Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:13][C:3]1[C:2]([NH:1][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:11][C:10]([Cl:12])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCCC1
Reactant: COC(=O)c1cc(Cl)cc(N)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(NC2CCCC2)c1Cl
Reaction time: 3 h
Yield: 8.3 %

Procedure:
To a stirred solution of methyl 3-amino-2,5-dichlorobenzoate (2.5 g, 11.5 mmol) and cyclopentanone (4.8 g, 57.1 mmol) in methanol (5 mL) was added acetic acid (0.6 g, 11.3 mmol) and stirring was continued at room temperature for 3 h. Then sodium cyanoborohydride (1.4 g, 22.2 mmol) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the product was purified by column chromatography to afford methyl 2,5-dichloro-3-(cyclopentylamino)benzoate (0.275 g, 8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.CCOCC>[N:11]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N+:12]=[N-:13]
Reactant: COc1ccc(CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 4-methoxybenzyl chloride (8.52 mL, 62.8 mmol) in DMF (40 ml) was added sodium azide (4.08 g, 62.8 mmol). The suspension formed was stirred at RT for 24 hrs. The reaction mixture was diluted with ether (400 ml) and washed with water (2×200 mL) and brine (20 ml). The organic layers were dried (MgSO4) and concentrated (water bath temp 20° C.) under reduced pressure to afford the title compound;
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][C:18]([NH:21]C=O)([CH3:20])[CH3:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:2]1>Cl.CO>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][C:18]([CH3:19])([NH2:21])[CH3:20])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:2][CH2:3]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC(C)(C)NC=O)ccc2n1CC1CC1
Agent: Cl
Solvent: CO
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC(C)(C)N)ccc2n1CC1CC1
Yield: 64.8 %

Procedure:
A solution of N-(2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-1,1-dimethylethyl)formamide (Step F, 330 mg, 0.814 mmol) in Hydrogen Chloride, Methanol Reagent 10 (TCI Co.: 4 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was extracted with dichloromethane (30 mL×3). The combined organic layer was washed with saturated sodium hydrogen carbonate aqueous solution (20 mL). The resulting solution was dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=15:1 as eluent) to afford the title compound (199 mg, 65%) as a white amorphous.
Reaction SMILES: Cl[C:2]([CH3:9])([CH3:8])[CH:3]([N:6]=[O:7])[CH2:4][CH3:5].Cl.Cl.Cl.[NH2:13][CH2:14][CH:15]([O:25][NH:26][C:27]([CH3:36])([C:29](=[N:34][OH:35])[CH2:30][CH2:31][CH2:32][CH3:33])[CH3:28])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[N+:22]([O-:24])=[O:23].C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:8][C:2]([CH3:9])([NH:13][CH2:14][CH:15]([CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[N+:22]([O-:24])=[O:23])[O:25][NH:26][C:27]([CH3:28])([CH3:36])[C:29](=[N:34][OH:35])[CH2:30][CH2:31][CH2:32][CH3:33])[C:3](=[N:6][OH:7])[CH2:4][CH3:5]
Reactant: CCCCC(=NO)C(C)(C)NOC(CN)Cn1ccnc1[N+](=O)[O-]
Reactant: CCC(N=O)C(C)(C)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCC(=NO)C(C)(C)NOC(CNC(C)(C)C(CC)=NO)Cn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Chloro-4-methyl-3-nitrosopentane (0.52 g, 3.5 mmol, Example 27(A)) was added to a mixture of the hydrochloride title product of step B above (0.62 g, 1.5 mmol) and diisopropylethylamine (0.45 g, 3.5 mmol) in acetonitrile (10 mL), and the mixture was stirred at room temperature for 12 hrs. Acetonitrile was removed on a rotary evaporator and the thick oil obtained was basified with potassium carbonate solution. The light green oil obtained was extracted with ethyl acetate and dried (Na2SO4). Ethyl acetate was removed on a rotary evaporator and the oil obtained was purified by column chromatography (silica gel, ethyl acetate:hexane, 6:4). Fractions containing the product were collected and evaporated to give a colorless oil, which was dried under vacuum to afford a foamy solid. The solid obtained was dissolved in acetonitrile and left at room temperature for 2 hrs. The solid that formed was filtered and recrystallized from acetonitrile. Yield: 0.32 g (47%). mp. 153°-154° C. 1HNMR (DMSO): ε 0.86, 0.96, 1.11, and 1.35 [m, 22H, C(CH3)2, CH2CH3 and CH2CH2CH2CH3)], 2.15 (m, 4H, CH2CH2CH2CH3 and CH2CH3), 2.30 (m, 2H, HNCH2CHOH), 3.80 (m, 1H, CHO), 4.5 (m, 2H, CHOHCH2N<), 7.14 and 7.56 (s, 2H, imiH), 10.35 (s, 1H, NOH), and 10.37 (s, 1H, NOH). MS:(M+H)+ =456 Anal. Calcd. for C20H37N7O5 : C, 52.71; H, 8.19; N, 21.53. Found: C, 52.94; H, 8.26; N, 21.63.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=1)[O:14][CH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[Cl:31][C:32]1[N:37]=[C:36](Cl)[C:35](=[O:39])[N:34]([CH2:40][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[C:33]=1[CH3:51]>C(OCC)(=O)C>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][N:34]1[C:33]([CH3:51])=[C:32]([Cl:31])[N:37]=[C:36]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=2)[O:14][CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[C:35]1=[O:39])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(CCN)c1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)nc(NCCc2cccc(OC[C@H]3CCCN3C(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 95.7 %

