Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]1[O:22][C:23]([C:26]2[C:27]([O:36][CH3:37])=[N:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][N:25]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][N:39](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C.CCOC(C)=O>[CH3:37][O:36][C:27]1[C:26]([C:23]2[O:22][C:21]([C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:39][CH3:38])=[O:19])=[N:25][CH:24]=2)=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1
Reactant: COc1nc2ccccc2cc1-c1cnc([C@H](CCCCCC(=O)O)NC(=O)OCc2ccccc2)o1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1ncc(-c2cc3ccccc3nc2OC)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of F5 in DMF (0.1 M) were added HATU (2.0 eq.) and DIPEA (3.0 eq.) followed after 10 min by methylamine (2.0 M solution in THF, 5.0 eq.). Reaction mixture was stirred at room temperature for 16 h. Then, reaction mixture was diluted with EtOAc, washed with sat. aq. NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by column chromatography (eluent: Petroleum ether/EtOAc from 1:1 to 100% EtOAc, then EtOAc/MeOH=95:5) to give the title compound as pale yellow solid. MS (ES+) C29H32N4O5: 517 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([C:17]([O:19]C)=[O:18])=[CH:11][CH:12]=2)[N:7]=1.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([C:17]([OH:19])=[O:18])=[CH:11][CH:12]=2)[N:7]=1
Reactant: COC(=O)c1ccc2c(=O)[nH]c(Cc3ccc(Cl)c(Cl)c3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc2c(=O)[nH]c(Cc3ccc(Cl)c(Cl)c3)nc2c1
Yield: 103 %

Procedure:
A mixture of 100 mg of methyl 2-(3,4-dichlorobenzyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate which was synthesized in Production Example 2, 0.5 mL of 1N sodium hydroxide and 1 mL of water was heated under reflux for about 3 hours. After cooling off, 1N hydrochloric acid was added to the reaction solution to render the latter acidic, and the resulting precipitate was recovered by filtration and dried to provide 99 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([NH2:11])=[CH:9][N:8]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.C[Al](C)C.CCCCCCC.[Cl:42][C:43]1[CH:44]=[CH:45][CH:46]=[C:47]2[C:51]=1[C:50](=O)[O:49][CH2:48]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.C(Cl)Cl.O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([N:11]3[CH2:48][C:47]4[C:51](=[C:43]([Cl:42])[CH:44]=[CH:45][CH:46]=4)[C:50]3=[O:49])=[CH:9][N:8]([C:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C1OCc2cccc(Cl)c21
Reactant: Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: C[Al](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2c(Cl)cccc2CN1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Reaction time: 0.5 h
Yield: 37.2 %

Procedure:
2-bromo-5-trityl-pyrrolo[2,3-b]pyrazin-7-amine (4.82 g, 10.59 mmol) suspended in PhMe (72 mL) and AlMe3 in heptane (31 mL of 1.0 M, 31 mmol) added at RT under N2. After 30 minutes, a solution of 7-chloro-3H-isobenzofuran-1-one (3.570 g, 21.18 mmol) in DCM (72 mL) added with cooling on an ice bath. Reaction mixture stirred overnight, temperature rising to ambient. Reaction mixture re-cooled on an ice bath and water (˜30 mL) added slowly. After 5 minutes mixture diluted with DCM. Resulting mixture stirred vigorously for 30 mins then filtered through celite to remove bulk of Al salts. Layers separated. Aqueous extracted with DCM (×2). Combined organics dried and concentrated to a brown solid. This material dissolved in THF (200 mL) under N2 and Ph3P (4.165 g, 15.88 mmol) then DEAD (2.00 mL, 12.71 mmol) added. Reaction mixture stirred overnight at RT then concentrated. Residue partitioned between DCM and brine. Aqueous phase extracted with DCM and combined organics dried and concentrated. Resulting black residue taken up in DCM. Some product precipitates and is collected by filtration. Filtrate purified by chromatography (silica, 0-5% MeOH-DCM gradient elution). Product fractions concentrated to a brown solid and further purified by trituration with DCM/MeOH (˜1:1) to give a yellow solid. Combined product dried under vacuum at 60° C. to give the title compound as a yellow solid (2.39 g, 37% over two steps); 1H NMR (400 MHz, DMSO) δ 5.85 (2H, s), 7.76-7.84 (15H, m), 7.97 (1H, d), 8.12 (1H, t), 8.21 (1H, d), 8.54 (1H, s), 9.22 (1H, s) ppm; MS (ES+) 606.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18](CC2C=CC(OC)=CC=2)[CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([Cl:43])[CH:37]=2)=[O:34])=[C:4]([F:44])[CH:3]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([Cl:43])[CH:37]=2)=[O:34])=[C:4]([F:44])[CH:3]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(Cl)c3)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(Cl)c3)c(F)cc2Cl)cc2cnc(NC)cc21
Yield: 74.2 %

