Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]2[CH2:26][C@H:25]([OH:27])[CH2:24][C@@H:23]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][C:38]3=[O:43])=[CH:33][CH:32]=2)=[O:29])=[O:21])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]2[CH2:26][C:25](=[O:27])[CH2:24][C@@H:23]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][C:38]3=[O:43])=[CH:33][CH:32]=2)=[O:29])=[O:21])=[CH:15][CH:14]=1
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1C(=O)Nc1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1C[C@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2)N(C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.1 %

Procedure:
0.21 g (0.98 mmol) of pyridinium chlorochromate (PCC) is added to the solution of 0.3 g (0.65 mmol) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(1R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide (Example 7) in 15 ml of methylene chloride, and the reaction mixture is stirred at room temperature for 48 hours. The precipitate is subsequently filtered off, and the filtrate is washed three times with 20 ml of water each time and dried over sodium sulfate. After the solvent has been stripped off, the residue is purified by preparative HPLC, giving 140 mg (47%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(R)-4-oxopyrrolidine-1,2-dicarboxamide as a white powder, ESI 457, m.p. 154°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29](I)=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[O:35]1[CH2:40][CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH2:37][CH2:36]1>>[O:35]1[CH2:36][CH:37]=[C:38]([C:29]2[CH:30]=[C:31]([CH3:32])[C:26]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[C:10]4[C:6]=3[CH2:7][CH2:8][C@H:9]4[O:11][C:12]3[CH:25]=[CH:24][C:15]4[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=4[CH:13]=3)=[C:27]([CH3:34])[CH:28]=2)[CH2:39][CH2:40]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(I)cc5C)ccc(F)c43)ccc21
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C6=CCOCC6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4-iodo-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane following a procedure analogous to that described in Step 4 of Intermediate 2. LC (method 8): tR=0.92 min; Mass spectrum (ESI+): m/z=551 [M+Na]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:19]1CCOCC1.C(OC(Cl)=O)C(C)C.[OH-].[NH4+]>O1CCCC1.O>[C:12]([C:11]1[CH:15]=[CH:16][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:9]([CH3:17])[CH:10]=1)(=[O:13])[NH2:19]
Reactant: Cc1cc(C(=O)O)ccc1C(=O)OC(C)(C)C
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(N)=O)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-tert-butoxycarbonyl-3-methyl-benzoic acid (40 g) was suspended in tetrahydrofuran (160 mL). This solution was cooled to −30 C then N-methyl morpholine (18.7 mL) followed by isobutylchloroformate (24.2 mL) were added. A white precipitate appeared. The solution was stirred for 8 hours then a solution of ammonium hydroxide (100 mL) was added. The reaction mixture was slowly allowed to warm to room temperature over 48 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over sodium sulfate and concentrated to give a solid which was further triturated with a mixture of dichloromethane/ethyl acetate, filtered, to give tert-butyl 4-carbamoyl-2-methyl-benzoate (29.9 g) as a white solid. 1H-NMR (CDCl3, 400 MHz): 7.90 (d, 1 H), 7.72 (s, 1 H), 7.65 (d, 1 H), 2.63 (s, 3 H), 1.62 (s, 9 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1Br)=[O:4].[Cu](C#N)[C:13]#[N:14]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1[C:13]#[N:14])=[O:4]
Reactant: N#C[Cu]C#N
Reactant: COC(=O)c1sc(C)cc1Br
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1sc(C)cc1C#N
Temperature: 220 °C
Yield: 74.4 %

Procedure:
A mixture of 3-Bromo-5-methyl-thiophene-2-carboxylic acid methyl ester (0.54 g, 2.3 mmol), and Copper cyanide (0.27 g, 2.99 mmol) in NMP (3 ml) was heated in a microwave at 220° C. for 30 min. The reaction mixture was cooled and diluted with EtOAc. The organic layer was washed with aqueous NH4OH, and brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (0-20% EtOAc in hexane) to give 0.31 g (74%) white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH2:11]([N:13]([CH2:28][CH3:29])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH2:21])=[CH:16][CH:15]=1)[CH3:12].C([O-])(=O)C.[Na+]>ClCCCl.O>[CH2:28]([N:13]([CH2:11][CH3:12])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:21][CH:8]=[O:9])=[CH:16][CH:15]=1)[CH3:29]
Reactant: CN(C)C=O
Reactant: C=C(c1ccccc1)c1ccc(N(CC)CC)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)c1ccc(C(=CC=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 57 %

