Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:17][NH:18][C:19]([CH:21]2[CH:26]3[CH:22]2[CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25]3)=[O:20])[CH:7]=1)[CH:3]([CH3:5])[CH3:4].CCCCCC.C(OCC)(=O)C>CO>[ClH:1].[CH2:2]([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:17][NH:18][C:19]([CH:21]2[CH:26]3[CH:22]2[CH2:23][NH:24][CH2:25]3)=[O:20])[CH:7]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)Cc1cc(CNC(=O)C2C3CN(C(=O)OC(C)(C)C)CC32)nn1-c1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)Cc1cc(CNC(=O)C2C3CNCC32)nn1-c1ccccc1
Reaction time: 3 h
Yield: 100.1 %

Procedure:
1.25 M hydrochloric acid solution (9.76 mL, 12.2 mmol) dissolved in methanol was added dropwise to the tert-butyl 6-((5-isobutyl-1-phenyl-1H-pyrazole-3-yl)methylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (268 mg, 0.610 mmol) prepared in Example 10 and stirred for 3 hours. The completion of the reaction was confirmed by TLC (hexane:ethyl acetate=1:2). After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 229 mg (100%) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:18])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[N:19]([O-])=O.[Na+].[CH2:23]1[C:31]2[C:26](=[CH:27][C:28]([N:32]3[C:36](=[O:37])[CH2:35][C:34]([CH3:38])=[N:33]3)=[CH:29][CH:30]=2)[CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>Cl.C(O)C>[F:8][C:6]1[CH:7]=[C:2]([NH:1][N:19]=[C:35]2[C:36](=[O:37])[N:32]([C:28]3[CH:27]=[C:26]4[C:31](=[CH:30][CH:29]=3)[CH2:23][CH2:24][CH2:25]4)[N:33]=[C:34]2[CH3:38])[C:3]([OH:18])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=2)[CH:5]=1
Reactant: CC1=NN(c2ccc3c(c2)CCC3)C(=O)C1
Reactant: O=N[O-]
Reactant: Nc1cc(F)cc(-c2cccc(C(=O)O)c2)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1=NN(c2ccc3c(c2)CCC3)C(=O)C1=NNc1cc(F)cc(-c2cccc(C(=O)O)c2)c1O
Temperature: 25 °C
Yield: 15.3 %

Procedure:
Upon cooling by an ice-water bath, 3′-amino-5′-fluoro-2′-hydroxy-biphenyl-3-carboxylic acid 2f (296 mg, 1.20 mmol) was dissolved in 10 mL of hydrochloric acid (1 N) followed by addition of 10 mL of aqueous sodium nitrite (91 mg, 1.32 mmol) and 2-indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one 1i (257 mg, 1.20 mmol). The mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate, followed by addition of 10 mL of ethanol. The mixture was warmed up to room temperature overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered, dried and recrystallized from methanol to obtain the title compound 5′-fluoro-2′-hydroxy-3′-[N′-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene)-hydrazino]-biphenyl-3-carboxylic acid 2 (87 mg, yield 14.1%) as a red solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:34])[C@@H:5]([NH2:33])[CH2:6][C:7]1[CH:32]=[CH:31][C:10]2[O:11][C@@H:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=4)[CH:16]=3)[CH2:13][O:14][C:9]=2[CH:8]=1.C([O-])(O)=O.[Na+].[N+:40]([C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1)([O-:42])=[O:41]>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:34])[C@@H:5]([NH:33][S:49]([C:46]1[CH:45]=[CH:44][C:43]([N+:40]([O-:42])=[O:41])=[CH:48][CH:47]=1)(=[O:50])=[O:51])[CH2:6][C:7]1[CH:32]=[CH:31][C:10]2[O:11][C@@H:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=4)[CH:16]=3)[CH2:13][O:14][C:9]=2[CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
(S)-2-Amino-3-{(S)-2-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro benzo[1,4]dioxin-6-yl}-propionic acid methyl ester hydrochloride (0.35 g) was taken in 2 mL of EtOAc and cooled to 0° C., NaHCO3 solution (1 mL) and 4-nitrobenzensulfonyl chloride (178 mg) were added and stirred for 10 minutes. Reaction was stirred at room temperature for 4 hours. EtOAc layer was seperated and washed with water and brine, and then dried (Na2SO4), filtered and evaporated. The residue was purified by silica gel column (10% EtOAc in hexanes to 50% EtOAc in hexanes) to get pure (S)-3-{(S)-2-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (0.37 g). 1H NMR (400 MHz, acetone-d6): 8.33 (m, 2H), 7.89 (m, 2H), 7.73 (d, 1H), 7.62 (d, 1H), 7.37-7.53 (m, 3H), 7.04-7.21 (m, 3H), 6.64-6.72 (m, 3H), 5.22 (s, 2H), 5.09 (m, 1H), 4.35 (m, 1H), 4.21 (m, 1H), 3.97 (m, 1H), 3.61 (s, 3H), 3.03 (m, 1H), 2.76 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH:21]([CH3:23])[CH3:22])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1.[CH3:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].N1C(C)=CC=CC=1C.N1C=CC(C)=CC=1C.N1C=CC=C(C)C=1C.N1C=CC(C)=C(C)C=1.N1C=C(C)C=CC=1C.N1C=C(C)C=C(C)C=1>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH:21]([CH3:22])[CH3:23])[N:5]([C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Reactant: CCCCC(=O)Cl
Agent: Cc1ccc(C)nc1
Agent: Cc1cccnc1C
Agent: Cc1cncc(C)c1
Solvent: Cc1ccncc1C
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccnc(C)c1
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OC)C(C)C

