Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]([CH3:13])([CH3:12])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:11])[CH2:8][CH:9]=O.[CH2:14]([O:16][C:17]([CH:19]=[C:20]([CH3:30])[CH2:21]P(=O)(OCC)OCC)=[O:18])[CH3:15].[CH:31]([O-])(C)C.[Na+]>CN(C)C=O>[CH3:1][S:2][C:3]([CH3:13])([CH3:12])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:11])[CH2:8][CH:9]=[CH:21][C:20]([CH3:30])=[CH:19][C:17]([O:16][CH:14]([CH3:15])[CH3:31])=[O:18]
Reactant: CSC(C)(C)CCCC(C)CC=O
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 10 g. of 7-methylthio-3,7-dimethyloctan-1-al, 17 g. of diethyl 3-ethoxycarbonyl-2-methylprop-2-enyl-phosphonate (77% trans), and 150 ml. of dimethylformamide, under nitrogen, 0°, with stirring, is added sodium isopropanolate (prepared from 1.5 g. of sodium in 150 ml. of isopropanol). After addition is complete, the reaction is stirred for 18 hours at room temperature and then worked up by extraction with hexane to yield isopropyl 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoate (mostly trans-2,trans-4) which can be chromatographed and distilled for further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:23][C@H:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:25][CH3:26])[CH2:5][C:6]1[CH:22]=[CH:21][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:23][C@H:24]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:25][CH3:26])[CH2:5][C:6]1[CH:22]=[CH:21][C:9]2[O:10][C@@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:40](=[O:42])[CH3:41])=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(O)cc1)O2)C(=O)OC)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OC(C)=O)cc1)O2)C(=O)OC)c1ccccc1
Reaction time: 2.5 h

Procedure:
To a solution of (S)-3-[(S)-2-(4-hydroxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (120 mg) in DCM (3 mL) was added pyridine at 0° C. To this mixture was added acetic anhydride. The mixture was stirred for 2-3 h. After completion of the reaction, the mixture was diluted with DCM (20 mL) and was washed with water, 1N HCl and brine solution. The organic layer was dried and concentrated to get the desired product as a white solid (110 mg). LCMS (m/z): 491.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1O.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[O:4][CH2:1][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Yield: 141.3 %

Procedure:
Potassium carbonate (4.14 g; 30 mmol) was added to a solution of 3,4-dihydroxy-1-nitrobenzene (1.55 g; 10 mmol) and benzyl bromide (3.42 g; 20 mmol) in acetone (100 ml). The reaction mixture was refluxed for 12 hours. After the removal of the solvent under reduced pressure, the residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The ethyl acetate layer was washed with water (100 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 2.37 g of 3,4-Dibenzyloxy-1-nitro benzene. (Yield=70%)
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][C:14]1[C:22]([Cl:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(O)C.C(Cl)(Cl)(Cl)Cl>[Cl:13][C:14]1[C:22]([Cl:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: O=C(Cl)c1cc(F)c(F)c(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.3 %

Procedure:
Magnesium turnings (0.77 g) and carbon tetrachloride (0.4 ml) was added to absolute ethanol (5.3 ml). To the stirring suspension was added a solution of diethyl malonate (4.89 g) and absolute ethanol (8.5 ml) in toluene (21.3 ml) dropwise during 40 minutes at 20° to 40° C. The mixture was stirred at 50° to 60° C. for 2 hours, and then cooled in an acetone-dry ice bath. A solution of 2,3-dichloro-4,5-difluorobenzoyl chloride (6.00 g) in anhydrous toluene (7.1 ml) was added dropwise to the resulting solution at -18° to -13° C. during 10 minutes. The mixture was warmed gradually to room temperature during 2 hours and then mixed with ice water (17 ml) containing concentrated sulfuric acid (1.1 ml). The resulting organic layer was collected and the water layer was extracted with toluene. The combined organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated to give the title compound (9.68 g) as pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][C:7]1([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]2[O:34][CH:33]([CH2:35]Br)[CH2:32][C:31]=2[CH:37]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][C:7]1([OH:13])[CH2:8][CH2:9][N:10]([CH2:35][CH:33]2[CH2:32][C:31]3[CH:37]=[C:27]([O:26][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:28]=[CH:29][C:30]=3[O:34]2)[CH2:11][CH2:12]1
Reactant: OC1(Cc2cccc(C(F)(F)F)c2)CCNCC1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Product: OC1(Cc2cccc(C(F)(F)F)c2)CCN(CC2Cc3cc(OCc4ccccc4)ccc3O2)CC1

Procedure:
The title compound MS: m/e=498.6 (M+H+) was prepared from 4-(3-trifluoromethyl-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: [Br:1][C:2]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2Cl.[NH3:26]>CO>[Br:1][C:2]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2[NH2:26]
Reactant: N
Reactant: COc1cc(Cn2cnc3c(Cl)nc(N)nc32)c(Br)c(OC)c1OC
Solvent: CO
Product: COc1cc(Cn2cnc3c(N)nc(N)nc32)c(Br)c(OC)c1OC