Procedure:
After adding dropwise 3.9 g of phosphorus oxychloride to a solution of 2.2 g of dimethylformamide (DMF) and 50 ml of 1,2-dichloroethane at from 0° to 5° C., the mixture was stirred at that temperature for 30 minutes. Then, a solution of 5.2 g of 1-(p-diethylaminophenyl)-1-phenylethylene in 50 ml of 1,2-dichloroethane solution was added dropwise thereto at that temperature over 30 minutes, and the mixture was reacted from 5 hours at room temperature. Hydrolysis was conducted with an addition of 100 cc of water containing 10 g of sodium acetate. After separating and water-washing an organic layer, the solvent was distilled off to obtain 4.8 g of an oily substance which was subsequently separated and purified on silica gel column chromatography to obtain 3.3 g (yield: 57% (theory)) of an oily product.
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[F:19][C:20]([F:40])([F:39])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:36][CH:35](O)[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=3)[O:28]2)=[CH:23][CH:22]=1>>[F:40][C:20]([F:19])([F:39])[C:21]1[CH:22]=[CH:23][C:24]([CH:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=3)[O:28]2)=[CH:25][CH:26]=1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccc(C(F)(F)F)cc1)O2
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: Oc1ccc2c(c1)CCC(c1ccc(C(F)(F)F)cc1)O2

Procedure:
2-(4-Trifluoromethyl phenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 730 mg of 2-(4-trifluoromethylphenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 8.82 (s, 1H), 7.75 (d, 2H, J 8.3 Hz), 7.65 (d, 2H, J 8.3 Hz), 6.67 (d, 1H, J 8.6 Hz), 6.53 (d, 1H, J 2.9 Hz), 6.51 (dd, 1H, 8.6, 2.9 Hz), 5.12 (d, 1H, J 8.3 Hz), 2.90 (m, 1H), 2.63 (m, 1H), 2.16 (m, 1H), 1.92 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([F:10])=[CH:8][C:7]([OH:11])=[CH:6][C:5]=1[F:12])([O-:3])=[O:2].[C:13](=O)([O-])[O-].[K+].[K+].IC.CN(C)C=O>O.C(OCC)(=O)C>[N+:1]([C:4]1[C:5]([F:12])=[CH:6][C:7]([O:11][CH3:13])=[CH:8][C:9]=1[F:10])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1c(F)cc(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(F)c([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-nitro-3,5-difluorophenol (D10) (440 mg, 2.5 mmol), potassium carbonate (600 mg, 4.6 mmol), iodomethane (1 ml), and dimethylformamide (5 ml) stirred overnight at room temperature then ethyl acetate and water added and the solution washed with water then dried over MgSO4, filtered and evaporated to yield the title compound, pale brown oil, 370 mg.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:25]=[CH:24][C:17]([CH:18]=[CH:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[O:9][C:8]2=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[C].[Pd].O1CCCC1>[C:1]1([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:25]=[CH:24][C:17]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[O:9][C:8]2=[O:26])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C=Cc1ccc(OCC2CN(c3ccccc3)C(=O)O2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCC2CN(c3ccccc3)C(=O)O2)cc1
Yield: 90.3 %

