Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].CC(C)=O.[OH-].[Na+:37]>CCO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:37]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 80.8 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to acetone (30 ml) and the solution was stirred at room temperature. NaOH (1 eq.) in EtOH (3 ml) was added to the solution. The mixture was stirred overnight. The product that precipitated was isolated by filtration under nitrogen, washed with acetone (100 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 2.45 g (80.8%) of fluvastatin sodium Form XLIV.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:20]=1[Cl:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[C:23]([N:27]2[CH2:28][CH2:29][CH:30]([C:33]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:34])[CH2:31][CH2:32]2)[CH:22]=[CH:21][C:20]=1[Cl:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(C1CCNCC1)N1CCCC1
Reactant: COc1ccc2c(c1)nc(-c1cc(Br)ccc1Cl)n2C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)nc(-c1cc(N3CCC(C(=O)N4CCCC4)CC3)ccc1Cl)n2C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 80.7 %

Procedure:
Method F—Step a 2-(5-Bromo-2-chloro-phenyl)-5-methoxy-benzoimidazole-1-carboxylic acid tert-butyl ester (obtained as described in general method 4, step c) (0.10 g, 0.23 mmol), piperidin-4-yl-pyrrolidin-1-yl-methanone (0.05 g, 0.30 mmol) and cesium carbonate (0.37 g, 1.14 mmol) were placed into a dried vial and 3 cycles of vacuum/nitrogen were performed, then dry toluene (0.20 mL) was added. At the same time palladium acetate (0.01 g, 0.05 mmol), and BINAP (0.04 g, 0.07 mmol) were placed into a dried 4 mL vial under nitrogen and 3 cycles of vacuum/nitrogen were performed. Then dry toluene (0.40 mL) was added, at room temperature under nitrogen, and the mixture was added to the first vial. The reaction mixture was heated at 80° C. overnight, cooled to room temperature, EtOAC (3 mL) was added and the mixture filtered off. Solvent was removed and the crude recovered with EtOAc (3.5 mL) and filtered through a 2 g silica column (eluent EtOAc) to afford 0.10 g of the title compound (82%) without further purifications.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.[CH3:19][C:20]1(C)[C:24](C)(C)OB(C(C)=C)O1>O1CCOCC1.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>[CH2:19]=[C:20]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12)[CH3:24]
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Temperature: 100 °C
Yield: 96.7 %

Procedure:
118-1. A mixture of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (750 mg, 2.12 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (712 mg, 4.24 mmol) Cs2CO3 (1.72 g, 5.29 mmol) and Pd(PPh3)4 (122 mg, 0.11 mmol) in dioxane/H2O (9:1, mL) was heated to 100° C. for 2 h in a microwave reactor. The mixture was then concentrated in vacuo and the residue purified by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 85:15) to give the title compound (550 mg). UPLC-MS: MS 269.2 (M+H+); UPLC rt 0.83 min.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]=[O:27])=[CH:18]2)C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=[O:27])=[CH:18]1
Reactant: O=Cc1cn(CCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cn(CCOCCOCCO)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.6 g of 1-(2-(2-(2-triphenylmethoxyethoxy)ethoxy)ethyl)-1H-indole-3-carbaldehyde (5.0 mmol) in 50 mL dichloromethane is added 4.0 mL of triethylsilane (2.9 g, 25 mmol) followed by 4.0 mL of trifluoroacetic acid (5.5 g, 50 mmol). The solution is stirred at room temperature for 2 hrs and then washed 3×100 mL saturated NH4CO3. The solution is dried over anhydrous Na2SO4 and the solvent is removed via vacuum. The resultant residue is purified via column chromatography over alumina, eluting with a gradient of methanol in dichloromethane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21]O)[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:46]1[CH:50]=[N:49][N:48]=[N:47]1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][N:46]3[CH:50]=[N:49][N:48]=[N:47]3)[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCO)CC1
Reactant: c1nnn[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCn2cnnn2)CC1
Reaction time: 12 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.0 g, 2.77 mmol), triphenylphosphine (0.73 g, 2.78 mmol), and tetrazole (0.24 g, 3.38 mmol) in tetrahydrofuran (25 mL). Add a solution of diethylazodicarboxylate (0.59 g, 3.38 mmol) in tetrahydrofuran (1 mL). After 12 hours, concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/hexane to give 1-(t-butoxycarbonyl)-4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.57 (silica gel, 1/1 hexane/ethyl acetate).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[C:24]([O:26][CH2:27]Cl)=[O:25].[Cl-].[NH4+]>CN(C)C=O>[F:19][C:20]([F:32])([F:33])[C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[C:24]([O:26][CH2:27][N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)=[O:25]
