Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]2[N:10]3[C@H:11]4[CH2:16][CH2:15][CH2:14][C@H:12]4[N:13]=[C:9]3[N:8]([CH3:17])[C:7](=[O:18])[C:6]=12.Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:25][CH:26]=2)[CH:4]=[C:5]2[N:10]3[C@H:11]4[CH2:16][CH2:15][CH2:14][C@H:12]4[N:13]=[C:9]3[N:8]([CH3:17])[C:7](=[O:18])[C:6]=12
Reactant: CN1C(=O)c2c(c[nH]c2Cl)N2C1=N[C@@H]1CCC[C@@H]12
Reactant: ClCc1ccc(-c2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2c(cn(Cc3ccc(-c4ccccn4)cc3)c2Cl)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-2-(4-methoxy-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (95 mg, 0.25 mmol) in CH2Cl2 is slowly added TFA and trifluoromethanesulfonic acid (TFMSA). The mixture is stirred at room temperature overnight. Solvents and TFA are removed under reduced pressure. The residue is neutralized and dissolved in DMF, and then purified by a semi-preparative HPLC to give 77 mg of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one. A suspension of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (79 mg, 0.3 mmol), 2-(4-(chloromethyl)phenyl)pyridine (61 mg, 0.3 mmol) and cesium carbonate (192 mg, 0.6 mmol) in anhydrous DMF is stirred at room temperature for 4 h. The mixture is filtered through a 0.2 μL microfilter. The filtrate is purified by a semi-preparative HPLC to give pure product. MS (ESI) m/z 432.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:63])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:24]([O:57][CH3:58])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:55][CH3:56])[C@@H:34]([CH3:54])[C:35]([NH:37][C@@H:38]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:39]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:64]=[C:65]1[CH:69]=[CH:68][C:67](=[O:70])[N:66]1[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][C:76]([NH:78][NH2:79])=[O:77]>>[O:70]=[C:67]1[CH:68]=[CH:69][C:65](=[O:64])[N:66]1[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][C:76]([NH:78][NH:79][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:63])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:24]([O:57][CH3:58])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:55][CH3:56])[C@@H:34]([CH3:54])[C:35]([NH:37][C@@H:38]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:39]([N:41]1[CH2:42][CH2:43][O:44][CH2:45][CH2:46]1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:77]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCOCC1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCOCC1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
This compound was prepared in analogy to the synthesis described in Intermediate 157 from N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(2S)-1-(morpholin-4-yl)-1-oxo-3-phenylpropan-2-yl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)=[CH:5][C:4]([C:16]2[C:21]([CH:22]=[O:23])=[C:20]([N:24]3[CH2:36][CH2:35][N:27]4[C:28]5[CH2:29][CH2:30][CH2:31][CH2:32][C:33]=5[CH:34]=[C:26]4[C:25]3=[O:37])[N:19]=[CH:18][CH:17]=2)=[CH:3]1.O.[Li+].[OH-]>C1COCC1>[OH:23][CH2:22][C:21]1[C:20]([N:24]2[CH2:36][CH2:35][N:27]3[C:28]4[CH2:29][CH2:30][CH2:31][CH2:32][C:33]=4[CH:34]=[C:26]3[C:25]2=[O:37])=[N:19][CH:18]=[CH:17][C:16]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3C=O)cn(C)c2=O)n[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)n[nH]1
Yield: 0 %