Procedure:
Reacting pure N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VI) with n-valeryl chloride in the presence of a heterocyclic amine base selected from 2,6-lutidine, 2,4-lutidine, 2,3-lutidine, 3,4-lutidine, 2,5-lutidine, 3,5-lutidine to produce pure N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VII) substantially free from alkene impurity of formula (VIIa).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[N:24]=[CH:25][NH:26]C=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1.CCN(C(C)C)C(C)C.N1CCOCC1>CN(C=O)C.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>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][C:22]2[N:26]=[CH:25][N:24]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=3)[CH:23]=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCCc1c[nH]cn1)c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCN1
Product: CCCCn1c(=O)n(CCCc2cn(Cc3cccc(C(F)(F)F)c3)cn2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.3 %

Procedure:
A solution of 3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (150 mg, 0.38 mmol) in anhydrous DMF (3 ml) was treated with 1-(chloromethyl)-3-(trifluoromethyl)benzene (65 μl, 0.42 mmol) and DIPEA (73 μl, 0.42 mmol). The mixture was left to stir at rt under nitrogen for 3 days. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The crude product was purified on a silica SPE column using a DCM to load the material onto the column and wash through the impurities then a 0-5% MeOH/DCM gradient to elute the compound. The product fractions were combined and concentrated and the residues dissolved in anhydrous DMF (3 ml). The solution was degassed then Pd(PPh3)4 (30 mg, 0.027 mmol) and morpholine (156 μl, 1.8 mmol) were added and the mixture left to stir at rt under nitrogen for 3 h. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 0-5% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated by high vacuum to leave the title compound as a white solid (18 mg, 9%).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=[O:13].O[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1(C)C=CC=CC=1>S(=O)(=O)(O)O.O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][O:13][C:12](=[O:14])[CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][C:3]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:2]=1[CH3:1]
Reactant: OCc1ccccn1
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)OCc1ccccn1
Temperature: 5 °C

