Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH:7]([NH2:9])[CH3:8].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([C:22](=O)[CH3:23])[C:18]([O:20][CH3:21])=[O:19].C(O)(=O)C>CO>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH:7](/[N:9]=[C:22](\[CH3:23])/[CH:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[Br:10])[C:18]([O:20][CH3:21])=[O:19])[CH3:8]
Reactant: CC(N)C1COCCO1
Reactant: COC(=O)C(C(C)=O)c1ccccc1Br
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(/C(C)=N/C(C)C1COCCO1)c1ccccc1Br
Reaction time: 8 h

Procedure:
To a solution of 1-(1,4-dioxan-2-yl)ethanamine (2.5 g, 19 mmol) in methanol (100 mL) was added methyl 2-(2-bromophenyl)-3-oxobutanoate (5.4 g, 20 mmol) and acetic acid (1.8 g, 30 mmol). The resulting reaction system was warm to reflux and allowed to stir overnight. The reaction mixture was concentrated and purified by column chromatographed on silica gel (eluted: dichloromethane/methanol 50:1→20:1→5:1) the title compound (1 g, 14%) as a brown solid. LCMS (M+H+) m/z: calcd. 383.07. found 384.9.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]1=O)C.[CH3:13][NH:14]N>CO>[CH3:13][N:14]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:5]=2[CH:4]=[N:2]1
Reactant: CNN
Reactant: CN(C)C=C1C(=O)CCCC1=O
Solvent: CO
Product: Cn1ncc2c1CCCC2=O
Temperature: 0 °C

Procedure:
To an ice-cold solution of 67 grams of 2-dimethylaminomethylene-1,3-cyclohexanedione in 600 ml of methanol was added slowly a solution of 21.3 ml of methylhydrazine in 200 ml of methanol and the resulting solution was heated at reflux for 2 hours. The solvent was removed under reduced pressure and the residue was triturated with ethyl ether to give 1,5,6,7-tetrahydro-1-methyl-4H-indazol-4-one as a tan crystalline solid melting at about 88°-91° C.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[O:6].[NH:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:14][CH2:13]1.[I-].[K+]>CN(C)C=O>[O:27]=[C:19]1[N:18]([CH:15]2[CH2:14][CH2:13][N:12]([CH2:2][CH2:3][NH:4][C:5]([C:7]3[O:8][CH:9]=[CH:10][CH:11]=3)=[O:6])[CH2:17][CH2:16]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C(NCCCl)c1ccco1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccco1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6.9 parts of N-(2-chloroethyl)-2-furancarboxamide, 9.8 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.6 parts of potassium iodide and 135 parts of N,N-dimethylformamide is stirred first for 3 hours at reflux and further overnight at room temperature. The reaction mixture is evaporated. The residue is taken up in water and the whole is alkalized. The product is extracted with 4-methyl-2-pentanone. The layers are separated and the aqueous phase is set aside. The organic phase is washed with water, dried, filtered and evaporated. The solid residue is crystallized from 2-propanone. The product is filtered off and dried, yielding a first fraction of 1 part of N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-2-furancarboxamide; mp. 228.9° C. The aqueous phase, which was set aside (see above), is allowed to stand overnight. The precipitated product is filtered off and crystallized from methanol, yielding a second fraction of 4 parts of N-{2-[ 4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-2-furancarboxamide; mp. 231.7° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:17]=1[CH2:18][C:19]1[O:23][N:22]=[C:21]([C:24](O)=[O:25])[N:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:24]([C:21]1[N:20]=[C:19]([CH2:18][C:17]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:16]=2[F:15])[O:23][N:22]=1)=[O:25]
Reactant: O=C(O)c1noc(Cc2cc(F)ccc2F)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2cc(F)ccc2F)n1
Yield: 12.4 %

Procedure:
This compound was prepared following Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 5-(2,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylic acid (0.102 g; 0.424 mmol), HATU (0.161 g: 0.424 mmol) and N,N-diisopropylethylamine (0.222 mL; 1.27 mmol) in DMF (3 mL). The purification by flash chromatography on silica gel (eluent: 1 to 10% of ethyl acetate in dichloromethane) gave 0.022 g (12%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=2)[CH2:3]1.[H][H]>C(O)C.[Pd]>[NH2:12][C:9]1[CH:8]=[N:7][C:6]([N:4]2[CH2:3][CH:2]([OH:1])[CH2:5]2)=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CC(O)C2)nc1