Procedure:
A 100-mL single-neck round-bottomed flask was charged with 115b (190 mg, 0.35 mol) in THF/iPA/H2O (5 mL/5 mL/2 mL) and LiOH (85 mg, 3.5 mmol) while stirring. This mixture was stirred at 50° C. for 0.5 h. Then 20 mL H2O was added and the mixture was extracted with EA (30 mL×3). The combined organic layer was dried over Na2SO4 and concentrated to give a yellow solid, which was further purified by reverse-phase prep-HPLC to afford 115 as a white solid (48 mg, 30% yield). LCMS: [M+H]+ 500. 1H NMR (500 MHz, CDCl3) δ 8.44 (d, J=6.0, 1H), 7.95 (s, 1H), 7.69 (s, 1H), 7.44 (s, 1H), 7.30 (d, J=6.0, 2H), 6.87 (s, 1H), 5.74 (s, 1H), 4.59-3.86 (m, 7H), 3.69 (s, 3H), 2.57-2.56 (m, 4H), 2.25 (s, 3H) 1.88-1.77 (m, 4H)
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH3:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:37])=[CH:12][C:11]=1[O:17][CH3:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1OC(=O)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: COc1cc(CBr)ccc1OC(=O)c1ccccc1

Procedure:
The synthesis of this compound proceeded in the same fashion as in Example 2 using 22.59 g (0.093 mol) of 2-methoxy-4-methylphenyl benzoate, a catalytic amount of benzoyl peroxide and 19.92 g (0.11 mol) of N-bromosuccinimide. The crude product (29.36 g) was purified by HPLC to give 8.95 g, m.p. 86°-88° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7]>C(OC(=O)C)(=O)C>[CH2:5]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][C:14]=1[N+:1]([O-:4])=[O:2])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Fuming nitric acid (0.8 ml) was added over 10 minutes to a stirred solution of 4'-isobutyl-2-biphenylsulphonyl chloride (3.09 g) in acetic anhydride (18 ml) at -20° C. The solution was kept at -20° C. for 1.5 hours and then allowed to warm to ambient temperature. The solution was stirred for 1.5 hours and then added to ice (300 g) with vigorous stirring. The mixture was stirred for 30 minutes and extracted with ether (3×100 ml) while still below 10° C. The ethereal solution was dried (MgSO4) and the solvent was removed by evaporation. The resulting oil was purified by flash chromatography, eluting with ethyl acetate/hexane (1:9 v/v), to give 4'-isobutyl-3'-nitro-2-biphenylsulphonyl chloride (2.01 g); 1H NMR (CDCl3): 0.95 (d,6H), 1.9-2.05 (m,1H), 2.9 (d,2H), 7.35-7.5 (m,2H), 7.6 (d,1H), 7.7 (d,1H), 7.8 (t,1H), 8.0 (s,1H), 8.25 (d,1H); mass spectrum (EI): 353(M+).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:26]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:26])[C:3](=[O:2])[N:13]([C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:11]=1[CH3:12])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)N[C@@H](C)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n([C@@H](C)c2ccccc2)c1C
Temperature: 25 °C
Yield: 42 %

Procedure:
MeOH (150 mL) was added to a flask containing (5)-4-[1-(1-phenyl-ethylamino)-ethylidene]-pent-2-enedioic acid dimethyl ester (4.81 g, 15.9 mmol). NaOMe solution (3.6 mL, 15.9 mmol, 4.375 M in MeOH) and N-bromosuccinimide (3.4 g, 19 mmol) were added, and the resulting mixture was refluxed for 6 h. After cooling to r.t., the solvent was evaporated in vacuo. Saturated NH4Cl (100 mL) was added, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-25% EtOAc/hexanes) to give 2.34 g of the title compound as a yellow solid. MS: (+) m/z 372.20, 374.16 (M+Na, 79/81Br).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][NH:20]2)=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][N:20]2[C:2]2[C:3]3[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:16][CH:15]=1
Reactant: Cc1[nH]c2ncnc(Cl)c2c1C
Reactant: Brc1ccc2c(c1)NCC2
Product: Cc1[nH]c2ncnc(N3CCc4ccc(Br)cc43)c2c1C

Procedure:
This product is prepared in a manner analogous to that described in Example 1 from 4-chioro-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine and 6-bromo-2,3-dihydroindole (1.1 equivalents, see WO 95/23141; CAS Reg. No. 63 839-24-7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[CH:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)[NH:8][CH2:7][CH2:6]2.C1C=CC=CC=1.[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>N1C=CC=CC=1>[CH:34]1([C:40]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)/[C:9]/2=[CH:15]/[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1cc2c(cc1OC)C(=Cc1cc(OC)c(OC)c(OC)c1)NCC2
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C/c1cc(OC)c(OC)c(OC)c1)N(C(=O)C1CCCCC1)CC2