Procedure:
Triethylamine (0.51 ml, 3.67 mmol) was added to a solution of tert-butyl (2R)-2-{[3-(2-aminoethyl)phenoxy]methyl}-1-pyrrolidinecarboxylate (preparation 134) (588 mg, 1.84 mmol) and benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (60 mg, 1.83 mmol) in ethyl acetate (10 ml), and the reaction heated under reflux for 6 hrs. The cooled mixture was partitioned between water and ethyl acetate, and the layers separated. The organic phase was washed with water, then brine, dried over MgSO4 and evaporated under reduced pressure to give the title compound, (1.07 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8](S(C3C=CC=CC=3)(=O)=O)[CH:7]=[CH:6][C:5]=2[C:4]=1[CH:21]=O.[CH3:23][NH:24][CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl.[OH-].[Na+]>[CH3:1][O:2][C:3]1[C:4]([CH2:21][N:24]([CH3:25])[CH3:23])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1C=O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2[nH]ccc2c1CN(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
5-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (366 mg, 1.16 mmol; Intermediate 75) was dissolved in DCE, dimethylamine (3.48 mmol as 2M in MeOH) and sodium triacetoxyborohydride (738 mg, 3.48 mmol) was added in sequence. The reaction mixture was left stirring at r.t. for 23 h, diluted with DCM, NaOH (2M aq) was added until sustained pH at 10. The organic phase was separated, and the water-phase extracted once DCM. The combined organic phases were dried over Na2SO4 and purified by preparative HPLC. Yield: 57 mg residue mauve color
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.CS(O[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:27][CH:28]=2)=[CH:18][CH:17]=1)(=O)=O>>[CH3:1][C:2]1[N:3]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:27][CH:28]=3)=[CH:20][CH:21]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CS(=O)(=O)OCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 42 %

