Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[O:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][NH:25][C:26]2[N:27]=[N+:28]([O-:39])[C:29]3[CH:38]=[C:37]4[C:33]([CH2:34][CH2:35][CH2:36]4)=[CH:32][C:30]=3[N:31]=2)[CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[O:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][NH:25][C:26]2[N:27]=[N+:28]([O-:39])[C:29]3[CH:38]=[C:37]4[C:33]([CH2:34][CH2:35][CH2:36]4)=[CH:32][C:30]=3[N+:31]=2[O-:4])[CH2:18][CH2:17]1
Reactant: [O-][n+]1nc(NCCN2CCCOCC2)nc2cc3c(cc21)CCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: [O-][n+]1nc(NCCN2CCCOCC2)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 41.5 %

Procedure:
H2O2 (70%, 1.25 mL, ca. 25.8 mmol) was added dropwise to a stirred solution of TFAA (3.6 mL, 25.8 mmol) in DCM (35 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 48 (0.85 g, 2.58 mmol) and TFA (0.43 mL, 5.50 mmol) in CHCl3 (35 mL) at 0° C. The solution was stirred at 20° C. for 5 h, diluted with dilute aqueous NH3 solution until basic and extracted with CHCl3 (4×60 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (3-6%) of MeOH/DCM, to give 1,4-dioxide 49 (0.37 g, 42%) as a red gum: 1H NMR δ 8.13 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.45 (br s, 1H, NH), 3.82 (t, J=6.1 Hz, 2H, CH2O), 3.74 (t, J=4.6 Hz, 2H, CH2O), 3.54 (q, J=5.7 Hz, 2H, NCH2), 2.97-3.04 (m, 4H, H-6, H-8), 2.73-2.80 (m, 6H, CH2), 2.15 (p, J=7.4 Hz, 2H, H-7), 1.91 (p, J=5.9 Hz, 2H, CH2); 13C NMR δ 158.7, 154.6, 148.8, 143.3, 129.8, 120.5, 114.7, 69.3, 68.7, 57.4, 55.8, 53.6, 38.7, 33.1, 32.3, 29.9, 25.7; HRMS (FAB+) calcd for C17H24N5O3 (MH+) m/z 346.1879, found 346.1877.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36](OC(=O)C)(=[O:38])[CH3:37].N1C=CC=CC=1>O1CCCC1>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCNCC3)cc2C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(COc2ccc3c(c2)CN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N,N′-ditert-butoxycarbonyl-7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran (1.5 ml) were added acetic anhydride (0.021 ml) and pyridine (0.025 ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (100 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[OH:8][C:9]1[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11][N:10]=1>C1C=CC=CC=1>[Cl:1][CH2:2][C:3]([NH:5][C:6]([N:10]1[C:9](=[O:8])[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11]1)=[O:7])=[O:4]
Reactant: CCOc1nc(O)ns1
Reactant: O=C=NC(=O)CCl
Solvent: c1ccccc1
Product: CCOc1nc(=O)n(C(=O)NC(=O)CCl)s1
Temperature: 20 °C
Reaction time: 17 h
Yield: 58 %

Procedure:
31.5 g of α-chloroacetyl isocyanate were added dropwise to a solution of 18.98 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 200 ml of benzene and after stirring the mixture for 17 hours at 20° C, it was vacuum filtered. The recovered crystals were dried to obtain 20 g of 2-(N-α-chloroacetylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at 132° C.
Reaction SMILES: [C:1]1([CH:7]([SiH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]2N(C)C(C)(C)C[O:22]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.Cl>C(OC)(C)(C)C>[C:1]1([CH:7]([SiH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]=[O:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1C(c2ccccc2[SiH2]C(c2ccccc2)c2ccccc2)OCC1(C)C
Agent: Cl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=Cc1ccccc1[SiH2]C(c1ccccc1)c1ccccc1
Yield: 86.2 %

Procedure:
2.35 g of the product of Step (e), above, is heated in a mixture 12 ml of THF and 6 ml of 2N hydrochloric acid, at 60° for 5 hours. The reaction mixture is then diluted with methyl tert.-butyl ether and washed with 2N hydrochloric acid and then brine. The aqueous phases are combined and extracted thrice with methyl tert.-butyl ether. The combined organic extracts are washed with aqueons sodium carbonate, dried and concentrated to give 1.58 g of the title aldehyde product of this step, NMR(CDCl3) δ0.95 (3H, s), 7.2-7.7(13H, m), 7.85-8.05(1H, m), 10(1H, s).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:28][NH2:29]>C(O)CCC>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][C:6]=2[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)=[O:18])=[CH:12][CH:11]=2)[NH:29][N:28]=1
Reactant: NN
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3ccnc(Cl)c3C#N)cc2)c1
Solvent: O
Solvent: CCCCO
Product: Cc1cccc(NC(=O)Nc2ccc(-c3ccnc4[nH]nc(N)c34)cc2)c1