Procedure:
To a suspension of 5 parts of 3,4-dihydro-6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methylene]isoquinoline in 50 parts of benzene is added 15 parts of pyridine, followed by 3 parts of cyclohexanecarbonyl chloride. The resultant mixture is heated at the boiling point under reflux in a nitrogen atmosphere for 2 hours, then cooled, consecutively washed with water and aqueous 5% sodium becarbonate, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is crystallized from a mixture of ethyl acetate and ether to afford (Z)-2-cyclohexanecarbonyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methylene]isoquinoline melting at 162°-164°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([S:7]([NH2:10])(=[O:9])=[O:8])[S:5][CH:6]=1.C[Al](C)C.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([NH:25][C:26](=O)[O:27]C)[N:18]=1.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([O:16][CH3:15])[N:18]=[C:19]([NH:25][C:26]([NH:10][S:7]([C:4]2[S:5][CH:6]=[C:2]([Cl:1])[N:3]=2)(=[O:9])=[O:8])=[O:27])[N:20]=1
Reactant: NS(=O)(=O)c1nc(Cl)cs1
Reactant: COC(=O)Nc1nc(OC)cc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2nc(Cl)cs2)n1
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
To a suspension of 1.6 g of 4-chloro-2-thiazolesulfonamide in 100 ml methylene chloride under a nitrogen atmosphere, 4.4 ml of a 2.0M solution of trimethylaluminum in toluene was added slowly via a syringe. The reaction mixture was stirred 10 minutes; 1.9 g of methyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate was added, and the reaction mixture refluxed for 18 hours. The reaction mixture was cooled to 0°, and 55 ml of 5% hydrochloric acid was added dropwise giving a flocculant solid. The reaction mixture was extracted with 100 ml of ethyl acetate. The organic solution was washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated. The resulting tan solid was slurried in 1-chlorobutane, collected, washed with hexane and dried giving 1.25 g of the title compound as a white solid, m.p. 182°-183°(d). IR: 2.98 and 3.25μ(NH), 5.80μ (C=O).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>C1(C)C=CC=CC=1.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>[CH:12]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[CH2:13]
Reactant: Clc1ccc2ccccc2n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2ccccc2n1
Yield: 99.2 %

Procedure:
A solution of 2-chloroquinoline (1 g, 6.11 mmol) and vinyl tributyl tin (2.69 mL, 9.17 mmol) in toluene (30 mL) was treated with Pd(PPh3)4 (0.706 g, 0.611 mmol) and heated to reflux for 1.5 h. The reaction mixture was concentrated and the resulting material was purified directly by gradient elution on silica gel (0 to 25% EtOAc in hexanes) to afford the title compound as a colorless oil (941 mg, 99%). All spectral data matched literature values.1 LRMS m/z (M+H) 156.1 found, 156.2 required. (1 Fakhfakh, M. A.; Franck, X.; Fournet, A.; Hocquemiller, R.; Figadère, B. Tetrahedron Lett. 2001, 42, 3847.)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[S:27]1[CH2:33][C:31](=[O:32])[NH:30][C:28]1=[S:29].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:13]([C:9]1[CH:8]=[C:7]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH:23]=[C:33]3[S:27][C:28](=[S:29])[NH:30][C:31]3=[O:32])=[CH:25][CH:26]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[O:11][CH3:12])([CH3:14])([CH3:15])[CH3:16]
Reactant: O=C1CSC(=S)N1
Reactant: COc1c(C(C)(C)C)cc(COc2ccc(C=O)cc2)cc1C(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(C(C)(C)C)cc(COc2ccc(C=C3SC(=S)NC3=O)cc2)cc1C(C)(C)C
Temperature: 70 °C
Yield: 22.7 %

