Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([O:22]C)[C:10]2[C:19]3[NH:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13](=[O:20])[NH:12][C:11]=2[CH:21]=1)[CH3:5].B(Br)(Br)Br.O>ClCCl>[CH3:5][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([OH:22])[C:10]2[C:19]3[NH:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13](=[O:20])[NH:12][C:11]=2[CH:21]=1)[CH3:3]
Reactant: COc1cc(CN(C)C)cc2[nH]c(=O)c3c(c12)NCCC3
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN(C)Cc1cc(O)c2c3c(c(=O)[nH]c2c1)CCCN3
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
8-[(Dimethylamino)methyl]-10-methoxy-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5-(6H)-one (28 mg, 0.084 mmol) prepared in Example 72 was dissolved in dichloromethane (10 ml), added dropwise with boron tribromide (0.6 mmol, 152 mg) at 0° C. The mixture was stirred at room temperature for 2 hours and then water was added carefully. The solution was washed with chloroform, the water layer was concentrated under reduced pressure, and the residue was purified by flash column chromatography (chloroform:ethanol=1:5) to obtain the title compound (14 mg, yield: 58%, white solid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH:18](O)[CH3:19])=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:33]([CH:18]([C:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[CH3:19])=[N+:34]=[N-:35]
Reactant: CC(O)c1ccc2cccnc2c1-c1ccccc1F
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(N=[N+]=[N-])c1ccc2cccnc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-[8-(2-fluorophenyl)quinolin-7-yl]ethanol (0.039 g, 0.14 mmol) in methylene chloride (0.9 mL) was added triethylamine (0.0305 mL, 0.22 mmol), followed by methanesulfonyl chloride (0.014 mL, 0.18 mmol). After stirred at room temperature for 30 minutes, the resultant mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The crude mesylate was dissolved in N,N-dimethylformamide (0.4 mL) and treated with sodium azide (0.0474 g, 0.73 mmol) at room temperature overnight. After diluting with ethyl acetate, the mixture was washed with water and brine, dried over magnesium sulfate and then evaporated to dryness. The crude product was used in next step (33 mg, 77%). LCMS calculated for C17H14FN4(M+H)+: m/z=293.1; found: 293.1.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([CH3:14])[NH:6][N:5]=1.[H][H].Br[CH2:18][CH2:19][O:20][CH3:21]>C1COCC1>[CH3:21][O:20][CH2:19][CH2:18][N:6]1[C:7]([CH3:14])=[C:8]([C:9]([OH:11])=[O:10])[C:4]([CH3:3])=[N:5]1
Reactant: [H][H]
Reactant: CCOC(=O)c1c(C)n[nH]c1C
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCn1nc(C)c(C(=O)O)c1C
Yield: 34 %

Procedure:
Sodium hydride (60%, 120 mg, 3.0 mmol) was suspended in THF (2 ml) at 0 C. Ethyl 3,5-dimethyl-1H-pyrazole-4-carboxylate (168 mg, 1.0 mmol) dissolved in THF (2 mL) was added drop-wise. Stirring was maintained until the evolution of hydrogen stopped. 1-Bromo-2-methoxyethane (208 mg, 1.5 mmol) was added and the reaction was heated at reflux at 70 C for 48 hours. Reaction was quenched with water at 0 C, acidified to pH=1-2 with HCl (2M) and was extracted with EtOAc. The organic layer was washed with water, NH4Cl aq., and brine, and dried with Na2SO4, and concentrated. The residue was subjected to HPLC purification. White solid (67 mg, 0.34 mmol, 34%) was obtained after stripping of solvents and drying. ESI-MS m/z 199.4 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]([F:41])([F:40])[CH:9]([CH:11]1[C:17](=[O:18])[N:16]2[CH:12]1[CH2:13][C:14](OS(C1C(C)=CC=CC=1)(=O)=O)=[C:15]2[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[OH:10].C(OC(=O)C)C>CN(C=O)C>[F:41][C:8]([F:7])([F:40])[CH:9]([CH:11]1[C:17](=[O:18])[N:16]2[CH:12]1[CH2:13][C:14]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[C:15]2[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[OH:10]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(O)C(F)(F)F)C2C1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1=C(N2CCOCC2)CC2C(C(O)C(F)(F)F)C(=O)N12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Morpholine (17.5 μl) is added to an ice-cold, stirring solution of benzyl 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (51 mg) in anhydrous DMF (0.5 ml). The resulting solution is allowed to warm to room temperature (25° C.) and then stirred at room temperature for 4 hrs. Ethylacetate (10 ml) is added and the solution is washed with water (5×2 ml), pH 3 phosphate buffer, 5% NaHCO3, brine, dried with MgSO4, and filtered. Evaporation of the solvent in vacuo leaves benzyl 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-morpholino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1C