Procedure:
A mixture of 1.0 g of [o-(2-methyl-6-chloro-anilino)-phenyl]-acetic acid, 15 ml of 2-hydroxymethyl-pyridine and 15 ml of anhydrous toluene is treated with 2 drops of concentrated sulphuric acid. The solution is heated to 130°C for 1 hour, during which the resulting water is distilled off azeotropically with the toluene. A further 20 ml of anhydrous toluene are added and again distilled off. The solution is then poured onto 150 g of ice. The mixture is twice extracted with 50 ml of ether at a time. The combined ether extracts are shaken with 15 ml of 2 N-hydrochloric acid at 5°C. The hydrochloric acid solution is separated off and rendered alkaline with 2 N-sodium hydroxide solution at 5°C. The suspension is extracted with 50 ml of ether and the ether solution is separated off, washed with 10 ml of water, dried over magnesium sulphate and evaporated to dryness under 0.1 mm Hg at 40°C. The residue is crystallised from ether-petroleum ether. [o-(2-methyl-6-chloro-anilino)-phenyl]-acetic acid (2-pyridyl)-methyl ester melts at 80°-82°C.
Reaction SMILES: [CH:1]1([CH:4]([CH:12]2[CH2:14][CH2:13]2)[N:5]([CH2:9][CH2:10][CH3:11])[C:6]([NH2:8])=[S:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH:23]([CH3:34])[C:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])=O>C(O)C>[Cl:33][C:27]1[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:26]=1[C:24]1[N:8]=[C:6]([N:5]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH:12]2[CH2:13][CH2:14]2)[CH2:9][CH2:10][CH3:11])[S:7][C:23]=1[CH3:34]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: CCCN(C(N)=S)C(C1CC1)C1CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(C1CC1)C1CC1
Yield: 88 %

Procedure:
To 1 g of N-(dicyclopropylmethyl)-N-propylthiourea (Compound 88) dissolved in 25 ml of anhydrous ethanol, add 0.54 ml of triethylamine, then slowly 1 g of 2-bromo-1-(2,4-dichlorophenyl)-1-propanone (Compound 15). After two hours of heating under reflux of the ethanol, evaporate to dryness. Take up the residue in methylene chloride and wash with water until bromide ions have been removed completely. Dry the organic phase over anhydrous sodium sulphate and then evaporate to dryness. Purify the residue on a silica column, using a mixture of cyclohexane and ethyl acetate (20:1 V/V) as eluent, to obtain the expected product in the form of an oil.
Reaction SMILES: [OH:1][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H:5]([OH:6])[C@H:3]1[OH:4].C(=O)CCCC=O>P([O-])([O-])([O-])=O>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:8])[OH:6])[OH:4].[O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:8])[OH:6])[OH:4]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=CCCCC=O
Agent: O=P([O-])([O-])[O-]
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 60 °C

Procedure:
Pure lactose, demineralised whey and skimmed milk are used as lactose sources for the glutaraldehyde-treated DEAE-cellulose immobilised cells and the results obtained are given in the accompanying diagram, FIG. 10. A 5% solution of lactose in 50 mM phosphate buffer, pH 7.0 (line 1); a solution of demineralised, ultrafiltered whey containing 48.95 mg per ml of lactose and at pH 6.55 (line 2); and skim milk containing 48.50 mg per ml of lactose and at pH 6.86 (line 3), are eluted through a column maintained at 60° C. containing glutaraldehyde-treated DEAE-cellulose immobilised cells (bed volume 41 ml). The flow rates are 28.3, 29.5 and 29.5 ml per hour respectively for the three substrates. The amount of glucose/galactose formed in samples of eluate is determined and the percentage hydrolysis calculated.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.BrN1C(=O)CCC1=O.C(#N)N(C)C>C(OC)(=O)CC.[Hg]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[O:7][CH2:11]2
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=C1CCC(=O)N1Br
Agent: [Hg]
Solvent: CN(C)C#N
Solvent: CCC(=O)OC
Product: O=C1OCc2cc(Br)ccc21
Reaction time: 1 h

Procedure:
A solution of 0.43 g (2.0 mmol) of 4-bromo-2-methyl-benzoic acid, 0.34 g (1.9 mmol) of N-bromosuccinimide and 20 mg of azaisobutyronitrile in 7 ml of methyl propionate is heated to boiling for 1 hour under a nitrogen atmosphere and irradiated with a mercury vapour lamp. The reaction mixture is concentrated, taken up in methylene chloride, washed with H2O, dried with Na2SO4 and purified by flash chromatography (silica gel; ethyl acetate/petroleum ether=5:95 to 15:85).
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:14][C:15]([F:20])([F:19])[C:16](O)=O>>[F:14][C:15]([F:20])([F:19])[C:16]1[N:4]2[CH:5]=[CH:6][C:7]3[C:12]([C:3]2=[N:1][N:2]=1)=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3
Reactant: Cc1ccc2ccnc(NN)c2c1
Reactant: O=C(O)C(F)(F)F
Product: Cc1ccc2ccn3c(C(F)(F)F)nnc3c2c1
Yield: 20 %

