Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:28])([CH3:27])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.C(NC(C)C)(C)C.C[Si](C)(C)[C:38]#[C:39][C:40]1([CH3:44])[CH2:43][O:42][CH2:41]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].[Cu]I.CN(C=O)C>[F:24][C:23]([F:26])([F:25])[C:22]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[C:2]([C:38]#[C:39][C:40]2([CH3:44])[CH2:43][O:42][CH2:41]2)[CH:3]=1)([OH:28])[CH3:27]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2)c(Br)c1)C(F)(F)F
Reactant: CC1(C#C[Si](C)(C)C)COC1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC1(C#Cc2cc(C(C)(O)C(F)(F)F)ccc2N2CCN(S(=O)(=O)c3cccs3)CC2)COC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A 20 mL vial was charged with 2-(3-bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (0.500 g, 1.00 mmol), diisopropylamine (2.14 mL, 15.0 mmol), 2 mL of DMF, tetrakis(triphenylphosphine)palladium (0) (0.116 g, 0.100 mmol, Strem Chemical Inc, Newburyport, Mass.), copper (I) iodide (0.019 g, 0.100 mmol, Strem Chemical Inc, Newburyport, Mass.), and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.506 g, 3.00 mmol, published PCT patent application no. WO2010030954). The vial was sealed and heated at 100° C. for 3 h. After that time, an additional 20 mol % of both tetrakis(triphenylphosphine)palladium (0) and copper (I) iodide were added and heating was continued for an additional 12 h. The mixture was concentrated and purified by column chromatography (40 g of silica, 0 to 60% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(3-((3-methyl-3-oxetanyl)ethynyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.150 g) as a mixture of two enantiomers.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:38]O)[C:22]1[CH:36]=[CH:35][C:25]([O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:24]([F:37])[CH:23]=1>>[F:37][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:38]=2)[CH:36]=[CH:35][C:25]=1[O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: CC(C)(C)OC(=O)COc1ccc(C(N)=NO)cc1F
Product: COCc1cc(-c2nc(-c3ccc(OCC(=O)OC(C)(C)C)c(F)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 28 (1 281.50 mg; 5 mmol) and Intermediate 49 (1 421.44 mg; 5 mmol). The reaction mixture was filtered through a SPE NH2 column (10 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (10 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a white powder. 1H NMR (CDCl3) δ 8.41 (d, J=1.3 Hz, 1H), 8.15 (dd, J=7.8, 1.8 Hz, 1H), 7.98-7.91 (m, 2H), 7.36-7.23 (m, 4H), 7.13 (d, J=7.1 Hz, 1H), 7.03-6.97 (m, 1H), 4.68 (s, 2H), 4.22 (s, 2H), 3.33 (s, 3H), 2.07 (s, 3H), 1.49 (s, 9H). LC/MS (Method B): 505.2 (M+H)+. HPLC (Method A) Rt 6.36 min (Purity: 98.6%).
Reaction SMILES: [S:1]([Cl:3])Cl.[CH3:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[Cl:3][S:1][N:5]([CH3:4])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: ClSCl
Reactant: CNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(SCl)C(=O)OC(C)(C)C
Temperature: 5 °C
Yield: 103.1 %

Procedure:
To a solution of 62 g (0.6 mole) of sulfur dichloride in 200 ml of methylene chloride cooled to 0° C. under a nitrogen atmosphere was added a solution made up of 50.9 g (0.4 mole) of t-butyl N-methylcarbamate, 44.5 g (0.44 mole) of triethylamine and 100 ml of methylene chloride. The temperature was maintained at -2° to 5° C. during the addition. After stirring for one additional hour at 5° C., the mixture was filtered under a positive nitrogen atmosphere, and the filtrate was concentrated. Solid was removed by extracting the product with hexane. After filtration the hexane solution was concentrated to give 81.5 g of t-butyl N-chlorothio-N-methylcarbamate.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]#[N:30])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.CN(C=O)C.[N-:38]=[N+:39]=[N-:40].[Na+].[Cl-].[NH4+]>O>[N:30]1[NH:38][N:39]=[N:40][C:29]=1[CH2:28][CH:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:20]=[CH:21][C:16]([C:13]3[N:14]=[N:15][C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:4][CH:5]=4)=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)[CH2:27][CH2:26]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Nc2ccc(-c3ccc(C4CCC(Cc5nn[nH]n5)CC4)cc3)nn2)cn1
Temperature: 140 °C