Procedure:
A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea (91 mg, 0.143 mmol) and anisole (77 mg, 0.713 mmol) was stirred in TFA (3 mL) at RT for 3 h. The mixture was concentrated to near-dryness, dissolved in EtOAc and treated with satd. NaHCO3. The layers were separated, the organic layer washed with brine and dried over Na2SO4. Solids precipitated, so THF, MeOH and DMF were added and the mixture was warmed to afford a clear solution, then filtered to remove salts. The filtrate was concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue neutralized with satd. NaHCO3, extracted with warm EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea (55 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 8.83 (s, 1H), 8.41 (s, 1H), 8.09 (d, J=8.6 Hz, 1H), 7.74 (s, 1H), 7.55 (d, J=10.9 Hz, 1H), 7.36 (s, 1H), 7.27 (dt, J=11.2, 2.1 Hz, 1H), 7.06-6.98 (m, 2H), 6.24 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.86 (d, J=4.8 Hz, 3H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 518.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][C:7]([CH3:22])([CH2:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=1)[C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:6][C:7]([CH3:22])([CH2:12][C:13](=[O:21])[C:14]1[CH:15]=[CH:16][C:17]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:18][CH:19]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)CC(=O)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
Imidazole (0.70 g, 0.013 mol) and methyl α,α-dimethyl-4-fluoro-γ-oxobenzene butanoate (2.85 g, 0.012 mol) are dissolved in dimethyl sulfoxide (12.0 ml) in which freshly pulverized potassium carbonate (5.80 g, 0.042 mol) is suspended. The resulting mixture is stirred and heated at 100°-110° for 12 hours. The mixture is then cooled to room temperature and poured into 100 ml of ice water and stirred for ten minutes. The solid is filtered to give 2.14 g of methyl α,α-dimethyl-4-(1H-imidazol-1-yl)-γ-oxobenzene butanoate, mp 89°-93° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@@H:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1.[CH3:14][S:15]([O-:17])=[O:16].[Na+].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[CH3:14][S:15]([C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@@H:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1)(=[O:17])=[O:16]
Reactant: OC[C@@H]1COc2ccc(Br)cc2O1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc2c(c1)O[C@H](CO)CO2
Yield: 78.2 %

Procedure:
Two batches of [(2R)-7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (2.2 g, 8.9 mmol), sodium methanesulfinate (85%) (1.6 g, 13.3 mmol), CuI (0.2 g, 0.9 mmol), L-proline (0.2 g, 1.8 mmol) and K2CO3 (0.2 g, 1.8 mmol) in DMSO (20 ml) were heated under microwave radiation at 140° C. for 3 h in nitrogen-flushed vials. Water and EtOAc were added. The water layer was extracted with EtOAc (3×100 ml) and the combined organic phases were washed with LiCl (5%), HCl (1 N) and brine. The resulting solution was dried (Na2SO4) and evaporated to dryness. The residue was purified by flash column chromatography (isooctane/EtOAc) to give the title compound (1.7 g). MS m/z (rel. intensity, 70 eV) 244 (M+, bp), 213 (39), 165 (26), 134 (22), 79 (23).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14](COCC[Si](C)(C)C)[N:13]=[CH:12][C:11]=2[NH:23]C(=O)OC(C)(C)C)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:14][N:13]=[CH:12][C:11]=2[NH2:23])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1-c1c(NC(=O)OC(C)(C)C)cnn1COCC[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ncc(Cl)cc1-c1[nH]ncc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To a solution of tert-butyl 5-(5-chloro-2-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ylcarbamate (211.7 mg, 0.4652 mmol) in 5 mL ethyl acetate was added tin tetrachloride (0.52 mL, 4.4 mmol). The reaction mixture was stirred at room temperature for 2 hours and then evaporated in vacuo. The residual oil was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, and the aqueous layer extracted twice more with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 20% methanol in dichloromethane) to yield 32.4 mg (31%) of 5-(5-chloro-2-methoxypyridin-3-yl)-1H-pyrazol-4-amine LCMS (ESI) m+H=225.1.
Reaction SMILES: [N+:1]([C:4]1[N:8]2[N:9]=[C:10]([S:13]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)([O-:3])=[O:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[N+:1]([C:4]1[N:8]2[N:9]=[C:10]([SH:13])[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)nn12
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccc(S)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
A solution of 1.0 g (2.28 mmol) of 3-nitro-6-tritylsulfanylimidazo[1,2-b]pyridazine in 10 ml of anhydrous dichloromethane is treated with 0.73 ml (4.56 mmol) of triethylsilane and 1.0 ml (13 mmol) of trifluoroacetic acid under an argon atmosphere and stirred at room temperature for 3 h. 10 ml of 2N sodium hydroxide solution is then added and the mixture is extracted with 3×20 ml of ethyl acetate. The aqueous phase is then adjusted to pH 2 using hydrochloric acid and subsequently extracted with 3×20 ml of ethyl acetate. The organic extracts are washed with 20 ml of water, dried over magnesium sulfate and concentrated. The residue is crystallized by addition of a little diethyl ether. 0.34 g (76%) of the title compound is isolated as a pale yellow solid. M.p. 175-177° C.
Reaction SMILES: [Na+].[Cl-:2].[CH:3]1[C:4]2[C:19](=[O:20])[C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]([CH:24]3[CH2:26][CH2:25]3)[C:5]=2[CH:6]=[C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[C:8]=1[F:9]>O>[CH:3]1[C:4]2[C:19](=[O:20])[C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]([CH:24]3[CH2:25][CH2:26]3)[C:5]=2[CH:6]=[C:7]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[C:8]=1[F:9].[ClH:2]
Reactant: [Cl-]
Agent: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: [Na+]
Solvent: O
Product: Cl
Reaction time: 1 h

