Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.ClC(N(C)C)=C(C)C.[NH2:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH3:34])([CH3:33])[C:25](=[O:32])[N:26]2[CH:29]2[CH2:31][CH2:30]2)=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH:29]1([N:26]2[C:27]3[C:23](=[CH:22][CH:21]=[C:20]([NH:19][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][N:10]=[C:2]([CH3:1])[CH:3]=4)[CH:28]=3)[C:24]([CH3:33])([CH3:34])[C:25]2=[O:32])[CH2:31][CH2:30]1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ccc21
Reactant: Cc1cc(C(=O)O)ccn1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C(=O)Nc2ccc3c(c2)N(C2CC2)C(=O)C3(C)C)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methylisonicotinic acid (95.1 mg, 694 μmol) in dry dichloromethane (3.64 ml) under an argon atmosphere at 0° C. was added a solution of 1-chloro-N,N,2-trimethylpropenylamine (104 mg, 763 μmol) in dry dichloromethane (1 ml). After 2 hours 6-amino-1-cyclopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one (example 14c, 150 mg, 694 μmol) and triethyl amine (140 mg, 193 μl, 1.39 mmol) were added at 0° C. The reaction mixture was warmed to room temperature, kept at this temperature for 16 hours, then diluted with dichloromethane, water and 1 M aqueous sodium carbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with 1 M aqueous sodium carbonate solution, dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as light yellow oil (207 mg).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:4][N:3]=1.[C:20]1(C)[C:21]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1.[CH2:31](N(CC)CC)C>C1COCC1>[CH3:31][C:24]1[CH:25]=[CH:20][C:21]([S:26]([O:1][C:2]2[CH:6]=[C:5]([CH:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[O:4][N:3]=2)(=[O:27])=[O:28])=[CH:22][CH:23]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(O)no2)CC1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2cc(C3CCN(C(=O)OC(C)(C)C)CC3)on2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A cooled (0° C.) solution of tert-butyl 4-(3-hydroxyisoxazol-5-yl)piperidine-1-carboxylate (493 mg, 1.84 mmol) in 5 mL of THF was treated with toluenesulfonyl chloride (386 mg, 2.02 mmol) followed by triethylamine (295 μL, 2.12 mmol). The resulting mixture was warmed to rt and stirred for 2 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by MPLC (silica, 50% ethyl acetate/hexanes) to furnish tert-butyl 4-(3-{[(4-methylphenyl)sulfonyl]oxy}isoxazol-5-yl)piperidine-1-carboxylate. 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 6.06 (s, 1H), 4.15 (br m, 2H), 2.88 (m, 3H), 2.49 (s, 3H), 2.00 (dd, J=13, 2.5 Hz, 2H), 1.62 (dq, J=4.5, 12.5 Hz, 2H), 1.49 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24](C(=O)C)[CH2:23][CH2:22]2)[N:3]=1.FC(F)(F)C(O)=O.[CH3:37][S:38](N1CCC(N)CC1)(=[O:40])=[O:39]>>[NH2:1][C:2]1[C:7]([C:8]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1ccc(OC)c(C(=O)c2cnc(NC3CCN(C(C)=O)CC3)nc2N)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC)c(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)c1

