)CC#N
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C=CCC(C)(C)C=C(C#N)C(=O)OCC

Procedure:
A solution of 2,2-dimethyl-pent-4-enal (5.0 g, 44 mmol), cyano-acetic acid ethyl ester (5.12 mL, 48 mmol), piperidine (1.3 mL, 14 mmol) and acetic acid (4.52 mL, 80 mmol) in 170 mL of toluene was heated under reflux for 18 hours in a flask equipped with a Dean-Stark separator. Several mL of water was collected in the trap. The reaction was cooled and washed with 1N HCl, NaHCO3 and brine, successively. The organic layers were dried over Na2SO4 and concentrated to an oil. This oil was chromatographed eluting with 20% of EtOAc in hexane to give a combination of two lots total 8.3 g (91%). 1H NMR (400 MHz; CDCl3) 1.28 (s, 6H), 1.32 (t, 3H, J=7 Hz), 2.26 (d, 2H, J=7.6 Hz), 4.27 (q, 2H, J=7.2 Hz), 5.08 (d, 1H, J=12 Hz), 5.10 (d, 1H, J=4 Hz), 5.72 (m, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](Cl)=[N:18][CH:19]=[N:20]3)=[CH:15][C:14]=2[O:24][CH3:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH:26][C:27]1[CH:28]=[C:29]2[C:33](=[N:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([O:26][C:27]4[CH:28]=[C:29]5[C:33](=[N:34][CH:35]=4)[NH:32][CH:31]=[CH:30]5)=[N:18][CH:19]=[N:20]3)=[CH:15][C:14]=2[O:24][CH3:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Oc1cnc2[nH]ccc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-chloro-6-methoxyquinazoline (224 mg, 0.61 mmol), (prepared as described for the starting material in Example 28), 5-hydroxy-7-azaindole (91 mg, 0.68 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (94 mg, 0.68 mmol) in DMA (5 ml) was stirred at 85° C. for 2 hours, allowed to cool to ambient temperature and the solvent evaporated under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (95/5) to give a white solid. This was triturated with acetone, filtered and dried to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-(7-azaindol-5-yloxy)-6-methoxyquinazoline (227 mg, 80%).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:40][CH:41]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([S:42]([NH:45][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH2:12][C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[S:8][CH:9]=3)[CH:15]=2)(=[O:44])=[O:43])=[CH:40][CH:41]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1cccc(OCc2csc(-c3ccccc3)n2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)c2cccc(OCc3csc(-c4ccccc4)n3)c2)cc1
Reaction time: 1 h
Yield: 18.3 %

Procedure:
To a solution of 5.48 g (0.0176 mol) of 3-[(2-phenyl-4-thiazolyl)methoxy]benzoic acid in 100 ml of toluene are added 3.24 g (0.0200 mol) of 1,1'-carbonyldiimidazole and the solution is stirred for 1 hour. To this solution, 3.01 g (0.0176 mol) p-toluenesulfonamide are added and the solution is refluxed for 16 hours. After cooling, the bottom layer is isolated and concentrated in vacuo to obtain a clear oil. The clear oil is dissolved in methylene chloride and is washed twice with pH 4 buffer solution, twice with water and is concentrated in vacuo to obtain a residue. Recrystallization from toluene/ethyl acetate gives 1.5 g (18%) of crystals, m.p. 170°-172° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10](#[N:12])[CH3:11].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[NH2:7][C:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:11][C:10]#[N:12]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CC=C(N)c1ccc(F)cc1
Reaction time: 24 h
Yield: 92.6 %

Procedure:
To a solution of 4-fluorobenzonitrile (5.00 g, 41.3 mmol) and acetonitrile (4.35 mL, 82.5 mmol) in toluene (100 mL) was added potassium tert-butoxide (13.9 g, 124 mmol). The mixture was stirred for 24 h, and then quenched by slow addition of aqueous sodium bicarbonate. The resulting suspension was extracted with dichloromethane (3×50 mL). The organic solution was washed with water, dried (Na2SO4), and concentrated under reduced pressure. The residue was triturated with EtOH/Et2O to afford 3-amino-3-(4-fluorophenyl)acrylonitrile (6.20 g, 93%) as a white solid. 1H NMR (300 MHz, acetone-d6) δ 4.23 (s, 1H), 6.20 (s, 2H), 7.22 (ddd, 2H), 7.71 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])=[N:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([C:3]3[CH:4]=[CH:5][O:1][N:2]=3)[CH:7]=2)=[O:26])=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: Nc1cccc(-c2ccon2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccon2)c1

