Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]=[C:5]([NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[Na].[OH2:27]>>[N+:1]([CH:4]=[C:5]([NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[NH:6][CH2:7][CH2:8][S:9]([CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)=[O:27])([O-:3])=[O:2]
Reactant: O
Reactant: O=[N+]([O-])C=C(NCCSCc1nccs1)NCCSCc1nccs1
Agent: [Na]
Product: O=[N+]([O-])C=C(NCCSCc1nccs1)NCCS(=O)Cc1nccs1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Nitro-2,2-bis-[2-(2-thiazolylmethylthio)ethylamino]ethylene (4.5 g) was added to a stirred solution of an equivalent amount of sodium methaperiodate (2.3 g) in water (1600 ml), and the resulting solution was stirred at room temperature for 20 hours. Evaporation of the solvent and chromatographic purification of the residue on silica gel gave the title product as an oil. The structure of the product was confirmed by the 100 mHz n.m.r. spectrum in 2H6 -dimethylsulphoxide which showed the following resonances:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1I.[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.[Li]CCCC>CCOCC>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[CH:14]1[CH2:13][CH:12]2[CH:11]=[CH:10]1
Reactant: Fc1cccc(F)c1I
Reactant: C1=CCC=C1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Fc1cccc2c1C1C=CC2C1

Procedure:
A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 mmol) and cyclopentadiene (2.07 g, 31.3 mmol) was stirred at 0° C. in P. ether (70 mL, 40–60° C.) under N2 and treated with n-BuLi (8.74 mL, 2.5M in hexanes, 21.8 mmol) dropwise over 10 minutes. The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution and the product was extracted with hexanes (3×50 mL). The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL), dried (MgSO4), filtered and evaporated. Chromatography on Silica gel provided product as an oil (1.5 g, 45%). (TLC hexanes Rf 0.55). 1H NMR (400 MHz, CDCl3) δ 7.08 (ddd, J=7.0,1.0,0.8 Hz, 1H), 6.96 (ddd, J=8.5, 8.3, 7.0 Hz, 1H), 6.86 (br s, 2H), 6.72 (ddd, J=8.5,8.3,0.8 Hz, 1H), 4.25 (br s, 1H), 3.98 (br s, 1H), 2.36 (ddd, J=7.2, 1.7, 1.7 Hz, 1H), 2.30 (ddd, J=7.2, 1.7, 1.5 Hz, 1H). GCMS m/e 160 (M+).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CCN)CCCCC1.C1(=O)CCCCC1>C(OC(=O)C)C>[CH:1]1([N:7]([CH2:21][CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: NCCC1CCCCC1
Solvent: O=C1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(O)CSc1cnc(NC(=O)N(CCC2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 2-cyclohexylehylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])([CH3:11])[CH3:10].[CH3:19][S:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl.CCCCCC>[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][S:20][CH3:21])[C:13]=1[NH2:14])([CH3:11])[CH3:10]
Reactant: CSC
Reactant: CC(C)c1ccccc1N
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: CSCc1cccc(C(C)C)c1N
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
15.51 g (116 mmol) of N-chlorosuccinimide were added over a period of 20 minutes to a solution of 11.2 g (82.9 mmol) of 2-isopropylaniline and 7.22 g (116 mmol) of dimethyl sulfide in 200 ml of methylene chloride, whilst maintaining the internal temperature at between 15° and 20° C. After 15 minutes, 11.73 g (116 mmol) of triethylamine were added to the mixture, which was then heated under reflux for 9 hours. At the end of this time, the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with diethyl ether and insoluble materials which appeared were filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through 300 g of silica gel, using a gradient elution method, with mixtures of hexane and methylene chloride ranging from 4:1 to 0:1 as the eluent, to give 10.45 g (yield 65%) of the title sulfide derivative as an oil.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[N+:23]([C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28])([O-:25])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2]([NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N+:23]([O-:25])=[O:24])[CH:14]=[CH:13][C:5]=2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
To toluene 3.0 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.30 g were added 2-nitroaniline 0.17 g, cesium carbonate 0.53 g, tris(dibenzylideneacetone)dipalladium(0) 8.0 mg, palladium acetate 4.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 20 mg at room temperature, and it was heated and refluxed under nitrogen atmosphere for 2 hours. Tris(dibenzylideneacetone)dipalladium(0) 8.0 mg, palladium acetate 4.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 20 mg were added to it, and it was heated and refluxed for 3 hours. Tris(dibenzylideneacetone)dipalladium(0) 8.0 mg, palladium acetate 4.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 20 mg were added to it, and it was heated and refluxed for 7 hours. After the reaction mixture was cooled to room temperature, toluene, ethyl acetate and 10% citric acid aqueous solution were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-(4-fluoroanilino)-4-(2-nitroanilino)benzoate 0.35 g of a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.Cl.[NH:10]1[CH2:13][CH2:12][CH2:11]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[Na]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:4]1[CH:3]=[C:2]([N:10]2[CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C1CNC1
Reactant: Brc1cccc(Br)c1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Brc1cccc(N2CCC2)c1
Temperature: 80 °C
Yield: 12 %

