Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15]CC3C=CC=CC=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[CH:7]=1)=O.O.[PH2]([O-])=O.[Na+]>O1CCOCC1.O.[Pd]>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[N:8]([CH3:23])[CH:7]=1
Reactant: COC(=O)C(=O)c1cn(C)c2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)Cc1cn(C)c2cc(O)ccc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 52.1 %

Procedure:
To a solution of (6-benzyloxy-1-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.68 g, 2.10 mmol) in 1,4-dioxane (12 mL) is added a slurry of Pd/C (10%, 0.25 g). The flask is evacuated and re-filled with N2 three times. The mixture is heated to 100° C. and a solution of sodium hypophosphite, hydrate (5.0 g, 47 mmol) in water (5 mL) is added dropwise. The mixture is stirred at 100° C. for 16 hours and cooled to room temperature. The mixture is filtered through a pad of diatomaceous earth and the filtrate is concentrated under reduced pressure. The residue is purified via silica gel chromatography eluting with 25-50% EtOAc/Hexanes to provide the title compound (0.24 g, 52%). ES/MS m/e 220.0 (M+1), 218.0 (M−1).
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1C[CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C[C@@H]1CCN1C(OC(C)(C)C)=O)C1C=CC=CC=1>>[O:1]([CH2:8][C@@H:9]1[CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:15])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C1=O
Agent: CC(C)(C)OC(=O)N1CC[C@H]1COc1ccccc1
Product: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Yield: 63 %

Procedure:
(S)-5-(2-Phenoxymethyl-azetidine-1-sulfonyl)-1H-indole-2,3-dione (17) was prepared according to the same procedure for compound 10, except using compound 16, and purified with ether to afford 715 mg (63%) of 17 as a yellow solid, mp 173.2-174.5° C. 1H NMR (300 MHz, DMSO) δ 11.48 (s, 1H), 7.98 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.77 (s, 1H), 7.27 (m, 2H), 7.10 (d, J=8.1 Hz, 1H), 6.91 (d, J=7.8 Hz, 3H), 4.20-4.02 (m, 3H), 3.70 (m, 1H), 3.55 (m, 1H), 2.22 (m, 1H), 2.02 (m, 1H). LRMS (FAB) m/e: 373.0 (M+H, 100). Anal. Calcd for C18H16N2O5S.0.5H2O: C, 56.68, H, 4.49; N, 7.34. Found: C, 56.96, H, 4.39; N, 7.30.
Reaction SMILES: C([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:25][CH3:26])=[CH:10][CH:9]=1)(=O)CC.[Li+].[OH-]>CO.C1COCC1>[CH2:25]([C:15]1[N:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][OH:5])=[CH:13][CH:12]=2)[C:18]2=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]2[N:16]=1)[CH3:26]
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3c(C)cc(C)nc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl propionate (step 5, 1.75 g, 5.1 mmol) in methanol/THF (v/v, 1:1, 28 mL) was added 4N aqueous LiOH (4.6 mL, 18.4 mmol) and the resulting mixture was stirred at room temperature. After 3 h, the mixture was concentrated. The residue was dissolved in water (30 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 2:1 to 0:1) to afford 1.3 g (86%) of the title compound as pale brown solids: 1H-NMR (CDCl3) δ 7.40 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 6.91 (1H, s), 3.81–3.75 (2H, m), 3.47 (1H, br.s), 2.92 (2H, t, J=6.9 Hz), 2.81 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.51 (3H, s), 1.27 (3H, t, J=7.6 Hz).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:26]([O-])([OH:28])=[O:27].[N+]([O-])([O-])=O.[Na+].O>C(O)(=O)C>[C:7]1([C:6]2[C:5]3[CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:4]=3[O:3][C:2]=2[N+:26]([O-:28])=[O:27])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)c(Br)oc12
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
A solution of 6 g. (0.018 mole) of the product of step E in hot acetic acid is treated with 6 ml. of 70 percent nitric acid while the solution is maintained at about 80° C. Sodium nitrate (2.7 g., 2 equivalents) is added gradually, and the mixture is heated on a steam bath for 45 minutes. The mixture is then poured into 500 ml. of water. The solid is filtered, recrystallized twice from acetone, then from an ethyl acetate-hexane mixture to provide yellow crystals of 3,5-diphenyl-2-nitrobenzofuran-7-carboxylic acid, m.p. 207°-209° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=2.[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19]>>[C:17]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:3][O:2][CH3:1])(=[O:21])[CH:18]([CH3:20])[CH3:19]
Reactant: COCc1cc2ccc(C(=O)OC)cc2[nH]1
Reactant: CC(C)C(=O)Cl
Product: COCc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C