Procedure:
In a round bottom flask under nitrogen purge 4-[[3,5-di (t-butyl)-4-methoxyphenyl]methoxy]benzaldehyde (530 mg, 1.5 mmol) is admixed with rhodanine (240 mg, 1.8 mmol) and sodium acetate (490 mg, 6.0 mmol) in 10 ml of acetic acid. The reaction mixture is then refluxed overnight with stirring. After the refluxing, the reaction mixture was allowed to cool to 70° C. The precipitate was removed by filtration and washed lightly with acetic acid. The precipitate was triturated with ethyl ether, filtered, triturated with water, and then filtered again and washed with ethyl ether. The solvents were removed in vacuo to yield 160 mg (23%) of the title product. mp 213-218° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:18][CH2:17][CH2:16][C:11]21OCC[O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(C)=O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:18][CH2:17][CH2:16][C:11]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCC2CCCC23OCCO3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCCC1COCc1ccccc1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 136.8 %

Procedure:
A mixture of 4 (7.95 g, 32.0 mmol) and p-toluenesulfonic acid monohydrate (0.30 g, 1.58 mmol) in acetone (160 mL) was stirred at ambient temperature for 100 min. The mixture was neutralized with NaHCO3 solution and acetone was evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with NaCl solution and dried over Na2SO4. Filtration and concentration gave 8.94 g of an oily material, which was purified by column chromatography (SiO2 gel 50 g EtOAc in n-hexane 5-10%), to give 5.83 g (89.2%) of 5, as a pale yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:19]([C:12]2[N:13]([CH3:18])[C:14]3[C:10]([CH:11]=2)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=3)=[O:21])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCCCc1ccccc1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Product: Cn1c(C(=O)NCCCCc2ccccc2)cc2c(O)cccc21

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and 4-phenylbutylamine the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=323.
Reaction SMILES: C1(C)C(C)=CC=CC=1.[CH:9]1[CH:14]=[C:13]([OH:15])[C:12]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1.[Na+:20].[C:21]1(=[O:35])[N:25]([CH2:26][C:27](Cl)=[O:28])[C:24](=[O:30])[C:23]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:22]12>CC(C)=O>[C:24]1(=[O:30])[N:25]([CH2:26][C:27]([O:15][C:13]2[CH:14]=[CH:9][CH:10]=[CH:11][C:12]=2[S:16]([O-:19])(=[O:17])=[O:18])=[O:28])[C:21](=[O:35])[C:22]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:23]12.[Na+:20]
Reactant: O=S(=O)([O-])c1ccccc1O
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CC(C)=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)Oc1ccccc1S(=O)(=O)[O-]
Reaction time: 15 h

Procedure:
500 g of xylene are added to 98.0 g (0.5 mol) of anhydrous sodium phenolsulfonate and 112.0 g (0.5 mol) of α-phthalimidoacetyl chloride and the mixture is kept at 140° C. for 15 hours. After cooling, the reaction mixture is taken up in acetone, the solvent is filtered off with suction over a Buchner funnel and the crystal sludge is washed twice more with 80 ml of acetone each time. After recrystallization from 90% strength ethanol, the resulting product is dried at 40° C. under a water pump vacuum.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:24][CH2:25][CH3:26])[C:13]([C:15]1[CH:16]=[C:17]2[CH:23]=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1)=[O:14])=O)(C)(C)C>Cl>[CH2:24]([C:9]1([C:13]([C:15]2[CH:16]=[C:17]3[CH:23]=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)=[O:14])[CH2:10][CH2:11][CH2:12][NH:8]1)[CH2:25][CH3:26]
Reactant: CCCC1(C(=O)c2cnc3[nH]ccc3c2)CCCN1C(=O)OC(C)(C)C
Agent: Cl
Product: CCCC1(C(=O)c2cnc3[nH]ccc3c2)CCCN1
Yield: 97 %