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To 2-methyl-4-nitrobenzoic acid (10.5 g, 58.0 mmol) in CH2Cl2 (80 ml) was added 2.0 M oxalyl chloride in methylene chloride (39.9 ml, 80 mmol), followed by DMF (0.224 ml, 2.90 mmol). The mixture was stirred at 40° C. for 1.5 h and then at rt for 0.5 h. Solvent was removed and the residue was put on high vacuum for 0.5 h. The acyl chloride prepared was then dissolved in methylene chloride (40 mL) and cooled at 0° C., MeOH (40 mL) was added and the mixture was stirred at 0° C. for 0.5 h. Solvent was removed, the crude was diluted with EtOAc, washed with sat. sodium bicarbonate, brine. The organic layer was dried over sodium sulfate and concentrated to give Intermediate 3A (11.35 g, 58.2 mmol, 100% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.98-8.11 (m, 3H) 3.93 (s, 3H) 2.67 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>ClCCl.N1C=CC=CC=1>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[O:13]
Reactant: Cc1ccccc1N
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1C
Yield: 3.9 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and o-toluidine (1.25 g, 11.7 mmol) in 10 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate and ethanol and recrystallized from acetonitrile-DMF to yield 0.11 g of the title compound, mp 224-225° C. (dec.).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]=2[C:18]([CH3:29])([CH3:28])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH2:30](O)[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]=2[C:18]([CH3:29])([CH3:28])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:30][CH3:31])=[O:26])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C2=C(C(C)(C)COCCCCC(=O)O)C(C)(C)CO2)c1
Reactant: CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CCCCOCC(C)(C)C1=C(c2cccc(OC(C)=O)c2)OCC1(C)C
Reaction time: 0.33 h

Procedure:
In a nitrogen atmosphere at room temperature, to a THF (2.5 mL) solution having 5-(3-acetoxyphenyl)-4-(7-carboxy-1,1-dimethyl-3-oxaheptyl)-3,3-dimethyl-2,3-dihydrofuran (compound (15)) (209 mg, 0.5167 mmol) dissolved, ethanol (48 mg, 1.042 mmol, 2.0 eq.) and triphenyl phosphine (275 mg, 1.048 mmol, 2.0 eq.) were added, and further diethyl azodicarboxylate (185 mg, 1.062 mmol, 2.1 eq.) dissolved in THF (0.5 mL) was added, followed by stirring for 20 minutes. This reaction solution was put into a 1N hydrochloric aqueous solution and a saturated sodium chloride aqueous solution, and extracted with ethyl acetate. The aqueous layer was again extracted with ethyl acetate, and the extract was put together with the previous organic layer, followed by washing with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain a residue. This residue was subjected to silica gel column chromatography with a developing solvent (ethyl acetate:hexane=1:20). As a result, the desired 5-(3-acetoxyphenyl)-4-(7-ethoxycarbonyl-1,1-dimethyl-3-oxaheptyl)-3,3-dimethyl-2,3-dihydrofuran (compound (17)) was obtained as a colorless oil (172 mg, 0.3976 mmol, 77.0%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:19])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([C:4]2[S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[N:3]=2)[N:17]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NCCCCCCNC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCCCCCNC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 3 h
Yield: 56 %

Procedure:
tert-Butyl [[[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]carbonyl]amino]hexylcarbamate (0.30 g, 0.62 mmol) was dissolved in ethyl acetate (15 ml), and a solution of 4 N hydrochloric acid in ethyl acetate (2.0 ml, 8.0 mmol) was added thereto under ice cooling condition. The reaction mixture was stirred at the same temperature for 3 hrs. The precipitated crystals were collected by filtration and recrystallized from methanol-diethyl ether to give the titled compound (0.15 g, 56%).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=O)=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[BH4-].[Na+].[CH2:21](O)[CH3:22]>O>[CH2:21]([CH:14]([OH:16])[CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:11][CH:10]=1)[CH3:22]
Reactant: CCOC(=O)CCc1ccc(C(=O)OCC)cc1
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(CCC(O)CC)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
The ethyl 3-(4-carboethoxyphenyl)propionate (1.23 g, 4.91 mmol) was dissolved in 11 ml of absolute ethanol, cooled in an ice bath, and treated with 0.25 ml of a 2 N cupric sulfate solution in water. Sodium borohydride (0.93 g, 24.6 mmol) was added in small portions over one hour. The reaction was stirred at room temperature over night and then evaporated. The residue was slurried in brine and extracted twice with chloroform. The extracts were filtered through celite, dried over MgSO4, and concentrated to afford 1.0 g (98%) of the subtitle compound.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[C:9]2[C:10]([CH3:28])=[CH:11][C:12]([O:15][CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)=[C:13]([CH3:14])[C:8]=2[S:7][CH:6]=1.CO.[OH-].[Na+]>C1COCC1>[CH3:28][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:29])=[O:2])=[CH:6][S:7][C:8]=2[C:13]([CH3:14])=[C:12]([O:15][CH2:16][C:17]2[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2c(C)c(OCc3ccc(C(F)(F)F)nc3C)cc(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1COc1cc(C)c2c(CC(=O)O)csc2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a mixture of methyl(4,7-dimethyl-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (124.6 mg), MeOH (2.0 mL) and THF (dry) (2.0 mL) was added 1N NaOH (0.883 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated. The residue was neutralized with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The solid was crystallized from EtOAc-hexane to give the title compound (108 mg).
Reaction SMILES: [CH2:1](I)[CH3:2].BrC(C)C.C[C:9]1([CH3:19])[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1.C([O-])([O-])=[O:21].[K+].[K+]>CN(C=O)C>[CH2:1]([O:21][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[C:9]([CH3:19])[CH:18]=[CH:17]2)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCI
Reactant: CC1(C)C=Cc2ccccc2N1
Agent: [K+]
Solvent: CC(C)Br
Solvent: CN(C)C=O
Product: CCOc1cccc2ccc(C)nc12

Procedure:
Ethyl iodide (3.9 g, 25.0 mmol) or 2-bromopropane (2.4 g, 19.2 mmol) was added to a stirred solution of 2-methylquinaldine (3.0 g, 18.8 mmol) and K2CO3 (6.5 g 47 mmol; 5.2 g, 37.6 mmol) in 30 ml DMF at 60° C. for 14 h. The reaction mixture was quenched by H2O (200 ml) and extracted with EtOAc (50 ml×2). The organic layer was concentrated by evaporation in vacuum. The residue was purified by flash column chromatography with Hex/EA (6:1) and recrystallized with Hexane/EA to give 8-ethoxy-2-methylquinoline as intermediate (2.75 g, 78%) in solid but liquid form for 8-isopropopxy-2-methylquinoline (2.92 g, 77%). LHMDS (2.2 equiv.) was treated with a stirred solution of different intermediates in THF solution at 0° C. for 1 h. Corresponding Br(CH2)n−1OH (1.1-1.2 equiv.) was added to a reaction mixture and recover to RT for further 12 to 30 h. The solvent was removed under a reduced pressure. The brown oily residue was purified by flash column chromatography with Hex/EA or DCM/BA and recrystallized by Hexane/EA to afford compound D and E.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S.[S:34](=O)(=O)(O)O>C(Cl)Cl>[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[S:34])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(O)O