Procedure:
Methyl 3-isobutyryl-2-methoxymethylindole-6-carboxylate (146 mg) was prepared from methyl 2-methoxymethylindole-6-carboxylate (396 mg) and isobutyryl chloride (0.53 ml) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9](=[O:11])[CH3:10].CN(C=O)C.[Cl:17][C:18]1[C:27]([OH:28])=[C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>O>[Cl:17][C:18]1[C:27]([O:28][CH2:8][C:9]([CH3:10])=[O:11])=[C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CC(=O)CCl
Reactant: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1OCC(C)=O
Temperature: 80 °C

Procedure:
0.922 g (7.2 mmol) of K2CO3, 0.179 g (1.10 mmol) of KI and 0.454 g (4.7 mmol) of chloroacetone were introduced into 30 ml of DMF. 1.000 g (3.6 mmol) of methyl 2-chloro-3-hydroxy-4-ethylsulfonylbenzoate were added at RT and the mixture was then heated for 4 hours at 80° C. The mixture was then poured into water and extracted with diisopropyl ether. The combined organic phases were washed with water, dried over Na2SO4 and evaporated to dryness. The resulting crude methyl 2-chloro-3-(methylcarbonylmethoxy)-4-ethylsulfonyl benzoate viscous oil was sufficiently pure for the subsequent reactions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([O:31]CC4C=CC=CC=4)=[CH:27][CH:26]=3)=[C:9]2[CH3:39])=[CH:4][CH:3]=1>CCO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)=[CH:11][C:10]([CH2:23][O:24][C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)=[C:9]2[CH3:39])=[CH:6][CH:7]=1
Reactant: Cc1c(COc2ccc(OCc3ccccc3)cc2)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1c(COc2ccc(O)cc2)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1

Procedure:
Compound 8 (from Example B) (1 mmol.) is dissolved in EtOH (25 mL) and 10% Pd/C (25 mg) is added. The reaction mixture is stirred under an atmosphere of H2 and monitored by tlc. When the reaction is complete, the solution is filtered and evaporated to afford a residue which, after purification by HPLC, affords title compound 9.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:14][C:15]1[C:21]([Cl:22])=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[Cl:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:71]1[CH:80]=[CH:79][CH:78]=[CH:77][C:72]=1[C:73]([O:75][CH3:76])=[O:74]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:7]([O:14][C:15]1[C:16]([Cl:23])=[CH:17][C:18]([NH:19][C:71]2[CH:80]=[CH:79][CH:78]=[CH:77][C:72]=2[C:73]([O:75][CH3:76])=[O:74])=[CH:20][C:21]=1[Cl:22])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Reactant: COC(=O)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1Nc1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Temperature: 100 °C
Yield: 94 %

