Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:28])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)C1C=CC=CC=1>[Pd].C1COCC1>[CH2:26]([O:25][C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9]([OH:28])=[O:8])=[CH:13][CH:14]=1)[CH3:27]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)OCc2ccccc2)cc1)OCC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of ethyl(2S)-3-{4-[2-(benzyloxy)-2-oxoethoxy]phenyl}-2-ethoxypropanoate (22.33 g, 57.8 mmol) in freshly distilled THF (290 mL) was added Pd/C (10%, 3.1 g) and the reaction mixture was hydrogenated under atmospheric pressure at room temperature overnight. The mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to afford 16.6 g (97%) of a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1[O:13][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:15][N:16]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:11][C:12]2[O:13][C:14]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)=[CH:15][N:16]=2)[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1

Procedure:
To a solution of 4-[2-(2-Methyl-5-nitro-phenylamino)-oxazol-5-yl]-benzonitrile (500 mg, 1.56 mmol) in ethanol (15 mL) was added tin(II) chloride dihydrate (677 mg, 3 mmol). The reaction mixture was heated under reflux for 4 h. The mixture was then concentrated, saturated aqueous NaHCO3 was added and the resultant suspension was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous MgSO4 and concentrated. The residue was alumina column chromatographed (dichloromethane/ethanol: 99/1). 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was obtained as pale yellow powder (172 mg, 38%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])([O-:3])=[O:2].BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:45]1(=[O:55])[NH:49][C:48](=[O:50])[C:47]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:46]12.[K]>C(Cl)(Cl)(Cl)Cl.[Cl-].[Na+].O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:49]2[C:48](=[O:50])[C:47]3=[CH:51][CH:52]=[CH:53][CH:54]=[C:46]3[C:45]2=[O:55])=[CH:6][C:5]=1[O:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:14])=[O:13])([O-:3])=[O:2]
Reactant: Cc1ccc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
A mixture of 4-nitro-3-trifluoromethanesulfonyloxytoluene (5.7 g, 20 mmol), N-bromosuccinimide (5.7 g, 32 mmol), and benzoyl peroxide (1 g) in carbon tetrachloride (75 mL) was refluxed for 18 h. The insoluble material formed was removed by filtration and the filtrate was concentrated. The residue was dissolved in DMF (40 mL) and potassium phthalimide (2.6 g, 14 mmol) was added. The mixture was stirred for 5 h at room temperature, poured into brine, and extracted with a 1:1 mixture of toluene and ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 9:1 to 1:1 hexane/ethyl acetate to give 3.4 g of the title compound (39%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:44]=[CH:45][CH:46]=2)[C:15]([NH:17][C:18]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:28]=[CH:27][C:19]=2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=O)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:48].C(=O)(O)[O-].[Na+]>COCCOC>[C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:44]=[CH:45][CH:46]=2)[C:15]([NH:17][C:18]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)(=[O:36])=[O:35])[CH:28]=[CH:27][C:19]=2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[S:48])[S:8][CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(OCc2nc(C(C)(C)C)cs2)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=S)c1cccc(OCc2nc(C(C)(C)C)cs2)c1
Reaction time: 5 h
Yield: 76.9 %

