Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](=[O:16])[CH2:11][C:12](=[O:15])[CH2:13][CH3:14])[CH:6]=[CH:7][CH:8]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[CH3:21][N:22]1[CH:24]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:4]=2)[C:10](=[O:16])[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:23]1
Reactant: CCC(=O)CC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Product: CCC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 60 h

Procedure:
A 29.1 g. portion of 1-(3-trifluoromethylphenyl)-2,4-hexanedione was combined with 120 ml. of N,N-dimethylformamide dimethyl acetal and the mixture was stirred under reflux overnight. The mixture was then evaporated to a thick dark brown oil under vacuum, and the residue was dissolved in 250 ml. of methanol. Forty g. of methylamine hydrochloride was added and the mixture was stirred under reflux for 2 hours, and at ambient temperature for 60 hours. The mixture was then evaporated under vacuum to dryness, and the residue was taken up in water and diethyl ether. The organic layer was dried over magnesium sulfate and evaporated under dryness to a dark brown solid, which was chromatographed on a 500 g. silica gel column with ethyl acetate as the eluting solvent. The product-containing fractions were combined and evaporated under vacuum to obtain a light orange solid, which was crystallized from diisopropyl ether to obtain 3.04 g. of the desired product, m.p. 136°-138°. Nmr analysis in DMSOd6 showed peaks at δ7.6-8.3 (m, 6H, aromatic); 3.8 (s, 3H, N--CH3); 2.9-3.3 (q, 2H, COCH2CH3); 0.9-1.1 (t, 3H, COCH2CH3).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][C:10]([C@@H:12]1[C@@H:16]([N:17]=[N+:18]=[N-:19])[C@@H:15]([O:20]C(=O)C)[C@H:14]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][CH:27]=[N:28][C:29]=3[Cl:33])[O:13]1)=[O:11]>CO>[CH3:8][NH:9][C:10]([C@@H:12]1[C@@H:16]([N:17]=[N+:18]=[N-:19])[C@@H:15]([OH:20])[C@H:14]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][CH:27]=[N:28][C:29]=3[Cl:33])[O:13]1)=[O:11]
Reactant: CNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](OC(C)=O)[C@@H]1N=[N+]=[N-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1N=[N+]=[N-]
Reaction time: 15 h
Yield: 72467.5 %

Procedure:
Triethylamine (4.4 mL, 0.032 mL) was added to a solution of (2S,3S,4R,5R)3-azido-5-(6-chloro-purin-9-yl)-4-acetoxy-tetrahydro-furan-2-carboxylic acid methylamide (4 g, 0.011 mmol) in methanol (80 mL). After stirring for 15 hours, the mixture was concentrated and the residue purified by flash chromatography (5% methanol/dichloromethane) to afford 2.7 g (77%) of the title compound as a colorless solid. MS 339 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H); 8.2 (s, 1H); 7.62 (bs, 1H); 5.98 (d, 1H, J=6.7 Hz); 5.07 (t, 1H, J=6.2 Hz); 4.65 (dd, 1H, J=5.4, 2.7 Hz); 4.58 (m, 1H); 4.2 (bs, 1H); 2.88 (d, 1H, J=4.9 Hz); 1.67 (bs, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7](Cl)[N:6]=1.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].[OH-].[Na+]>O>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[Cl:16])[N:6]=1
Reactant: OCCNc1nc(Cl)nc(NCCO)n1
Reactant: Nc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCNc1nc(NCCO)nc(Nc2ccccc2Cl)n1
Temperature: 90 °C
Yield: 82 %

