Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:12])[N:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:12][C:4]1[N:3]=[C:2]([NH:14][NH2:15])[CH:7]=[CH:6][C:5]=1[C:8]([F:11])([F:10])[F:9]
Reactant: NN
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Solvent: O
Solvent: CCO
Product: NNc1ccc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To the solution of 2,6-Dichloro-5-trifluoromethyl-pyridine (18, 2 g, 9.26 mmol) in ethanol (30 mL) was added hydrazine hydrate (2.9 g, 46 mmol). The reaction mixture was stirred for 4 h at room temperature, then concentrated to remove the solvent, and added ethyl acetate, washed with water. The organic layer was dried over anhydrous Na2SO4. Column chromatography (Silica, petroleum ether/ethyl acetate=4/1˜3/1) afforded compound 19 as white solid (yield: 56%) and another isomer 20 (yield: 18%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CC(C)=O>[CH2:23]([O:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]([CH3:15])[CH3:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)c(CC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccccc1
Reaction time: 4 h
Yield: 88.6 %

Procedure:
Ethyl 4-hydroxy-3-isobutylbenzoate (25.6 g), potassium carbonate (31.8 g), and benzyl bromide (23.6 g) were refluxed in acetone (150 ml) with stirring for 4 hours. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was concentrated under a vacuum. The resulting residue, with water (50 ml), potassium hydroxide (12.9 g), and ethanol (100 ml) added thereto, was refluxed with stirring for 2 hours. The reaction mixture, with water added thereto, was neutralized with hydrochloric acid and then extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid and water successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. Thus obtained solid was recrystallized (from n-hexane/ethanol) so as to yield 29.0 g of the aimed compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:37][NH:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C(N(CC)CC)C>[ClH:31].[CH:39]1([N:38]([CH3:37])[CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:24]=[CH:23][C:22]4[CH2:21][C@@H:20]([C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=5)[C:19]5[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=5[C:17]=4[N:16]=3)=[CH:10][CH:9]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C3)cc1
Reactant: CNC1CCCCC1
Solvent: CCN(CC)CC
Product: CN(CCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C3)cc1)C1CCCCC1
Product: Cl

Procedure:
This was synthesized by using (S)-4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-methylcyclohexanamine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=175-185° C. 1H NMR 400 MHz (DMSO-d6) δ 10.54 (s, 1 H), 9.71 (s, 1 H), 8.33-8.28 (m, 2 H), 7.78-7.76 (m, 2 H), 7.51-7.42 (m, 3 H), 7.25-7.23 (m, 2 H), 7.11-7.10 (d, 1 H), 7.02-7.00 (m, 1 H), 4.46 (t, J=6.8 Hz, 1 H), 3.28-3.21 (m, 4 H), 3.00-2.98 (m, 2 H), 2.71-2.69 (d, 3 H), 2.09-1.96 (m, 2 H), 1.79 (d, J=12 Hz, 2 H), 1.59 (d, J=12.8 Hz, 2 H). 1.44-1.38 (m, 2 H), 1.26-1.06 (m, 4 H). LCMS m/e 557 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>ClCCl>[Cl:8][C:6]1[N:7]=[C:2]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]=1
Reactant: CN1CCNCC1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Solvent: ClCCl
Product: CN1CCN(c2nc(Cl)nc(N3CCOCC3)n2)CC1
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (1.40 g, 5.96 mmol, 1.0 eq.) was dissolved in dichloromethane (21 ml). N-Methylpiperazine (727 μl, 6.56 mmol, 1.1 eq.) was added to the reaction mixture at 0° C. and stirred for 30 minutes at the same temperature. The solvent was evaporated under reduced pressure and purification by flash chromatography yielded the title compound as a white solid (690 mg, 39%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]1[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([Pb+3])[CH:46]=2)=[CH:41][CH:40]=1>ClCCl>[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([CH:10]3[C:11](=[O:13])[CH2:12][CH:7]([CH2:6][CH:2]4[O:3][CH2:4][CH2:5][O:1]4)[CH2:8][C:9]3=[O:14])[CH:46]=2)=[CH:43][CH:44]=1
Reactant: O=C1CC(=O)CC(CC2OCCO2)C1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)CC(CC2OCCO2)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-[1,3]dioxolan-2-ylmethylcyclohexane-1,3-dione (1.43 g, 7.22 mmol) in a mixed solvent system of chloroform (72 ml) and toluene (18 ml) is added N,N-dimethylaminopyridine (4.40 g, 36.08 mmol) and the solution is stirred at room temperature for 10 minutes. To this mixture is then added 4′-chloro-4-methylbiphenyl-3-yllead triacetate (described in WO 2008/071405) (4.95 g, 7.91 mmol) in one portion, followed by heating at 80° C. for 2 hours. After cooling to room temperature the solution is diluted with dichloromethane (90 ml) and quenched with 1M hydrochloric acid (90 ml). The resulting precipitate is filtered through celite and the residue washed with additional dichloromethane (20 ml). The biphasic solution is separated and the organic layer further washed with 1M hydrochloric acid (45 ml). Organics are finally passed through a phase separator then concentrated in vacuo to afford the crude product as a yellow oil. After flash column chromatography on silica (7:1 ethyl acetate/hexane eluant) 2-(4′-chloro-4-methylbiphenyl-3-yl)-5-[1,3]dioxolan-2-ylmethylcyclohexane-1,3-dione is afforded as a cream solid.
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)\[CH3:5].[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Br:1][CH2:2][CH:3]1[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4]1([CH3:5])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: C/C(=C\CBr)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1C(CBr)C1(C)c1cccc([N+](=O)[O-])c1
Yield: 9.4 %

