Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH:22]([CH2:29][CH3:30])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([O:19][CH2:30][CH2:29][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1c(O)c2cccc(O)c2oc1=O
Reactant: CCOC(=O)CC(Br)CC
Product: CCCCCCOc1c(O)c2cccc(OCCCCC(=O)OCC)c2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-hexyloxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopentanoate was used in place of ethyl bromoacetate in Reference Example 3, 3-hexyloxy-4-hydroxy-8-(4-ethoxycarbonylbutoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [OH:1][C:2]1([CH:5]2[CH2:9][CH:8]([O:10][CH3:11])[CH2:7][N:6]2[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:4][CH2:3]1.[CH3:22]I.[H-].[Na+]>C1COCC1>[CH3:11][O:10][CH:8]1[CH2:7][N:6]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH:5]([C:2]2([O:1][CH3:22])[CH2:3][CH2:4]2)[CH2:9]1
Reactant: CI
Reactant: COC1CC(C2(O)CC2)N(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CC(C2(OC)CC2)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of benzyl 2-(1-hydroxycyclopropyl)-4-methoxypyrrolidine-1-carboxylate (312 mg, 1.07 mmol) dissolved in THF (3.6 mL) at 0° C. was added methyl iodide (0.23 mL, 3.68 mmol) followed by sodium hydride (56.5 mg, 2.36 mmol). The mixture was stirred for 2 hours at room temperature. The reaction was quenched with ice, and diluted with diethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% methanol/dichloromethane, linear gradient) to afford benzyl 4-methoxy-2-(1-methoxycyclopropyl)pyrrolidine-1-carboxylate. MS ESI calc'd. for C17H23NO4 [M+H]+ 306. found 306.
Reaction SMILES: C1([C@H]([N:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)C)C=CC=CC=1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>ClCCl>[CH2:24]([O:23][C:21]([N:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C[C@H]1CCN([C@H](C)c2ccccc2)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 16 h
Yield: 76 %

Procedure:
A 12 g (45.9 mmol) portion of (3R)-ethyl 1-[(R)-1-phenylethyl]pyrrolidine-3-acetate known in literatures was dissolved in 100 ml of dichloromethane to which was subsequently added dropwise 7.87 ml (55.1 mmol) of benzyl chloroformate at room temperature. After completion of the dropwise addition, the mixture was stirred for 16 hours at the same temperature. After completion of the reaction, the reaction mixture was concentrated. Thereafter, the resulting residue was applied to a silica gel column chromatography to yield 10.1 g (76%) of the title compound as an oily substance from the eluate of n-hexane:ethyl acetate=5:1.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:40][CH2:41][CH3:42]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:40][CH2:41][CH3:42])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 8.0 mg, 0.018 mmol) in DMF (1.0 ml) was reacted with K2CO3 (8.0 mg, 0.055 mmol) and 1-iodopropane (9.0 μl, 0.092 mmol) to yield the title compound as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](=[O:11])([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[OH:7][CH:1]([CH3:6])[CH2:2][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:3][CH:4]([CH3:5])[CH2:8][OH:11]
Reactant: Oc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)COc1ccccc1CC(C)CO
Temperature: 25 °C

Procedure:
To the phenol T81-6(S) (1.4 g, 8.42 mmol, 1.0 eq) in DMF (16 mL) was added potassium carbonate (1.6 g, 8.42 mmol, 1 eq), and (R)-methylcarbonate (T81-A, 0.73 mL, 8.42 mmol, 1.0 eq). The resulting mixture was stirred at 85° C. for 72 h with monitoring of the reaction by TLC [(ethyl acetate/hexanes:2/8); Rf=0.30, UV, CMA]. The mixture was cooled to room temperature and brine was added. The aqueous phase was extracted with ethyl acetate and the combined organic phases were extracted with brine. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/hexanes, 2/8, Rf=0.30) to give T81-7(1R,8S) (1.45 g, 76%). Use of (S)-methylcarbonate in this reaction led to T81(1S,8S) containing a (1S)-stereocenter through the same transformations as described below for the corresponding (1R)-isomer.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16](=[O:17])[C:10]2([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:9]1)=O)(C)(C)C.CS(O)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][C:10]12[C:16](=[O:17])[N:15]([CH2:18][C:19]([F:21])([F:22])[F:20])[C:14](=[O:23])[N:11]1[CH2:12][CH2:13][NH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)C2(Cc2ccccn2)C1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1N(CC(F)(F)F)C(=O)C2(Cc3ccccn3)CNCCN12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of 1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (prepared as described in Step 5, 1.89 g, 4.4 mmol) in CH2Cl2 (20 mL) was added MeSO3H (2.14 g, 22 mmol). The reaction mixture was stirred at room temperature for one hour. Triethylamine (2.45 g, 24.2 mmol) was added to the solution. The organic layer was washed with 100 mL of H2O, brine, dried over MgSO4, and concentrated to give a 1.4 g of the title compound as a yellow oil (97%). The oil solidified upon granulation in hexane or upon cooling.
Reaction SMILES: [C:1]1([OH:8])[C:5](=O)[C:3](=[O:4])[C:2]=1[OH:7].[CH3:9][C:10]([C:13]1[O:14][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][C:17](=[CH:19]C2C(Cl)(Cl)C(=O)C=2Cl)[CH:18]=1)([CH3:12])[CH3:11]>OS(C(F)(F)F)(=O)=O>[CH3:12][C:10]([C:13]1[O:14][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][C:17](=[CH:19][C:5]2[C:3](=[O:4])[C:2](=[O:7])[C:1]=2[OH:8])[CH:18]=1)([CH3:9])[CH3:11]
Reactant: O=c1c(O)c(O)c1=O
Reactant: CC(C)(C)C1=CC(=CC2=C(Cl)C(=O)C2(Cl)Cl)C=C(C(C)(C)C)O1
Agent: O=S(=O)(O)C(F)(F)F
Product: CC(C)(C)C1=CC(=Cc2c(O)c(=O)c2=O)C=C(C(C)(C)C)O1
Reaction time: 5 h
Yield: 87 %

