Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH:16]=[CH:17][CH:18]=O.[BH4-].[Na+].Cl>C(Cl)Cl>[CH2:1]([NH:4][CH2:18][CH:17]=[CH:16][C:15]1[CH:20]=[C:21]([Cl:23])[CH:22]=[C:13]([Cl:12])[CH:14]=1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=CC=Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: ClCCl
Product: C=CCNCC=Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4.5 ml (60 mmol, 3.4 g) of allylamine and 17.0 g of sodium sulfate were added to 12.0 g (59.7 mmol) of 3,5-dichlorocinnamaldehyde in 180 ml of methylene chloride, and the mixture was stirred at room temperature for 24 h. The sodium sulfate was then filtered and washed with methylene chloride, and the filtrate was evaporated to dryness. The resulting yellow oil was dissolved in 200 ml of absolute methanol and, under nitrogen, 2.5 g (66.0 mmol) of sodium borohydride were added in portions. The temperature of the mixture rose slightly and it was then stirred for 1 h and subsequently neutralized (pH=7) with 10% strength hydrochloric acid. The solvent was removed under reduced pressure, and the residue was taken up in methylene chloride. The organic phase was washed twice with water, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, methylene chloride +5% methanol). Yield: 9.2 g (63%) of yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[OH:23][CH2:24][CH2:25][NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([S:27]([NH:26][CH2:25][CH2:24][OH:23])(=[O:29])=[O:28])=[CH:31][CH:32]=3)[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Reactant: O=S(=O)(NCCO)c1ccc(B(O)O)cc1
Product: CC(On1ccc2ncc(-c3ccc(S(=O)(=O)NCCO)cc3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and {4-[(2-hydroxyethyl)sulfamoyl]phenyl}boronic acid according to the procedure described in example 4.
Reaction SMILES: C[N:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]1[C:28]([OH:30])=O.Cl.CN.[CH2:34]([N:36](CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:34][NH:36][C:28]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:14][CH:13]=3)[CH:9]=[N:8][CH:7]=2)[N:2]=1)=[O:30]
Reactant: CCN(CC)CC
Reactant: CN1c2c(cncc2-c2ccc(OCCOC3CCOCC3)cc2)C=CC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2cncc(-c3ccc(OCCOC4CCOCC4)cc3)c2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 10.4 %

Procedure:
N-methyl-8-{4-[2-(tetrahydro-2H-pyran-4-yloxy)ethoxy]phenyl}-1,6-naphthyridine-2-carboxylic acid (281 mg, 0.71 mmol), an intermediate product of the synthetic process in Example 9 (9a), was dissolved in N,N-dimethylformamide (7 mL), to which methylamine hydrochloride (478 mg, 7.13 mol), triethylamine (1.2 mL, 8.56 mmol), 1-hydroxybenzotriazole (33 mg, 0.21 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (681 mg, 3.56 mmol) were added, followed by stirring at room temperature for 48 hours. The resulting reaction liquid was filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 40:60-0:100, V/V) to give the desired title compound (30 mg, yield 10%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1)=O.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)(=O)C.O1CCCC1>[CH3:7][O:8][CH2:9][CH2:10][NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1
Reactant: COCC(=O)N[C@@H]1CCCN(Cc2ccccc2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCN[C@@H]1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a 50 ml anhydrous tetrahydrofuran suspension of 0.87 g (2.0 eg.) of lithium aluminum hydride in a 300 ml round-bottomed flask was added dropwise a 20 ml anhydrous tetrahydrofuran solution of 3.00 g (11.4 mmol) of (R)-3-(2-methoxyacetylamino)-1-phenylmethylpiperidine. After stirred for 1 hour at room temperature, the reaction mixture was refluxed for 3 hours. Further, 0.87 g (2.0 eg.) of lithium aluminum