Procedure:
A 200 mg quantity of 10% palladium carbon was added to a tetrahydrofuran (50 ml) solution of 1.75 g of methyl 4-(3-phenyl-2-oxooxazolidin-5-yl)methoxycinnamate (compound 185) obtained in Example 29. The mixture was stirred at room temperature for 2.5 hours in a stream of hydrogen at 3 atmospheric pressure. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and washed with methanol to give 1.59 g of the title compound (compound 189) in a yield of 88%.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:18]C(=O)C(Br)C1C=CC=CC=1.NC1C=CC=CC=1S>CN(C=O)C.CCOC(C)=O.O>[C:1]1([CH:7]2[C:12](=[O:18])[NH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: c1ccc(C2CNc3ccccc3S2)cc1
Agent: Nc1ccccc1S
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2SC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Phenyl-3,4-dihydro-2H-1,4-benzothiazine: To bromo-phenyl-acetic acid methyl ester (4.88 g, 21 mmol) in DMF (15 mL) under an argon atmosphere was added 2-amino-benzenethiol (2.3 mL, 21 mmol) and the reaction was stirred at rt overnight. The reaction mixture was diluted with EtOAc (5 mL) and water (50 mL) and the crude product was collected by filtration, washed with warm EtOAc, and dried to give 2-phenyl-4H-1,4-benzothiazin-3-one as a white solid (3.49 g). LC/MS m/z 242 (M+H)+. To this intermediate (3.48 g, 14.4 mmol) in THF (50 mL) under an argon atmosphere was added 1M BH3.THF (50 mL, 50 mmol) and the reaction was stirred at rt overnight. The reaction was quenched with 1N HCl and extracted with ether. The combined organic fractions were dried over MgSO4 and concentrated. 201A was purified by recrystallization from hot EtOAc/hexanes to yield pale pink crystals (1.5 g). LC/MS m/z 228.2 (M+H)+.
Reaction SMILES: CC1(C)[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-:21])=[O:20])[CH:8]=2)=N1.C[OH:24].O>S(=O)(=O)(O)O>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:4]([O:5][CH3:6])=[O:24])([O-:21])=[O:20]
Reactant: CO
Reactant: CC1(C)COC(c2cccc(-c3ccccc3[N+](=O)[O-])c2)=N1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cccc(-c2ccccc2[N+](=O)[O-])c1

Procedure:
4,4-Dimethyl-2-[3-(2-nitrophenyl)phenyl]4,5-dihydrooxazole (1.7 g) was heated to reflux for 19 hours in 95% methanolic sulfuric acid (28.7 ml) (prepared by mixing methanol (15 ml), concentrated sulfuric acid (1.15 ml), and water (1.44 ml) and bringing the total volume to 28.7 ml with additional methanol). After cooling, the solution was concentrated to ca. 7 ml and poured into ether (60 ml). The ethereal solution was washed with aqueous potassium carbonate solution and brine,then dried over magnesium sulfate and concentrated in vacuo to yield methyl 3-(2-nitrophenyl)benzoate as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][Br:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(OCc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cccc(OCc2ccccc2)c1
Reaction time: 4 h
Yield: 88.9 %

Procedure:
3-Benzyloxybenzyl alcohol (5.00 g) was dissolved in methylene chloride (70 ml), triphenylphosphine (6.52 g) and N-bromosuccinimide (4.43 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 4 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the object product (5.75 g) as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=O.[S:37]1([CH2:43][CH2:42][CH:41]([NH:44][NH2:45])[CH2:40]1)(=[O:39])=[O:38].Cl>O1CCCC1.O>[S:37]1([CH2:43][CH2:42][CH:41]([NH:44][N:45]=[CH:1][C:3]2[CH2:4][S:5][C@@H:6]3[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[C:25](=[O:36])[N:7]3[C:8]=2[C:9]([O:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:10])[CH2:40]1)(=[O:39])=[O:38]
Reactant: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: NNC1CCS(=O)(=O)C1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=NNC3CCS(=O)(=O)C3)CS[C@H]12
Reaction time: 5 h
Yield: 73 %