Procedure:
6.8 g (0.053 mol) of 2,4-bis-(2-hydroxyethylamino)-6-chloro-1,3,5-triazine, 11.7 g (0.05 mol) of 2-chloroaniline and 85 ml of water are placed in a 250 ml flask equipped with a stirrer, a dropping funnel, a reflux condenser and a thermometer. The mixture is heated with stirring to 90° C., in the course of which a clear solution is formed. A solution of 2 g of sodium hydroxide in 15 ml of water is added dropwise to this mixture, and the whole mixture is heated under reflux for 3 hours. After cooling, the aqueous system is in 2 phases. The supernatant inorganic phase is discarded. The lower phase is extracted by boiling with toluene, the product being obtained in the residue. The melting point is 108°-110° C. and, after reprecipitation with ethyl acetate/petroleum ether, is 112°-114° C. The yield is 82% of theory.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[Cl:8][C:6]1[CH:7]=[C:2]([C:15]2[CH:16]=[C:11]([Cl:10])[CH:12]=[CH:13][C:14]=2[Cl:17])[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Nc1nc(Cl)cc(-c2cc(Cl)ccc2Cl)n1
Reaction time: 6 h
Yield: 31.5 %

Procedure:
To a mixture of 4,6-dichloro-pyrimidin-2-yl-amine (0.625 g, 3.81 mmol), 2,5-dichloro-phenyl boronic acid (0.726 g, 3.81 mmol), palladium (II) acetate (0.128 g, 0.57 mmol) and triphenylphosphine (0.30 g, 1.14 mmol) was added a solution of sodium carbonate (2.0 g, 19.0 mmol) in water (5 ml) followed by glyme (20 ml). The mixture was stirred under an argon atmosphere for 6 hours. Filtration and concentration of the filtrate yielded the crude product which was purified by flash chromatography on silica gel eluting with ethyl acetate-chloroform (1:8). After evaporation of solvents under reduced pressure, the residue was dissolved in ethanol (100 ml) and stirred while a solution of hydrogen chloride in dioxane (4.0 M, 2.5 ml) was added. After evaporation of volatiles under reduced pressure, the residue was treated with ethyl acetate (25 ml) and stirred for 16 hours. Filtration provided the hydrochloride salt of 4-chloro-6-(2,5-dichloro-phenyl)-pyrimidin-2-yl-amine (0.330 g, 28% yield) as a white powder.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:29]\[OH:30])/[C@:18]5(O)[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.CC1C=CC(S(O)(=O)=[O:39])=CC=1.O.C([O-])(O)=O.[Na+]>CC(C)=O>[OH:30]/[N:29]=[C:17]1\[CH2:16][C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[C:18]\1=[CH:19][C:20](=[O:39])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:2]
Reactant: C[C@]12CC[C@H]3[C@@H](C/C(=N\O)[C@@]4(O)CCCC[C@]34C)[C@@H]1CC13OCCOC12OCCO3
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)C=C1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 67 %

Procedure:
A solution of 3,3:17,17-bis(ethylendioxy)-5α-hydroxy-6-(E)-hydroxyimino-androstane (Prepn. 27) (1.05 g) and pTSA H2O (4.00 g) in acetone (100 mL) was stirred at room temperature for 5 h. The solution was neutralized by addition of 5% aqueous NaHCO3 and acetone was evaporated. The aqueous suspension was extracted with CH2Cl2 (3×). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/CH2Cl2/acetone 80/10/10) to give the title compound II-bw in 67% yield. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 11.60 (1H, s), 5.90 (1H, s), 3.36 (1H, d), 2.60-1.15 (16H, m), 1.08 (3H, s), 0.82 (3H, s)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22]1[O:30][CH:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:30][CH:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCC(O)c2ccccc2)c1

Procedure:
Alkylation reaction of phenol 58 with styrene oxide gave 2-(3-(3-(2-hydroxy-2-phenylethoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.78 g, 58%): 1H NMR (400 MHz, CDCl3) δ 7.50-7.54 (m, 2H), 7.42-7.47 (m, 2H), 7.31-7.41 (m, 5H), 7.16-7.20 (m, 1H), 6.80-6.84 (m, 2H), 6.71 (dd, J=8.4, 2.2 Hz, 1H), 5.10 (dd, J=8.4, 3.2 Hz, 1H), 4.08 (d, J=6.4 Hz, 2H), 3.44-3.49 (m, 2H), 2.68 (t, J=7.4 Hz, 2H), 1.90-1.98 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:17][C:18]=1[CH3:19])[CH:6]=[O:7].OC1C=CC(C=O)=CC=1OC.CC1OC(C2C=CC=CC=2)=NC=1CCOS(C)(=O)=O.[CH2:56]([C@H:63]1[CH2:67][O:66][C:65](=[O:68])[N:64]1[C:69](=[O:74])[CH2:70][O:71][CH2:72][CH3:73])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC>>[CH2:56]([C@H:63]1[CH2:67][O:66][C:65](=[O:68])[N:64]1[C:69](=[O:74])[C@@H:70]([O:71][CH2:72][CH3:73])[C@H:6]([OH:7])[C:5]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: COc1cc(C=O)ccc1OCCc1nc(-c2ccccc2)oc1C
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Agent: COc1cc(C=O)ccc1O
Agent: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c(OC)c1