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: O=C(OCCl)c1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(OCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.07 g of sodium hydride (60% oily), and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 15 minutes, 0.33 g of chloromethyl 3-trifluoromethylbenzoate was added, and the mixture was stirred at 70° C. for 6 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.32 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 3-trifluoromethylbenzoate (present compound (44)).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:6]2=[N:5][C:4]=1[CH3:29])[CH3:2].Cl.[Cl:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:31].[CH2:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:28])[C:21]4[CH:22]=[CH:23][C:24]([O:27][CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:25][CH:26]=4)=[CH:16][CH:15]=3)[C:6]2=[N:5][C:4]=1[CH3:29])[CH3:2]
Reactant: CCc1c(C)nc2n(Cc3ccc(C(=O)c4ccc(O)cc4)cc3)ccn2c1=O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c(C)nc2n(Cc3ccc(C(=O)c4ccc(OCCN5CCOCC5)cc4)cc3)ccn2c1=O
Yield: 70 %

Procedure:
A solution of 6-ethyl-1-[4-(4-hydroxybenzoyl)-benzyl]-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one (136 mg), 4-(2-chloroethyl)morpholine hydrochloride (154 mg) and potassium carbonate (205 mg) in DMF (7 ml) was stirred at 100° C. for 6 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, and dried. Then, hydrogen chloride/ethyl acetate was added and the precipitated hydrochloride was collected by filtration and dried to provide the title compound as colorless solid (132 mg).
Reaction SMILES: C([O:4][C:5]1[CH:9]=[C:8]([N:10](C(=O)C)[C:11](=[O:13])[CH3:12])[N:7]([C:17]2[CH:22]=[C:21]([S:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:20]([CH3:29])=[CH:19][C:18]=2[F:30])[N:6]=1)(=O)C.O.N>C(O)C>[C:11]([NH:10][C:8]1[N:7]([C:17]2[CH:22]=[C:21]([S:23][CH2:24][C:25]([F:26])([F:27])[F:28])[C:20]([CH3:29])=[CH:19][C:18]=2[F:30])[N:6]=[C:5]([OH:4])[CH:9]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Oc1cc(N(C(C)=O)C(C)=O)n(-c2cc(SCC(F)(F)F)c(C)cc2F)n1
Agent: N
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
10.6 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole was dissolved in 200 mL of toluene, and to this solution, 20.0 g of acetyl chloride was added, followed by reflux with heating for 12 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 9.4 g of 3-acetoxy-5-(N,N-diacetylamino)-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazole. Then, 9.4 g of the obtained 3-acetoxy-5-(N,N-diacetylamino)-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazole was dissolved in 100 mL of ethanol, and 10 mL of a 25 mass % ammonia water was added, followed by stirring at room temperature for 30minutes. Then, the solvent was distilled off under reduced pressure, and the obtained solid was washed with diisopropyl ether to obtain 7.0 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole in the form of white crystals (melting point: 223-225° C.).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].C(O[CH:15]=[CH:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>CCO.C(Cl)(Cl)Cl>[F:19][C:18]([F:21])([F:20])[C:17]1[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=[CH:15][CH:16]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(O)c1ccc(-n2nccc2C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-hydrazinobenzoic acid (0.501 g, 3.29 mmol) and 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (0.48 mL, 3.4 mmol) in EtOH (15 mL) was heated to 75° C. for 17 hours, allowed to cool to room temperature, and concentrated under reduced pressure to provide a solid. The obtained solid was suspended in CHCl3 (15 mL), treated with P2O5 (0.50 g, 3.5 mmol), and heated at 65° C. for 6 hours. After cooling to room temperature, the mixture was treated with 1N NaOH (5 mL) and stirred for 30 minutes. The mixture was quenched with 1N HCl (6 mL) and extracted with CH2Cl2 (3×8 mL). The extracts were combined, dried (Na2SO4), filtered, and the filtrate concentrated to provide the title compound as a solid.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[CH:32][CH:31]=1)[CH:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].Cl.C(=O)([O-])O.[Na+]>C(OCC)C.[Cl-].[Zn+2].[Cl-].O>[OH:3][CH:4]([C:30]1[CH:31]=[CH:32][C:33]([O:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[CH:34][CH:35]=1)[CH:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: O=C(OCc1ccccc1)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(Oc2cccnc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CCOCC
Product: O=C(OCc1ccccc1)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of zinc chloride (2.95 g, 21.6 mmol) in diethyl ether (100 ml) was added sodium borohydride (1.64 g, 43.3 mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off, and a solution of benzyl 3-oxo-3-[4-(pyridin-3-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (6.0 g, 10.8 mmol, crude) in diethyl ether (50 ml) was added to the filtrate at 0° C. The mixture was stirred for 30 min. and 1N hydrochloric acid was added to stop the reaction. After neutralization with saturated aqueous sodium hydrogen carbonate, water (200 ml) was further added and the mixture was extracted with ethyl acetate (200 ml×2). The extract-was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) and recrystallized from ethyl acetate-hexane to give the objective substance (3.13 g, 73%).
