Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:22]2[CH2:26][CH2:25][O:24][C:23]2=[O:27])[CH:7]=1)C.[OH-].[Li+]>CO.O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:28])=[O:3])[CH:11]=[C:10]([Cl:12])[CH:9]=2)=[C:15]([CH2:21][N:22]2[CH2:26][CH2:25][O:24][C:23]2=[O:27])[CH:16]=1
Reactant: CCOC(=O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
{3-[4-Bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-5-chloro-phenyl}-acetic acid ethyl ester (0.06 g, 0.13 mmol) in MeOH and H2O was treated with lithium hydroxide, and the reaction was stirred at 60° C. for 30 minutes to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.O=[C:23]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=1)[CH:3]=[C:2]2[NH:1][CH:23]1[CH2:27][CH2:26][NH:25][CH2:24]1
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Product: CNc1nccc(-c2cc(NC3CCNC3)c3cc(OC)ccc3c2)n1

Procedure:
4-(6-methoxy-4-(pyrrolidin-3-ylamino)naphthalen-2-yl)-N-methylpyrimidin-2-amine 148 was synthesized according to General Procedure E utilizing compound 33 and replacing tert-butyl 4-oxopiperidine-1-carboxylate with tert-butyl 3-oxopyrrolidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](Cl)=[CH:4][C:5]([F:8])([F:7])[F:6].[OH-].[Na+]>COCCOCCOC.[Ni]>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C=C(Cl)C(F)(F)F
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: FC(F)(F)CCC(F)(F)F
Yield: 75.3 %

Procedure:
1,1,1,4,4,4-Hexafluoro-2-chloro-2-butene (199 g, 1 mole) in 800 ml diglyme was hydrogenated in the presence of sodium hydroxide (45 g) and Raney nickel (30 g) at a temperature of 20° to 40° C. and under a pressure of 20 to 40 bar. The solid constituents were filtered off and the filtrate was extracted with water. The organic phase was separated and purified by fractional distillation, giving 125 g (75% of theory) of 1,1,1,4,4,4-hexafluorobutane, boiling point 24°-27° C. at 1013 mbar. The 19F-nmr spectrum showed a resonance at -10.7 ppm (standard: CF3CO2H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:9][CH2:10][C:11](=[O:25])[N:12]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:9][CH2:10][C:11]([N:12]([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[CH2:13][C:14]1[NH:18][CH:17]=[CH:16][N:15]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)N(Cc1ncc[nH]1)C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCC(=O)N(Cc1ncc[nH]1)C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the white solid (2.60 g, 5.8 mmole) isolated in Step B above, in dichloromethane (45 mL) was added trifluoroacetic acid (45 mL). The resulting solution was stirred at room temperature for 2 hours. The solution was then concentrated. Hydrochloric acid solution (1N, 10 mL) was added and the resulting solution washed with diethyl ether one time. Sodium bicarbonate was added until there was no bubbling observed from the aqueous solution. The solution was extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried over magnesium sulfate. The resulting solution was filtered and concentrated to yield 4-amino-4-(S),N-dicyclohexyl-N-(1H-imidazol-2-ylmethyl)-butyramide as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].S(Cl)(Cl)=O.[CH:17]1[N:25]2[C:20]([C:21]3([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[O:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=32)=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C.O1CCOCC1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:32]2[CH2:31][CH2:30][C:21]3([O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]4[CH:17]=[CH:18][CH:19]=[C:20]34)[CH2:34][CH2:33]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Reactant: COc1cc(C(=O)O)ccc1O
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.8 %