Procedure:
A solution of 1-hydrazino-7-methylisoquinoline in excess trifluoroacetic acid was allowed to reflux for two hours. Removal of the excess acid in vacuo, treatment of the residue with sodium bicarbonate solution and filtration provided the crude product which was recrystallized from cyclohexane to give the product in a yield of 20%; m.p. 205°-206°C.
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])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].S(Cl)(Cl)=O.[CH2:30](O)[CH3:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:17]=1[C:18]([O:20][CH2:30][CH3:31])=[O:19]
Reactant: CCO
Reactant: COc1cc2nccc(Sc3ccc(F)cc3C(=O)O)c2cc1OC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(F)ccc1Sc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Yield: 83 %

Procedure:
2-(6,7-Dimethoxy-quinolin-4-ylsulfanyl)-5-fluoro-benzoic acid (76 mg) was suspended in ethanol (387 mg), and the suspension was cooled at 0° C. Thionyl chloride (50 mg) was gradually added dropwise thereto, and the mixture was then heated under reflux for 20 min. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was neutralized with a 20% aqueous sodium hydroxide solution and was then extracted with ethyl acetate. Next, the ethyl acetate layer was washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (68 mg, 84%).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]#[N:17].[CH3:18][N:19]1[CH:23]=[C:22](C=O)[CH:21]=[N:20]1.[CH2:26](OCC)C>C(O)C.O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2/[C:15](=[CH:26]/[C:21]1[CH:22]=[CH:23][N:19]([CH3:18])[N:20]=1)/[C:16]#[N:17]
Reactant: Cn1cc(C=O)cn1
Reactant: COc1ccc2[nH]cc(CC#N)c2c1
Reactant: CCOCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3ccn(C)n3)c2c1
Temperature: 50 °C

Procedure:
To a solution of sodium methanolate (204 mg, 3.8 mmol, 1.4 eq.) in anhydrous ethanol (30 mL) were added, under an argon atmosphere, (5-methoxy-1H-indol-3-yl)-acetonitrile (500 mg, 2.7 mmol, 1.0 eq.) and, after 30 minutes stirring, 1-methyl-1H-pyrazole-4-carbaldehyde (326 mg, 3.0 mmol, 1.1 eq.). The reaction apparatus was protected from light and the mixture heated at 50° C. for 18 hours. The reaction was allowed to cool to room temperature and then, the solvent was removed under reduced pressure and the crude taken up in ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4 and then, evaporated. The residue was purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 99/1 to 98/2) to afford, after trituration with diethyl ether, the compound (51) as a beige powder (640 mg, 85%). mp: 178° C.; 1H NMR (DMSO, 300 MHz) δ (ppm): 3.81 (3H, s, 5′-methoxy), 3.92 (3H, s, N-methyl), 6.90 (1H, dd, J6′-7′=8.7 Hz, J6′-4′=2.3 Hz, H6′), 7.37 (1H, d, J7′-6′=8.7 Hz, H7′), 7.38 (1H, m, H4′), 7.55 (1H, s, H3), 7.61 (1H, s, H2′), 8.00 (1H, s, H3″), 8.24 (1H, s, H5″), 11.43 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 38.8 (N-methyl), 55.6 (5′-methoxy), 101.5 (C2), 101.5 (C4′), 109.8 (C3′), 111.9 (C6′), 112.9 (C7′), 117.4 (C4″), 119.3 (C1), 124.0 (C3a′), 125.6 (C2′), 128.5 (C3), 131.0 (C5″), 132.1 (C7a′), 138.8 (C3″), 154.1 (C5′); MS: ESI-MS: m/z 264.1 ([M+H]+), 286.1 ([M+Na]+); HRESI-MS: m/z 301.1060 (calcd for C16H14N4ONa+, 301.1065); Anal. Calcd for C19H14N4O, 0.1 H2O: C, 68.61; H, 5.11; N, 20.00; O, 6.55. Found: C, 68.73; H, 5.33; N, 19.69.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:16]([O:18]C)=O)[C:8]([C:12]([O:14]C)=O)=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[C:7]3[C:16]([OH:18])=[N:31][N:30]([C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[C:12](=[O:14])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(NN)cc1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Yield: 112 %

