Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[OH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1.[CH3:14][C:15]1[N:24]=[C:23]2[N:17]([CH2:18][CH2:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[CH:22]2O)[C:16]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:14][C:15]1[N:24]=[C:23]2[N:17]([CH2:18][CH2:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[CH:22]2[O:6][CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[C:16]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1nc2n(c1-c1ccccc1)CCc1ccccc1C2O
Reactant: CN1CCC(O)CC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc2n(c1-c1ccccc1)CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methanesulfonic acid (1.5 mL) and 4-hydroxy-N-methylpiperidine (658 mg, 5.72 mmoles) in CHCl3 (1 mL) cooled at 0° C. is added a solution of 2-methyl-1-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-4-ol (example 123B) (166.1 mg, 0.573 mmole) in CHCl3 (2 mL) dropwise. The reaction mixture is allowed to slowly reach room temperature and is stirred at room temperature for 2 hours. The reaction mixture is poured into a solution of saturated Na2CO3 (final pH 9-10). The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) with a gradient from (100:0:0) to (95:5:0.5) to give 2-methyl-4-(1-methylpiperidin-4-yloxy)-1-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]1[CH2:18][C:17](=O)[CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH3:14])[CH:17]2[CH2:16][O:15][CH2:18]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(CC1CN(C(=O)OC(C)(C)C)C1)C1COC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
A mixture of 3-(methylamino)methylazetidine-1-carboxylic acid tert-butyl ester (450 mg, 2.25 mmol), oxetan-3-one (135 mg, 1.88 mmol), in dichloromethane (10 mL) was stirred at RT for 1.5 h. Sodium triacetoxyborohydride (797 mg, 3.76 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 18 h. The mixture was diluted with water, the phases were separated and the aqueous phase was extracted with EtOAc (2×25 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvents reduced in vacuo The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 5:95) to afford the title compound as a colourless oil (330 mg, 69%). 1H NMR (400 MHz, CDCl3): δ 4.64 (2H, t, J=6.58 Hz), 4.57 (2H, t, J=6.26 Hz), 4.01 (2H, t, J=8.40 Hz), 3.57-3.55 (3H, m), 2.71-2.61 (1H, m), 2.41 (2H, d, J=7.57 Hz), 2.08 (3H, s), 1.44 (9H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:6]#[N:7])[CH3:2].[CH:19]([O:22][C:23](=[O:28])[CH2:24][C:25](=[NH:27])[NH2:26])([CH3:21])[CH3:20].CC[O-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[C:24]([C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[O:28])=[C:25]([NH2:26])[NH:27][C:6]=1[NH2:7])=[O:18])[CH3:2]
Reactant: CC(C)OC(=O)CC(=N)N
Reactant: CCOC(=O)C(C#N)=Cc1ccccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OC(C)C)C1c1ccccc1[N+](=O)[O-]
Yield: 54 %

Procedure:
Upon heating a solution of 12.3 g 2-nitrobenzylidenecyanoacetic acid ethyl ester, 7.2 g amidinoacetic acid isopropyl ester and 0.6 g sodium ethylate in 150 ml ethanol for 4 hours, 2,6-diamino-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-isopropyl ester 5-ethyl ester of m.p. 110° C is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[Cl:19][C:20]1[C:21]([F:31])=[CH:22][C:23]([F:30])=[C:24]([S:26](Cl)(=[O:28])=[O:27])[CH:25]=1.N12CCN(CC1)CC2>C(#N)C>[Cl:19][C:20]1[C:21]([F:31])=[CH:22][C:23]([F:30])=[C:24]([S:26]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)(=[O:28])=[O:27])[CH:25]=1
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Yield: 43.9 %

Procedure:
N-(2,4-Dimethoxybenzyl)pyrimidin-4-amine (Preparation 111, 1.80 g, 7.35 mmol), 5-chloro-2,4-difluorobenzene-1-sulfonyl chloride (1.81 g, 7.35 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.82 g, 7.35 mmol) in acetonitrile (50 mL) were stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between dichloromethane (30 mL) and water (15 mL). The organic layer was separated and dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 10% dichloromethane in ethyl acetate to give the title compound (1.47 g, 44%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].C(N=[C:18]=[O:19])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]=[C:18]=[O:19])(=[O:10])=[O:11]
Reactant: NS(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: O=C=NS(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 138 °C
Reaction time: 2 h