Procedure:
4-Hydroxy-3-methoxy-benzoic acid (304 mg, 1.81 mmol) was stirred with thionyl chloride (645 mg, 395 μL, 5.42 mmol) in dichloromethane and 2 drops of DMF were added. After stirring for 2.5 h, the excess thionyl chloride and dichloromethane were removed in vacuo. The residue was added to a mixture of spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (500 mg, 1.81 mmol), 1,4-dioxane (6.5 mL), and triethylamine (760 μL, 5.42 mmol). The mixture was stirred for 18 h at 90° C. before it was cooled to room temperature and was evaporated to dryness. The residue was dissolved in ethyl acetate, filtered and washed with 1N HCl (2×), a saturated sodium bicarbonate solution (2×), and brine. The organic layer was dried over sodium sulfate and was evaporated to dryness. The residue was purified by column chromatography (0-100% EtOAc/hexane) to give (4-hydroxy-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (394 mg, 56%). ESI-MS m/z calc. 390.2, found 391.2 (M+1)+; Retention time: 2.56 minutes (4 min run).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH2:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41]>CO.ClCCl>[CH2:40]([S:42]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:7][CH:8]=3)[N:14]=[C:15]([N:23]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:24][CH2:25][OH:26])[C:16]=2[CH2:22]1)(=[O:44])=[O:43])[CH3:41]
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (100 mg, 0.23 mmol, Example 1) was dissolved in MeOH (0.5 mL) and dichloromethane (5 mL). Triethylamine (0.033 mL, 0.23 mmol) was added followed by ethanesulphonyl chloride (0.022 mL, 0.23 mmol). The reaction mixture was stirred at room temperature for 1 h before the solvent was evaporated under reduced pressure. The crude was dissolved in dimethylformamide and acetonitrile and purified by preparative HPLC yielding 2-((6-(ethylsulfonyl)-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (22.0 mg, 18.11%). MS (ESI) (M+1) m/z 521;
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([OH:9])[C:6]([NH:10][C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][N:4]=1)=[O:2].[O-:26]Cl=O.[Na+].[OH-].[K+]>CC(O)(C)C.O>[C:19]1([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]([NH:10][C:6]2[C:7]([OH:9])=[N:8][C:3]([C:1]([OH:26])=[O:2])=[N:4][CH:5]=2)=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1ncc(NC(=O)C(c2ccccc2)c2ccccc2)c(O)n1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1ncc(NC(=O)C(c2ccccc2)c2ccccc2)c(O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of compound 3-h (1 g, 3.0 mmol) in t-BuOH (20 mL) was added to a solution of NaH2PO4H2O (0.86 g, 2.4 mmol) in H2O (4 mL) and NaClO2 (0.8 g, 9 mmol). After being allowed to stir at room temperature for 3 h, the reaction mixture was added to aq. KOH (2M, 15 mL) and extracted with EA (30 mL). The aqueous layer was adjusted to pH=2 by addition of HCl, and then extracted with EA (30 mL) to afford the crude product, 3-1-a, (300 mg). LC-MS (M+H)+ 350.1
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+]>C1COCC1.O>[F:18][C:14]1[CH:13]=[C:12]([CH:4]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:19])=[O:2])[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C(Nc1ccccc1)c1cccc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(Nc1ccccc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
(3-Fluoro-phenyl)-phenylamino-acetic acid methyl ester (I97) (229 mg, 0.88 mmol) and lithium hydroxide hydrate (74.1 mg, 1.77 mmol) are dissolved in THF/water (6 mL/2 mL) and stirred at RT for 2 hours. THF is evaporated, the resulting basic aqueous solution is acidified till pH 1 with 1M HCl. The precipitate is recovered by suction filtration and washed with 1M HCl. The compound is dried at 40° C. under vacuum overnight to get intermediate I146 as a white solid (186 mg, 75% yield).
Reaction SMILES: C(O)C(O)C.C1(C)CCC(C(C)C)C(O)C1.C(F)[O:18][CH:19]([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21]>>[CH:19]([OH:18])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21]
Reactant: FCOC(C(F)(F)F)C(F)(F)F
Agent: CC1CCC(C(C)C)C(O)C1
Solvent: CC(O)CO
Product: OC(C(F)(F)F)C(F)(F)F