Procedure:
To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (0.500 g, 1.69 mM) in ethanol (17mL) was added 4-methoxyphenyl hydrazine hydrochloride (2.07 g, 11.83 mM). Triethylamine (1.88 mL, 13.52 mM) was added, and the mixture was heated to reflux for 40 hours. The resulting suspension was filtered hot, and the collected solids were washed with ethanol to give the 4-methoxyphenyl hydrazine salt of the title compound (0.700 g) as a light tan solid. This material was heated to reflux in glacial acetic acid (20 mL) for 2 hours to give a brown suspension. The suspension was cooled to room temperature. The solids were collected and washed with glacial aceticacid, methanol and ether to give the title compound (0.331 g, 53%) as a tanpowder, mp 365° C. (decomp.); MS(CI): 370 (M+H). Analysis for C18H12ClN3O4 : Calculated: C, 58.50; H, 3.27; N, 11.36; Found: C, 58.29; H, 3.41; N, 11.14; NMR: 13.79 (br s, 1H, exchangeable), 8.22 (br d, J=8.70 Hz, 2H, 1H exchangeable), 7.88 (d, J=1.79 Hz, 1H), 7.57 (dd, J=1.79, 8.70 Hz, 1H), 6.78 (s, 4H), 3.67 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.Cl[S:9]([C:12]1[N:16]=[CH:15][N:14]([C:17](=[O:21])[N:18]([CH3:20])[CH3:19])[N:13]=1)(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([S:9]([C:12]2[N:16]=[CH:15][N:14]([C:17](=[O:21])[N:18]([CH3:19])[CH3:20])[N:13]=2)(=[O:10])=[O:11])[N:3]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: CN(C)C(=O)n1cnc(S(=O)(=O)Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(C)n(S(=O)(=O)c2ncn(C(=O)N(C)C)n2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
A mixture of 3,5-dimethylpyrazole (100 mg), 3-chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 54-a) (480 mg), anhydrous potassium carbonate (280 mg), and acetonitrile (1.5 ml) was heated and stirred for 2 hours on an oil bath at 50° C. The reaction solution was extracted with ethyl acetate-water. The organic layer was washed with saturated aqueous sodium chloride solution, and concentrated. The residue was subjected to a silica-gel column chromatography with 20 to 30% (20% 2-propanol/ethyl acetate)/hexane, and the title compound (210 mg) was obtained by crystallization in ethyl acetate-hexane.
Reaction SMILES: C([O:3][C:4]([C@:6]12[CH2:11][C@H:10]1[CH2:9][CH2:8][NH:7]2)=O)C.[NH3:12]>CO>[C@:6]12([C:4]([NH2:12])=[O:3])[CH2:11][C@H:10]1[CH2:9][CH2:8][NH:7]2
Reactant: N
Reactant: CCOC(=O)[C@]12C[C@H]1CCN2
Solvent: CO
Product: NC(=O)[C@]12C[C@H]1CCN2

Procedure:
A mixture of (1S,5R)-2-aza-bicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester (2.5 g, prepared by the procedure of Hercouet Tetrahedron Asymmetry 1996, 7, 1267-1268.) and 7 M ammonia in MeOH (20 ml) was heated in a sealed vessel at 80° C. for 5 days. The cooled RM was evaporated and triturated with hexanes/DCM to give the title compound as a beige solid. 1H-NMR (DMSO-d6, 400 MHz): 7.15 (s, 1H), 7.04 (s, 1H), 3.00-2.91 (m, 1H), 2.67 (q, 1H), 1.94-1.83 (m, 1H), 1.74-1.67 (m, 1H), 1.64-1.55 (m, 1H), 1.38-1.31 (m, 1H), 0.90 (t, 1H)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29](=[O:30])[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[CH:4][CH:3]=2)=[CH:35][CH:34]=1)[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(Cl)c1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3NC(C)CCc3cccc(Cl)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(3-chloro-phenyl)-1-methyl-propyl]-amine and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]1[CH:24]=[C:25](O)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:28]=[C:27]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Oc1cccc(F)c1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: N#Cc1ccc(N(CCOc2cccc(F)c2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 3-fluorophenol: MS (APCI) m/z 407 (M+1).