Procedure:
A suspension of 0.34 g (1.74 mmol) of 2-(3-hydroxyazetidin-1-yl)-5-nitropyridine, prepared in the preceding stage, and 9 mg of Pd/C at 10% in 10 mL of ethanol is stirred vigorously at 20° C. under 5 atm of hydrogen for 4 hours. After this time, the mixture is filtered on a Celite pad and then concentrated at reduced pressure. The resultant product is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol. We thus obtain 0.1 g of the expected product, which will be used as it is in the rest of the synthesis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([S:31]([CH3:30])(=[O:33])=[O:32])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reactant: CS(=O)(=O)Cl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(S(C)(=O)=O)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 99 above with the compound from Example 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydro-pyrido[2,3-b]indol-2-one, and methanesulphonyl chloride.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][CH2:8][CH2:9][S:10]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23](=[O:39])[N:24]([CH3:38])[C:25]2[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[CH:29][N:28]=[N:27][CH:26]=2)[CH:14]=1)(=[O:12])=[O:11])(C)(C)C.FC(F)(F)C(O)=O>>[CH3:38][N:24]([C:25]1[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])=[CH:29][N:28]=[N:27][CH:26]=1)[C:23]([C:15]1[CH:14]=[C:13]([S:10]([CH2:9][CH2:8][CH2:7][C:6]([OH:40])=[O:5])(=[O:11])=[O:12])[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=1)=[O:39]
Reactant: Cc1ccccc1-c1cnncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)CCCC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1cnncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)CCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
The title compound was prepared in analogy to example 10, from 4-{3-[methyl-(5-o-tolyl-pyridazin-4-yl)-carbamoyl]-5-trifluoromethyl-benzenesulfonyl}-butyric acid tert-butyl ester (example 16), adding another batch of trifluoroacetic acid after 3 hours (395 mg, 267 μL, 3.46 mmol) and stirring at room temperature for additional 64 hours. The product was further purified by a second chromatography using an MPLC (Flashmaster) system eluting with a gradient of CH2Cl2:methanol (100:0 to 90:10). Colorless oil (57%). MS (ESI+): m/z=522.13 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[CH:4][C:3]=1[CH3:31].FC(F)(F)S(O)(=O)=O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(Cl)Cl>[F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[CH3:31]
Reactant: Cc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1F
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)nc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
3-(6-Fluoro-5-methylpyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine was dissolved in trifluoroacetic acid (5 mL) and methylene chloride (5 mL). To the solution was added trifluoromethanesulfonic acid (104.2 uL, 1.18 mmol) and triethylsilane (18.1 uL, 1.18 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was then concentrated, and the residue was purified by reverse phase HPLC to afford 274 as an off-white solid (7.8 mg, 11%). 1H NMR (400 MHz, DMSO) δ 9.29-9.21 (m, 2H), 8.81 (s, 1H), 8.62 (dd, J=4.7, 1.4 Hz, 1H), 8.42 (dt, J=8.0, 1.9 Hz, 1H), 8.06 (dd, J=7.6, 1.6 Hz, 1H), 8.01-7.95 (m, 1H), 7.55 (dd, J=8.0, 4.8 Hz, 1H), 2.34 (s, 3H); ESI MS m/z=306.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[N:4]([CH3:10])[N:3]=1.S(Cl)([Cl:13])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([Cl:13])=[O:8])[N:4]([CH3:10])[N:3]=1
Reactant: Cn1nc(Cl)cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cn1nc(Cl)cc1C(=O)Cl

