Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][N:10]=[C:9]1[CH:16]=CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[O+][O-].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(O)[O-].[NH2:40][NH:41][C:42]([NH2:44])=[S:43]>CO.O>[CH2:1]([N:8]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][N:10]=[C:9]1[CH:16]=[N:40][NH:41][C:42]([NH2:44])=[S:43])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc(C=Cc2ccccc2)n1Cc1ccccc1
Reactant: NNC(N)=S
Agent: O=S([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: O=[O+][O-]
Solvent: O
Solvent: CO
Product: NC(=S)NN=Cc1ncc([N+](=O)[O-])n1Cc1ccccc1

Procedure:
0.5 g. (1.64 millimole) of β-(1-benzyl-5-nitro-2-imidazolyl)styrene in 95% aqueous methanol is treated with ozone until a clear solution is obtained. To this solution at 15° C., 0.312 g. (1.64 millimole) of sodium meta-bisulfite (Na2S2O5) in 3 ml. of water is added. The mixture is then evaporated to dryness under reduced pressure at 75° C. and the solid extracted with ethyl acetate. The ethyl acetate extracts are dried, evaporated to dryness to give a yellow-orange residue (probably bisulfite addition product) which solidifies upon standing. This material is dissolved in 20 ml. of aqueous methanol and 0.15 g. of thiosemicarbazide and a drop of 6N hydrochloric are added. After refluxing for 15 minutes and cooling, 0.25 g., melting point 193°-196° C., of 1-benzyl-5-nitro-2-imidazolecarboxaldehyde thiosemicarbazone is isolated. The use of a half of an equimolar amount of sodium meta-bisulfite affords the title aldehyde instead of the bisulfite addition product. When the ethyl acetate extract is evaporated to dryness and dissolved in 75% aqueous ethanol and semicarbazone is added, and the mixture is heated on a steam bath for 10 minutes, and sodium acetate is added, the semicarbazone derivative, melting point 226°-228° C. is obtained. Twelve grams of 1-benzyl-5-nitro-2-imidazolecarboxaldehyde thiosemicarbazone are added to a stirred solution of 76.2 g. of ferric ammonium sulfate dodecahydrate in 600 ml. of water at 50° C. and the slurry is heated at 90°-95° C. for 6 hours. The mixture is cooled in ice and the yellow-brown solid collected, washed with water, and dried under pressure. The yield of product is 10.9 g. Recrystallization from methanol gives analytically pure material melting at 213°-215° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]2[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[O:33][N:32]=2)[CH:30]=1)[C:25](O)=[O:26]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]2[N:35]=[C:34]([C:36]([F:38])([F:37])[F:39])[O:33][N:32]=2)[CH:30]=1)[C:25]([NH:19][CH2:18][C:12]1([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[O:26]
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Reactant: COc1cc(C(=O)O)cc(-c2noc(C(F)(F)F)n2)c1
Product: COc1cc(C(=O)NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)cc(-c2noc(C(F)(F)F)n2)c1
Yield: 46 %