Procedure:
Cesium carbonate (5.98 g, 19 mmol) was added to a stirring solution of 4-(benzyloxy)-3,5-dichloroaniline (5.27 g [crude from previous step], 19 mmol) in toluene. Rac-BINAP (0.6 g, 7.5 mol %) and methyl 2-bromobenzoate (1.84 ml 13 mmol,) were added. Palladium(II) acetate (0.147 g, 5 mol %) was added and the mixture heated to 100° C. After 12 h the mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with pH 7 buffer solution (50 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to afford a residue that was purified by column chromatography (3:1, petroleum ether/dichloromethane) to afford methyl 2-(4-(benzyloxy)-3,5-dichlorophenylamino)benzoate as a white solid (94% yield).
Reaction SMILES: Cl.Cl[C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([NH:17][C:18]3[C:23]4[CH2:24][CH2:25][O:26][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[C:8]([C:14]([NH2:16])=[O:15])[CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH3:27][S-:28].[Na+].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[Cu]I>[O:26]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:17][C:7]3[C:6]4[C:11](=[C:12]([CH3:13])[C:3]([S:28][CH3:27])=[CH:4][CH:5]=4)[N:10]=[CH:9][C:8]=3[C:14]([NH2:16])=[O:15])[C:23]=2[CH2:24][CH2:25]1
Reactant: Cc1c(Cl)ccc2c(Nc3cccc4c3CCO4)c(C(N)=O)cnc12
Reactant: C[S-]
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc2c(Nc3cccc4c3CCO4)c(C(N)=O)cnc2c1C
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
A stirred mixture of Intermediate 104 (0.50 g), sodium methanethiolate (0.35 g), potassium carbonate (0.43 g) and copper (I) iodide (0.025 g) in dry N,N-dimethylformamide (3 ml) was heated at 100° under nitrogen for 18 h. The mixture was cooled, poured into water (50 ml) and stirred for 15 min. The solid material was filtered off, dried in vacuo at 80° for 2 h, and boiled in ethanol:water 15:1 (50 ml) for 30 min. The insoluble material was filtered off, and the filtrate evaporated to dryness to give the title compound as a pale yellow solid (0.163 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:17]3[CH:18]=[CH:19][C:20]([C:22](O)=[O:23])=[CH:21][C:16]=3[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]2=[O:25])=[CH:5][CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([NH:51][CH2:52][CH2:53][N:54]4[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]4)=[O:23])=[CH:21][C:16]=3[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]2=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2c(=O)c3cccnc3c3cc(C(=O)O)ccc32)cc1
Reactant: NCCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)c3cccnc3c3cc(C(=O)NCCN4CCCCC4)ccc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 193.6 %

Procedure:
The compound (30 mg, 0.09 mmol) prepared in Step 1, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC, 48 mg, 0.25 mmol), and 1-hydroxy-benzotriazole hydrate (HOBt, 34 mg, 0.25 mmol) were dissolved in N,N-dimethylformamide (5 ml) and added with 1-(2-aminoethyl)piperidine (0.033 ml, 0.23 mmol) at room temperature. The resulting mixture was stirred for 18 hours and poured into ice water. After extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then purified by flash column chromatography (chloroform:methanol=7:1) to obtain the title compound (82 mg, yield: 92%, white solid).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC(O)CC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (54.5 mg, 0.65 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (30 mg) and CuI (5 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield rac-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 56 mg, 64%).
Reaction SMILES: [C:1]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1)(=[O:21])[C:2]1[CH:20]=[CH:19][CH:18]=[C:4]([C:5]([O:7][CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[O:6])[CH:3]=1.[C:33]([O:37]O)([CH3:36])([CH3:35])C>[Mo](=O)(=O)=O.C(C1C=CC=CC=1)C>[C:5]([O:7][CH:8]1[CH2:9][C:10]([CH3:17])([CH3:16])[N:11]([O:37][CH:33]([CH3:36])[C:35]2[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=2)[C:12]([CH3:14])([CH3:15])[CH2:13]1)(=[O:6])[C:4]1[CH:18]=[CH:19][CH:20]=[C:2]([C:1]([O:22][CH:23]2[CH2:24][C:25]([CH3:32])([CH3:31])[N:26]([O:37][CH:33]([CH3:36])[C:35]3[CH:19]=[CH:20][CH:2]=[CH:3][CH:4]=3)[C:27]([CH3:30])([CH3:29])[CH2:28]2)=[O:21])[CH:3]=1
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)c2cccc(C(=O)OC3CC(C)(C)NC(C)(C)C3)c2)CC(C)(C)N1
Agent: O=[Mo](=O)=O
Solvent: CCc1ccccc1
Product: CC(ON1C(C)(C)CC(OC(=O)c2cccc(C(=O)OC3CC(C)(C)N(OC(C)c4ccccc4)C(C)(C)C3)c2)CC1(C)C)c1ccccc1
Yield: 129.1 %