Procedure:
100 g of 3-chloro-1-methyl-5-pyrazole-carboxylic acid (the Compound No. 4.1 (a) of the present invention) were suspended in 200 ml of benzene, and 150 ml of thionyl chloride were added thereto dropwise. Then, the mixture was heat-refluxed for 4 hours. The reaction mixture was allowed to cool, and the solvent was then distilled off under reduced pressure. The resulting residue was distilled under reduced pressure to obtain 103 g of the intended 3-chloro-1-methyl-5-pyrazolecarbonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]2[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24](O)=[O:25])=[C:20]([CH3:29])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][C:8]=1[CH3:30])[CH3:2].B.C1COCC1>C1COCC1>[OH:25][CH2:24][CH2:23][O:22][C:21]1[CH:27]=[CH:28][C:18]([C:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:31])=[C:8]([CH3:30])[CH:9]=2)([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:19][C:20]=1[CH3:29]
Reactant: CCOC(=O)COc1ccc(C(CC)(CC)c2ccc(OCC(=O)O)c(C)c2)cc1C
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C(CC)(CC)c2ccc(OCCO)c(C)c2)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
To a solution of compound 4 (59.7 mg, 0.1393 mmol) in THF (1.25 mL) at −10° C. was added BH3•THF (140 μL of a 1.0 M solution in THF, 0.1393 mmol, 1.0 equiv.) and the resulting solution was warmed to RT and stirred for 16 h. the reaction was cooled to 0° C. and a further portion of BH3 THF (140 μL of a 1.0 M solution in THF, 0.1393 mmol, 1.0 equiv.) was added. After warming to RT and stirring for 3 h, the reaction was re-cooled to 0° C. and quenched by the addition of H2O and K2CO3 (ca. 20 mg). The resulting mixture was warmed to RT, diluted with H2O and extracted with Et2O (×4). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to afford a colourless oil which was purified by column chromatography (5:20:75 MeOH/EtOAc/hexanes) to afford the title compound 11 (52.4 mg, 91%)
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][O:6][C:7]1[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=1[O:9][CH2:10][CH:11]([OH:18])[CH2:12][NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:4].[CH2:23]=O>C(O)C>[CH3:1][NH:2][C:3]([CH2:5][O:6][C:7]1[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=1[O:9][CH2:10][CH:11]1[O:18][CH2:23][N:13]([C:14]([CH3:17])([CH3:15])[CH3:16])[CH2:12]1)=[O:4]
Reactant: C=O
Reactant: CNC(=O)COc1ccccc1OCC(O)CNC(C)(C)C
Solvent: CCO
Product: CNC(=O)COc1ccccc1OCC1CN(C(C)(C)C)CO1

Procedure:
A mixture of 1.3 g. of 3-(o-N-methylcarbamoylmethoxyphenoxy)-1-t-butylaminopropan-2-ol, 20 ml. of absolute ethanol and 2 ml. of aqueous 36% w/v formaldehyde solution is heated under reflux for 24 hours. The solution is evaporated to dryness under reduced pressure and there is thus obtained as the residual oil 5-(o-N-methylcarbamoylmethoxyphenoxymethyl)-3-t-butyloxazolidine which is characterised by its proton magnetic resonance spectrum.
Reaction SMILES: [CH2:1]1[C@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:4][S:3][CH2:2]1.[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].[H-].[Na+]>CN(C)C=O>[S:3]1[CH2:2][CH2:1][C@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:12])[S:4]1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)CCCC[C@H]1CCSS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)CCCC[C@H]1CCSS1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
300 mg of (S)-α-lipoic acid were dissolved in 6 ml of anhydrous dimethylformamide, and 276 mg of N,N'-carbonyldiimidazole and 1 ml of anhydrous dimethylformamide were added to the solution, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour and 30 minutes. At the end of this time, 162 mg of methanesulfonamide and 74 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to the reaction mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour and then left to stand for 2 days. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1:1 and 3:1 by volume mixtures of ethyl acetate and hexane as eluent. It was then recrystallized form a 1:2 by volume mixture of ethyl acetate and hexane, to obtain 154 mg of the title compound, melting at 91° C. to 92° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH2:19]([O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[NH:26])[CH2:20][CH3:21].C(N(CC)CC)C>C(#N)C>[C:13]1([C:4]2[N:3]=[C:2]3[N:26]=[C:25]([C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[O:22][CH2:19][CH2:20][CH3:21])[NH:27][C:8](=[O:10])[C:7]3=[CH:6][N:5]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Reactant: CCCOc1ccccc1C(=N)N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1-c1nc2nc(-c3ccccc3)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 3 reaction of ethyl 4-chloro-2-phenyl-5-pyrimidine carboxylate (1.05 g) with 2-propoxybenzamidine (from sodium, 0.10 g, in ethanol, 10 ml, and 2-propoxybenzamidine methanesulphonate, 1.20 g) and triethylamine (0.40 g) in acetonitrile (25 ml) for 3 days at ambient temperature yielded a crude product which was recrystallised from methanol to yield the title compound, 0.52 g, m.p. 203°-4° C.
Reaction SMILES: [CH:1]1[C:18]2[C:17](=[O:19])[C:16]3[C:7](=[CH:8][C:9]4[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6](=[O:20])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:21](C(OC)=O)[C:22]([O:24]C)=[O:23].Cl>C(O)(=O)C>[CH:1]1[C:18]2[C:17](=[O:19])[C:16]3[C:7](=[CH:8][C:9]4[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6](=[O:20])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: COC(=O)C(C(=O)OC)c1ccc2c(c1)C(=O)c1cc3ccccc3cc1C2=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1cc3ccccc3cc1C2=O