Procedure:
To a mixture of (4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetonitrile (0.12 g, 0.29 mmol, 1.0 equiv) in 3 Ml DMF was added sodium azide (0.057 g, 0.88 mmol, 3.0 equiv), followed by solid ammonium chloride (0.062 g, 4.0 equiv). The reaction was heated to 140° C. over the weekend. The cooled reaction mixture was diluted with 10 Ml water and then acidified to Ph 4-5. The precipitate was filtered to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 103-1.16 (m, 2 H) 1.33-1.45 (m, 2 H) 1.73 (t, J=14.27 Hz, 5 H) 2.60-2.68 (m, 3 H) 7.27 (dd, J=17.94, 8.84 Hz, 3 H) 7.79 (d,J=8.84 Hz, 1 H) 7.86-7.95 (m, 2 H) 8.01 (d, J=9.09 Hz, 1 H) 8.63 (dd, J=8.59, 1.77 Hz, 1 H) 8.87 (d, J=2.27 Hz, 1 H) 9.99 (s, 1 H); (M+H)+ 481.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[S:25][CH:26]=[CH:27][N:28]=4)=[O:22])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:29]([OH:31])=[O:30].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:62][O:63][CH2:64][CH2:65]N>CN(C)C=O.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23][C:24]4[S:25][CH:26]=[CH:27][N:28]=4)=[O:22])=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:29]([O:31][CH2:65][CH2:64][O:63][CH3:62])=[O:30]
Reactant: COCCN
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)cc3)c2cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4nccs4)cc3)ccnc2cc1OC
Yield: 24.5 %

Procedure:
After dissolving 7-methoxy-4-(4-(((1,3-thiazol-2-ylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxylic acid (87.3 mg, 0.20 mmol) in dimethylformamide (1 ml), there were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol), 1-hydroxy-1H-benzotriazole monohydrate (41 mg, 0.30 mmol), triethylamine (0.084 ml, 0.60 mmol) and 2-methoxyethylamine (0.052 ml, 0.60 mmol) while stirring on ice, and the mixture was stirred at room temperature for 5 hours. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, ethyl acetate and then hexane was added to precipitate crystals, which were filtered out and dried under reduced pressure to obtain the title compound (24.4 mg, 0.049 mmol, 24.7%) as white crystals.
Reaction SMILES: [CH3:1]C1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.CC(S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.[C:40]([OH:50])(=[O:49])[C@H:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[OH:42]>>[CH3:1][O:49][C:40](=[O:50])[C@@H:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[OH:42]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: COC(=O)[C@H](O)c1ccccc1

