Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[C:23]([F:24])=[CH:22][C:21]([NH:25][C:26]([C:28]3([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])[CH2:30][CH2:29]3)=[O:27])=[C:20]([F:41])[CH:19]=2)[CH:14]=[CH:13][N:12]=1)=[O:9])C1C=CC=CC=1.Cl.[OH:43][CH:44]1[CH2:47][NH:46][CH2:45]1.C(=O)([O-])O.[Na+]>CCCCCC.C(N(CC)CC)C.CN(C)C=O>[F:41][C:20]1[CH:19]=[C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([N:46]3[CH2:47][CH:44]([OH:43])[CH2:45]3)=[O:9])[CH:16]=2)[C:23]([F:24])=[CH:22][C:21]=1[NH:25][C:26]([C:28]1([C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])[CH2:29][CH2:30]1)=[O:27]
Reactant: OC1CNC1
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)N1CC(O)C1
Reaction time: 0.17 h
Yield: 45.1 %

Procedure:
Triethylamine (0.100 ml) was added to a mixture of benzyl 1-({[4-({2-[(phenoxycarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]amino}carbonyl)cyclopropanecarboxylate (200 mg), 3-hydroxyazetidine hydrochloride (39.1 mg) and N,N-dimethylformamide (4.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 6 hours and 10 minutes. 3-Hydroxyazetidine hydrochloride (10.0 mg) and triethylamine (0.025 ml) were added at room temperature, and the mixture was stirred for 1 hour and 20 minutes. A saturated aqueous solution of sodium hydrogencarbonate (16 ml) and hexane (5 ml) were added to the mixture, and the precipitated solid was collected by filtration. The solid was washed with water (2 ml, three times), and dried under aeration. The resultant solid was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). The fractions containing the target compound was concentrated under reduced pressure to give the title compound (86.7 mg, 45%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)C(F)(F)F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@@H]1CCNC1)C(F)(F)F
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a stirred solution of 1,1-dimethylethyl(3S)-3{[(trifluoroacetyl)amino]methyl}-1-pyrrolidinecarboxylate (2.96 g, 10.0 mmole), in CH2Cl2 (50 mL) at RT was added TFA (25 mL). After 2 h, the reaction contents were concentrated under vacuum. The remaining residue was dissolved in (CHCl3/i-PrOH, 10:1) and washed with saturated aqueous NaHCO3. The organic phase was separated and dried over Na2SO4. Concentration under vacuum afforded the title compound (1.86 g, 95%) as a yellow oil: LC-MS (ES) m/e 197 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:26]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:8]([NH2:28])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:30][CH2:31][CH2:32][CH3:33]>>[NH2:28][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:26])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:25]1
Reactant: CCCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCCC3CCN(CCCC)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[5-(4-piperidinyl)pentyl]-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5]C=CC=1.[CH2:8]1[O:10][C@H:9]1[CH2:11]Cl.N1CCCCC1.[OH-:19].[Na+].Cl>CN(C)C=O>[CH2:11]([O:7][CH2:1][CH:6]1[O:19][CH2:5]1)[CH:9]1[O:10][CH2:8]1
Reactant: [OH-]
Reactant: Oc1ccccc1
Reactant: ClC[C@H]1CO1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: C(OCC1CO1)C1CO1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
The starting phenol derivative (10.0 g) of the following formula: ##STR19## and the same R-(-)-epichlorohydrin (18.6 g) as used in Preparation 2, piperidine (367 ml) and dimethylformamide (1 ml) are mixed and stirred at 60° C. for 10 hours. The reaction mixture is distilled under reduced pressure to remove the solvent, and thereto is added acetone (5 ml) and further added dropwise 24 wt. % aqueous sodium hydroxide (1.2 equivalent) with stirring at room temperature, and the mixture is reacted for 30 minutes. The reaction mixture is adjusted to pH 7 with 2N hydrochloric acid and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue is purified by silica gel chromatography to give S isomer of glycidyl ether (1.58 g) of the following formula: ##STR20##
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21].[NH:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1>>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([N:6]1[CH:7]([C:24]2[NH:23][CH:27]=[CH:26][CH:25]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:21]
Reactant: O=C(Cl)c1ccco1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: c1cc[nH]c1
Product: O=C(c1ccco1)N1c2ccccc2-c2ccccc2C1c1ccc[nH]1

