Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[C:8]([F:11])=[CH:9][CH:10]=1.[C:27](Cl)(=[O:29])[CH3:28]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:27](=[O:29])[CH3:28])[CH2:24][CH3:25])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1F
Reactant: CC(=O)Cl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1F)C(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-fluoro-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:15]([CH:16]=2)[N:14]=[C:13]([C:17]2[C:18]([C:23]([F:26])([F:25])[F:24])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11]3)=[CH:4][C:3]=1[N+:27]([O-])=O>CCO.CC(O)=O.[Fe]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:15]([CH:16]=2)[N:14]=[C:13]([C:17]2[C:18]([C:23]([F:25])([F:24])[F:26])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11]3)=[CH:4][C:3]=1[NH2:27]
Reactant: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1N
Temperature: 70 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A mixture of 2-(4-methyl-3-nitro-phenyl)-6-[2-(trifluoromethyl)-3-pyridyl]imidazo[2,1-f]pyridazine (7.986 g, 0.02 mol) in EtOH—AcOH (48 mL, 1:1) is added slowly to a solution of iron powder (6.702 g, 0.12 mol) in EtOH—AcOH (60 mL, 2:1) at 60° C. The mixture is stirred at 70° C. for 60 min, cooled to room temperature, filtered through celite, washed with EtOAc and concentrated. The oily residue is dissolved in EtOAc (500 mL) and washed twice with saturated aqueous NaHCO3 (200 mL). Organic layer is dried and concentrated to afford the title compound as a solid (7.3 g). LCMS (m/z)=370.5 [M+H]+, tR=1.85 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH2:11]([NH2:17])[C:12]1[O:16][CH:15]=[CH:14][CH:13]=1>>[CH2:9]1[O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:17][CH2:11][C:12]3[O:16][CH:15]=[CH:14][CH:13]=3)=[CH:3][C:4]=2[O:10]1
Reactant: NCc1ccco1
Reactant: Brc1ccc2c(c1)OCO2
Product: c1coc(CNc2ccc3c(c2)OCO3)c1
Yield: 86.1 %

Procedure:
Using the general procedure, 4-bromo-1,2-(methylenedioxy)benzene (120 μL, 1.0 mmol) was coupled with furfurylamine (132 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (8:1) as eluent afforded the desired product as a colorless oil (187 mg, 87% yield). Rf=0.5 (hexane/ethyl acetate=5:1).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([N:13]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:14]2[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)=[O:12])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[CH:29]1([N:13]([C:14]2[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)[C:11](=[O:12])[NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:35])=[O:2])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COC(=O)c1cccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c1

Procedure:
In analogy to the procedure described in example 2.2, 3-[3-cyclohexyl-3-(2-phenyl-2H-indazol-3-yl)-ureido]-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 5 h at ambient temperature to give the title compound as yellow foam. MS: m/e=455.1 [M+H+].
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:9][C@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11].I>ClCCl>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:11][C@@H:10]([C@H:12]3[O:13][C@@H:18]4[O:19][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:17][C@H:16]4[C@H:14]3[OH:15])[CH2:9][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C1CCCCC1
Agent: I
Solvent: ClCCl
Product: O[C@@H]1[C@@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1[C@H]1COC2(CCCCC2)O1
Temperature: 65 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a mixture of 150 ml of cyclohexanone and 120 ml of dichloromethane were added 10.0 g of D-mannose and 175 mg of hydriodic acid (57%) and the mixture was refluxed with stirring in a water bath at 65° C. for 8 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. The reaction mixture was diluted with benzene, washed with aqueous sodium bicarbonate and water and dried over anhydrous magnesium sulfate. The solvent and cyclohexanone were distilled off under reduced pressure to give 11.9 g (82.6%) of 2,3:5,6-di-O-cyclohexylidene-α-D-mannofuranose. After recrystallization from cyclohexane, it melted at 122°-124° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:12]([CH3:13])=[CH:11][N:10]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:9]=1)(O)=[O:6]>C(Cl)(Cl)Cl>[Cl:3][C:5]([C:8]1[C:12]([CH3:13])=[CH:11][N:10]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1cn(-c2ccnc3ccccc23)cc1C(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1cn(-c2ccnc3ccccc23)cc1C(=O)Cl
Reaction time: 1 h
Yield: 100 %