Procedure:
A solution of 2-propyl-2-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.240 g, 0.672 mmol) in 1N methanolic HCl (10.1 mL) was stirred at 20° C. under nitrogen for 18 hours. The reaction mixture was concentrated in vacuo then triturated with DCM (5 mL) and concentrated in vacuo to yield (2-propyl-pyrrolidin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-5-yl)-methanone (0.215 g, 0.652 mmol, 97%) as a white powder and as a monohydrochioride salt, MS=258 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:22][C:23]1([CH3:29])[CH2:25][CH:24]1[C:26](Cl)=[O:27]>ClCCl>[CH3:22][C:23]1([CH3:29])[CH2:25][CH:24]1[C:26]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1)=[O:27]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC1(C)CC1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-amino-1-benzylpiperidine (100 mg, 0.526 mmol) was dissolved into dichloromethane (10 ml) and then added with triethylamine (150 mg, 1.5 mmol) and 2,2-dimethylcyclopropanecarbonylchloride (159 mg, 1.2 mmol), which was further stirred at the room temperature for 14 hours. After the reaction was completed, the resultant was extracted with ethyl acetate and then washed, dried and concentrated according to the conventional manner and purified by using silica gel column chromatography (ethyl acetate, hexane), thus obtained a white crystal of 4-(2,2-dimethylcyclopropanecarbonylamino)-1-benzylpiperidine. The white crystal was dissolved into an ethanol (10 ml)-ethyl acetate (1 ml) mixed solvent, wherein 5% palladium carbon (150 mg) and formic acid (160 mg) were dissolved into the ethanol (10 ml) and applied thereto with dropping, which was stirred at the room temperature over night. After the palladium was filtered, the solvent was distilled out and aqueous solution of 2M sodium hydroxide was added therein to make pH>13, the solution was extracted with dichloromethane and further washed with a saturated saline solution, dried and vacuum concentrated, thus obtained 4-(2,2-dimethylcyclopropanecarbonylamino)piperidine (23:R =2,2-dimethylcyclopropane) (11.2 mg, 11%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13](=[O:16])([O-])[O-:14].[K+].[K+]>CN(C)C=O>[C:13]([CH:3]1[CH2:2][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][O:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)([OH:14])=[O:16]
Reactant: CC(C(=O)O)c1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1cccc(OCC2CCCCC2C(=O)O)c1
Temperature: 170 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
To 2-(3-hydroxyphenyl)propionic acid (19.2 g) were added cis-2-(hydroxymethyl)cyclohexanecarboxylic acid lactone (19.5 g), potassium carbonate (19.2 g) and dimethylformamide (200 ml). The mixture was heated with stirring for 3 hours in an oil bath maintained at 170° C. The reaction mixture was treated in substantially the same manner as in Reference Example 2. There was obtained the title compound (14 g) as an oil. IR νmaxfilm cm-1 : 1700 (C=O). MS m/e: 306 (M+).
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7](S(=O)(=O)NC)[CH:6]=1)=[O:4].[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][NH2:27]>C(O)(=O)C.O>[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][NH:27][C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)OC)c1)OCCO2
Reactant: CN1CCCC1CN
Solvent: O
Solvent: CC(=O)O
Product: CN1CCCC1CNC(=O)c1cccc2c1OCCO2
Yield: 112 %

Procedure:
169 g of methyl-7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate, 53 ml of water and 81 g of 1-methyl-2-aminomethylpyrrolidine were introduced into a balloon flask provided with a reflux condenser. The mixture was heated on a water bath until a test sample was totally soluble in dilute acids. The resulting crystals were dissolved in a solution of 50 ml of acetic acid in 1,250 ml of water and then the solution was filtered over carbon black and the base was reprecipitated by the addition of 100 ml of 20% ml of 20% ammonia. The crystals were dried off, washed with water and dried. 182 g of N-(1-methyl-2-pyrrolidylmethyl)-1,4-benzodioxane-5-carboxamide was produced (M.P.: 189°-190° C.; yield 83.6%).