Procedure:
The same procedure as described in Example 326 was used, starting with 1-[4-[4-amino-5-(2,5-dimethoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone (Example 330) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,5-dimethoxy-phenyl)-methanone. MS (M+H)+, 436
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=CC=2F)=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.[C:37](O)([C:39]([F:42])(F)F)=O>C(Cl)Cl>[F:42][C:39]1[CH:37]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=3)[C:33]#[N:34])[CH2:24][C:23](=[O:35])[NH:22][C:9]=2[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4cc(F)ccc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2′,5′-difluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K92) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (49 mg).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH:13]1[C:24](=[O:25])[N:15]2[CH:16]([C:21]([OH:23])=[O:22])[C:17]([CH3:20])([CH3:19])[S:18][C@H:14]12.F[C:27]1[NH:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>CN(C=O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[N:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[NH:31][C:27]=1[NH:12][CH:13]1[C:24](=[O:25])[N:15]2[CH:16]([C:21]([OH:23])=[O:22])[C:17]([CH3:20])([CH3:19])[S:18][C@H:14]12
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1C(=O)O
Reactant: Fc1nc2ccccc2[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CC1(C)S[C@@H]2C(Nc3nc4ccccc4[nH]3)C(=O)N2C1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a solution of anhydrous 6-amino-2,2-dimethylpenam-3-carboxylic acid toluene-p-sulphonate (171 mg.) in dry DMF was added 2-fluorobenzimidazole (150 mg.) in one portion and the mixture stirred at ambient temperature for 1.5 hours. The mixture was evaporated to dryness under reduced pressure at room temperature and the resulting residue, a mobile oil, was triturated with EtOAc (2×10 ml.) and then dry acetonitrile (2 ml.) whereupon the product crystallised. The solid was filtered and washed with acetonitrile and ether to give 6-(benzimidazol-2-yl)amino-2,2-dimethylpenam-3-carboxylic acid toluene-p-sulphonate (185 mg.), m.p. 181°-183°, having the following n.m.r. spectrum in d6DMSO: 1.49 (s, 3H); 1.62 (s, 3H); 2.29 (s, 3H); 4.39 (s, 1H); 5.54 (br, 1H); 5.68 (d, 1H); 7.0-7.56 (m, 8H); 9.93 (br, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:32]1([C:38]2[O:39][C:40]([CH3:56])=[C:41]([CH2:43][CH2:44]OS(C3C=CC(C)=CC=3)(=O)=O)[N:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:44][CH2:43][C:41]2[N:42]=[C:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:39][C:40]=2[CH3:56])=[C:9]([CH2:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1OCCc1nc(-c2ccccc2)oc1C
Temperature: 55 °C
Yield: 60 %

Procedure:
A solution of 3-(4-hydroxy-3-propylphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (266 mg, 1.0 mmol) in DMF (10 mL) was treated with cesium carbonate (407 mg, 1.25 mmol) and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester and then heated at 55° C. for 18 h. After cooling to ambient temperature, the mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and then the organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (100 mL SiO2, hexanes to 30% EtOAc/hexanes) to provide the desired product (315 mg, 60%) as a clear, colorless oil: MS (EI) 528.3 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CC(N(C)C)=O>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)C1CC1
Reactant: NCc1ccccn1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1nc2cccc(NCc3ccccn3)n2n1)C1CC1
Temperature: 150 °C

Procedure:
To a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (0.05 g, 0.178 mmol) in dimethylacetamide (1 mL) in a microwave vial, 2-aminomethylpyridine (0.096 g, 0.89 mmol) was added and the solution was heated in the microwave at 150° C. for 15 min. The crude was purified straight away by preparatory chromatography after filtration. LCMS method: 2, RT: 2.07 min, MI: 309 [M+1]. NMR (1H, DMSO, 300 MHz): 10.91 (s, 1H), 8.57 (d, 1H), 7.77 (t, 1H), 7.30-7.49 (m, 4H), 6.85 (d, 1H), 6.08 (d, 1H), 4.67 (d, 2H), 2.07 (brs, 1H), 0.83 (d, 4H)
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20](=[O:26])[CH:21](OCC)O)[C:11]=2[O:10]1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:46])([CH3:45])[CH2:29][C:30]1[CH:44]=[CH:43][C:33]([O:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32][CH:31]=1.O.[C:48]([OH:53])(=O)[C:49](O)=O>C(OCC)(=O)C.C(OCC)C>[CH2:48]([O:53][C:17]1[CH:18]=[C:19]([CH:20]([OH:26])[CH2:21][NH:27][C:28]([CH3:45])([CH3:46])[CH2:29][C:30]2[CH:44]=[CH:43][C:33]([O:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32][CH:31]=2)[C:11]2[O:10][CH2:9][C:14](=[O:15])[NH:13][C:12]=2[CH:16]=1)[C:49]1[CH:18]=[CH:19][CH:11]=[CH:12][CH:16]=1
Reactant: CCOC(O)C(=O)c1cccc2c1OC(OCc1ccccc1)C(=O)N2
Reactant: CCOC(=O)CCCOc1ccc(CC(C)(C)N)cc1
Reactant: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)cc1