Procedure:
A mixture of ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (176 mg, 0.26 mmol), diphosphorus pentasulfide (69 mg, 0.31 mmol), sodium bicarbonate (28 mg, 0.33 mmol) and 1,2-dimethoxyethane (5 ml) was stirred for 5 hours with heating under reflux, and insoluble matter was removed by filtration. The resulting filtrate was diluted with ethyl acetate, washed with water and brine in that order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (eluent=hexane:ethyl acetate=3:1-2:1) to give ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]thiobenzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (143 mg, 0.20 mmol, 78%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:15]([OH:16])=[CH:14][N:13]=[CH:12][C:11]=1[OH:17])(C(C)(C)C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:26][C:27]1[C:28]([C:33]2[N:37]([CH:38]([CH3:40])[CH3:39])[N:36]=[CH:35][CH:34]=2)=[N:29][CH:30]=[CH:31][CH:32]=1>CN(C=O)C>[OH:8][CH2:9][C:10]1[C:11]([O:17][CH2:26][C:27]2[C:28]([C:33]3[N:37]([CH:38]([CH3:40])[CH3:39])[N:36]=[CH:35][CH:34]=3)=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:12][N:13]=[CH:14][C:15]=1[OH:16]
Reactant: CC(C)(C)[Si](C)(C)OCc1c(O)cncc1O
Reactant: CC(C)n1nccc1-c1ncccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1nccc1-c1ncccc1COc1cncc(O)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
A mixture of 4-((tert-butyldimethylsilyloxy)methyl)pyridine-3,5-diol (100 mg, 0.39 mmol, 2 eq.) and Cs2CO3 (381 mg, 1.17 mmol, 3 eq.) in DMF (15 mL) was stirred at rt for 30 min. To this mixture was added 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (53 mg, 0.39 mmol, 1 eq.) at rt. The mixture was continued to stir at rt O/N, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 4-(hydroxymethyl)-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)pyridin-3-ol (36 mg, 27%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.51 (dt, J=33.0, 16.5 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.69 (s, 1H), 7.47 (s, 1H), 7.33 (s, 1H), 7.21 (dd, J=7.8, 4.8 Hz, 1H), 6.10 (d, J=1.8 Hz, 1H), 4.84 (s, 2H), 4.68 (s, 1H), 4.44 (sep, 6.6 Hz, 1H), 1.24 (d, J=6.6 Hz, 6H). LRMS (M+H+) m/z 341.1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=[C:9](Br)[CH:8]=1)[CH3:2].N.[CH3:25][N:26](C)C=O>[C-]#N.[Zn+2].[C-]#N.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]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([C:25]#[N:26])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(Br)cc2c1OCC2
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: [C-]#N
Product: CCOC(=O)CN(CC(=O)OCC)c1cc(C#N)cc2c1OCC2
Temperature: 100 °C
Yield: 37 %

Procedure:
To N,N-dimethylformamide (50 ml) were added the compound (6.04 g, 15.6 mmol) obtained in step C, zinc cyanide (1.84 g, 15.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.61 g, 3.12 mmol), and the mixture was stirred with heating at 100° C. for 5 hr. The reaction mixture was cooled to room temperature, diluted aqueous ammonia was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (1.91 g, yield 37%) as a pale-bistered solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11](SC)=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:27][CH:28]([NH2:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([NH:33][CH:28]([CH3:27])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CSC(Nc1ccc2c(c1)OCO2)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(N)C(C)(C)C
Product: CC(NC(Nc1ccc2c(c1)OCO2)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)C(C)(C)C
Yield: 49 %

Procedure:
3-(Benzo[1,3]dioxol-5-ylamino-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.327 g, 0.8 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 22 h at 100° C. under nitrogen in a sealed flask. Work up as described in Example 1, 2) gave 182 mg (49%) of the title compound. Mp 160.5-162° C. 1H NMR (200 MHz, CDCl3): δ=0.78 (s, 9H), 0.9 (d, 3H), 3.22 (m, 1H), 6.0 (br s, 2H), 6.48 (m, 2H), 6.78 (br d, 1H), 7.48 (d,2H), 7.83 (d, 2H). MA C22H24ClN3O4S.0.30 H2O (corrected bruttoformula); calc 56.54%; C, 5.31%; H, 8.99%; found 56.47%; C, 5.25%; H, 8.90%; N,
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[C:25]1[N:26]=[C:27]2[C:33]([C:34]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][NH:31][C:28]2=[N:29][CH:30]=1.CN(C=O)C>O.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.[Cu](I)I>[C:37]([NH:36][C:34]([C:33]1[C:27]2[C:28](=[N:29][CH:30]=[C:25]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:26]=2)[NH:31][CH:32]=1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Agent: I[Cu]I
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: O
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Temperature: 25 °C
Yield: 82 %