Procedure:
To a solution of 1-[(E)-3-bromo-1-methyl-1-propenyl]-3-nitrobenzene (Preparation 4, 4 g, 15.6 mmol) in dichloromethane (5 ml) was added rhodium (II) acetate dirner (100 mg, 0.22 nmnol). To the mixture was added dropwise at room temperature over 4.5 h a solution of ethyl diazoacetate (3.1 ml, 2.84 g, 25 mmol) in dichloromethane (15 ml). The mixture was filtered, concentrated in vacuo, and the residue purified by silica column (100 g) chromatography, eluting with 2:1 hexane/dichloromethane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo, then purified further by preparative HPLC (Condition 1). Combination and evaporation of appropriate fractions gave the title compound as a colourless oil (0.5 g, 11%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Na+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Cl:35]CCl>O1CCCC1.C(OCC)(=O)C.FC(F)(F)C(O)=O>[F:32][C:31]([F:33])([F:34])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:20][C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:19][CH:18]=2)=[CH:26][CH:27]=1.[ClH:35]
Reactant: ClCCl
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cl
Product: FC(F)(F)c1ccc(COc2ccc(N3CCNCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(4-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.5 g, 5.4 mmol) in dry tetrahydrofuran (5 mL) is added to suspension of sodium hydride (431 mg, 60% in oil, 10.8 mmol) in dry tetrahydrofuran (35 mL). After 15 minutes reaction time, a solution of 1-bromomethyl-4-trifluoromethyl-benzene (1.9 g, 8.1 mmol) in tetrahydrofuran (5 mL) is added. The reaction is stirred for 16 hours at room temperature, is filtered and concentrated under vacuum. The residue obtained is diluted in ethyl acetate (40 mL) and the organic layer is washed with water (3×20 mL), is dried over magnesium sulfate, filtered and concentrated under vacuum. The residue obtained is dissolved in a 1 to 1 mixture of dichloromethane and trifluoroacetic acid (30 mL), and stirred for 30 minutes. The mixture is then concentrated under vacuum, and co-evaporated in dichloromethane (30 mL). The resulting residue is diluted in diethylether (5 mL) and a molar solution of hydrochloric acid in diethylether is added (10 mL). The precipitate formed is filtered, washed with diethylether (10 mL) and dried under vacuum. The desired product is isolated as hydrochloride as a colorless solid in the presence of traces of solvent.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][O:11][C:12]=1[CH3:13])=[O:7].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:23]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:22]=1.O[C:40]1C=CC(Cl)=CC=1N1CCNCC1>C(OCC)(=O)C>[CH2:13]([C:12]1[O:11][N:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]=1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:30]1[CH2:31][CH2:32][N:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][C:23]=2[O:33][CH2:34][C:35]([F:37])([F:36])[F:38])[CH2:28][CH2:29]1)=[O:7])[CH3:40]
Reactant: Fc1ccc(N2CCNCC2)c(OCC(F)(F)F)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NCCCCl
Reactant: Oc1ccc(Cl)cc1N1CCNCC1
Solvent: CCOC(C)=O
Product: CCc1onc(-c2ccccc2)c1C(=O)NCCCN1CCN(c2ccc(F)cc2OCC(F)(F)F)CC1
Yield: 64 %

