Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]2[CH:31]=[CH:30][C:21]([O:22][CH2:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:20]([CH3:32])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][C:8]=1[CH3:33])(C)(C)C.C[Mg+].[Br-].[CH3:39]CCC[N+](CCCC)(CCCC)CCCC.[F-].CCN(CC)CC.[O:64](S(C(F)(F)F)(=O)=O)[S:65]([C:68]([F:71])([F:70])[F:69])(=[O:67])=[O:66]>C1COCC1.CCOC(C)=O>[CH2:16]([C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:64][S:65]([C:68]([F:71])([F:70])[F:69])(=[O:67])=[O:66])=[C:8]([CH3:33])[CH:9]=1)([C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][C:24]([OH:29])([CH3:39])[C:25]([CH3:26])([CH3:28])[CH3:27])=[C:20]([CH3:32])[CH:19]=1)[CH2:14][CH3:15])[CH3:17]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Mg+]
Agent: [Br-]
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(OCC(C)(O)C(C)(C)C)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of 1-(4-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one (5.63 g, 11.40 mmol) in THF (100 mL) is treated with 3.0 M CH3MgBr (5.7 mL, 17.24 mmol). The reaction is stirred for 1 h, quenched with satd NH4Cl (50 mL) at 0° C., diluted with EtOAc (100 mL), washed with 0.1 M HCl (2×50 mL), MgSO4 dried, and concentrated. The resulting residue is dissolved in THF (50 mL), and reacted with 1.0 M TBAF (12.6 mL, 12.6 mmol) for 1 h. The reaction is diluted with EtOAc (100 mL), washed with 0.1 M HCl (3×50 mL), brine (50 mL), MgSO4 dried, and concentrated. The resulting residue is dissolved in CH2Cl2 (100 mL), cooled to 0° C., treated with Et3N (1.7 mL, 12.38 mmol) and Tf2O (1.9 mL, 11.35 mmol). After stirring 5 m, the reaction is washed with 0.1 M HCl (2×50 mL), MgSO4 dried, concentrated, and chromatographed to give the title compound (5.30 g, 10.0 mmol, 87% for 3-steps). 1H NMR (CDCl3), δ 0.61 (t, J=7.1 Hz, 6H), 1.05(s, 9H), 1.34 (s, 3H), 2.05(q, J=7.1 Hz, 4H), 2.21 (s, 3H), 2.33 (s, 3H), 3.84 (d, J=8.9 Hz, 1H), 4.01 (d, J=8.9 Hz, 1H), 6.71 (d, J=8.3 Hz, 1H), 6.87 (d, J=2.2 Hz, 1H), 6.93 (dd, J=8.8, 2.6 Hz, 1H), 7.02-7.11 (m, 3H). LC/MS (m/z): calcd for C27H41NF3O5S (M+NH4)+: 548.7; found: 548.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][NH2:22])=[O:20])(=[O:15])=[O:14]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:22]/[NH:21][C:19](=[O:20])[C:18]2[CH:23]=[CH:24][CH:25]=[C:16]([S:13]([CH3:12])(=[O:14])=[O:15])[CH:17]=2)/[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: CS(=O)(=O)c1cccc(C(=O)NN)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(C)(=O)=O)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 63.5 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (55 mg, 0.322 mmol) and 3-(methylsulfonyl)benzohydrazide (69.1 mg, 0.322 mmol) were dissolved in methanol (5 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (3% CH3OH/CH2Cl2) affording the title compound (75 mg, 63.4% yield) as a solid. 1H NMR (400 MHz, CD3OD): δ 8.49 (s, 1H), 8.26 (d, 1H, J=8.4 Hz), 8.18 (d, 1H, J=7.6 Hz), 7.80 (t, 1H, J=7.6 Hz), 7.60 (d, 1H, J=2.4 Hz), 7.27 (m, 1H), 6.93 (d, 1H, J=8.8 Hz), 3.19 (s, 3H), 2.49 (s, 3H). ESI-MS: 367.8 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:35]=[CH:34][C:13]3=[N:14][N:15]([C:17]4[CH:18]=[C:19]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=4[OH:29])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:16]=[C:12]3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][N:37]1[C:42]([CH3:44])([CH3:43])[CH2:41]C(O)[CH2:39][C:38]1([CH3:47])[CH3:46].C([Sn](=O)CCCCCCCC)CCCCCCC>>[C:1]1([S:7]([C:10]2[CH:35]=[CH:34][C:13]3=[N:14][N:15]([C:17]4[CH:18]=[C:19]([CH:26]=[C:27]([C:30]([CH3:32])([CH3:31])[CH3:33])[C:28]=4[OH:29])[CH2:20][CH2:21][C:22]([O:24][CH:25]4[CH2:41][C:42]([CH3:44])([CH3:43])[N:37]([CH3:36])[C:38]([CH3:47])([CH3:46])[CH2:39]4)=[O:23])[N:16]=[C:12]3[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: COC(=O)CCc1cc(-n2nc3ccc(S(=O)(=O)c4ccccc4)cc3n2)c(O)c(C(C)(C)C)c1
Agent: CCCCCCCC[Sn](=O)CCCCCCCC
Product: CN1C(C)(C)CC(OC(=O)CCc2cc(-n3nc4ccc(S(=O)(=O)c5ccccc5)cc4n3)c(O)c(C(C)(C)C)c2)CC1(C)C
Temperature: 160 °C
Yield: 70 %

Procedure:
Methyl 3-(5-phenylsulfonylbenzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydro-cinnamate (5 g, 0.01 mol), xylenes (18 g, 0.17 mol), 1,2,2,6,6-pentamethyl-4-hydroxy-piperidine (2.1 g, 0.012 mol) and dioctyltin oxide (0.5 g, 0.0014 mol) are charged to a reactor and heated to 160° C. while being vigorously stirred. At the end of six hours, any remaining xylene is removed by distillation under vacuum. The crude yellow oil obtained is chromatographed through a pad of silica gel using ethyl aetate as the eluent. The title compound is obtained in a 70% yield as a low melting yellow solid, melting at 45-52° C., whose structure is consistent with 1Hnmr and mass spectrometry.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([CH3:35])[N:26]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([CH3:35])[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)c1cn(C)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (7.63 g), ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (3.0 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.78 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazole-4-carboxylate as pale-brown crystals (8.03 g, yield 98%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:47])[CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][C@@H:24]2[C@@H:28]([S:29][CH2:30][C:31]([OH:38])([CH3:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:27]([O:39]C3CCCCO3)[CH2:26][CH:25]2[OH:46])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC1C=CC(OC(=O)C([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)CCC)=CC=1)(=O)C1C=CC=CC=1.[H-].[Na+].C(O)(=O)C>O.C1COCC1>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:47])[CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][C@@H:24]2[C@@H:28]([S:29][CH2:30][C:31]([OH:38])([CH3:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:27]([OH:39])[CH2:26][CH:25]2[OH:46])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC(C)(O)CS[C@H]1C(OC2CCCCO2)CC(O)[C@@H]1CC=CCCCC(=O)Oc1ccc(NC(=O)c2ccccc2)cc1
Agent: CCCC(C(=O)Oc1ccc(NC(=O)c2ccccc2)cc1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCC(C)(O)CS[C@H]1C(O)CC(O)[C@@H]1CC=CCCCC(=O)Oc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
0.25 g. of 9,15-dihydroxy-15-methyl-11-tetrahydropyranyloxy-13-thia-5-prostenoic acid p-benzoylaminophenyl ester (obtainable by the reaction of 2-(2-hydroxy-2-methylheptylthio)-5-hydroxy-3-tetrahydropyranyloxy-acetaldehyde lactol with triphenylphosphoniopentanoic acid p-benzoylaminophenyl ester in the presence of 2 moles of NaH) is stirred for 5 hours at 45° C. in 7 ml. of a mixture of acetic acid, THF and water (3:1:1). The solvent is distilled off, and after chromatographic purification of the residue (silica gel/ethyl acetate), 9,11,15-trihydroxy-15-methyl-13-thia-5-prostenoic acid p-benzoylaminophenyl ester is obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2Cl)[CH2:6]1)(=[O:3])[CH3:2].[Cl:27][C:28]1[N:36]=[CH:35][N:34]=[C:33]2[C:29]=1[NH:30][CH:31]=[N:32]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2[N:32]2[CH:31]=[N:30][C:29]3[C:33]2=[N:34][CH:35]=[N:36][C:28]=3[Cl:27])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(Cl)=C(C=O)C[C@@H]32)C1
Reactant: Clc1ncnc2nc[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4cnc5c(Cl)ncnc54)=C(C=O)C[C@@H]32)C1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 13 (2.43 g, 6.46 mmol), 6-chloropurine (0.5 g, 3.23 mmol) and TBAF (1.69 g, 6.46) in dry THF (40 mL) was stirred at 50° C. under Ar for 48 h. After cooling to room temperature, the reaction mixture concentrated and poured onto ice-cold water (250 mL) and the resulting precipitate was filtered, washed with water and dried to give a crude product. Purification by FCC [DCM/Methanol (9.7:0.3)] and then recrystallized with hot ethanol to give 0.82 g (51.3%) of pure 21a: mp 140-142° C.; IR (Neat) 2943, 2853, 1729, 1672, 1584, 1556, 1435, 1236, 1032, 939, cm-1; 1H NMR (500 MHz, CDCl3) δ 1.07 (s, 3H, 18-CH3), 1.09 (s, 3H, 19-CH3), 2.04 (s, 3H, 3β-OCOCH3), 4.61 (m, 1H, 3α-H), 5.43 (br, 1H, 6-H), 8.20 (s, 1H, 2′-H), 8.79 (s, 1H, aromatic-H), and 9.53 (s, 1H, 16-CHO).