Procedure:
This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-methoxy-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (70 mg, yield 46%): 1H NMR (400 MHz, CDCl3) δ 8.75 (t, J=6.3 Hz, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.91 (d, J=7.0 Hz, 2H), 7.63 (m, 1H), 7.57 (m, 1H), 7.38-7.35 (m, 2H), 7.30-7.26 (m, 1H), 3.85 (s, 3H), 3.83 (m, 2H), 3.56 (d, J=6.5 Hz, 2H), 3.41-3.36 (m, 2H), 2.23 (d, J=13.5 Hz, 2H), 2.01-1.94 (m, 2H). MS (ESI) m/z: Calculated for C26H23F3N4O4S: 544.14. found: 545.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[O:19])[CH3:18])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[O:19])[CH:18]=[CH:22][N:23]([CH3:25])[CH3:24])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Product: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 2-(4-fluorophenyl)-3-acetylpyrazolo[1,5-a]pyridine (1.0 g, 3.93 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) was stirred and heated at reflux for 17 h. The mixture was cooled to room temperature and the volatiles evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluded with 1% MeOH/CH2Cl2) to afford the title compound as an orange solid, 0.830 g (68%). 1H NMR (CDCl3) 88.50 (d, 1H, J=6.9 Hz), 8.39 (d, 1H, J=9.0 Hz), 7.83 (d, 2H, J=12.6 Hz), 7.73 (m, 2H), 7.39 (m, 1H), 7.20 (m, 2H), 6.93 (m, 1H), 5.13 (d, 1H, J=12.5 Hz), 3.10 (s. 3H), 2.56 (s, 3H). MS (+ve ion electrospray) 310 (90), (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)NCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
N-(4-Nitrobenzyl)methanesulfonamide (881 mg, 3.83 mmol) was dissolved in methanol/tetrahydrofuran (1:1, 35 mL). 10% Pd/C (264 mg, 3 eq) was added to it. The resulting mixture was stirred at room temperature for overnight under H2. TLC showed complete consumption of starting material. The mixture was filtered through celite bed and the filterate was concentrated under reduced pressure. The crude was purified by column chromatography to give N-(4-aminobenzyl)methanesulfonamide (352 mg, 46%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:9]=1[N:19]1[C:23]([NH2:24])=[C:22]([N+:25]([O-:27])=[O:26])[CH:21]=[N:20]1.Br[CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31]>C(#N)C>[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([Cl:18])[C:9]=1[N:19]1[C:23]([NH:24][CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[C:22]([N+:25]([O-:27])=[O:26])[CH:21]=[N:20]1
Reactant: COC(=O)C(C)Br
Reactant: Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 89 %

Procedure:
2.8 g (0.02 mole) of potassium carbonate are added to 3.4 g (0.01 mole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-nitro-5-amino-pyrazole, dissolved in 30 ml of acetonitrile, and 3.7 g (0.022 mole) of methyl α-bromopropionate, dissolved in 10 ml of acetonitrile, are added dropwise at room temperature in the course of 10 minutes. The reaction mixture is heated under reflux for 21/2 hours and filtered hot and the solvent and excess α-bromopropionate are removed by concentration of the filtrate in vacuo. The residue is crystallized from petroleum ether. 3.8 g (88% of theory) of methyl α-{N-[1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-nitro-pyrazol-5-yl]amino}-propionate of melting point 123° C.-130° C. are obtained.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([N:17]1C[CH2:23][CH2:22][CH:18]1C(O)=O)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]>CN(C)C=O.C(Cl)Cl>[CH2:10]([O:9][C:7]([N:17]1[CH2:18][CH2:22][CH2:23][CH:1]1[C:2]([Cl:4])=[O:3])=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
Oxalyl chloride (1.21 mL, 14.0 mmol) was added dropwise (15 minutes) to a 0° C. solution of N-carbobenzyloxy-D,L-proline (2.50 g, 10.0 mmol), dimethylformamide (1 drop, cat.) and methylene chloride (anhydrous, 25 mL) under a nitrogen atmosphere. The mixture was removed from the ice-bath and stirred at ambient temperature for 1 h. The reaction mixture was concentrated to afford 2.63 g (98%) of 2-chlorocarbonyl-pyrrolidine-1-carboxylic acid benzyl ester as an orange oil. The product was used directly in subsequent steps.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:44])[CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]2)=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:44])[CH2:35][CH2:36][N:37]2[CH2:38][CH2:39][CH:40]([OH:43])[CH2:41][CH2:42]2)=[CH:17][N:16]=1
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Reactant: COc1cc(-c2csc3c(NC(=O)CCN4CCC(O)CC4)cnc(N)c23)ccc1N
Product: COc1cc(-c2csc3c(NC(=O)CCN4CCC(O)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using 1-methyl-1H-indole-2-carbonyl chloride, N-[4-Amino-3-(4-amino-3-methoxyphenyl)-thieno[3,2-c]pyridin-7-yl]-3-(4-hydroxy-piperidin-1-yl)propionamide, and the procedure described in General Procedure F. m/z (M+H)+ 599.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([CH2:13][OH:14])=[CH:12][C:5]=2[O:4][CH2:3]1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1>>[CH3:1][C:2]1([CH3:15])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([CH2:13][O:14][C:21]3[CH:22]=[CH:23][C:18]([S:17][CH3:16])=[CH:19][CH:20]=3)=[CH:12][C:5]=2[O:4][CH2:3]1
Reactant: CSc1ccc(O)cc1
Reactant: CC1(C)COc2ccc(CO)cc2OC1
Product: CSc1ccc(OCc2ccc3c(c2)OCC(C)(C)CO3)cc1