Procedure:
10 mL (137 mmol) of sulphinyl chloride are added at a temperature in the region of 20° C. under an argon atmosphere to 1 g (3.97 mmol) of 3-carboxy-4-methyl-1-(quinol-4-yl)-1H-pyrrole dissolved in 20 mL of chloroform. After stirring at the reflux point of the solvent for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in 20 mL of chloroform and then brought back to dryness to give 1.07 g (3.97 mmol) of 3-chlorocarbonyl-4-methyl-1-(quinol-4-yl)-1H-pyrrole in the form of a beige-coloured solid which is used directly in the following step.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:27])[CH2:6][S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:3])[CH3:2].[C:28](NC(=S)CCC1C=CC=CC=1)(=O)C>>[C:1]([N:4]([CH3:28])[C:5](=[O:27])[CH2:6][S:7][CH2:8][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)NC(=S)CCc1ccccc1
Product: CC(=O)N(C)C(=O)CSCc1ccccc1

Procedure:
Employing the procedure described above, but substituting for the N-acetyl-2-(triphenylmethylthio) acetamide an equivalent amount of N-acetyl-2-benzylthio acetamide, there is provided N-acetyl-N-methyl-2-(benzylthio) acetamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCCO)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([O:19][CH2:2][CH2:1][O:8][CH2:9][CH3:10])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Solvent: CCOCCO
Product: CCOCCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC

Procedure:
The ester can be prepared by acid catalysed esterification of 3-[4-(benzyloxy)phenyl]-2-ethoxypropanoic acid with/in 2-ethoxyethanol. Isocratic HPLC method 2 (4.34 min.): 97.6%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][C@@H:22]4[CH2:24][C@H:19]3[CH2:20][N:21]4C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][C@@H:22]4[CH2:24][C@H:19]3[CH2:20][NH:21]4)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCC(N3C[C@@H]4C[C@H]3CN4)CC2)ccc1[N+](=O)[O-]
Yield: 52.2 %