Reaction SMILES: [Cl-].[NH4+].O.[CH2:4]([N:6]([CH2:27][CH3:28])[C:7](=[O:26])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:10]=1[N+:23]([O-])=O)[CH3:5].C(OCC)(=O)C>C(O)C.[Fe]>[CH2:27]([N:6]([CH2:4][CH3:5])[C:7](=[O:26])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:10]=1[NH2:23])[CH3:28]
Reactant: CCN(CC)C(=O)Cc1cccc(Oc2ccccc2F)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)Cc1cccc(Oc2ccccc2F)c1N
Yield: 98.7 %

Procedure:
A mixture of iron powder (5 g.), ammonium chloride (0.5 g.), ethanol (40 ml.) and water (20 ml.) and a solution of N,N-diethyl-2-[2-nitro-3-(2-fluorophenoxy)phenyl]acetamide (5.1 g.) in ethanol (5 ml.) were treated in a similar manner to that of Example 1-(1) [extraction solvent: ethyl acetate] to give oily N,N-diethyl-2-[2-amino-3-(2-fluorophenoxy)phenyl]acetamide (4.6 g.). This substance was dissolved in a mixture of methanol and hydrochloric acid. The solution was evaporated and the residue was pulverized with ethyl acetate. The resultant product (4.15 g.). was recrystallized from a mixture of ethanol and ethyl acetate to give white needles of the captioned compound (2.95 g.). mp 159° to 160° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C@@H:11]([CH:13]=[CH2:14])[C@H:10]([O:15][Si](CC)(CC)CC)[C:9]=2[CH3:23])=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>C1COCC1>[CH3:23][C:9]1[C@@H:10]([OH:15])[C@H:11]([CH:13]=[CH2:14])[CH2:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: C=C[C@@H]1CC(c2ccc(C)cn2)=C(C)[C@H]1O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=C[C@@H]1CC(c2ccc(C)cn2)=C(C)[C@H]1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a solution of compound 95 (50 mg, 0.152 mmol) in THF (1 ml) at 0° C. was added tetrabutylammonium fluoride (0.152 ml of 1 M solution in THF, 0.152 mmol) dropwise. The reaction mixture was stirred at 0° C. for 30 min and water (1 ml) and ethyl acetate (2 ml) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×2 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography on silica (16-50% EtOAc/hexanes) afforded pure alcohol 96 (28 mg, 83%) as a white solid: [α]22D=−26.0 (c 0.3, CHCl3); TLC Rf=0.25 (silica gel, 50% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 8.43 (s, 1H), 7.47-7.44 (dd, 1H, 3J=1.8 Hz, 2J=7.8 Hz), 7.19-7.17 (d, 1H, 3J==7.8 Hz), 6.0-5.95 (m, 1H), 5.12-5.17 (d, 1H, 3J=16.8 Hz), 5.09-5.06 (d, 1H, 3J=10.2 Hz), 4.48 (s, 1H), 2.96-2.91 (m, 1H), 2.69-2.60 (m, 2H), 2.32 (s, 3H), 2.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.62, 149.90, 140.25, 139.41, 136.65, 135.55, 131.19, 122.32, 115.43, 86.42, 52.26, 38.52, 18.49, 13.17; HRMS calcd for C14H17NO+Na+ 238.1208; found 238.1191 [M+Na+].