Procedure:
The transformed strain XL10-Gold (pTrcFadLPL) prepared in Example 3 was inoculated again in 250 mL Erlenmeyer flask including 100 mL of LB liquid medium containing 50 μg/L of ampicillin, and then cultured at 37° C. Gene expression was induced by adding 0.1 mM of IPTG, when absorbance was 0.5 at 600 nm wavelength by spectrophotometer. 5 hours after inducing the expression, culture broth was centrifuged at 4° C., 600 rpm for 5 minutes to collect cells, and then, the collected cells were washed with 50 mM Tris-HCl solution (pH 8.0), followed by resuspending in 3 mL of buffer. Said re-suspension was put into a 10 mL flask, to which 30 mg of racemic mandelic acid methyl ester was added and allowed to react for 48 hours with stirring. Then, the suspension was centrifuged at 4° C. and 6000 rpm for 5 minutes to remove cells. The supernatant was collected and adjusted to a pH of 3.0. After extraction of the supernatant with 10 mL of ethyl acetate and hexane, the extract was analyzed by liquid chromatography. The analysis results showed that (S)-mandelic acid and (R)-mandelic acid methyl ester were obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[S:26][C:25]([C:27]#[N:28])=[C:24]([CH3:29])[CH:23]=1.[Br:30]C(Br)(Br)Br>O1CCCC1>[Br:30][CH2:21][C:22]1[S:26][C:25]([C:27]#[N:28])=[C:24]([CH3:29])[CH:23]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(CO)sc1C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(CBr)sc1C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
44 g (167 mmol) of triphenylphosphine were added to a solution of 24 g (152 mmol) of 5-hydroxymethyl-3-methylthiophene-2-carbonitrile in 180 ml of tetrahydrofuran. Then, a solution of 55 g (167 mmol) of tetrabromomethane in 100 ml of tetrahydrofuran was added. The mixture was stirred for 90 minutes at room temperature. The reaction mixture was concentrated on a rotary evaporator under a water pump vacuum, and the residue was purified by column chromatography (eluant hexane:ethyl acetate 8:2). This gave 34 g of the title compound which still contained a small amount of solvent. 1H NMR (270 MHz, DMSO-d6): δ=2.4 (s, 3H), 5.0 (s, 2H), 7.3 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])=[O:6].N1C=CC=CC=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>CN(C)C(=O)C>[C:31]([NH:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=1)[CH3:9])=[O:6])(=[O:35])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)C(=O)Cl
Reactant: CC(NC(=O)c1ccnc(N)c1)c1ccc(OCC(F)(F)F)nc1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CC(C)C(=O)Nc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To a mixture of 2-amino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (25 mg, 0.073 mmol, Step-1, single enantiomer) and pyridine (0.024 mL, 0.29 mmol) in N,N-dimethylacetamide (1 mL) is added isobutyryl chloride (16 mg, 0.15 mmol) at room temperature. After stirring at room temperature for 2 hours, the mixture is poured onto water (2 mL), and the mixture is extracted with ethyl acetate (3 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on NH-silica gel eluting with ethyl acetate and then by preparative LC-MS to give 12.9 mg (43% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:26]1[CH:31]=[C:30]([OH:32])[CH:29]=[C:28]([CH:33]([OH:36])[CH2:34][NH2:35])[CH:27]=1>>[OH:36][CH:33]([C:28]1[CH:27]=[CH:26][CH:31]=[C:30]([OH:32])[CH:29]=1)[CH2:34][NH:35][CH:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]([NH:12][S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])=[CH:18][CH:17]=2)[CH2:24][CH2:23]1
Reactant: NCC(O)c1cccc(O)c1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4cccc(O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-methoxy-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 218) and DL-norphenylephrine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.25-1.60 (m, 2H), 2.00-2.15 (m, 2H), 2.50-3.10 (m, 5H), 3.60-3.70 (m, 2H), 3.79 (s, 3H), 4.80-4.90 (m, 1H), 6.05 (brs, 1H), 6.70-6.80 (m, 1H), 6.80-6.85 (m, 4H), 6.90 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.0 Hz, 2H), 7.16 (t, J=7.7 Hz, 1H), 7.60 (d, J=9.0 Hz, 2H), 9.45 (s, 1H), 9.70 (s, 1H); MS (ES) m/z: 498.5 (MH+); HRMS Calcd. for C26H31N3O5S(M+): 497.1984. Found: 497.1961.
Reaction SMILES: [CH2:1]([N:3]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][OH:21])[CH:16]=2)[O:11][C:10]([CH3:23])([CH3:22])[CH2:9]1)[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].[H-].[Na+].[CH2:26](I)[CH3:27]>CC(N(C)C)=O>[CH2:26]([O:21][CH2:20][CH2:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([CH3:22])([CH3:23])[CH2:9][CH:8]2[N:3]([CH2:1][CH3:2])[S:4]([CH3:7])(=[O:5])=[O:6])[CH3:27]
Reactant: CCI
Reactant: CCN(C1CC(C)(C)Oc2ccc(OCCO)cc21)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOCCOc1ccc2c(c1)C(N(CC)S(C)(=O)=O)CC(C)(C)O2