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([O:17]C)=[O:16])[CH:9]=1)[C:3]([O:5]C)=O.[NH2:19][C:20](N)=[S:21].Cl.C([OH:26])C>>[O:26]=[C:20]1[NH:19][C:3](=[O:5])[CH:2]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH:9]=2)[C:15]([OH:17])=[O:16])[S:21]1
Reactant: CCO
Reactant: COC(=O)c1cc(CC(Br)C(=O)OC)ccc1F
Reactant: NC(N)=S
Agent: Cl
Product: O=C1NC(=O)C(Cc2ccc(F)c(C(=O)O)c2)S1
Temperature: 0 °C
Yield: 39 %

Procedure:
To a solution of methyl 2-bromo-3-(3-methoxycarbonyl-4-fluorophenyl)propionate (1.22 g) in ethanol (40 ml), thiourea (356 mg) was added and the mixture was refluxed for 11 hours under heat. After cooling, this was concentrated under reduced pressure and water (50 ml) was added to the residue. After pH was adjusted to around 8 with saturated aqueous solution of sodium bicarbonate under stirring, ether (20 ml) and n-hexane (40 ml) were added, which was stirred for 10 minutes as it was. The crystals were collected by filtration, washed with water, and then dried. The solids thus obtained were dissolved into sulforane (10 ml) and, after 6N hydrochloric acid (20 ml) was added, the mixture was refluxed for 8 hours under heat. After cooling, this was poured into ice water and the crystals deposited were collected by filtration, washed with water, and then dried to obtain 403 mg (39%) of aimed compound as crystals.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[F:30][C:31]1[CH:36]=[C:35](F)[CH:34]=[CH:33][C:32]=1[CH2:38][C:39](=[O:41])[CH3:40]>>[F:30][C:31]1[CH:36]=[C:35]([O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)[CH:34]=[CH:33][C:32]=1[CH2:38][C:39](=[O:41])[CH3:40]
Reactant: CC(=O)Cc1ccc(F)cc1F
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Na+]
Product: CC(=O)Cc1ccc(OCCCc2c[nH]cn2)cc1F

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 10 mmol of (2,4-difluorophenyl)propanone are treated as described in Example 61 (method A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C(NC(C)C)(C)C.[Li].C1(C)C=CC(S([Cl:31])(=O)=O)=CC=1>C1COCC1>[Cl:31][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)C(=O)C(Cl)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-Methoxy-3,4-dihydro-2H-naphthalen-1-one (25.6 g, 145.28 mmol) in THF (300 ml) is slowly added under an atmosphere of argon at −78° C. to a solution of lithium diisopropyl amine in THF (300 ml; prepared from 22.6 ml of diisopropylamine (160 mmol) and 100 ml of 1.6 M n-BuLi in hexane (160 mmol)). After 30 minutes at −78° C., a solution of para-tolylsulfonyl chloride (30.5 g, 159.8 mmol) in THF (300 ml) is added during 20 minutes. The dry ice cooling bath is removed, and the reaction mixture is allowed to reach RT. After 1 h, TLC analysis indicates complete consumption of starting material. A sat. aqueous solution of NH4Cl (100 ml) is added, and the mixture is stirred at RT for 15 minutes. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated. Purification by FCC (hexane/EtOAc 3:1) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 2.32-2.52 (m, 2H), 2.82-2.90 (m, 2H), 3.10-3.18 (m, 2H), 3.78 (s, 1H), 4.52-4.58 (m, 1H), 7.01-7.05 (m, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.47-7.48 (m, 1H). ES+-MS: 211.3, 213.3 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[CH2:28])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:24])[C:12]([CH3:23])=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14]2)=[C:9](C(=O)C)[CH:8]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=O.[CH2:39]([OH:41])[CH3:40]>O>[CH3:23][C:12]1[C:11](=[O:24])[C:10]2[C:15](=[C:16]([C:39](=[O:41])[CH:40]=[CH:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH3:29])[CH:32]=3)[C:7]([O:6][CH2:5][C:4]([CH3:3])=[CH2:28])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=C(C)COc1cc(C(C)=O)c2c(=O)c(C)c(-c3ccccc3)oc2c1
