Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:34])[C:12]=1[NH:13][C:14]1[C:23]2[C:18](=[C:19]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[O:17][C:16](=[O:33])[CH:15]=1.[P:35](OC)([O:39]C)([O:37]C)=[O:36]>O>[P:35]([OH:39])([OH:37])([O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:19]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[C:23]2[C:18]=1[O:17][C:16](=[O:33])[CH:15]=[C:14]2[NH:13][C:12]1[C:11]([Cl:34])=[CH:10][N:9]=[CH:8][C:7]=1[Cl:6])=[O:36]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCO
Reactant: COP(=O)(OC)OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCOP(=O)(O)O
Reaction time: 1 h

Procedure:
Phosphoryl trichloride (69.4 mg, 0.46 mmol) was added to a solution of 4-(3,5-dichloropyridin-4-ylamino)-8-(5-hydroxypentyloxy)-7-methoxy-2H-chromen-2-one (100 mg, 0.22 mmol, Example 72) and trimethyl phosphate (2 mL). After 1 h at rt, water (0.5 mL) was added, and the reaction was stirred for an additional 2 h. The solution was directly purified by reverse-phase HPLC to give 5-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)pentyl dihydrogen phosphate: 1H NMR (400 MHz, DMSO-d6): δ 10.88 (br, 2H), 9.52 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 3.98 (t, 2H), 3.92 (s, 3H), 3.82 (m, 2H), 1.70 (m, 2H), 1.62 (m, 2H), 1.51 (m, 2H); MS (ESI): 518.9.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C=O)C>[CH2:24]([O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
A solution of 4-(4-fluorophenoxy)phenol (4.75 g, 23.30 mmol), potassium carbonate (4.17 g,. 30.30 mmol) and allyl bromide (2.22 mL, 25.60 mmol) in DMF (50 mL) was stirred for 5 h at 60° C. After cooling, the reaction mixture was neutralized with 1 N HCL and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated to afford an oil which was chromatographed on silica gel (15% ethyl acetate/hexane) to afford the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:9][C:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=[C:12]3[NH:21][CH:22]=[CH:23][C:11]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:24][Si:25]([CH2:28][CH2:29][O:30][CH2:31]Cl)([CH3:27])[CH3:26]>CN(C=O)C>[CH:3]1([NH:9][C:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=[C:12]3[N:21]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:22]=[CH:23][C:11]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1NC1CCCCC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1NC1CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 102.4 %

