Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:28])=[C:4]([CH:19]=[N:20][C:21]([O:23][Si](C)(C)C)=[CH2:22])[C:5]([O:8][CH2:9][CH2:10][O:11][Si](C(C)(C)C)(C)C)=[CH:6][CH:7]=1.C(OC([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([Cl:45])[CH:43]=2)/[C:38](=[CH:46]/[C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=2)/[C:37]1=[O:54])=O)(C)(C)C.CO>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([F:28])=[C:4]([CH:19]2[C:38]3([C:39]4[C:44](=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=4)[NH:36][C:37]3=[O:54])[CH:46]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=3)[CH2:23][C:21](=[O:22])[NH:20]2)[C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: C=C(N=Cc1c(OCCO[Si](C)(C)C(C)(C)C)ccc(Br)c1F)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2c(OCCO)ccc(Br)c2F)N1
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
To a solution of 1-{3-bromo-2-fluoro-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl}-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 183c in toluene (30 mL) was added E/Z-6-chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.5 g, 1.28 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 45 min. After the solution was cooled to room temperature, methanol (10 mL) was added. The reaction mixture was filtered through a short pad of celite gel and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane (20 mL) and trifluoroactic acid (15 mL) was added. After the reaction mixture was stirred at room temperature for 1 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was dissolved in tetrahydrofuran (10 mL) and tetrabutylammonium fluoride solution (1M in THF, 10 mL) was added. The reaction mixture was stirred at room temperature for 10 min, then poured into water and extracted with ethyl acetate. The combined organic layer was dried over MgSO4 and concentrated. The residue was purified by chromatography to give racemic (2′R,3R,4′S)-2′-[3-bromo-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 0.4 g, 65.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=2[CH2:15][OH:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[H][H].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([O:16][CH2:15][C:14]1[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH:19]([CH3:21])[CH3:20])[C:10]=1[S:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)n1c(Sc2cc(Cl)cc(Cl)c2)c(CO)n(C)c1=O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(Sc2cc(Cl)cc(Cl)c2)c(COCc2ccccc2)n(C)c1=O
Reaction time: 1 h

Procedure:
To 50 mg of 4-(3,5-dichlorophenylthio)-5-(hydroxymethyl)-3-isopropyl-1-methyl-1,3-dihydro-2-imidazolone in 1 ml of dimethylformamide was added 7 mg of sodium hydride (60% dispersion in oil). The reaction mixture was stirred at rt for 30 min until hydrogen gas evolution had ceased. The solution was then treated with 20 μL of benzyl bromide and stirring continued for 1 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, dried and evaporated to dryness to give 190 mg of an oily residue. This residue was purified by flash chromatography on silica gel using ethyl acetate/hexane (1:1) for the elution to give 55 mg of a colourless oil. Mass spectrum (ESI) m/z 437 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>>[Cl:8][C:5]1[CH:4]=[C:3]([CH3:9])[C:2]([Cl:1])=[CH:7][C:6]=1[S:11]([Cl:10])(=[O:13])=[O:12]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc(Cl)ccc1Cl
Product: Cc1cc(Cl)c(S(=O)(=O)Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A dry flask under argon was charged with chlorosulfonic acid (30 mL) and cooled to 0° C. 2,5-Dichlorotoluene (10 g, 62.1 mmol) was then added dropwise, and once the addition was complete, the reaction was heated to 60° C. and stirred for 30 min. After cooling to room temperature, the reaction mixture was poured slowly onto ice. The aqueous mixture was extracted twice with methylene chloride, and the organics were dried and concentrated to provide 2,5-dichloro-4-methylbenzenesulfonyl chloride (14.14 g, 88%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8]CC)=[O:7])[CH:3]=[N:2]1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[N:2]1[CH:3]=[C:4]([C:6]([OH:8])=[O:7])[CH:5]=[N:1]1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: C1=COCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cnn(C2CCCCO2)c1
Temperature: 80 °C

