Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:29]([O:31]C)=O)[C:12]3[NH:13][C:14]4[CH:15]=[C:16]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)[CH:17]=[CH:18][C:19]=4[C:20]=3[N:21]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[NH3:33]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:29]([NH2:33])=[O:31])[C:12]3[NH:13][C:14]4[CH:15]=[C:16]([N:22]5[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]5)[CH:17]=[CH:18][C:19]=4[C:20]=3[N:21]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: N
Reactant: COC(=O)c1cc(-c2ccc(O)c(Cl)c2)nc2c1[nH]c1cc(N3CCN(C)CC3)ccc12
Solvent: CO
Product: CN1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccc(O)c(Cl)c4)nc23)CC1
Temperature: 80 °C
Yield: 74 %

Procedure:
A mixture of methyl 2-(3-chloro-4-hydroxyphenyl)-7-(4-methylpiperazin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (100 mg, 0.222 mmol) and 7N NH3 in MeOH (5 mL) in a sealed microwave vessel was heated in an oil bath at 80° C. for 16 h. After cooling to RT, the solid was collected by filtration, and washed with MeOH, and air-dried to afford 2-(3-chloro-4-hydroxyphenyl)-7-(4-methylpiperazin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxamide (75 mg, 0.16 mmol, 74% yield). MS (ESI) m/z 436.10 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:16])=[C:6]([CH:8]2[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:7]=1.[Mn]([O-])(=O)(=O)=[O:24].[K+].O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH2:17]([S:15]([C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[CH:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])(=[O:24])=[O:16])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCCCS(=O)c1ccc(Cl)cc1C1NC(=O)NC1=O
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCS(=O)(=O)c1ccccc1C1NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 29.1 %

Procedure:
To a solution of 5-(5-chloro-2-hexylsulfinylphenyl)hydantoin (4.8 g, 0.014 mol) in glacial acetic acid (50 ml) was added potassium permanganate (2.2 g, 0.014 mol) and water (5 ml). The mixture was stirred at room temperature for 45 minutes then poured into 10% sodium bisulfite solution (50 ml). The resulting solution was extracted with ether, the ethereal extract then dried (MgSO4) and evaporated under reduced pressure. The brown oily residue was chromatographed on silica gel and the product eluted with ethyl acetate:hexane (40:60). Evaporation of the eluate under reduced pressure afforded 1.32 g of product as a white solid (26% yield). M.P. 188°-189° C.
Reaction SMILES: NO.CC1[N:5]([C:10]2[S:11][C:12]([C:19]3[C:20]([CH3:34])=[N:21][N:22]4[C:27]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:26][C:25]([CH3:33])=[N:24][C:23]=34)=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)C(C)=CC=1.C(OCC)C>C(O)(=O)C>[CH2:29]([CH:28]([C:27]1[N:22]2[N:21]=[C:20]([CH3:34])[C:19]([C:12]3[S:11][C:10]([NH2:5])=[N:14][C:13]=3[C:15]([F:16])([F:18])[F:17])=[C:23]2[N:24]=[C:25]([CH3:33])[CH:26]=1)[CH2:31][CH3:32])[CH3:30]
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(-n4c(C)ccc4C)nc3C(F)(F)F)c(C)nn12
Agent: NO
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N)nc3C(F)(F)F)c(C)nn12
Temperature: 25 °C
Yield: 86.2 %

Procedure:
Add hydroxylamine (2 mL, 50% in water) to a solution of 3-[2-(2,5-dimethyl-pyrrol-1-yl)-4-trifluoromethyl-thiazol-5-yl]-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (1.1 g, 2.3 mmol) in acetic acid (10 mL). Heat the reaction to 80° C. for 6 h. Cool to room temperature. Pour into diethyl ether and wash with 2 M NaOH (2×) and then once with water. Dry the organic portion over sodium sulfate, filter, and concentrate to dryness under vacuum. Purify the resulting residue by silica gel chromatography (40% ethyl acetate in hexanes) to give the title compound (0.76 g, 87%). ES/MS m/z 384 (M+1)+.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([O:16][CH3:17])=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=O)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.[C:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[S:1]1[C:5]([C:6]2[C:7]([O:16][CH3:17])=[C:8](/[CH:9]=[CH:23]/[C:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)=[O:24])[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2
Reactant: COc1ccc(C=O)c(OC)c1-c1cc2ccccc2s1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1ccc(/C=C/C(=O)c2ccc(C(=O)O)cc2)c(OC)c1-c1cc2ccccc2s1
Yield: 64 %