Procedure:
The title compound was obtained following the procedure described in Example 2 but substituting Compound 19A for Compound 2B and 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine for 1-(2-hydroxy-5-chlorophenyl)piperazine. The crude was taken up with ethyl acetate and the crude was purified by flash chromatography (ethyl acetate-2 N ammonia in methanol 98:2) to afford the title compound (64%). M.p. 115-117° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH:16]([NH:20][C:21]([NH:23][CH3:24])=[S:22])([CH2:18][CH3:19])[CH3:17]>>[BrH:1].[CH:16]([N:20]=[C:21]1[N:23]([CH3:24])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:22]1)([CH2:18][CH3:19])[CH3:17]
Reactant: CCC(C)NC(=S)NC
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Product: Br
Product: CCC(C)N=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1C

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 2.19 g of 1-sec.-butyl-3-methylthiourea were reacted according to the prescription given in Example 23 and the crystals were filtered off.
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]([CH2:20][C:21](O)=O)[C@@H:15](C(=O)N)[NH2:16])[C:8]2=[O:13])([O-:3])=[O:2].S(Cl)(Cl)=O.[OH2:28].[C:29](=O)([O-])[O-:30].[Na+].[Na+]>CN(C)C=O.CO>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:20][CH2:21][C:29](=[O:30])[NH:16][C:15]1=[O:28])[C:8]2=[O:13])([O-:3])=[O:2]
Reactant: O
Reactant: O=C([O-])[O-]
Reactant: NC(=O)[C@@H](N)C(CC(=O)O)N1Cc2c(cccc2[N+](=O)[O-])C1=O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C1CCC(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)N1
Yield: 78 %

Procedure:
To a mixture of 3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-isoglutamine (9 g) in N,N-dimethylformamide (80 ml), was added thionyl chloride (6.6 g) by droplet below 0° C. for stirred reaction in heat preservation for 2˜3 hours. The resulting solution was added by droplet into mixture of ice and water and pH value was adjusted to 7˜8 with sodium carbonate. The mixture was stirred for 30 minutes and filtered to get light yellow crude. Refining with methanol gave 6.6 g of target yield as a light yellow solid. yield: 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=O)[CH3:11])[CH:5]=[CH:6][CH:7]=1.[N+:19]([CH2:22][C:23](=O)[CH3:24])([O-:21])=[O:20].C([O-])(=O)C.[NH4+:30]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:10]([CH3:11])[NH:30][C:23]([CH3:24])=[C:22]2[N+:19]([O-:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C[N+](=O)[O-]
Reactant: CC(=O)C(=Cc1cccc(Cl)c1)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC1=C(c2ccccc2)C(c2cccc(Cl)c2)C([N+](=O)[O-])=C(C)N1
Reaction time: 24 h

Procedure:
12.82 g (50 mmol) of 1-(3-chlorophenyl)-2-phenyl-3-oxo-1-butene in 75 ml of ethanol are heated under reflux with 5.15 g (50 mmol) of nitroacetone and 3.85 g (50 mmol) of ammonium acetate for 16 hours. A further 5.15 g of nitroacetone and 3.85 g of ammonium acetate are added and the mixture is boiled for 24 hours, and 5.15 g of nitroacetone and 3.85 g of ammonium acetate are added and the mixture is boiled for 24 hours. It is cooled and concentrated, the residue is taken up in ethyl acetate, and the solution is extracted by shaking twice with water, dried and concentrated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[NH:5][C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC(OC)=CC=3)=[C:19]([O:33][CH3:34])[CH:18]=2)[C:9]2=[N:10][CH:11]=[C:12]([I:14])[CH:13]=[C:8]2[N:7]=1)[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:1]([O:3][C:4](=[O:35])[NH:5][C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:33][CH3:34])[CH:18]=2)[C:9]2=[N:10][CH:11]=[C:12]([I:14])[CH:13]=[C:8]2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(O)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of ethyl(6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (Example 3-34-2) (2.40 g, 4.08 mmol) in dichloromethane (50 mL) at 0° C. was added trifluoroacetic acid (4.47 g, 3.0 mL, 39.18 mmol). The resulting mixture was allowed to stir at 0° C. After 2 h, the mixture was treated with 2M potassium carbonate solution to adjust the pH to 9. The basic mixture was extracted with 1:1 methanol/dichloromethane solution (3×50 mL). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to provide 1.30 g (70%) of ethyl(3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:15])[CH2:13][CH2:12][O:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[BrH:16].S(Cl)(Cl)=O.[CH3:21]O>C(O)(=O)C>[CH3:21][O:11][C:10](=[O:14])[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([CH3:15])[CH2:13][CH2:12][Br:16]
Reactant: Br
Reactant: CC1(c2ccc(Cl)c(Cl)c2)CCOC1=O
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)C(C)(CCBr)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 94 %