Procedure:
According to the method described in example 23, the title compound is prepared from (3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-methanol (31) and 4-(methylthio)phenol. MS (ESI) 331.3 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([NH2:20])=[O:19].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[CH3:23][N:24]([CH:26]=[N:20][C:18]([C:3]1[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=1)=[O:19])[CH3:25]
Reactant: NC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 130 °C
Yield: 76 %

Procedure:
A slurry of 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (0.54 g, 1.91 mmol) in N,N-dimethylformamide dimethylacetal (10 mL) was heated under microwave heating conditions at 130° C. for 15 min. After that time the reaction was cooled on an ice water bath and the resulting crystals collected by filtration and washed with hexanes to give 0.491 g (76%) of N-[(dimethylamino)methylidene]-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide as off white crystals. 1H NMR (300 MHz, CDCl3) δ ppm 3.16 (s, 3H), 3.22 (s, 3H), 6.72 (d, J=8.1 Hz, 1H), 7.57-7.71 (m, 2H), 7.74-7.85 (m, 1H), 7.89 (s, 1H), 8.25 (d, J=8.1 Hz, 1H), 8.70 (s, 1H).
Reaction SMILES: C[C@@]1(O)[C@H](NC)[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)[C@@H](O)[C@H](O)[C@H]3O)[C@@H](N)C[C@H]2N)OC1.CC(N)C1OC(OC2C(O)C(OC3OCC(O)(C)C(NC)C3O)C(N)CC2N)C(O)C(O)C1O.C[C@@:69]1([OH:100])[C@H:74]([NH:75][CH3:76])[C@@H:73]([OH:77])[C@@H:72]([O:78][C@@H:79]2[C@@H:84]([OH:85])[C@H:83]([O:86][C@H:87]3[O:92][C@H:91]([CH2:93][OH:94])[C@@H:90]([OH:95])[C@H:89]([OH:96])[C@H:88]3[NH2:97])[C@@H:82]([NH2:98])[CH2:81][C@H:80]2[NH2:99])[O:71][CH2:70]1.CN[C@@H]1C(O)[C@@H](OC2[C@@H](O)[C@H](O[C@H]3OC(CO)[C@@H](O)[C@H](O)C3NO)C(N)C[C@H]2N)OC[C@H]1O>>[CH3:76][NH:75][CH:74]1[CH:73]([OH:77])[CH:72]([O:78][CH:79]2[CH:84]([OH:85])[CH:83]([O:86][CH:87]3[O:92][CH:91]([CH2:93][OH:94])[CH:90]([OH:95])[CH:89]([OH:96])[CH:88]3[NH2:97])[CH:82]([NH2:98])[CH2:81][CH:80]2[NH2:99])[O:71][CH2:70][CH:69]1[OH:100]
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: CNC1C(O)C(OC2C(N)CC(N)C(OC3OC(C(C)N)C(O)C(O)C3O)C2O)OCC1(C)O
Agent: CN[C@@H]1C(O)[C@@H](OC2[C@H](N)CC(N)[C@@H](O[C@H]3OC(CO)[C@@H](O)[C@H](O)C3NO)[C@@H]2O)OC[C@H]1O
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)[C@@H](O)[C@H](O)[C@H]3O)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Product: CNC1C(O)COC(OC2C(N)CC(N)C(OC3OC(CO)C(O)C(O)C3N)C2O)C1O

Procedure:
In like manner, the sulfate salt of gentamicin B, gentamicin B1 and gentamicin X may be prepared. In order to prepare sulfate salts of a mixture of gentamicin A, B, B1 and X, the lyophilized or spray dried product of Example 2 is treated as described in this example.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.O=S(Cl)Cl.[CH3:18][NH:19][CH3:20].C1COCC1.CCN(CC)CC>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:19]([CH3:20])[CH3:18])=[O:13])[S:10][C:3]=12
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Reactant: CNC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cc2nccc(Cl)c2s1
Yield: 84 %