Procedure:
To a solution of 1,3-dibromobenzene (472 mg, 2 mmol) in toluene (5 mL), were added azetidine hydrochloride (187 mg, 2 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), racemic BINAP (93 mg, 0.15 mmol) and sodium tert-butoxyde (230 mg, 2.4 mmol). The reaction was heated to 80° C. for 12 hr under nitrogen gas. The reaction mixture was filtered through celite and the filtered mixture was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate: methanol=10:0:0 to 9:1:0.1) gave the product (51 mg, 12%). 400 M Hz 1H-NMR (CDCl3) δ: 7.04 (t, J=8.0 Hz, 1H), 6.82 (dd, J=8.0 Hz and 1.1 Hz, 1H), 6.55 (t, J=2.0 Hz, 1H), 6.33 (dd, J=7.7 Hz and 2.0 Hz, 1H), 3.87 (t, J=7.2 Hz, 4H), 2.40-2.34 (m, 2H); LCMS: 212[M+H].
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C)C=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[N:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[CH:3]=1
Reactant: Ic1ccccc1
Reactant: Brc1ccc2c(c1)[nH]c1cc(Br)ccc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c3ccc(Br)cc3n(-c3ccccc3)c2c1
Temperature: 130 °C
Yield: 78 %

Procedure:
A mixture of 32.5 g (100 mmole) 2,7-dibromo-9H-carbazole, 20.4 g (100 mmole) iodobenzene, 9.5 g (150 mmole) of copper powder, 27.6 g (200 mmole) of potassium carbonate, and 600 ml dimethylformamide were heated at 130° C. under nitrogen overnight, then cooled to room temperature, the solution was filtered. The filtrate was extracted three times with dichloromethane and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica(hexane-dichloromethane) afforded a white solid (31.3 g, 78 mmol, 78%).
Reaction SMILES: [N+:1]([C:4]1[C:5](N)=[C:6]([Br:13])[C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].N(OS(=O)(=O)O)=O.O[PH2]=O.CCOC(C)=O>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:5]=[C:6]([Br:13])[C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-:3])=[O:2]
Reactant: Nc1c([N+](=O)[O-])cc2ncsc2c1Br
Agent: O=NOS(=O)(=O)O
Agent: O=S(=O)(O)O
Agent: O=[PH2]O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Br)c2scnc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.5 %

Procedure:
To a solution of 5-nitro-6-amino-7-bromobenzothiazole (1.0 g, 3.7 mmol) in 4 mL of sulfuric acid was added nitrososulfuric acid (1.2 g, 9.5 mmol) in a portion. The resulting reaction mixture was stirred for 12 h at 25° C. The reaction mixture was then cooled to 0° C. and 1 mL of H3PO2 was added into the solution. It was stirred for 12 h at another 25° C. and for 2 h at 50° C. The reaction mixture was then poured into EtOAc and washed with aq. NaHCO3. Organic layer was dried over Na2SO4 and concentrated in vacuo to provide an oil (0.85 g, 3.2 mmol, 89%), which was characterized as the desired product(>95% pure) and subjected to a following reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[C:21]([CH:25]=O)[CH:20]=[CH:19][C:18]=2[CH:17]=[CH:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[F:13][C:2]([F:1])([F:12])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][CH2:25][C:21]2[N:22]=[C:23]3[C:18]([CH:17]=[CH:16][C:15](=[O:14])[NH:24]3)=[CH:19][CH:20]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: NC1CCN(C(=O)C(F)(F)F)CC1
Reactant: O=Cc1ccc2ccc(=O)[nH]c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: O=C(N1CCC(NCc2ccc3ccc(=O)[nH]c3n2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61.7 %