hydride were added and the mixture was refluxed for 3 hours. The reaction mixture was stirred under cooling with ice and, after added 180 ml of ethyl acetate and a 10 ml aqueous solution of sodium hydroxide (1.82 g, 4.0 eg.) in turn to this and stirred for 30 minutes, anhydrous magnesium sulfate was added and it was filtered with celite. The filtrate was distilled off under reduced pressure and the residue thus obtained was purified by column chromatography (alumina, ethyl acetate:n-hexane=1:2) to obtain 2.03 g (yield 72 %) of title compound as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].O[CH2:18][C:19]1[CH:20]=[C:21]([C:25]2[N:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH3:36])=[O:34])=[CH:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:16]=[C:13]1[N:14]([CH2:18][C:19]2[CH:20]=[C:21]([C:25]3[N:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH3:36])=[O:34])=[CH:29][N:30]=3)[CH:22]=[CH:23][CH:24]=2)[N:15]=[C:10]([C:4]2[CH:5]=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:12]1
Reactant: COC(=O)/C=C/c1cnc(-c2cccc(CO)c2)nc1
Reactant: O=c1ccc(-c2cc(F)c(F)c(F)c2)n[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
47.2 90 mg (0.4 mmol) of 6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one and 111 mg (0.41 mmol) of methyl (E)-3-[2-(3-hydroxymethylphenyl)-pyrimidin-5-yl]acrylate are suspended in 3 ml of THF with 200 mg (0.6 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g), and the mixture is shaken at room temperature for 30 min. The mixture is cooled to 0° C., and 95 μl (0.6 mmol) of diethyl azodicarboxylate are added. The reaction mixture is shaken at room temperature for 24 h. The reaction mixture is purified by means of preparative HPLC; yield: 7 mg of “A283”; HPLC: Rt=3.41 min (method C);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:18]([CH:19]=[O:20])=[CH:17][C:16]2[C:11](=[C:12]([CH3:21])[CH:13]=[CH:14][CH:15]=2)[N:10]=1.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:18]([CH2:19][OH:20])=[CH:17][C:16]2[C:11](=[C:12]([CH3:21])[CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: COc1ccccc1-c1nc2c(C)cccc2cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1nc2c(C)cccc2cc1CO

Procedure:
Prepared according to Procedure B using 2-(2-methoxyphenyl)-8-methylquinoline-3-carbaldehyde (0.250 g, 0.9 mmol), and sodium borohydride (0.0378 g, 1.35 mmol, 1.5 eq), in THF (5 mL). (2-(2-Methoxyphenyl)-8-methylquinolin-3-yl)-methanol was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (1 H, s), 7.92 (1 H, d, J=7.8 Hz), 7.64 (1 H, d, J=7.0 Hz), 7.50-7.59 (2 H, m), 7.33 (1 H, dd, J=7.4, 1.6 Hz), 7.22 (1 H, d, J=7.8 Hz), 7.16 (1 H, t, J=7.2 Hz), 5.37 (1 H, t, J=5.5 Hz), 3.79 (3 H, s), 2.72 (3 H, s) Mass Spectrum (ESI) m/e=280.1 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([F:15])=[CH:9][CH:8]=3.[OH-].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C)C=O>[F:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([F:1])=[CH:3][CH:4]=3
Reactant: Fc1ccc2[nH]c3ccc(F)cc3c2c1
Reactant: BrCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)c1cc(F)ccc1n2CC1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a stirred solution of 3,6-difluoro-9H-carbazole (0.500 g, 2.5 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added 85% potassium hydroxide (0.195 g, 3.0 mmol) and the mixture was stirred for 1 hr. Epibromohydrin (0.407 mL, 4.9 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% methylene chloride/hexanes) to afford the desired product as a white solid (0.575 g, 90%). 1H NMR (300 MHz, CDCl3) δ 7.69 (dd, 2H, J=8.7, 2.7 Hz), 7.39 (dd, 2H, J=9.0, 3.9 Hz), 7.24 (td, 2H, J=9.0, 2.7 Hz), 4.68 (dd, 1H, J=15.9, 3.0 Hz), 4.33 (dd, 1H, J=15.9, 5.1 Hz), 3.35 (m, 1H), 2.84 (t, 1H, J=4.5 Hz), 2.55 (dd, 1H, J=4.8, 2.4 Hz).
