Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([OH:14])[C:9]([OH:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[C:21]([NH:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([OH:14])[C:9]([OH:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1)(=[O:23])[CH3:22]
Reactant: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O

Procedure:
Approximately 1 mmol of 1-aminomethyl-3-phenyl-5,6-dihydroxy-3,4-dihydronaphthalene, from Example 2, was reacted with 1.2 mmol of acetic anhydride in the presence of 1.2 mmol of triethylamine in an excess of methylene chloride. The mixture was washed with 0.1N HCl, and dried. The product was precipitated by addition of ether, collected, and dried. mp 238° C. MS M/Z: 310. Anal. calc. for C19H19NO3.HBr C: 65.03; H, 5.72; N, 3.61; found: C, 73.46; H, 6.13; N, 4.49.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[I:18].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH:13]=[C:12]2[I:18]
Reactant: Fc1cccc(Cl)c1-c1ccc2[nH]cc(I)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4c(F)cccc4Cl)ccc32)cc1
Yield: 46.7 %

Procedure:
This title compound was prepared analogously to compound 25d using 5-(2-chloro-6-fluorophenyl)-3-iodo-1H-indole (23 g, 0.07 mol) and tosyl chloride (17.7 g, 0.09 mol) to obtain the title compound (17.2 g, 46%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12]>>[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]1[O:12][CH2:4]1
Reactant: O=Cc1ccccc1Br
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: Brc1ccccc1C1CO1

Procedure:
Following the procedure of Example 7 and employing 42.0 g of 57% of sodium hydride in mineral oil, 200 g (0.1 mol) of trimethylsulfonium iodide and 70.4 g (0.50 mol) of o-bromo-benzaldehyde there is obtained o-bromostyrene oxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.N1C=NN=N1.[C:18](=[O:21])([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:8]([O:21][CH2:18][N:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[N:12][N:11]=[N:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccccc1-c1nnn[nH]1
Agent: [K+]
Agent: c1nnn[nH]1
Solvent: CN(C)C=O
Product: Brc1ccccc1-c1nnnn1COCc1ccccc1
Yield: 70 %

Procedure:
5-(2-Bromophenyl)-[1H]-tetrazole was nitrogen-protected as the benzyloxymethyl (BOM) ether by reaction of a solution of the tetrazole in anhydrous dimethylformamide with technical grade BOM-chloride and anhydrous potassium carbonate. The reaction was complete in less than 60 minutes and the work up involved filtration through Celite and evaporation of the solvent under reduced pressure. The residue obtained was purified by chromatography to afford the title product in 70% yield as an oil which crystallized on standing.
Reaction SMILES: [C:1]([O:11]C)(=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:23](#[N:25])[CH3:24]>>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:1](=[O:11])[CH2:24][C:23]#[N:25])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(OC)cc1
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=O)CC#N)cc1
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of methyl p-anisate in acetonitrile was cooled to −10° C. Lithium bis(trimethylsilyl)amide (1 M in THF) was added dropwise over a minimum of 3 hr. The mixture was held at −10 to 0° C. until reaction completion. The reaction mixture was quenched with water and the pH adjusted to 3-4 with conc HCl. The mixture was stirred for 1 hr. The product was isolated by filtration, washed with water and dried in a vacuum oven. The yield was 73%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[CH:18]2)#[N:2].[C:24](=[O:27])([O-:26])[O-:25].[K+].[K+].Br[CH2:31][CH:32]1[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]1.O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([O:27][C:24]([O:26][C:3]([CH3:4])([CH3:12])[CH3:1])=[O:25])[CH2:34][CH2:33]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[CH:18]2)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: N#Cc1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)ON1CCC(COc2cc3nccc(Oc4ccc5[nH]ccc5c4)c3cc2C#N)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 118.6 %

Procedure:
After dissolving 6-cyano-4-(1H-indol-5-yloxy)-7-hydroxyquinoline (1.72 g, 5.7084 mmol) in N,N-dimethylformamide (20 ml), there were added potassium carbonate (0.87 g, 6.2792 mmol) and tert-butyl 4-bromomethylpiperidine-1-carboxylate (1.75 g, 6.2792 mmol), and the mixture was heated and stirred at 70° C. for 7 hours. After allowing it to cool to room temperature, water was added, extraction was performed with ethyl acetate and tetrahydrofuran, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure, after which the residue was adsorbed onto silica gel. Purification was performed by silica gel column chromatography (hexane/ethyl acetate system), and then ethyl acetate/ethanol/hexane was added to the obtained yellow oil to precipitate crystals. The crystals were filtered out, washed with hexane:ethanol=10:1 and dried by aspiration to obtain the title compound (1.786 g, 3.3852 mmol, 59.30%) as light yellow crystals.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])([O:3][CH3:4])=[O:2].Br[CH2:13][CH2:14][CH:15]1[O:19][CH2:18][CH2:17][O:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:16]1[CH2:17][CH2:18][O:19][CH:15]1[CH2:14][CH2:13][C:5]1([C:1]([O:3][CH3:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11]
Reactant: COC(=O)C1CCCCC1=O
Reactant: BrCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(CCC2OCCO2)CCCCC1=O