Procedure:
To 1,1-dimethylethyl (1S,4S)-5-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 2.3 mmol) in DCM (10 mL) was added TFA (10 mL). After reaction was shown to be complete by TLC, the volume is reduced on the rotovap until it weighs 4 g. The solution is diluted with DCM and poured into saturated NaHCO3 solution. The layers are separated and the aqueous layer washed with DCM. The organics are combined, dried (MgSO4), filtered and rotovaped to give the title compound of step B (400 mg, 1.2 mmol, 50%). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J=9.3 Hz, 1H), 6.37 (dd, J=9.3, 2.6 Hz, 1H), 6.27 (d, J=2.6 Hz, 1H), 3.90 (s, 3H), 3.80-3.73 (m, 2H), 3.60 (br s, 2H), 3.20 (d, J=10.6 Hz, 1H), 3.12-2.95 (m, 4H), 2.87-2.81 (m, 1H), 2.64-2.55 (m, 1H), 2.36 (d, J=9.3 Hz, 1H), 1.94-1.77 (m, 3H), 1.64 (d, J=9.3 Hz, 1H), 1.59-1.46 (m, 2H). The aqueous layer is re-extracted with EtOAc and then with 85:15 DCM:iPrOH to give more of the title compound of step B (400 mg, 1.2 mmol, 50%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=2)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl:46][C:47]1[CH:48]=[C:49]([C:54]2[O:58][C:57]([CH2:59][CH2:60][NH2:61])=[CH:56][CH:55]=2)[CH:50]=[CH:51][C:52]=1[Cl:53]>C(Cl)Cl>[Cl:46][C:47]1[CH:48]=[C:49]([C:54]2[O:58][C:57]([CH2:59][CH2:60][NH:61][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH:8]=3)=[O:14])=[CH:56][CH:55]=2)[CH:50]=[CH:51][C:52]=1[Cl:53]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: O=C(O)C1=NN=C(c2ccncc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(-c2ccncc2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a stirred solution of 5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid (1.78 g, 9.42 mmol) in DCM (10 ml) was added DIPEA (2.46 ml, 14.1 mmol), EDCI (2.71 g, 9.42 mmol) and HOBt (1.91, 14.1 mmol). 2-(5-(3,4-dichlorophenyl)furan-2-yl)-ethanamine hydrochloride (2.75 g, 9.42 mmol) was dissolved in DCM (15 ml) and DIPEA (1.64 ml, 9.42 mmol). The resulting solution was added to the reaction mixture, which was stirred at RT overnight. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution and water. The organic phase was dried over Na2SO4, evaporated and purified by chromatography (CombiFlash, silica column, eluent 0-15% MeOH/DCM). Product containing fractions were collected, evaporated and crystallized from DCM and re-crystallized from 2% MeOH/DCM and heptane. Thus, 1.18 g (29%) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 2.97 (t, 2H), 3.59 (q, 2H), 6.35 (d, 1H), 7.03 (d, 1H), 7.33 (s, 1H), 7.62 (d, 2H), 7.75 (m, 2H), 7.84 (t, 1H), 8.57 (br s, 1H), 8.63 (m, 2H), 13.95 (s, 1H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.N1C=CC=CC=1.[F:29][C:30]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:31]=1[CH2:32][O:33][C:34]1[C:35]2[N:36]([C:40]([C:44]([NH:46][C@H:47]([CH2:50][CH2:51][CH2:52][CH3:53])[CH2:48][OH:49])=[O:45])=[C:41]([CH3:43])[N:42]=2)[CH:37]=[CH:38][CH:39]=1.[OH-].[Na+]>ClCCl>[F:29][C:30]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:31]=1[CH2:32][O:33][C:34]1[C:35]2[N:36]([C:40]([C:44]([NH:46][C@H:47]([CH2:50][CH2:51][CH2:52][CH3:53])[CH:48]=[O:49])=[O:45])=[C:41]([CH3:43])[N:42]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC[C@H](C=O)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Reaction time: 2 h

Procedure:
1.14 g of Dess-Martin periodinane (2.7 mmol, 1.5 equivalents) were initially charged in 25 ml of dichloromethane, and 0.145 ml of pyridine (1.8 mmol, 1 equivalent) and 750 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (Example 3A, 1.8 mmol) were added at −20° C. The reaction mixture was stirred at this temperature for 2 h. 1 N aqueous sodium hydroxide solution was added with ice cooling, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. This gave 899 mg (about 70% pure; 90% of theory) of the target compound which were not purified any further.
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].[CH2:8]1[O:17][C:16]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[O:9]1.CO>O1CCOCC1>[O:17]1[C:16]2[CH:15]=[CH:14][C:12]([NH:13][C:2](=[O:3])[CH3:1])=[CH:11][C:10]=2[O:9][CH2:8]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc2c(c1)OCO2
Temperature: 16 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
Ac2O (21.4 mL, 226 mmol) was added dropwise to a stirred solution of 3,4-methylendioxyaniline (217) (25.87 g, 189 mmol) in dioxane (200 mL) at 0° C. and the mixture was stirred at 16° C. for 16 h. MeOH (10 mL) was added to decompose excess Ac2O and the solvent evaporated. The residue was dissolved in EtOAc (200 mL), dried and the solvent evaporated. The residue was filtered through a short column of silica, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 218 (29.17 g, 86%) as a white solid: mp 133-135° C. [lit (Krasso, A. & Ramuz, H., U.S. Pat. No. 4,599,347, 1986) mp (toluene) 138-139° C.]; 1H NMR δ 7.09 (d, J=1.8 Hz, 1H, H-4), 7.06 (br s, 1H, NH), 6.77 (dd, J=8.3, 1.8 Hz, 1H, H-6), 6.72 (d, J=8.3 Hz, 1H, H-7), 5.94 (s, 2H, H-2), 2.14 (s, 3H, CH3).
Reaction SMILES: [CH2:1]([CH:3]([CH2:25][CH3:26])[CH:4]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].[CH3:27][NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH2:1]([CH:3]([CH2:25][CH3:26])[CH:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([N:28]([CH3:27])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:22])=[CH:23][CH:24]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2]
Reactant: CCOC(=O)CCNC
Reactant: CCC(CC)C(Nc1ccc(C(=O)O)cc1)c1sc2ccccc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3ccccc3c2C)C(CC)CC)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 77.4 %

