Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]=[C:17]([O:20][CH2:21][CH3:22])[CH2:18]Br)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[I-:23].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]=[C:17]([O:20][CH2:21][CH3:22])[CH2:18][I:23])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CCOC(CBr)=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(CI)=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 3.8 parts of 5-chloro-2-(2-bromo-1-ethoxyethylideneamino)benzophenone in 30 parts by volume of acetone is added with stirring a solution of 1.5 parts of sodium iodide in 12 parts by volume of acetone. After about one hour, the resulting precipitate is removed by filtration. The filtrate is concentrated under reduced pressure. The concentrate is treated with petroleum ether to give 5-chloro-2-(1-ethoxy-2-iodoethylideneamino)benzophenone as crystals. The crystals are recrystallized from n-hexane to give pale brown pillars melting at 67°-68° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:6].[BH4-].[Na+].Cl>CO>[OH:6][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCCl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 50 mg of 4-(4-chloro-1-oxobutyl)α,α-dimethylphenylacetic acid, prepared in accordance with Example 4, in 3 mL of methanol is added 50 mg of NaBH4. The mixture is stirred for 30 minutes, acidified with 2N HCl, and the methanol is removed in vacuo. The concentrate is extracted with EtOAc. The organics are dried over Na2SO4, filtered, and concentrated to afford 4-(1-hydroxy-4-chlorobutyl)-α,α-dimethylphenylacetic acid.
Reaction SMILES: IC1C=[CH:10][C:9]2[C:4](=CC=C[CH:8]=2)N=1.C([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=O)C>C(Cl)Cl.CCOC(C)=O>[C:16]([O:15][C:9]([CH3:8])([CH3:4])[CH3:10])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(=O)OC(C)(C)C
Reactant: Ic1ccc2ccccc2n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
HClO4 (1.17 mL, 13.6 mmol) is added to a suspension of 48k (3.40 g, 9.06 mmol) in t-butyl acetate (100 mL) and DCM (150 mL). The reaction mixture is stirred at RT overnight then is diluted with EtOAc (150 mL). The solution is washed twice with aqueous 5% NaHCO3 solution, dried (MgSO4), filtered and concentrated under reduced pressure. The residue is purified by flash chromatography (Combi-Flash; EtOAc/hexane) to give t-butylether 481 (2.76 g, 71% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:27].C([Li])CCC.CCCCCC.[CH3:39][S:40]SC>C(OCC)C>[F:27][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:2]=1[S:40][CH3:39])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CSSC
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(Br)c(F)c2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CSc1ccc(COC[C@@H]2C[C@@H]2C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
tert-butyl 4-((1R,2R)-2-(((4-bromo-3-fluorobenzyl)oxy)methyl)cyclopropyl)piperidine-1-carboxylate (Step A product, 7.7 g, 17.4 mmol) was dissolved in Diethyl ether (70 ml) and cooled to −78° C. The mixture was stirred for 5 min, then n-Butyllithium in hexane (2.5 M, 7.66 ml, 19.15 mmol) was added dropwise. The mixture was stirred at −78° C. for 10 min and dimethyl disulfide (1.85 ml, 20.9 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min and TLC showed the SM was almost consumed. The mixture was quenched with sat. NH4Cl at −78° C., extracted with EtOAc (2×). The EtOAc phase was washed with brine, dried over MgSO4, and concentrated to afford 7.13 g (100%) of the designed product. This crude product was used for the next step without further purification.
Reaction SMILES: Cl[C:2](=O)[CH2:3][C:4]([O:6]C)=[O:5].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH2:19])(=[O:18])=[O:17].[OH-].[Na+].Cl>C(OCC)C.CN(C)C(=O)C>[O:17]=[S:16]1(=[O:18])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:2]([CH2:3][C:4]([OH:6])=[O:5])=[N:19]1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: COC(=O)CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: O=C(O)CC1=NS(=O)(=O)c2ccccc2N1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
Methyl 3-chloro-3-oxopropionate (3.36 mL, 31.3 mmol) was added to a solution of 2-aminobenzenesulfonamide (4.91 g, 28.5 mmol) in a 1:1 mixture of N,N-dimethylacetamide and diethylether (100 mL) at 0° C. The cloudy reaction mixture was stirred at 0° C. for 3 h, and then was partitioned between half-saturated aqueous sodium bicarbonate (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo. The residue was then dissolved in water (75 mL) containing sodium hydroxide (3.42 g, 85.5 mmol) at 25° C. The mixture was heated at 100° C. for 1 h, and then was cooled to 0° C. Concentrated (12.0 M) aqueous hydrochloric acid solution (10.0 mL, 120 mmol) was added dropwise via addition funnel over 10 min, resulting in the formation of a white precipitate. The reaction mixture was stirred at 0° C. for an additional 15 min, and then was filtered through a medium frit. The collected material was washed with water (30 mL) and was air-dried overnight to afford the desired product, (1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (6.37 g, 26.6 mmol, 93%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.58 (2H, s), 7.30 (1H, d, J=7.4 Hz), 7.44 (1H, t, J=8.2 Hz), 7.64-7.68 (1H, m), 7.79 (1H, dd, J1=1.5 Hz, J2=7.8 Hz), 12.19 (1H, s).
Reaction SMILES: C(=O)=O.CO.C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:16]([O:20][C:21]([C@@:23]1([CH2:37][CH2:38][CH2:39][OH:40])[CH2:27][C:26](=[O:28])[N:25]([C@@H:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[C:16]([O:20][C:21]([C@@:23]1([CH2:37][CH2:38][CH:39]=[O:40])[CH2:27][C:26](=[O:28])[N:25]([C@@H:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCCO)(C(=O)OC(C)(C)C)CC1=O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@H](c1ccccc1)N1C[C@@](CCC=O)(C(=O)OC(C)(C)C)CC1=O
Reaction time: 1 h
Yield: 100.7 %