Reaction SMILES: [Mg].[CH3:2]I.[F:4][C:5]([F:15])([F:14])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.Cl>CCOCC.O>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][C:6]([C:5]([F:14])([F:15])[F:4])=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CI
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CC(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
Magnesium (3.71 g/0.153 mol) was placed into a flask of the egg-plant type, followed by the replacement of air by nitrogen and addition of 30 ml of ether. While gently stirring the mixture, a solution of methyl iodide (24.4 g/0.172 mol) in ether (20 ml) was slowly added dropwise to the mixture, and the resulting mixture was refluxed with heating for 30 minutes. The mixture was cooled to room temperature, and a solution of 4-trifluoromethylbenzaldehyde (25.1 g/0.144 mole) in ether (20 ml) was slowly added dropwise to the mixture. The mixture was refluxed with heating for 2 hours, 30 ml of water was added dropwise to the mixture with ice cooling, and hydrochloric acid (2N) was further added until the aqueous layer became transparent. The aqueous layer was separated from an ethereal layer, the aqueous layer was subjected to extraction with ether, and the ethereal layers were combined, and the combined layer was washed with an aqueous solution of common salt three times. After removal of ether, the layer was distilled at a reduced pressure, giving 1-(1-hydroxylethyl)-4-trifluoromethylbenzene [compound (I)] represented by the formula CF3C6H4CH(OH) CH3, b.p. 53°~55° C. (50.5 Pa), colorless transparent liquid, yield 98.3%.
Reaction SMILES: B.C1COCC1.[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17].CO.Cl>C1COCC1>[ClH:7].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
BH3/THF (279 mL; 279 mmol) was added to a solution of 4-chloro-3-nitrobenzonitrile (30 g; 164 mmol) in THF (100 mL) over 30 min at 0° C. and the resulting mixture was stirred over night and allowed to reach rt. MeOH (150 mL) and conc. HCl (60 mL) was added and the resulting mixture was refluxed for 4 h and thereafter concentrated. The residue was treated with water (500 mL) and the resulting precipitate was filtered off. The filtrate was treated with NaCl (120 g) and heated and the resulting precipitate was filtered off to give the sub-title compound. Yield: 24.059 g (65%).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][C:18]([C:24]([NH:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([O:37][CH2:38][CH2:39][N:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[CH:28]=3)=[O:25])=[CH:17]4)[CH:10]=[CH:9][N:8]=2)=[N:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][C:18]([C:24]([NH:26][C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:30]=[C:29]([O:37][CH2:38][CH2:39][N:40]5[CH2:41][CH2:42][CH2:43][CH2:44]5)[CH:28]=3)=[O:25])=[CH:17]4)[CH:10]=[CH:9][N:8]=2)=[N:4][CH:3]=1
Reactant: CC1CN=C(c2cc(Oc3ccc4ncc(C(=O)Nc5cc(OCCN6CCCC6)cc(C(F)(F)F)c5)cc4c3)ccn2)N1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: Cc1cnc(-c2cc(Oc3ccc4ncc(C(=O)Nc5cc(OCCN6CCCC6)cc(C(F)(F)F)c5)cc4c3)ccn2)[nH]1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 6-{[2-(5-methyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-4-yl]oxy}-N-[3-(2-pyrrolidin-1-ylethoxy)-5-(trifluoromethyl)phenyl]quinoline-3-carboxamide I-218 (0.500 g, 0.83 mmol) in DCM (20 mL) at 0° C. was added Dess-Martin periodinane (0.701 g, 1.65 mmol). The reaction mixture was allowed to stir at 0° C. overnight. Additional Dess-Martin periodinane (0.140 g, 0.32 mmol) was added and the reaction mixture was allowed to warm to rt until reaction was complete. Aq Na2S2O3 was added and the reaction mixture was allowed to stir at rt for 10 min before the addition of sat. aq. NaHCO3. The reaction mixture was extracted with DCM, concentrated, and purified by column chromatography to give 6-{[2-(5-methyl-1H-imidazol-2-yl)pyridin-4-yl]oxy}-N-[3-(2-pyrrolidin-1-ylethoxy)-5-(trifluoromethyl)phenyl]-quinoline-3-carboxamide I-409. 