Procedure:
Table 2 resumes the tests realized with the agents propylene glycol and menthol proposed for the stabilization of sevoflurane against the degradation by alumina and the results for total impurity and for the single impurity HFIP obtained with and without alumina after stress at 60° C. for 22 hours. The total impurity is the sum of the ratio between the area for each impurity and the area of the internal standard (toluene) and HFIP is the ratio between the area of HFIP and the area of toluene obtained in the chromatograms.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:23]=2[C:24]([NH:26][C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][C:33](=[O:38])[N:34]3[CH3:37])=[CH:29][CH:28]=2)=[O:25])[CH2:17][CH2:16]1)C1C=CC=CC=1>ClCCCl>[Cl:43][C:41]1[CH:40]=[CH:39][C:23]([C:24]([NH:26][C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][C:33](=[O:38])[N:34]3[CH3:37])=[CH:29][CH:28]=2)=[O:25])=[C:22]([NH:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH:42]=1
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NC3CCN(Cc4ccccc4)CC3)cc21
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NC3CCNCC3)cc21
Reaction time: 1 h

Procedure:
Under ice-cooling, 1-chloroethyl chloroformate was added to a 1,2-dichloroethane solution of 2-[(1-benzylpiperidin-4-yl)amino]-4-chloro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)benzamide. This was stirred for 1 hour under heat reflux and then concentrated under a reduced pressure. After dissolving in methanol, this was stirred for 2 hours under heat reflux. After concentration of the reaction liquid under a reduced pressure, the residue was purified by silica gel column chromatography to obtain 4-chloro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-(piperidin-4-ylamino)benzamide.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][O:4][C:3]1=[O:14].[C:15]([CH2:17][CH2:18][C@H:19]([CH2:23][C:24]([O-:26])=[O:25])[C:20]([O-:22])=[O:21])#[N:16].CO>O=[Pt]=O.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][O:4][C:3]1=[O:14].[NH2:16][CH2:15][CH2:17][CH2:18][C@H:19]([CH2:23][C:24]([O-:26])=[O:25])[C:20]([O-:22])=[O:21]
Reactant: N#CCC[C@H](CC(=O)[O-])C(=O)[O-]
Agent: O=[Pt]=O
Agent: CN1C(=O)OC[C@H]1Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NCCC[C@H](CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 71 (2.0 g, 5.8 mmol), PtO2 (0.8 g), CH3OH (50 mL), and CHCl3 (5 mL) were shaken on the Parr apparatus under a hydrogen atmosphere (60 PSI) at ambient temperature for 3 hours. The reaction mixture was filtered through a celite pad and then concentrated to furnish the crude amine HCl 72 as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Cl[C:12]1[NH:21][C:20](=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=2)[N:13]=1>>[CH2:9]([O:8][C:6]([C:4]1[CH:5]=[N:1][N:2]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:13]=2)[CH:3]=1)=[O:7])[CH3:10]
Reactant: O=c1[nH]c(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: CCOC(=O)c1cn[nH]c1
Product: CCOC(=O)c1cnn(-c2nc3ccc([N+](=O)[O-])cc3c(=O)[nH]2)c1
Temperature: 130 °C
Reaction time: 18 h
Yield: 97.8 %

Procedure:
Ethyl pyrazole-4-carboxylate (1.83 g, 13.1 mmol) was added to a suspension of 2-chloro-6-nitro-3H-quinazolin-4-one (2.95 g, 13.1 mmol) in xylenes (52 mL). The reaction mixture was heated to 130° C. for 1 h, allowed to cool, and stirred at room temperature for 18 h. The precipitate was collected and rinsed with ether (20 mL) to yield the titled compound (4.22 g, 98%). MS (ESI/Cl): mass calcd. for C14H11N5O5, 329.1; m/z found, 330.1 [M+H]+.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([OH:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[CH2:11]([O:23][C:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCO
Reactant: O=CC=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C=Cc1ccccc1
Yield: 87 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), SeO2 (11.3 mmol), dodecanol (5 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of neutral alumina (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with ethylacetate (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Dodecylcinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═C12H25) is isolated in 87% yield. 1H-NMR (CDCl3, 300 MHz) δ7.51 (1H, d), 7.28 (2H, m), 7.14 (3H, m), 6.26 (1H, d), 4.02 (2H, t), 1.50 (2H, t), 1.11 (18H, m), 0.73 (3H, d); 13C-NMR (CDCl3, 75.4 MHz) δ166.4, 144.2, 134.4, 129.6, 128.6, 127.9, 118.2, 64.3, 31.9, 29.7, 29.6, 29.4, 28.7, 26.0, 22.7, 14.0.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>CCO.C1COCC1.[Pd]>[OH:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccc(C(=O)O)c(O)c2)cc1
Reaction time: 0.42 h
Yield: 35 %