Procedure:
To a mixture of 4-{[2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl]amino}benzoic acid (250 mg) synthesized in Example A134(3), ethyl 3-(methylamino)propanoate (134 mg), 1-hydroxybenzotriazole monohydrate (156 mg), triethylamine (284 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (196 mg), and the mixture was stirred at room temperature 2.5 days. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine and saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (253 mg, 77%) as a colorless oil.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)[CH:8]=[CH:9][C:2]=12.[C:19]([C:22]1[CH:23]=[C:24]([NH:29]C(=O)C)[CH:25]=[CH:26][C:27]=1O)(=[O:21])[CH3:20].N1CCCC1.Cl>CO.C(O)C>[NH2:29][C:24]1[CH:25]=[CH:26][C:27]2[O:18][C:15]3([CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]4[CH:8]=[CH:9][C:2]5[C:3]([CH:6]=4)=[N:4][O:5][N:1]=5)[CH2:13][CH2:14]3)[CH2:20][C:19](=[O:21])[C:22]=2[CH:23]=1
Reactant: CC(=O)Nc1ccc(O)c(C(C)=O)c1
Reactant: O=C1CCN(CCc2ccc3nonc3c2)CC1
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: C1CCNC1
Product: Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc4nonc4c3)CC1)O2
Yield: 77.3 %

Procedure:
1-[2-(Benzofurazan-5-yl)ethyl]-4-piperidinone (0.98 g, 4 mmol), N-(3-acetyl-4-hydroxyphenyl)acetamide (0.77 g, 4 mmol) and pyrrolidine (0.33 ml, 0.28 g, 4 mmol) in methanol (20 ml) were heated under reflux for 3 hours, cooled and the solvent was evaporated under reduced pressure. Water (50 ml) and aqueous sodium hydroxide (20%, 10 ml) were added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure to give a yellow solid. Ethanol (40 ml) and aqueous HCl (6N, 40 ml) were added and the mixture was heated under reflux for 2 hours. The mixture was cooled and the ethanol was evaporated under reduced pressure. Water (40 ml) was added and the mixture was washed with ethyl acetate (50 ml). Aqueous sodium hydroxide (20%, 60 ml) was added slowly, with stirring and cooling, and the mixture was extracted with dichloromethane (3×100 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The residue was triturated with ethyl acetate-hexane (1:1, 20 ml) and the solid was collected and dried in vacuo to give a yellow solid (1.17 g, 77%). A sample was recrystallized from chloroform-hexane to give the pyranone as a yellow solid, m.p. 191°-193° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]3[CH:21]=2)[CH:6]=[CH:7][CH:8]=1.C(O)C>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]3[CH:21]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cn3c(ccc4ccccc43)n2)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cccc(-c2cn3c(n2)CCc2ccccc2-3)c1
Reaction time: 5 h

Procedure:
2-(3-Methoxyphenyl)imidazo[1,2-a]quinoline (2.74 g) together with 0.5 g. of 10% palladium on charcoal, 35 ml. of ethanol and 25 ml. of acetic acid is hydrogenated at 90° C. and 10 atmospheres for five hours. After filtration of the catalyst, the solution is evaporated to dryness and the residue is washed with water and aqueous solution carbonate. The resulting solid is extracted with ethyl ether and the organic solution, after drying, is evaporated to yield a product which, after crystallization from a hexane dichloromethane mixture, melts at 107°-9° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8](=[O:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>P([O-])([O-])([O-])=O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(=O)c1ccccc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)COC(=O)c1ccccc1

