Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:10]([O:13][CH3:14])[O:11][CH3:12])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH:10]([O:13][CH3:14])[O:11][CH3:12])=[C:4]([O:9][CH:16]([F:21])[F:20])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COC(OC)c1c(O)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)c1c(OC(F)F)ccc(F)c1Cl
Temperature: 90 °C
Yield: 62.8 %

Procedure:
In a single neck flask, 3-chloro-2-dimethoxymethyl-4-fluorophenol (22 g, 100 mmol), sodium chlorodifluoroactate (30.3 g, 200 mmol) and potassium carbonate (27.5 g, 200 mmol) were taken up in DMF (145 mL) under nitrogen atmosphere and heated at 90° C. for 16 h. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate (2×200 mL, 100 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated to give crude product, which was purified by column chromatography on silica gel using 10% ethyl acetate in hexane as an eluent to give 17 g (63% yield) of the title compound. 1H NMR (CDCl3, 300 MHz): δ=7.11-7.13 (m, 2H), 6.45 (t, J=75 Hz, 1H), 5.70 (s, 1H), 3.46 (s, 6H).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[I:10]I.[OH-].[K+]>CN(C=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+].O>[I:10][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][N:2]=1
Reactant: II
Reactant: c1cc2cn[nH]c2cn1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1n[nH]c2cnccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1H-pyrazolo[3,4-c]pyridine [271-47-6](4.00 g, 33.6 mmol) in DMF (50 mL) were added iodine (12.8 g, 50.4 mmol) and potassium hydroxide (4.70 g, 84.0 mmol). The reaction mixture was stirred at RT for 16 h. The mixture was diluted with 10% sodium thiosulfate and water, then extracted (3×) with EtOAc. The combined organic extracts were washed with brine, dried (Phase separator) and concentrated under vacuum. MS (LC/MS): 246.0 [M+H]+; tR (HPLC conditions d): 0.48 min.
Reaction SMILES: C(Cl)CCl.Cl.[O:6]=[C:7]1[NH:16][C:15]2[N:14]=[CH:13][C:12](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:11][C:10]=2[CH2:9][CH2:8]1.[OH:22][CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH2:34][NH:35][CH3:36])=[CH:26]1.C1C=CC2N(O)N=NC=2C=1.O.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:22][CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH2:34][N:35]([CH3:36])[C:19](=[O:21])/[CH:18]=[CH:17]/[C:12]2[CH:13]=[N:14][C:15]3[NH:16][C:7](=[O:6])[CH2:8][CH2:9][C:10]=3[CH:11]=2)=[CH:26]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1cn(CCO)c2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN(Cc1cn(CCO)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reaction time: 8 h
Yield: 27.1 %

Procedure:
EDC (0.54 g, 2.80 mmole) was added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt (0.71 g, 2.80 mmole), 1-(2-hydroxyethyl)-3-(methylaminomethyl)-1H-indole (0.52 g, 2.55 mmole), HOBt H2O (0.38 g., 2.80 mmole) and diisopropylethylamine (1.11 mL, 6.40 mmole) in DMF (25 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (20% EtOH/EtOAc) gave title compound (0.28 g, 27%) as an off-white solid after drying in vacuo: MS (ES) m/e 405 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][OH:13].C[O-].[Na+]>C(=O)=O.C(O)(C)C>[CH3:12][O:13][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CO
Agent: C[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ncc([N+](=O)[O-])cc1C
Temperature: 0 °C
Yield: 97 %

