Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:30])([OH:29])[OH:28])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+:40]>C(O)C.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:28])([O-:29])[O-:30])(=[O:24])=[O:25])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[K+:40].[K+:40].[K+:40]
Reactant: O=P(O)(O)NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=P([O-])([O-])NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a suspension of ((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonyl)phosphoramidic acid (2) (0.030 g, 0.054 mmol) in ethanol (3 mL) was added KOH (9.0 mg, 0.16 mmol) in 0.5 mL of water. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The reaction mixture was concentrated to dryness and the residue was washed with ethyl acetate (2×8 mL), acetone (2×8 mL) and acetonitrile (2×8 mL) to afford tri-potassium(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonylphosphoramidate (6) (0.028 g, 0.043 mmol, 78% yield) as a brown solid. 1H NMR (400 MHz, deuterium oxide) δ ppm 4.52 (s, 2H), 7.09 (d, J=7.78 Hz, 1H), 7.19-7.24 (m, 2H), 7.28-7.40 (m, 5H), 7.61-7.77 (m, 3H), 8.28 (d, J=4.27 Hz, 1H), 8.91 (t, J=1.88 Hz, 1H), 9.08 (d, J=2.26 Hz, 1H), 9.21 (d, J=1.76 Hz, 1H); LCMS Method A: retention time 1.60 min, [M+1]=549.2. HPLC Method B: Purity 96.0%, retention time 6.09 min, HPLC Method C: Purity 96.0%, retention time 5.86 min. Elemental analysis: MF C25H18N6SPO5.2.6 K.4.5 H2O, Calculated C 41.22; H, 3.72; N, 11.54; K, 14.12; H2O, 11.00; Found C, 40.79; H, 3.56; N, 11.17; K, 13.76; H2O, 10.49.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([Cl:9])=[N:7][OH:8])=[CH:4][CH:3]=1.[CH2:12]([S:15](Cl)(=[O:17])=[O:16])[CH2:13][CH3:14]>>[CH2:12]([S:15]([O:8][N:7]=[C:6]([Cl:9])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=1)(=[O:17])=[O:16])[CH2:13][CH3:14]
Reactant: CCCS(=O)(=O)Cl
Reactant: Cc1ccc(C(Cl)=NO)cc1
Product: CCCS(=O)(=O)ON=C(Cl)c1ccc(C)cc1

Procedure:
Eight and one-half grams of 4-methylbenzohydroximoyl chloride, prepared as in Example VI-A, was treated with 7.1 g of propanesulfonyl chloride in the same manner as described in Example VI-B. Recrystallization of the oil from ethanol gave 8.1 g of N-(propanesulfonyloxy)-4-methylbenzimidoyl chloride, m.p. 57.5°-60.5°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH2:5][CH3:6].S(O[CH2:20][C:21]1[O:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[O:23][CH:22]=1)(C)(=O)=O.O>CN(C=O)C>[CH3:3][CH:4]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:20][C:21]2[O:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[O:23][CH:22]=2)=[CH:12][CH:13]=1)[CH2:5][CH3:6]
Reactant: CS(=O)(=O)OCC1=COc2ccccc2O1
Reactant: CCC(C)Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCC2=COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To sodium hydride (0.53 g, 50% in oil, 11.0 mmol) in 40 ml of DMF, under N2 at 5°, is added, dropwise and with vigorous stirring, a solution of 4-(1-methylpropoxy)phenol (1.66 g, 10.0 mmol) in 10 ml of DMF. After the mixture is stirred at RT for 1 hour, a solution of 2-mesyloxymethyl-1,4-benzodioxin (2.70 g, 11.0 mmol) in 10 ml of DMF is slowly added. The resulting reaction mixture is stirred at RT for 48 hours and is then mixed with water and extracted with ether. The combined organic extracts are washed with water and with brine, dried and solvent removed and the product is purified by column chromatography to give 2-[4-(1-methylpropoxy)phenoxymethyl]-1,4-benzodioxin, MS m/e 315 (M+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25]([CH:26]=O)=[CH:24][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:22]=3)=[CH:15][CH:14]=2)[N:10]=1.[CH2:35]([P:44](=[O:51])([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25](/[CH:26]=[CH:35]/[P:44](=[O:51])([O:45][CH2:46][CH3:47])[O:48][CH2:49][CH3:50])=[CH:24][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:22]=3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)nc1)OCC
Reaction time: 15 h
Yield: 73.4 %