Procedure:
8 g (20.6 mmol) of dimethyl (2-naphthacene-5,12-dionyl)-malonate (Example 36), 60 ml of glacial acetic acid and 60 ml of concentrated HCl solution are stirred under reflux for 4.5 hours. The mixture is poured onto ice/water. The crystals are filtered off, washed with diethyl ether and recrystallized from THF/pentane. Yield 4.88 g (75%); melting point >220° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10]>[Pd]>[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: Ic1ccccc1
Agent: [Pd]
Product: CCOC(=O)C=Cc1ccccc1
Yield: 66.4 %

Procedure:
The procedure described in Example 9 is repeated, but using 2.79 ml (25 mmols) of iodobenzene and 2.98 ml (27.5 mmols) of ethyl acrylate. After a reaction time of 4.5 hours at 130° C., 2.92 g (16.6 mmols) of ethyl cinnamate are obtained, corresponding to a yield of 66% of theory (conversion figure 6600; Pd content 0.01 mol %).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[C:7]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1)#[N:2].[CH2:18](N)[CH2:19][NH2:20]>C(=S)=S>[NH:2]1[CH2:18][CH2:19][N:20]=[C:1]1[CH2:3][C:4]1[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[C:7]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:6][CH:5]=1
Reactant: NCCN
Reactant: CS(=O)(=O)Nc1ccc(CC#N)c2ccoc12
Solvent: S=C=S
Product: CS(=O)(=O)Nc1ccc(CC2=NCCN2)c2ccoc12
Yield: 93.7 %

Procedure:
A mixture of N-(4-cyanomethyl-benzofuran-7-yl)-methanesulfonamide (1.0 g, 4.0 mmole), ethylene diamine (8 mL, 119.7 mmoles), and carbon disulfide (one drop) was microwaved at 140° C. for 30 minutes in a Smith creators. The reaction mixture was transferred into a large beaker (1 L) and the reaction vessel was rinsed with methanol (5 mL). Ether (600 mL) was added to the reaction mixture and insoluble material settled at the bottom of the container. The ether solution was removed by decantation. The residue was purified by flash column chromratography over silica gel eluting with 8% methanol in dichloromethane with 0.1% concentrated ammonium hydroxide to give N-[4-(4,5-dihydro-1H-imidazol-2-ylmethyl)-benzofuran-7-yl]-methanesulfonamide as a solid (1.1 g, 85%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][CH:20]=[C:21]([Br:23])[CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[SH:38]>CO>[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38][CH:17]([C:18]1[S:19][CH:20]=[C:21]([Br:23])[CH:22]=1)[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: Nc1ccccc1S
Reactant: COC(=O)/C(=C/c1cc(Br)cs1)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Sc1ccccc1N)c1cc(Br)cs1
Yield: 45.8 %