Procedure:
The title compound was prepared by condensing 3-benzo[b]thiophen-2-yl-2,4-dimethoxy-benzaldehyde (Ex-44B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 237° C. (dec.), 64% yield. 1H-NMR (DMSO-d6) δ 13.37 (bs, 1H), 8.20–8.25 (m, 3H), 8.11 (d, J=8 Hz, 2H), 8.02 (d, J=8 Hz, 1H), 7.96 (d, J=9 Hz, 2H), 7.88–7.91 (m, 1H), 7.65 (s, 1H), 7.35–7.43 (m, 2H), 7.14 (d, J=9 Hz, 1H), 3.90 (s, 3H), 3.53 (s, 3H). HRMS m/z=calc. 445.1110, found 445.1112.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)CCC1(c2ccc(F)c(F)c2)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC1(c2ccc(F)c(F)c2)CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
To a solution of ethyl 3-(1-(3,4-difluorophenyl)cyclohexyl)propanoate (540 mg, 1.822 mmol) in MeOH (15 mL) was added 1N NaOH (3.64 mL, 3.64 mmol), and the mixture was stirred at room temperature for 20 hrs. Since the reaction was not complete on TLC, an additional 1.82 mL of 1N NaOH was added, and it was continued to stir for 3 hrs. TLC showed that the reaction was complete. Next, the reaction mixture was acidified with the addition of 6 mL of 1N HCl, and the product was extracted with EtOAc. The extract was washed with water and brine, dried over Na2SO4, and evaporated to give 3-(1-(3,4-difluorophenyl)cyclohexyl) propanoic acid (489 mg, 1.822 mmol, 100% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[O:20]1[CH2:19][CH:18]1[CH2:16][O:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: ClCC1CO1
Reactant: Cc1ccc(C2=NNC(=O)CC2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1ccc(C2=NNC(=O)CC2)cc1OCC1CO1
Yield: 77 %

Procedure:
A mixture of powdered 6-(3-hydroxy-4-methylphenyl)-4,5-dihydro-3(2H)-pyridazinone (5.0 g, 0.024 mole), epichlorohydrin (19.3 ml, 0.24 mole), and piperidine (0.2 ml) was heated on a steam bath for 1 hour. Evaporation of the solution under reduced pressure gave an oil which was dissolved in a small volume of dichloromethane and stirred with dilute sodium hydroxide solution (15 ml). The organic phase was washed with water, dried, and evaporated to an oil which under reduced pressure gave a solid, 6.2 g, 98%. Trituration with ethanol-ether gave crude 6-[3-(2,3-epoxypropoxy)-4-methylphenyl]-4,5-dihydro-3(2H)-pyridazinone 4.81 g, 76%, m.p. 128°-132°C. Purification, by recrystallisation from ethanol, or by column chromatography (silica, chloroform) gave the pure epoxide, m.p. 140°-142.5°C.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[CH2:16]([NH2:19])[CH2:17][CH3:18]>C1C=CC=CC=1.CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:19][CH2:16][CH2:17][CH3:18])[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: CCCN
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Solvent: c1ccccc1
Product: CCCNC(C)=C1C(=O)OC(=O)C(C(C)=O)=C1O

Procedure:
To a boiling solution of 4.2 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of benzene/methanol is added 1.2 g. (0.02 m.). of n-propylamine and the resulting mixture is refluxed overnight. The reaction mixture is concentrated, filtered and the solid treated with water to give pure 5-acetyl-4-hydroxy-3-[1-(n-propylamino)-ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 145° -148° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1.Cl.CCN(C(C)C)C(C)C.Cl[C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1>CC(N(C)C)=O>[CH3:1][N:2]([C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1)[CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1
Reactant: CNCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN(CC[C@H]1CC[C@H](C(=O)O)CC1)c1nccc(C(F)(F)F)n1

Procedure:
A solution of 0.250 g (1.13 mmol) of trans-4-(2-methylamino-ethyl)-cyclohexanecarboxylic acid•HCl, 1.04 mL (6.09 mmol, 5.3 eq) of Huenig's base and 0.412 g (2.26 mmol, 2 eq) of 2-chloro-4-(trifluoromethyl)pyrimidine in 4 mL of DMA were reacted at RT for 19 h. The solvent was evaporated and the residue partitioned between Et2O (×3)/aqueous 10% KH2PO4, dried over Na2SO4, and evaporated to yield 0.422 g (quantitative) of trans-4-{2-[methyl-(4-trifluoromethyl-pyrimidin-2-yl)-amino]-ethyl}-cyclohexanecarboxylic acid, MS: 330 (M−H−), MP: 110-112° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]([N:18]=[C:19]=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCOCC1>[C:8]([C:7]1[C:2]([NH:1][C:19]([NH:18][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])=[N:3][CH:4]=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1cccnc1N
Reactant: O=C=NC(=O)c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1cccnc1NC(=O)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 2-amino-3-cyanopyridine (300 mg, 2.5 mmol) in 1,4-dioxane (5 mL) was added benzoyl isocyanate (370 mg, 2.5 mmol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The precipitation was collected by filtration, washed with EtOAc/Hexanes (1:4), and dried under vacuum to give N-(3-cyanopyridin-2-ylcarbamoyl)benzamide as a white solid (360 mg, 54%). MS 266 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.O>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 80 °C