Procedure:
The mixture of 6-fluoro-3-(tributylstannyl)-1H-indazole (500 mg, 1.17 mmol), 2-bromo-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (258 mg, 0.9 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol), copper iodide (10 mg 0.052 mmol) in 15 ml, of dry DMF was heated to 90° C. for 2.5 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with 50 mL of water and filtered. The solid was washed with dichloromethane and hot methanol, then filtered to give N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as a yellow solid (260 mg, 82%). 1H NMR (300 MHz, DMSO): δ 13.82 (s, 1H), 12.96 (s, 1H), 9.10 (s, 1H), 8.48-8.43 (m, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.44-7.41 (m, 1H), 7.12-7.06 (m, 1H), 3.14 (d, 1H, J=5.1 Hz), 1.51 (s, 9H). LCMS: 353.0, [M+H]+.
Reaction SMILES: O.O.Cl[Sn]Cl.Cl.[N+:7]([C:10]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[C:13]([I:20])[C:11]=1[NH2:12])([O-])=O.[OH-].[Na+].CO.[CH3:25]COC(C)=O>>[I:20][C:13]1[C:11]2[N:12]=[CH:25][NH:7][C:10]=2[CH:16]=[C:15]([NH2:17])[CH:14]=1
Reactant: CCOC(C)=O
Reactant: Nc1c(I)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cc(I)c2nc[nH]c2c1
Yield: 33 %

Procedure:
A solution of 10 g of SnCl2.2H2O and 20 ml of HCl was added into 2,4-dinitro-6-iodoaniline (4.1 g, 13 mmol) and resulting reaction mixture was stirred at reflux for 48 h. The reaction mixture was then basified by adding 15% aq. NaOH and extracted with CHCl3 several times. Combined extracts ere dried over MgSO4 and concentrated in vacuo, yielding oily residue which was subjected to column chromatography (5% MeOH/EtOAc) to yield 1.1 g (4.4 mmol, 33%) of the amine. The amine was stirred at ref lux in 10 ml of formic acid and 10 ml of acetic anhydride for 12 h. The reaction mixture was concentrated in vacuo to yield an oily residue which was stirred in 30 ml of HCl sat'd EtOH for 2 h. The oily reaction mixture after concentration was subjected to column chromatography (5% NH, sat'd MeOH/EtOAc) to provide 0.69 g (2.7 mmol,60%) of the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:16])=[C:8]([CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14])[CH:9]=1)(=[O:3])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[Cl:16][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:19][N:20]([CH3:22])[CH3:21])=[CH:9][C:8]=1[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)NCc1cc(C(C)=O)ccc1Cl
Solvent: Cc1ccccc1
Product: COC(=O)NCc1cc(C(=O)C=CN(C)C)ccc1Cl
Temperature: 135 °C
Yield: 81.2 %