Procedure:
Dichloromethane (35 ml) was cooled with dry ice-methanol in a nitrogen atmosphere. Oxalyl chloride (3.45 ml, 39.5 mmol) and dimethyl sulfoxide (4.68 ml, 66.0 mmol) were added, and the mixture was stirred under cooling for 15 minutes. A solution of (3S)-3-(3-hydroxy-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.58 g, 13.2 mmol) in dichloromethane (31 mL) was added, and the mixture was stirred under cooling for one hour. Triethylamine (11.1 ml, 79.5 mmol) was added under cooling, and the mixture was stirred under cooling for one hour and then at room temperature for one hour. A saturated ammonium chloride solution (100 ml) was added to the reaction solution, followed by extraction with chloroform (100 ml×1, 80 ml×1). The organic layer was washed with brine (120 ml) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→66:34→60:40→50:50→40:60→34:66→25:75) to give 4.59 g of the title compound as white crystals.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[CH:13]=[CH:12][NH:11][C:7]2=[C:8]([Cl:10])[N:9]=1.I[CH3:15].[Cl-].[NH4+].[Cl-].[Na+]>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[CH:13]=[CH:12][N:11]([CH3:15])[C:7]2=[C:8]([Cl:10])[N:9]=1
Reactant: CI
Reactant: Clc1nc(Br)cc2cc[nH]c12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1ccc2cc(Br)nc(Cl)c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 112.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 1.45 g, 36.3 mmol) was added portionwise to a 0° C. solution of 5-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine (CAS 1198096-48-8) (4.2 g, 18.14 mmol) and tetrahydrofuran (42 mL). After 15 minutes at 0° C. iodomethane (1.7 mL, 27.2 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes and at ambient temperature for 2 hours. The reaction mixture was cooled to 0° C. and 30 mL saturated aqueous ammonium chloride solution was added, followed by addition of saturated aqueous sodium chloride. The mixture was extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford 5 g yellow solid. The crude product was purified by flash chromatography (silica gel, 2-20% ethyl acetate in heptanes) to provide 3.7 g (84%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH3:22])[C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O)(=O)C>ClCCCl>[CH3:7][N:8]([CH3:22])[C:9]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH:12]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:13][CH2:14]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: C1CCNCC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Piperidine (400 μl, 4 mmole) and 4-dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmole) were dissolved in dry 1,2-dichloroethane (10 ml). Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg, 2.8 mmole) were added to this mixture and the whole was stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and the mixture was adjusted to pH 11 with 5M NaOH. The alkaline phase was diluted with water (10 ml) and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. Dimethyl-(1-phenyl-4-piperidine-1-ylcyclohexyl)-amine was purified by chromatography with ethanol. The non-polar diastereoisomer (15 mg) still contained impurities, which also could not be removed by further purification attempts. The polar diastereoisomer was obtained as a colourless oil in a yield of 92 mg (16%).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:23])[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([C:19]([O:21]C)=[O:20])[C:16]=2[C:17]=1[OH:18])=[O:8])C.OC1C2C(=CC=CC=2I)C(=O)C=1C(NCC(OCC)=O)=O.[C]=O>CO>[C:4]([CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:23])[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([C:19]([OH:21])=[O:20])[C:16]=2[C:17]=1[OH:18])=[O:8])([OH:24])=[O:3]
Reactant: CCOC(=O)CNC(=O)C1=C(O)c2c(C(=O)OC)cccc2C1=O
Agent: CCOC(=O)CNC(=O)C1=C(O)c2c(I)cccc2C1=O
Agent: [C]=O
Solvent: CO
Product: O=C(O)CNC(=O)C1=C(O)c2c(C(=O)O)cccc2C1=O