Procedure:
A suspension of NaH (60 wt % in mineral oil, 0.077 g, 1.9 mmol) in DMF (15 mL) was cooled to about 0° C. Ethyl 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.52 g, 1.8 mmol) was added and the resulting mixture was stirred for about 20 min at about 0° C. SEMCl (0.308 g, 1.84 mmol) was added and the resulting mixture was stirred for about 2 h while warming to rt. The solvent was removed under reduced pressure and the residue partitioned between EtOAc (120 mL) and saturated aqueous NH4Cl (40 mL). The organic phase was isolated, washed with brine (50 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give ethyl 4-(cyclohexylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.77 g, 100%): LC/MS (Table 2, Method b) Rt=3.29 min.; MS m/z: 418 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:22][O:23][C:24](=[O:33])[C@H:25]([CH2:27][C:28]1[N:32]=[CH:31][NH:30][CH:29]=1)[NH2:26].C(N(CC)CC)C.CC(C)=O.C(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH3:22][O:23][C:24](=[O:33])[C@H:25]([CH2:27][C:28]1[N:32]=[CH:31][NH:30][CH:29]=1)[NH:26][C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
43.73 g (164 mmol) of N-tert.-butoxycarbonyl-L-phenylalanine and 34.5 g (142 mmol) of L-histidine methyl ester dihydrochloride are taken in 400 ml of methylene chloride. 100 g (1 mol) of triethylamine are added at -20° C. (acetone/dry ice bath), while stirring. 111 ml (0.171 mol) of propanephosphonic acid anhydride solution (50% strength in methylene chloride) are now added dropwise to the cooled mixture. The mixture is allowed to warm to room temperature overnight. The solvent is stripped off and the crude product is taken up in 500 ml of ethyl acetate. The organic phase is washed 4 times with 200 ml of saturated sodium bicarbonate solution each time, 3 times with 0.1N hydrochloric acid and once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:27](=[O:39])[N:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:29]=[CH:30][CH:31]=2)=[O:25])=[CH:19][C:18]=1[F:40])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[F:40][C:18]1[CH:19]=[C:20]([NH:23][C:24]([C:26]2[C:27](=[O:39])[N:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:21]=[CH:22][C:17]=1[O:16][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])[C:10]=1[CH2:9][OH:8]
Reactant: CC(C)(C)OC(=O)Nc1nccc(Oc2ccc(NC(=O)c3cccn(-c4ccc(F)cc4)c3=O)cc2F)c1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nccc(Oc2ccc(NC(=O)c3cccn(-c4ccc(F)cc4)c3=O)cc2F)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To tert-Butyl 3-((tert-butyldimethylsilyloxy)methyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2-ylcarbamate (119 mg, 0.176 mmol) in THF (2 mL) at rt was added tetrabutylammonium flouride (260 μL, 0.264 mmol, 1 M in THF). After stirring at rt for 30 min, the reaction was diluted with ethyl acetate (20 mL), washed with water followed by brine (10 mL each), dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (5% MeOH/EtOAc) to give the title compound (66 mg, 66%) as a yellow oil. 1H NMR (CD3OD) δ 8.62 (dd, 1H, J=7.2, 2 Hz), 8.04 (d, 1H, J=6 Hz), 7.94-7.90 (m, 2H), 7.50-7.46 (m, 2H), 7.33-7.25 (m, 3H), 7.20 (t, 1H, J=8.8 Hz), 6.67 (t, 1H, J=6.8 Hz), 6.40 (d, 1H, J=5.2 Hz), 4.78 (s, 2H), 1.49 (s, 9H); MS(ESI+) m/z 565.17 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([CH2:15][C:16](O)=[O:17])[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[CH2:47][CH2:48][CH2:49][NH:50][CH3:51]>C1COCC1.C(Cl)Cl.C(Cl)CCl>[NH:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[CH2:47][CH2:48][CH2:49][N:50]([CH3:51])[C:16](=[O:17])[CH2:15][C:2]1([OH:1])[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)CC1(O)CC2CCC1C=C2c1cccs1
Reactant: CNCCCc1nc2ccccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN(CCCc1nc2ccccc2[nH]1)C(=O)CC1(O)CC2CCC1C=C2c1cccs1
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
100 mg of rac-(1R*,2R*,4R*)-(2-hydroxy-5-thiophen-2-yl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid were dissolved in THF (0.15 mL)/DCM (0.6 mL). 0.194 mL of DIPEA, 77 mg of HOBt and 109 mg of EDC were added sequentially at rt. The reaction mixture was stirred for 10 min then 86 mg of [3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amine were added at rt. The reaction mixture was stirred on at rt then diluted with DCM and washed with sat.-NaHCO3 and brine. The organic phase was dried over anh. Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by CC using EtOAc/MeOH/NEt3 as eluant from 98/2/1 to 70/30/1 to yield 82 mg of rac-(1R*,2R*,4R*)-N-[3-(1H-benzoimidazol-2-yl)-propyl]-2-(2-hydroxy-5-thiophen-2-yl-bicyclo[2.2.2]oct-5-en-2-yl)-N-methyl-acetamide as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH:20]=[CH2:21])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].Br[CH:23]([C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=1)[C:24]([F:27])([F:26])[F:25].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[Cl:1][C:2]1[CH:19]=[C:18](/[CH:20]=[CH:21]/[CH:23]([C:28]2[CH:29]=[C:30]([Cl:35])[CH:31]=[C:32]([Cl:34])[CH:33]=2)[C:24]([F:27])([F:26])[F:25])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: C=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Reactant: FC(F)(F)C(Br)c1cc(Cl)cc(Cl)c1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 180 °C
Reaction time: 24 h
Yield: 38.1 %