Procedure:
2.3 g (6.7 mmol) of N-ethyl-N-[6-(2-hydroxyethoxy)-2,2-dimethylchroman-4-yl]methanesulfonamide (Example 8) were alkylated with 0.48 g (about 10 mmol) of NaH (80 percent dispersion) and 1.6 ml (about 20 mmol) of ethyl iodide in 50 ml of DMA under nitrogen. After working up and purification by column chromatography on silica gel, 1.0 g of the title compound was crystallized from corresponding fractions using petroleum ether, m.p. 73-75° C.
Reaction SMILES: NC[C:3]([C:5]1[N:6]=[CH:7][N:8]([C@@H:15]2[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@@H:16]2[F:23])[C:9]=1[N:10]=[CH:11][N:12](C)[CH3:13])=[O:4].C(=O)=O>C[O-].[Na+].CO>[F:23][C@H:16]1[C@H:17]([OH:18])[C@@H:19]([CH2:21][OH:22])[O:20][C@H:15]1[N:8]1[C:9]2[N:10]=[CH:11][NH:12][CH2:13][C:3](=[O:4])[C:5]=2[N:6]=[CH:7]1
Reactant: CN(C)C=Nc1c(C(=O)CN)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F
Agent: C[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CO
Product: O=C1CNC=Nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F
Reaction time: 8 h
Yield: 30.3 %

Procedure:
Compound (41) (18 mg) obtained in item (8) above was dissolved in a 0.1M sodium methylate solution (0.72 ml) in methanol, and the resultant solution was allowed to stand at room temperature overnight. The reaction solution as formed was neutralized with addition of dry ice and then concentrated to leave a residue. The residue was purified by silica gel column chromatography (developer: the lower layer of water-methanol-chloroform, 1:2:4), affording the titled compound (42) (4.7 mg) as a colorless solid. Yield: 30%.
Reaction SMILES: [CH2:1]([C:14]1[NH:18][CH:17]=[C:16]([C:19]([O:21]CC)=[O:20])[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>C(O)C>[CH2:1]([C:14]1[NH:18][CH:17]=[C:16]([C:19]([OH:21])=[O:20])[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCc1cc(C(=O)OCC)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCc1cc(C(=O)O)c[nH]1
Yield: 85.8 %

Procedure:
To an ethanol solution (40 ml) of 2.60 g (8.1 mmol) of ethyl 5-tridecylpyrrole-3-carboxylate prepared in Example 5 was added 10 ml of an aqueous solution containing 1.40 g (33 mmol) of sodium hydroxide. The mixture was heated under reflux for 36 hours. After removing the ethanol, the mixture was acidified with hydrochloric acid, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give crystals, which were purified by subjecting them to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/2) to obtain 2.04 g (86% yield) of pure 5-tridecylpyrrole-3-carboxylic acid, m.p. 82°-84° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][N:15]=[C:16]([C:17](O)=[O:18])[C:10]=2[CH:9]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([P+](ON1N=[N:44][C:39]2C=[CH:41][CH:42]=[CH:43][C:38]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.N1CCCCC1>CN(C=O)C.O>[C:20]1([CH:9]2[C:10]3[C:16]([C:17]([N:44]4[CH2:41][CH2:42][CH2:43][CH2:38][CH2:39]4)=[O:18])=[N:15][O:14][C:11]=3[CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCc2onc(C(=O)O)c2C1c1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCNCC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCc2onc(C(=O)N3CCCCC3)c2C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a solution of 5-(tert-butoxycarbonyl)-4-phenyl-4,5,6,7-tetrahydroisoxazolo-[4,5-c]pyridine-3-carboxylic acid (1.747 mmol, 1.0 eq.) in DMF (2 ml) was added BOP reagent (2.27 mmol, 1.3 eq.) and N-methyl morpholine (5.24 mmol, 3.0 eq.). The reaction mixture was stirred at room temperature for 15 min. A solution of piperidine (1.747 mmol, 1.0 eq.) in DMF (0.5 ml) was added to the reaction mixture and it was stirred for 12 h. The mixture was poured into water and resulting aqueous solution was extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica). Yield: 23%.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:12]=[N+:13]([O-:24])[C:14]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][CH2:21]3)=[CH:17][C:15]=2[N:16]=1>COCCOC>[N:1]1([CH2:7][CH2:8][NH:9][C:11]2[N:12]=[N+:13]([O-:24])[C:14]3[CH:23]=[C:22]4[C:18]([CH2:19][CH2:20][CH2:21]4)=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: NCCN1CCOCC1
Solvent: COCCOC
Product: [O-][n+]1nc(NCCN2CCOCC2)nc2cc3c(cc21)CCC3
Yield: 97.7 %