Procedure:
1.20 g (3.36 mmol) of benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 0.90 g (3.22 mmol) of ethyl 4-[4-(2-amino-2-methylpropyl)phenoxy]butyrate are reacted in the manner described for Example 8(d). The crude product is dissolved in 10 mL ethyl acetate and 10 mL water and combined with oxalic acid with stirring. The solution is diluted with diethyl ether and the solid precipitated is suction filtered and washed with diethyl ether. Yield: 1.20 g (54%, oxalate); melting point 223° C.-227° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([S:24]([CH3:23])(=[O:26])=[O:25])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Reaction time: 16 h
Yield: 79.1 %

Procedure:
To a solution of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (1.72 g, 8 mmol) in dichloromethane (10 mL) was added triethylamine (1.30 mL, 8.8 mmol) followed by methanesulphonyl chloride (0.68 mL, 8.8 mmol). After stirring for 16 hours the reaction mixture was then diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography using 50% ethyl acetate in petroleum ether as the eluent to yield 4-(methanesulfonyl-methyl-amino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.85 g, 75%). Treatment of this compound with trifluoroacetic acid in dichloromethane yielded N-methyl-N-piperidin-4-yl-methanesulfonamide, which was isolated as the TFA salt.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([Cl:9])[C:6](=[O:8])[CH:7]=1.OS(O)(=O)=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([Cl:9])[C:6](=[O:8])[C:7]=1[C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([O:17][CH3:16])[CH:19]=2)[NH:23][CH:22]=1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: O=C1C=C(Cl)C(=O)C=C1Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2[nH]cc(C3=C(Cl)C(=O)C=C(Cl)C3=O)c2c1
Reaction time: 2 h
Yield: 96.3 %

Procedure:
To a solution of 2,5-dichloro-1,4-benzoquinone (0.242 g, 1.37 mmol) in THF (3 mL) was added H2SO4 (35 μL, 0.68 mmol) at room temperature. To this mixture was added 5-methoxyindole (0.100 g, 0.68 mmol). After the reaction mixture was stirred for 1 hour at room temperature under nitrogen protection, DDQ (0.232 g, 1.02 mmol) was added. After stirring for 2 hours, the mixture was diluted with ethyl acetate (100 mL). The organic layer was washed with sat. NaHCO3 (3×20 mL) and brine (20 mL), and dried over Na2SO4. The solution was concentrated and purified by flash column chromatography using 15% EtOAc in hexane as eluent to afford 2,5-dichloro-3-(5-methoxy-1H-indole-3-yl)-[1,4]benzoquinone (0.211 g, 96%) as blue needles from benzene/hexane. Melting Point 195–196° C. 1H NMR (CDCl3): 6.78 (1H, d, J=2.4 Hz), 6.93 (1H, dd, J=2.1, 8.4 Hz), 7.23 (1H, s), 7.34 (1H, d, J=9.0 Hz), 7.54 (1H, d, J=3.0 Hz), 8.62 (1H, br s). 13C NMR (d6-acetone): 55.2, 103.8, 106.7, 112.4, 112.8, 126.5, 130.9, 131.0, 131.4, 133.4, 139.8, 143.7, 154.8, 177.8, 178.0. IR (KBr): 3328, 3043, 2924, 2855, 1675, 1638, 1543, 1484, 1260, 1227 cm−1. Anal. Calcd. for C15H9Cl2NO3: C, 55.93; H, 2.82; N, 4.35. Found: C, 55.72; H, 2.99; N, 4.24.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:2]=1.[Br:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([OH:27])[CH:26]=1.C(O)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([O:27][CH2:1][CH3:2])[CH:26]=1
Reactant: Oc1cncc(Br)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (0.461 g, 1.758 mmol) is added to a mixture of 3-bromo-5-hydroxy pyridine (0.3 g, 1.724 mmol) in THF (10 ml). Ethanol (0.103 ml) is added the reaction mixture is cooled to 0° C. (ice-bath). DEAD (0.277 ml, 1.758 mmol) is finally added and the mixture is warmed to room temperature and stirred overnight. The crude material is purified by flash chromatography by wet loading onto a 50 g silica column eluting with 3:1 iso-hexanes:EtOAc to afford the title compound as a yellow oil, [MH+ 201.88].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:10][C:11]1([CH3:19])[O:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[O:12]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCCC1C(O)=O>C(#N)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]2[C:15](=[O:17])[O:16][C:11]([CH3:19])([CH3:10])[O:12][C:13]2=[O:18])=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccccc1
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CC1(C)OC(=O)C(C(c2ccccc2)c2c[nH]c3ccccc23)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Using the procedure described in Tetrahedron 56 (2000) 5479-5492, indole (5.0 g, 42.7 mmole) and 2,2-dimethyl-[1,3]dioxane-4,6-dione (6.15 g, 42.7 mmole) were mixed in acetonitrile (50 ml). To this mixture was added benzaldehyde (9.06 g, 85.4 mmole) and d,l-proline (0.25 g). The mixture was stirred at room temperature for 18 hours after which time much of the reaction mixture had turned solid. The solvent was evaporated at reduced pressure and the residue was triturated with ether and filtered. The filter cake was washed with several portions of ether to afford pure 5-[(1H-indol-3-yl)-phenyl-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione, 11.83 g, as a light pink solid (MS (M−H)=348) which was used without further purification in the next step.
Reaction SMILES: [Na].[CH2:2](Br)[CH3:3].[CH:5]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>N>[CH2:2]([C:5]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:3]
Reactant: CCBr
Reactant: N#CC1CCCCCCC1
Agent: N
Agent: [Na]
Product: CCC1(C#N)CCCCCCC1