Procedure:
A solution of 2-carbomethoxycyclohexanone (2.0 g, 12.8 mmoles) in 50 mL of DMF was reacted at 70° C. for 15 h with 2-(2-bromoethyl)-1,3-dioxolane (4.6 g, 25 moles) and potassium carbonate (4.8 g, 34.8 mmoles). The reaction mixture was diluted to 500 mL with water and extracted with ethyl ether/ethyl acetate. The organic extracts were dried over sodium sulfate, and the solvent was evaporated to generate the title compound as an oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[C:29]([CH3:34])([CH3:33])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CC(C)(C)C(=O)O
Agent: Cl
Product: CC(C)(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (78 mg, 75%), MS (ISP) m/z=415.5 [(M+H)+], mp 194.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 2,2-dimethyl-propionic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O>[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1ccc(O)c(F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 85.2 %

Procedure:
A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.496 g, 12.03 mmol) in THF (33.4 mL) at room temperature was treated with 2-fluoro-4-methoxyphenol (1.181 mL, 10.03 mmol) and triphenylphosphine (3.16 g, 12.03 mmol). The reaction mixture was cooled to 0° C. and DEAD (40 wt % in toluene, 5.95 mL, 15.04 mmol) was added dropwise via syringe. The resulting reaction mixture was stirred at 65° C. for 5 h, then at room temperature overnight. Flash silica gel chromatography using a gradient of 10% to 100% EtOAc in hexanes gave tert-butyl 4-(2-fluoro-4-methoxyphenoxy)piperidine-1-carboxylate (2.78 g, 85%) as a light yellow oil. ESI-MS m/z [M+Na]+ 348.2.
Reaction SMILES: N[CH2:2][CH2:3][C:4](O)=O.O.[P:8]([O-:17])([O-:16])([O:10][CH2:11][CH:12]([OH:15])[CH2:13]Cl)=[O:9].[Na+:18].[Na+].[OH-].[Na+].[CH2:22](O)C>>[P:8]([O-:17])([O:10][CH2:11][CH:12]1[O:15][CH2:13]1)([O:16][CH2:4][CH2:3][CH2:2][CH3:22])=[O:9].[Na+:18]
Reactant: O=P([O-])([O-])OCC(O)CCl
Reactant: NCCC(=O)O
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCOP(=O)([O-])OCC1CO1
Temperature: 70 °C
Reaction time: 6 h
Yield: 99.3 %

