Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:19]([N:23]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1)[CH2:20][CH2:21][CH3:22].O>FC(F)(F)C(O)=O>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:10][C:8]=2[C:9]=1[CH:32]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:35][CH:34]=1)[OH:33])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Reactant: CCCCN(CCCC)CCCOc1ccc(C=O)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(O)c1ccc(OCCCN(CCCC)CCCC)cc1
Temperature: 40 °C
Reaction time: 10 h
Yield: 32.9 %

Procedure:
5.34 g of N-(2-butyl-1-benzofuran-5-yl)methanesulfonamide (II) (0.02 mol, 1 eq) is dissolved in 40 mL of trifluoroacetic acid and 8.7 g of 4-(3-dibutylamino-propoxy)-benzaldehyde (V) (0.03 mol, 1.5 eq) is added to the solution. The reaction mixture is heated to 40° C. and stirred for 10 hours at this temperature. The mixture is cooled to room temperature and 100 mL of water is added. After 15 min of stirring, the product is extracted with 2×50 mL of dichloromethane. The organic phase is concentrated and the crude product is purified by column chromatography (spheric silica; eluent:toluene:MTBE:methanol=50:40:10) to obtain 3.68 g of compound (VI) (33%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[CH2:43]Cl>>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[CH2:43][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: Fc1ccc(Br)c(CCl)c1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc(F)ccc2Br)cc1

Procedure:
Analogously to Method D, 1.45 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.816 g of 1-bromo-2-chloromethyl-4-fluorobenzene are reacted. The title compound is obtained as a yellowish oil. Rf=0.35 (1:2 EtOAc-heptane); Rt=6.39.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:13][CH:10]1[O:11]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:34](F)(F)C(O)=O>O.C(OCC)(=O)C>[CH3:34][C:10]1([O:13][C@@H:14]([CH2:24][O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:11]
Reactant: O=C(O)C(F)(F)F
Reactant: COC1O[C@@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(O)O[C@@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Methyl 2,3,5-tri-O-benzyl-L-xylofuranoside (22.7 g, 56.30 mmol) is dissolved at 0° C. in a 9:1 mixture of trifluoroacetic acid and water (200 mL) and stirred at 0° C. overnight. The mixture is put to dryness under reduced pressure. The oily residue is dissolved in ethyl acetate and washed three times with a saturated solution of sodium bicarbonate. The organic layer is dried over sodium sulfate, filtered and put to dryness under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 7:3 mixture of cyclohexane and ethyl acetate yield methyl 2,3,5-tri-O-benzyl-L-xylofuranose as an oil (11.7 g, 53%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])=[C:9]([CH3:25])[C:8]([O:26][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([O:44][CH3:45])[C:6]=1[O:46][CH3:47])(=[O:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:4][C:5]1[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])=[C:9]([CH3:25])[C:8]([OH:26])=[C:7]([O:44][CH3:45])[C:6]=1[O:46][CH3:47])(=[O:3])[CH3:2]
Reactant: COc1c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)c(CCCCCCCCCCOC(C)=O)c(OC(C)=O)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(O)c(C)c(CCCCCCCCCCOC(C)=O)c(OC(C)=O)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
1-Acetoxy-6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylbenzene (0.483 g) was dissolved in tetrahydrofuran (5 ml), and tetrabutylammonium fluoride trihydrate (0.5 g) was added. The mixture was stirred at room temperature for 30 minutes. After concentration under reduced pressure, the residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (7:3) to obtain the desired compound (0.24 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[O:11][C:10]2=[O:20])[CH:5]=[CH:4][N:3]=1.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>N1C=CC=CC=1>[O:20]=[C:10]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26]([CH2:25][O:24][C:21](=[O:23])[CH3:22])=[O:27])[CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[O:11]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (600 mg, see preparation 7b) in pyridine (5 ml) was added acetoxyacetyl chloride (0.29 ml). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. The remaining oil was dissolved in EtOAc and washed with water and brine. The organic layer was concentrated to ca. 10 ml under reduced pressure. The resulting solid material was isolated by filtration and dried in vacuo, affording acetic acid [4-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-ylcarbamoyl]-methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([OH:29])[CH:5]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:5]=[C:6]([O:29][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH3:32])[CH:7]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(C(=O)OC)c1
Yield: 92.5 %