Procedure:
To 1.00 g (7.14 mmol) ethyl 4-pyrazolecarboxylate and 0.98 mL (10.7 mml) 3,4-dihydro-2H-pyran an 20 mL THF are added 0.94 mL (12.1 mmol) TFA and the reaction mixture is stirred at 80° C. over night. Afterwards the reaction mixture is diluted with DCM and charged with aq. NaHCO3 solution. The layers are separated and the org. layer is dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#N)=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-:12].[Na+].[CH2:16](OCC)[CH3:17]>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]=[CH:6][C:7]=1[C:8](=[O:12])[CH2:16][CH3:17]
Reactant: CCOCC
Reactant: Cc1ccncc1C#N
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: CCC(=O)c1cnccc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methylnicotinonitrile (5.90 g) in diethyl ether (75 ml) was cooled to 5° C. and an ethylmagnesium bromide diethyl ether solution (3.0M, 25 ml) was gradually added thereto. The reaction mixture was heated under reflux for 2 hrs. and added to 1N hydrochloric acid (200 ml). The mixture was stirred at room temperature for 30 min. Sodium bicarbonate was added to neutralize the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=3:1–2:1) for purification to give the title compound (5.07 g) as a pale-red oil.
Reaction SMILES: C(N(CC)CC)C.Cl[Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11].ClCCl.[C:19]([O:22][C@@H:23]1[C@@:34]([OH:36])([CH3:35])[CH2:33][CH2:32][C@@H:31]([OH:37])[CH2:30][C:29](=[O:38])[O:28][C@H:27](/[C:39](/[CH3:43])=[CH:40]/[CH:41]=[CH2:42])[C@@H:26]([CH3:44])[CH:25]=[CH:24]1)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:19]([O:22][C@@H:23]1[C@@:34]([OH:36])([CH3:35])[CH2:33][CH2:32][C@@H:31]([O:37][Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11])[CH2:30][C:29](=[O:38])[O:28][C@H:27](/[C:39](/[CH3:43])=[CH:40]/[CH:41]=[CH2:42])[C@@H:26]([CH3:44])[CH:25]=[CH:24]1)(=[O:21])[CH3:20]
Reactant: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](OC(C)=O)C=C[C@@H]1C
Reactant: CC[Si](Cl)(CC)CC
Agent: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](OC(C)=O)/C=C/[C@@H]1C
Agent: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O[Si](CC)(CC)CC)CC[C@@](C)(O)[C@@H](OC(C)=O)/C=C/[C@@H]1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O[Si](CC)(CC)CC)CC[C@@](C)(O)[C@@H](OC(C)=O)C=C[C@@H]1C
Reaction time: 5 h

Procedure:
Triethylamine (260 μl, 1.80 mmol), 4-dimethylaminopyridine (4.26 mg, 0.349 mmol) and chlorotriethylsilane (48 μl, 0.286 mmol) were added to an anhydrous dichloromethane (1.5 ml) solution of (2S,3S,4E,6S,7R,10R)-7,10-dihydroxy-3,7-dimethyl-2-[(1E)-1-methylbuta-1,3-dien-1-yl]-12-oxooxacyclododec-4-en-6-yl acetate (30.0 mg, 0.082 mmol) at room temperature and the reaction solution was stirred at the same temperature for five hours. The reaction solution was diluted with ethyl acetate and washed with a saturated sodium hydrogen carbonate aqueous solution, distilled water and brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto, commercial name Silica Gel 60N, 40-100 μm; heptane:ethyl acetate=1:2) to obtain the title compound (33 mg) as a white solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[N+:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:18]([O-:20])=[O:19])[CH:26]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2cccc([N+](=O)[O-])c2)o1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and 3-nitrophenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in a mixture of ethylene glycol dimethyl ether and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M in diethyl ether) was added and the solution was evaporated. Recrystallisation from methanol/diethyl ether gave the hydrochloride salt of the title compound as a yellow solid; MS (ES+) 342 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](O)=[N:7][C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:5][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:7][C:8]=2[Cl:23])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc3nc(Cl)ccc3c(O)n2)cc1
Product: COc1ccc(-c2cc3nc(Cl)ccc3c(Cl)n2)cc1
Yield: 96.2 %