Procedure:
A mixture of Example 35D (0.08 g, 0.22 mmol) and hydrazine hydrate (0.11 mL, 2.2 mmol) in n-butanol (5 mL) was heated at 110° C. for 2 h, then concentrated. The residue was purified via HPLC on an Agilent Zorbax Stablebond C-18 (7 micron particle size) preparative column using a solvent gradient of 20% to 100% acetonitrile in 0.1% aqueous TFA at a flow rate of 15 ml/min over 50 min, to give the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 6.81 (d, J=7.32 Hz, 1H) 6.93 (d, J=4.58 Hz, 1H) 7.17 (t, J=7.63 Hz, 1H) 7.26 (d, J=7.63 Hz, 1H) 7.33 (s, 1H) 7.54 (d, J=8.24 Hz, 2H) 7.66 (d, J=7.93 Hz, 2H) 8.38 (d, J=4.27 Hz, 1H) 8.80 (s, 1H) 9.04 (s, 1H); MS (ESI(+)) m/e 359 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:10](=[CH:11][S:12][C:13]=2[N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O.NN>C(O)C>[NH2:15][C:13]1[S:12][CH:11]=[C:10]2[CH2:9][C:8]3[C:3]([C:2](=[O:1])[C:14]=12)=[CH:4][CH:5]=[CH:6][CH:7]=3
Reactant: O=C1c2ccccc2Cc2csc(N3C(=O)c4ccccc4C3=O)c21
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1scc2c1C(=O)c1ccccc1C2
Temperature: 25 °C

Procedure:
To a suspension of 2-[4-oxo-9H-naphtho[2,3-c]thiophene-3-yl]-isoindole-1,3-dione (0.45 mmol, Example 32, Part G) in absolute ethanol (5 mL) is added hydrazine hydrate (0.5 mmol). The mixture is heated to reflux for one hour, cooled to room temperature, concentrated in vacuo, and the residue dissolved in methylene chloride. The solution is chilled to 5° C. for one hour, during which time the phthaloyl hydrazide precipitates. The precipitate is removed by filtration, the filtrate concentrated in vacuo, and the residue purified by column chromatography on silica gel, eluting with a 4:1 mixture of petroleum ether:ethyl acetate. Fractions containing the product are collected, evaporated, and the product recrystallized.
Reaction SMILES: [CH2:1]([C@@H:5]1[C@@H:14]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].Cl>CC(C)=O>[CH2:1]([C@@H:5]1[CH2:6][C:7](=[O:8])[CH2:12][CH2:13][C@@H:14]1[NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC2(CC[C@@H]1NC(=O)OCc1ccccc1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: CCCC[C@@H]1CC(=O)CC[C@@H]1NC(=O)OCc1ccccc1
Yield: 115.4 %

Procedure:
A solution of benzyl ((7S,8S)-7-(butyl)-1,4-dioxa-spiro[4.5]dec-8-yl)-carbamate (3 g, 0.008 mol) in acetone (30 mL) is treated with 1 N HCl (30 mL) and heated to reflux for 2 hrs. The mixture is concentrated on a rotary evaporator and the residue neutralized with 1 N NaOH and extracted into CH2Cl2. The organic extracts were washed with water, brine, and the solvent remove under vacuum to give 2.8 g of the benzyl (1S,2R)-2-butyl-4-oxocyclohexylcarbamate. This is used without further purification.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[C:13]([CH3:19])=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1.[C:20]([O:24][C:25]([N:27]1[CH2:36][CH2:35][C:30]2([CH2:33][C:32](=[O:34])[CH2:31]2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:28][CH2:29][C:30]2([CH2:31][C:32]([CH2:19][C:13]3[C:12]([Br:11])=[CH:17][N:16]=[C:15]([Cl:18])[CH:14]=3)([OH:34])[CH2:33]2)[CH2:35][CH2:36]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1cc(Cl)ncc1Br
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)(Cc1cc(Cl)ncc1Br)C2
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 mol/L in tetrahydrofuran; 8.0 mL) is added dropwise to 5-bromo-2-chloro-4-picoline (0.81 g) dissolved in tetrahydrofuran (10 mL) at −45° C. under Ar atmosphere. The solution is stirred at −35 to −45° C. for 0.5 h prior to dropwise addition of 2-oxo-7-aza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (1.00 g) dissolved in tetrahydrofuran (5 mL). The reaction mixture is stirred at −40° C. for 45 min before the cooling bath is removed. At room temperature the reaction is quenched with aqueous NH4Cl solution and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:1) to give the title compound. LC (method 1): tR=1.36 min; Mass spectrum (ESI+): m/z=445 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][C:11]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[O:6].N#N.I[CH:32]([CH3:34])[CH3:33]>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][C:11]=1[N:12]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:32]([CH3:34])[CH3:33])=[O:6]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1Cl
Reactant: CC(C)I
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54.9 %