Procedure:
To a mixture of 3.3 g (13.5 mmol) 3-(3,4-dichloro-phenyl)-3-methyl-dihydro-furan-2-one in 15 mL acetic acid was added 48 mL HBr (33%) in acetic acid and after 63 h 20 mL HBr (33%) in acetic acid and stirred for another 21 h at room temperature. The mixture was pored onto ice-water and extracted with ethyl ether. The combined organic phases were washed with NaCl aq. sat., dried with Na2SO4, filtered and evaporated to dryness. The residue was taken up in 150 mL toluene and 6.5 mL (89 mmol) thionylchloride were added. The mixture was heated to 75° C. for 4 h, cooled to 0° C., treated with 20 mL methanol and allowed to stand for 16 h at room temperature. The mixture was evaporated to dryness and subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product containing fractions were evaporated to yield 4.32 g (94%) of the title compound as light yellow oil. MS(m/e): 341.9 (MH+).
Reaction SMILES: C1(=O)C=C[C:4](=[O:7])C=C1.CS(O)(=O)=O.[CH:14]1[CH2:19][CH2:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][OH:21]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:4][O:7][C@@H:15]1[CH2:14][CH2:19][C@H:18]([O:21][CH3:20])[CH:17]=[CH:16]1
Reactant: CO
Reactant: C1=CCCC=C1
Reactant: O=C1C=CC(=O)C=C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Product: CO[C@@H]1C=C[C@H](OC)CC1
Reaction time: 16 h
Yield: 61 %

Procedure:
Lit., J. Org. Chem., 53:5695 (1988). To a stirred solution of 0.70 g (3.1 mmol) palladium acetate, 16.9 g (156 mmol) benzoquinone and 0.4 ml (6.2 mmol) methanesulphonic acid in 200 ml methanol at room temperature was added via syringe pump over 4 h a solution of 5.95 ml (62 mmol) 1,3-cyclohexadiene in 5 ml methanol, and stirring continued for an additional 16 h. The reaction mixture was extracted three times with ether and the combined organic extracts washed successively with water, 2 M sodium hydroxide solution and saturated brine. The organic phases were dried over sodium sulphate and concentrated in vacuo. Kugelrohr distillation (6 mbar, oven temp 120° C.) afforded 5.42 g (61%) of the title compound as a colorless oil. 1H NMR d (250 MHz, CDCl3) 5.92 (2H, s), 3.70 (2H, t, J=5 Hz), 3.37 (6H, s), 1.90-1.65 (4H, m).
Reaction SMILES: S1C2C=CC=CC=2N=C1NN=CC1OC([N+]([O-])=O)=CC=1.[N+:21]([C:24]1[S:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22].[NH:31]([C:33]1[S:34][C:35]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:36]=2[N:37]=1)[NH2:32]>>[F:45][C:42]([F:43])([F:44])[C:40]1[CH:39]=[CH:38][C:36]2[N:37]=[C:33]([NH:31][N:32]=[CH:29][C:27]3[S:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[S:34][C:35]=2[CH:41]=1
Reactant: NNc1nc2ccc(C(F)(F)F)cc2s1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: O=[N+]([O-])c1ccc(C=NNc2nc3ccccc3s2)o1
Product: O=[N+]([O-])c1ccc(C=NNc2nc3ccc(C(F)(F)F)cc3s2)s1