Procedure:
Sodium (3.7 g, 0.16 mole) was added to liquid ammonia (300 ml.) at 35° C. A catalytic amount of ferric nitrate was then added. After the solution had become grey in colour, ethyl bromide (17.4 g, 0.16 mole) and cyclooctyl cyanide (20.0 g, 0.14 mole) were added very slowly. The liquid ammonia was then allowed to evaporate over a period of 20 hours. Benzene and then water were added to the residue. The benzene layer was dried (MgSO4) and distilled to give 1-ethylcyclooctyl cyanide, bp. 130-132°/17 mm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][C:22]3([CH3:26])[CH2:24][CH2:25][CH:19]2[C:20](=[O:27])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl.[NH2:32][OH:33]>NO.CO.Cl>[OH:33][NH:32][C:20]([CH:19]1[CH2:25][CH2:24][C:22]([OH:21])([CH3:26])[CH2:23][N:18]1[S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16])=[O:27]
Reactant: CC12CCC(C(=O)O1)N(S(=O)(=O)c1ccc(OCc3ccccc3)cc1)C2
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(O)CCC(C(=O)NO)N(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
5-(4-Benzyloxy-benzenesulfonyl)-1-methyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (0.035 g, 0.09 mmol) was dissolved in 0.80 mL of a 0.81 M solution of hydroxylamine in methanol (prepared by treating 7.25 mL of a 0.81 M solution of sodium methoxide in methanol with 0.52 g of hydroxylamine hydrochloride). The resulting mixture was shaken at 60° C. for 10 minutes. After cooling to room temperature, the mixture was diluted with 1M HCl, extracted twice with ethyl acetate, and the combined organic layers were washed twice with 50% saturated aqueous NaHCO3, once with 1M pH 7.0 phosphate buffer, dried over Na2SO4, filtered and concentrated in vacuo. Trituration of the residue with CH2Cl2-hexane afforded 0.027 g of 1-(4-benzyloxy-benzenesulfonyl)-5-hydroxy-5-methyl-piperidine-2-carboxylic acid hydroxyamide as a colorless solid:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2>S(=O)(=O)(O)O>[Br:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2c(Br)cccc2N1
Agent: O=S(=O)(O)O
Product: O=C1Cc2c(ccc([N+](=O)[O-])c2Br)N1
Reaction time: 1 h