Reactant: O=C(O)CCCNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCC(O)=S)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.2 g (20 mmol) of triethylamine and a solution of 1.4 ml (10 mmol) of isobutyl chloroformate in 20 ml of dry methylene chloride are added dropwise, in succession, to a solution, cooled to -10°, of 2.37 g (10 mmol) of 4-benzyloxycarbonylaminobutyric acid in 50 ml of dry methylene chloride. The reaction mixture is stirred for one hour at -10° and then a strong current of hydrogen sulphide is passed through for 11/2 hours. After warming to room temperature, the mixture is cooled again and acidified with 2N sulphuric acid. The organic phase is separated, dried and concentrated in vacuo. The 4-benzyloxycarbonylaminothiobutyric acid obtained can be used without further purification.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][OH:13]>>[OH:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([O:13][CH3:12])=[O:5]
Reactant: CO
Reactant: O=C(Cl)c1c(I)ccnc1O
Product: COC(=O)c1c(I)ccnc1O

Procedure:
Thionyl chloride (3.81 ml, 52.2 mmol) was added to a suspension of 2-hydroxy-4-iodonicotinic acid (3.46 g, 13.1 mmol) in dichloromethane (12 mL) in a pressure vessel at room temperature. The reaction mixture was then heated at 75° C. for 3 h. An aliquot was taken and hydrolyzed with methanol. LCMS analysis showed the derived methyl ester seen as major compound. The reaction mixture was cooled to room temperature and was concentrated in vacuo to give 2-hydroxy-4-iodonicotinoyl chloride. 2-hydroxy-4-iodonicotinoyl chloride in MeOH (100 mL) was stirred at room temperature for 2 h. Concentration in vacuo of the reaction mixture afforded methyl 2-hydroxy-4-iodonicotinate (3.64 g, 13.1 mmol, quantitative yield). MS (ESI pos. ion) m/z: 280 (MH+). Calc'd exact mass for C7H6INO3: 279.
Reaction SMILES: [H-].[Na+].[O-:3][CH2:4][CH3:5].[Na+].[Cl:7][C:8]1[C:9]([C:40]([NH2:42])=[O:41])=[N:10][CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:38])[N:26]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:27]=[CH:28][C:29]=2I)=[O:23])=[CH:17][C:16]=1[F:39].ClC1C(C(N)=O)=NC=CC=1OC1C=CC(NC(C2C(=O)N(C3C=CC(F)=CC=3)C=CC=2Cl)=O)=CC=1F>C1COCC1.C(O)C>[Cl:7][C:8]1[C:9]([C:40]([NH2:42])=[O:41])=[N:10][CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:38])[N:26]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:27]=[CH:28][C:29]=2[O:3][CH2:4][CH3:5])=[O:23])=[CH:17][C:16]=1[F:39]
Reactant: CC[O-]
Reactant: NC(=O)c1nccc(Oc2ccc(NC(=O)c3c(I)ccn(-c4ccc(F)cc4)c3=O)cc2F)c1Cl
Agent: NC(=O)c1nccc(Oc2ccc(NC(=O)c3c(Cl)ccn(-c4ccc(F)cc4)c3=O)cc2F)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
Sodium hydride (1.89 g, 47.2 mmol, 60% dispersion in mineral oil, Aldrich) was added slowly to a solution of ethanol (77 mL, Aldrich>99.5% 200 proof) and THF (77 mL) under N2 and the resulting mixture was stirred at rt for 5 min. The sodium ethoxide solution was then added to a mixture of 3-chloro-4-(2-fluoro-4-(1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-picolinamide and 3-chloro-4-(4-(4-chloro-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide (22.6 g, ˜36.3 mmol) and stirred for 1 h at rt. The reaction mixture was concentrated in vacuo. The resulting crude solid was suspended in ethyl acetate, saturated aqueous sodium bicarbonate solution, and water (to dissolve any precipitated salts). This mixture was sonicated and stirred until the remaining solid became a filterable powder. This powder was filtered off to yield 17.2 g (88%) of the desired product as a pale yellow solid. The layers of the remaining filtrate were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting solid was triturated with ethyl acetate, sonicated, and filtered to give an additional 3.02 g of the desired product as a pale brown solid. 1H NMR (CD3OD) δ 8.34 (d, 1H, J=5.6 Hz), 7.94 (dd, 1H, J=12.4, 2.4 Hz), 7.80 (d, 1H, J=8 Hz), 7.48-7.46 (m, 3H), 7.31-7.28 (m, 3H), 6.86 (d, 1H, J=5.6 Hz), 6.61 (d, 1H, J=7.2 Hz), 4.34 (q, 2H, J=7.2 Hz), 1.45 (t, 3H, J=7.2 Hz); MS(ESI+) m/z 541.11 (M+H)+.
