Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][C@H:9]([OH:13])[CH2:8][O:7]2)([O-:3])=[O:2].Cl.[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH2:22]Cl)[CH:21]=1.[H-].[Na+]>CN(C=O)C>[Br:15][C:16]1[CH:21]=[C:20]([CH2:22][O:13][C@@H:9]2[CH2:8][O:7][C:6]3=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]3[CH2:10]2)[CH:19]=[N:18][CH:17]=1
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](O)C2
Reactant: ClCc1cncc(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1cncc(Br)c1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.2 %

Procedure:
A solution of (S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxa-zin-6-ol (3.63 g, 19.6 mmol) and 3-bromo-5-(chloromethyl)pyridine hydrochloride (4.78 g, 19.6 mmol, 1 eq) in dry DMF (80 mL) was treated with NaH (1.88 g, 47 mmol, 2.4 eq, 60% in mineral oil) at 0-5° C., then stirred at room temperature overnight (16 h), quenched with water (150 mL), and extracted into EtOAc. Chromatography of the crude product on silica gel, eluting with MeOH/CH2Cl2 (1:19), gave the title product (2.10 g, 30%) as white solid. APCI MS m/z 355.7, 357.7 (M+H). 1H NMR (400 MHz, (CD3)2SO) δ 8.64 (d, J=2.3 Hz, 1H), 8.52 (d, J=1.7 Hz, 1H), 8.03 (s, 1H), 7.97 (br t, J=2.1 Hz, 1H), 4.73 (d, J=12.6 Hz, 1H), 4.70-4.65 (m, 2H), 4.48 (d, J=12 Hz, 1H), 4.31-4.20 (m, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([OH:16])[CH:15]=1.C(N(CC)CC)C.[Si:25](OS(C(F)(F)F)(=O)=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].CCOC(C)=O>C(Cl)Cl>[C:28]([Si:25]([CH3:27])([CH3:26])[O:16][C:14]1[CH:15]=[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:11]=[CH:12][C:13]=1[CH3:17])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc3ccccc3o2)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 5-(1,3-benzoxazol-2-yl)-2-methylphenol (0.8 g, 3.5 mmol) and triethylamine (0.6 mL, 4.3 mmol) in CH2Cl2 (20 mL) was cooled to 0° C. and TBDMS-OTf (900 mL, 3.9 mmol) was added. The reaction was slowly warmed to rt and EtOAc (200 mL) was added. The mixture was washed with H2O (3×50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 2-(3-{[tert-butyl-(dimethyl)silyl]oxy}-4-methylphenyl)-1,3-benzoxazole as light yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].CO>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: O=C(O)c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cnc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 50 °C
Yield: 76.2 %

Procedure:
The product from Example 311a (1.0 g, 3.03 mmol) and borane tetrahydrofuran complex (6.06 mL, 6.06 mmol) were combined in tetrahydrofuran (15.15 mL) and heated at 50° C. for 2 hours, cooled, treated with 10 mL of methanol, heated at 50° C. for 1 hour, cooled and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate in heptanes) afforded the title compound (0.73 g, 76%).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[N:9]([CH2:24][CH2:25][N:26]=3)[C:10]3[C:15]([N+:16]=2[O-:17])=[CH:14][CH:13]=[C:12]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](O)(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:27]([N:21]1[CH2:20][CH2:19][N:18]([C:12]2[CH:11]=[C:10]3[C:15]([N+:16]([O-:17])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8]4[N:9]3[CH2:24][CH2:25][N:26]=4)=[CH:14][CH:13]=2)[CH2:23][CH2:22]1)(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(N3CCNCC3)ccc21
Reactant: CCCCCCCC(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)N1CCN(c2ccc3c(c2)N2CCN=C2C(c2ccccc2)=[N+]3[O-])CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
To a stirred suspension of 1,2-dihydro-4-phenyl-8piperazinylimidazo [1,2-a]quinoxaline 5-oxide (1.5 g, 0.0043 mol) in dimethylformamide (20 ml) under an atmosphere of nitrogen and cooled in an ice-bath, was added octanoic acid (0.67 g, 0.0043 mol.) and diphenylphosphorylazide (1.29 g, 0.0047 mol). The reaction mixture was allowed to stand for 15 minutes. Triethylamine (0.95 g, 0.0047 mol) was added to the reaction mixture and the resulting mixture was allowed to stand for 1 hr, then warmed to room temperature over an additional 1 hr period. The solvent was removed in vacuo and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium hydrogen carbonate and then water, dried over anhydrous magnesium sulphate and concentrated in vacuo to yield an orange solid. The orange solid was recrystallized from chloroform:ethyl acetate to yield 1,2-dihydro-8-(4-octanoylpiperazinyl)-4-phenylimidazo[1,2-a]quinoxaline 5-oxide, (1.6 g) as yellow crystals, m.p. 212°-213° C. (Found: C,70.72; H,7.44; N,14.77%; C28H35N5O2 requires C,71.01; H,7.45; N,14.78%), represented by the structural formula: ##STR25##
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH:16]=O)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23][N:24]([CH3:26])[CH3:25].C(N(CC)CC)C>>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][NH:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23][N:24]([CH3:26])[CH3:25])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C)C/C=C/CN
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)C/C=C/CNCc1cc(CO[Si](C)(C)C(C)(C)C)ccn1