Procedure:
This Example illustrates the preparation, by a reaction analogous to D→E shown in FIG. 1, of the squaric acid derivative of Formula II in which Q1 is a 2,6-bis(1,1-dimethylethyl)-4-pyrylidene grouping and R1 is a hydrogen atom. 3-[2,6-Bis(1,1-dimethylethyl)-(4H-pyran-4-ylidene)-methyl]-2,4,4-tri-chlorocyclobut-2-en-1-one (100 mg, 0.27 mmole, prepared in Example 47 above), was dissolved in triflic acid (1 mL) and the resultant solution heated at 60° C. for 1 hour, 80° C. for a further 2 hours, and finally at 105° C. for 5 hours. The hot mixture was then poured over ice, and the resultant mixture stirred to give a solid precipitate. The mixture was extracted several times with dichloromethane, and the extracts were combined, washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was redissolved in dichloromethane and applied to two preparative silica gel chromatography plates. Elution with 8% methanol in dichloromethane resulted in the development of many minor bands, with a major yellow band streaking from the origin. The major yellow band was extracted with methanol, the resultant solution evaporated to dryness, the residue dissolved in dichloromethane, and the solution filtered and evaporated to dryness. Pumping under high vacuum gave a yellow-brown solid (70 mg, 87% yield). The structure of the product was confirmed by proton NMR spectroscopy.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cccnc2)C1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CN(C(=O)c2ccco2)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl)amine 17 (99 mg, 0.34 mmol) and piperidinomethyl polystyrene resin (100 mg) in 1 mL of dry CH2Cl2 was added 2-furoyl chloride (95%, 56.0 mg, 1.2 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded furan-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amide 20 (80 mg, 61%). LRMS 286 (M−100)+.
Reaction SMILES: [Na].[CH3:2][NH:3][C:4](=[O:6])[CH3:5].[CH3:7][CH:8]=[CH:9][SiH:10](Cl)Cl>C1(C)C=CC=CC=1>[CH3:7][CH:8]=[CH:9][SiH:10]([N:3]([CH3:2])[C:4](=[O:6])[CH3:5])[N:3]([CH3:2])[C:4](=[O:6])[CH3:5]
Reactant: CC=C[SiH](Cl)Cl
Reactant: CNC(C)=O
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC=C[SiH](N(C)C(C)=O)N(C)C(C)=O

Procedure:
The amidosilanes can be prepared, by the following illustration: mixing a sodium salt of N-methylacetamide with methylvinyldichlorosilane in an inert organic solvent such as toluene, filtering the by-produced sodium chloride from the toluene-product solution and thereafter removing the toluene by vacuum distillation to obtain the product, methylvinyldi-(N-methylacetamido)silane.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.B(O)O>>[N:8]1([C:6]2[N:7]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([CH2:24][OH:23])=[CH:26][CH:27]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Agent: OBO
Product: OCc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 4-(hydroxymethyl)phenylboronic acid as a boronic acid, the desired compound was obtained.
Reaction SMILES: C(=O)([O-])[O-].[Sr+2:5].[C:6]([OH:14])(=[O:13])[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>O>[C:6]([O-:14])(=[O:13])[CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11].[Sr+2:5]
Reactant: O=C(O)CCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Sr+2]
Solvent: O
Product: O=C([O-])CCCC(=O)[O-]