Procedure:
Furan-2-yl-[6-(1H-pyrrol-2-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, 2-furoyl chloride, and pyrrole according to GP 2. Yield, 25%. 1H-NMR (DMSO-d6): δ=5.16 (s, 1H), 5.68 (q, J=2.7 Hz, 1H), 6.52-6.59 (m, 2H), 6.74 (s, 1H), 6.78 (d, J=3.3 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 7.11 (td, J=7.7 Hz, J=1.1 Hz, 1H), 7.22 (td, J=7.5 Hz, J=1.2 Hz, 1H), 7.39 (td, J=7.4 Hz, J=0.9 Hz, 1H), 7.44-7.54 (m, 2H), 7.68 (s, 1H), 7.91 (dd, J=7.9 Hz, J=1.1 Hz, 1H), 8.00 (d, J=7.6 Hz, 1H), 10.61 (s, 1H); (+)-ESI-MS: m/z=274 [M-pyrrole]+.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.CN(C=O)C.C(N(CC)CC)C.[CH2:28]([O:30][SiH:31]([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])[CH3:29]>CCOCC>[CH2:28]([O:30][Si:31]([O:35][CH2:36][CH3:37])([O:32][CH2:33][CH3:34])[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[CH3:29]
Reactant: O=C(c1ccccc1)c1ccc(I)cc1
Reactant: CCO[SiH](OCC)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCO[Si](OCC)(OCC)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
[Rh(cod)(MeCN)2]BF4 (11.0 mg, 0.0300 mmol, 0.0300 equiv) and 4-iodobenzophenone (307 mg, 1.00 mmol, 1.00 equiv) were charged in 10 mL vial capped with a rubber septum. The vial was evacuated and backfilled with nitrogen. To this vial, DMF (4 mL), triethylamine (0.420 mL, 3.00 mmol, 3.00 equiv) and triethoxysilane (0.360 mL, 2.00 mmol, 2.00 equiv) were added. The reaction mixture was stirred at 80° C. for 2 h, then cooled to 23° C. The mixture was diluted with ether (50 mL) and washed three times with water (3×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Kugelrohr distillation to give 275 mg of the title compound as a colorless oil (80% yield). Rf=0.45 (hexanes/EtOAc 3:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23° C., δ): 7.82−7.77 (m, 6H), 7.59 (t, J=7.5 Hz, 1H), 7.48 (dd, J=7.5 Hz, 7.5 Hz, 2H), 3.90 (q, J=7.0 Hz, 6H), 1.27 (t, J=7.0 Hz, 9H). 13C NMR (125 MHz, CDCl3, 23° C., δ): 196.84, 139.05, 137.29, 136.34, 134.66, 132.54, 130.11, 129.00, 128.28, 58.91, 18.21. Mass Spectrometry: HRMS-FIA (m/z): Calcd for [M+Na]+, 367.13361. Found, 367.13347.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH2:35][CH3:36])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:37][Li].[Cl-].[NH4+]>O1CCCC1>[CH2:35]([C:11]1[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([OH:3])([CH3:37])[CH3:2])[CH:5]=2)[C:15](=[O:16])[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=1)[CH3:36]
Reactant: CCCc1nc(CC)n(-c2cccc(C(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1nc(CC)n(-c2cccc(C(C)(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 4′-{[1-(3-acetylphenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.63 g) in tetrahydrofuran (10 mL) was added methyllithium (1.2 mL, 2.2 M diethyl ether solution) under ice-cooling, and the mixture was stirred for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.54 g, 83%).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1>CO>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:2][CH3:1])=[O:11])=[C:6]([CH2:10][OH:9])[CH:5]=1
Reactant: CN
Reactant: O=C1OCc2cc(Cl)ccc21
Solvent: CO
Product: CNC(=O)c1ccc(Cl)cc1CO
Temperature: 25 °C