Reaction SMILES: [N:1]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:38])[CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[CH:25][CH:24]=3)=[O:21])=[CH:15][C:14]=2[O:39][CH3:40])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([CH:29]([CH3:38])[CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=3)=[O:21])=[CH:15][C:14]=2[O:39][CH3:40])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(CC(=O)Nc2ccc(C(C)CC(=O)OC(C)(C)C)cc2)ccc1NC(=O)N1CCc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CC(=O)Nc2ccc(C(C)CC(=O)O)cc2)ccc1NC(=O)N1CCc2ccccc21
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A solution of tert-butyl 3-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetylamino)-phenyl]-butyrate [580 mg, Reference Example 1(a)] in dichloromethane (20 ml) was treated with treated with trifluoroacetic acid (1 ml). After 2 hours at room temperature further (1 ml) trifluoroacetic acid was added and the solution was then kept at room temperature overnight. The reaction mixture was evaporated and the residue was suspended in water. This suspension was treated with 1.0 M sodium hydroxide solution (5 ml) and then washed twice with ethyl acetate, then acidified to pH 1 with hydrochloric acid and then filtered. The resultant white solid was washed with water then dried to give the title compound (450 mg) as a white powder, m.p. 152-154° C. [Elemental analysis: C, 67.35; H, 6.02; N, 8.46%. Calculated for C28H29N3O5.0.63H2O: C, 67.41; H, 6.11; N, 8.42%].
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C[C@@H](O)C[C@H](N(C)C)[C@@H](O)C=O.[F:64]OC(F)(F)F.Cl(F)(=O)(=O)=O>>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@:9]([F:64])([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: FOC(F)(F)F
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: C[C@@H](O)C[C@@H]([C@@H](O)C=O)N(C)C
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Yield: 35 %

Procedure:
According to such a synthesis an enol-ether function (2) is generated in the molecule of erythromycin A (1) and subsequently the N-dimethyl group of desosamine is protected as N-oxide (3) to avoid the partial or total N-demethylation of the basic sugar during the fluorination; fluorination of (3) with trifluoromethyl hypofluorite or perchloryl fluoride, followed by hydrogenolysis, gives (8S)-8-fluoroerythromycin A (5). As a matter of fact, by operating according to the disclosure of the second Application erythromycin A can be converted into (8S)-8-fluoroerythromycin A, with a yield of about 35% in four subsequent steps (scheme II):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[CH:18])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([CH:14]1[CH2:16][CH2:15]1)[CH3:13])[CH2:7]2.C(=O)([O-])O.[K+].O.Cl[C:26](=[N:32][OH:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[O:33][N:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:18]=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([CH:14]1[CH2:16][CH2:15]1)[CH3:13])[CH2:7]2
Reactant: CCOC(=O)C(Cl)=NO
Reactant: C#Cc1cc(Cl)c2c(c1)CN([C@@H](C)C1CC1)C2=O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(-c2cc(Cl)c3c(c2)CN([C@@H](C)C2CC2)C3=O)on1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.2 %

Procedure:
7-chloro-2-((S)-1-cyclopropylethyl)-5-ethynylisoindolin-1-one (28.66 g, 110.35 mmol) and potassium hydrogen carbonate (110.0 g, 1103.45 mmol) were dissolved in a solution consisting of 1200 mL of ethyl acetate and 400 mL of water. To this solution was added ethyl 2-chloro-2-(hydroxyimino)acetate (66.9 g, 441.38 mmol). The ethyl 2-chloro-2-(hydroxyimino)acetate was added at room temperature as a solution in 160 mL of ethyl acetate via syringe pump at a rate of 5 mL/Hr. Following the addition of the ethyl 2-chloro-2 (hydroxyimino)acetate, the reaction was allowed to continue stirring at room temperature for an additional 12 hours. The ethyl acetate layer was extracted in a reparatory funnel, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel eluting with a gradient of 0 to 25% ethyl acetate in hexane to afford the title compound as a white solid (17.05 g, 41.2%). 1H NMR (300 MHz, CDCl3) δ ppm 0.36-0.53 (m, 3H) 0.63-0.73 (m, 1H) 0.98-1.12 (m, 1H) 1.38 (d, 3H) 1.47 (t, 3H) 3.80 (dq, 1H) 4.43-4.65 (m, 4H) 7.05 (s, 1H) 7.83 (s, 2H). MS ESI, m/z=375 (M+H). HPLC Method B: 0.82 min