Procedure:
To a stirred solution of 2-(2-chloro-4-vinylbenzyl)isoindoline-1,3-dione (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (3.48 g, 11.36 mmol), CuCl (112 mg, 1.13 mmol) and 2,2-bipyridyl (0.35 g). The resultant reaction mixture was degassed with argon for 30 min and then was stirred at 180° C. for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in n-hexane) to afford the title compound as solid (1.3 g, 50%): mp 141-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42 (m, 2H), 7.24 (m, 2H), 7.20 (m, 2H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.10 (m, 1H); ESIMS m/z 524.07 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25]O>>[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: CC(C)(C)CCO
Product: CC(C)(C)CCOC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 85 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3,3-dimethylbutanol (26 mg, 0.26 mmol) as the coupling partner. Concentration (no chromatography) yielded 54 mg (85%) of the titled compound. ESI-MS m/z 376 (MH+), 374 (M−H−).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:15][OH:16])([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].CO[C:19](OC)([CH3:21])[CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:20][C:19]1([CH3:21])[O:1][CH2:2][C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][O:16]1
Reactant: COC(C)(C)OC
Reactant: CCOC(=O)C(CO)(CO)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C1(c2cccnc2)COC(C)(C)OC1
Reaction time: 12 h

Procedure:
To a mixture of 1.25 g of ethyl 3-hydroxy-2-(hydroxymethyl)-2-(pyridin-3-yl)propanoate in 13 ml of acetone were added 0.75 ml of 2,2-dimethoxypropane and 105 mg of p-toluenesulfonic acid monohydrate, followed by stirring for 12 hours. Then, 1.06 g of p-toluenesulfonic acid monohydrate was added thereto, followed by stirring for 6 hours. Further, 0.75 ml of 2,2-dimethoxypropane was added thereto, followed by stirring at 50° C. for 30 minutes, and the solvent was evaporated under reduced pressure. To the obtained residue were added 13 ml of acetone and 0.78 ml of 2-methoxy-1-propene at room temperature, followed by stirring for 30 minutes. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.16 g of ethyl 2,2-dimethyl-5-(pyridin-3-yl)-1,3-dioxane-5-carboxylate.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH:22][C:8]1[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:16][CH3:17])[CH2:1][CH3:2])=[O:15])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: CN(C)CCN
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Product: CCN(CC)C(=O)c1ccc(NCCN(C)C)c([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 14 h
Yield: 89.9 %

Procedure:
Following general procedure 2B, N,N-diethyl-4-fluoro-3-nitrobenzamide (0.534 g, 2.22 mmol) and N1,N1-dimethyl-1,2-ethanediamine (0.22 mL, 2.02 mmol) were stirred at 85° C. for 14 h. The crude product was purified through dissolution in 1 N HCl and extraction with Et2O (2×15 mL). The aqueous phase was adjusted to pH 11 with 5 N NaOH and then extracted with CH2Cl2 (4×15 mL). The combined CH2Cl2 phases were dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (0.560 g, 82%) as an orange oil. 1H-NMR (CD3OD): δ 8.22 (d, J=2.8 Hz, 1H), 7.56 (dd, J=8.4 Hz, J=2.8 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 3.53–3.40 (overlapping t, J=6.4 Hz, and br s, 6H), 2.67 (t, J=6.4 Hz, 2H), 2.33 (s, 6H), 1.22 (t, J=7.6 Hz, 6H). MS (ESI) (M+H)+=309
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[CH3:22][C:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:28])[CH2:24][C:25](O)=[O:26]>>[CH3:28][C:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:22])[CH2:24][C:25]([NH:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21])=[O:26]
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Reactant: CC(C)(CC(=O)O)c1ccccc1
Product: CC(C)(CC(=O)Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O)c1ccccc1