Reactant: COc1cccc(C=O)c1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=C(C)COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1cccc(OC)c1
Temperature: 25 °C

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-(2-methylallyloxy) -acetyl-3methylflavone (2.61 g, 0.0075 mol) and 3-methoxy-benzaldehyde (1.01 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.4 g of product m.p. 131-34° C., 1H-NMR (CDCl3)δ:1.76 (s, 3H); 2.20 (s, 3H); 3.82 (s, 3H) 4.62 (s, 2H); 5.05 (d, 2H, J=18 Hz); 6.95-7.10 (m, 3H); 7.09 (d, 1H, J=9 Hz); 7.10 (d, 1H, J=9 Hz); 7.31 (d, 1H, J=16 Hz); 7.40-07.45 (m, 3H); 7.55-7.58 (m, 2H); 7.31 (s, 2H); 8.32 (d, 1H, J=8.9 Hz).
Reaction SMILES: [OH:1][CH:2]([CH2:12][Cl:13])[CH2:3][N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[N:6]=[N:5]1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1>[ClH:13].[OH:1][CH:2]([CH2:12][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:3][N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[N:6]=[N:5]1
Reactant: O=[N+]([O-])c1cn(CC(O)CCl)nn1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: Cl
Product: O=[N+]([O-])c1cn(CC(O)CN2CCCCC2)nn1

Procedure:
A mixture of 0.5 g of 1-(2'-hydroxy-3'-chloropropyl)-4-nitro-1,2,3-triazole and 3 g of piperidine in 10 ml of THF is refluxed for 1 hr with stirring. The solvent and excess piperidine are removed. The residue is dissolved in chloroform and washed with 5 ml of 1% NaOH solution. The solvent is evaporated to dryness, dissolved in dilute HCl solution washed with chloroform.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[H-].[Na+].I[CH3:15].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[O:11][CH3:15]
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Br)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-6-nitrophenol (5.1 g, 23.4 mmol) was dissolved in DMF (60 mL), then 95% NaH (900 mg, 35.6 mmol) was added in a few portions, followed by the addition of iodomethane (3.0 mL, 6.8 g, 48.5 mmol). The reaction was stirred at room temperature overnight, then heated at 50° C. for 3 hours. The reaction was cooled, poured into water, and the solids filtered off and dried. The product (5.5 g, 100%) was recovered as tan solids. 1H NMR (300 MHz, DMSO-d6) δ 8.02 (dd, J=8.1, 1.7 Hz, 1H), 7.96 (dd, J=8.1, 1.7 Hz, 1H), 7.83 (dd, 8.1, 8.1 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: Br.[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=2)[NH:15][C:16](=[O:28])[C:17]2[CH:22]=[C:21]([O:23]C)[C:20]([N+:25]([O-:27])=[O:26])=[CH:19][N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].CCOC(C)=O>CC(O)=O>[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=2)[NH:15][C:16](=[O:28])[C:17]2[CH:22]=[C:21]([OH:23])[C:20]([N+:25]([O-:27])=[O:26])=[CH:19][N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:11])([F:12])[F:13]
Reactant: COc1cc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ncc1[N+](=O)[O-]
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1cc(O)c([N+](=O)[O-])cn1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a solution of 30% HBr in AcOH (10 mL, Spectrochem, India) was added (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-4-methoxy-5-nitropicolinamide (1 g, 0.002 mol), and the resulting reaction mixture was stirred for 12 h at 90° C. The reaction progress was monitored by TLC (50% EtOAc in petroleum ether). After completion of the reaction, the reaction mixture was concentrated and neutralized with sat'd NaHCO3 solution (pH˜7-7.5) and the aqueous solution was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated to afford the title compound as a pale yellow solid. 1H NMR (DMSO-d6) δ: 9.84 (d, J=7.5 Hz, 1H), 8.77 (s, 1H), 8.53 (d, J=4.5 Hz, 1H), 7.83-7.70 (m, 1H), 7.57-7.49 (m, 3H), 7.38-7.31 (m, 2H), 6.56 (d, J=7.5 Hz, 1H). MS (ESI, positive ion) m/z: 471.