Procedure:
Methyl 2-((2-ethoxy-2-oxoethyl)carbamoyl)-3-hydroxy-1-oxo-1H-indene-4-carboxylate. The title compound is prepared by metal mediated carbonylation of ethyl 2-(3-hydroxy-4-iodo-1-oxo-1H-indene-2-carboxamido)acetate with carbon monoxide in MeOH according to literature procedures.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH2:12][C@@H:13]([CH3:18])[CH2:14][CH2:15][CH2:16][CH3:17])[C:9]([OH:11])=[O:10].[N+](=[CH2:21])=[N-]>C(OCC)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH2:12][C@@H:13]([CH3:18])[CH2:14][CH2:15][CH2:16][CH3:17])[C:9]([O:11][CH3:21])=[O:10]
Reactant: C=[N+]=[N-]
Reactant: CCCC[C@H](C)C[C@@H](OC1CCCCO1)C(=O)O
Solvent: CCOCC
Product: CCCC[C@H](C)C[C@@H](OC1CCCCO1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 171.9 %

Procedure:
A solution of 1.17 g of (2R,4S)-2-tetrahydropyranyloxy-4-caprylic acid obtained in Step 7 in 100 ml of diethyl ether was cooled to -50° C., and 200 ml of a diethyl ether solution of 75.68 mmol of diazomethane was poured thereinto. The mixture was stirred at room temperature for 1 hour, and diethyl ether was removed from the reaction mixture by distillation to obtain 2.12 g (100%) of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([CH3:10])=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14](CC2C=CC=CC=2)[CH2:13][CH2:12]1.Cl[C:25]([O:27][CH:28]([Cl:30])[CH3:29])=[O:26].CCCCCC.CCOC(C)=O>ClCCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([CH3:10])=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][N:14]([C:25]([O:27][CH:28]([Cl:30])[CH3:29])=[O:26])[CH2:15][CH2:16]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: Cc1cc(N2CCN(Cc3ccccc3)CC2)c(C)cc1C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCCl
Product: Cc1cc(N2CCN(C(=O)OC(C)Cl)CC2)c(C)cc1C=O
Yield: 63.7 %

Procedure:
The 4-(2,5-dimethyl-4-formylphenyl)-1-benzylpiperazine (9 g, 29 mmol) was dissolved in anhydrous 1,2-dichloroethane (100 mL) and 1-chloroethyl chloroformate (4.5 g, 31.5 mmol) was added. The solution was refluxed for 30 minutes or until TLC analysis indicated the disappearance of the starting material. The product was just slightly less polar than the starting material by TLC using hexane/EtOAc (3/1). Dichloroethane was evaporated and the residue was chromatographed using gradient hexane/EtOAc (10/0 to 8/2) to give the product (6 g, 64%) as an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[K+:10].O=[C:12]([CH3:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].O>C(OC(C)C)(=O)C>[K+:10].[CH2:17]([O:16][C:14](=[O:15])[CH:13]=[C:12]([NH:1][C@H:2]([C:6]([O-:8])=[O:7])[CH:3]([CH3:5])[CH3:4])[CH3:19])[CH3:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: CCOC(=O)C=C(C)N[C@H](C(=O)[O-])C(C)C