1H NMR (300 MHz, d6-DMSO, HCl salt) δ: 11.21 (s, 1H), 10.67-10.85 (br s, 1H), 9.45 (s, 1H), 9.11 (s, 1H), 8.71 (d, 1H), 8.29 (d, 1H), 8.13 (m, 1H), 8.04 (m, 1H), 7.94-7.91 (br s, 2H), 7.88-7.82 (m, 1H), 4.49-4.40 (m, 2H), 3.67-3.55 (m, 5H), 3.18-3.05 (m, 3H), 2.32 (s, 3H), and 2.08-1.84 (m, 5H). LCMS: (FA) ES+ 603.2, ES− 600.8.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.ClC1C=CC(NC(=O)N[C@H]2CC[C@H](OC3C=CC(C(O)=O)=CC=3)CC2)=CC=1C(F)(F)F>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:11])[NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([O:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[CH:7][CH:8]=1
Reactant: N[C@H]1CC[C@H](Oc2ccc(C(=O)O)cc2)CC1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N[C@H]1CC[C@H](Oc2ccc(C(=O)O)cc2)CC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N[C@H]1CC[C@H](Oc2ccc(C(=O)O)cc2)CC1

Procedure:
Compound 2372 was prepared in 70% yield from 4-(trifluoromethyl)phenyl isocyanate and trans-4-(4-amino-cyclohexyloxy)-benzoic acid using the procedure detailed for compound 2221 in Example 4. 1H NMR (400 MHz, DMSO-d6): δ 12.62 (s, 1H), 9.00 (s, 1H), 7.86 (d, J=9 Hz, 2H), 7.60-7.53 (m, 4H), 7.02 (d, J=9 Hz, 2H), 6.52 (d, J=8 Hz, 1H), 4.50-4.40 (m, 1H), 3.60-3.48 (m, 1H), 2.11-2.01 (m, 2H), 1.98-1.89 (m, 2H), 1.56-1.32 (m, 4H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][C:4]1=[O:10])[CH3:2].[H-].[Na+].[I-].CS[C:16]1[S:20][CH:19]=[CH:18][S+:17]=1>CN(C)C=O>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[C:5](=[C:16]2[S:20][CH:19]=[CH:18][S:17]2)[C:4]1=[O:10])[CH3:2]
Reactant: CCN1CCC(=O)CC1=O
Reactant: CSc1scc[s+]1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC(=O)C(=C2SC=CS2)C1=O
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
1-Ethyl-2,4-dioxopiperidine (1.06 g) is dissolved in N,N-dimethylformamide (50 ml), and the solution is added dropwise to a suspension of sodium hydride (60% dispersion in oil, 332 mg) in N,N-dimethylformamide (50 ml) under ice-cooling. The mixture is stirred for 20 minutes, and thereto is added 2-methylthio-1,3-dithiolium iodide (1.89 g). After stirring at room temperature overnight, the reaction mixture is poured onto water and extracted with ethyl acetate. The extract is washed with water, dried and distilled to remove the solvent. The residue is purified by silica gel column chromatography (developer: ethyl acetate) and then recrystallized from ethyl acetate-isopropyl ether to give 1-ethyl-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (1.10 g) as pale yellow needles. m.p. 114.5°-117° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.[SH:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[S:11][CH2:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOC(=O)CCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Br)ccc2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (0.49 g, 2.62 mmol) and ethyl 3-mercaptopropionate (0.37 ml, 2.88 mmol) in N,N-dimethylformamide (10 ml) was added potassium carbonate (0.90 g, 6.55 mmol), and the mixture was stirred at room temperature for 1 hour and then at 70° C. for 15 hours. The mixture was poured into ice-water, and made pH 4 with 1N hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography [hexane:ethyl acetate (5:1)] to give ethyl 6-bromo-2H-thiochromene-3-carboxylate (0.45 g, 58%) as yellow powder, a part of which was recrystallized from ethanol to give pale yellow needles.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2([CH3:17])[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-].C1COCC1.O>C(O)C>[CH3:17][C:14]1([C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:13])[CH2:15][CH2:16]1
Reactant: CCOC(=O)C1CCN(C(=O)C2(C)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(=O)N2CCC(C(=O)O)CC2)CC1
Yield: 85.7 %

Procedure:
1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (6.34 g, 26.5 mmol) and LiOH (1.67 g, 39.7 mmol) were stirred in a mixture of ethanol (30 mL), THF (30 mL) and water (15 mL) for 90 min at ambient temperature. After evaporation of the volatiles the residue was taken up in dichloro methane and extracted with 1N HCl. The organic phase was dried over sodium sulfate, filtered and evaporated to yield the title product (4.8 g, 86%) as colorless solid.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[CH2:5].[CH:13]1([CH:19]=[CH:20][C:21]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[OH:30])=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CS(C)=O>[CH:13]1([CH:19]([CH2:3][C:4]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)=[O:5])[CH2:20][C:21]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[OH:30])=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(C=CC1CCCCC1)c1cc(F)ccc1O
Reactant: C=C(O[Si](C)(C)C)c1ccco1
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1cc(F)ccc1O)C1CCCCC1)c1ccco1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(furan-2-yl)ethylene (1.64 g, 9.0 mmol; prepared according to J. Chem. Soc., Perkin Trans. I 1989, 1585) and CSF (0.41 g, 2.7 mmol) were added to a suspension of 3-cyclohexyl-1-(2-hydroxy-5-fluorophenyl)-2-propen-1-one on Wang resin (3.0 g, 1.8 mmol) in dimethyl sulfoxide (40 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 3.31 g of 3-cyclohexyl-1-(2-hydroxy-5-fluorophenyl)-5-(furan-2-yl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [CH2:1]([C@H:5]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]([O:8]CC1C=CC([N+]([O-])=O)=CC=1)=[O:7])[CH:2]([CH3:4])[CH3:3]>C(OCC)(=O)C.[Pd]>[CH2:1]([C@H:5]([CH2:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[C@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](CC(=O)OC(C)(C)C)C(=O)O
Reaction time: 3.5 h
Yield: 72.1 %

Procedure:
4.4 g of 4-tert.butyl 1-(4-nitrobenzyl) 2(R)-isobutylsuccinate were dissolved in 50 ml of ethyl acetate and hydrogenated for 3.5 hours at room temperature and atmospheric pressure in the presence of 0.6 g of 5% palladium/carbon. The catalyst was removed by filtration and the solution was extracted three times with cold 2N hydrochloric acid. The organic layer was then washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the crude product was purified by chromatography on silica gel using chloroform for the elution. 2.0 g (72%) of 4-tert.butyl hydrogen 2(R)-isobutylsuccinate were obtained in the form of an oil. Rf (System C) 0.65.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2ccc(N)nc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 6-amino-nicotinic acid and 1-methylpiperazine. The reaction mixture was stirred overnight at 0° C. DCM was used for dilution and extraction instead of EtOAc. The dried organic phase was concentrated to afford an impure sample of the title compound which was used without further purification.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:28]=[CH:27][C:9]2[N:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:11](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:12][C:8]=2[CH:7]=1)([O-])=O>C(O)C.O.[Fe]>[NH2:3][C:6]1[CH:28]=[CH:27][C:9]2[N:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:11](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:12][C:8]=2[CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Yield: 70.4 %

Procedure:
Iron powder (1.95 g, 35 mmol) and ammonium chloride (200 mg, 3.7 mmol) was added to a solution of (E)-5-nitro-1-(2-pyridyl)-2-styryl-1H-benzimidazole (2.41 g, 7.0 mmol) in ethanol (50 ml) and water (25 ml). After the reaction mixture was refluxed for 3 h, the hot reaction mixture was filtered through a pad of celite and the filtrate was evaporated under reduced pressure. The obtained residue was partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (200 ml). The combined extracts were washed with brine (20 ml), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 200 g; n-hexane/ethyl acetate (1/2)) and obtained solids (1.54 g, 70%) were recrystallized from ethyl acetate to afford the titled compound as brown solids.