Procedure:
2-Chloro-3-methyl-5-nitropyridine (139 g, 0.806 mol) from the above procedure was divided into two portions and placed in two 2-L round bottom flasks with methanol (500 mL). The solutions were cooled in dry ice/isopropanol baths as solid sodium methoxide (26.5 g, 0.467 mol) was added portion-wise to each flask so that the temperature was remained below 20° C. When the additions were complete, the resulting mixtures were heated to reflux for 1 h. The mixtures were cooled and diluted with ice water (500 mL) to give white precipitates, which were collected by filtration. The combined filtrates were washed with water and air dried to give 2-methoxy-3-methyl-5-nitropyridine (127 g, 97% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J=2.0 Hz, 1H), 8.16 (s, 1H), 4.06 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.83, 141.91, 139.37, 132.92, 121.77, 54.83, 15.84. An analytical sample was recrystallized from hexane to give white needles, mp 95-96.5° C. Anal. calcd. for C7H8N2O3: C, 50.00, H, 4.79, N, 16.66. Found: C, 49.73, H, 5.02, N, 16.48.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[O:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35]2[NH:39][CH:38]=[N:37][N:36]=2)[CH2:30][CH2:29]1>>[F:27][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:18])[N:34]([CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)[C:35]2[N:36]([N:37]=[CH:38][N:39]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Reactant: c1nnc(NC2CCOCC2)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCOCC2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1.1 g) and N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.57 g, 81%).
Reaction SMILES: [F-].[Cs+].[Cl:3][C:4]1[CH:9]=[C:8]([S:10][Si](C(C)C)(C(C)C)C(C)C)[CH:7]=[CH:6][C:5]=1[NH:21][C:22](=[O:30])[C@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25].Br[C:32]1[CH:33]=[N:34][CH:35]=[C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:37]=1.C(OCC)(=O)C>CC(N(C)C)=O.[Cl-].[Na+].O.[Cu]Cl>[Cl:3][C:4]1[CH:9]=[C:8]([S:10][C:32]2[CH:33]=[N:34][CH:35]=[C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:37]=2)[CH:7]=[CH:6][C:5]=1[NH:21][C:22](=[O:30])[C@:23]([OH:29])([CH3:28])[C:24]([F:25])([F:26])[F:27]
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: CC(C)[Si](Sc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1)(C(C)C)C(C)C
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1cncc(Sc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)c1
Temperature: 155 °C
Reaction time: 17 h
Yield: 53 %

Procedure:
Caesium fluoride (0.26 g) was added to a solution of (R)-N-(2-chloro-4-(triisopropylsilylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3 trifluoropropanamide (0.74 g) (Method 28) in anhydrous DMA (5 ml) under argon and the mixture was stirred for 17 hours. Copper(I) chloride (0.17 g) followed by 3-bromo-5-carboethoxypyridine (0.37 g) were added and the mixture was heated to 155° C. for 4 hours and allowed to cool to ambient temperature. Ethyl acetate (20 ml) and brine (20 ml) were added and the mixture was filtered through a pad of diatomaceous earth which was washed with ethyl acetate (3×50 ml). The filtrates were combined, washed with brine (3×50 ml) and then dried. Volatile material was removed by evaporation and the residue was purified on a silica gel Mega Bond Elut column eluting with 10-40% ethyl acetate/iso-hexane to give the title compound (in 53% yield) as a foam. NMR (CDCl3): 1.39 (t, 3H), 1,57 (s, 3H), 4.00 (s, 1H), 4.40 (q, 2H), 7.34-7.37 (m, 1H), 7.46 (d, 1H), 8.18 (s, 1H), 8.42 (d, 1H), 8.62 (s, 1H), 9.03 (s, 1H), 9.04 (s, 1H); MS (ESP−): 447.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](C3C=CC(SC)=CC=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.[C:29](O)(=O)[CH3:30]>O.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([S:7]([C:1]3[CH:6]=[CH:5][C:29]([CH3:30])=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc1
Reactant: CC(=O)O
Agent: OO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-phenylsulfonyl-3-(4-methylthiophenyl)indole (8.89 g, 23.4 mmol) in glacial acetic acid (15 mL) was added 30% H2O2 solution (2.45 g, 72 mmol) and the resulting 2-phase mixture was heated at reflux for 30 min during which time it became a solid mass. The reaction mixture was cooled to ambient temperature and diluted with H2O and ethyl acetate and the solid was filtered off. The filtrate layers were separated and the organic phase was washed with saturated aqueous NaHCO3, H2O, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate/ether and the resulting solid was combined with the solid obtained above and recrystallized from ethyl acetate to give 8.15 g of 1-phenylsulfonyl-3-(4-methylphenylsulfonyl)indole. mp 188.9°-189.7° C.
Reaction SMILES: [F:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][CH2:8][CH2:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[C:25]3[N:24]=[C:23]([C:26]([F:29])([F:28])[F:27])[S:22][C:21]=3[NH:20][C:19]3[CH:30]=[CH:31][CH:32]=[CH:33][C:18]=3[N:17]=2)[CH2:11]1.C(N(C(C)C)CC)(C)C>ClCCl>[F:1][CH2:2][C:3]([N:15]1[CH2:14][CH2:13][N:12]([C:16]2[C:25]3[N:24]=[C:23]([C:26]([F:28])([F:29])[F:27])[S:22][C:21]=3[NH:20][C:19]3[CH:30]=[CH:31][CH:32]=[CH:33][C:18]=3[N:17]=2)[CH2:11][C@@H:10]1[CH2:9][CH2:8][O:7][CH3:6])=[O:4]
Reactant: O=C(Cl)CF
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1C(=O)CF
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Add a solution of fluoroacetyl chloride (0.133 g, 1.38 mmol) in anhydrous dichloromethane (1-2 mL) dropwise to a 0° C. solution of (S)-10-[3-(2-Methoxy-ethyl)-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.283 g, 0.688 mmol) and diisopropylethylamine (0.240 mL, 1.38 mmol) in anhydrous dichloromethane, and stir at 0° C. for 3 hours. Concentrate the reaction under reduced pressure to afford an oil. Purify the oil by flash chromatography, eluting with a gradient of a solution of 2% 2M ammonia in methanol, in dichloromethane (0-100% in dichloromethane over 30 minutes, then 100% for 28 minutes) to give the title compound: 0.18 g (56%). Mass spectrum (APCI+, m/e): 472 (M+1).
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=O)[C:7]2=[O:15].Cl.[NH2:17][NH:18][C:19]([NH2:21])=[S:20]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=[N:17][NH:18][C:19]([NH2:21])=[S:20])[C:7]2=[O:15]
Reactant: NNC(N)=S
Reactant: COc1ccc2c(=O)c(=O)c(=O)c2c1
Agent: Cl
Solvent: O
Product: COc1ccc2c(=O)c(=NNC(N)=S)c(=O)c2c1