Procedure:
L-Valine (117.2 g, 1.0 mol), KOH (85%, 66.0 g, 1 mol) and ethyl 3-oxobutanoate (140.2 mL, 1.1 mol) are dissolved in isopropyl acetate (1 L). The reaction mixture is heated to reflux using a Dean-Stark apparatus. 32 mL water are isolated during 1.75 h. A small quantity of precipitate is formed. 500 mL are distilled off.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=[O:30])[CH:23]=1>>[CH:17]([O:16][CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=2)=[O:30])[CH:4]=1)[C:11]([OH:13])=[O:12])([CH3:18])[CH3:19]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(Cc1cccc(CO)c1)OC(C)C
Product: CC(C)OC(Cc1cccc(COC(=O)Nc2cccc(C(F)(F)F)c2)c1)C(=O)O

Procedure:
Using ethyl 3-[3-(hydroxymethyl)phenyl]-2-isopropoxypropanoate and α,α,α-trifluoro-m-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:33][O:34][C:35](=[O:41])[C@@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1.C(N(CC)CC)C>CN(C=O)C>[CH3:33][O:34][C:35](=[O:41])[C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:9](=[O:11])[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
To a solution of 3,3 Diphenylpropionic acid (2.00 g, 8.85 mmol) in DMF (20 mL) was added EDC (2.04 g, 10.62 mmol), HOBT (1.44 g, 10.62 mmol) and L-proline methyl ester hydrochloride (1.76 g, 10.62 mmol) with stirring at ambient temperature. Triethylamine (2.96 mL, 21.24 mmol) was added to adjust the pH of the mixture to 8.5. After 24 hrs the DMF was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL)- H2O (50 mL). The aqueous layer was washed with EtOAc (2×50 mL), organics combined, washed with 10% citric acid soln, aq satd NaHCO3 soln, brine and dried (Na2SO4). Filtration and concentration to dryness gave 3.50 g of crude product which was chromatographed (SiO2)eluting with 99 CH2Cl2 :1 MeOH to 98 CH2Cl2 :2 MeOH to give 2.48 g (83%) of N-(3,3-diphenylpropionyl)-L-proline methylester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[N:4]=[C:5]([S:30][CH3:31])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([OH:28])=[CH:22][C:21]=1[F:29])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.Br[CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].COC(=O)N=C(SC)C(C1C=C(OC)C=C(O)C=1F)=NC1C=CC(C2N=C(C)ON=2)=CC=1.FCCI>>[CH3:1][O:2][C:3](=[O:32])[N:4]=[C:5]([S:30][CH3:31])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[CH:22][C:21]=1[F:29])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(O)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O)c1F
Agent: FCCI
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OCCO[Si](C)(C)C(C)(C)C)cc1F

Procedure:
The same procedure was carried out as in Example (3e), except that {2-(2-fluoro-4-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester and (2-bromoethoxy)-t-butyldimethylsilane were used instead of respectively the [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester and 1-fluoro-2-iodoethane, to give the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1>CO.O=[Pt]=O>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1
Reactant: OCCc1cnccn1
Agent: O=[Pt]=O
Solvent: CO
Product: OCCC1CNCCN1