Procedure:
The title compound was prepared according to the method of Example 94b, employing methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(4-bromo-2-thienyl)acrylate (96a) (8.13 g, 20.5 mmol), triethylamine (1.43 g, 14.1 mmol), and 2-aminothiophenol (14.0 g, 112 mmol) in anhydrous methanol (80 mL). Purification by flash chromatography on silica gel eluting with 4:1 (v/v) hexane/ethyl acetate yielded a solid, which was recrystallized from 6:1 (v/v) hexane/ethyl acetate to afford the title compound (4.90 g, 46%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.44 (s, 3H), 4.63 (t, 1H, J=8.1 Hz), 4.92 (d, 1H, J=7.4 Hz), 5.09 (m, 21H), 5.46 (bs, 2H), 6.38 (t, 1H, J=7.5 Hz), 6.66 (d, 1H, J=8.3 Hz), 6.80 (s, 1H), 6.99-7.03 (m, 2H), 7.32-7.39 (m, 5H), 7.52 (s, 1H), 8.28 (d, 1H, J=9.2 Hz). MS APCI, m/z=521, 523. LC/MS: 2.71 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])(Cl)Cl.[F:18][C:19]1[CH:24]=[C:23]([OH:25])[C:22]([OH:26])=[CH:21][C:20]=1[C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[O:25][C:23]2[CH:24]=[C:19]([F:18])[C:20]([C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:21][C:22]=2[O:26]1
Reactant: Clc1ccccc1C(Cl)(Cl)c1ccccc1Cl
Reactant: O=C(c1cc(O)c(O)cc1F)N1CCOCC1
Product: O=C(c1cc2c(cc1F)OC(c1ccccc1Cl)(c1ccccc1Cl)O2)N1CCOCC1
Temperature: 150 °C
Yield: 4.5 %

Procedure:
A mixture of bis-(2-chlorophenyl)dichloromethane (Example 182, 258 mg, 0.84 mmol, 2.6 eq.) and (2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 87b, 72 mg, 0.32 mmol) were heated 5 h at 150° C. in a sealed glass tube. Purification by flash chromatography afforded the title compound (6.8 mg, 4.5%) as an off-white solid, m.p.: 98° C.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:8]1[CH2:7][CH2:6][C:5]2([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: Brc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccccn3)CC2)C1
Temperature: 120 °C
Yield: 69 %

Procedure:
Sodium t-butylate (5.4 mmol, 3.0 eq.) was added to a stirred mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1.8 mmol, 1.0 eq.) and 2-bromopyridine (1.8 mmol, 1.0 eq.) in toluene (30 ml) and the reaction mixture was degassed with N2 for 15-20 min. BINAP (0.108 mmol, 0.06 eq.) and Pd(OAc)2 (0.036 mmol, 0.02 eq.) were added and the reaction mixture obtained is heated at 120° C. for 12 h. The reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo in order to obtain the crude product, which was purified by column chromatography (silica gel, 30% ethyl acetate in hexane). Yield: 69%
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[CH:3][N:2]([CH3:1])[C:6]=3[CH:7]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: Cn1cnc2ccc(C(=O)O)cc21
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1cnc2ccc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)cc21
Yield: 91 %

Procedure:
The title compound is prepared from 3-methyl-3H-benzoimidazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 91% of theory; LC (method 4): tR=1.65 min; Mass spectrum (ESI+): m/z=346 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[N:17]1([CH2:22][CH2:23][CH2:24][N:25]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:21][CH2:20][CH2:19][CH2:18]1>O>[N+:8]([C:3]1[CH:4]=[CH:5][C:6]([N:28]2[CH2:29][CH2:30][CH2:31][N:25]([CH2:24][CH2:23][CH2:22][N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:26][CH2:27]2)=[CH:7][CH:2]=1)([O-:10])=[O:9]
Reactant: C1CCN(CCCN2CCCNCC2)C1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCN(CCCN3CCCC3)CC2)cc1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Fluoronitrobenzene (5.56 g, 39.43 mmol) is dissolved in water, and then potassium carbonate (6.55 g, 47.31 mmol) and 1-(3-pyrrolidinopropyl)-homopiperazine (10 g, 47.31 mmol) are added. The medium is heated at 85° for 4 hours and then cooled to room temperature. The medium is filtered and a yellow solid is recovered after drying in a vacuum oven at 45° C. (12.5 g, yield=95.5%).