Procedure:
A mixture of 40.0 g (90.0 mmol) of di-(2,2,6,6-tetramethylpiperidin-4-yl) isophthalate, 2.0 g of molybdenum trioxide, and 250 ml of ethylbenzene is heated to 110° C. t-Butyl hydroperoxide (70%, 69.5 g, 540 mmol) is added dropwise over a 45 min. period. The reaction mixture turns red during the addition. Water is removed by azeotropic distillation. The mixture is refluxed for 4 hours after the addition is complete. The catalyst is filtered, and the filtrate is evaporated to obtain a yellow oil. A kugelrohr distillation (110° C., 0.1 mm Hg) is performed to remove volatile by-products. The residue, a viscous oil, is dissolved in hexane and passed through silica gel. Evaporation yields a crude solid which is recrystallized from ethanol to yield 39.8 g (65% yield) of the title compound, a white powder, m.p. 118°-34° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](Cl)=[O:14])[CH3:11].O.CCOC(C)=O>N1C=CC=CC=1>[CH2:10]([N:12]([CH2:16][CH3:17])[C:13]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:14])[CH3:11]
Reactant: c1ccc2c(c1)CCN2
Reactant: CCN(CC)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)C(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6 g of indoline in 10 ml of pyridine is cooled to 0° C., 6.4 ml of diethylcarbamoyl chloride are added dropwise and the mixture is stirred for 18 hours at RT. Water is added to the reaction mixture, extraction is carried out with AcOEt, the organic phase is washed with water and with a 5% solution of potassium hydrogensulfate and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM as the eluent to give 8 g of the expected product, which is used as such.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1[Cl:21])C(OC)=O.[Cl-].[Li+].O.C(OCC)(=O)C>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1[Cl:21]
Reactant: COC(=O)C(C(=O)OC)c1c(Cl)cnc2ccc(OC)nc12
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c(Cl)cnc2ccc(OC)nc12
Temperature: 100 °C

Procedure:
To a solution of dimethyl[3-chloro-6-(methyloxy)-1,5-naphthyridin-4-yl]propanedioate (56.23 g, 173 mmol) in DMSO (1210 ml) was added lithium chloride (14.9 g, 350 mmol) and water (3.24 ml, 180 mmol). The mixture was heated to 100° C. for 16 h then cooled and treated with ethyl acetate and water. The organic phase was washed twice with water, the aqueous extracted with ethyl acetate and this water-washed. The combined organic phases were dried and the solvent was removed. The residue was subjected to column chromatography on silica gel using a hexane and ethyl acetate gradient to provide the desired compound containing a little of the starting material (43.3 g, 94%).
Reaction SMILES: [Na+].[C:2]([C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([S:14][C:15]3[C@H:16]([CH3:29])[C@@H:17]4[C@@H:24]([C@H:25]([OH:27])[CH3:26])[C:23](=[O:28])[N:18]4[C:19]=3[C:20]([O-:22])=[O:21])[CH2:11]2)[S:8][CH:9]=1)(=[O:4])[NH2:3].[C:30]([O:36][CH2:37]I)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(OCC)(=O)C>CC(N(C)C)=O>[C:2]([C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([S:14][C:15]3[C@H:16]([CH3:29])[C@@H:17]4[C@@H:24]([C@H:25]([OH:27])[CH3:26])[C:23](=[O:28])[N:18]4[C:19]=3[C:20]([O:22][CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:21])[CH2:11]2)[S:8][CH:9]=1)(=[O:4])[NH2:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(SC3CN(c4nc(C(N)=O)cs4)C3)[C@H](C)[C@H]12
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(SC3CN(c4nc(C(N)=O)cs4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of (1R,5S,6S)-2-[1-(4-carbamoyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid sodium salt (402 mg, 0.90 mmol) (obtained as described in Example 3) in dimethylacetamide (5 ml) was added iodomethyl pivalate (261 mg, 1.08 mmol) at 0° C. under an atmosphere of nitrogen and the mixture was stirred for 1 hour. At the end of this time, to the reaction mixture was added ethyl acetate and the organic layer was washed sequentially with 10% aqueous sodium chloride solution 10% aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the residue was added diethyl ether to afford pivaloyloxymethyl (1R,5S,6S)-2-[1-(4-carbamoyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (450 mg, yield 93%) as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][NH:10][C:9](=[O:12])[C:8]=2[CH:13]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]#[N:23].Cl>CN(C)C=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([O:12][CH2:21][C:22]#[N:23])[C:8]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]sc2ccc([N+](=O)[O-])cc12
Reactant: N#CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCOc1nsc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
A mixture of 5-nitro-1,2-benzisothiazol-3(2H)-one (17.5 g, 89.2 mmol) in N,N-dimethylformamide is treated with potassium carbonate (18.5 g, 134 mmol), stirred at room temperature for 30 minutes, treated with bromoacetonitrile (16.0 g, 133 mmol), stirred at room temperature overnight, and poured onto ice. The resultant aqueous mixture is acidified to pH 3 with hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Column chromatography of the solid using silica gel and methylene chloride gives the title product as a yellow solid (15.0 g, mp 123-124.5° C.).
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]1[CH:15]=[C:14]([O:16]COC)[C:13]([CH:20]([CH3:22])[CH3:21])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH:3]=[CH2:4]>CO>[CH2:2]([O:5][C:6]1[CH:15]=[C:14]([OH:16])[C:13]([CH:20]([CH3:22])[CH3:21])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH:3]=[CH2:4]
Reactant: C=CCOc1cc(OCOC)c(C(C)C)cc1C(=O)OC
Agent: Cl
Solvent: CO
Product: C=CCOc1cc(O)c(C(C)C)cc1C(=O)OC
Temperature: 25 °C
Yield: 98.5 %