Procedure:
The product from Example 68B and 3-methyl-3-phenylbutanoic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.56 (d, J=8.2, 1H), 8.41-8.34 (m, 1H), 8.14-8.08 (m, 1H), 8.04-7.96 (m, 3H), 7.84-7.77 (m, 1H), 7.68 (dd, J=10.8, 5.0, 2H), 7.38 (dd, J=8.4, 1.1, 2H), 7.33-7.27 (m, 2H), 7.20-7.14 (m, 1H), 2.54 (s, 2H), 1.32 (s, 6H); MS (DCI+) M/Z 479 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[C:15]3[CH2:14][CH2:13][N:12](CC4C=CC(OC)=CC=4OC)[C:11](=[O:36])[C:10]=3[C:9]=2[CH3:37])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[C:15]3[CH2:14][CH2:13][NH:12][C:11](=[O:36])[C:10]=3[C:9]=2[CH3:37])=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CCc3c(c(C)c(-c4ccc(Cl)cc4)n3-c3ccc(Cl)cc3Cl)C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c2c(n(-c3ccc(Cl)cc3Cl)c1-c1ccc(Cl)cc1)CCNC2=O
Yield: 72.9 %

Procedure:
A solution of 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-(2,4-dimethoxybenzyl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (1.13 g, 2.03 mmol, Table 2, entry 176) in trifluoroacetic acid (40 mL) was heated at reflux temperature for 2 h. Trifluoroacetic acid was removed by evaporation under reduced pressure, and the residue was purified by silica gel chromatography. Elution first with 50% ethyl acetate in hexane followed by ethyl acetate gave a yellow solid (600 mg, 73%). LC-MS m/z (MH+) 405.0, retention time 3.84 min (method 2).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][S:12][C:11]3[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:10]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>>[N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][S:12][C:11]3[CH:15]=[C:16]([NH:19][C:26]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[NH:27])[CH:17]=[CH:18][C:10]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)SCCN2CCN1CCCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Product: N=C(Nc1ccc2c(c1)SCCN2CCN1CCCCC1)c1cccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A suspension of 4-(2-(piperidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (0.90 g, 3.24 mmol) and methyl thiophene-2-carbimidothioate hydroiodide (1.85 g, 6.49 mmol) was stirred at room temperature overnight (16 hours) under an argon atmosphere. The reaction was concentrated, and the residue was partitioned between saturated sodium bicarbonate solution (50 mL) and dichloromethane (25 mL). After stirring for an hour, the mixture was poured into a separatory funnel. The organic layer was removed, and the aqueous layer was extracted into dichloromethane (2×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was subjected to column chromatography on silica gel (2:98 to 5:95 MeOH:CH2Cl2 followed by 5:95 (2M NH3 in MeOH):CH2Cl2) to give compound 14 as yellow solid (0.288 g, 23%). 1H-NMR (DMSO-d6) δ 7.69 (d, J=3.3 Hz, 1H), 7.57 (d, J=4.5 Hz, 1H), 7.09-7.06 (m, 1H), 6.67 (d, J=8.7 Hz, 1H), 6.52-6.47 (m, 2H), 6.39 (brs, 2H), 3.56-3.53 (m, 2H), 3.39-3.33 (m, 2H), 3.03-3.01 (m, 2H), 2.45-2.39 (m, 6H), 1.49-1.48 (m, 4H), 1.39-1.38 (m, 2H); ESI-MS (m/z, %): 387 (MH+, 77), 276 (46), 194 (100).
Reaction SMILES: [CH2:1]([N:18]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][C:20]([OH:22])=[O:21])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12].[OH-:27].[Na+]>>[CH2:8]([N:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])[CH2:7][N:9]([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][C:7]([OH:6])=[O:27].[CH2:8]([N:9]([CH2:10][C:11]([OH:13])=[O:12])[CH2:14][C:15]([OH:17])=[O:16])[CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH2:23][C:24]([OH:26])=[O:25]
Reactant: [OH-]
Agent: O=C(O)CN(CCOCCOCCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na+]
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O