Procedure:
Using the same method as in Example 15-(i), 3-(isoxazole-3-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(isoxazole-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 82%).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[C:5]1[CH2:6][S:7][C@@H:8]2[CH:28]([NH:29][C:30](=[O:60])/[C:31](/[C:35]3[N:36]=[C:37]([NH:40][C:41]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[S:38][CH:39]=3)=[N:32]\[O:33][CH3:34])[C:27](=[O:61])[N:9]2[C:10]=1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[I-:62].[Na+]>CC(C)=O.C(OCC)(=O)C>[I:62][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH2:6][S:7][C@@H:8]2[CH:28]([NH:29][C:30](=[O:60])/[C:31](/[C:35]3[N:36]=[C:37]([NH:40][C:41]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[S:38][CH:39]=3)=[N:32]\[O:33][CH3:34])[C:27](=[O:61])[N:9]2[C:10]=1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: [I-]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A mixture of diphenylmethyl 3-[(Z)-3-chloro-1-propen-1-yl]-7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-3-cephem-4-carboxylate (IXb) (392 mg, 0.45 mmol) and sodium iodide (204 mg, 1.36 mmol) in acetone (3.9 ml) was stirred at room temperature for 2 hours and diluted with ethyl acetate. The organic solution was successively washed with an aqueous sodium thiosulfate solution, water and brine, dried over anhydrous magnesium sulfate and concentrated to afford 394 mg (91% yield) of the title product.
Reaction SMILES: O.O.O.[F:4][C:5]([F:13])([F:12])[C:6]([C:8]([F:11])([F:10])[F:9])=[O:7].[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH2:17]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:4][C:5]([F:13])([F:12])[C:6]([C:20]1[CH:19]=[C:18]([CH3:22])[C:16]([NH2:17])=[C:15]([CH3:14])[CH:21]=1)([OH:7])[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Temperature: 130 °C
Reaction time: 14 h
Yield: 87 %

Procedure:
Hexafluoroacetone trihydrate (9.68 g, 44 mmol) was added to 2,6-dimethylaniline (4.84 g, 40 mmol) and p-toluenesulfonic acid (304 mg, 1.6 mmol) at room temperature. The mixture was stirred at 130° C. for 14 hours under a nitrogen atmosphere. After cooling down, the solidified mixture was washed with sodium bicarbonate solution, water, and hexane and dried to afford 10 g of 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2,6-dimethylaniline. 1H NMR (DMSO): δ 8.11 (s, 1H), 7.08 (s, 2H), 4.89 (s, 2H), 2.10 (s, 6H). MS (ES) m/z 288.1 ([M+H]+).
Reaction SMILES: [CH2:1](O)[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C>[Br:36][CH2:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC/C=C/CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCC/C=C/CCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of trans-oct-3-en-1-ol (1.28 g, 10.0 mmol) in DMF (25 mL) was added triphenylphosphine (2.92 g, 11.1 mmol). The solution was cooled to 0° C. and NBS (1.92 g, 10.8 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (100 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford trans-1-bromo-oct-3-ene (1.40 g, 73%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.54 (1H, m), 5.39 (1H, m), 3.37 (2H, t, J=7.2 Hz), 2.54 (2H, m), 2.02 (2H, m) 1.34 (4H, m), 0.89 (3H, t, J=7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 134.09, 126.45, 36.34, 33.21, 32.48, 31.73, 22.45, 14.24.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][O:7][CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])[N:3]=[CH:2]1.N1C=CC=C[CH:18]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>O.C(Cl)(Cl)Cl.C(O)C.C(N(CC)CC)C>[CH3:18][N:3]1[C:4]([CH2:6][O:7][CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[CH:5][N:1]=[CH:2]1
Reactant: OC(COCc1c[nH]cn1)c1ccccc1
Reactant: c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cn1cncc1COCC(O)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 500 mg of 2-[(imidazol-4-yl)methoxy]-1-phenylethanol, 1.1 ml of pyridine, 1.1 ml of triethylamine and 1.1 ml of acetic anhydride was stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature. The solvent was removed by distillation under reduced pressure. To the residue were added 1.1 ml of methyl iodide and 5 ml of acetonitrile. The mixture was allowed to stand at room temperature for 24 hours. The solvent was removed by distillation under reduced pressure. To the residue thus obtained were added 4 ml of ethanol and 6.8 ml of a 5% aqueous sodium hydroxide solution. The resulting mixture was stirred at room temperature for 6 hour. The solvent was removed by distillation under reduced pressure. To the residue thus obtained were added 30 ml of chloroform and 20 ml of water. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting oily product was purified by column chromatography (eluant: chloroform/ethanol=10/1). Diisopropyl ether was added to the resulting white crystals, and the resulting mixture was filtered to obtain 450 mg of 2-[(1-methylimidazol-5-yl)methoxy]-1-phenylethanol (compound No. 214).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:12][CH2:13][CH2:14][OH:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:12][CH2:13][CH2:14][OH:15])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OCCCO
Yield: 39.6 %