Procedure:
To a solution of diphenylmethyl 3-formyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (155 mg) in tetrahydrofuran (15 ml) is added a solution of (sulfolane-3-yl) hydrazine (70 mg) and 1.5 equivalents of hydrochloric acid in water (3 ml), and the mixture is kept at room temperature 5 hours. The crystals obtained by concentration of the reaction mixture are collected by filtration, washed with ether and water, and dried to give diphenylmethyl 3-(sulfolan-3-ylhydrazono)methyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (142 mg). m.p. 117°-125° C. Yield: 76%. IR: νmaxNujol 3275, 1785, 1715, 1675, 1530cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][NH:14][O:15][CH3:16].CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1ccc(O)cc1O
Agent: Cl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a cooled solution of 2,4-dihydroxybenzoic acid (8 g, 52 mmol), N,O-dimethylhydroxylamine hydrochloride (6.1 g, 62 mmol) and N-methylmorpholine (13.18 g, 130 mmol) in methylene chloride (50 mL) at 0° C. was added EDC batchwise (11.95 g, 62.3 mmol). Stirred at room temperature for 3 days. The reaction was quenched by the addition of water and then extracted with methylene chloride (2 times). The combined organic extracts were successively washed with a 10% aqueous citric acid solution, a 5% sodium bicarbonate solution, water and saturated salt solution and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-33% ethyl acetate in hexanes to yield the title compound, mass spectrum (CI) m/e=198 (M+1)+.
Reaction SMILES: [C:1](O)(=O)[CH2:2]C.[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O.[CH3:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[C:31](=[O:32])[C:20]=12.N>O.S(=O)(=O)(O)O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([C:23]1[N:22]=[C:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[C:31](=[O:32])[C:20]2=[C:19]([CH3:18])[CH:24]=1)[CH3:2]
Reactant: Cc1ccnc2c1C(=O)c1ccccc1-2
Reactant: CCC(=O)O
Agent: [Ag+]
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1cc(C)c2c(n1)-c1ccccc1C2=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 418 %

Procedure:
At 25° C., 3.6 g of silver nitrate (0.018 mol) and 26.4 g (0.3 mol) of propionic acid and, at 70° C. in the course of 40 minutes, a solution of 27.4 g (0.12 mol) of ammonium peroxodisulfate in 60 ml of water were added dropwise to a solution of 11.7 g (0.006 mol) of 4-methyl-5H-indeno[3,2-b]pyridin-5-one in 130 ml of 2N sulfuric acid. The mixture was stirred at 80° C. for a further 90 minutes, then cooled and rendered alkaline at about 10° C. with a 28% strength aqueous ammonia solution and extracted three times with methylene chloride, and the combined organic extracts were washed with 50 ml of water and concentrated. The residue was crystallized at 0° C. using 5 ml of diethyl ether. 5.6 g (41.8% of theory) of 2-ethyl-4-methyl-5H-indeno[3,2-b]pyridin-5-one were obtained as slightly yellow crystals of m.p. 68°-70° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:10])[CH:8]=[CH2:9].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])[CH:8]=[CH2:9]
Reactant: C=CC(=O)Cl
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Benzene (1 mL), acryloyl chloride (0.4 mL), and aluminium chloride (0.33 g) were added to dichloromethane (4 mL), followed by stirring at 0° C. for 2 hours. After reaction, 1 N hydrochloric acid and dichlormethane (5 mL) were added in order. The organic phase was concentrated. The obtained residue was applied to a silica gel column to obtain the title compound (120 mg).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[C:12](=O)[CH3:13].[S-:15][C:16]#[N:17].[K+].Cl>C(O)C.O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[NH:3][C:16](=[S:15])[NH:17][CH:12]2[CH3:13]
Reactant: N#C[S-]
Reactant: COc1cccc(C(C)=O)c1N
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cccc2c1NC(=S)NC2C
Temperature: 65 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Under an atmosphere of nitrogen and at a temperature of 65° C., sodium borohydride (154 mg, 4 mmol) was added to a solution of 1-(2-amino-3-methoxy-phenyl)-ethanone (960 mg, 6 mmol) in ethanol (8 ml). After stirring at 65° C. overnight, water (5 ml), a solution of potassium thiocyanate (620 mg, 6 mmol) in water (3 ml), and a solution of conc. HCl (3 ml) in water (4 ml) were added subsequently. The mixture was then stirred for an additional 3 h at 65° C. Upon cooling, the solvent was evaporated and the residue was taken up in water/ethyl acetate. The organic phase was dried (Na2SO4), and the solvent was evaporated. Chromatography (silica gel, heptan/ethyl acetate=100/0-70/30) gave the title compound (700 mg, 58%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[N:9]=2)[CH2:4][CH2:3][CH2:2]1.[ClH:19]>>[ClH:19].[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCc1ccc2c(n1)NCCC2
Agent: Cl
Product: O=C(O)CCCc1ccc2c(n1)NCCC2