Procedure:
In analogy to the procedures described in examples 11 a] to 11 c], 3-methoxy-4-[2-(5-methyl2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (prepared from 4-hydroxy-3-methoxy-benzaldehyde and methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester in analogy to the procedure described in example 114 b]) was reacted with (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-((2S,3R) -2-ethoxy-3-hydroxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-((2S)-2-ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-((2S)-2-ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (2S)-2-ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid. The enantiomeric excess was judged according to chiral HPLC (Chiralcel-OJ) to be 98.7%.
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:48])[C:7]1[CH:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:10]=[C:9]([O:17][C:18]2[CH:23]=[CH:22][C:21]([P:24]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([F:47])[CH:40]=3)([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[CH:29]=3)=[O:25])=[CH:20][CH:19]=2)[CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.CCOC(C)=O>[F:36][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[O:34][CH3:35])[CH2:27][O:26][P:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][C:9]2[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:10]=2)[C:6]([OH:48])=[O:5])=[CH:19][CH:20]=1)([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([F:47])[CH:40]=1)=[O:25]
Reactant: COc1ccc(COP(=O)(OCc2ccc(OC)c(F)c2)c2ccc(Oc3cc(OC(C)C)cc(C(=O)OCC[Si](C)(C)C)c3)cc2)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COP(=O)(OCc2ccc(OC)c(F)c2)c2ccc(Oc3cc(OC(C)C)cc(C(=O)O)c3)cc2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 3-{-4-[bis-(3-fluoro-4-methoxy-benzyloxy)-phosphoryl]-phenoxy}-5-isopropoxy-benzoic acid 2-trimethylsilanyl-ethyl ester (536 mg, 0.735 mmol) in DMF (10 mL) was added tetrabutylammonium fluoride (1.0 M solution in THF) (1.84 mL, 1.84 mmol). Stirred at rt for 16 h. The reaction mixture was diluted with EtOAc and washed with H2O (2×) and brine (2×). Dried with MgSO4 and evaporated solvent to provide 462 mg (100%) of 3-{4-[bis-(3-fluoro-4-methoxy-benzyloxy)-phosphoryl]-phenoxy}-5-isopropoxy-benzoic acid. 1H NMR (300 MHz, DMSO-d6): δ 13.20 (bs, 1H), 7.74 (dd, J=13, 9 Hz, 2H), 7.27 (dd, J=2, 1 Hz, 1H), 7.13 (m, 9H), 6.94 (t, J=2 Hz, 1H), 4.97 (dd, J=9, 2 Hz, 4H), 4.67 (m, 1H), 3.82 (s, 6H), 1.27 (s, J=6 Hz, 6H).
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([CH2:25][O:26]C(=O)C2C=CC=CC=2)[C@H:21](O)[CH2:20]1)(=O)C1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N-:50]=[N+:51]=[N-:52].[Li+]>CN(C=O)C.C(Cl)(Cl)Cl.O.ClCCl.N1C=CC=CC=1>[N:50]([C@@H:21]1[C@@H:23]([CH2:25][OH:26])[O:24][C@@H:19]([N:14]2[C:15]3[N:16]=[CH:17][N:18]=[C:10]([NH2:9])[C:11]=3[N:12]=[CH:13]2)[CH2:20]1)=[N+:51]=[N-:52]
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@@H](O)[C@@H](COC(=O)c2ccccc2)O1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(N)ncnc32)O[C@@H]1CO
Reaction time: 0.33 h