Procedure:
5-methoxyindan-1,2,3-trione, monohydrate, thiosemicarbazide hydrochloride
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[OH:13]O>O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[N+:1]1([O-:13])[C:2]([C:10]([OH:12])=[O:11])=[CH:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cccc(C(=O)O)n1
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccc(C(=O)O)[n+]1[O-]
Temperature: 90 °C

Procedure:
50 g of pyridine-2,6-dicarboxylic acid was suspended in 275 g of water. 47 g of 30% hydrogen peroxide aqueous solution and 2.8 g of sodium tungstate were added to the resulting suspension. The suspension was heated to a temperature of 90° C. for 24 hours. As a result, the carboxylic acid as starting material was gradually dissolved in the aqueous solution during heating, and fresh crystals were then deposited. 24 g of 30% hydrogen peroxide aqueous solution was further added to the solution. The solution was heated for 12 hours and then allowed to cool to obtain 48 g of colorless prismatic creptais of pyridine-2,6-dicarboxylic acid N-oxide.
Reaction SMILES: [C:1]([C:3]([C:18]1[S:22][C:21](Br)=[CH:20][CH:19]=1)([CH:15]([CH3:17])[CH3:16])[CH2:4][CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])#[N:2].C([Li])CCC.CN(C)[CH:31]=[O:32].[Cl-].[NH4+]>O1CCCC1.CCCCCC.[Cl-].[Na+].O>[C:1]([C:3]([C:18]1[S:22][C:21]([CH:31]=[O:32])=[CH:20][CH:19]=1)([CH:15]([CH3:17])[CH3:16])[CH2:4][CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])#[N:2]
Reactant: CN(C)C=O
Reactant: CC(C)C(C#N)(CCCO[Si](C)(C)C(C)(C)C)c1ccc(Br)s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)C(C#N)(CCCO[Si](C)(C)C(C)(C)C)c1ccc(C=O)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of [4-cyano-5-methyl-4-(2-bromo-5-thienyl)hexyloxy]-t-butyldimethyl silane, 1.42 g 3.41 mmol, in tetrahydrofuran 20 ml was cooled to −70° C. A solution of 1.53 M butyl lithium in hexane 1.52 ml was added dropwise thereto and stirred for 10 minutes. N,N-dimethylformamide 1.52 ml was added thereto, and the temperature was raised to room temperature. Aqueous saturated ammonium chloride and brine were added to the reaction mixture which was then extracted with ether. The organic layer was washed with brine, dried over magnesium sulfate anhydride and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane system), whereby the title compound, 515 mg 1.41 mmol, 41.3%, was obtained as a yellow syrup.
Reaction SMILES: [C:1]([NH:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(=O)[CH3:2].[H-].COCCO[Al+]OCCOC.[Na+].[H-].C1(C)C=CC=CC=1.S(=O)(=O)(O)O.[Cl-].[Na+]>O1CCCC1>[CH2:1]([NH:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)[CH3:2]
Reactant: CC(=O)Nn1nnnc1S
Agent: COCCO[Al+]OCCOC
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCNn1nnnc1S
Yield: 66.9 %