Procedure:
By General Procedure A from 4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2-carbaldehyde (1.0 equiv.), [(2E)-4-aminobut-2-en-1-yl]dimethylamine hydrochloride (1.0 equiv.), and triethylamine (1.0 equiv.). Purification by column chromatography (0-10% MeOH in DCM) gave the title product as yellow oil. 1H NMR (300 MHz, chloroform-d): δ ppm 8.45 (d, 1H), 7.20 (s, 1H), 7.11 (d, 1H), 5.67 (m, 2H), 4.68 (s, 2H), 3.85 (s, 2H), 2.89 (s, 2H), 2.19 (s, 6H), 0.89 (m, 9H), 0.07 (m, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([O:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[C:37](=[O:49])[N:38]([C:42]5[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=5)[CH:39]=[CH:40][CH:41]=4)=[O:35])=[CH:29][C:28]=3[F:50])=[CH:21][CH:22]=[N:23]2)=[CH:18][C:17]=1[O:51][CH3:52])C1C=CC=CC=1.Br.CCOCC>CC(O)=O>[F:50][C:28]1[CH:29]=[C:30]([NH:33][C:34]([C:36]2[C:37](=[O:49])[N:38]([C:42]3[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=3)[CH:39]=[CH:40][CH:41]=2)=[O:35])[CH:31]=[CH:32][C:27]=1[O:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([OH:15])=[C:17]([O:51][CH3:52])[CH:18]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccnc2cc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COc1cc2c(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccnc2cc1O
Reaction time: 1.17 h
Yield: 58.9 %

Procedure:
A mixture of N-(4-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide trifluoroacetic acid salt (40 mg, 0.056 mmol) and HBr in HOAc (3 mL of 33% solution) was allowed to stay at rt for 70 minutes. Ether (25 mL) was added to the reaction mixture, stirred for 20 minutes, and the solid was filtered and dried to obtain the product (17 mg, 59%) as a light brown solid. 1H NMR (DMF-d7) δ 12.35 (s, 1H), 8.94 (d, 1H, J=6.6 Hz), 8.70 (d, 1H, J=7.7 Hz), 8.23-7.50 (m, 12H), 7.12 (d, 1H, J=6.6 Hz), 6.84 (m, 1H), 4.17 (s, 3H); MS(ESI+) m/z 516.2 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:37][CH2:38][CH:39]([N:46]([CH3:48])[CH3:47])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CS(C)=O.C(N(CC)CC)C>C(#N)C>[CH3:47][N:46]([CH3:48])[CH:39]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:38][NH:37][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CN(C)C(CN)c1ccccc1
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCC(c4ccccc4)N(C)C)n3Cc3ccccc32)cc1
Temperature: 82 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a suspension of 2,2,2-trichloro-1-{10-[(2′-methoxy-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 1 (1.21 g, 2.25 mmole) in acetonitrile (25 mL) was added a solution of (2-amino-1-phenylethyl) dimethylamine (0.250 g, 1.52 mmole) in acetonitrile (5 mL), followed by dimethylsulfoxide (5 equivalents) and triethylamine (2.2 equivalents). The mixture was stirred at 82° C. under nitrogen for 18 hours. The solvent was evaporated, and the residue diluted with dichloromethane. The solution was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was flash chromatographed over silica gel Merck-60 using a gradient of 30 to 80% ethyl acetate in dichloromethane to provide the title compound as a light brown amorphous solid (0.777 g). MS [(+)ESI, m/z]: 585.19 [M+H]+ Anal. Calcd for C37H36N4O3.0.2 C4H8O2: C, 75.38; H, 6.29; N, 9.30. Found: C, 75.42; H, 6.38; N, 9.04.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:25][OH:26]>>[CH2:10]([O:9][C:8]([NH:7][C@@H:4]([CH2:25][OH:26])[CH2:3][C:2]([O:6][CH3:5])=[O:1])=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CO
Reactant: O=C1C[C@@H](NC(=O)OCc2ccccc2)CO1
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
(R)-Benzyl 5-oxotetrahydrofuran-3-ylcarbamate (INTERMEDIATE 3, 27.0 g, 114.78 mmol) was dissolved in methanol (75 ml) and triethylamine (75 ml) was added at room temperature. The resulting mixture was allowed to stir overnight at this temperature. The mixture was concentrated in vacuo to provide the title product. This material was used to prepare INTERMEDIATE 5 without further purification.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([C:17]1[CH:18]=[C:19]([CH2:33][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][C:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:22]2[OH:32])=O.[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(O)(=O)C>C(O)C.C1COCC1>[CH2:40]([NH:47][CH2:15][C:17]1[CH:18]=[C:19]([CH2:33][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][C:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:22]2[OH:32])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(=O)c1cnc2c(C=O)cc(CN3CCOCC3)cc2c1O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2c(CNCc3ccccc3)cc(CN3CCOCC3)cc2c1O
Reaction time: 1.5 h
Yield: 107 %