Procedure:
To 350 mL of dry xylenes was added 44 g of 2,3-dichlorobenzenesulfonamide, 23 mL of n-butyl isocyanate and 0.3 g 1,4-diazobicyclo[2.2.2]octane. This mixture was heated to reflux (138° C.) under a nitrogen atmosphere. After two hours, liquid phosgene was added to the refluxing mixture in portions over 1.5 hours at such a rate that kept the temperature between 130°-138° C. The phosgene addition was ceased when the reflux temperature had fallen to 130° C. and failed to rise, indicating that consumption of the starting material was complete (13.5 mL phosgene). The mixture was refluxed for an additional hour, cooled to room temperature, and filtered under nitrogen. Evaporation of the filtrate under reduced pressure gave 55 g of crude 2,3-dichlorobenzenesulfonyl isocyanate as a dark oil. This oil was taken up in dry acetonitrile (total solution volume 140 mL) and used as such for subsequent experiments: IR (Neat): 2250 (NCO) cm-1
Reaction SMILES: I[CH2:2][CH3:3].[CH3:4][O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[OH:16].C(=O)([O-])[O-].[K+].[K+]>>[CH3:4][O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[O:16][CH2:2][CH3:3]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(C(C)=O)cc1C(=O)OC
Yield: 43.5 %

Procedure:
Iodoethane (16.4 g, 0.105 mol) was added to a stirred mixture of 5-acetyl-2-hydroxybenzoic acid methyl ester (10 g, 51.5 mol) and anhydrous potassium carbonate (14.4 g, 0.104 mol) in 2-butane (200 ml) and the resulting mixture heated under reflux for 3 days. The solvent was removed by evaporation under vacuum and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous phase was removed and extracted with further ethyl acetate (4×100 ml). The organic solutions were combined, dried (Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel (130 g), using a methanol in dichloromethane elution gradient (0-1% methanol), to give the title compound as colourless crystals (10.15 g, 89%), m.p. 50°-55° C. Found: C,64.88; H,6.38. C12H14O4 requires C,64.85; H,6.35%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:9]=[C:10]([C:20]#[N:21])[NH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[CH3:22][C:23]1[C:27]([S:28](Cl)(=[O:30])=[O:29])=[C:26]([CH3:32])[O:25][N:24]=1.O>C(#N)C>[Cl:7][C:8]1[N:9]=[C:10]([C:20]#[N:21])[N:11]([S:28]([C:27]2[C:23]([CH3:22])=[N:24][O:25][C:26]=2[CH3:32])(=[O:30])=[O:29])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1
Reactant: Cc1ccc(-c2[nH]c(C#N)nc2Cl)cc1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(-c2c(Cl)nc(C#N)n2S(=O)(=O)c2c(C)noc2C)cc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 47.8 %

Procedure:
2.0 g (15 mmol) of potassium carbonate are added to a solution of 2.2 g (10 mmol) of 4-chloro-5-(4-tolyl)-imidazole-2-carbonitrile in 30 ml of acetonitrile, and the mixture is stirred at 20° C. for 10 minutes. The mixture is subsequently admixed with 1.9 g (10 mmol) of 3,5-dimethylisoxazole-4-sulphonyl chloride and stirred at 20° C. for 4 hours. The reaction mixture is then poured into 150 ml of water and extracted with 50 ml of ethyl acetate. The combined organic phases are dried over sodium sulphate and then concentrated under reduced pressure. The residue that remains is chromatographed over silica gel using methylene chloride as mobile phase. Concentration of the eluate under reduced pressure gives 1.8 g (50% of theory) of 4-chloro-1-(3,5-dimethylisoxazol-4-yl-sulphonyl)-5-(4-tolyl)-imidazole-2-carbonitrile in the form of a colourless solid of melting point 103 to 108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][N:17]([CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[C:18]3=[O:23])=[O:10])=[CH:4][CH:3]=1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4ccc(Cl)cc4)cccc3C2=O)C(=O)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
4-Chlorophenyl isocyanate (0.4 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL) and concentrated. The residue was stirred with 1NHCl (30 mL) for 30 minutes. The mixture was filtered, and the solid was slurried with hot acetone (10 mL) to give 1-(4-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.7 g, 73%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.33-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.36-4.58 (m, 4H, 2CH2), 5.11-5.18 (dd, J=5.0 and 12.5 Hz, 1H, CH), 6.77 (t, J=5.0 Hz, 1H, NH), 7.27 (d, J=10.0 Hz, 2H, Ar), 7.40 (d, J=10 Hz, 2H, Ar), 7.47-7.64 (m, 3H, Ar), 8.77 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.18, 39.68, 45.19, 51.58, 119.29, 121.56, 124.66, 128.30, 128.44, 130.35, 131.64, 135.46, 139.31, 139.92, 155.08, 168.07, 171.00, 172.84; Anal. calcd. for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 58.85; H, 4.35; N, 12.97; Cl, 8.19.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)=[CH:6][C:5]([C:17]2[CH:18]=[C:19]([C:23]([NH:26][S:27]([CH2:30][C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:28])([CH3:25])[CH3:24])[CH:20]=[CH:21][CH:22]=2)=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S([CH2:51][N+:52]#[C-:53])(=O)=O)=CC=1.[N+](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-]>CO.O>[CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[O:16][CH:53]=[N:52][CH:51]=3)=[CH:13][CH:14]=2)=[CH:6][C:5]([C:17]2[CH:18]=[C:19]([C:23]([NH:26][S:27]([CH2:30][C:31]([F:34])([F:32])[F:33])(=[O:28])=[O:29])([CH3:25])[CH3:24])[CH:20]=[CH:21][CH:22]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C=O)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(-c2cnco2)cc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 3 %