Procedure:
A slurry of 2-hydroxy-4-(4-nitro-phenoxy)benzoic acid (950 mg; 3.5 mmol) in 99% EtOH (30 mL) and THF (0.5 mL) was added 5% Pd/C (100 mg) and stirred under H2 atmosphere (1 atm.) for 25 minutes. The black solution was filtered through celite and evaporated to dryness yielding 300 mg (35%) of a brown powder. Mp. 187-188° C.; MS (ESI+): 246 (MH+).
Reaction SMILES: P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)O>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Reactant: c1c[nH]cn1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1ccnc1
Yield: 81.2 %

Procedure:
A mixture of toluene (20 ml), triphenyl phosphite (2.07 g, 6.7 mmole), imidazole (1.09 g, 16 mmole) and o-chlorophenyldiphenylmethanol (2.95 g, 10 mmole) obtained in Example 1 (B) was refluxed for 4 hours. The reaction mixture was treated in the same manner as in Example 3 to give 2.80 g of 1-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 81%. M.P., 142°-143° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:34])[C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[C:14]([O:26]CC2C=CC=CC=2)[CH:13]=1.[H][H]>C(O)(C)C.O.[C].[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:34])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:26])[CH:13]=1
Reactant: COc1ccc(CCNCC(O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(CCNCC(O)c2ccc(O)c(O)c2)cc1OC
Yield: 104.1 %

Procedure:
3 g of α-(3,4-dimethoxyphenethylaminomethyl)-3,4-dibenzyloxybenzylalcohol hydrochloride are suspended in a mixture of 80 ml of isopropanol and 20 ml of water. One g of 10 % palladium-carbon is added to the suspension. Then, the mixture is subjected to catalytic hydrogenation in a hydrogen atmosphere at room temperature for 1 hour under atmospheric pressure. After the reaction is completed, the mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure, and the residue thus obtained is recrystallized from isopropanol. 2.1 g of α-(3,4-dimethoxyphenethylaminomethyl)-3,4-dihydroxybenzylalcohol hydrochloride are obtained. Yield: 90 % M.p. 98° - 109°C(decomp.)
Reaction SMILES: [N:1]1([CH2:6][C:7](=[O:16])[C:8]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.O>CS(C)=O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:7](=[O:16])[C:8]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)([CH3:10])[CH3:9])=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C(=O)Cn1ccnc1)C1OCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C(=O)C(Cc1ccc(Cl)cc1)n1ccnc1)C1OCCO1
Reaction time: 15 h
Yield: 30.6 %