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (3.1 g, 20 mmol), 3-bromo-propan-1-ol (4.1 mL, 24 mmol), K2CO3 (5.5 g, 4 mmol) and KI (0.5 g) were mixed in DMF (20 mL). Then the mixture was irradiated under microwave at 200° C. for 1 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N NaOH. Then the organic layer was separated, dried over Na2SO4 and concentrated to give title compound (Yield: 1.7 g, 59%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[S:13]([CH2:15][CH2:16][CH2:17][OH:18])=[O:14].[CH3:19][O:20][CH:21]([O:32][CH3:33])[C:22]1[CH:27]=[C:26](Cl)[CH:25]=[CH:24][C:23]=1[N+:29]([O-:31])=[O:30].[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[S:13]([CH2:15][CH2:16][CH2:17][O:18][C:26]1[CH:25]=[CH:24][C:23]([N+:29]([O-:31])=[O:30])=[C:22]([CH:21]([O:20][CH3:19])[O:32][CH3:33])[CH:27]=1)=[O:14]
Reactant: Cc1ccccc1-n1ccnc1S(=O)CCCO
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(OC)c1cc(OCCCS(=O)c2nccn2-c2ccccc2C)ccc1[N+](=O)[O-]
Yield: 65.5 %

Procedure:
To 50 ml of dimethylformamide were added 2.9 g of 3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propanol and 3.4 g of 5-chloro-2-nitro-benzaldehyde dimethylacetal. To the mixture being stirred was added 0.75 g of 60% sodium hydride slowly. The mixture was stirred at 60° C. overnight. Thereto was added an aqueous solution saturated with ammonium chloride. The reaction mixture was concentrated. The residue was extracted with ethyl acetate. The extract was washed with water and an aqueous solution saturated with sodium chloride, dried with magnesium sulfate, and subjected to distillation to remove ethyl acetate. The residue was purified by a silica gel column chromatography (eluant: dichloromethane/methanol=1/0→50/1) to obtain 3.3 g of 1-(2-methylphenyl)-2-[3-(3-dimethoxymethyl-4-nitrophenoxy)propylsulfinyl]imidazole as a light yellow oil.
Reaction SMILES: C(Cl)Cl.[CH2:4]([C@:7]12[CH2:18][CH:13]3[O:14][C@@:15]1([O:16][CH3:17])[C@@H:11]([C@:12]3([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH2:10][CH:9]=[C:8]2[O:26][CH3:27])[CH:5]=[CH2:6].C(=O)([O-])[O-:29].[Cs+].[Cs+].O=O>[OH-].[Pd+2].[OH-].C(OO)(C)(C)C.CCOC(C)=O.CCCCCC>[CH2:4]([C@:7]12[CH2:18][CH:13]3[O:14][C@@:15]1([O:16][CH3:17])[C@@H:11]([C@:12]3([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:23])[CH3:24])[C:10](=[O:29])[CH:9]=[C:8]2[O:26][CH3:27])[CH:5]=[CH2:6]
Reactant: O=C([O-])[O-]
Reactant: C=CC[C@]12CC3O[C@@]1(OC)[C@H](CC=C2OC)[C@]3(C)CCC=C(C)C
Agent: [Pd+2]
Agent: CC(C)(C)OO
Agent: O=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: C=CC[C@]12CC3O[C@@]1(OC)[C@H](C(=O)C=C2OC)[C@]3(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 26.3 %