Procedure:
Concentrated hydrochloric acid (0.4 ml) was added to a solution of methyl 2-allyloxy-5-isopropyl-4-(methoxymethyloxy)benzoate (1049 mg, 3.57 mmol) in methanol (25 ml) and the mixture was stirred and held at reflux for 3 hours. Upon cooling to room temperature the volatile material and solvent were removed in vacuo to afford methyl 2-allyloxy-4-hydroxy-5-isopropylbenzoate (880 mg, 98%) as a pale green oil. 1H NMR (DMSO-d6) 10.18 (1H, s), 7.54 (1H, s), 6.51 (1H, s), 6.03 (1H, m), 5.51 (1H, dm), 5.27 (1H, dm), 4.52 (2H, m), 3.73 (3H, s), 3.10 (1H, m), 1.15 (6H, d). MS: [M+Na]+ 273.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:30])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:29])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:29][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:30])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][N:20]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(C)(=O)=O)cn2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
Lithium hydroxide monohydrate (0.0045 g, 0.107 mmol) was added to a mixture of [6-fluoro-4-(5-methanesulfonyl-pyridin-2-yl)-3-methyl-naphthalen-2-yl]acetic acid methyl ester (0.014 g, 0.036 mmol) in a 1:1 mixture of THF—H2O mixture (2 mL). The reaction mixture was stirred for 5 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the aqueous residue was combined with a 1.0 N aqueous solution of hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The collected organic layers were dried over anhydrous MgSO4, filtered, and concentrated to provide [6-fluoro-4-(5-methanesulfonyl-pyridin-2-yl)-3-methyl-naphthalen-2-yl]acetic acid (0.009 g) as a white solid. The final product contained a significant amount of water as an impurity. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.35 (br. s, 1 H), 9.26 (dd, J=2.42, 0.60 Hz, 1 H), 8.49 (dd, J=8.00, 2.26 Hz, 1 H), 8.03 (dd, J=8.80, 6.80 Hz, 1 H), 7.95 (s, 1 H), 7.73 (d, J=8.15 Hz, 1 H), 7.40 (td, J=8.80, 2.40 Hz, 1 H), 6.75 (dd, J=11.00, 2.40 Hz, 1 H), 3.87 (s, 2 H), 3.45 (s, 3 H), 2.07 (s, 3 H). MS calcd. for C19H17FNO4S [(M+H)+] 374, obsd. 374.0.