Procedure:
The bandage was placed in a capped vial containing 1 ml of 0.9% NaCl in distilled water at 25° C. After 1 hr of gentle stirring, the aqueous phase was collected and the bandage was placed in a fresh 1 ml portion of 0.9% NaCl. This process was repeated for a total of 24 one hour periods. The following procedure for HPLC analysis of ciprofloxacin was essentially that of Darouiche, R. et al, [J. Inf Dis 162, 1124-1125 (1990)]. The conditions were a Whatman Partisil 50D5-3 (C8) column with a mobile phase of 25 ml 0.5M Bu4NHPO4 made up to 2.5 L with distilled water, pH adjusted to 2.34 with 85% H3PO4, which was added to 278 ml HPLC grade acetonitrile, filtered through a 0.2μ membrane and degassed. The flow rate was 1.5 ml/min at 25° C. with a 500 μl injection loop with detection at 280 nm. Under these conditions ciprofloxacin eluted as a single peak at 9 min. HPLC analysis of the 24 aqueous fractions gave the elution profile shown in Table 2. The data in Table 2 showed that 74% of the initial charge of ciprofloxacin was released in the first 4 hrs and the release of ciprofloxacin in the subsequent 5 to 24 hrs was remarkably constant. This was thought to be due to the gradual release of ciprofloxacin trapped in the cryogel matrix.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1.[CH3:15][O:16][CH2:17][CH2:18]Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:6]1[S:10][C:9](=[NH:11])[N:8]([CH2:18][CH2:17][O:16][CH3:15])[CH:7]=1
Reactant: COCCBr
Reactant: Nc1ncc(Cc2cccc(F)c2)s1
Product: COCCn1cc(Cc2cccc(F)c2)sc1=N

Procedure:
A mixture of 5-(3-fluoro-benzyl)-thiazol-2-ylamine (330 mg, 1.59 mmol) and 2-bromoethyl methyl ether (0.50 mL, 5.34 mmol) was processed according to the method of Example 43A to afford the title compound: MS (LC/MS) m/z 267 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:22][N+:23](C)([CH3:25])[CH3:24].[Cl-].CN(C)CC(O)CO.CC(C)([O-])C.[K+].C1(C)C=CC(S(OCCCCCCCC/C=C\CCCCCCCC)(=O)=O)=CC=1>>[CH2:28]([O:27][CH:21]([CH2:20][O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:22][N:23]([CH3:25])[CH3:24])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC/C=C\CCCCCCCC
Agent: CC(C)(C)[O-]
Agent: CCCCCCCC/C=C\CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: CN(C)CC(O)CO
Product: CCCCCCCC/C=C\CCCCCCCCOCC(CN(C)C)OCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DOTMA (N-(1-(2,3,-Dioleyloxy(propyl)-N,N,N-trimethylammonium chloride) was prepared as outlined. A mixture of 3-(dimethylamino)-1,2-propanediol (Aldrich Chemical Co., 1.19 g, 10 mmol), potassium tert-butoxide (3.36 g, 30 mmol) and oleyl p-toluenesulfonate (12.7 g, 30 mmol) in xylenes (50 ml) was stirred at room temperature and reduced pressure (30 Torr) for 30 min, and was then heated to 50° C. with stirring for an additional 15 min. The reaction vessel was purged with nitrogen, and the mixture was heated to reflux (approximately 140° C.) for 3 hrs. After cooling, the reaction mixture was diluted with hexane (100 ml), and the resulting solution was extracted with water (2×50 ml). The organic layer was concentrated, and the residue was chromatographed over silica gel by elution with a mixture of hexanes and ether (1:2) to afford the intermediate 2,3-dioleyloxy-1-(dimethylamino)-propane as a colorless oil. Quaternizaton was carried out by condensation of methyl chloride (50 ml) into a Parr pressure apparatus cooled to -78° C. containing this compound (10 g). The sealed vessel was heated behind a safety shield at 70° C. for 48 h. After cooling to 0° C., the reaction vessel was opened, and the excess methyl chloride was allowed to evaporate under a stream of nitrogen in a well-ventilated hood. The crude residue was recrystallized from acetonitrile to afford DOTMA as an off-white solid, mp. 35°-38° C. Full details of the synthesis of DOTMA and analogs will be published elsewhere (Gadek and Felgner, in preparation).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[C:7]([C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[N:10]=1)=[O:8].C(O)(C(F)(F)F)=O>ClCCl>[CH:3]([C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[C:7]([C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]3)=[CH:25][CH:26]=2)[N:10]=1)=[O:8])=[O:2]
Reactant: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1cccc(C(OC)OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1cccc(C=O)c1