Reaction SMILES: [Li].[CH3:2]Br.[CH:4]([CH:7]([CH:12]=[CH:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:9]C#N)([CH3:6])[CH3:5].[Cl-].[NH4+].C([O:21][CH2:22][CH3:23])C>C1(C)C=CC=CC=1>[OH:16][C:14]([CH3:15])([CH3:2])[CH:13]=[CH:12][CH:7]([CH:4]([CH3:5])[CH3:6])[CH2:8][CH2:9][C:22](=[O:21])[CH3:23]
Reactant: CCOCC
Reactant: CBr
Reactant: CC(=O)C=CC(CCC#N)C(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(=O)CCC(C=CC(C)(C)O)C(C)C
Temperature: 25 °C

Procedure:
Into a 12-liter reaction vessel equipped with stirrer, thermometer, condenser, gas addition tube (straight, not a dispersion tube), heating mantle and nitrogen blanket apparatus, is placed 4.5 liters of diethylether anhydrous and 120 grams (17.4 moles) of 4-16 mesh lithium shot. The contents of the flask are stirred and refluxed for one hour in order to activate the lithium. The heating mantle is removed and the contents of the flask are allowed to cool to room temperature. 828 grams (8.7 moles) of methyl bromide gas is then added to the reaction mass over a six hour period at a rate such that little gas escapes from the top of the condenser. The reaction is exothermic and will cause the solvent to reflux. When the addition of the methyl bromide is complete and the lithium has dissolved, one liter of toluene is added to the reaction mass. The resulting mixture is cooled to 0°-5° C. and the gas addition tube is replaced by an addition funnel. A toluene solution containing 470 grams of 4-isopropyl-7-oxo- 5-octenenitrile prepared according to Example IV is added dropwise to the reqction mass over a one hour period while maintaining the reaction mass at 0°-5° C. When addition is complete, the reaction mass is allowed to warm to room temperature. A GLC sample at this point shows no starting material and no nitrile present. When the reaction is complete, 800 ml of saturated ammonium chloride solution is added to the reaction mass with stirring. The resulting mixture is stirred for one hour and the organic layer is separated from the aqueous layer. The diethylether solvent is stripped from the reaction mass and the reaction mass is distilled through an 8" stone-packed column yielding the following fractions:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH:18]([CH3:20])[CH3:19].Cl>CN(C)C=O.O.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CC(C)CI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(C=O)cc1O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
In 50 ml of N,N-dimethylformamide are suspended 5.0 g of 3,4-dihydroxybenzaldehyde, 10.0 g of potassium carbonate and 8.3 ml of isobutyl iodide. The suspension is stirred at 80° C. for 2 hours. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 3.3 g of 3-hydroxy-4-isobutoxybenzaldehyde as a light yellow solid product.