Procedure:
β-Alanine, 30.0 g (0.337 mol), was charged into a reaction vessel, into which 100 ml of water was added and the mixture was stirred. Its temperature was raised to 70° C. and the mixture was homogenized. Then, while maintaining the temperature, an ethanol solution of 750 g (0.112 mol) of sodium butyl glycidyl phosphate, which was prepared by the reaction of 30.2 g (0.112 mol) of sodium 2-hydroxy-3-chloropropyl phosphate and sodium hydroxide in ethanol, followed by purification by desalting, was added dropwise, and stirring was continued for further 6 hours. The reaction was terminated, when the analysis by HPLC indicated extinction of the peak for the raw material and appearance of the peak for the new product. Upon completion of the reaction, the product was collected by fractionation by HPLC. The solvent was evaporated in vacuo to produce 35.8 g of sodium 2-hydroxy-3-N-carboxyethylammoniopropyl phosphate at a yield of 99.3%.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].N1C=CC=CC=1.[F:12][C:13]([F:18])([F:17])[C:14](Cl)=[O:15]>C(Cl)Cl>[CH2:1]([O:3][CH:4]=[CH:5][C:14](=[O:15])[C:13]([F:18])([F:17])[F:12])[CH3:2]
Reactant: O=C(Cl)C(F)(F)F
Reactant: C=COCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC=CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In 150 ml of methylene chloride, 21 ml (0.22 mol) of ethyl vinyl ether and 26.1 g (0.33 mol) of pyridine were dissolved, and 43.8 g (0.33 mol) of trifluoroacetyl chloride was blown into this solution over a period of 30 minutes at room temperature. The mixture was further stirred at room temperature for 2.5 hours. Then, the reaction solution was extracted by an addition of 100 ml of methylene chloride and 100 ml of ice water.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=1[CH2:7]O.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=1[CH2:7][Br:17]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(F)cc1OCC(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Fc1ccc(CBr)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-(2,2,2-trifluoroethoxy)-4-fluorobenzyl alcohol (1.2 g, 5.3 mmol) from Step 2 above in ether (30 mL) was added CBr4 (3.0 g, 9.2 mmol) and triphenylphosphine (2.4 g, 9.2 mmol). The mixture was stirred at ambient temperature for 14 h. Triphenylphosphine oxide was removed by filtration and the filtrate was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (2×50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressureized silica gel column chromatography using a gradient elution of 0-5% EtOAc:hexanes to give 2-(2,2,2-trifluoroethoxy)-4-fluorobenzyl bromide as a colorless oil (HPLC retention time=10.4 min (method A)).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[S:12][C:13]([CH3:15])=[CH:14][C:7]=2[C:6]1=[O:16].C[I:19]>CC(C)=O>[I-:19].[CH3:15][C:13]1[S:12][C:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][NH+:2]([CH3:17])[CH3:1])[C:6](=[O:16])[C:7]=2[CH:14]=1
Reactant: CI
Reactant: Cc1cc2c(s1)CCCN(CCN(C)C)C2=O
Solvent: CC(C)=O
Product: Cc1cc2c(s1)CCCN(CC[NH+](C)C)C2=O
Product: [I-]
Reaction time: 0.5 h

Procedure:
To a solution of 0.9 g of 5-(2-dimethylaminoethyl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one in 30 ml of acetone was added 0.4 ml of methyl iodide at room temperature. After being allowed to stand 30 minutes, the precipitated crystals were collected by filtration and washed with acetone to give 1.1 g of N-[2-(5,6,7,8-tetrahydro-2-methyl-4-oxo-4H-thieno[3,2-c]azepin-5-yl)ethyl]-N,N-dimethylammonium iodide as white crystals, melting at 237°-239° C.
Reaction SMILES: C(OCC1CSC2N(C(=O)C2NC(=O)CC2N=C(C3C=CC=CC=3O)SC=2)C=1C(O)=O)(=O)C.C1(C([O:47][C:48]([C:50]2[N:51]3[CH:54]([S:55][CH2:56][CH:57]=2)[CH:53]([NH:58][C:59](=[O:74])[CH2:60][C:61]2[N:62]=[C:63]([C:66]4[C:71]([OH:72])=[CH:70][CH:69]=[CH:68][C:67]=4[OH:73])[S:64][CH:65]=2)[C:52]3=[O:75])=[O:49])C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[OH:72][C:71]1[CH:70]=[CH:69][CH:68]=[C:67]([OH:73])[C:66]=1[C:63]1[S:64][CH:65]=[C:61]([CH2:60][C:59]([NH:58][CH:53]2[C:52](=[O:75])[N:51]3[CH:54]2[S:55][CH2:56][CH:57]=[C:50]3[C:48]([OH:49])=[O:47])=[O:74])[N:62]=1
Reactant: O=C(Cc1csc(-c2c(O)cccc2O)n1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCSC12
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C(Cc1csc(-c2c(O)cccc2O)n1)NC1C(=O)N2C(C(=O)O)=CCSC12
Yield: 86.3 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8g (145 mg, 0.242 mmol), Et3SiH (0.387 mL, 2.42 mmol), and trifluoroacetic acid (0.746 mL, 9.68 mmol) in dry ClCH2CH2Cl (6 mL) at 0° C. under nitrogen to give 9g (90.5 mg, 86%) as a white solid after crystallization from THF/CH2Cl2 /hexane. mp 165° C. (dec); IR (KBr) 3550-2550 (br), 3282, 1779, 1725, 1665, 1469, 1235 cm-1 ; 1H NMR (DMSO-d6) δ3.43-3.62 (2H, m), 3.76 (2H, s, CH2), 5.00 (1H, d, J=4.8 Hz), 5.67-5.73 (1H, m), 6.42 (3H, d, J=8.1 Hz), 7.07 (1H, t, J=8.1 Hz), 7.41 (1H, s), 9.11 (1H, d, J=8.2 Hz, NH), 12.17 (2H, br s, OH), 13.16 (1H, br s, CO2H); FDMS m/z 433 (M+), 434 (M+ +1); HRMS m/z Calcd for C18H16N3O6S2 (M+ +1): 434.0481, Found: 434.0448.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH2:7])C=C.C[O:9][C:10]([O:13]C)([CH3:12])[CH3:11].[C:15]1([CH3:25])[C:16](S(O)(=O)=O)=[CH:17]C=[CH:19][CH:20]=1.CO>C1(C)C=CC=CC=1>[CH2:16]([C:15]1([CH2:25][O:4][CH2:5][CH:6]=[CH2:7])[CH2:20][CH2:19][O:13][C:10]([CH3:12])([CH3:11])[O:9]1)[CH3:17]
Reactant: COC(C)(C)OC
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: C=CCOCC=C
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CCOCC1(CC)CCOC(C)(C)O1
Yield: 94 %