Procedure:
A solution of 920 mg (2 mmol) of N6 -benzoyl-9-(5-O-benzoyl-2-deoxy-β-D-threopentofuranosyl)-adenine in 20 ml of abs. dichloromethane (and 2 ml of pyridine) is cooled to -30° C. Then 5 ml (3 mmol) of a solution of trifluoromethanesulfonic anhydride in abs. dichloromethane are added dropwise. The cooling bath is removed, the mixture is stirred for a further 20 min, and 980 mg (20 mmol) of lithium azide in 20 ml of DMF are added to the solution. After stirring at RT for a further 2 h, 50 ml of water and 150 ml of chloroform are added, and the organic phase is taken up and washed with distilled water. The solvent is removed in a ®Rotavapor and the product is treated with ammoniacal methanol solution overnight to remove the base protective group. Renewed removal of solvent is followed by purification by flash chromatography (chloroform:methanol 95:5) on silica gel. Yield: 430 mg (1.6 mmol, 79%) of white crystalline powder. IR: 2,100 cm-1 azido group.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]=1[CH3:23].[NH3:24]>C(O)C>[NH2:24][CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]=1[CH3:23]
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NCCCl
Reactant: N
Agent: Cl
Solvent: CCO
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NCCN

Procedure:
Dissolve N-(2-chloroethyl)-2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)aniline hydrochloride (19.3 g, 50 mmol) in 100 ml ethanol, and bubble in NH3 (8.5 g, 0.50 mol). Heat in a steel bomb 16 hours at 100°. Let cool and partition between ether and water. Extract the ether with 1.0 N HCl. Basify the aqueous with Na2CO3, extract with ether, dry and concentrate. Recrystallize from ether-hexane to give the title compound as a solid product, m.p. 158°-161° C.
Reaction SMILES: C(SC1SC=CC=1)(=O)C.C([S:13][C:14]1[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[C:16]([OH:23])[C:15]=1[CH3:24])(=O)C.[OH-].[K+]>CO>[OH:23][C:16]1[C:15]([CH3:24])=[C:14]([SH:13])[S:18][C:17]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1sc(SC(C)=O)c(C)c1O
Agent: CC(=O)Sc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1sc(S)c(C)c1O

Procedure:
The acetylthiothiophene of (f) above (10 mmol) was added to 30 ml of 1M potassium hydroxide in methanol. After acidification of the mixture, the mercapto thiophene was obtained, recrystallising from hexane, m.p. 86°-88° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[N:37]=[N:38][CH:39]=[CH:40][CH:41]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[N:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cccnn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 17.6 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (100 mg, 0.22 mmol), 3-tributylstannanyl-pyridazine (119 mg, 0.32 mmol) and PdCl2(PPh3)2 (30 mg, 0.043 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was dissolved in anhydrous MeOH (40 mL). Concentrated H2SO4 (10 drops) was added, and the mixture was refluxed overnight. After cooling to r.t., pH of the mixture was adjusted to about 3-4, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-100% EtOAc/hexanes+1% AcOH) to give 18 mg of the title compound as a light brown solid. MS: (+) m/z 465.35 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:11][N:10]=2)=[CH:5][CH:4]=1.P([O-])(O)(O)=[O:25].[Na+].CC(=CC)C.Cl([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].Cl>O.O1CCCC1.C(O)(C)(C)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]([OH:25])=[O:18])=[N:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1cccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)o2)c1
Agent: CC=C(C)C
Agent: Cl
Agent: O=S([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C(O)c1cccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)o2)c1
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a mixture of 3-[5-(4-trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl]benzaldehyde (0.800 g), sodium dihydrogen phosphate (0.300 g), 2-methyl-2-butene (1.2 ml), t-butanol (10 ml), tetrahydrofuran (20 ml) and water (10 ml) was added sodium chlorite (0.570 g) at 0° C., and the mixture was stirred for 2 hrs. To the mixture was added aqueous sodium sulfite solution, and the mixture was stirred at room temperature for 30 min., acidified by adding 1 M hydrochloric acid, and extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 3-[5-(4-trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl]benzoic acid (0.730 g, yield 87%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: 239–240° C.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH:25]1([CH2:31]Br)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>CN(C=O)C.[Na+].[I-]>[CH:25]1([CH2:31][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2CC2CCCCC2)CCCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A 0° C. suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (1.0 g, 4.11 mmol), a catalytic amount of NaI (ca. 10 mg) and K2CO3 (1.1 g, 8.22 mmol) in 10 mL of DMF was treated with cyclohexylmethyl bromide (0.631 mL, 4.52 mmol). After stirring overnight at ambient temperature, an additional 0.63 mL cyclohexylmethylbromide was added, and the resulting mixture was heated at 60° C. for 3 hours. The mixture was poured into H2O (30 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with H2O (4×50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by radial chromatography on silica gel (elution with a gradient of 20% to 40% EtOAc/hexanes) to afford 1.36 g (4.01 mmol; 97%) of 9-[(cyclohexyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a white foam. IR (CHCl3, cm−1) 3011, 2932, 2857, 1725, 1649, 1469, 1446, 1288 and 1120. MS (ES) m/e 340 (M+1), 453 (M+AcO−). FAB HRMS m/e, Calcd for C21H26NO3: 340.1913. Found: 340.1916 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])[CH:7]=1.[CH2:18](I)[CH3:19]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([N:8]2[C:12](=[O:13])[CH2:11][N:10]=[C:9]2[S:15][CH2:18][CH3:19])[CH:7]=1
Reactant: COc1ccc(Cl)cc1NC(=S)NCC(N)=O
Reactant: CCI
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1cc(Cl)ccc1OC
Yield: 53.3 %