Procedure:
This material was prepared from 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (0.57 g, 2.67 mmole), SOCl2 (5 ml), 2.0 M N,N-dimethylamine in THF (1.60 ml, 3.20 mmole) and Et3N (0.447 ml, 3.20 mmole) in a manner as previously described for example 9d to give a brown solid (0.54 g, 84%). 1H NMR (300 MHz, CDCl3) δδδ1H, d, J=5.0 Hz), 7.74 (1H, s), 7.35 (1H, d, J=5.0 Hz), 3.28 (3H, s), 3.22 (3H, s); ESIMS (MH+): 240.95.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.Cl.[NH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:9])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NN1CCCC1
Agent: Cl
Product: COc1ccc(C(=O)NN2CCCC2)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluormethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 1-aminopyrrolidine hydrochloride in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:25]3[N:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][N:26]=3)[C:16]=2[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:31][C:28]1[CH:29]=[N:30][C:25]([O:24][CH2:23][CH2:22][O:21][C:17]2[C:16]([C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)=[C:15]([NH:14][S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:10][CH:9]=3)(=[O:13])=[O:12])[N:19]([CH3:20])[N:18]=2)=[N:26][CH:27]=1
Reactant: Cc1ccc(-c2c(OCCOc3ncc([N+](=O)[O-])cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(-c2c(OCCOc3ncc(N)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 47.1 %

Procedure:
A solution of 4-(tert-butyl)-N-(1-methyl-4-(4-methylphenyl)-3-{2-[(5-nitro-2-pyrimidinyl)oxy]ethoxy}-1H-pyrazol-5-yl)benzenesulfonamide (Example 36) (1276 mg) in ethanol (20 ml) was placed under an atmosphere of hydrogen at 50 psi for 12 hrs using palladium on carbon (5%) as catalyst. The catalyst was filtered through Celite (30 g), and washed with ethanol (3×10 ml). Concentration of the filtrate under reduced pressure afforded a yellow residue. The crude material was purified by column chromatography on silica gel (150 g), eluting with ethyl acetate:hexane (1:1), to yield the title compound as a yellow solid (569 mg).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH2:8])[N:6]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29](O)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29]([NH:8][CH2:7][C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: Cc1nc(CN)cs1
Product: Cc1nc(CNC(=O)c2sc(-n3ccc(OCc4ccccc4)cc3=O)nc2C)cs1
Yield: 74 %

Procedure:
Following the procedure as described in Example 25, making variation only as required to use (2-methylthiazol-4-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 74% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.74 (t, J=5.7 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 7.45-7.31 (m, 5H), 7.16 (s, 1H), 6.38 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.42 (d, J=5.7 Hz, 2H), 2.59 (s, 3H), 2.54 (s, 3H); MS (ES+) m/z 453.1 (M+1).
Reaction SMILES: CCOCC.N.[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1)[CH3:8].[Li]>C(O)C>[CH2:7]([C:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH:10]=1)[CH3:8]
Reactant: CCc1ccc(OC)cc1
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: CCO
Product: CCC1=CCC(=O)CC1
Reaction time: 0.25 h

Procedure:
To a stirred refluxing mixture of 600 ml. of dry ether and 1600 ml of liquid ammonia was added 136 g of p-ethylanisole. After 15 minutes, there was added portionwise, at -35° to -32° C., 26.4 g of lithium ribbon over 0.5-1 hour. After an additional 15 minutes, 193 g of dry ethanol was added dropwise at -35° to -32° C. Stirring was continued until the blue color disappeared, and the ammonia was allowed to evaporate on standing overnight. The residue was poured into 1 l of ice water and extracted twice with ether. The combined ether extracts concentrated to a volume of about 300 ml was stirred with 250 ml of water containing 46 g of oxalic acid overnight at ambient temperature. This mixture was diluted with 1 liter of water and extracted twice with ether. The combined ether extracts was washed with 5% sodium bicarbonate and then with water. After drying, the ether solution was vacuum-concentrated to a residue of 104.4 g of desired product; it was 94% pure by GLC analysis and used without distillation.
Reaction SMILES: [N:1]1([C:8]2[C:9]3[C:10]4[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:12](=[O:24])[C:11]=4[CH:25]=[CH:26][CH:27]=3)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:9]1([CH2:27][CH2:26][CH2:25][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[C:9]4[C:10]5[C:14](=[CH:15][CH:16]=3)[N:13]([CH2:17][CH2:18][CH2:19][C:20]([F:21])([F:22])[F:23])[C:12](=[O:24])[C:11]=5[CH:25]=[CH:26][CH:27]=4)[CH2:2][CH2:3]2)[CH:10]=[CH:14][CH:15]=[CH:16][CH:8]=1
Reactant: O=C1c2cccc3c(N4CCCNCC4)ccc(c23)N1CCCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2cccc3c(N4CCCN(CCCc5ccccc5)CC4)ccc(c23)N1CCCC(F)(F)F
Reaction time: 18 h
Yield: 54 %