Procedure:
To a mixture of 3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}pyridin-3-yl)methoxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.40 g), tetraethyl methylenediphosphonate (0.28 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature, and the mixture was stirred at the same temperature for 15 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. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (3:1, v/v) to give diethyl (E)-2-{3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}pyridin-3-yl)methoxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.38 g, yield 71%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][C:19]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:20])=[CH:17][C:11]2=[N:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:39]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:39])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][C:19]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:20])=[CH:17][C:11]2=[N:10]1
Reactant: BrBr
Reactant: Cc1ccc(O)c(-n2nc3ccc(OC(C)(C)CC(C)(C)C)cc3n2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)CC(C)(C)Oc1ccc2nn(-c3cc(CBr)ccc3O)nc2c1
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-5′-bromomethyphenyl)-5-tert-octyloxybenzotriazole was prepared from the bromination of 2-(2′-hydroxy-5′-methyphenyl)-5-tert-octyloxybenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 8.236 g (0.0223 mol) 2-(2′-hydroxy-5′-methyphenyl)-5-tert-octyloxy benzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-hydroxy-5′-methyphenyl)-5-tert-octyloxybenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-5′-bromomethyphenyl)-5-tert-octyloxybenzotriazole was 7.8 g (81%).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([O:27][CH2:28][CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:26])C.[Li+].[OH-]>>[C:22]([C:18]1[O:19][C:20]([CH3:21])=[C:16]([CH2:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:27][CH2:28][CH3:29])[C:4]([OH:30])=[O:3])=[C:8]([CH3:26])[CH:9]=2)[N:17]=1)([CH3:24])([CH3:25])[CH3:23]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(C(C)(C)C)oc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCCc2nc(C(C)(C)C)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 46 d], [rac]-3-{4-[2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-{4-[2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless liquid.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:36][CH2:37][CH2:38][C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=1>>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13](=[O:15])[N:14]1[CH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]#[N:44])=[CH:45][CH:46]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: N#Cc1ccc(CCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCc1ccc(C#N)cc1)Cc1ccccc1
Yield: 69.4 %

Procedure:
Analogous to the procedure described for Example 1A, Step D, the anion derived from 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one (262.8 mg, 0.756 mmol) and NaHMDS (0.83 mL, 0.83 mmol) was reacted with 4-(3-bromo-propyl)-benzonitrile (186 mg, 0.832 mmol) at 70° C. for 24 h. Purification by medium pressure chromatography (5:1 hexanes:EtOAc to 1:1 hexanes:EtOAc to 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzonitrile (257.6 mg). 1H NMR (CDCl3) δ7.56 (m, 2H), 7.26 (m, 5H), 7.13 (m, 2H), 3.85 (m, 1H), 3.62 (m, 1H), 3.48 (m, 1H), 2.93 (m, 1H), 2.82-2.60 (m, 4H), 2.29 (m, 2H), 1.88-1.25 (m, 7H); MS 491.5 (M+1).
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:16])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[N:11][CH:10]=2)=O)C.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].C(=O)(O)[O-].[Na+]>>[NH:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:24]=[C:4]1[C:6]1[C:7](=[O:16])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[N:11][CH:10]=2
Reactant: CCOC(=O)c1cc2ccncc2[nH]c1=O
Reactant: Nc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]c2cnccc2cc1-c1nc2ccccc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 6-3 (300 mg, 1.37 mmol, 1 equiv) and 1,2-phenylenediamine (223 mg, 2.06 mmol, 1.5 equiv) in polyphosphoric acid (8 mL) was heated at 200° C. for 3 h. The hot rxn mixture was poured into ice water (50 mL), and the resulting mixture was allowed to stand until all polyphosphoric acid had dissolved. The acidic suspension was neutralized with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (5×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (EtOAc) to afford 3-(1H-benzoimidazol-2-yl)-1H-[1,7]naphthyridine-2-one (6-4) as a yellow solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.75 (s, 1H), 12.71 (s, 1H), 9.13 (s, 1H), 8.79 (s, 1H), 8.43 (d, 1H, J=5.2 Hz), 7.91 (d, 1H, J=5.2 Hz), 7.74 (m, 1H), 7.68 (m, 1H), 7.24 (m, 2H). HRMS (electrospray FT/ICR) calculated for C15H11N4O [M+H]+ 263.0933, found 263.0930.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:20]=2)[N:15]=1.C(#N)C>O>[O:24]([C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([NH:13][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:1])[CH3:12])[CH:4]=3)=[N:15]2)=[CH:20][CH:19]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Solvent: O
Solvent: CC#N
Product: CN(C)c1cccc(C(=O)Nc2ccc3ccc(Oc4ccccc4)nc3n2)c1
Temperature: 4 °C
Yield: 83.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-dimethylaminobenzoic acid (23.1 g), N,N'-carbonyldiimidazole (22.7 g) and 2-amino-7-phenoxy-1,8-naphthyridine (23.7 g). The product produced by precipitation in water (44 g; m.p. approximately 90° C.) is dissolved in boiling acetonitrile (1000 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×50 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-3-dimethylaminobenzamide (32 g) is produced (m.p. 120° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[Na].[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18]>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[CH2:9][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18]
Reactant: Cc1cccc(Cl)c1C
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Product: Cc1ccccc1CSc1cccc[n+]1[O-]
Yield: 85 %