Procedure:
In substantially the same manner as in Working Example 8, 2-methylimidazole was allowed to react with 4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl methanesulfonate to give 4-[4-[4-(2-methyl-1-imidazolyl)butyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 42%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 122-123° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]1=[O:13].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C1C(=O)N([I:41])C(=O)C1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH3:12])=[C:4]([I:41])[C:3]1=[O:13]
Reactant: Cc1cc(C(F)(F)F)n(C)c(=O)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C(F)(F)F)n(C)c(=O)c1I
Temperature: 77.5 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of 1,4-dimethyl-6-(trifluoromethyl)-1H-pyridin-2-one (1.44 g, 7.23 mmol), trifluoroacetic acid (9 mL) and trifluoroacetic anhydride (1.53 mL, 10.85 mmol) was added NIS (2.569 g, 10.85 mmol) at room temperature. Then, the mixture was heated to 70-85° C. and was stirred for 2 h. The reaction mixture was cooled to room temperature and saturated sodium carbonate solution was added slowly to neutralize the solution. Then, the aqueous mixture was extracted with ethyl acetate (2×50 mL). The combined extracts were washed successively with saturated sodium thiosulfate solution (100 mL) and brine solution (100 mL) and were dried over anhydrous sodium sulfate. Filtration of the drying agent and concentration of the solvent gave a crude product, which was purified by silica gel chromatography on a Biotage (40m) column to afford 1.02 g (45% yield) of 1,4-dimethyl-3-iodo-6-(trifluoromethyl)-1H-pyridin-2-one as an amorphous white solid. ES-LRMS: m/z 318.1 (M+H), 381.2 (M+Na+CH3CN).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([Cl:16])=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([N:23]([CH3:31])C(=O)OC(C)(C)C)[CH2:18]1)[C:2]#[C:3][CH3:4].Cl.[NH2:33][CH:34]1CCCN(C2N(CC#CC)C3C(=O)N(CC4C=CC=CC=4C#N)C(C#N)=NC=3N=2)C1>>[ClH:16].[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([C:34]#[N:33])=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([NH:23][CH3:31])[CH2:18]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCCC(N)C2)nc2nc(C#N)n(Cc3ccccc3C#N)c(=O)c21
Reactant: CC#CCn1c(N2CCCC(N(C)C(=O)OC(C)(C)C)C2)nc2nc(Cl)n(C)c(=O)c21
Agent: Cl
Product: CC#CCn1c(N2CCCC(NC)C2)nc2nc(C#N)n(C)c(=O)c21

Procedure:
The title compound was synthesized by using t-butyl N-[1-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]-N-methylcarbamate according to the method described in Example 242 (f) and (g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]([CH2:33][NH:34][C:35]([NH:37][CH3:38])=[O:36])[C:30](O)=[O:31])=[CH:25][CH:24]=1)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C>[NH:60]([C:30](=[O:31])[CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]([NH:20][C:10]2[CH:11]=[C:12]([C:15]3[CH:19]=[CH:18][S:17][CH:16]=3)[CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:22])=[CH:28][CH:27]=1)[CH2:33][NH:34][C:35]([NH:37][CH3:38])=[O:36])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: Nc1ccccc1
Reactant: CNC(=O)NCC(C(=O)O)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h

Procedure:
2-[4-({[2-[(tert-Butoxycarbonyl)amino]-5-(3-thienyl)phenyl]amino}-carbonyl)phenyl]-3-{[(methylamino)carbonyl]amino}propanoic acid (104 mg, 0.19 mmol), EDCI (54 mg, 0.28 mmol), and HOBT (34 mg, 0.25 mmol) were combined in DMF (3 mL) and stirred for 10 minutes before adding aniline (26 μL, 0.28 mmol). The reaction was then stirred at room temperature for 2 h. The mixture was directly purified by reverse phase HPLC (45-95% MeCN/water) to give the title compound as a white solid. MS (ESI) calcd [M+H]+ 614.2, found 614.1.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[C:33]([Cl:38])[C:32]=1[C@@H:39](O)[CH3:40].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[C:33]([Cl:38])[C:32]=1[C@H:39]([O:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:40]
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: C[C@H](O)c1c(Cl)ccc(F)c1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1cccnc1[N+](=O)[O-])c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.2 %