Procedure:
A DCM (0.5 mL) solution of 9 (3.3 mg, 9.9 mmol, 1 equiv.) and cesium carbonate (17.5 mg, 50 mmol, 5 equiv.) was cooled to 0° C. open to the air in a 10-mL heart-shaped flask, and palladium(II) hydroxide on carbon (20 wt % Pd, 0.3 mg, 0.50 mmol, 0.05 equiv.) and tert-butyl hydroperoxide (70 wt % in H2O, 5 μL, 50 μmol, 5 equiv.) were added sequentially. The flask was capped with a rubber septum, an oxygen-filled balloon was attached, and the flask was purged with oxygen. The flask was then placed in a 4° C. refrigerator and stirred vigorously. After 19.5 h, the slurry was diluted with DCM, warmed to room temperature, and filtered through a short plug of SiO2, rinsing with DCM followed by EtOAc. The resulting solution was concentrated in vacuo. Flash column chromatography (2 mL SiO2 in pipette, 9:1 to 4:1 to 1:1 hexane:EtOAc) afforded 0.9 mg (2.6 mmol, 26% yield) of 10 as a colorless residue. TLC Rf 0.56 (1:1 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 5.98 (td, J=17.1, 7.9 Hz, 1H), 5.35 (s, 1H), 5.06-5.01 (m, 2H), 4.99 (t, J=7.1 Hz, 1H), 3.91 (d, J=5.5 Hz, 1H), 3.71 (s, 3H), 3.48 (s, 3H), 2.69 (s, 1H), 2.53 (dd, J=14.2, 6.7 Hz, 1H), 2.39 (dd, J=14.2, 7.9 Hz, 1H), 2.06 (d, J=13.1 Hz, 1H), 2.04-1.98 (m, 2H), 1.73-1.67 (m, 1H), 1.64 (s, 3H), 1.55 (s, 3H), 1.43-1.36 (m, 1H), 1.34-1.28 (m, 1H), 1.25 (s, 3H). 13C NMR (125 MHz; CDCl3): δ 197.8, 180.7, 136.8, 132.1, 124.2, 117.3, 115.2, 100.9, 80.9, 56.8, 56.5, 52.1, 48.3, 48.1, 38.2, 38.0, 34.1, 27.8, 25.8, 22.8, 17.8. HRMS-ESI (m/z): [M+Na]+ calculated for C21H30O4, 369.2036. found, 369.2034.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=[O:13].OS(O)(=O)=O.[CH3:20][CH2:21]O>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([O:14][CH2:20][CH3:21])=[O:13]
Reactant: CCO
Reactant: COc1cccc(CC(=O)O)c1OC
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(OC)c1OC

Procedure:
To a solution of 2,3-dimethoxyphenylacetic acid (2.52 g, 12.8 mmol) in EtOH (abs.; 20 mL) was added H2SO4 (30 μL), and the solution was refluxed for 20 hours. The resultant solution was concentrated, dissolved in ether, and the ether solution was washed with NaHCO3/aq (2×30 mL) and brine, dried (MgSO4) and concentrated to yield the sub-title compound.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[NH2:9][C@@H:10]([CH3:26])[CH2:11][N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)=[N:13]1>>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[O:8])[CH3:26])[N:13]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cocn1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cocn1
Yield: 32.9 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 4-oxazolecarboxylic acid (0.212 g, 1.841 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.534 mmol). The product was triturated using diethyl ether. Yield 32.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.11 (d, 3H), 4.31 (dd, 1H), 4.38 (dd, 1H), 4.41-4.49 (m, 1H), 6.95 (d, 1H), 7.84 (d, 1H), 7.97-8.01 (m, 2H), 8.15 (dd, 1H), 8.52 (d, 1H), 8.52 (d, 1H), 8.59 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26]>C(N(CC)CC)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:32]([C:31]2[CH:35]=[CH:36][C:28]([O:27][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:29][CH:30]=2)=[O:33])=[CH:20][CH:21]=1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 41 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was suspended in triethylamine/methylene chloride (3 ml/2 ml), commercially available 4-butoxybenzoyl chloride (0.07 ml) was added, and the admixture was stirred at room temperature for 30 hours. The reaction mixture was then purified in the same manner as described in Example 62 to obtain 34 mg of the title compound (yield: 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:19](=[O:20])[N:18]([CH:21]([F:23])[F:22])[C:17]([CH3:24])=[N:16]2)=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=[O:7].[C:25]1([CH3:37])[CH:30]=[CH:29][C:28]([S:31]([N:34]=C=O)(=[O:33])=[O:32])=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:37][C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:34][C:6](=[O:7])[CH:5]([O:4][C:3]2[CH:10]=[C:11]([N:15]3[C:19](=[O:20])[N:18]([CH:21]([F:23])[F:22])[C:17]([CH3:24])=[N:16]3)[C:12]([F:14])=[CH:13][C:2]=2[Cl:1])[CH3:9])(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Cc1nn(-c2cc(OC(C)C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)C(C)Oc2cc(-n3nc(C)n(C(F)F)c3=O)c(F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.2 %

Procedure:
A stirred mixture of 0.78 g (0.0021 mole) of 2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionic acid, 0.42 g (0.0021 mole) of p-toluenesulfonyl isocyanate and 0.05 g (0.0004 mole) of 4-dimethylaminopyridine in 50 mL of toluene was heated at reflux for approximately 18 hours. The mixture was allowed to cool to room temperature and was stirred for 24 hours. The solvent was removed by evaporation at reduced pressure to leave a residue. This residue was purified by column chromatography on silica gel, eluting with toluene:ethyl acetate (1:1). The appropriate fractions were combined and evaporated under reduced pressure to yield 0.7 g of N-(4-methylphenylsulfonyl)-2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionamide as a solid, Compound C10.