Procedure:
2-(4-Morpholinyl)ethylamine (3.93 mL, 30.0 mmol) was added to a stirred solution of chloride 21 (2.21 g, 10.0 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue stirred with water (150 mL) at room temperature for 30 min. The solid was filtered, washed with water (3×10 mL) and dried to give 1-oxide 44 (3.08 g, 98%) as an orange solid: mp (water) 178-179° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.79 (br s, 1H, NH), 3.72 (br t, J=4.6 Hz, 4H, CH2O), 3.59 (q, J=5.6 Hz, 2H, CH2N), 2.97-3.05 (m, 4H, H-6, H-8), 2.63 (t, J=5.9 Hz, 2H, CH2N), 2.51 (br t, J=4.6 Hz, 4H, CH2N), 2.10-2.19 (m, 2H, H-7); 13C NMR δ 158.6, 154.6, 148.7, 143.3, 129.8, 120.5, 114.6, 66.9 (2), 56.8, 53.3 (2), 37.5, 33.1, 32.3, 25.7. Anal. calcd for C16H21N5O2: C, 60.9; H, 6.7; N, 22.2. Found: C, 61.0; H, 6.8; N, 22.3%.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[C:21]([Br:22])=[CH:20][CH:19]=[C:18]([OH:23])[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O>O>[CH2:9]([C:16]1[C:21]([Br:22])=[CH:20][C:19]([I:1])=[C:18]([OH:23])[N:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(Br)c(Cc2ccccc2)n1
Solvent: CN(C)C=O
Solvent: O
Product: Oc1nc(Cc2ccccc2)c(Br)cc1I
Reaction time: 8 h
Yield: 85.8 %

Procedure:
1.19 g of N-iodosuccinimide was added to a mixture of 1.16 g of 2-benzyl-3-bromo-6-hydroxypyridine (Production Example 3-b) and 10 ml of N,N-dimethylformamide at room temperature, followed by stirring at the same temperature overnight. 50 ml of water was added to the reaction solution and the resulting crystals were collected by filtration, washed with water and then vacuum-dried, to give 1.47 g of the target compound.
Reaction SMILES: [C:1]([C:3]1([OH:16])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)#[CH:2].[C:17]1(O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:16]1[C:3]2([C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]3[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:1]=[CH:2][C:24]2[CH:23]=[CH:22][C:21]3[C:26]([C:25]1=2)=[CH:17][CH:18]=[CH:19][CH:20]=3
Reactant: C#CC1(O)c2ccccc2-c2ccccc21
Reactant: Oc1cccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C1=CC2(Oc3c1ccc1ccccc31)c1ccccc1-c1ccccc12

Procedure:
3.09 g of 9-ethynyl-9-fluorenol (15 mmoles) and 2.49 g of 1-naphthol (17.25 mmoles) were dissolved under reflux in 30 ml of anhydrous toluene in an inert atmosphere. 0.03 g of PTSA was then added. The reaction mixture was refluxed in an inert atmosphere for 2 hours 30 minutes. On returning to room temperature, the mixture was poured onto an aqueous 10% caustic soda solution. After decanting, the aqueous phase was continuously extracted with dichloromethane. The organic phases were combined and dried over magnesium sulphate. The solvent was removed under reduced pressure. The compound was precipitated out with hexane then recrystallised from toluene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][O:18][CH3:19]>N1C=CC=CC=1>[CH3:19][O:18][N:17]=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: CON
Reactant: O=C(Cc1ccncc1)c1cccc(F)c1
Solvent: c1ccncc1
Product: CON=C(Cc1ccncc1)c1cccc(F)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of 1-(3-fluorophenyl)-2-(pyridin-4-yl)ethanone, (18) (3.6 g, 16.17 mmol) in pyridine (20 mL) was added NH2OMe (2.8 g, 33.4 mmol), at room temperature. The mixture was stirred at 80° C. for 3 h. The reaction was cooled to room temperature and quenched with water (20 mL). The aqueous layer was extracted with dichloromethane (3×, 100 ml). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered. The solvents were removed under vacuum. Purification by MPLC (0 to 10% methanol in dichloromethane) gave 1-(3-fluorophenyl)-2-(pyridin-4-yl)ethanone O-methyl oxime, (19): as a oil (3.15 mg, 77% yield).