Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[C:14]([OH:19])(=[O:18])[C:15]([CH3:17])=O.C([BH3-])#N.[Na+]>O>[C:14]([CH:15]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH3:17])([OH:19])=[O:18]
Reactant: CC(=O)C(=O)O
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CC(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O
Yield: 91.5 %

Procedure:
A solution of L-alanyl-L-proline (372 mg) and pyruvic acid (881 mg) in water is adjusted to pH 7 and treated with 377 mg of sodium cyanoborohydride at room temperature until reaction is complete. The product is absorbed on strong acid ion-exchange resin and then eluted with 2% pyridine in water. Freeze drying gives 472 mg of N-(1-carboxyethyl)-L-alanyl-L-proline. Nmr and mass spectrogram are consistent with structure. The nmr spectrum shows multiplets centered at 4.5, 3.7, and 2.2 ppm, and a pair of doublets at 1.6 ppm.
Reaction SMILES: [ClH:1].Cl.[NH2:3]/[C:4](=[N:25]\[OH:26])/[C:5]1[CH:24]=[CH:23][C:8]2[CH:9]=[C:10]([C:12]([NH:14][C@@H:15]3[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)=[O:13])[S:11][C:7]=2[CH:6]=1.[H-].[Na+].[C:29](OC)(=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C=O)C.C1COCC1>[ClH:1].[N:17]12[CH2:18][CH2:19][CH:20]([CH2:21][CH2:22]1)[C@@H:15]([NH:14][C:12]([C:10]1[S:11][C:7]3[CH:6]=[C:5]([C:4]4[N:3]=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[O:26][N:25]=4)[CH:24]=[CH:23][C:8]=3[CH:9]=1)=[O:13])[CH2:16]2
Reactant: COC(=O)c1ccccc1
Reactant: N/C(=N\O)c1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3noc(-c4ccccc4)n3)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
110 mg (0.26 mmol) of 6-[amino(hydroxyimino)methyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride (Example 27A) are dissolved in 2 ml of DMF and 0.75 ml of THF. 250 mg of 4 Å molecular sieves are added and the mixture is stirred at room temperature for 30 min. Addition of 31.2 mg (0.79 mmol) of sodium hydride (60% suspension in mineral oil) is followed by heating at 60° C. for 20 min and then cooling to room temperature. A solution of 100 μl (0.79 mmol) of methyl benzoate in 1 ml of THF is added to the reaction mixture, and it is heated at 80° C. for 14 h. A further 20.8 mg (0.52 mmol) of sodium hydride (60% suspension in mineral oil) and 0.99 ml (7.91 mmol) of methyl benzoate in 1 ml of THF are added, and the mixture is heated at 70° C. for a further 24 h. The reaction is stopped by adding water. Purification takes place by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 4N hydrogen chloride in dioxane, again concentrated. Drying under high vacuum results in 45.7 mg (32% of theory) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14][C:13]=3[CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27]C1C=C2C(=CC=1)C(=O)C(C1C=CC=CC=1)CC2.ClC1C=CC([N+]([O-])=O)=CN=1.[F-].[K+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:27])[CH:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccc(O)cc2CCC1c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)C3)nc1
Agent: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [F-]
Agent: [K+]
Product: O=C1c2ccc(Oc3ccc([N+](=O)[O-])cn3)cc2CCC1c1ccccc1