Procedure:
EGTA was purchased from the Aldrich Chemical Company (Milwaukee, Wis.). EGTA was dissolved in 0.04 M PPB according to the procedure described by Harafuji and Ogawa (J. Biochem. 87:1305-1312 (1980)). After heating EGTA for 15 minutes at 80° C., the pH was adjusted to 7.0 by addition of NaOH. EGTA was filter-sterilized using a 0.2 μm Acro disc filter (Gelman Sciences; Ann Arbor, Mich.) prior to the assay. Further dilutions were made in sterile PPB. The results of these studies, in Table D-3, show that Na2 -EDTA and EGTA were ineffective against S. typhimurium in our model on viability testing.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([CH2:17][O:18][C:19](=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.[C:38]([NH:45][C@H:46]([C:51](O)=[O:52])[C@H:47]([CH2:49][CH3:50])[CH3:48])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:38]([NH:45][C@H:46]([C:51]([O:1][CH2:2][CH2:3][C@@H:4]([CH2:17][O:18][C:19](=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)=[O:52])[C@H:47]([CH2:49][CH3:50])[CH3:48])([O:40][C:41]([CH3:43])([CH3:44])[CH3:42])=[O:39]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCO)Cn1cnc2c(=O)[nH]c(N)nc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC)Cn1cnc2c(=O)[nH]c(N)nc21

Procedure:
(R)-9-[4-Hydroxy-2-(stearoyloxymethyl)butyl]guanine (135 mg, 0.26 mmole) and N-BOC-L-isoleucine (180 mg, 0.78 mmole) were coevaporated with dry DMF twice and dissolved in the same solvent (3.5 ml). To the solution was added 1,3-dicyclohexylcarbodiimide (160 mg, 0.78 mmole) and 4-dimethylaminopyridine (4.8 mg, 0.039 mmole). After reaction for 18 hours, the reaction mixture was filtered through Celite and worked up in a conventional manner. The product was isolated by silica gel column chromatography, eluting at 5% MeOH in CH2Cl2. (Yield 160 mg).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([O:22][Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]([F:21])([F:20])[F:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[F:20][C:18]([F:19])([F:21])[CH:17]([CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)[O:22][Si:23]([CH2:24][CH3:25])([CH2:28][CH3:29])[CH2:26][CH3:27]
Reactant: CC[Si](CC)(CC)OC(C1CCN(C(=O)OCc2ccccc2)CC1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CC[Si](CC)(CC)OC(C1CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.6 %

Procedure:
Ten percent palladium/carbon (170 mg) was suspended in ethanol (5.0 mL). To this, an ethanol solution (25 mL) of 1-benzyloxycarbonyl-4-[2,2,2-trifluoro-1-(triethylsiloxy)-ethyl]piperidine (1.69 g, 3.92 mmol) was added and the mixture was stirred under a hydrogen atmosphere at room temperature for 2.5 hours. The reaction mixture was filtered through Celite and the solvent was evaporated off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 4-[2,2,2-trifluoro-1-(triethylsiloxy)ethyl]piperidine (1.15 g, yield: 99%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[C:13]([CH:15]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[Cl:38])[C:16](=[O:30])[CH:17]([S:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])[CH3:18])#[N:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:8][C:7]1[C:2]([O:26][C:24]2[CH:23]=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[C:20]([S:19][CH:17]([CH3:18])[C:16](=[O:30])[CH:15]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])[C:13]#[N:14])[CH:25]=2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CC(Sc1cc(O)ccc1[N+](=O)[O-])C(=O)C(C#N)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Sc1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)C(C#N)c1ccc(Cl)cc1Cl
Temperature: 80 °C
Yield: 55 %

Procedure:
2,3-Dichloro-5-trifluoromethylpyridine (1.08 g), 2.05 g of 1-cyano-1-(2,4-dichlorophenyl)-3-(5-hydroxy-2-nitrophenylthio)-2-butanone and 2.07 g of potassium carbonate were refluxed in 50 ml of acetonitrile under heat at 80° C. for 3 hours. The reaction liquid was filtered, and the filtrate was concentrated. A 10% hydrochloric acid aqueous solution was added to the residue, and the mixture was extracted with chloroform, followed by concentrating the extract. The residue was purified by silica gel chromatography to obtain 1.62 g of compound No. 148 which was a pale yellow viscous substance. The yield was 55.0%. The results of analysis of compound No. 148 are shown in Table 1.