Procedure:
A mixture of 1-bromo-4-nitrobenzene (5 g, 24.8 mmol) and 1-benzylpiperazine (8.6 ml, 49.5 mmol, 2 equiv) is heated to 80° C. for 17 h. The reaction mixture is allowed to cool to RT, and is diluted with DCM/H2O. The layers are separated and the aqueous phase is extracted with DCM. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel column chromatography (Hex/EtOAc, 1:1) affords the title compound as a yellow solid: ESI-MS: 298.3 [MH]+; tR=3.25 min (purity: 100%, system 1).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C@@:21]([OH:32])([CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[C@@H:22]([CH3:25])[CH2:23][OH:24].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C@:21]([OH:32])([C@@H:22]([CH3:25])[CH2:23][O:24][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CO)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](COS(C)(=O)=O)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 101 %

Procedure:
61 mg (0.61 mmole) of triethylamine and 64 mg (0.56 mmole) of methanesulfonyl chloride were added at 0° C., whilst stirring, to a solution of 74 mg (0.231 mmole) of (2S*,3R*)-3-(2,4-dichlorophenyl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1,3-butanediol in 2 ml of methylene chloride. Fifteen minutes later the reaction mixture was mixed with a dilute aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, and the solvent was removed by evaporation under reduced pressure, to give 92 mg of a crude product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31])([O-:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=1)=[O:31])([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 104.7 %

Procedure:
To a stirring solution of tert-butyl [3-(aminomethyl)phenyl]carbamate (2.0 g, 9.0 mmol) and triethylamine (1.3 mL, 9.4 mmol) in dry tetrahydrofuran (25 mL) at 0° C. slowly added a solution of 3-nitrobenzoyl chloride (1.75 g, 9.45 mmol) in tetrahydrofuran (7.3 mL). The resulting mixture was slowly warmed up to rt and stirred for one additional hour at rt. The reaction mixture was treated with Na2CO3 (aq), separated. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as an off-white powder (3.5 g, 100%). LCMS for C19H21N3O5 (M-tBu+H)+: m/z=316.0. 1H NMR (400 MHz, CD3OD): δ 8.71 (t, J=2.0 Hz, 1H), 8.38 (ddd, J=8.4, 1.6, 1.2 Hz, 1H), 8.23 (ddd, J=8.0, 1.6, 0.8 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.28 (m, 1H), 7.20 (t, J=7.6, 1H), 7.00 (d J=7.6 Hz, 1H), 4.90 (s, 2H), 1.49 (s, 9H).
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]([O:10][CH2:11][CH2:12][C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=4[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Li+].[OH-].Cl>C1COCC1.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=4[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=3)=[CH:31][CH:32]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(-n3ccnc3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1COc1ccc(CCOc2ccc(-n3ccnc3)cc2)cc1
Yield: 4.7 %

Procedure:
Methyl 2-[(4-{2-[4-(1H-imidazol-1-yl)phenoxy]ethyl}phenoxy)methyl]benzoate (0.12 g, 0.28 mmol) was dissolved in a mixture of THF/water (7/1, 5 ml) and LiOH (0.03 g, 1.13 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). Workup by addition of HCl (1 ml, 1M), extract the product by adding two portions of EtOAc (5 ml). The pooled organic phases were dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (starting with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Evaporation gave 6 mg of 2-[(4-{2-[4-(1H-imidazol-1-yl)phenoxy]ethyl}-phenoxymethyl]benzoic acid (yield 4.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH:11][C@H:12]1[C@@H:19]2[N:15]([C:16](=[O:33])N(C3C4CCCCC=4C(C#N)=CC=3)[C:18]2=[O:20])[CH2:14][CH2:13]1>>[Cl:10][C:4]1[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([N:1]2[C:18](=[O:20])[C@@H:19]3[C@H:12]([OH:11])[CH2:13][CH2:14][N:15]3[C:16]2=[O:33])[CH:3]=1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: N#Cc1ncc(N)cc1Cl
Product: N#Cc1ncc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)cc1Cl