Procedure:
A solution of 9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine (see example 51) in MeOH was treated with NH3 (7N in MeOH) in a pressure vessel at 90° C. for 16 h. Work-up and purification by preparative TLC (EtOAc:hexane 3:1) gave the title compound. HPLC Rt: 4.884 min. 1H-NMR (DMSO-d6): δ 7.67 (s, 1H), 6.71 (s, 2H), 6.60 (s, 1H), 5.84 (s, 2H), 5.17 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.66 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=2[Cl:34])=[CH:22][C:18]=1[C:19](Cl)=[O:20])[CH3:15]>C1(C)C=CC=CC=1>[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=2[Cl:34])=[CH:22][C:18]=1[C:19]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:20])[CH3:15]
Reactant: CCSc1ccc(Oc2ccc(Br)cc2Cl)cc1C(=O)Cl
Reactant: OC1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCSc1ccc(Oc2ccc(Br)cc2Cl)cc1C(=O)OC1CCOC1
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-ethylthio-5-(2-chloro-4-bromophenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-ethylthio-5-(2-chloro-4-bromophenoxy)benzoate.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42]N>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:38]4[C:37](=[C:36]([CH3:35])[CH:41]=[CH:40][CH:39]=4)[NH:42][C:22]=3[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccc([N+](=O)[O-])cc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 538.8 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1)=[O:3].[N+:11]([O-])([OH:13])=[O:12].OS(O)(=O)=O>>[CH3:1][C:2]([C:4]1[CH:5]=[C:6]([Cl:10])[CH:7]=[CH:8][C:9]=1[N+:11]([O-:13])=[O:12])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1cccc(Cl)c1
Agent: O=S(=O)(O)O
Product: CC(=O)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
The intermediates, 5-alkylamino-2-aminoacetophenones (60-62) were prepared according to the methods reported before. As shown in Scheme 6, the starting 3-chloroacetophenone (54) was first nitrated with HNO3/H2SO4 to form the 5-chloro-2-nitroacetophenone (55) and 5-chloro-4-nitroacetophenone (56). Compound 55 was reacted separately with various alkylamines to yield the corresponding 5-alkylamino-2-nitroacetophenones (57-59). Catalytic hydrogenation of compounds 57-59 yielded the corresponding 5-alkylamino-2-aminoacetophenones (60-62). L. Ll, K. K. Wang, S. C. Kuo, T. S. Wu, D. Lednicer, C. M. Lin, E. Hamel and K. H. Lee, J. Med. Chem., 37, 1126-35. (1994), which is herein incorporated by reference in its entirety.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])([O-])=O.[H][H]>[Pd].CN(C=O)C>[CH:11]1[CH:10]=[C:9]2[C:8](=[O:13])[N:7]([CH:14]3[C:15](=[O:21])[NH:16][C:17](=[O:20])[CH2:18][CH2:19]3)[CH2:6][C:5]2=[C:4]([NH2:1])[CH:12]=1
Reactant: O=C1CCC(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 30 °C

Procedure:
Into a 5.0 L 4 necked RB flask, charged 100.0 g of 3-(4-nitro-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione, 10.0 g of 10% Pd/C and 3200 ml of DMF under nitrogen atmosphere. Stirred the mass and raise the reaction mass temperature to 60 -65° C. Started the hydrogen gas bubbling into reaction mass at temperature 60-65° C. for 6 hours. The progress of the reaction is monitored by TLC. Cooled the mass to temperature 25to 30° C. Filtered the catalyst Pd/C under plant vacuum in the presence of nitrogen atmosphere and wash with dimethylformamide; wet Pd/C is transferred into a polythene bag for recovery. Distilled off the above organic layer solvent completely under vacuum below 60° C. Charged ethyl acetate 800 ml (lot-I) to the mass and stirred for 60 min. Filtered the solid and wash with 200 mL of ethyl acetate (Lot-II). Dried the above wet material in a oven at temperature 65-75° C. for 120-180 min. Dried Weight of the compound is 78.0 g.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([O:16][CH:17]([F:19])[F:18])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[N:12]2)=[CH:7][CH:6]=1)C.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[F:19][CH:17]([F:18])[O:16][C:15]1[N:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][CH:9]=2)[N:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=1
Reactant: CCOC(=O)c1ccc(-n2nc(C(F)(F)F)cc2OC(F)F)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCc1ccc(-n2nc(C(F)(F)F)cc2OC(F)F)cc1
Yield: 112.1 %