Procedure:
1-Acetoamido-5-mercapto-1H-tetrazole (1.59 g) was dissolved in anhydrous tetrahydrofuran (27 ml), and the mixture was refluxed. 70% Sodium bis(2-methoxyethoxy)aluminum hydride-toluene solution (5 ml) was added dropwise thereto under stirring. After the addition, the mixture was refluxed for 4 hours. The reaction mixture was evaporated under reduced pressure to remove solvent. Ice-water was added to the residue, and the aqueous solution thus obtained was adjusted to pH 3 with 20% sulfuric acid. The mixture was salted out with sodium chloride, and extracted with ethyl acetate. The extracts were washed with a saturated sodium chloride solution, dried and then evaporated to remove solvent. The residue was recrystallized from isopropyl ether-hexane (1:2) to give 0.97 g of 1-ethylamino-5-mercapto-1H-tetrazole as colorless prisms. mp 90°-91° C.
Reaction SMILES: [I-].C(OC([NH:9][C@@H:10]1[C:40](=[O:41])[N:12]2[C:13]([C:24]([O:26]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:25])=[C:14]([CH2:17][N+:18]3[N:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[CH2:15][S:16][C@H:11]12)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl>[NH2:9][C@@H:10]1[C:40](=[O:41])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[N:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[CH2:15][S:16][C@H:11]12
Reactant: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Agent: [I-]
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: Cn1ccc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Yield: 176.6 %

Procedure:
To a solution of benzhydryl 7β-tert-butoxycarbonylamino-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (22.3 g) and anisole (22 ml) in methylene chloride (66 ml) was added trifluoroacetic acid (44 ml) under ice-cooling. After the mixture was stirred at ambient temperature for an hour, the reaction mixture was added dropwise to diisopropyl ether (600 ml). The resultant precipitates were collected by filtration to give bis(trifluoroacetic acid) salts of 7β-amino-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (16.83 g).
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13]3[C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][NH:4][CH2:3]1.Cl.Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][N:4]1[CH2:3][C:2](=[O:1])[C:14]2[C:13]3[C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5]1
Reactant: CN(C)CCCl
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CNC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(CCN(C)C)C3
Temperature: 50 °C
Yield: 38.1 %

Procedure:
Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (183 mg, 0.75 mol) was dissolved in DMF (20 ml) and 2-chloro-N,N-dimethylethanamine hydrochloride (107 mg, 0.75 mmol), and K2CO3 (207 mg, 1.5 mmol) were subsequently added. The reaction was stirred at 50° C. until the starting material was disappeared. The reaction mixture was then diluted with CH2Cl2 (15 ml) and washed with water three times. The organic layer was dried with MgSO4. Evaporation of most of the solvent and the crude product was purified by chromatography column on silica gel (elution with CH2Cl2/MeOH/NH3.H2O) to provide 0.09 g of methyl 2-(2-(dimethylamino)ethyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate. MS (ESI) m/e [M+1]+ 316.
Reaction SMILES: [OH:1][CH:2]([C:17]1[N:18]=[CH:19][N:20]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:21]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[CH:6]2.CN(C)C(=O)C.C(OC(C)C)(C)C>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[CH3:16][NH:15][C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([C:17]3[N:18]=[CH:19][N:20]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:21]=3)=[O:1])[CH:4]=2)[CH:9]=1)=[O:14]
Reactant: CNC(=O)c1ccc2cc(C(O)c3cn(S(=O)(=O)c4ccccc4)cn3)ccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CC(C)OC(C)C
Product: CNC(=O)c1ccc2cc(C(=O)c3cn(S(=O)(=O)c4ccccc4)cn3)ccc2c1
Temperature: 60 °C
Reaction time: 9.5 h
Yield: 71.4 %