Procedure:
Strontium carbonate (1.0 g, 6.77 mmol) and glutaric acid (0.89 g, 6.77 mmol) in water (30 ml) were stirred over night at 70.degree. C. The mixture was filtered and the filtrate was evaporated to dryness and dried in vaccuo at ambient temperature. The title compound was isolated. Yield 1.23 g (83%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)(Cl)Cl>[Br:17][CH2:16][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC=C(C(=O)OC)c1cccc(Cl)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(C(=O)OC)c1cccc(Cl)c1CBr
Temperature: 25 °C

Procedure:
27.0 g of methyl α-(3-chloro-2-methylphenyl)-β-methoxy-acrylate and 21.5 g of N-bromosuccinimide were stirred in 300 ml of anhydrous tetrachloromethane. After 1 g of Porofor N had been added, the mixture was refluxed for 4 hours. After cooling to room temperature (=25° C.), the succinimide was removed. The combined organic phases were washed with water, dried over sodium sulfate and concentrated. This gave 23 g of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.CS([C:18]1[N:23]=[CH:22][C:21]2=[CH:24][CH:25]=[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[N:20]2[N:19]=1)=O.[F-].[Cs+].C(N(CC)C(C)C)(C)C.C(O)(C)(C)C>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]1[N:20]2[C:21]([CH:22]=[N:23][C:18]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:13][N:12]=3)=[N:19]2)=[CH:24][CH:25]=1
Reactant: CN1CCN(c2ccc(N)nc2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCN(C)CC4)cn3)nn12
Temperature: 120 °C

Procedure:
Into a 8-dram vial, 5-(4-Methyl-piperazin-1-yl)-pyridin-2-ylamine (0.154 g, 0.804 mmol), 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.105 g, 0.365 mmol), Cesium fluoride (0.139 g, 0.914 mmol), N,N-Diisopropylethylamine (0.1400 mL, 0.8039 mmol) and tert-Butyl alcohol (2.00 mL, 20.9 mmol) were added. The reaction was heated at 120° C. overnight. LCMS suggested presence of desired product. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[5-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-amine as a yellow solid (30 mg, 22%). LCMS (E/I+) 416.18 (M+H). NMR 1H (DMSO-d6)-9.80 (s, 1H), 9.72 (bs, 1H), 9.01 (s, 1H), 7.99 (s, 1H), 7.90 (d, 1H, J=9.58 Hz), 7.80 (d, 1H, J=7.49), 7.53 (d, 1H, J=9.38 Hz), 7.47 (d, 1H, J=7.59 Hz), 7.24 (d, 1H, J=8.04 Hz), 7.14 (t, 1H, J=7.15 Hz), 7.01 (s, 2H), 3.80 (bs, 5H), 3.55 (d, 2H, J=11.72 Hz), 3.19 (q, 2H, J=10.34 Hz), 2.96 (t, 2H, J=11.72 Hz), 2.83 (s, 3H).
Reaction SMILES: N(OCCC(C)C)=O.[Cl:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=1.[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:20]=1N>>[Cl:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][C:15]=1[C:20]1[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:19]=1[Cl:18]
Reactant: COc1cccc(Cl)c1
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Agent: CC(C)CCON=O
Product: COc1ccc(-c2cc(Cl)c(Cl)cc2Cl)c(Cl)c1
Reaction time: 18 h