Procedure:
A mixture of 1.0 g (2.45 mmol) of 3-hydroxy-5-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid methyl ester, 0.73 ml (2.69 mmol) of 1-bromotetradecane and 0.7 g (4.9 mmol) of potassium carbonate in 20 ml of anhydrous DMF was stirred and heated at 80° for 22 hours. The usual workup followed by chromatography on 30 g of silica gel using 10% ethyl acetate-hexane, trituration of the combined pure fractions with methanol and filtration gave 1.37 g (93% yield, mp 69°-70°) of 3-[3-[4-(phenylmethoxy)phenoxy]propoxy]-5-(tetradecyloxy)benzoic acid methyl ester.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17])(=O)=O.[Cl-:20].[Li+]>CN(C=O)C>[Cl:20][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Cl

Procedure:
2,6-Dimethyl-4-nitrophenyl trifluoromethanesulfonate (8.54 g) and 3.63 g of lithium chloride in 40 ml DMF are heated at 150° for four hours. Solvent is then evaporated, the residue stirred with water and ethyl acetate, filtered, and the filtrate separated. The ethyl acetate is then dried, filtered and stripped, and the residue chromatographed on silica gel with 98:2 hexane:ethyl acetate, affording 4-chloro-3,5-dimethyl-nitrobenzene. NMR (CDCl3): δ 2.5 (6H,s), 7.9 (2H,s).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH2:2][C:3]#[C:4][CH2:5][CH3:6]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCC#CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC#CCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-hexyn-1-ol (880 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][S:13]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([NH:22][CH2:23][C:24]([OH:26])=O)=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:5].[N:34]1([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:38][CH2:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([NH:22][CH2:23][C:24](=[O:26])[N:44]2[CH2:43][CH2:42][N:41]([CH2:40][CH2:39][N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[CH2:46][CH2:45]2)=[O:21])=[CH:27][CH:28]=1)(=[O:14])=[O:15])=[O:5]
Reactant: C1CCN(CCN2CCNCC2)C1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1
Product: O=C(NCC(=O)N1CCN(CCN2CCCC2)CC1)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared from {4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzoylamino}-acetic acid and 1-(2-pyrrolidin-1-yl-ethyl)-piperazine (EMKA-Chemie) according to the method described in Example 1.1/f. MS (EI) 673.2 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:11][CH:12]\2[OH:13])[CH:3]=[N:2]1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[CH3:38][O:37][C:35]([CH2:34][N:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][CH2:11][CH:12]\2[OH:13])[CH:3]=[N:2]1)=[O:36]
Reactant: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cn[nH]c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)cn1
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of (E)-3-[(1H-pyrazol-4-yl)methylidene]-1-(triphenylmethyl)piperidin-4-ol (10.31 g) and methyl bromoacetate (7.0 ml) in N,N-dimethylformamide (150 ml) were added potassium carbonate (10.20 g) and potassium iodide (12.30 g) with stirring at room temperature, and the resulting mixture was refluxed for 1 hour. After water was added, the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate, hexane, and dichloromethane (2:1:1) as the eluent to afford the title compound (4.74 g, yield: 39%) as a pale yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[OH:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:42]3[CH2:43][CH2:44][CH:39]([OH:38])[CH2:40][CH2:41]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OC1CCNCC1
Product: CCOc1cc(C(F)(F)F)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-hydroxy-piperidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C32H33N3O3F3Cl2 [(M+H)+] 634.1846, observed 634.1846.
Reaction SMILES: [F:1][C:2]1([F:25])[C@@H:11]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[O:10][C@H:5]([O:6]C(=O)C)[C@H:4]([O:17][C:18](=[O:20])[CH3:19])[C@H:3]1[O:21][C:22](=[O:24])[CH3:23].C(OCC)(=O)C.[BrH:32]>C(O)(=O)C>[Br:32][C@@:5]1([O:10][C@H:11]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[C:2]([F:25])([F:1])[C@H:3]([O:21][C:22](=[O:24])[CH3:23])[C@H:4]1[O:17][C:18](=[O:20])[CH3:19])[OH:6]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C1(F)F
Reactant: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@](O)(Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)C1(F)F
Temperature: 0 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
300 mg (0.8 mmol) of tetraacetate 46 are dissolved in 13 ml of 33% strength HBr in glacial acetic acid and left to stand at room temperature for 6 hours. The reaction solution is then poured into a mixture of 10 g of ice and 10 ml of ethyl acetate. The organic phase is washed twice more with aqueous NaCl solution, filtered through a little silica gel and concentrated. The residue is separated by chromatography on silica gel (ethyl acetate/heptane 1:1). 112 mg (35%) of 47 are obtained as a colorless solid. C12H15BrF2O7(389.15) MS(DCl): 389.2 (M+H+).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:16][CH2:17][CH3:18].[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:33][C:34](O)=[O:35])[N:25]=1>>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:34](=[O:35])[CH2:33][N:26]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:32]4[C:24]([C:20]4[NH:19][CH:23]=[CH:22][N:21]=4)=[N:25]3)[CH2:14][CH2:15]2)=[CH:6][C:5]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(N2CCNCC2)ccc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: Cl
Product: CCOc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)ccc1Cl