Procedure:
2-Chloro-7-(4-methoxyphenyl)-[1,6]naphthyridin-5-ol (135 mg, 0.47 mmol) was dissolved in phosphorus oxychloride (2 mL, 21.5 mmol) and refluxed for 3 hours. An orange solid precipitated. The reaction mixture was diluted with dichloromethane (25 mL) and concentrated to an orange solid. The solid was re-dissolved in EtOAc (300mL) and washed with saturated sodium bicarbonate solution (100 mL), brine (100 mL) and dried over magnesium sulfate. Filtration and concentration yielded 2,5-dichloro-7-(4-methoxy-phenyl)-[1,6]naphthyridine (138 mg, 86%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:29](I)=[C:11]2[N:12]=[C:13]([CH3:28])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C:19]([NH:25][CH2:26][CH3:27])([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]3)[N:10]2[N:9]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>C(O)C.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:29]([C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)=[C:11]2[N:12]=[C:13]([CH3:28])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C:19]([NH:25][CH2:26][CH3:27])([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]3)[N:10]2[N:9]=1
Reactant: CCNC1(C(N)=O)CCN(c2nc(C)nc3c(I)c(-c4ccccc4Cl)nn23)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCNC1(C(N)=O)CCN(c2nc(C)nc3c(-c4ccc(F)cc4)c(-c4ccccc4Cl)nn23)CC1
Temperature: 80 °C
Yield: 266 %

Procedure:
A mixture of 1-[7-(2-chlorophenyl)-8-iodo-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl]4-ethylaminopiperidine-4-carboxylic acid amide (I-1A-1i; 20 mg, 0.037 mmol) and 4-fluorophenylboronic acid (7.8 mg, 0.056 mmol) in ethanol (1.3 ml), toluene (1.3 ml) and 2M aqueous Na2CO3 (0.3 ml) was degassed (3×) by pulling a vacuum followed by refilling with nitrogen gas. Tetrakis(triphenylphosphine)palladium (6 mg, 0.005 mmol) was added and the mixture was heated at 80° C. for 5 hours. After cooling to room temperature, the mixture was extracted from water with ethyl acetate, the combined organic layers were washed with brine, dried (MgSO4), filtered through a 0.45 μm filter disk, and then concentrated, in vacuo, to afford the crude product (50 mg). Purification on a Chromatotron using 0-3% methanol in methylene chloride as eluant afforded a light yellow oil, which was crystallized from diethyl ether, and dried, in vacuo, to afford 1A-1 (11 mg, 58%) as a colorless solid: +ESI MS (M+1) 508.4; 1H NMR (400 MHz, CD3OD) δ 7.46-7.34 (m, 4H), 7.32 (dd, J=8.7, 5.4 Hz, 2H), 6.96 (t, J=8.7 Hz), 4.70-4.58 (br m, 2H), 4.40-4.25 (br m, 2H), 2.51 (q, J=7.1 Hz, 2H), 2.46 (s, 3H), 2.20-2.12 (br m, 2H), 1.83-1.75 (m, 2H), 1.10 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.CCOC(C)=O>O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:14]2[CH2:15][O:16]2)=[CH:7][CH:6]=1
Reactant: ClCC1CO1
Reactant: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(OCC2CO2)cc1
Temperature: 100 °C
Yield: 48 %

Procedure:
A solution of NaOH (0.35 g) in 10 mL of water was added to a mixture of 4-methoxyphenol (1.10 g, 8.5 mmol) and epichlorohydrin (0.80 mL, 10.2 mmol). The mixture was heated at 100° C. for 3 h. After cooling, the mixture is taken up with AcOEt (50 mL). The organic phase was separated, washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (Petroleum ether/AcOEt, 4:1, as eluent) to afford pure compound in 48% yield. 1H NMR (CDCl3): δ 2.73-2.75 (m, 1H), 2.89 (app t, 1H), 3.31-3.36 (m, 1H), 3.76 (s, 3H), 3.88-3.93 (m, 1H), 4.14-4.20 (m, 1H), 6.81-6.88 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH:24](OCC)[C:23]3[CH:22]=[C:21]4[CH:28]=[CH:29][CH:30]=[CH:31][C:20]4=[CH:19][C:18]=3[C:17]2=[O:32])=[O:8])=[CH:5][CH:4]=1.[CH2:35]([O:37][C:38]([O:40][Si](C)(C)C)=[CH2:39])[CH3:36].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH:24]([CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:40])[C:23]3[CH:22]=[C:21]4[CH:28]=[CH:29][CH:30]=[CH:31][C:20]4=[CH:19][C:18]=3[C:17]2=[O:32])=[O:8])=[CH:33][CH:34]=1
Reactant: CCOC1c2cc3ccccc3cc2C(=O)N1c1ccccc1NC(=O)c1ccc(OC)cc1
Reactant: C=C(OCC)O[Si](C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CC1c2cc3ccccc3cc2C(=O)N1c1ccccc1NC(=O)c1ccc(OC)cc1
Yield: 50.9 %