Procedure:
6-(5-Nitro-pyridin-2-yloxy)-2-phenyl-3,4-dihydro-2H-naphthalen-1-one was prepared as described for 5-nitro-2-(6-phenyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-pyridine in Example 5(d) using 50 mg 6-hydroxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one, 33 mg 2-chloro-5-nitropyridine and 37 mg potassium fluoride. 1H NMR (400 MHz, d6-DMSO) δ: 9.07 (d, 1H, J 2.8 Hz), 8.68 (dd, 1H, J 9.0, 2.9), 8.01 (d, 1H, J 8.5), 7.37 (d, 1H, J 9.1 Hz), 7.21-7.38 (m, 7H), 3.96-4.04 (m, 1H), 3.15-3.23 (m, 1H), 2.98-3.04 (m, 1H), 2.39-2.48 (m, 1H), 2.25-2.31 (m, 1H).
Reaction SMILES: [Mg].II.Br[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[Br-].[Mg+2].S1C=CC=C1.[Br-].[CH3:18][C:19]([C:22]1[C:27]([OH:28])=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:24]([C:33](N(OC)C)=[O:34])[N:23]=1)([CH3:21])[CH3:20]>C(OCC)C.O1CCCC1.C(O)(C)C>[CH3:21][C:19]([C:22]1[C:27]([OH:28])=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:24]([C:33]([C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)=[O:34])[N:23]=1)([CH3:18])[CH3:20]
Reactant: CON(C)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reactant: Brc1cccs1
Agent: II
Agent: [Br-]
Agent: [Mg+2]
Solvent: c1ccsc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C(=O)c2cccs2)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
To a mixture of magnesium turnings (1.22 g, 50.7 mmol) in dry ethyl ether (16 mL) under nitrogen atmosphere is added a single crystal of iodine followed by freshly distilled 2-bromothiophene (2.50 mL, 30.0 mmol) dropwise over 1 hour. This mixture is refluxed 1 hour then cooled to room temperature. The molarity of the solution (1.06M) is determined by titration of a small sample with isopropanol. A portion of this 1.06M solution of thiophene magnesium bromide in ether (3.5 mL, 3.71 mmol) is added dropwise under nitrogen atmosphere to a solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamide (0.50 g, 1.7 mmol) in tetrahydrofuran (15 mL) dropwise. The resulting mixture is stirred 16 hours, diluted with ethyl ether (15 mL), quenched with aqueous saturated ammonium chloride solution, and washed with water and brine solution. Concentration of the organic phase followed by purification by flash chromatography (SiO2, dichloromethane) and recrystallization from methanol and water gave 0.40 g (74 %) of title compound, mp 157.5°-159° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CN=[N+]=[N-])C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(CN)C1
Reaction time: 5 h
Yield: 95.8 %

Procedure:
A mixture of 3-azidomethylpiperidine-1-carboxylic acid tert-butyl ester (5.0 g, 20.8 mmol), ethanol (125 mL) and 10% palladium on charcoal (1.5 g) was shaken under a hydrogen atmosphere (60 psig) for 5 hours. The mixture was filtered. The filtrate was concentrated to provide a colorless oil (4.27 g, 96%) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ3.91 (b, 1H), 3.82 (dt, J=13, 4 Hz, 1H), 2.90 (m, 1H), 2.8-2.5 (m, 3H), 1.85 (m, 1H), 1.75 (s, 2H), 1.66 (m, 1H), 1.6-1.4 (m, 2H), 1.47 (s, 9H), 1.20 (m, 1H). Mass spec (AP+) m/z 215.2 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[C:13]([CH2:14][NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.CCN(CC)CC.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[CH3:22][O:21][CH:3]([O:2][CH3:1])[C:4]1[C:13]([CH2:14][N:15]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:30](=[O:32])[CH3:31])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1nc2c(cc1CNCCN(C)C)CCCN2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(OC)c1nc2c(cc1CN(CCN(C)C)C(C)=O)CCCN2
Reaction time: 0.17 h

Procedure:
To a solution of N1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-N2,N2-dimethylethane-1,2-diamine (intermediate 199, 300 mg, 0.973 mmol) and NEt3 (0.270 mL, 1.937 mmol) in DCM (10 ml) was added acetyl chloride (0.075 mL, 1.055 mmol) at room temperature and the reaction mixture was stirred for approximately 10 min. The reaction mixture was quenched with saturated aqueous NaHCO3 and diluted with DCM. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined, dried using Na2SO4, filtered and concentrated to yield the title compound, which was directly used in the next step without further purification. (UPLC-MS 3) tR 0.30 min, ESI-MS 351.2 [M+H]+. 1H NMR (600 MHz, DMSO-d6) (indicates an overlapping mixture of rotamers of the title compound in an approximate mixture of 0.5:0.5) δ 6.94 (s, 0.5H), 6.92 (s, 0.5H), 6.52-6.48 (m, 0.5H), 6.48-6.43 (m, 0.5H), 4.98 (s, 0.5H), 4.96 (s, 0.5H), 4.53 (s, 2H), 3.32 (s, 3H), 3.31 (s, 3H), 3.28-3.22 (m, 3H), 3.19 (t, 1H), 2.65 (t, 1H), 2.61 (t, 1H), 2.31 (t, 1H), 2.26 (t, 1H), 2.15-2.06 (m, 7.5H), 1.97 (s, 1.5H), 1.79-1.71 (m, 2H).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH:13]([CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14]>>[OH:14][CH2:13][C@@H:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)C=O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCOC(=O)[C@H](C)CO
Temperature: 30 °C
Reaction time: 72 h