Procedure:
To a solution of 0.53 g of 1-(trifluoroacetyl)piperidin-4-amine in 100 mL of dichloromethane, 0.47 g of 7-oxo-7,8-dihydro-1,8-naphthyridine-2-carbaldehyde and 0.16 mL of acetic acid were added, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was added with 0.86 g of sodium triacetoxyborohydride and stirred at the same temperature for 5 hours. Thereto were added water, a saturated aqueous sodium hydrogen carbonate solution and chloroform, the organic layer was separated, and the aqueous layer was extracted with chloroform. Sodium chloride was further added to the aqueous layer, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=20:1 to obtain 0.59 g of 7-(((1-(trifluoroacetyl)piperidin-4-yl)amino)methyl)-1,8-naphthyridin-2(1H)-one as a light orange foam.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:10][OH:11])=[C:4](F)[CH:3]=1.N12CCCN=C1CCCCC2>O1CCCC1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:10][O:11][C:4]=2[CH:3]=1
Reactant: ON=C(c1ccncc1)c1cc(F)c(Br)cc1F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Fc1cc2c(-c3ccncc3)noc2cc1Br
Yield: 27.6 %

Procedure:
A solution of Z/E (4-bromo-2,5-difluorophenyl)(4-pyridinyl)methanone oxime (Intermediate 5, 124 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (40 mg) in tetrahydrofuran (1.5 ml) was heated at 150° C. in a microwave oven for 30 min. The solvent was removed under vacuum and the residue was triturated with a small quantity of methanol to give the title compound as a cream coloured solid (32 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH2:33][NH:1][CH2:2][CH2:3][N:4]6[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]6)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: NCCN1CCNCC1
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2sc(-c3ccc(CNCCN4CCNCC4)cc3)cc2n1

Procedure:
The title compound was prepared from N-(2-aminoethyl)-piperazine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by the procedure analogous to example 17. M.P. 178-191° C.; LC-MS: 484 (MH+); HPLC RT: 3.41 minutes.
Reaction SMILES: N1C2C=CC=CC=2N=C1C1C2C(=CC(C(O)=O)=CC=2)NN=1.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[CH:40]=[C:39]3[C:35]([C:36]([CH:41]=O)=[N:37][NH:38]3)=[CH:34][CH:33]=2)=[O:31])=[CH:25][CH:24]=1.[F:43][C:44]1[C:49]([F:50])=[CH:48][C:47]([NH2:51])=[C:46]([NH2:52])[CH:45]=1>>[F:43][C:44]1[C:49]([F:50])=[CH:48][C:47]2[NH:51][C:41]([C:36]3[C:35]4[C:39](=[CH:40][C:32]([C:30]([NH:29][C:26]5[CH:25]=[CH:24][C:23]([OH:22])=[CH:28][CH:27]=5)=[O:31])=[CH:33][CH:34]=4)[NH:38][N:37]=3)=[N:52][C:46]=2[CH:45]=1
Reactant: O=Cc1n[nH]c2cc(C(=O)Nc3ccc(O)cc3)ccc12
Reactant: Nc1cc(F)c(F)cc1N
Agent: O=C(O)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Product: O=C(Nc1ccc(O)cc1)c1ccc2c(-c3nc4cc(F)c(F)cc4[nH]3)n[nH]c2c1