Procedure:
The title compound was prepared following Protocol A. 1-(4-Chloro-3-ethoxyphenyl)piperazine dihydrochloride and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (4% to 15% MeOH in CH2Cl2) to provide 1-[4-(4-chloro-3-ethoxyphenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid (25 mg): 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 0.6H), 8.66 (dd, 0.4H), 8.57-8.54 (m, 1H), 7.29-7.19 (m, 4H), 6.49-6.40 (m, 2H), 5.45 (s, 0.7H), 5.43 (s, 1.3H), 4.10-4.04 (m, 2H), 3.81-3.69 (m, 4H), 3.23-3.16 (m, 4H), 1.50-1.45 (m, 3H); LC/MS m/z (M+H)+ 466.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([N+:12]([O-])=O)=[CH:5][C:4]=1[O:15][CH3:16].[O:17]=[CH:18][C:19](OCC)=O>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[O:15][CH3:16])[NH:12][C:18](=[O:17])[CH:19]=[N:9]2
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Reactant: CCOC(=O)C=O
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc2ncc(=O)[nH]c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
A mixture of 1,2-dimethoxy-4,5-dinitrobenzene (5.7 g, 25.0 mmol) in ethanol/acetic acid (140 mL, 1:1) was hydrogenated over palladium on carbon (10%, 1 g) at normal pressure and room temperature for 3 hours, then filtered through a pad of celite. The filtrate containing the crude diamine was treated with ethyl oxoacetate (50 wt % in toluene, 10 mL, 50 mmol) and the reaction was stirred at room temperature overnight. The resulting precipitate was collected by filtration. This material was suspended in a mixture of methanol/dichloromethane and solvent was removed under reduced pressure to remove traces of acetic acid to give 2.0 g (38%) of product as a solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:5]=1[C:6](/[CH:19]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:8]2.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>CN(C)C=O>[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:5]=1[C:6](/[CH:19]=[CH:20]/[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]2[S:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1/C=C/C(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(/C=C/C(=O)OC(C)(C)C)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccccc1
Reaction time: 0.75 h