Procedure:
The yeast Candida humicola NRRL Y-1266 was cultivated on an agar slant with 7.5 ml of medium 1 consisting of 1 wt.% of yeast extract, 1 wt.% of peptone, 2 wt.% of glucose, 1.6 wt.% of agar and 94.4 wt.% of distilled water. After incubation at 30° C. for 3 days the batch was treated with 9 ml of 0.9% (wt./vol.) sodium chloride solution and the cells were suspended. Subsequently, a shaking flask containing 100 ml of medium 1 without the addition of agar (i.e. a medium consisting of 1 wt.% of yeast extract, 1 wt.% of peptone, 2 wt.% of glucose and 96 wt.% of distilled water) was inoculated with 1 ml of the suspension obtained. After an incubation period of 3 days while shaking at 30° C. the cells were centrifuged off and suspended in 100 ml of 5% (wt./vol.) of glucose solution. The suspension obtained was treated with 0.1 g of ethyl α-formylpropionate and incubated further at 30° C. while shaking. After 5 hours the batch was extracted with ethyl acetate, there being obtained ethyl (R)-(-)-3-hydroxy-isobutyrate in an optical purity of 95.2% ee.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@@H:7]([N:17]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:1]([O:5][C:6](=[O:31])[C@@H:7]([NH2:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(F)c(Br)c1)N=C(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reaction time: 8 h
Yield: 124.8 %

Procedure:
A solution of (S)-2-(benzhydrylidene-amino)-3-(3-bromo-4-fluoro-phenyl)-propionic acid tert-butyl ester (300 mg, 0.622 mmol) in THF (3 mL) was treated with 10% citric acid (3 mL). The mixture was stirred overnight, diluted with water, and extracted with Et2O (2×). The aqueous layer was basified to pH=10 with satd. aq. K2CO3 and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4) and concentrated to give the title compound (247 mg, 64%). MS (ESI+): mass calcd. for C13H17BrFNO2, 318.18; m/z found, 262.2 [M-t-Bu]+. 1H NMR (400 MHz, CDCl3): 7.42 (dd, J=6.6, 2.1 Hz, 1H), 7.16-7.11 (m, 1H), 7.08-7.02 (m, 1H), 3.56 (dd, J=7.3, 5.9 Hz, 1H), 2.85-2.78 (m, 1H), 2.99-2.92 (m, 1H), 1.43 (m, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([C:17]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[CH:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:14](S(C3C=CC=CC=3)(=O)=O)[C:11]2=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:44])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([C:17]([C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=3)=[CH:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[NH:14][C:11]2=[N:12][CH:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cnc2c(c1)cc(C(=CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnc2[nH]c(C(=CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
A mixture of {1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (670 mg, 1.05 mmol) and tetrabutylammonium fluoride in tetrahydrofuran (1 M, 21 mL, 21 mmol) was stirred for 3 h at 60° C. After cooling to room temperature, the mixture was poured into brine (20 mL), extracted with ethyl acetate (2×100 mL), washed with a saturated aqueous ammonium chloride solution (3×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give {2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (0.52 g, 100%) which was used in the next step without purification: LC/MS m/e calcd for C26H31N3O5S [M+H]+ 498.62, observed 498.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)[CH:13]=1)[C:7]([O:9]C)=[O:8].[OH-].[Li+].OS(O)(=O)=O>O1CCOCC1.O>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)[CH:13]=1)[C:7]([OH:9])=[O:8]
Reactant: COCc1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COCc1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 3-(methoxymethyl)-5-(5-methylpyridin-2-yl)benzoate (75 mg, 0.28 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was added lithium hydroxide (66 mg, 2.8 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified with 2N aq. H2SO4 to pH=7-8, and then extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried (MgSO4), and concentrated to afford the title compound. 1H NMR (D2O, 400 MHz): 8.10 (s, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 4.41 (s, 2H), 3.32 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:18])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:18])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:30])[CH3:6])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(C)c(Br)cc21
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C)N1C(=S)COc2cc(C)c(Br)cc21
Yield: 80.9 %