Procedure:
A solution of N-(4-methoxybenzoyl)-2-(1-ethoxy-1,3-dihydro-3-oxo-2H-benz [f]isoindol-2-yl)benzeneamine (0.75 g, 1.7 mmol) and 1-ethoxy-1-trimethylsilyloxyethylene (0.80 g, 5.0 mmol) in methylene chloride at −78° C. was treated dropwise with boron triflouride etherate (0.23 mL, 1.8 mmol). Upon complete addition, the cooling bath was removed and the mixture was allowed to warm for 0.5 h. The mixture was poured into a mixture of ethyl acetate and aqueous saturated sodium bicarbonate solution. The organic layer was washed with water, saturated sodium chloride solution, dried (potassium carbonate), and filtered. Concentration and purification of the residue by radial chromatography (silica gel, hexanes/ethyl acetate) yielded 428 mg (44%) of the title compound. An analytical sample was obtained by recrystallization from ethyl acetate/hexanes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:12]([CH3:16])([CH3:15])[C:13]#[CH:14])(=O)C.CCN(CC)CC>C1COCC1.Cl[Cu]>[CH3:15][C:12]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:16])[C:13]#[CH:14]
Reactant: Nc1ccccc1
Reactant: C#CC(C)(C)OC(C)=O
Agent: Cl[Cu]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CC(C)(C)Nc1ccccc1
Yield: 65.9 %

Procedure:
A solution of aniline (19 mL, 0.20 mol), 3-acetoxy-3-methyl-1-butyne (26 g. 0.20 mol), CuCl (1.0 g, 10 mmol) and Et3N (28 mL, 0.20 mol) in THF (120 mL) was heated at reflux for 5 h and was filtered through a pad of Celite™. Removal of solvent and chromatography of the crude mixture (silica gel, EtOAc/hexane, 3/7) afforded 21 g (67%) of 3-methyl-3-phenylamino-1-butyne. Treatment of the aminobutyne with CuCl (0.70 mg, 7.0 mmol) in THF (200 mL) at 70° C. for 16 h followed by chromatography (silica gel, EtOAc/hexane, 3/7) afforded 13 g (60%) of 1,2-dihydro-2,2-dimethylquinoline (structure 75A of Scheme LII, where R1 =H, R2-3 =methyl). Treatment of the quinoline with di-tert-butyl dicarbonate (22 g, 0.10 mol) and DMAP (12 g, 0.10 mol) in THF (100 mL) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) afforded 15 g (71%) of 1-tert-butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline. 1-tert-Butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline (3.0 g, 11 mmol) in THF (30 mL) was treated with 1.0M BH3 -THF in THF (29 mL, 29 mmol) at rt for 3 h and was quenched with 3M KOH (20 mL). To the above solution 30% H2O2 (5 mL) was added and the mixture was stirred for 60 min, then 5mL of water was introduced. The mixture was extracted, washed with brine and concentrated. Chromatography of the crude mixture on a silica gel column using a 10-30% mixture of EtOAc/Hexane as eluents afforded a 2:1 mixture of two isomers (0.87 g, 3.1 mmol), which was oxidized with PCC (2.5 g, 11 mmol) in 60 mL of methylene chloride at rt for 60 min. Removal of solvent and chromatography of the black oil on a silica gel column using a 20% mixture of EtOAc and hexane as solvent afforded 0.58 g (68%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone as a white solid. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.93 (d, J=7.8, 1H), 7.42 (t, J=7.8, 1H), 7.31 (d, J=7.8, 1H), 7.02 (t, J=7.8, 1H), 2.73 (s, 2H), 1.56 (s, 9H), 1.49 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[C:6](I)[C:5]2=O.[C:14]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)#[CH:15].C(N(C(C)C)CC)(C)C.[NH2:32][NH2:33]>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.[Cu]I.CC#N>[NH2:20][C:19]1[CH:21]=[CH:22][C:16]([C:14]#[C:15][C:6]2[C:5]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=3[OH:8])=[N:32][NH:33][CH:7]=2)=[CH:17][CH:18]=1
Reactant: NN
Reactant: C#Cc1ccc(N)cc1
Reactant: O=c1c(I)coc2ccc(Cl)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1
Yield: 48.7 %