Procedure:
Sodium Hydride (60% dispersion in oil, 190 mg, 5.2 mmol) was added to an ice-cold solution of 3-(2,4-Dichloro-benzoylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (2) (1.5 g, 3.69 mmol) in 350 ml of N,N-dimethylformamide in an atmosphere of N2. After 5 min, 2-Iodo-propane (941 mg, 5.54 mmol) was added to the solution and then the reaction mixture was stirred for 30 min at 0° C. and 64 h at room temperature. The mixture was partitioned between ether (200 mL) and water (350 mL) and the organic layer was separated. The aqueous phase was washed twice with ether (2×70 mL) and the combined ether layer was dried (MgSO4), concentrated and the residue was purified by flash chromatography (10% EtOAc/Hexane) to obtain 908 mg (55%) of 3-[(2,4-Dichloro-benzoyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): Rotamere 95/05: 7.54 ppm (dd, 2H, Haro); 7.49-7.35 ppm (m, 3H, Haro); 7.29-7.25 ppm (m, 2H, Haro); 7.15 ppm (d, 1H, Haro); 7.05 ppm (d, 1H, Haro) 5.09 ppm (hex, 1H, N—CH(CH3), major rotamere); 3.99 ppm (hex, N—CH(CH3), minor rotamere); 3.89 ppm (s, 3H); 1.40 ppm (d, 3H, N—CH(CH3), major rotamere); 1.28 ppm (d, N—CH(CH3), minor rotamere); 1.09 ppm (d, 3H, N—CH(CH3), major rotamere); 1.01 ppm (d, N—CH(CH3), minor rotamere).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:26])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([O:24]C)[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.CO.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:26])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:24])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(C)N2CC(c3cccc(Cl)c3)OC2=O)cc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(Cc1ccc(O)c(O)c1)N1CC(c2cccc(Cl)c2)OC1=O
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 92.7 %

Procedure:
Twenty grams of [R-(R*,R*)]-5-(3-chlorophenyl)-3-[2-(3,4-dimethyloxyphenyl)-1-methylethyl]-2-oxazolidinone, prepared by the procedure described in U.S. Pat. No. 5.061,727, is dissolved in 100 ml of methylene chloride and cooled to 5° C. under a stream of argon. Ten ml of boron tribromide in 10 ml of methylene chloride is added dropwise over 25 minutes. The reaction mixture is stirred for 20 minutes at 0°-5° C. One hundred and fifty ml of methyl alcohol is added over 40 minutes and the reaction is allowed to warm to room temperature over 1 hour. The solvent is removed by distillation (pot temperature 90° C.) leaving an oil in the bottom of the flask. The reaction flask is charged with 36.9 g of methyl alcohol, cooled to room temperature and 148 g of water is added over 1.5 hours. The reaction is stirred at room temperature for 72 hours, followed by cooling to 5° C. and stirring at this temperature for 1 hour. The resulting precipitate is collected, rinsed with water, and dried to give 17.1 g of the desired product (Yield 92.7% theory).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][NH:24][CH2:25]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][N:24]([C:11]1[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:15])[CH2:25]2
Reactant: Nc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1cccc2c1CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 51 %

Procedure:
133 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 81 mg of 4-aminoisoindoline, 182 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 97 mg of the target compound.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Na+].[OH2:11]>>[OH:11][C:5]1[CH:6]=[CH:7][C:2]([C:1]([OH:9])=[O:8])=[CH:3][N:4]=1
Reactant: O=C([O-])c1cccnc1
Reactant: O
Agent: [Na+]
Product: O=C(O)c1ccc(O)nc1
Temperature: 30 °C
Reaction time: 7 h