Procedure:
The crude product from step 3 was dissolved in 30 ml acetonitrile and distributed into 30 vials (2 ml size) preloaded with potassium carbonate (300 mg, 2.3 mmol). Next, 1-bromo-3-phenylporpane (135 μl, 0.135 mmol) was then added and the mixture was shaked on a robital shaker for 18 hours at room temperature. The reaction was then worked up by pipetting out most of the solution and running through a prep HPLC using the Gilson system. The product (62 mg, 54%) was obtained by stripping off the solvent on a speed-vac.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:19][CH:20]([F:22])[F:21])=[C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][NH:13][C:12](=[O:18])[CH:11]=2)[CH:9]=1.FC(F)(F)S(O[CH:29]([CH2:35][CH3:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=O)=O>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:19][CH:20]([F:22])[F:21])=[C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]([CH:29]([CH2:35][CH3:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:12](=[O:18])[CH:11]=2)[CH:9]=1
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Reactant: CCOC(=O)C(CC)OS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon and at RT, 105 mg (2.64 mmol, 1.3 eq.) of sodium hydride (60% in mineral oil) were added to a solution of 618 mg (2.03 mmol) of 4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxypyridin-2(1H)-one in 25 ml of tetrahydrofuran, the mixture was stirred at RT for 60 min 871 mg (2.64 mmol, 1.3 eq.) of ethyl 2-{[(trifluoromethyl)sulphonyl]oxy}butanoate (racemate) [J. Castells et al. Tetrahedron, 1994, 50, 13765-13774] were then added dropwise and the mixture was stirred at RT for 1 h. A further 38 mg (0.96 mmol) of sodium hydride (60% in mineral oil) were added, the reaction mixture was stirred at RT for 5 min, a further 871 mg (2.64 mmol, 1.3 eq.) of ethyl 2-{[(trifluoromethyl)sulphonyl]oxy}butanoate (racemate) were added dropwise, and the reaction mixture was stirred at RT for 15 min and then quenched with water. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate gradient). Yield: 415 mg (48% of theory)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](OCC(Cl)(Cl)Cl)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1.C(N(C(C)C)C(C)C)C.C([O-])(O)=O.[Na+]>CS(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1
Reactant: OC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)N2CCC(O)CC2)CC1
Yield: 34.3 %

Procedure:
A solution of 2,2,2-trichloroethyl 4-(2-tert-butylphenyl)piperazine-1-carboxylate (Example 60, 0.40 g, 1.02 mmol), piperidin-4-ol (0.50 g, 4.94 mmol), and N-ethyl-N-(1-methylethyl)propan-2-amine (0.158 g, 1.22 mmol) in DMSO (5 mL) was stirred for 3 days at 110° C. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give a crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=50:50 to 0:100 then ethyl acetate/methanol=100/0 to 70/30) to provide 1-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}piperidin-4-ol (0.121 g, 34%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1>C(O)(=O)C.[Fe]>[CH3:13][N:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1)[CH3:1]
Reactant: CN(C)Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: CN(C)Cc1ccc(N)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To a solution of dimethyl-(4-nitro-benzyl)-amine (1 g, 5.55 mmol) in acetic acid (10 ml) was added activated iron powder (3 g) and the reaction mixture was stirred for 5 hr at 80° C. The reaction mixture was filtered; the filtrate diluted with water and neutralized with 10% sodium hydroxide solution. The product was extracted with ethyl acetate, the organic layer was dried and evaporated to give a residue. Purification by column chromatography using chloroform/methanol (98:2) to give 4-dimethylaminomethyl-phenylamine (0.7 g, 85%)