Procedure:
A solution of 4-(5-difluoromethoxy-3-trifluoromethyl-pyrazol-1-yl)-benzoic acid ethyl ester (0.4 g, 1.1 mmol) in dry toluene (8.0 mL) was stirred and 1M solution of DIBAL-H in toluene (1.33 mL, 1.33 mmol) was added. The resultant solution was stirred at room temperature for 10 minutes. The mixture was quenched with saturated aqueous NH4Cl (40 mL) and extracted with EtOAc (3×40 mL). The organics were washed with water and brine. The solvent was removed under reduced pressure and purification of the resulting residue by chromatography (SiO2, 10:1 Hexane/EtOAc) gave [4-(5-difluoromethoxy-3-trifluoromethyl-pyrazol-1-yl)-phenyl]-methanol (380 mg, 99% yield) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][O:17][CH2:18][C:19](Cl)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:19]([CH2:18][O:17][CH3:16])=[N:15][N:14]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)Cl
Reactant: NNc1ccc(-c2cccc(Cl)c2)nn1
Product: COCc1nnc2ccc(-c3cccc(Cl)c3)nn12

Procedure:
As for Example 4, 6-(3-chlorophenyl)-3-hydrazinopyridazine (prepared as in Example 51 of U.S. Pat. No. 4,112,095) is reacted with methoxyacetyl chloride to give the product of the Example.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:31])=[C:7]([C:22]([N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])=[O:23])[C:8]([I:21])=[C:9]([C:19]=1[I:20])[C:10]([N:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15])=[O:11])(=[O:3])[CH3:2].[OH-:32].[K+].B(O)(O)O.[O:38]1[CH2:40][CH:39]1[CH2:41][C:42]([CH2:48][CH:49]1[CH2:51][O:50]1)([OH:47])[CH2:43][CH:44]1[CH2:46][O:45]1>CO.O>[OH:18][CH2:17][CH2:16][N:12]([CH2:13][CH2:14][OH:15])[C:10]([C:9]1[C:19]([I:20])=[C:5]([N:4]([CH2:51][CH:49]([OH:50])[CH2:48][C:42]2([OH:47])[CH2:41][CH:39]([CH2:40][OH:38])[O:45][CH:44]([CH2:46][N:4]([C:5]3[C:19]([I:20])=[C:9]([C:10]([N:12]([CH2:13][CH2:14][OH:15])[CH2:16][CH2:17][OH:18])=[O:11])[C:8]([I:21])=[C:7]([C:6]=3[I:31])[C:22]([N:24]([CH2:25][CH2:26][OH:27])[CH2:28][CH2:29][OH:30])=[O:23])[C:1](=[O:32])[CH3:2])[CH2:43]2)[C:1](=[O:3])[CH3:2])[C:6]([I:31])=[C:7]([C:22](=[O:23])[N:24]([CH2:25][CH2:26][OH:27])[CH2:28][CH2:29][OH:30])[C:8]=1[I:21])=[O:11]
Reactant: CC(=O)Nc1c(I)c(C(=O)N(CCO)CCO)c(I)c(C(=O)N(CCO)CCO)c1I
Reactant: [OH-]
Reactant: OC(CC1CO1)(CC1CO1)CC1CO1
Agent: OB(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)N(CC(O)CC1(O)CC(CO)OC(CN(C(C)=O)c2c(I)c(C(=O)N(CCO)CCO)c(I)c(C(=O)N(CCO)CCO)c2I)C1)c1c(I)c(C(=O)N(CCO)CCO)c(I)c(C(=O)N(CCO)CCO)c1I
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-Acetylamino-N,N,N′,N′-tetrakis-(2-hydroxy-ethyl)-2,4,6-triiodo-isophthalamide (5 g, 6.45 mmol) was added to a stirring solution of potassium hydroxide (0.57 g, 10.1 mmol) in a mixture of methanol (3.5 ml) and water (3.5 ml). To the clear and slightly yellow solution which was obtained was added boric acid (0.35 g, 5.6 mmol). The pH was continuously maintained at pH 12.6 by addition of potassium hydroxide (10 M) and then 1,3-bis-oxiranyl-2-oxiranylmethyl-propan-2-ol (0.22 g, 1.09 mmol) was added. The pH of the solution was continuously maintained within the interval 12 and 13 by addition of solid boric acid for 5 hours. And the mixture stirred at ambient temperature overnight (20 hours). LC-MS investigation showed formation of the expected product. Using 18.5 M HCl ({umlaut over ( )}50%), the mixture was made acidic, pH 3.5-4.5 and stirred overnight again. Precipitation of unreacted monomer had occurred and removed by filtration of the mixture (funnel sinter 3) and the filter cake washed with water (2×5 ml). The filtrate was then treated with ion exchangers (AMB200C, 9 ml) and (IRA-67, 10 ml). The resins were removed by filtration and rinsed with water and the combined aqueous volume was reduced in vacuo. The crude product was purified by preparative HPLC (column Phenomenex Luna C18 (2) 10 μm 250×50.0 mm, solvents: A=water and B=acetonitrile; gradient 0-10% B over 60 min; flow 50.0 ml/min, UV detection at 214 nm and 254 nm). After freeze-drying, 290 mg of the title product was obtained.
Reaction SMILES: [CH2:1]1[O:15][C:4]2([CH2:9][CH2:8][C:7]([CH2:11][CH2:12][CH:13]=C)([OH:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[BH4-].[Na+].C[OH:19]>>[CH2:1]1[O:15][C:4]2([CH2:9][CH2:8][C:7]([CH2:11][CH2:12][CH2:13][OH:19])([OH:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: CO
Reactant: C=CCCC1(O)CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Product: OCCCC1(O)CCC2(CC1)OCCO2