Procedure:
6-(Hydroxy(1-(phenylsulfonyl)-1H-imidazol-4-yl)methyl)-N-methyl-2-naphthamide (8.8 g, 20.88 mmol) and manganese dioxide (16.4 g, 187.9 mmol) were added to N,N-dimethylacetamide (75 mL), and the mixture was stirred at 60° C. for 9.5 hr. The insoluble material was filtered off from the reaction mixture at 60° C., and washed with DMAc (35 mL). The filtrate and washing were combined, and cooled to 40° C., water (53 mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 0.5 hr or more, and then at room temperature for 1 hr or more to give crystals. The obtained crystals were collected by filtration, and washed with water (44 mL) to give wet crystals. The obtained wet crystals were dried under reduced pressure at an outside temperature of 50° C. to give crude crystals (6.3 g). Ethyl acetate (63 mL) was warmed to 40° C., and the crude crystals (6.3 g) were added thereto. The obtained mixture was warmed to 50° C., and stirred for 0.5 hr or more. 13 mL of the solvent was evaporated under reduced pressure to give a residue. The obtained residue was allowed to cool to room temperature, diisopropyl ether (53 mL) was added dropwise thereto at the same temperature, and the mixture was stirred to give crystals. The obtained crystals were collected by filtration, and washed with a mixed solvent (20 mL) of diisopropyl ether/ethyl acetate (1:1, volume ratio) to give wet crystals. The obtained wet crystals were dried under reduced pressure at an outside temperature of 50° C. to give N-methyl-6-[(1-(phenylsulfonyl)-1H-imidazol-4-yl)carbonyl]-2-naphthamide (6.2 g, 14.9 mmol). yield 72%.
Reaction SMILES: FC1C(NC2C=C(OC(C)C)NN=2)=NC([NH:10][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][OH:13])=C(C=1)C#N.[CH3:31][OH:32]>[Ni]>[NH2:10][C:11]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)([CH2:12][OH:13])[CH2:31][OH:32]
Reactant: CO
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(C#N)cc2F)n[nH]1
Agent: [Ni]
Product: NC(CO)(CO)c1ccc(F)cc1
Reaction time: 2 h
Yield: 61 %

Procedure:
A suspension of 2-(4-fluorophenyl)-2-nitroproane-1,3-diol (Method 11; 4.5 g, 20.9 mmol) and Raney nickel (0.45 g, 5.23 mmol) in MeOH (50 ml) was degassed and stirred under H2 (48 psi) for 2 hours. The catalyst was removed by filtration. The filtrate was concentrated and recrystallized from hexane:EtOAc (1:1) to give the title compound (2.35 g, 61%) as a white solid. NMR (400 MHz) 7.55 (m, 2H), 7.07 (m, 2H), 4.65 (t, J=5.2 Hz, 2H), 3.49 (m, 4H), 1.76 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].[C:28]1([C:34]#[CH:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCOCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:19]=[C:14]1[C:13]2[NH:20][CH:21]=[CH:22][C:12]=2[C:11]2[CH:10]=[C:9]([C:35]#[C:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:18]=[CH:17][C:16]=2[NH:15]1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: C#Cc1ccccc1
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CCC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(C#Cc3ccccc3)cc2c2cc[nH]c12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
20 mg (0.11 mmol) of copper iodide, 28 mg (0.27 mmol) of triethylamine and 14 mg (0.02 mmol) of dichlorobis(triphenylphosphine)-palladium (II) are added to a suspension of 80 mg (0.21 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 2.4 ml of anhydrous dioxan, then this mixture is degassed under argon. After 15 minutes, 32 mg (0.31 mmol) of phenylacetylene is added, then the mixture is heated at 100° C. for 3 hours. The raw reaction product is filtered on celite, the filtrate is evaporated to dryness and the residue is purified by chromatography on silica (eluent cyclohexane/ethyl acetate) to give 70 mg (93%) of 4-oxo-8-phenylethynyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a yellow solid.