Procedure:
Trimethololpropane monoallyl ether (174 g) was stirred in toluene (400 ml) with dimethoxypropane (110 g) and toluenesulfonic acid (1 g). The reaction mixture was heated until methanol distilled over and heating continued until distillate was no longer collected. Concentration and vacuum distillaiton (bp 85°-95° C., 1 mm Hg) gave the product in 94% yield.
Reaction SMILES: [C:1](=[O:10])([O:6][CH2:7][CH:8]=[CH2:9])OCC=C.[H-].[Na+].[CH3:13][C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15].Cl>C(OCC)C.O.O1CCCC1>[CH:16]1([C:14]([CH2:13][C:1]([O:6][CH2:7][CH:8]=[CH2:9])=[O:10])=[O:15])[CH2:18][CH2:17]1
Reactant: C=CCOC(=O)OCC=C
Reactant: CC(=O)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)CC(=O)C1CC1

Procedure:
Preparation of the β-ketoester. To a round bottom flask equipped with an addition funnel and cold water condenser was added, 21.3 grams (0.15 mol.) of diallyl carbonate and 50 mL of tetrahydrofuran and the mixture was stirred. Next, sodium hydride, 8.4 grams (0.21 mol.), was added portion-wise. To the reaction mixture was added, 12.6 grams (0.15 mol.) of cyclopropyl methyl ketone (dissolved in 25 mL of tetrabydrofuran) via the addition funnel. The mixture was heated to relux and heated for an additional 1 hour. Subsequently, the mixture was allowed to cool and the solvent was stripped. Next, cold water (50 mL) and 1N hydrochloric acid (50 mL) were added. The reaction mixture was transferred to a separatory funnel and diethyl ether was added. The organic layer was dried over MgSO4 and stripped under vacuum to yield the β-ketoester, carboallyloxymethyl cyclopropyl ketone. ##STR15## (B) Preparation of aryl β-triketone. To a round bottom flask was added 23.6 grams (0.14 mol.) of the β-ketoester, 16 grams (0.14 mol.) of magnesium ethoxide and 100 mL of tetrahydrofuran. The reaction mixture was then refluxed for 2 hours and the solvent stripped to insure complete removal of the ethanol by-product. The flask was then recharged with 100 mL of tetrahydrofuran and 29.3 grams (0.14 mol.) of the aryl acid chloride. The solution was refluxed for several hours, after which the mixture was stripped under vacuum, extracted with diethyl ether and washed with water. The 46.4 grams of β-triketone product, trifluoromethylbenzoylcarboallyloxy-methyl cyclopropyl ketone were confirmed by infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C(Cl)CCl.Cl.[CH3:30][NH:31][O:32][CH3:33]>ClCCl.C(N(CC)CC)C>[CH3:33][O:32][N:31]([CH3:30])[C:12]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]1)=[O:14]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution containing 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (60.4 g, 0.30 mol), hydroxybenzotriazole (49 g, 0.36 mol), EDC (69.4 g, 0.36 mol), and triethyamine (142 ml) in 620 ml of dichloromethane was added N,O-dimethylhydroxyl-amine hydrochloride (35.4 g, 0.36 mol). The mixture obtained was stirred overnight at room temperature. The solution was partitioned between 500 ml of water and 200 ml of dichloromethane, and the aqueous layer was washed with 200 ml of dichloromethane. The combined organic layers were washed with 250 ml of brine, dried over magnesium sulfate, filtered and concentrated to afford tert-butyl 3-{[methoxy(methyl)amino]carbonyl}azetidine-1-carboxylate, which was used without additional purification.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([I:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][NH:19][CH3:20].O>CS(C)=O>[I:11][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1)[N:19]([CH3:20])[CH3:18]
Reactant: CNC
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)c1cc(I)cc([N+](=O)[O-])c1