Procedure:
The intermediate 2-(2-methylphenylmethylthio)-pyridine N-oxide is prepared by the procedure described in Example 2 from α -chloro o-xylene and 2-mercaptopyridine N-oxide sodium salt. Melting point 134° - 136°C. Yield 85% theory. Structure confirmed by IR and NMR.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.Br[CH2:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH:21]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[CH:3]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[C:4](=[O:34])[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]1=2)([CH3:23])[CH3:22]
Reactant: BrCc1cccc2ccccc12
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cccc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
To a stirring solution of 300 mg (0.66 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 10 mL DMF at 0° C. is added dropwise over 5 min 1.45 mL (0.72 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, then a solution of 160 mg (0.72 mmol, 1.1 equiv) of 1-bromomethylnaphthalene in 3 mL DMF is added. The resulting solution is stirred 2 h at RT and then quenched with 5 mL of H2O. The reaction mixture is then poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel MPLC on an Si60 column using hexane/EtOAc 2/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 385 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ8.01 (d, 1H, J=8.0), 7.80 (d, 1H, J=7.4), 7.69 (d, 1H, J=8.0), 7.50-6.94 (m, 16H), 6.84 (dd, 1H, J=1.5, 8.3), 5.04 (m, 1H), 4.36 (d, 1H, J=16.4), 4.17 (d, 1H, J=16.4), 3.92 (m, 2H), 3.85 (s, 3H), 3.82 (m, 1H), 1.09 (t, 6H, J=7.1); low resolution MS (FAB)m/e 598 (MH+), 597 (M+), 433.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:15][CH:14]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ccc(Sc2ccc3ccccc3n2)cc1
Yield: 39.6 %

Procedure:
2-Chloroquinoline (0.04 moles, 6.54 g), 4-aminothiophenol (0.04 moles, 5.0 g) and potassium carbonate (0.04 moles, 5.52 g) were stirred at room temperature in 200 ml of ethanol for 18 hr. The reaction mixture was concentrated, ethyl acetate was added and the solution washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with ethyl acetate/hexane to yield 2-(4-aminophenylthio)quinoline 4.0 g, 40%. Mass Spec (FD) 252. Calculated for C15H12N2S: C, 71.40; H, 4.79, N, 11.10. Found: C, 71.11; H, 4.98 N, 11.20.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37]C(C3C=CSC=3)=O)[CH:32]=2)=[O:28])[CH:24]=[C:23]([CH3:45])[C:5]=1[C:6]([NH:8][C@H:9]([C:19]([O:21]C)=[O:20])[CH2:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=[O:13])=[O:7]>CO>[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)=[O:28])[CH:24]=[C:23]([CH3:45])[C:5]=1[C:6]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=[O:13])=[O:7]
Reactant: COC(=O)[C@H](CNC(=O)c1ccsc1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(OC(=O)c3ccsc3)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)NCc2cccc(O)c2)cc(Cl)c1C(=O)N[C@@H](CNC(=O)c1ccsc1)C(=O)O
Reaction time: 8 h
Yield: 59.3 %