Procedure:
N-(2-{3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]phenyl}propan-2-yl)-2,2,2-trifluoroethanesulfonamide (340 mg, 0.69 mmol, 1 equiv) was added to a suspension of potassium carbonate (237 mg, 1.72 mmol, 2.5 equiv) stirring in MeOH (3.4 mL) at 22° C. 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene isocyanomethyl 4-methylphenyl sulfone (161 mg, 0.82 mmol, 1.2 equiv) was added and the resulting mixture was stirred at 22° C. for 30 minutes. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (0-40% EtOAc:Hex). Fractions were identified, combined and concentrated in vacuo but the isolated material was not pure. The residue was then purified by reversed phase HPLC (0-95% acetonitrile:water with 0.025% TFA). Pure fractions were identified, combined, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (3% yield). Calc'd (M+1)+: 535.1. Found: 535.1.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N(CC)CC)C.[CH2:19]([C@@H:26]1[CH2:31][C@@H:30]([N:32]([CH2:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43]=[CH:42][CH:41]=2)[C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[CH2:29][CH2:28][NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:19]([C@@H:26]1[CH2:31][C@@H:30]([N:32]([CH2:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43]=[CH:42][CH:41]=2)[C:33](=[O:38])[C:34]([F:36])([F:37])[F:35])[CH2:29][CH2:28][N:27]1[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reaction time: 16 h

Procedure:
67 μl (0.468 mmol) of benzyl chloroformate and 72 μl (0.515 mol) of triethylamine are added to a solution of 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine in 4 ml methylene chloride at 0°, and the mixture is left to stir at this temperature for 16 hours. Then a further 34 μl (0.234 mmol) of benzyl chloroformate and 36 μl (0.257 mmol) of triethylamine are added and stirred at room temperature for 3 hours. This is followed by dilution with methylene chloride, and the organic phase is washed with brine, dried over magnesium sulfate and evaporated to dryness. The oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (1000:50:1). The title compound is obtained as oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.61, FD-MS: M+ =561.
Reaction SMILES: CO.[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21]C)=[O:20])=[O:9])([CH3:6])([CH3:5])[CH3:4].O[Li].O>O>[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19]([OH:21])=[O:20])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(F)cc1OCCCCCNC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCOc1cc(F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
Methanol (500 ml) and water (500 ml) were added to the crude reaction mixture obtained in Example 24. LiOH hydrate (1.4 mol) was added and the reaction mixture was stirred at room temperature for 16 h. Then, water (500 ml) was added and the organic solvent was evaporated under vacuum. The mixture was extracted with methyl tert-butyl ether to remove impurities. The water layer was adjusted to pH 8-9 and extracted again with ethyl acetate (3×500 ml). The water layer was adjusted to pH 4-5 and ethyl acetate was added. The organic layer was separated, washed with brine, dried and concentrated in vacuo. Yield: 120 g (purity 80%, 75% yield over 2 steps).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li:15])CCC>C(OCC)C.CCCCC>[CH3:1][C:2]1[CH:10]([Li:15])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: [Li]CCCC
Reactant: CC1=Cc2ccccc2C1
Solvent: CCCCC
Solvent: CCOCC
Product: [Li]C1C(C)=Cc2ccccc21
Temperature: 25 °C