Procedure:
To a solution of methyl N-[(5-acetyl-2-chlorophenyl)methyl]carbamate (10 g, 41.5 mmol) (prepared by the method given in European Patent Publication EP 1586552) in toluene was added N,N-dimethylformamide dimethyl acetal (9.88 g, 82.9 mmol) and the reaction mixture was heated at 135° C. for 2 days. TLC analysis (50% ethyl acetate/pet ether) showed the reaction was complete. The solvent was evaporated under vacuum and water was added to the residue. The water layer was extracted with ethyl acetate three times. The combined the organic phases were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to give the title compound (10 g, 81% yield) as solid.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:18])[O:11][CH:12]([CH2:15][CH2:16][I:17])[C:13]=1[OH:14])C1C=CC=CC=1.C(OC(=O)C)(=O)C.N1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl.[Cl-].[Na+].O>[OH:8][C:9]1[C:10](=[O:18])[O:11][CH:12]([CH2:15][CH2:16][I:17])[C:13]=1[OH:14]
Reactant: O=C1OC(CCI)C(O)=C1OCc1ccccc1
Agent: ClB(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C1OC(CCI)C(O)=C1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a dry flask flushed with argon was added 0.72 g (2.0 mmol) of 3-benzyloxy-4-hydroxy-5-(2-iodoethyl)-2(5H)-furanone and 10 mL of CH2Cl2. The solution was cooled with stirring in an ice-water bath, and 0.38 mL (4.0 mmol) of acetic anhydride and 0.34 mL (4.2 mmol) of pyridine were added. The ice bath was removed and the solution was stirred for 1 hour. All volatile substances were removed in vacuo (2 h at 1 mm Hg, 25° C.). Argon was introduced to the reaction flask and the residue was taken up in 20 mL of dry CH2Cl2, cooled to −78° C. and 5.2 mL (2.6 mmol) of 1.0M BCl3 in CH2Cl2 was added with stirring. The reaction mixture was kept at −78° C. for 1 hour and at room temperature for 30 minutes. The mixture was poured into 50 mL of brine and extracted with 3×30 mL of ether. The combined ether extracts were washed with 5 mL of H2O and extracted into saturated NaHCO3 solution (3×15 mL). The bicarbonate fractions were pooled and washed with 15 mL of ether, acidified to pH 1 with 25% aqueous HCl solution, and extracted with 3×30 mL of ether. The ether extracts were combined and washed with 15 mL of brine, dried (MgSO4) and concentrated to provide 360 mg (67% yield) of 3,4-dihydroxy-5-(2-iodoethyl)-2(5H)-furanone as a white crystalline solid: mp 150-151° C.; 1H NMR (acetone-d6) δ 4.80 (dd, 1H, J=3.5, 8.0 Hz), 3.50-3.25 (m, 2H), 2.60-2.35 (m, 1H), 2.20-1.95 (m, 1H). Anal Calcd for C6H7O4I: C, 26.69; H, 2.61. Found: C, 26.54; H, 2.59.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:18]=[C:19]([C:24]([I:27])=[CH:25][N:26]=2)[C:20]([O:22]C)=[O:21])=[C:14]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[OH-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[F:34][C:2]([F:1])([F:33])[C:3]([C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:18]=[C:19]([C:24]([I:27])=[CH:25][N:26]=2)[C:20]([OH:22])=[O:21])=[C:14]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cc(C(=O)OC)c(I)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cc(C(=O)O)c(I)cn1
Yield: 100.3 %

Procedure:
To a solution of methyl 2-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-5-iodoisonicotinate (450 mg, 0.741 mmol) in methanol (3.5 mL), 3N aqueous solution of sodium hydroxide (3.5 mL) was added and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, 5% aqueous solution of hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate were added, extracted with chloroform/methanol, and the organic layer was dried using sodium sulfate. After filtration, the filtrate was concentrated in vacuo, and 2-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-5-iodoisonicotinic acid (441 mg, yield >100%) was obtained as a yellow oil.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][N:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[C:1]1([C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][N:21]=2)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Product: CCOC(=O)c1ccnc(-c2ccccc2)c1

Procedure:
Phenylboronic acid (147 mg) and ethyl 2-chloroisonicotinate (200 mg) were treated in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-])=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH2:36]([C:38]1[C:46]2[C:45]([NH2:47])=[CH:44][CH:43]=[CH:42][C:41]=2[N:40]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=2)[N:39]=1)[CH3:37]>CN1C(=O)CCC1>[CH2:36]([C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][C:45]=2[NH:47][C:20]([C:17]2[N:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:12][C:13]3=[N:19][CH:18]=2)=[O:21])[N:40]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=2)[N:39]=1)[CH3:37]
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Reactant: CCc1nn(Cc2ccc(F)cn2)c2cccc(N)c12
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: CCc1nn(Cc2ccc(F)cn2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)CC5)ccn34)c12
Temperature: 0 °C
Yield: 17.4 %