Procedure:
Using the same procedure as for the synthesis of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid in Example 53(a), step (ii), N-(4-hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamide and 4,5-difluoro1,2-phenylenediamine gave 3-(5,6-difluoro-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide as a tan solid. 1H NMR (DMSO-d6) δ 13.99 (1H, s), 13.27 (1H, s), 10.21 (1H, s), 9.25 (1H, s), 8.52 (1H, d, J=8.7 Hz), 8.21 (1H, s), 7.85 (1H, d, J=9.0 Hz), 7.80 (1H, t, J=9.8 Hz), 7.55 (2H, d, J=8.7 Hz), 7.47 (1H, t, J=9.8 Hz), 6.75 (2H, d, J=8.7 Hz). MS (APCI positive) 406.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[O:18][C:19]4[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=4[C:21]=3[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]=2)[C:8]=1[Br:31])C.[OH-].[K+]>C1COCC1.O>[Br:31][C:8]1[C:9]2[C:14](=[CH:13][C:12]([C:17]3[O:18][C:19]4[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=4[C:21]=3[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:5][C:4]([OH:32])=[O:3]
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)OCC)ccc3c2)oc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)O)ccc3c2)oc2ccccc12
Yield: 76.1 %

Procedure:
Following the procedure described in Step 4 of Example 6, [1-bromo-6-(3-pentyl-benzofuran-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester (1.25 g, 2.53 mmol), was hydrolyzed with potassium hydroxide (0.70 g, 12.5 mmol) in THF (30 mL) and water (10 mL). Crystallization from ethyl acetate/hexane furnished the title compound as an off-white solid (0.90 g), mp 159-161° C. Mass spectrum (+APCl, [M+H]+) m/z 467. 1HNMR (400 MHz, DMSO-d6): δ13.2 (br s, 1H), 8.32 (d, 1H, J=1.5 Hz), 8.22 (d, 1H, J=9.0 Hz), 8.10 (d, 1H, J=9.0 Hz), 8.03 (dd, 1H, J=9.0, 1.5 Hz), 7.69-7.67 (m, 1H), 7.61 (d, 1H, J=8.0 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.35-7.28 (m, 2H), 5.00 (s, 2H), 3.00 (t, 2H, J=7.8 Hz), 1.75-1.66 (m, 2H), 1.40-1.27 (m, 4H), and 0.84-0.79 ppm (m, 3H). Elemental Analysis for C25H23BrO2.1.0H2O: Calculated: C, 61.86; H, 5.19; N, 0.00. Found: C, 61.87; H, 4.70; N, 0.04.
Reaction SMILES: [BH4-].[Na+].[N:3]([C:6]1[CH:11]=[C:10]([C:12]2[O:16][CH:15]=[N:14][CH:13]=2)[N:9]=[C:8]([Cl:17])[C:7]=1[Cl:18])=[N+]=[N-]>CO>[NH2:3][C:6]1[CH:11]=[C:10]([C:12]2[O:16][CH:15]=[N:14][CH:13]=2)[N:9]=[C:8]([Cl:17])[C:7]=1[Cl:18]
Reactant: [N-]=[N+]=Nc1cc(-c2cnco2)nc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1cc(-c2cnco2)nc(Cl)c1Cl
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
Sodium borohydride (0.174 g, 4.6 mmol) was added to a stirred suspension of 4-azido-2,3-dichloro-6-(5-oxazolyl)pyridine (1.17 g, 4.6 mmol) in methanol (25 mL) at room temperature. The solvent was removed and water (100 mL) was added to the residue. After 10 minutes of stirring, the solid formed was collected, washed with water and dried to give 4-amino-2,3-dichloro-6-(5-oxazolyl)pyridine (1.05 g, 4.55 mmol), mp 207-08° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.ClCCCl.C(N(CC)CC)C.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>CO>[F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([O:9][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)nc1I
Reactant: COCCOCCl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COCCOCOc1ccc(F)nc1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
A dry, 100 mL one neck round bottom flask was charged with 6-fluoro-2-iodopyridin-3-ol (2.59 ml, 11.9 mmol), a stirbar, and 50 mL dry DCE. The flask was fitted with an inert atmosphere/vacuum inlet, and the flask was cooled with a ice-water bath. The solution was carefully evacuated to <5 mm Hg, and refilled with nitrogen. The slurry was treated with triethylamine (2.49 ml, 17.9 mmol). To the stirring solution was added 2-methoxyethoxymethyl chloride (1.93 g, 15.5 mmol) dropwise over 30 minutes via syringe pump. The reaction was stirred for 2 h at 0° C., and then treated with 1 mL MeOH. The slurry was filtered cold, and the precipitate was washed with cold DCE (2×50 mL). The combined filtrates were concentrated in vacuo, and heated into 50 mL toluene. The slurry was cooled to room temperature, and then to −5° C. (refrigerator) overnight. The slurry was filtered, and the precipitate was washed with toluene (2×20 mL). The combined filtrates were concentrated in vacuo to afford 6-fluoro-2-iodo-3-((2-methoxyethoxy)methoxy)pyridine (3.91 g, 100% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.36 (s, 3H) 3.53-3.57 (m, 2H) 3.85-3.89 (m, 2H) 5.30 (s, 2H) 6.83 (dd, J=8.71, 3.62 Hz, 1H) 7.46 (dd, J=8.71, 6.46 Hz, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −74.58 (dd, J=5.85, 3.25 Hz, 1 F). 13C NMR (101 MHz, chloroform-d) δ ppm 59.01 (s, 1 C) 68.37 (s, 1 C) 71.39 (s, 1 C) 94.74 (s, 1 C) 106.51 (d, J=14.30 Hz, 1 C) 108.53 (d, J=38.15 Hz, 1 C) 126.55 (d, J=7.80 Hz, 1 C) 152.04 (d, J=4.77 Hz, 1 C) 156.71 (d, J=240.59 Hz, 1 C). HPLC-MS: 1.96 min (93.4%@215 nm; 97.2% @254 nm; m/z=327.9, calculated for C9H11FINO3+H+=328.1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH2:7])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC1CCOC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Racemic (tetrahydrofuran-3-yl)methanamine (3.84 g, 38.0 mmol) and diisopropylethylamine (13.26 ml, 76 mmol), were dissolved in dichloromethane (100 ml) and cooled to 0° C. The mixture was treated dropwise via an addition funnel with benzyl carbonochloridate (6.19 ml, 41.8 mmol) dissolved in 30 ml dichlormethane. After the addition the cooling bath was removed and the homogeneous solution was stirred at ambient temperature overnight. The reaction mixture was partitioned between water and ethyl acetate and the separated aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. Chromatography provided the title compound.
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([OH:9])[C@@H:7]([CH2:10][OH:11])[O:6][C@@H:3]1[O:4]C.F[C@@H]1[C@H](O)[C@@H](CO)O[C@H:14]1[O:15]C>>[F:1][C@@H:2]1[C@H:8]([OH:9])[C@@H:7]([CH2:10][OH:11])[O:6][CH:3]([OH:4])[C@@H:14]1[OH:15]
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Product: OC[C@H]1OC(O)[C@H](O)[C@H](F)[C@@H]1O
Yield: 99 %