Procedure:
Ester 2-4 (1.8 g, 7.25 mmol) in 36 mL 6 N HCl was heated at 50° C. for 4 h, then concentrated, providing 2-5 as a yellow solid.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:7][C@H:6]([OH:8])[C@@H:5]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=2)[CH2:4][CH2:3]1>CCCCCC.C(O)(C)C>[F:23][C:2]1([F:1])[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(Cn2cc([C@H]3CCC(F)(F)C[C@@H]3O)cn2)cc1
Solvent: CC(C)O
Solvent: CCCCCC
Product: COc1ccc(Cn2cc([C@@H]3CCC(F)(F)C[C@H]3O)cn2)cc1

Procedure:
The (1S*,2R*)-5,5-difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexanol prepared in Example 143d was optically resolved with CHIRALPAK IA (Daicel Corp.; hexane/isopropanol=8:2) to yield the title compound as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:14](=[O:18])(=O)(O)[OH:15]>C1(S(O)(=O)=O)C=CC=CC=1.ClC1C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[C:11]([S:14]([C:11]3[CH:10]=[CH:9][C:8]([OH:13])=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:12]=3)(=[O:18])=[O:15])[CH:10]=[CH:9][C:8]=2[OH:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccccc1-c1ccccc1
Agent: O=S(=O)(O)c1ccccc1
Solvent: Clc1ccccc1
Product: O=S(=O)(c1ccc(O)c(-c2ccccc2)c1)c1ccc(O)c(-c2ccccc2)c1
Reaction time: 10 h
Yield: 85 %

Procedure:
To a mixture of 391 g (2.3 mol) of o-phenylphenol, 100 g (1 mol) of 98% by weight sulfuric acid, and 100 g of chlorobenzene was added 9.5 g (0.05 mol) of benzenesulfonic acid and heated with stirring. While the generated water was distilled away with chlorobenzene and the organic phase of the distillate was refluxed into the reaction vessel, the reaction was carried out for 10 hours. At the time when the distilled water amounted to 36 milliliters and the temperature in the reaction vessel rose to 165° C., the reaction mixture was cooled by adding 500 milliliters of xylene to precipitate crystals. The crystals were recrystallized from acetone-cyclohexane mixture solution to obtain 340 g of a product (yield: 85%). The melting point of the product was between 251° to 252° C. and the results of 1H-NMR (acetone d6) were as follows.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:15]([O-:17])=[O:16])[C:6]([C:12]([OH:14])=O)=[N:7][C:8]=1[O:9][CH2:10][CH3:11])#[N:2].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.Cl.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[S:51][C:52]([CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([CH2:62][NH2:63])[CH2:58][CH2:57]2)=[CH:53][N:54]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[C:5]([N+:15]([O-:17])=[O:16])[C:6]([C:12]([NH:63][CH2:62][CH:59]2[CH2:60][CH2:61][N:56]([CH2:55][C:52]3[S:51][C:50]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=4)=[N:54][CH:53]=3)[CH2:57][CH2:58]2)=[O:14])=[N:7][C:8]=1[O:9][CH2:10][CH3:11])#[N:2]
Reactant: CCOc1nc(C(=O)O)c([N+](=O)[O-])cc1C#N
Reactant: NCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)c([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 47.2 %

Procedure:
To a stirred solution of the compound prepared in Example 447 (94 mg) and 1-hydroxybenzotriazole hydrate (67 mg) in N,N-dimethylformamide (2.5 mL) at ambient temperature was added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (84 mg). The resulting solution was stirred at ambient temperature for 40 minutes, and then the compound prepared in Example 214 (189 mg) was added, followed immediately by N,N-diisopropylethylamine (0.35 mL). The resulting mixture was stirred at ambient temperature for 1 hr 50 minutes, and then diluted with water (25 mL). After stirring for 30 minutes, the resulting precipitate was collected by filtration, washed with a small amount of water, and dried under vacuum to provide the title compound (95 mg) with the following physical data.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([C:19](=[O:20])[CH:2]=[CH:1][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][CH:5]=2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1cccc2ccccc12
Product: O=C(C=Cc1cccc2ccccc12)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from commercial 1-acetylnaphthalene and 4-chlorobenzaldehyde, 1-(4-chlorophenyl)-3-(1-naphthalenyl)prop-2-en-1-one was obtained as yellow solid.