Procedure:
A solution of 3 g (20 mmol) of 2-methylindene (C. F. Koelsch, P. R. Johnsen, J. Am. Chem. Soc. 65, 567, (1943)) in 50 ml of diethyl ether is cooled to -78° C. and admixed with 14.6 ml of a 1.58 molar solution of n-butyllithium in n-pentane. The solution is warmed to room temperature and the 2-methylindenyllithium formed is filtered off and dried under reduced pressure. The yield is 2.5 g (91.9% of theory).
Reaction SMILES: [H-].[Na+].C(COC)OC.P(=O)([O-])O[CH2:11][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17](C)C.[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[C:38]([CH:39]=O)=[C:37]([O:41][CH3:42])[CH:36]=[CH:35][C:34]=1[O:43][CH3:44])([O:25][CH3:26])=[O:24]>C(O)(=O)C>[CH3:44][O:43][C:34]1[CH:35]=[CH:36][C:37]([O:41][CH3:42])=[C:38](/[CH:39]=[CH:11]/[C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:33]=1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CCCCCCc1c(OC)ccc(OC)c1C=O
Reactant: CC(C)CCCCC(=O)CO[PH](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: CCCCCC(=O)/C=C/c1c(OC)ccc(OC)c1CCCCCCC(=O)OC
Temperature: 85 °C

Procedure:
To a slurry of 278 mg. of a dispersion of sodium hydride in mineral oil in 40 ml. of dimethoxyethane is added a solution of 1.33 g. of dimethyl(2-oxoheptyl) phosphonate in 40 ml. of dimethoxyethane and the mixture is stirred for one hour. 1.41 g. of the aldehyde in 40 ml. of dimethoxyethane is added and the mixture heated at 85° C. for eighteen hours. The mixture is then cooled and neutralized with acetic acid and the solvent is removed in vacuo. The residue is then chromatographed on a silica gel column to yield 1,4-dimethoxy-2-(6-carbomethoxyhexyl)-3-(3-oxo-trans-1-octenyl)benzene as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([N:35]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:40][C:39]3[CH:38]=[CH:37][C:36]([N:35]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:43][CH:42]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc(N(c5ccccc5)c5ccccc5)cc4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-diphenylamino-benzaldehyde. MS (ESI) m/z 636.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:13][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C(N(CC)CC)C>O1CCCC1>[C:1]([O:13][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 15 h
Yield: 70.1 %

Procedure:
A solution of decanoyl chloride (5.0 g) in tetrahydrofuran (20 ml) was dropwise added to a mixture of N-hydroxysuccinimide (3.06 g) and triethylamine (3.7 ml) in tetrahydrofuran (30 ml) with stirring under ice-cooling. The mixture was stirred at the same temperature for one hour and then at ambient temperature for 15 hours. A precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 ml). The solution was washed with water (50 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give N-decanoyloxysuccinimide as a crystal (4.95 g).
Reaction SMILES: [CH2:1]([C:5]1([CH2:23][CH3:24])[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:26][OH:27].Cl>O>[CH2:1]([C:5]([CH2:23][CH3:24])([CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:7])[CH:6]=[N:26][OH:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CC)C=NC(c2ccccc2)CC=CCCC=CC1
Reactant: NO
Agent: Cl
Solvent: O
Product: CCCCC(C=NO)(CC)CC=CCCC=CCC(N)c1ccccc1
Yield: 100 %

Procedure:
The procedure described in Example 1(b) is repeated, except that 283.4 g (0.875 mol) of 3-n-butyl-3-ethyl-12-phenyl-1-aza-1,5,9-cyclododecatriene, 60.8 g (0.87 mol) of hydroxylamine hydrochloride, 50 ml of concentrated hydrochloric acid and 250 ml of water are used. Working up yields 310 g (0.87 mol) of 2-n-butyl-2-ethyl-11-phenyl-11-amino-undeca-4,8-dienal oxime; yield 99.5% of theory.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][C:20]([NH2:22])=[O:21])=[C:5]([CH3:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][C:20]([NH2:22])=[O:21])=[C:5]([CH3:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:33]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1c(CC(N)=O)c2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCCOc1cccc2c1c(CC(N)=O)c(C)n2Cc1ccccc1
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A solution of 294 mg (1 mmol) of 4-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide was treated with 40 mg (1 mmol) of 60% NaH/mineral oil and after 1 hour, 0.15 mL (1 mmol) of ethyl 4-bromobutyrate was added. The mixture was stirred for 2 hours, diluted with water and extracted with EtOAc. The EtOAc solution was washed with NaCl solution, dried (MgSO4), and concentrated at reduced pressure. The residue was crystallized from MeOH/hexane to give a total of 235 mg (58% yield) of 4-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]butanoic acid ethyl ester, mp, 115-116° C.