Temperature: 125 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
1-Fluoro-3-iodo-5-nitrobenzene (500 mg, 1.87 mmol), and potassium carbonate (260 mg, 1.88 mmol) were suspended in DMSO (7 ml) and dimethylamine (2M in THF, 3 ml, 6 mmol) was added. The vial was sealed under argon and stirred for 15 min at 125° C. under microwave conditions. The reaction mixture was poured into 50 ml of water and extracted with ethyl acetate (3×40 ml). The organic phase was washed with brine (1×100 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to obtain 320 mg (59% yield) of the title compound as a brown solid. Purity 100%.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[N+:19]([O-])=O)[CH2:8][C@@H:7]([CH2:22][O:23]C(=O)C)[C@@H:6]1[O:27]C(=O)C)(=O)C.[CH:31](O)(C)[CH3:32]>[Ni]>[Cl:18][C:14]1[C:15]([Cl:17])=[CH:16][C:11]2[N:10]([C@@H:9]3[C@@H:5]([OH:4])[C@@H:6]([OH:27])[C@H:7]([CH2:22][OH:23])[CH2:8]3)[C:31]([CH3:32])=[N:19][C:12]=2[CH:13]=1
Reactant: CC(=O)OC[C@@H]1C[C@H](Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)O
Agent: [Ni]
Product: Cc1nc2cc(Cl)c(Cl)cc2n1[C@H]1C[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
(±)-(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (1.00 g, 2.16 mmol), Raney nickel (Aldrich, slurry in water, 100 mg wet), and isopropanol (200 mL) were shaken under hydrogen (50 psi) for 1.25 hours. Catalyst was filtered off with Celite and the filtrate-wash evaporated to dryness. The residual yellow oil was dissolved in triethylorthoaceate (20 mL) with 1 drop of methanesulfonic acid and the solution stirred at ambient temperature for 18 hours. Volatiles were removed in vacuo and the residue stirred in dioxane (20 mL)-1N sodium hydroxide (10 mL) for 5 hours at ambient temperature. The pH was then adjusted to 1 with concentrated hydrochloric acid and stirring continued for 15 minutes, at which point TLC (silica gel, developed with 20 % methanol-chloroform) showed one UV-absorbing spot at Rf 0.25. The solution was neutralized with sodium hydroxide and volatiles evaporated in vacuo. The residue was chromatograped on a silica gel column and title compound eluted with 10-15% methanol-chloroform. Crystallization from ethanol-methanol-water gave (±)-(1R*,2S*,3S*,5S*)-5-(5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol as fine white crystals (0.482 g, 67%), m.p. 222°-226° C.; 1H-NMR(DMSO-d 6) δ: 8.30 and 7.72 (both s, 2,2 aromatic CH), 5.0-4.8 (m, 3,2 OH and NCH), 4.56 (t, J=5.1 Hz, 1, CH2OH), 4.2-4.1 (m, 2,2 OCH), 3.8-3.5 (m, 2, CH2O ), 2.58 (s, 3, CH3), 2.4-2.2 (m, 1, CH), 2.2-1.9 (m, 2, CH2); mass spectrum (CI): 332 (M+1).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:11])=O.[C:13]1([S:19][C@@H:20]2[CH2:24][NH:23][C@H:22]([C:25](O)=[O:26])[CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[ClH:11].[C:13]1([S:19][C@@H:20]2[CH2:24][NH:23][C@H:22]([C:25]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:26])[CH2:21]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1
Reactant: O=C(O)[C@@H]1C[C@H](Sc2ccccc2)CN1
Solvent: CCOCC
Product: Cl
Product: O=C(OCc1ccccc1)[C@@H]1C[C@H](Sc2ccccc2)CN1

Procedure:
Six hundred ml. of benzyl alcohol are cooled to 10° and, with vigorous stirring, there is added over the course of 30 minutes, 100 grams of thionyl chloride, while the temperature is maintained at 10°. To this solution there is added, at 10°, 50 grams of cis-4-(phenylthio)-L-proline and the mixture stirred for 48 hours at room temperature. To this reaction mixture there is then added 4 liters of anhydrous ether and the mixture stirred vigorously with cooling. The precipitated solid is filtered, washed with ether and dried to yield the desired 4-(S)-(phenylthio)-L-proline, phenylmethyl ester hydrochloride salt.