Procedure:
A method for preparing each of the foregoing compounds is presented in the following examples. In general, however, the preparation is one wherein 2-(2-hydroxyethyl)-pyrazine (L. J. Kitchen and E. S. Hanson, Antibiot. Chemo., 73, 1838 (1951)) was reduced with H2 and PtO2 in MeOH to yield 2-(2-hydroxyethyl)piperazine (E. F. Rogers and H. J. Becker, U.S. Pat. No. 3,281,423 (1966)) which, in turn, was converted to the chloride. Ring closure in base afforded 1,4-diazabicyclo[ 3.2.1]octane which was acylated with ethylchloroformate to give 4-carbethoxy-1,4-diazabicyclo[ 3.2.1] octane or with diethylcarbamyl chloride to give 4-diethylcarbamyl-1,4-diazabicyclo[ 3.2.1] octane.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].C([Li])CCC.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:31])[C:29]=1[F:30])[CH:25]=O>C1COCC1.CCCCCC.O.C([O-])([O-])=O.[Na+].[Na+]>[CH3:7][C:6](=[CH:25][C:24]1[CH:23]=[C:22]([F:21])[C:29]([F:30])=[C:28]([F:31])[CH:27]=1)[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C)=Cc1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4.3 ml of triethyl 2-phosphonopropionate are dissolved in 30 ml of anhydrous THF and 12.5 ml of a 1.6 N solution of n-butyllithium in hexane are added dropwise at 0° C. The mixture is stirred at RT for 15 minutes and a solution of 3.2 g of 3,4,5-trifluorobenzaldehyde in 8 ml of anhydrous THF is then added dropwise. It is stirred at RT for one hour and allowed to stand at RT for 16 hours. The reaction mixture is diluted with 300 ml of water, 30 ml of a saturated aqueous Na2CO3 solution are added and it is extracted 3 times using 100 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using EA/HEP 1:8 yields 3.8 g if colorless crystals; m.p. 54° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11].S(OC)(O[CH3:21])(=O)=O>[OH-].[K+]>[CH3:21][O:11][C:10]1[C:9]([CH3:12])=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[F:1]
Reactant: Cc1cccc(Oc2ccccc2F)c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Product: COc1c(C)cccc1Oc1ccccc1F
Yield: 80.7 %

Procedure:
Aqueous solution (50 ml) of potassium hydroxide (10.4 g) was added portionwise to a mixture of 6-(2-fluorophenoxy)-o-cresol (13.5 g) and dimethyl sulfate (15.5 g) with stirring under ice-cooling, and the mixture was refluxed under heating for an hour. After cooling, the reaction mixture was extracted with n-hexane, and the extract was washed with 10% aqueous sodium hydroxide and water, dried and then evaporated. The residue was purified by column chromatography (silica gel, benzene.n-hexane) to give oily 2-fluorophenyl 2-methoxy-3-methylphenyl ether (11.6 g).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21](O)[CH:22]=2)[CH:17]=1)=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:21]3[CH:22]=[C:23]4[C:18](=[CH:19][CH:20]=3)[CH:17]=[C:16]([C:14]([O:13][CH3:12])=[O:15])[CH:25]=[CH:24]4)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCC2(CCCC2)CC1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Yield: 61 %

Procedure:
The mixture of spiro[4.5]decan-8-ol (0.915 g, 0.00593 mol), 6-hydroxy-naphthalene-2-carboxylic acid methyl ester (1.00 g, 0.00494 mol) and triphenylphosphine (1.56 g, 0.00593 mol) in toluene (10 mL, 0.1 mol) was heated to reflux, and diisopropyl azodicarboxylate (1.17 mL, 0.00593 mol) was added dropwise and was stirred and refluxed for 6 hours. The mixture was taken up into DCM and subjected to chromatography purification with EtOAc/hexane (0:100 to 40:60) to give product as a white solid (1.02 g, 61%). LCMS Rt=2.58 min, m/z=339.34, (M+1, 100%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:22]=[CH:23][C:24]([F:29])=[C:25]([CH:28]=1)[CH:26]=[O:27].[O:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>C([Sn](CCCC)(CCCC)C1OC=CC=1)CCC>[F:29][C:24]1[CH:23]=[CH:22][C:21]([C:31]2[O:30][CH:34]=[CH:33][CH:32]=2)=[CH:28][C:25]=1[CH:26]=[O:27]
Reactant: C1CCOC1
Reactant: O=Cc1cc(Br)ccc1F
Agent: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1cc(-c2ccco2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Tri(dibenzylideneacetone)-dipalladium (0.18 g, 0.2 mmol), and triphenylphosphine (0.21 g, 0.8 mmol) were dissolved in tetrahydrofuran (60 mL), followed by stirring at room temperature for 30 minutes. Then, 5-bromo-2-fluorobenzaldehyde (0.4 g, 2.0 mmol) and 2-(tributylstannyl)-furan (1.25 mL, 4. 0 mmol) were added thereto, followed by heating under reflux for 10 hours. The mixture was cooled to room temperature, and after the conventional treatment, the residue was purified by silica gel column chromatography (hexane: ethyl acetate=8:1), to give 2-fluoro-5-(2-furyl)benzaldehyde (0.38 g, 100%).