Procedure:
A mixture of concentrated sulfuric acid (3.6 mL) and concentrated nitric acid (0.7 mL) was added slowly to a solution of 4-bromo-1,3-dihydro-2H-indol-2-one (2 g, 9.48 mmol) (see Kosuge et al., supra) in concentrated sulfuric acid (20 mL) at −5° C. with stirring. The mixture was stirred for an additional 1 h at −5° C. then poured into ice. After standing for 1 h, precipitate formed was collected by filtration and washed with water, and dried in a vacuum oven to give the above product. (Yield 2.33 g, 96%).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:22]([O:21][C:17](=[O:20])[CH:18]=[CH:19][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Brc1ccc2c(c1)CCc1ccccc1N2
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C=Cc1ccc2c(c1)CCc1ccccc1N2
Temperature: 100 °C
Yield: 33.6 %

Procedure:
A mixture of 2-bromo-10,11-Dihydro-5H-dibenzo[b,f]azepin (4.11 g, 15 mmol, prepared as described in Tetrahedron (1992), 48, 4779) tert-butyl acrylate (2.91 g, 22.5 mmol), palladium acetate (40 mg, 0.2 mmol), tri-o-tolylphosphine (183 mg, 0.6 mmol) and triethylamine (20 ml) in an screw cap ampoule was heated at 100° C. for 20 h. The cooled reaction mixture was diluted with ethyl acetate (50 ml), washed with water (3×20 ml), dried (MgSO4), filtered and evaporated in vacuo. The residue (3.9 g) was purified by column chromatography on silicagel (600 ml) using a mixture of ethyl acetate and heptane (1:6) as eluent which afforded 1.62 g (34%) of 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-2-yl)acrylic acid tert-butyl ester as a solid.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH:12]2[CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:11]2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:10]1[CH:11]2[CH2:16][NH:15][CH2:14][CH:12]2[CH2:13][N:9]1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-butyl 5-benzoylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (100 mg) was dissolved in 10% TFA solution in CH2Cl2 (10 mL). The reaction was stirred at room temperature for 24 hours. After removal of solvents, the residue, (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(phenyl)methanone, was used in the further reactions without purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)C(C)C)(C)C>ClCCl.O>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:13](=[O:15])[CH2:12][CH2:11][C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][CH:5]=2)[CH2:31][CH2:30]1
Reactant: O=C(O)CCc1c[nH]c2c1C(=O)CCC2
Reactant: CN1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CN1CCN(C(=O)CCc2c[nH]c3c2C(=O)CCC3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a suspension of 10 g of the product of step 1 (48 mmol) in dichloromethane (60 mL) was added 9.3 g (57.6 mmol) of 1,1′-carbonyldiimidazole. The mixture was stirred at room temperature for 2 hours and then 5.3 mL (48 mmol) 1-methylpiperazine and 8.4 mL (48 mmol) N,N-diisopropylethyl-amine was added. The dark red reaction mixture was then stirred at room temperature overnight. The reaction was then poured into water, the organic layer separated and washed with brine, dried and concentrated to give 8 g (57%) of 3-[3-(4-methylpiperazin-1-yl)-3-oxo-propyl]-1,5,6,7-tetrahydroindol-4-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)[CH:3]=1.[Cu](C#N)[C:16]#[N:17].[CH3:20][N:21](C)C=O>>[C:16]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:20]#[N:21])[CH:9]=2)[CH:3]=1)#[N:17]
Reactant: N#C[Cu]C#N
Reactant: Clc1ccnc(-c2cccc(Br)c2)c1
Reactant: CN(C)C=O
Product: N#Cc1cccc(-c2cc(C#N)ccn2)c1

Procedure:
Starting from 4-chloro-2-(3-bromophenyl)-pyridine, the title compound is prepared by reaction with copper cyanide in boiling N,N-dimethylformamide.