Procedure:
To a solution of 2-(6-bromo-7-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (23.6 g, 69 mmol) in toluene (300 mL) was added Lawesson's reagent (30.7 g, 76 mmol) and the reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature water (300 mL) was added. The organic phase was separated and the aqueous portion was extracted with EtOAc (3×100 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give 2-(6-bromo-7-methyl-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as solid (20.0 g, 81%). 1H NMR (DMSO-d6, 400 MHz): δ 7.41 (s, 1H), 7.16 (s, 1H), 6.03 (m, 1H), 4.90 (s, 2H), 4.14 (m, 2H), 2.29 (s, 3H), 1.61 (d, J=6.8 Hz, 3H), 1.08 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:16](=O)[CH2:17][CH3:18])[C:12](=O)[CH2:13][CH3:14].Cl.[C:27]([CH2:32][NH:33][NH2:34])([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:16]([CH2:17][CH3:18])=[N:34][N:33]([CH2:32][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:12]=1[CH2:13][CH3:14]
Reactant: CCOC(=O)CNN
Reactant: CCC(=O)C(CCCCCCOc1ccc(OC)cc1Cl)C(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)Cn1nc(CC)c(CCCCCCOc2ccc(OC)cc2Cl)c1CC
Yield: 74.1 %

Procedure:
A mixture of 18.45 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-heptanedione, 7.73 g of carbethoxymethylhydrazine hydrochloride and 5 g of triethylamine in 100 ml of absolute ethanol was heated at reflux for 8 hours. The product was isolated and distilled to give 16.7 g of ethyl 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-diethyl-1H-pyrazol-1-acetate as a pale yellow oil, b.p. 205°-210° C. (0.05 mm); MIC=6-12 microg/ml (herpes 1 and 2).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[C:12]([NH:16][OH:17])([CH3:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[C:3]([OH:11])=[C:4]([CH:5]=[N+:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[O-:17])[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: CC(C)(C)NO
Reactant: O=Cc1cc(Br)cc(Br)c1O
Product: CC(C)(C)[N+]([O-])=Cc1cc(Br)cc(Br)c1O

Procedure:
The title compound was prepared according to the procedure described in Example 13 using 3,5-dibromo-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 68.7% yield as a yellow crystalline solid, m.p. 111.3° C. (Rf=0.54 on a silica gel plate using 7:3 hexanes/EtOAc as an eluant).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](I)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH3:13]
Reactant: CCI
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.7 %

Procedure:
To a solution of 4-chloro-3-nitrophenol (5.00 g, 29 mmol) in acetone (50 ml) were added ethyl iodide (4.95 g, 32 mmol) and potassium carbonate (4.37 g, 32 mmol), followed by stirring at room temperature for 20 hours. After filtration of the insoluble matter, the filtrate was subjected to evaporation under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent; chloroform) to give 4-ethoxy-1-chloro-2-nitrobenzene (5.71 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:23]=[C:10]2[CH:11]=[C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:13]=[C:14]([CH:15]=[O:16])[N:9]2[N:8]=1)=[O:5])[CH3:2].S([CH2:34][N+:35]#[C-:36])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:23]=[C:10]2[CH:11]=[C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:13]=[C:14]([C:15]3[O:16][CH:36]=[N:35][CH:34]=3)[N:9]2[N:8]=1)=[O:5])[CH3:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C=O)n2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cnco3)n2n1