Procedure:
30 g (0.131 mol) of 1-(imidazol-1-yl)-3-(dioxolan-2-yl)-3-methyl-butan-2-one are dissolved in 130 ml of dimethylsulphoxide, 7.5 g of powdered potassium hydroxide are added at 10° C., and 21 g of 4-chlorobenzyl chloride (0.131 mol), dissolved in 30 ml of dimethylsulphoxide, are added dropwise. After stirring has been carried out for 15 hours at 20° C., the suspension is poured onto 500 ml of water, the mixture is extracted with 600 ml of methylene chloride, the organic phase is extracted with 1 liter of water in each case, and the solvent is distilled off. The oily residue is taken up in 300 ml of diethyl ether, the other phase is filtered and the solvent is distilled off. 14 g (30.6% of theory) of 1-(4-chlorophenyl)-4-(dioxolan-2-yl)-2-(imidazol-1-yl)-4-methyl-pentan-3-one of refractive index nD20 =1.5490 are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][CH:34]([CH3:47])[CH2:35][CH2:36][O:37][C:38](=[O:46])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[CH:34]([CH3:47])[CH2:35][CH2:36][O:37][C:38](=[O:46])[CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:23])=[CH:24][CH:25]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: CC(C)NC(C)CCOC(=O)Cc1ccccc1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)C(C)CCOC(=O)Cc3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]-naphthyridin-6-yl)benzoic acid and rac-phenyl-acetic acid 3-isopropylamino-butyl ester as described for example 1.
Reaction SMILES: [N+:1]1([O-:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[O:21].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[OH-].[Na+]>O.ClCCl>[O-:13][N+:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:27][CH:28]=2)=[O:21])=[CH:3][CH:2]=1
Reactant: O=Cc1cc[n+]([O-])c2ccccc12
Reactant: Nc1ccsc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1sccc1NCc1cc[n+]([O-])c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of quinoline-4-carboxaldehyde 1-oxide (0.12 g, 0.69 mmol), 3-amino-N-[4-(trifluoromethoxy)phenyl]thiophene-2-carboxamide (0.21 g, 0.69 mmol), dichloromethane (2 ml) and trifluoroacetic acid (2 ml) was heated at 50° C. for 2 hr, then cooled to room temperature, treated with triethylsilane (0.22 ml, 1.38 mmol) and stirred at 50° C. for another 2 h. After this time the mixture was diluted with water (40 ml), basified (pH 9) with 2M NaOH (aq) and extracted with ethyl acetate (3×20 ml). The extracts were washed with water (30 ml) and brine (30 ml), then dried (MgSO4) and concentrated in vacuo to give crude product. This material was chromatographed over silica gel eluting with 15% acetonitrile/CH2Cl2, and the isolated product further purified by crystallization from acetonitrile to give 3-{[(1-oxidoquinolin-4-yl)methyl]amino}-N-[4-(trifluoromethoxy)phenyl]thiophene-2-carboxamide. MS (E+): 460 [MH+]. 1H NMR (DMSO-d6, 400 MHz): δ 5.00 (s, 2H), 6.87 (d, J=5.6 Hz, 1H), 7.25–7.40 (m, 3H), 7.65 (d, J=5.3 Hz, 1H), 7.73–7.91 (m, 4H), 8.04 (t, J=6.4 Hz, 1H), 8.30 (d, J=7.1 Hz, 1H), 8.56 (d, J=6.3 Hz, 1H), 8.61 (d, J=8.3 Hz, 1H), 9.60 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:13][C:12]([CH:22]([CH3:24])[CH3:23])=[CH:11][C:10]=1[CH:25]([CH3:27])[CH3:26])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH:25]([C:10]1[CH:11]=[C:12]([CH:22]([CH3:24])[CH3:23])[CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:9]=1[OH:8])([CH3:26])[CH3:27]
Reactant: [H][H]
Reactant: CC(C)c1cc(-c2ccc(F)cc2)c(OCc2ccccc2)c(C(C)C)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(-c2ccc(F)cc2)c(O)c(C(C)C)c1
Yield: 92.9 %

Procedure:
4 g of 10% Pd on carbon are added to a solution of 49.3 g (0.136 mol) of the benzyl ether from step 4 in 1 l of ethyl acetate and 100 ml of glacial acetic acid and the mixture is shaken in a hydrogen atmosphere (vigorous absorption of H2) for 20 minutes. The catalyst is filtered off, the filtrate is concentrated, the residue is taken up several times in toluene and the solution is in each case concentrated in vacuo. 34.4 g of the title compound are obtained as a colorless oil, b.p. 115° C./0.1 torr.