Procedure:
Methylamine gas was condensed into a sealed tube at −78° C., and a solution of 5-chloro-2-benzofuran-1(3H)-one (6.68 g, 39.8 mmol) in methanol (30 mL) was added. The solution was slowly warmed to room temperature overnight; The reaction was concentrated in vacuo, and the residue was partitioned between water and and chloroform. After three extractions with chloroform, the combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-chloro-2-(hydroxymethyl)-N-methylbenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[NH:17][C:16]2=[O:26])=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([CH3:14])[CH3:13])[CH2:7]2.[C:27](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:27])[C:16]2=[O:26])=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([CH3:13])[CH3:14])[CH2:7]2
Reactant: O=C([O-])[O-]
Reactant: CC(C)N1Cc2c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)ccc(Cl)c2C1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CC(C)N1Cc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)ccc(Cl)c2C1=O
Reaction time: 18 h
Yield: 70.3 %

Procedure:
A solution of 0.90 gram (0.0023 mole) of 3-[7-chloro-2-(1-methylethyl)-isoindolin-1-on-4-yl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 0.42 gram (0.0030 mole) of potassium carbonate, and 0.45 gram (0.0030 mole) of methyl iodide in 60 mL of DMF was stirred at 25 C. for about 18 hours. The reaction mixture was then poured into water and extracted with diethyl ether. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of methylene chloride and EtOAc as eluants. The fractions containing product were combined and concentrated under reduced pressure, yielding about 0.65 gram of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[N:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cncc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1cncc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of 6-chloro-pyrazin-2-ylamine (50 mg, 0.38 mmol) in acetic acid (1.9 mL) was treated with acetic anhydride (0.04 mL, 0.42 mmol). The mixture was heated to reflux for 1 h, cooled to room temperature, then poured into saturated NaHCO3 (30 mL) and extracted with ethyl acetate (2×30 mL). The organic layers were combined, washed with brine, dried (Na2SO4), filtered, and concentrated to dryness to give the title compound I-5a (58.6 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C.[Pd]>[N:10]1([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(O)c1
Agent: [Pd]
Solvent: CCO
Product: Oc1cccc(CN2CCCCC2)c1