Procedure:
A mixture of the product of Step 2 (40 mg, 0.13 mmol), tosylmethyl isocyanide (28 mg, 0.14 mmol) and K2CO3 (36 mg, 0.26 mmol) were stirred at room temperature in MeOH (5 mL) for a few minutes, then heated at reflux for 0.5 h. All solvent was then removed under reduced pressure, the residue taken up into MeOH/CH2Cl2, and dried onto silica. Purification was carried out by filtration through a plug of silica gel (5% MeOH/CH2Cl2 as eluant) to give the title compound as a solid. LCMS (APCI+) 350.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C>[OH:17][C:3]1[C:4]2[S:8][C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])=[N:6][C:5]=2[CH:15]=[CH:16][CH:2]=1
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCNC(=O)Nc1nc2cccc(O)c2s1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
General Procedure for 1-(6-bromo-7-alkoxy-2-benzothiazolyl)-3-ethyl-urea compounds 9–13. A mixture of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 6 and potassium carbonate (1.05 eq) in anhydrous DMF was stirred at about 20° C. for about 0.5 hour, and was cooled down to about 0° C. The mixture was treated with an alkyl halide (1.0 eq), and was stirred at about 0–85° C. for about 16 hours. To the reaction mixture was added methanol. The solid was filtered off and washed with methanol. The solvent was evaporated and the residue was dissolved in DMF. The crude reaction solution was purified by preparature LC/MS to give pure desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(O)(=O)C.C([BH3-])#N.[Na+].[CH3:36][C:37]1[N:42]=[C:41]([CH:43]=O)[CH:40]=[CH:39][CH:38]=1>>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][CH2:43][C:41]6[CH:40]=[CH:39][CH:38]=[C:37]([CH3:36])[N:42]=6)=[C:7]5[CH:8]=[CH:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:25][CH:24]=1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: Cc1cccc(C=O)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccc(CNC2=c3ccc4c5c([nH]c(=O)c-5c3N(C)C=C2)=CCN4c2ccc(F)cc2)n1
Yield: 43.5 %

Procedure:
A stock solution of Example 23e (0.164 M in N,N-dimethylacetamide, 255 mL, 0.042 mmol), acetic acid (4 M in methanol, 200 mL, 0.84 mmol), sodium cyanoborohydride (0.31 M in methanol, 200 mL, 0.063 mmol) and 6-methylpicolinaldehyde (0.40 M in N,N-dimethylacetamide, 156 mL, 0.063 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 50° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0085 g (44%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 10.85 (s, 1H), 8.41 (d, J=1.83 Hz, 1H), 7.96 (s, 1H), 7.81 (dd, J=8.24, 1.83 Hz, 1H), 7.38 (m, 2H), 7.04 (s, 1H), 6.87 (m, J=9.00, 9.00 Hz, 3H), 6.58 (m, 3H), 4.58 (m, 2H), 4.06 (s, 3H), 3.90 (s, 3H), 3.17 (s, 2H). MS (APCI+) m/z 466.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:3]=1[F:24].FOBOF.Br.Br.[CH2:32]([N:39]1[CH2:44][CH:43]2[CH2:45][CH:40]1[CH2:41][NH:42]2)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>CS(C)=O>[F:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:42]1[CH2:41][CH:40]3[CH2:45][CH:43]1[CH2:44][N:39]3[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[N:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])[CH:8]=[C:7]([C:20]([OH:22])=[O:21])[C:6]2=[O:23]
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)cc2c1=O
Agent: Br
Agent: FOBOF
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(N3CC4CC3CN4Cc3ccccc3)c(F)cc2c1=O
Yield: 39 %

Procedure:
Analogous to example 6 but utilizing 5.56 g (13.85 m Mol) of the mixed anhydride of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)1,4-dihydro-4-oxoquinoline-3-carboxylic acid and difluoroboronic acid, 5.82 g (16.62 m Mol) 2-benzyl-2,5-diazabicyclo(2.2.1)heptane dihydrobromide and 11.58 ml (83 m Mol)triethylamine in 50 ml dry DMSO yielded 2.73 g (39%) of the product, mp 233° C.-238° C. dec.