Procedure:
Sodium hydride (0:35 g) was dissolved in dry dimethylformamide (60 ml) and cooled at 0° then a solution of 4,6-dichloro-2ethoxycarbonyl-3-(E)-(2'-tert-butoxycarbonylethenyl)-1-H-indole (5.14 g) in dimethylformamide (40 ml) was added The reaction mixture was stirred for 45 min at 0° then phenylsulfonyl chloride (1.87 ml) was added and the solution stirred overnight at r.t. The solution was poured into a 0.5N aqueous solution of hydrochloric acid and extracted with ethyl acetate (400 ml). The organic phase was washed with a solution of sodium hydrogencarbonate and brine, then dried and evaporated obtaining the title compound as a yellow solid (6.64 g) Rf =0.78 (ethylacetate/cyclohexane=1/2 as eluant).
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4]>C(OCC)C.C1COCC1>[N:9]1[CH:10]=[CH:11][C:6]([C:3]([OH:5])([CH3:1])[CH3:4])=[CH:7][CH:8]=1
Reactant: [Li]C
Reactant: CC(=O)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1ccncc1
Yield: 45 %

Procedure:
A solution of methyllithium (1.4 M; 30 ml, 42 mmol) in diethyl ether was added dropwise to a stirred solution of 4-acetylpyridine (4.65 ml, 42 mmol) in dry THF (100 ml) at -76° C., and the deep blue solution allowed to reach ambient temperature. After 24 hours the mixture was partitioned between ether and saturated aqueous sodium bicarbonate, and the ether phase was concentrated. Chromatography, on elution with ethyl acetate-dichloromethane-triethylamine 60:40:1, gave the title compound (2.59 g, 45%) as an oil. 1H-NMR (CDCl3) δ1.58 (6H, s, CMe2), 7.40 (2H, d, J 6.2 Hz, Py 3 and 5-H), 8.55 (2H, d, J 6.2 Hz, Py 2 and 6-H); MS m/z 137 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[Cl:18].[F:21][C:22]([F:33])([F:32])[C:23]([F:31])([F:30])[C:24]([F:29])([F:28])[C:25](O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][C:9]=2[Cl:18])=[CH:6][C:5]2[NH:19][C:25]([C:24]([F:28])([F:29])[C:23]([F:30])([F:31])[C:22]([F:33])([F:32])[F:21])=[N:20][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2Cl)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc3[nH]c(C(F)(F)C(F)(F)C(F)(F)F)nc3cc2Cl)c(Cl)c1
Yield: 54 %

Procedure:
A solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenyl]benzene-1,2-diamine (120 mg, 0.37 mmol), heptafluorobutanoic acid (5 ml) was stirred overnight at 80° C. in an oil bath. The solution was diluted with water (100 ml), adjusted to pH 7 with saturated aqueous sodium carbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-[2-chloro-4-(trifluoromethyl)phenyl]-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a white solid (100.3 mg, 54%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]=[CH:6][CH:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)[CH3:2].[N+:15]([CH3:18])([O-:17])=[O:16]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([CH:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)[CH2:18][N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)C=CC1COC(C)(C)O1
Reactant: C[N+](=O)[O-]
Product: CCOC(=O)CC(C[N+](=O)[O-])C1COC(C)(C)O1

Procedure:
WO03/022853 in Example I provides a Wittig route which employs triethyl phosphono acetate (TEPA) to obtain 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-acrylic acid ethyl ester. The subsequent Michael addition to 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-acrylic acid ethyl ester, presents limitations in that it produces a nitromethane adduct, i.e. 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-4-nitro-butyric acid ethyl ester, with a syn:anti ratio of approximately 8:2. Subsequent reduction followed by Nef/cyclization reactions yields the (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol seriously contaminated with its exo-diastereoisomer, i.e. (3R,3aR,6aS) hexahydro-furo[2,3-b]furan-3-ol, with a ratio endo:exo of around 8:2. Although this process does not possess several of the disadvantages attached to the Knoevenagel process, it does not produce pure endo-diastereoisomer since there is no purification step available, such as crystallization, to remove the undesired exo-diastereoisomers that have been formed during the Michael addition in the anti configuration.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1Cl)([O:3][CH3:4])=[O:2].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:10]1[C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][N:7]=[CH:8][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cnccc1Cl
Reactant: NCc1ccccc1
Product: COC(=O)c1cnccc1NCc1ccccc1

Procedure:
The title compound is prepared from 3-carbomethoxy-4-chloropyridine and benzylamine according to the procedure of Winn, et.al. as described in J. Med. Chem., 36, 1993, 2676-2688.