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.[CH:18]1([CH2:24][S:25](Cl)(=[O:27])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([CH2:24][S:25]([NH:1][C:2]2[C:3](=[O:17])[N:4]([CH2:9][C:10]([OH:12])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=2)(=[O:27])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Product: Cc1ccc(NS(=O)(=O)CC2CCCCC2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 0.71 g of tert-butyl [3-amino-6-methyl-2-oxo-1,2-dihydropyridinyl]-acetate (WO 97/01338) at 0° C. under a nitrogen atmosphere was added 0.60 mL cyclohexylmethanesulfonyl chloride (J. F. King et al J. Am. Chem. Soc. 114, 1743 (1992)). After stirring at room temperature for 3 hours the reaction mixture was concentrated. The residue was dissolved in ethyl acetate, washed successively with 0.1 N hydrochloric acid, water and brine, dried over sodium sulphate and concentrated. The residue was dissolved in a mixture of 0.2 mL water and 1.8 mL trifluoroacetic acid. After stirring at room temperature for 4 h, water and ethyl acetate were added. The organic layer was separated, washed twice with 0.1 N hydrochloric acid, dried over sodium sulphate and concentrated. The solid residue was washed with a cold dichloromethane/diethyl ether mixture to give 0.72 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]#[N:12])[O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.NC1C2C(=CC=C(CN)C=2)C=CN=1>>[NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][NH2:12])[O:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1cc2c(N)nccc2o1
Agent: NCc1ccc2ccnc(N)c2c1
Product: NCc1cc2c(N)nccc2o1

Procedure:
This compound was prepared from 4-amino-furo[3,2-c]pyridine-2-carbonitrile (5.7 g), using the procedure described for 1-amino-7-(aminomethyl)isoquinoline . Yield: 3.5 g (60%); yellow crystals; m.p. 142-144° C.; EI-MS: 163 (M+).
Reaction SMILES: [CH3:1][C@@H:2]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17]CC2C=CC=CC=2)[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])[CH2:3][O:4][CH3:5]>C1COCC1.C(O)C.[Pd]>[OH:17][C:15]1[CH:14]=[C:9]([CH:8]=[C:7]([O:6][C@H:2]([CH3:1])[CH2:3][O:4][CH3:5])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC[C@@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC[C@@H](C)Oc1cc(O)cc(C(=O)OC)c1
Reaction time: 16 h

Procedure:
A solution of methyl 3-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoate in THF (5 mL) and ethanol (5 mL), containing 10% palladium on carbon, was stirred under an atmosphere of hydrogen for 16 hours. The palladium on carbon was removed by filtration and the filtrate evaporated under reduced pressure to give the desired material as a clear gum (723 mg).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C@H:9]([C:11]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(N(CC)CC)C>C(O)C.C1(C)C=CC=CC=1>[OH:7][CH2:8][C@H:9]([C:11]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:10]
Reactant: C[C@H](COC1CCCCO1)C1(O)CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](CO)C1(O)CCCC1
Reaction time: 10 h
Yield: 117 %

Procedure:
A mixture of 2a (3.42 g, 15.0 mmol) and pyridinium p-toluenesulfonate (188 mg) in ethanol (100 mL) was heated at 40°-50° C. with stirring for 10 hr. The mixture was diluted with toluene and a small amount of triethylamine was added to the mixture. After evaporation of ethanol, the residue was poured into brine and extracted with ethyl acetate until none of the product remained the in aqueous layer. The combined organic layers were washed with brine, and dried over sodium sulfate. Filtration and concentration gave 2.53 g of an oily material, which was purified by column chromatography (silica gel 20 g, ethyl acetate in n-hexane, 20-50%) to give 1.88 g (86.9%) of 3a, as a colorless oil.