Procedure:
A mixture of 2-[3-(5-chloro-2-methoxyphenyl)-thioureido]-acetamide (11.0 g) and ethyl iodide (12.5 g) in ethanol (400 mL) was heated at reflux for 4.5 hours. The solvent was evaporated. The residue was dissolved in chloroform (500 mL) and washed with water. The organic phase was dried over anhydrous MgSO4, then evaporated to dryness. The residue was crystallized from ethanol to give the title compound (6.1 g) as a tan solid, m.p. 113°-115° C. Anal. Calcd. for. C12H13Cl N2O2S: C, 50.61; H, 4.60; N,9.84. Found: C, 50.32; H, 4.59; N, 9.77. Mass spectrum (ESI+, [M+H]+) m/z 285/287. 1H-NMR (DMSO-d6; 400 MHz) 15 7.53 (m, 1H), 7.41 (d, 1H), 7.22 (d, 1H), 4.31 (dd, 2H), 3.77 (s, 3H), 3.05 (m, 2H), and 1.26 ppm (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.C([Mg]Cl)(C)C.[NH:17]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20](=[O:21])[C:18]1=[O:19]>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[OH:21][C:20]1([C:9]2[C:8]([OH:11])=[CH:7][C:5]3[N:6]=[C:2]([CH3:1])[S:3][C:4]=3[CH:10]=2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:17][C:18]1=[O:19]
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: O=C1Nc2ccccc2C1=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2cc(O)c(C3(O)C(=O)Nc4ccccc43)cc2s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.1 %

Procedure:
To a cooled (0° C.) solution of 2-methylbenzo[d]thiazol-5-ol (4.0 g, 24.0 mmol) in anhydrous tetrahydrofuran (50 mL) was added isopropylmagnesium chloride (2 M solution in tetrahydrofuran, 12.0 mL, 24.0 mmol). The resultant suspension was stirred at 0° C. for 0.5 h and isatin (3.1 g, 21.2 mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 48 h and was diluted with a saturated aqueous solution of ammonium chloride (80 mL) and ethyl acetate (200 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was triturated with boiling ethyl acetate (10 mL), filtered and dried in vacuo to afford 3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one (4.11 g, 62%) as an off-white microcrystalline solid: 1H NMR (300 MHz, DMSO-d6) δ10.34 (s, 1H), 10.02 (br s, 1H), 8.85 (br s, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.18-7.10 (m, 1H), 7.01-6.74 (m, 4H), 2.77 (br s, 3H); MS (ES+) m/z 313.1 (M+1).