Procedure:
A 3-liter reaction vessel was filled with 2250 ml of 5 percent sodium nicotinate solution (pH 6.5) and was heated to 30° C. A suspension of Achromobacter xylosoxydans DSM 2783 cells in 120 ml of water was added and the reaction mixture was aerated intensively while stirring it well. The pH, the temperature and the oxygen concentration in the reaction mixture were measured and regulated continuously. After 7 hours, the concentration of the dissolved oxygen rose. At this point, the reaction was completed. The reaction suspension was centrifuged off and the cells in the sediment were used for the next charge. The clear supernatant was brought to pH 1.5 with concentrated sulfuric acid and the 6-hydroxynicotinic acid obtained was drained off and dried. 121 g of white product was obtained which, according to HPLC analysis, contained 98.6 percent of 6-hydroxynicotinic acid. This corresponded to a 6-hydroxynicotinic acid yield of 93.7 percent, related to the nicotinic acid used.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)COC)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f48) and commercially available methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N:16]([O-:18])=[O:17].[Na+]>FC(F)(F)C(O)=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCCN2C(C)=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CCC2
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of 1-acetyl-6-(methyloxy)-1,2,3,4-tetrahydroquinoline (500 mg, 2.44 mmol, Aldrich) in trifluoroacetic acid (4 mL, Aldrich) was treated with sodium nitrite (169 mg, 2.45 mmol, added slowly in about 4 portions, Aldrich). The dark brown reaction was stirred for 2 h and then poured over ice. The mixture was extracted with ethyl acetate and the organic layer was separated, dried over magnesium sulfate, filtered, concentrated, and purified by chromatography on SiO2 (0 to 100% ethyl acetate/hexanes) to give 1-acetyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (357 mg, 59%). 1H NMR (400 MHz, DMSO-d6) is complicated due to amide rotomers δ ppm 1.83-1.94 (m, 2 H), 2.14-2.25 (m, 3 H), 2.76-2.85 (m, 2 H), 3.64-3.73 (m, 2 H), 3.86-3.92 (m, 3 H), 7.14-7.25 (m, 1 H), 8.38 (very broad singlet, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[C:15]([CH2:16][CH2:17][CH3:18])=[C:14]([C:19]([O:21]C)=[O:20])[N:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[C:15]([CH2:16][CH2:17][CH3:18])=[C:14]([C:19]([OH:21])=[O:20])[N:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(C(=O)OC)nnn1-c1ccc(NC(C)=O)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1c(C(=O)O)nnn1-c1ccc(NC(C)=O)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 1-[6-(acetylamino)pyridin-3-yl]-5-propyl-1H-1,2,3-triazole-4-carboxylate (0.55 g) obtained in Example 26d) in ethanol (5 ml) was added 8N aqueous sodium hydroxide solution (0.45 ml), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, toluene (5 ml) was added to the residue. The solvent was evaporated under reduced pressure. To a solution of the residue in acetonitrile (10 ml) was added 4N hydrochloric acid-ethyl acetate solution (0.9 ml) to give a solution of 1-[6-(acetylamino)pyridin-3-yl]-5-propyl-1H-1,2,3-triazole-4-carboxylic acid in acetonitrile. Then, cyclopropylamine (0.15 ml), triethylamine (0.31 ml), HOBt (0.34 g) and WSC (0.42 g) were successively added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a pale-green powder (0.22 g, 41%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([I:11])[CH:6]=[C:7]([O:9]C)[CH:8]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([I:11])[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COc1cc(I)cc(OC)c1
Agent: Br
Solvent: CC(=O)O
Product: Oc1cc(O)cc(I)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
3,5-Dimethoxyiodobenzene (1.19 g) is dissolved in acetic acid (10 ml), and thereto is added 47% hydrobromic acid (10 ml) at room temperature, and the mixture is refluxed for 15 hours. The reaction mixture is cooled to room temperature, and concentrated to dryness under reduced pressure. The residue is dissolved in ethyl acetate, and the organic layer is washed with water, dried, and concentrated under reduced pressure to give 3,5-dihydroxyiodobenzene (1.06 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1I)([O-:20])=[O:19].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:10][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N+:18]([O-:20])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1[N+](=O)[O-])c1ccccc1
Temperature: 110 °C
Yield: 64.6 %

Procedure:
To a degassed solution of ((R)-2-amino-1-phenyl-ethyl)-carbamic acid tert-butyl ester (400 mg, 1.69 mmol) in toluene (10 ml), was added 2-nitroiodobenzene (423 mg, 1.69 mmol), Pd2 (dba)3 (31 mg, 0.34 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (39 mg, 0.68 mmol) and Cs2CO3 (551 mg, 1.69 mmol). The mixture was heated at 110° C. for 24 h. It was then concentrated and the residue was purified using column chromatography (4:1, Hexanes/EtOAc) to give [(R)-2-(2-nitro-phenylamino)-1-phenyl-ethyl]-carbamic acid tert-butyl ester (390 mg, 64%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:17][C:16]3[NH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19]I>CN(C)C=O>[CH3:19][N:15]1[C:16]2[CH2:17][CH:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:10][C:11](=[O:18])[C:12]=2[CH:13]=[CH:14]1
Reactant: CI
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c1CC(c1ccccc1)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a suspension of 60% sodium hydride (0.14 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.6 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of methyl iodide (0.44 g) in dimethylformamide (1 ml) at 0° C., and the mixture was stirred at room temperature for 3.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 1-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.57 g).