Procedure:
Using 5 ml of Medium C described hereinbefore, the microorganisms indicated in Table 4 were cultured in the same manner as in Example 11. From 5 ml of each culture, the cells were centrifugally harvested, suspended in 0.5 ml of 100 mM phosphate buffer (pH 6.5) containing 0.05% of (5S)-6-benzoyloxy-5-hydroxy-3-oxohexanoic tert-butyl ester and 8% of glucose, and the reaction was carried out in the same manner. The results are shown in Table 4.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([O:11][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc([N+](=O)[O-])ccn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add 100 mL of toluene to a nitrogen purged mixture of 2-chloro-4-nitro-pyridine (4.32 g, 27.2 mmol), tert-butyl 4-hydroxypiperidine carboxylate (11.0 g, 54.5 mmol), cesium carbonate (13.3 g, 40.8 mmol), palladium acetate (122 mg, 0.544 mmol) and 2-(di-tert-butylphosphino)-1,1′-binapthyl (271 mg, 0.68 mmol). Stir the resulting mixture overnight at room temperature, then partition between water and ethyl acetate. Extract the aqueous layer with additional ethyl acetate, and dry the combined organic layer over sodium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with a gradient of 0 to 20% ethyl acetate in hexanes to afford 4-(4-nitro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester as a white waxy solid (5.37 g, 61%; LCMS ES+(m/z) 268 [M-tBu]+).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH3:6][C:7]1[C:8]2[CH2:24][CH2:23][CH2:22][CH2:21][C:9]=2[N+:10]2[CH2:11][CH2:12][C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]=2[CH:16]=1.N([CH:32]=[C:33]1[C:38](=[O:39])[N:37]([CH2:40][CH3:41])[C:36](=[S:42])[N:35]([CH2:43][CH3:44])[C:34]1=[O:45])C1C=CC=CC=1.CN(C)C(=N)N(C)C>C(#N)C>[CH2:40]([N:37]1[C:38](=[O:39])[C:33](=[CH:32][CH:6]=[C:7]2[CH:16]=[C:15]3[N:10]([CH2:11][CH2:12][C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=43)[C:9]3[CH2:21][CH2:22][CH2:23][CH2:24][C:8]2=3)[C:34](=[O:45])[N:35]([CH2:43][CH3:44])[C:36]1=[S:42])[CH3:41]
Reactant: Cc1cc2[n+](c3c1CCCC3)CCc1ccccc1-2
Reactant: CCN1C(=O)C(=CNc2ccccc2)C(=O)N(CC)C1=S
Agent: CN(C)C(=N)N(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: CCN1C(=O)C(=CC=C2C=C3c4ccccc4CCN3C3=C2CCCC3)C(=O)N(CC)C1=S

Procedure:
1,2,3,4,6,7-Hexahydro-13-methyldibenzo[a,f]quinolizinium perchlorate (0.7 g) and 5-anilinomethylene-1,3-diethyl-2-thiobarbituric acid (0.6 g) were dissolved in acetonitrile and tetramethylguanidine (0.22 g) was added. The precipitated dye was collected by filtration and recyrstallized from dimethylformamide. Yield 0.4 g (44%), m.p. 320°, λmax in pyridine 522 nm, ε = 8.2 × 104.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:22])[CH:19]([CH3:21])[CH3:20])=[N:16][C:15]3[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:22])[CH:19]([CH3:21])[CH3:20])=[N:16][C:15]3[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2nc(N(C)C(C)C)c(-c3ccc(F)cc3)nc2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2nc(-c3ccc(F)cc3)c(N(C)C(C)C)nc2cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-7-methoxy-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (120 mg, 0.31 mmol) in methanol (30 mL) and water (1.0 mL) was added sodium hydroxide (50 mg, 1.25 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL), and adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford 2-(4-fluorophenyl)-7-methoxy-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a light yellow solid (38.2 mg, 88%).