Procedure:
3-Hydroxybenzaldehyde (15 g) and piperidine (15 ml) in ethanol (500 ml) were hydrogenated over 10% palladium/carbon catalyst. The catalyst was removed by filtration and the solvent was evaporated off. The residue was triturated with light petroleum (b.p. 60°-80°) and the resulting solid was recrystallised from acetonitrile to give the title compound as a buff coloured solid (8.7 g) m.p. 134°-7°. TLC silica, methanol, Rf 0.56.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1(C(O)=O)[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[NH:4]1.S(Cl)(Cl)=O.[NH:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[S:40]([NH:43]C(C)(C)C)(=[O:42])=[O:41])=[CH:31][CH:32]=2)[CH2:27][CH2:26]1.[H-].[Na+].C1C[O:53][CH2:52]C1>C(#N)C>[C:14]([C:10]1[CH:9]=[C:8]([N:5]2[C:6]([C:52]([N:25]3[C:33]4[C:28](=[CH:29][C:30]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[S:40]([NH2:43])(=[O:42])=[O:41])=[CH:31][CH:32]=4)[CH2:27][CH2:26]3)=[O:53])=[CH:7][C:3]([C:2]([F:1])([F:19])[F:20])=[N:4]2)[CH:13]=[CH:12][CH:11]=1)#[N:15]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc2c(c1)CCN2
Reactant: C1CCOC1
Reactant: N#Cc1cccc(N2C=CC(C(=O)O)(C(F)(F)F)N2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: N#Cc1cccc(-n2nc(C(F)(F)F)cc2C(=O)N2CCc3cc(-c4ccccc4S(N)(=O)=O)ccc32)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To the solution of 3-(trifluoromethyl)-1-(3-cyanophenyl)-1H-pyrazolecarboxylic acid (0.2 g, 0.6 mmol) in dry acetonitrile (10 mL) was added thionyl chloride (0.37 g, 1.8 mmol). The reaction mixture was warmed up to 50° C. for 1 h. The solvent and excess thionyl chloride were removed under reduced pressure and dried on a vacuum pump over 18 h. This residue was dissolved in THF and treated with a mixture of 2-(2,3-dihydro-1H-indol-5-yl)-N-(1,1-dimethylethyl)benzenesulfonamide from Example 1 (0.3 g, 0.8 mmol) in THF (5 mL) and NaH (72 mg, 1.6 mmol). The reaction mixture was allowed to stir at ambient temperature for 0.5 h, then quenched with water and extracted with EtOAc (3×). Ethyl acetate extracts were dried over sodium sulfate and concentrated. The crude residue was purified by flash chromatography (hexane/EtOAc, 1:3) to afford the title product (0.38 g, 92%). LRMS (ES+): 593.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Cl[C:11]1[C:12](=[O:27])[N:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:14]=[C:15]([Cl:17])[N:16]=1>>[Br:8][C:7]1[C:2]([NH:1][C:11]2[C:12](=[O:27])[N:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH:14]=[C:15]([Cl:17])[N:16]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: COc1ccc(Cn2cc(Cl)nc(Cl)c2=O)cc1
Product: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(Cl)cc3Br)c2=O)cc1
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield from 2-amino-3-bromo-5-chloropyridine and 3,5-dichloro-1-(4-methoxy-benzyl)-1H-pyrazin-2-one in a manner analogous to that for the preparation of Compound 26. 1H NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1H), 8.51 (d, 1H, J=2.4 Hz), 8.40 (d, 1H, J=2.4 Hz), 7.51 (s, 1H), 7.36 (d, 2H, J=8.8 Hz), 6.92 (d, 2H, J=8.8 Hz), 5.00 (s, 2H), 3.73 (s, 3H). MS (ES) [m+H] calc'd for C17H13BrCl2N4O2, 455, 457, 459; found 455, 457, 459.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: OC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CC(C)=O
Product: O=C(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Yield: 95 %

Procedure:
To a suspension of (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-(7-fluoro-quinolin-6-yl)-methanol (1.8 g, 5.48 mmol) in acetone (200 mL) was added 2-iodoxybenzoic acid (8.52 g, 45%, 13.69 mmol) and the reaction mixture was stirred at reflux for 1 day. The solvent was removed under reduced pressure and the residue was dissolved in 200 mL of water. The solution was basified by 3N NaOH solution and the precipitate was collected, washed with water and dried over vacuum oven to afford 1.7 g (yield: 95%) title compound as a gray solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.04 (dd, 1H), 8.56 (d, 1H), 8.47 (m, 2H), 8.41 (s, 1H), 7.92 (d, 1H), 7.75 (d, 1H), 7.64 (q, 1H). LCMS (method B): [MH]+=327, tR=2.03 min.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.[CH:30]1[C:35]([NH:36][C:37]([CH2:39]Cl)=[O:38])=[CH:34][CH:33]=[C:32]([F:41])[CH:31]=1>>[F:41][C:32]1[CH:31]=[CH:30][C:35]([NH:36][C:37]([CH2:39][N:18]2[CH:17]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:9]=3[CH3:28])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19]2(=[O:27])=[O:26])=[O:38])=[CH:34][CH:33]=1
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: O=C(CCl)Nc1ccc(F)cc1
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2CC(=O)Nc2ccc(F)cc2)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and alpha-chloro-4-fluoroacetanilide. 1H NMR (DMSO-d6) δ 8.06-8.03 (m, 1H), 7.70-7.62 (m, 2H), 7.51-7.46 (m, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.17-7.13 (m, 2H), 7.02 (t, J=8.1 Hz, 1H), 6.80 (t, J=7.5 Hz, 1H), 6.72 (bs, 1H), 6.55 (s, 1H), 5.00 (s, 2H), 4.15 (d, J=17.4 Hz, 1H), 3.40 (d, J=17.4 Hz, 1H), 2.39 (s, 3H); MS: ESI (negative): 506 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17](=[O:18])[CH:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[CH2:25]([SH:27])[CH3:26]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17](=[O:18])[C:16]([S:27][CH2:25][CH3:26])=[C:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCCC1=CC(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O
Reactant: CCS
Solvent: CO
Product: CCCC1=C(SCC)C(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O
Temperature: 0 °C