Procedure:
3-Hydroxy-2-nitropyridine (175 mg, 1.21 mmol) and triphenylphosphine (440 mg, 1.65 mmol) were added sequentially to a stirred solution of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (229.8 mg, 1.1 mmol) in THF (10 mL) under a nitrogen atmosphere. The reaction mixture was maintained at room temperature for 1 h and then diisopropyl azo-dicarboxylate (0.34 mL, 1.65 mmol) was added at 0° C. The mixture was stirred for an additional 12 h. The reaction mixture was evaporated under vacuum to give an oil. The residue was purified by flash chromatography (eluting with 20→25% EtOAc in hexanes) to give the title compound as a white solid (321.5 mg; 0.97 mmol; 88.3% yield); MS (APCI) (M+H)+ 331; SFC-MS: 99.5% ee. 1H NMR (400 MHz, chloroform-D) δ ppm 1.85 (d, J=6.6 Hz, 3H) 6.10 (q, J=6.6 Hz, 1H) 7.04-7.13 (m, 1H) 7.21 (dd, J=8.5, 1.14 Hz, 1H) 7.30 (dd, J=9.0, 4.9 Hz, 1H) 7.37 (dd, J=8.6, 4.6 Hz, 1H) 8.04 (dd, J=4.6, 1.3 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH2:6][C@@H:7]2[C@H:10]([CH:11]=1)[C:9](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)CCC.O[C:21](C)(C(C)CC=C)CC(O)=O>>[CH3:1][C:5]1[CH2:6][C@H:7]2[C@@H:10]([C:11]=1[CH3:21])[C:9](=[CH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]2
Reactant: C=CCC(C)C(C)(O)CC(=O)O
Reactant: CCCCC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Product: CC1=C(C)[C@H]2C(=CC(=O)OC(C)(C)C)C[C@H]2C1

Procedure:
The compound of interest (4.2 g, 33%) was obtained as an oil substance (E/Z mixture) in the same way as in paragraph (10-c) using 3-hydroxy-3,4-dimethyl-6-heptenoic acid (10.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]=[C:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22]CC3C=CC=CC=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>[Pd].CO>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC(c1ccccc1)n1ccc2cc(O)ccc21
Reaction time: 24 h
Yield: 96 %

Procedure:
A mixture of 3-(5-benzyloxy-indol-1-yl)-3-phenyl-acrylic acid ethyl ester (1.94 g, 4.89 mmol) and palladium on carbon [10% w/w] (60 mg) in methanol (25 mL) was stirred under hydrogen atmosphere for 24 h. After removal of the catalyst by filtration, the crude product was purified by flash chromatography on silica gel with hexane/ethyl acetate (4:1) to give the title compound in 96% yield. 1H NMR (CDCl3) δ 7.10-7.30 (m, 7H), 6.99 (d, J=2.4 Hz, 1H), 6.69 (dd, J=2.4 and 8.7 Hz, 1H), 6.39 (d, J=3.2 Hz, 1H), 5.99 (t, J=7.6 Hz, 1H), 5.31 (br, 1H), 4.03 (q, J=7.2 Hz, 2H), 3.26 (m, 2H), 1.08 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3) δ 170.4, 149.7, 139.8, 131.5, 129.3, 128.8, 127.9, 126.2, 125.8, 111.6, 110.6, 105.2, 101.4, 61.1, 56.2, 40.4, 13.9. Mass Spectrum (LCMS, ESI) calculated for C19H20NO3 310.1 (M+H); found 310.1.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:36][CH2:37][CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[CH2:28][N:17]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]([CH2:36][CH2:37][CH3:38])=[N:10][C:11]=2[CH:16]=1
Reactant: CCCc1nc2cc(N(Cc3cccc(Cl)c3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3cccc(Cl)c3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[(3-Chloro-benzyl)-(4-fluoro-benzenesulfonyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.72 (m, 2H), 7.46 (m, 2H), 7.23 (m, 4H), 7.16 (d, 1H), 7.10 (d, 1H), 6.76 (dd, 1H), 4.82 (s, 2H), 4.32 (s, 2H), 2.67 (t, 2H), 1.72 (m, 2H), 0.94 (t, 3H). MS calculated for C25H23FClN3O4S—H: 514, observed: 514.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]2=[O:24])(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C=O)C>[O:38]1[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][N:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:9]3=[O:24])[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCN3CCOCC3)S(C)(=O)=O)cc2C1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
To a solution of tert-butyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (501 mg, 1.414 mmol) in dry DMF (15 ml) maintained under nitrogen atmosphere, K2CO3 (391 mg, 2.83 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (526 mg, 2.83 mmol) were added, and the mixture was stirred at 60° C. for 3 hours. The solid was filtered off, the solvent was evaporated and the resulting crude was purified by filtration on a silica gel cartridge (DCM/MeOH 9/1), obtaining tert-butyl 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (570 mg, 1.22 mmol, 86% yield, MS/ESI+ 468.2 [MH]+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[C:7]2[OH:18].[Cl-].[Li+].[CH2:21](C([SnH3])=C(CCCC)CCCC)[CH2:22]CC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]1([C:9]2[CH:8]=[C:7]([OH:18])[C:6]3[C:11](=[C:2]([CH:21]=[CH2:22])[CH:3]=[CH:4][CH:5]=3)[N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cc(-c2ccccc2)nc2c(Br)cccc12
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1cccc2c(O)cc(-c3ccccc3)nc12
Temperature: 90 °C
Yield: 43.1 %