Procedure:
Isoamyl nitrite (18.8 mL, 0.140 mol) was added portionwise over the course of 1 hour to a mixture of 3-chloroanisole (100 g, 0.70 mol) and 2,4,5-trichloroaniline (13.75 g, 0.070 mol) at 120° C. under nitrogen and the reaction was allowed to stir an additional 18 hours, and then distilled (0.2 mmHg, 160-185° C.) to yield 14.07 g (62%). A 300 mg portion of the distillate was further purified via flash chromatography (silica gel, hexane eluent). Fraction 1 (32.2 mg, Rf=0.33; GC RT=14.44 minutes) was identified as 2′,4,4′,5′-tetrachloro-2-methoxybiphenyl. Fraction 2 (75.2 mg, Rf=0.22) contained a mixture of two products in a 40:60 ratio. Through subsequent demethylation and separation, these were determined to be the 2,2′,4′,5′-tetrachloro-6-methoxy and 2,2′,4′,5′-tetrachloro-4-methoxybiphenyl derivatives (GC retention time=14.01, 14.69 minutes respectively).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]1([S:48](Cl)(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:42]1([S:48]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccccc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 86 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.171 g, 0.371 mmol) was dissolved in dichloromethane (3.5 mL), and the solution was treated with triethylamine (0.103 mL, 0.741 mmol) and benzenesulfonyl chloride (0.0570 mL, 0.446 mmol), followed by purification by flash column chromatography (chloroform/methanol=85/15) to obtain 4-benzenesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.192 g. yield 86%).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=3[F:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH2:9][CH3:10].[CH:31](=[O:34])[CH2:32][CH3:33].Cl>CCCCCC.O1CCCC1>[CH2:6]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:31]([OH:34])[CH2:32][CH3:33])=[C:25]([F:29])[C:24]=3[F:30])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCC=O
Reactant: CCCCCc1ccc(-c2ccc(-c3cccc(F)c3F)cc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(-c3ccc(C(O)CC)c(F)c3F)cc2)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
6.45 ml of 1.6N butyllithium solution in n-hexane are added dropwise within 5 minutes at -50° C. to a solution of 3.15 g of 1-[4-(4-pentylphenyl)-phenyl]-2,3-difluorobenzene and the reaction mixture is left to react at the same temperature for 3 hours. Then, a solution of 652 mg of propionaldehyde in 4 ml of tetrahydrofuran is added and the mixture is left to warm slowly to room temperature. After 15 hours it is treated with 10 ml of 1N hydrochloric acid, partitioned between methylene chloride and water, the organic phase is washed with saturated sodium bicarbonate solution and dried over anhydrous magnesium sulphate. Evaporation of the solvent and chromatography of the residue on silica gel with 5-20% ethyl acetate in petroleum ether gives 3.2 g of 1-[4-(4-pentylphenyl)-phenyl]-2,3-difluoro-4(1-hydroxypropyl)-benzene.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][C:20](O)=O)C1C=CC=CC=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[OH:44][C:45]1[CH:46]=[CH:47][C:48]2[O:53][CH2:52][CH:51]([CH2:54][NH2:55])[O:50][C:49]=2[CH:56]=1>CN(C=O)C>[OH:44][C:45]1[CH:46]=[CH:47][C:48]2[O:53][CH2:52][CH:51]([CH2:54][NH:55][CH2:20][CH2:19][CH2:18][C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=4)[NH:14][CH:13]=3)[O:50][C:49]=2[CH:56]=1
Reactant: O=C(O)CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: NCC1COc2ccc(O)cc2O1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)OC(CNCCCc1c[nH]c3ccc(O)cc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
5-Benzyloxyindole-3-propionic acid (1.5 g, 5.0 mmole), 1-hydroxybenzotriazole hydrate (0.8 g, 6.0 mmole) and 1,3-diisopropylcarbodiimide (1.9 ml, 12.0 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.1 g, 5.0 mmole) in 50 ml of DMF and the mixture was further stirred for 48 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on silica gel using ethyl acetate as eluant. Fractions containing product were concentrated and recrystallized from ethyl acetate to give 1.6 g (68%) of the desired product, (7-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-(5-hydroxy-1H-indol-3-yl)-propanamide, as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14](=[N:16][OH:17])[NH2:15])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:20](Cl)(=O)[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]3[N:15]=[C:20]([CH2:21][CH3:22])[O:17][N:16]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NC(=NO)c1ccc(OCCCn2ccnc2)cc1
Reactant: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCc1nc(-c2ccc(OCCCn3ccnc3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
There was suspended, in 5 ml of dry pyridine, 521 mg of 4-[3-(1H-imidazol-1-yl)propoxy]benzamidoxime. After gradual and dropwise addition of 194 mg of propionyl chloride and stirring at room temperature for one hour, the suspension was heated to a temperature ranging from 80° to 90° C. for 3.5 hours with stirring. The suspension was added to ice water and the pH thereof was adjusted to 9 to 10 by the addition of potassium carbonate. Then the suspension was extracted with ether and the extract was washed with water and then dried. After concentration of the extract, the resulting residue was purified by silica gel column chromatography (eluent: 98% chloroform-ethanol). n-Hexane was added to the resulting fraction to crystallize the product, followed by filtration to give 431 mg (yield 72.2%) of 3-[4 -[3-(1H-imidazol-1-yl)propoxy]phenyl]-5-ethyl-1,2,4-oxadiazole having a melting point of 74.0°-75.5 ° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:29])[CH3:28])[CH:22]=1)=[O:19]>>[CH3:29][N:27]([CH3:28])[C:23]1[CH:22]=[C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:15]([NH:14][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[O:12])[CH:16]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Reactant: O=C(Cl)c1ccc2ncccc2c1
Product: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc2ncccc2c1

Procedure:
Using an analogous procedure to that described in Example 2, 6-quinolylcarbonyl chloride was reacted with 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide to give the title compound; NMR Spectrum: (DMSOd6) 2.35 (s, 3H), 2.91 (s, 6H), 6.58 (m, 1H), 7.2 (m, 2H), 7.43 (d, 1H), 7.65 (m, l1H), 7.82 (d, 1H), 8.01 (s, l1H), 8.17 (m, 2H), 8.32 (d, 1H), 8.59 (d, 1H), 8.7 (d, 1H), 9.02 (s, 1H), 10.05 (s, 1H), 10.32 (s, 1H); Mass Spectrum: M+H+425.