Procedure:
To a suspension of 2-(4-methoxybenzyl)-3-methyl-5-propyl-4,7-benzofurandione (from Example 28) (0.988 g, 3.05 mmol)in MeOH (23 mL) was added ethanethiol (2.5 mL). After a few minutes, the yellow quinone passed into solution giving a reddish colour. The reaction was cooled to 0° C. and solid FeCl3 (2.5 g) was added. The reaction was quenched 10% HCl and extraction with CH2Cl2 afforded the crude product which was chromatographed on silica gel (5% EtOAc/hexane) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH3:35])[CH:9]([CH3:23])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=O)[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[Cl:46])[C:40](Cl)=[O:41].P([O-])([O-])([O-])=O>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH3:35])[CH:9]([CH3:23])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]#[N:22])[CH:19]=1)[N:16]([C:40](=[O:41])[C:39]1[CH:43]=[CH:44][C:45]([Cl:46])=[C:37]([Cl:36])[CH:38]=1)[CH2:15][CH2:14]2)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)NCC2
Agent: O=P([O-])([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc(C#N)c2c(c1)CCN2C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.5 %

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide (97 mg) in methylene chloride (1 ml) and pyridine (1 ml) was added 3,4-dichlorobenzoyl chloride (84 mg), and the mixture was stirred at room temperature for 20 hours. The pH of the reaction mixture was adjusted to pH 7 with phosphate buffer solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and ethyl acetate (4/1) as eluent to give 98 mg of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]-1-(3,4-dichlorobenzoyl)indoline-7-carbonitrile as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[NH:15][N:14]=[C:13]([CH3:16])[C:8]=2[C:9]([OH:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24].CN(C)C=O>O.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[NH:15][N:14]=[C:13]([CH3:16])[C:8]=2[C:9]([O:12][CH2:23][CH3:24])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cnc(O)c2c(C)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnc(OCC)c2c(C)n[nH]c12

Procedure:
2.2g. of 4-hydroxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester (0.01 mol.), 2.8 g. of potassium carbonate (0.02 mol.), and 1.6 g. of ethyl iodide (0.01 mol.) are suspended in 50 ml. of dimethylformamide and heated for 10 hours at 70°. After this time, the mixture is acidified with acetic acid and 30 ml. of water are added. 4-Ethoxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester precipitates, is filtered and recrystallized from methanol, yield 1.9 g. (79%), m.p. 200°.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9](=[O:12])[CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl/[C:21](=[N:27]\[OH:28])/[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[O:28][N:27]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:8]=2[C:9](=[O:12])[CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)/C(Cl)=N/O
Reactant: CCC(=O)C#Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1noc(-c2ccccc2)c1C(=O)CC
Temperature: 120 °C
Reaction time: 16 h
Yield: 23.2 %

Procedure:
To a solution of 1-phenylpent-1-yn-3-one (36.7 mg, 0.232 mmol) and triethylamine (0.113 mL, 0.812 mmol) in toluene (1 mL) at 120° C. was added (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (105 mg, 0.696 mmol) in toluene (1 mL) dropwise. The reaction mixture was stirred at 120° C. for 16 h. To the reaction mixture was added additional (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (105 mg, 0.696 mmol) and triethylamine (0.113 mL, 0.812 mmol), and the reaction mixture was stirred at 140° C. for 3 days. The reaction mixture was concentrated, diluted with ethyl acetate (5 mL), washed with water (1 mL), washed with a saturated aqueous solution of sodium bicarbonate (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (10/1) afforded ethyl 5-phenyl-4-propionylisoxazole-3-carboxylate (14.7 mg). The compound had an HPLC ret. time=3.15 min.−Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: 274+.