Procedure:
Sodium triacetoxyborohydride (1.0 g) is added to a stirred solution of ethyl 8-formyl-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxylate (Preparation 27, 515 mg), benzylamine (340 mg) and acetic acid (360 mg) in a mixture of ethanol/THF (10 mL, 1/1). The solution is stirred for 90 min. The solvents are evaporated. The residue is taken up in chloroform and is applied to a silica gel column which is eluted with 1-3% methanol/chloroform followed by 4% methanol/chloroform to afford 697 mg of the title compound which is crystallized from methanol/ether. Physical characteristics: 1H NMR (CDCl3) δ1.43, 2.47, 3.59, 3.72, 3.90, 4.26, 4.42, 7.34, 7.51, 8.23, 8.59. Anal. Found: C, 68.59; H, 6.65; N, 9.64.
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21]Br>C(#N)C>[N:5]1[N:6]2[C:2]([O:1][CH2:19][CH2:20][CH2:21]2)=[CH:3][C:4]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(O)[nH]n1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc2n(n1)CCCO2
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (10.34 g, 0.66 mol) and 36.62 g of potassium carbonate in 500 ml of acetonitrile was added 14.7 g of 1,3-dibromopropane, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. 8.80 g of the desired product was obtained (68%), m.p. 44-46° C. (M+H)+ 197.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:51][C:52]1[CH:60]=[CH:59][CH:58]=[CH:57][C:53]=1[CH:54]([OH:56])[CH3:55]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:56][CH:54]([C:53]2[CH:57]=[CH:58][CH:59]=[CH:60][C:52]=2[Cl:51])[CH3:55])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1ccccc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4ccccc4Cl)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 84 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (67 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (92 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 15 min. Subsequently, 2-chloro-α-methylbenzyl alcohol (48 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (88 mg, yield 79%).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.[CH2:32]([NH2:35])[CH2:33][NH2:34].[N+:36]([C:39]1[CH:52]=[CH:51][C:42]([CH2:43][O:44][C:45]([NH:47][C:48](=N)[CH3:49])=[O:46])=[CH:41][CH:40]=1)([O-:38])=[O:37]>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27](=[O:29])[NH:34][CH2:33][CH2:32][NH:35][C:48](=[N:47][C:45]([O:44][CH2:43][C:42]2[CH:51]=[CH:52][C:39]([N+:36]([O-:38])=[O:37])=[CH:40][CH:41]=2)=[O:46])[CH3:49])[CH2:10]1
Reactant: NCCN
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NCCNC(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 27.6 %