Procedure:
A mixture of 4-(3-Butenyl)-4-hydroxy-cyclohexanone ethylene ketal (1.8 g) in methanol (40 mL) was ozonized at -70° C. until a persistant blue color was obtained. The ozonide was decomposed with excess sodium borohydride at -60° C. The reaction was concentrated in vacuo and the residue was partitioned between brine and ethyl acetate. The aqueous layer was extracted several more times with ethyl acetate and the combined organic extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash chromatography with ethyl acetate as the eluent to afford 4-(3-Hydroxypropyl)-4-hydroxy-cyclohexanone ethylene ketal as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.C[C:12]([CH3:15])([O-:14])C.[K+].[Cl-].[NH4+].C1C[O:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[CH:20][C:21]([O:14][CH2:12][CH3:15])=[O:22]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Product: CCOC(=O)C=Cc1c(Cl)cccc1Cl
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a solution of 2,6-dichlorobenzaldehyde (350 mg, 2.0 mmol) and triethyl phosphonoacetate (448 mg, 2.6 mmol) in THF (5 mL), potassium tert-butoxide (291 mg, 2.6 mmol) was added under ice cooling, and at the same temperature, the mixture was stirred for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Further, the residue was purified by chromatography on a silica gel column (hexane/ethyl acetate=50/1) to yield the title compound as a colorless syrupy substance (yield: 65.1%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][CH:18]=[C:17]([C:21](Cl)=[O:22])[CH:16]=1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:17]1[CH:16]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1cccc(-c2ccccc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccccc2)c1
Yield: 35.5 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide was obtained following Method C starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g, 0.424 mmol), biphenyl-3-carbonyl chloride (0.0965 g; 0.445 mmol), and triethylamine (0.145 mL; 1.06 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.0565 g (36%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[CH3:7][C:8]1([CH3:36])[C@@H:10](/[CH:11]=[CH:12]\[C:13](=[O:15])Cl)[C@H:9]1[C:16]([O:18][C@H:19]([C:34]#[N:35])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=1)=[O:17].P(O)(O)([O-])=O.[Na+]>C(Cl)Cl>[CH3:7][C:8]1([CH3:36])[C@@H:10](/[CH:11]=[CH:12]\[C:13](=[O:15])[O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C@H:9]1[C:16]([O:18][C@H:19]([C:34]#[N:35])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:21]=1)=[O:17]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Cl
Reactant: OCC(F)(F)F
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Reaction time: 1.5 h

Procedure:
2 ml of 2,2,2-trifluoroethanol were added at 20° C. to a solution of 2.14 g of the product of Step D in 8 ml of methylene chloride and the mixture was stirred for 90 minutes and was poured into aqueous monosodium phosphate solution. The decanted organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 1--1 cyclohexane-ethyl acetate mixture to obtain 2.33 g of (S)α-cyano-3-phenoxy-4-fluoro-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropane-carboxylate melting at 56° C. and having a specific rotation of [αD20 =+42°±1° (c=1% in CHCl3).
Reaction SMILES: [N+:1](=[C:3]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:4]([O:6][CH3:7])=[O:5])=[N-].[C:16]1([NH:22][C:23](N)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClCCCl.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Rh+4]>[CH3:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]1[N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23](=[O:24])[NH:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: NC(=O)Nc1ccccc1
Reactant: COCCCCC(=O)C(=[N+]=[N-])C(=O)OC
Agent: [Rh+4]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCCc1c(C(=O)OC)[nH]c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
Methyl 2-diazo-7-methoxy-3-oxoheptanoate (6.93 g) and 1-phenylurea (5.41 g) were suspended in toluene (30 ml)-1,2-dichloroethane (30 ml), rhodium tetraacetate (230 mg) was added and the mixture was stirred at 80° C. for 2 hr. After cooling to room temperature, trifluoroacetic acid (7.5 ml) was added and the reaction mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (15:85-100:0) was concentrated under reduced pressure to give the object product (7.40 g).