Procedure:
A suspension of 500 mg (1.67 mmol) 8-bromo-2-phenyl-quinoline-4-ol (commercially available from Ubichem Research Ltd, Budapest, Hungary), 97 mg (0.09 mmol) Pd(PPh3)4, 71 mg (1.67 mmol) lithium chloride and 528 mg (1.67 mmol) tributylvinyl stannane in 20 ml dioxane was heated at 90° C. for 16 h. The resulting yellow suspension was filtered and the filtrate evaporated to dryness. The residue was suspended in ethyl acetate, filtered and the filtrate extracted with water. The organic layer was evaporated to dryness and the isolated crude product purified by silica gel chromatography (ethyl acetate) to yield 178 mg (43%) of the title compound as yellowish crystals. 1H-NMR (300 MHz, CDCl3): 5.59 (d, J=11.1 Hz, 1H); 5.75 (d, J=17.4 Hz, 1H); 6.42 (s, 1H); 7.04 (dd, J=17.4, 11.1 Hz, 1H); 7.23 (t, J=8.1 Hz, 1H); 7.40-7.60 (m, 6H); 8.21 (d, J=8.1 Hz, 1H); 8.70 (br, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=2)=[CH:11][CH:10]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH2:21]([N:18]1[CH2:17][CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)[CH2:20][CH2:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Fc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
13.8 g (100 mmol) of potassium carbonate were added to a solution of 10.0 g (46.8 mmol) of 4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride in 400 ml of ethanol and the reaction mixture was subsequently heated to reflux temperature. A solution of 5.8 ml (49 mmol) of benzyl bromide in 100 ml of ethanol was added dropwise within one hour and thereafter the mixture was stirred at this temperature for a further 1 hour. The reaction mixture was cooled to room temperature and filtered, the filtrate was extracted with water and ethyl acetate and finally the organic phase was dried over magnesium sulphate. After evaporation in a water-jet vacuum the crude product obtained was chromatographed on silica gel with hexane and ethyl acetate as the eluent. There were obtained 8.90 g (71% of theory) of 1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine; MS: 267 (M)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1)[CH3:4].[CH3:28][O:29][CH2:30][CH2:31][OH:32]>>[CH2:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([O:32][CH2:31][CH2:30][O:29][CH3:28])[CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1)[CH3:4]
Reactant: COCCO
Reactant: CCN1CCN(c2nc(-c3ccnc(Cl)c3)cc3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CCN1CCN(c2nc(-c3ccnc(OCCOC)c3)cc3ccccc23)CC1

Procedure:
60% oily sodium hydride (0.20 g) was added gradually to 2-methoxyethanol (50 ml), under ice-cooling. To the resulting solution was added 1-(4-ethylpiperazin-1-yl)-3-(2-chloropyridin-4-yl)isoquinoline (0.20 g) obtained in the previous Example, and the mixture was heated under reflux for 3 days. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound (0.12 g) as a pale yellow oil.