Procedure:
To a mixture of 6-chloro-3-iodo-chromone (1A, 6.12 g, 20 mmol) and 4-ethynylaniline (2.32 g, 24 mmol) and PdCl2(PPh3)2 (0.28 g, 0.4 mmol) and CuI (38 mg, 0.2 mmol) was added anhydrous CH3CN (200 mL). Upon stirring, diisopropylethylamine (DIPEA, 14 mL, 80 mmol) was added slowly to the above mixture. The reaction mixture was stirred at rt for 7 h. LCMS indicated all of 1A was consumed. Anhydrous hydrazine (5.3 mL, 80 mmol) was then added. The mixture was stirred at rt overnight. Solvent was removed. The residua was dissolved in dichloromethane and loaded onto a silica column eluting with dichloromethane/ethyl acetate (v/v 6/1, 2/1, 1/1, 1/2, 1/5) to afford the title compound 24A (3.02 g) as a yellowish solid in 48.7% yield. 1H NMR (CDCl3, 500 MHz) δ 10.05 (br s, 1H), 8.75 (d, 1H, J=2.0 Hz), 7.84 (s, 1H), 7.42 (d, 2H, J=8.5 Hz), 7.20 (dd, 1H, J=9.0, 2.0 Hz), 6.98 (d, 1H, J=8.5 Hz), 6.68 (d, 2H, J=8.0 Hz), 3.86 (s, 2H). LCMS (ESI) m/z 310.07 (MH+, 100); HPLC: tR=3.78 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:37])[CH2:9][O:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([F:36])[C:17]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[C:18]([CH:29]=2)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22]C(C)(C)C)=[O:12])=[C:4]([CH3:38])[CH:3]=1.Cl.C(N(CC)C(C)C)(C)C.[CH2:49](OC(ON1C(=O)CCC1=O)=O)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:37])[CH2:9][O:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([F:36])[C:17]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[C:18]([CH:29]=2)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:12])=[C:4]([CH3:38])[CH:3]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COCCCOc1c(F)cc(NC(=O)OC[C@H](C)c2ccc(Br)cc2C)cc1CN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCOc1c(F)cc(NC(=O)OC[C@H](C)c2ccc(Br)cc2C)cc1CN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 28B (450 mg, 0.753 mmol) in EtOAc (6 mL), was added HCl (4N, 6 mL). The mixture was stirred rt for 2 h, and concentrated. The residue was dissolved in DMF (10 ml), N,N-diisopropylethylamine (0.525 ml, 3.01 mmol) was added, followed by N-(benzyloxycarbonyloxy) succinimide (206 mg, 0.828 mmol). The mixture was stirred rt for 1 h, quenched with water, extracted with EtOAc (3×30 ml). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0-60% EtOAc in hexanes) to give 28C (376 mg, 0.595 mmol, 79% yield). MS (ESI) m/z: 631.0 (M+H)+.
Reaction SMILES: P(Cl)(Cl)Cl.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:8]2[S:7]1=O.C(OCC)(=O)C>CN(C)C=O>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][C:16]([Cl:17])([Cl:18])[Cl:19])=[O:13])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
Phosphorus trichloride (0.5 ml.) was dropwise added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate-1-oxide (0.72 g.) in dimethylformamide (5 ml.) and the mixture was stirred for 1 hour at the same temperature. After the reaction, the reaction mixture was poured into a mixture of ethyl acetate (40 ml.) and ice-water (40 ml.), and the ethyl acetate layer was separated. The aqueous layer was further extracted with ethyl acetate (10 ml.), and the ethyl acetate layer was combined. The combined solution was washed in turn with 5% hydrochloric acid, a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The dried solution was treated with activated charcoal and the solvent was distilled off. The residue was crystallized with a small amount of ether to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate (0.43 g.), mp 175° to 178° C.