Procedure:
To lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.108 g, 0.331 mmol) was added NMP (2 mL). The mixture was stirred with warming under nitrogen to form a solution. The solution was cooled to 0° C. and 2,4,6-trichlorobenzoyl chloride (0.0518 ml, 0.324 mmol) was added drop wise. The mixture was stirred for one hour at ambient temperature. 3-Ethyl-1-((5-fluoropyridin-2-yl)methyl)-1H-indazol-4-amine (0.064 g, 0.237 mmol) was then added and the reaction mixture heated to 88° C. for 16 hours. The mixture was allowed to cool and then concentrated under reduced pressure to remove the majority of the NMP. To this residue was added a 10% aqueous solution of sodium hydroxide (5 mL). The resulting clear solution was stirred at 80° C. for 30 minutes and then cooled to ambient temperature. The mixture was extracted multiple times with DCM. The combined organic phases were dried (sodium sulfate) and concentrated under reduced pressure (bath temperature at 80° C. to remove remaining NMP). To the resulting residue was added ether in order to triturate. The resulting solids were collected by filtration, dissolved in DCM and subjected to purification on silica using a Biotage system, eluting with a gradient of 1-10% 7N NH3 in MeOH/DCM. The resulting product was triturated with ether containing a small amount of DCM to give N-(3-ethyl-1-((5-fluoropyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide (23 mg). MS (APCI) m/z=557.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14](F)=[CH:13][C:12]=2[F:21])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[CH3:22][CH2:23][CH2:24][CH2:25][O:26][C:27]([CH2:29][OH:30])=[O:28].[F-].[K+].O>O1CCOCC1>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([O:30][CH2:29][C:27]([O:26][CH2:25][CH2:24][CH2:23][CH3:22])=[O:28])=[CH:13][C:12]=2[F:21])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: CCCCOC(=O)CO
Reactant: O=[N+]([O-])c1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1F
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCOC(=O)COc1cc(F)c(-n2nc3c(c2Cl)CCCC3)cc1[N+](=O)[O-]
Yield: 75.1 %

Procedure:
A suspension of 3-chloro-2-(2,4-difluoro-5-nitrophenyl)-4,5,6,7-tetrahydro-2H-indazole (10 g), butyl glycollate (5 g) and potassium fluoride (10 g) in dioxane (30 g) was refluxed for 1 hour. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was purified by liquid column chromatography using a mixture of hexane and ethyl acetate as an eluent to give 3-chloro-2-(2-fluoro-4-butyloxycarbonylmethoxy-5-nitro-phenyl)-4,5,6,7-tetrahydro-2H-indazole (10.2 g). m.p., 138°-139° C.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:30][N:31]1[CH:35]=[C:34]([S:36](Cl)(=[O:38])=[O:37])[C:33]([C:40]([F:43])([F:42])[F:41])=[N:32]1>C(Cl)Cl>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:2]([NH:1][S:36]([C:34]2[C:33]([C:40]([F:43])([F:41])[F:42])=[N:32][N:31]([CH3:30])[CH:35]=2)(=[O:38])=[O:37])[CH2:3][CH2:4]3)[CH:16]=1
Reactant: NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Reactant: Cn1cc(S(=O)(=O)Cl)c(C(F)(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(S(=O)(=O)NC2CCc3cc(Cn4cc(CO)c(C(F)(F)F)n4)ccc32)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.096 mmol, 30 mg) and triethylamine (0.193 mmol, 0.027 mL, 19.50 mg) in DCM (0.9 mL) was added 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride (0.096 mmol, 23.96 mg) and the whole stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue purified by RP-HPLC to give a clear film (12.0 mg, 0.023 mmol, 23.8%). MS (ESI): m/z [M+H]+ 524.0.