Procedure:
Following a procedure similar to that described in Preparation 17, but using 850 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 450 mg of ethylenediamine and 430 mg of N-(4-nitrobenzyloxycarbonyl)acetamidine, 295 mg of the title compound were obtained as a powder.
Reaction SMILES: O1CCCC1.[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[N:12][CH:13]=1)#[CH:7].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[N:31][OH:32])=[CH:25][CH:24]=1.C(N(CC)CC)C>O>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[O:32][N:31]=[C:30]([CH2:29][C:26]3[CH:25]=[CH:24][C:23]([CH2:22][O:21][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=4)=[CH:28][CH:27]=3)[CH:7]=2)=[CH:13][N:12]=1
Reactant: C#Cc1ccc(C)nc1
Reactant: ON=C(Cl)Cc1ccc(COc2ccccn2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(-c2cc(Cc3ccc(COc4ccccn4)cc3)no2)cn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a tetrahydrofuran (2 mL) solution of 5-ethynyl-2-methyl-pyridine (10 mg, 85 μmol) described in Manufacturing Example 190-1-1 were added 4-(pyridin-2-yloxymethyl)phenyl-acetohydroximoyl chloride (31 mg, 0.11 mmol) described in Manufacturing Example 2-1-5 and triethylamine (18 μL, 0.13 mmol), which was stirred for 2 hours and 30 minutes at 50° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrated was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (14 mg, 46%).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[C:27]([N+:34]([O-:36])=[O:35])=[CH:26][CH:25]=1.[Cl:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=1[C:45]1[C:50]([C:51]2[NH:52][CH:53]=[CH:54][N:55]=2)=[CH:49][N:48]=[C:47]([NH:56][CH2:57][CH2:58][NH:59]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:46]=1>>[Cl:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=1[C:45]1[C:50]([C:51]2[NH:55][CH:54]=[CH:53][N:52]=2)=[CH:49][N:48]=[C:47]([NH:56][CH2:57][CH2:58][NH:59][C:24]2[N:29]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[C:27]([N+:34]([O-:36])=[O:35])=[CH:26][CH:25]=2)[N:46]=1
Reactant: CC(=O)Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CC(=O)Nc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
N-{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)amino]-3-nitro-2-pyridyl}acetamide was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and N-(6-chloro-3-nitro-2-pyridyl)acetamide in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.[S:29]1[CH2:33][CH:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[NH:31][CH2:30]1.C(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:31]2[CH:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][S:29][CH2:30]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Reactant: CCOC(=O)C1CSCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C1CSCN1C(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
One-tenth mole of 4-(16-bromohexadecylamino)benzoyl chloride hydrochloride in methylene chloride is added to a solution of 0.1 mole of ethyl thiazolidine-4-carboxylate in chloroform containing two equivalents of triethylamine. After 5 hours at 20° C. the solution is filtered and evaporated to a white solid which is recrystallized from acetonitrile to yield 3-[4-(16-bromohexadecylamino)benzoyl]-4-carbethoxythiazolidine. By means of the alkaline hydrolysis method of Example 10, the ethyl ester is converted to the subject carboxylic acid. This acid is also prepared using the procedure of this Example except that the acylation of the thiazolidine-4-carboxylic acid is carried out in aqueous acetone sodium bicarbonate solution.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C1(C=CC(O)=CC=1)O.[C:29](OC)(=[O:33])[C:30]([CH3:32])=[CH2:31]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:29]([O:20][CH:18]([CH2:17][CH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=1)[CH3:19])(=[O:33])[C:30]([CH3:32])=[CH2:31]
Reactant: C=C(C)C(=O)OC
Reactant: CC(O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Oc1ccc(O)cc1
Product: C=C(C)C(=O)OC(C)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
A one-liter flask was charged with a mixture of 69.5 grams (0.25 mole) of 4-(3,5-di-t-butyl-4-hydroxyphenyl) butane-2-ol, 350 milliliters of methyl methacrylate, 0.5 gram of hydroquinone and 5 grams of tetraisopropyl titanate as the catalyst. The mixture was heated to reflux and a methanolmethylmethacrylate azeotrope slowly distilled off over a 3.5 hour period. The reaction flask was cooled slightly and 25 milliliters of water was added dropwise to hydrolyze the catalyst. The reaction mixture was allowed to cool to room temperature. The mixture was stirred 15 minutes longer and then filtered through diatomaceous earth. One hundred milliliters of hexane was added to the filtrate which separated into organic and inorganic phases. The organic phase containing the product in hexane was separated and dried over magnesium sulfate. The hexane was evaporated to obtain 82 grams (95 percent) of 4-(3,5-di-t-butyl-4-hydroxyphenyl)-2-butyl methacrylate. The boiling point of this compound was 150° C. to 155° C. at .15 milliliters of mercury pressure.
Reaction SMILES: [CH2:1]([NH:3][S:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)(=[O:6])=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]=O>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][S:4]([NH:3][CH2:1][CH3:2])(=[O:6])=[O:5])=[CH:9][CH:10]=1
Reactant: CCNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: O=[Pd]
Solvent: CCO
Product: CCNS(=O)(=O)Cc1ccc(N)cc1
Yield: 52.4 %

Procedure:
A solution of N-ethyl-4-nitrobenzenemethanesulphonamide (4.35 g) in warm ethanol (125 ml) was added to 10% palladium oxide on carbon (0.75 g, 50% aqueous paste) prereduced in ethanol (25 ml) and hydrogenated at atmospheric pressure. Hydrogen uptake (1400 ml) ceased after 20 minutes. The suspension was filtered and the catalyst was washed with methanol (100 ml) and ethanol (100 ml). Evaporation of the combined filtrate and washings produced a grey solid (2.0 g) which was crystallised from isoprpopanol (120 ml) to present the title compound as cream micro needles (1.48 g), m.p. 161°-164°.