Procedure:
The compound 3h was prepared according procedure described for 3a by employing 5-nitrothiophen aldehyde (157 mg, 1 mmol) and 2-hydrazino-6-trifluoromethyl-benzothiazole (233 mg, 1 mmol) at 70° C. for 2 h (yield 312 mg, 84%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1Br.Cl[P:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]2[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=2O1.Cl.C([O:38]CC)C>CCCCCC.CC1C=CC=CC=1C.O>[CH:31]1[C:24]2[C:25]3[C:30]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[OH:38])=[CH:29][CH:28]=[CH:27][C:26]=3[PH:21][C:23]=2[CH:34]=[CH:33][CH:32]=1
Reactant: CCOCC
Reactant: Brc1ccccc1-c1ccccc1Br
Reactant: ClP1Oc2ccccc2-c2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Solvent: O
Product: Oc1ccccc1-c1ccccc1-c1cccc2[pH]c3ccccc3c12
Temperature: 20 °C
Reaction time: 24 h

Procedure:
46 ml of a 1.6M solution of butyllithium in hexane are added dropwise to a solution of 11.4 g (36.54 mmol) of 2,2'-dibromobiphenyl in 60 ml of diethyl ether. The mixture is then stirred for 24 hours at 20° C. To this is then added, at 0C, a solution of 8.6 g (36.5 mmol) of 6-chloro-6H-dibenz[c,e][1,2]oxaphosphorine in 30 ml of o-xylene. The mixture is then stirred for a further 2 hours at 25° C. and 3 hours at 50° C. The mixture is cooled to room temperature and 100 ml of water are carefully added. The mixture is neutralized with dilute hydrochloric acid, the organic phase is separated off, dried with sodium sulfate and concentrated under reduced pressure. By crystallization of the residue with 2-butanone, 11.8 g (90%) of colorless crystals having melting point 152° to 155° C. are obtained.
Reaction SMILES: [CH3:1][C:2]([O-:5])([CH3:4])[CH3:3].[K+].[Cl:7][C:8]1[C:9]([Cl:18])=[C:10]([Cl:17])[C:11]([Cl:16])=[C:12]([OH:15])[C:13]=1[OH:14].[C:19]([O:23][C:24]([CH:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31](=[O:34])[CH2:32]Br)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[C:2]([O:5][C:24]([C@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31](=[O:34])[CH2:32][O:14][C:13]1[C:8]([Cl:7])=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([Cl:16])[C:12]=1[O:15][CH2:32][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C@@H:26]1[C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[O:34])=[O:23])([CH3:4])([CH3:3])[CH3:1]
Reactant: Oc1c(O)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)C1CCCN1C(=O)CBr
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1c(Cl)c(Cl)c(Cl)c(Cl)c1OCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Reaction time: 0.04 h
Yield: 45 %

Procedure:
To a solution of 185 mg (1.65 mmol) potassium tert-butylate in 1 ml dimethylformamide at room temperature was added dropwise a solution of 186 mg (0.75 mmol) tetrachlorocatechol in 1 ml dimethylformamide. Stirring was continued for 2-3 min and a solution of 438 mg (1.50 mmol) (R)-(1) -bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 2 ml dimethylformamide was added within 1-2 min. The reaction mixture was stirred for additional 4 h at room temperature. The solvent was removed in vacuo and the residue purified by flash-chromatography to yield 229 mg (45%) of the title compound as a white foam. MS m/e (%): 671 (M+H+, 100), 615 (19), 559 (14).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][P:26]([O:36]CC2C=CC=CC=2)([O:28]CC2C=CC=CC=2)=[O:27])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:10]2=[O:24])[CH:7]=1>C(OCC)(=O)C.C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][P:26]([OH:28])([OH:36])=[O:27])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[O:11][C:10]2=[O:24])[CH:7]=1
Reactant: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1OP(=O)(O)O
Reaction time: 0.67 h
Yield: 97.1 %

Procedure:
To a Parr hydrogenation flask containing 3.7 mg of 10% Pd/C was added a solution of 50 mg (0.080 mmol) of 3-[(5-chloro-2-[[bis[phenylmethyl]phosphono]oxy]phenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one dissolved in 2 mL of ethyl acetate and 5 mL of ethanol. The mixture was hydrogenated at 40 psi for 40 minutes, filtered through celite and the filtrate was concentrated to give 35 mg of 3-[(5-chloro-2-[phosphonooxy]phenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one as a white solid: m.p. 173-176° C. MS 449 (M--H)-.