Procedure:
The title compound was synthesized from compound 44D by procedures analogous to those described for Examples 2E to 2F. HPLC: 100% at 1.67 min. (retention time) (Conditions: Shim-Pak VP-ODS (4.6×50 mm); Eluted with 0% to 100% B, 4 min gradient, 1 min hold. (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 4 mL/min UV detection at 220 nm); MS (ES) m/z 293 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].CS(Cl)(=O)=O.[CH2:30]([N:32](CC)CC)[CH3:31]>O.C(#N)C>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:31][C:30]#[N:32])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
In a 50 ml-volume glass flask equipped with a stirrer and a thermometer were placed under argon atmosphere 200 mg (0.69 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde, 2 mL of acetonitrile and 41.5 mg (1.04 mmol) of sodium hydride (purity: 60%). The content was stirred at room temperature for 2 hours. The resulting mixture was chilled to 0° C. To the chilled mixture were added 0.08 mL (1.03 mmol) of methanesulfonyl chloride and 0.15 mL (1.08 mmol) of triethylamine, and the mixture was stirred for 3 hours at the same temperature. Subsequently, to the mixture was added 5 mL of chilled water, and the mixture was extracted with three portions of ethyl acetate (15 mL) which were previously chilled in an ice bath. The mixture was dried over anhydrous magnesium sulfate. The organic portion was then filtered, and the filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 180 mg (yield: 83%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile was produced.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][C:6]2[CH:17]=[CH:18][CH:19]=[N:20][C:5]1=2)=[O:3].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH2:35])[CH2:24][CH3:25])[CH3:22]>C(#N)C>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH:35][C:2]([N:4]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][C:6]2[CH:17]=[CH:18][CH:19]=[N:20][C:5]1=2)=[O:3])[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)CC1CCCCN1CCN
Reactant: Cc1ccc2c(c1)N(C(=O)Cl)c1ncccc1NC2=O
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2cc(C)ccc2C(=O)Nc2cccnc21
Yield: 40 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 40% of theory. Colourless crystals, m.p. 183°-185° C. (acetonitrile).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[NH:16])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[Br:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35](Cl)=[O:36]>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4](=[N:16][C:35]([C:30]1[C:31]2[C:26](=[C:25]([Br:24])[CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:28][CH:29]=1)=[O:36])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1cccc2c(Br)cccc12
Reactant: COC(=N)Cc1cccc2ccccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(Cc1cccc2ccccc12)=NC(=O)c1cccc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
According to the procedure of Soto et al, Synthesis, 483, (1983), to a stirred suspension of methyl-2-(1-naphthalenyl)acetimidate hydrochloride (prepared in Step 1) (11.7 g, 0.050 mol), in dry toluene (150 mL) was added triethylamine (11.5 g, 0.114 mol). 5-Bromo-1-naphthoyl chloride (13.4 g, 0.050 mol) was added in one portion and the resulting mixture was stirred at room temperature for 16 hours. The precipitated salt was removed by filtration and washed with toluene. The filtrate was concentrated in vacuo to give an orange oil (21.5 g, 100%) which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]([NH:14][NH:15]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][C:10](=[O:26])[CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=O)[C:36]([F:39])([F:38])[F:37]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]2[N:14]=[N:15][CH:34]=[C:35]([C:36]([F:39])([F:38])[F:37])[C:11]=2[C:10](=[O:26])[CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3ccccc3Cl)C2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CC(c2ccccc2Cl)Cc2nncc(C(F)(F)F)c21
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To a mixture of 5-(2-chlorophenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (2.74 g), anhydrous potassium carbonate (1.26 g) and methanol (30 ml) was added at room temperature 1-bromo-3,3,3-trifluoropropan-2-one (1.74 g), and the mixture was stirred at the same temperature for 0.5 hours. To the mixture was added anhydrous potassium carbonate (1.26 g), and the mixture was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in acetic acid (20 ml). To the solution was added concentrated sulfuric acid (1 ml), and the mixture was refluxed for 20 minutes. To the reaction solution was added water (120 ml), and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with sodium hydrogen carbonate solution and concentrated. The residue was purified with silica gel column chromatography to give 7-(2-chlorophenyl)-4-trifluoromethyl-5,6,7,8-tetrahydrocinnolin-5-one (1.02 g) as oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=[O:23])[CH2:19][CH2:20][O:21][CH3:22])[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)C>C1COCC1>[OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=[O:23])[C:19]([CH2:20][O:21][CH3:22])=[CH:29][N:30]([CH3:32])[CH3:31])[CH:17]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COCCC(=O)c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: C1CCOC1
Product: COCC(=CN(C)C)C(=O)c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1

Procedure:
4-(3-Methoxy-propionyl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide was treated with an excess of Bredereck's reagent in THF at room temperature to 50° C. for 3 days. The solvent was removed under reduced pressure and the concentrate was used directly in the next step. HPLC Method B, Rt=5.0 minutes “broad peak”.