Procedure:
An aqueous solution of sodium hydroxide (1 M; 0.5 mL, 0.5 mmol) was added to a solution of N-[2-chloro-4-[[[[3-[(thiophene-3-carbonyl)oxy]phenyl]methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(thiophene-3-carbonyl)amino]-L-alanine, methyl ester (160 mg, 0.25 mmol) in methanol (2 mL). The solution was allowed to stir overnight and then concentrated. The residue was purified by HPLC and lyophilized to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(thiophene-3-carbonyl)amino]-L-alanine (76.5 mg, 59%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)[CH3:2].[O:11]1CC[CH2:13][CH2:12]1.C([Li])CCC.[Cl-].[NH4+]>O.CN(C)C(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:12](=[O:11])[CH3:13])[N:5]=1)[CH3:2]
Reactant: CCOc1cccc(Br)n1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOc1cccc(C(C)=O)n1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
16.8 g of 2-ethoxy-6-bromopyridine were introduced into 220 ml of tetrahydrofuran at -75° C. 54.4 ml of n-butyllithium (1.6-molar solution in n-hexane) were added dropwise at this temperature. Stirring was continued for two hours at -75° C., and 7.6 g of N,N-dimethylacetamide were added dropwise at this temperature. The mixture was stirred for a further hour at -75° C. and then warmed to -10° C., and first approximately 170 ml of 20 percent strength aqueous ammonium chloride solution and then 200 ml of water were added dropwise at this temperature. The mixture was extracted 3 times using methyl tert-butyl ether. The combined organic phases were washed 3 times with water and subsequently dried over sodium sulfate. After the solvent had been stripped off, the residue which remained was chromatographed on silica gel using cyclohexane/methyl tert-butyl ether 8:1. This gave 5.5 g of 2-ethoxy-6-acetylpyridine as a colorless solid (m.p.: 36-37° C).
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([C:21]1[CH:26]=[CH:25][C:24](OC2C=CC=CC=2)=[CH:23][CH:22]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=1)=[O:7].F[C:37](F)(F)[C:38]([OH:40])=O>>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([N:8]2[CH:3]=[CH:4][N:5]([C:21]3[CH:26]=[CH:25][C:24]([O:40][C:38]4[CH:37]=[CH:11][CH:10]=[CH:9][CH:14]=4)=[CH:23][CH:22]=3)[C:6]2=[O:7])=[CH:14][CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(CN(C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(Oc2ccccc2)cc1)OC
Product: CN(C)CCOc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1

Procedure:
1-(2,2-Dimethoxyethyl)-3-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-phenoxy-phenyl)urea (0.33 g) was shaken with trifluoroacetic acid (5 ml) for 16 hours. Volatiles were removed and the residue was taken up in dichloromethane (10 ml) and washed with sodium hydroxide solution (0.1N; 1 ml). The aqueous phase was extracted with dichloromethane (10 ml), and the combined organic phases were concentrated. The residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 98:2 with 1% v/v 7N ammonia solution in methanol). The product with the molecular weight of 415.50 (C25H25N3O3); MS (ESI): 416 ([M+H]+), was obtained in this way.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60]/[CH:61]=[CH:62]/[CH3:63].FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:60]/[CH:61]=[CH:62]/[CH3:63])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: C/C=C/COC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: C/C=C/COC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (115 mg in 3 ml 33% methylene chloride in cyclohexane) trans-2-butenyl trichloroacetimidate (48 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 35 minutes the reaction was quenchedby the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate: hexane (1:1)+1% methanol) gave the title compounds (14 mg 4"-ether; 12 mg 3"-ether).