Procedure:
The mixture of compounds (4) and (5) obtained in item (2) above (10.0 g) was dissolved in pyridine (200 ml), to which benzoyl chloride (17.5 ml) was then added, and the resulting mixture was allowed to stand at room temperature for 30 minutes. After addition of a small amount of water, the resultant reaction solution was concentrated, and the syrup obtained was extracted with chloroform. The solution in chloroform was washed with a 5% aqueous potassium hydrogen sulfate solution, a 5% aqueous sodium hydrogen carbonate solution and water, successively, and then dried over anhydrous sodium sulfate and concentrated to afford a mixture of the titled compounds (6) and (7) (22.3 g) as colorless crystals. Yield: 99%.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:15])[C:8]([C:11]([O:13]C)=[O:12])=[N:9][CH:10]=1)#[N:2].[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:15])[C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1)#[N:2]
Reactant: COC(=O)c1ncc(OCC#N)cc1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(OCC#N)cnc1C(=O)O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(cyanomethoxy)-3-methylpicolinate (0.895 g, 4.34 mmol) and sodium iodide (0.354 ml, 8.68 mmol, Sigma-Aldrich Chemical Company, Inc.) in acetonitrile (4.34 ml) was added chlorotrimethylsilane (1.102 ml, 8.68 mmol, Strem Chemicals, Inc.). The reaction mixture was heated to 70° C. and allowed to stir overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with EtOAc. The organic extract was washed with water, 10% sodium thio sulfate solution and dried over MgSO4. The filtrate was concentrated in vacuo to give 5-(cyanomethoxy)-3-methylpicolinic acid which was used without further purification. MS m/z=192.9 [M+H]+. Calculated for C9H8N2O3: 192.03