Procedure:
A solution of Example 158B (200 mg, 0.4 mmol) in dichloromethane (10 ml) was treated with TFA (5 mL) at 40° C. overnight. The volatiles were removed and the residue was directly used in the next step without further purification. MS (DCI/NH3) m/z 474 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][N:29]=1)[C:6]([NH:8][C:9]1[O:10][C:11]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:16][CH:15]=[C:14]([O:25][CH3:26])[C:12]=2[N:13]=1)=[O:7].[H-].[Na+].[CH2:32]([OH:34])C>O1CCOCC1.CN(C=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:11]3[O:10][C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:27]=[CH:28][N:29]=[C:3]([CH2:2][O:34][CH3:32])[CH:4]=4)=[N:13][C:12]=3[C:14]([O:25][CH3:26])=[CH:15][CH:16]=2)=[CH:19][CH:20]=1
Reactant: CCO
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccnc(CCl)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COCc1cc(C(=O)Nc2nc3c(OC)ccc(-c4ccc(F)cc4)c3o2)ccn1

Procedure:
From 2-chloromethyl-N-[7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl]-isonicotinamide with sodium hydride and ethanol in dioxane and DMF. ES-MS m/e (%): 408 (M+H+, 100).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH2:12][CH2:13][CH3:14])[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>O>[CH3:11][N:10]1[C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]([CH2:12][CH2:13][CH3:14])=[N:9]1
Reactant: CCCc1cc(C(=O)OCC)n(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1cc(C(=O)O)n(C)n1
Temperature: 80 °C
Yield: 73.1 %

Procedure:
1-Methyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester (20.2 g, 0.10 mol) was suspended in 6N aqueous sodium hydroxide solution (50 ml, 0.30 mol). The mixture was heated to 80° C. for 2 hours then diluted with water (50 ml) and acidified with concentrated hydrochloric acid (25 ml). Filtration gave the carboxylic acid as pale brown crystals (12.3 g, 71%), m.p. 150-154° C. Found: C,56.99; H,7.25; N,16.90. C8H12N2O2 requires C,57.13; H,7.19; N,16.66%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH3:9])[CH2:4][CH2:3]1.[N+:10]([C:13]1[CH:14]=[C:15]2[C:20](=O)[O:19][C:17](=[O:18])[C:16]2=[CH:22][CH:23]=1)([O-:12])=[O:11].C(=O)(O)[O-]>C(Cl)(Cl)Cl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([N:1]2[C:20](=[O:19])[C:15]3=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:23][CH:22]=[C:16]3[C:17]2=[O:18])[CH2:3][CH2:4]1)[CH3:9]
Reactant: CCN1CCC(N)CC1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Product: CCN1CCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)CC1
Temperature: 25 °C
Yield: 16.5 %

Procedure:
6.50 Grams (0.05 mole) of 4-amino-N-ethyl piperidine and 9.65 grams (0.05 mole) of 4-nitrophthalic anhydride were dissolved in 150 milliliters of chloroform and the solution was stirred for an hour at room temperature. The chloroform was evaporated and the solid dissolved in 50 milliliters of acetic anhydride and the solution was refluxed for an hour. The acetic anhydride was evaporated off and the dark red residue treated with isopropyl alcohol and the solvent evaporated. The residue which was a gum was repeatly subjected to treatment with isopropyl alcohol and evaporation of the solvent until a crystalline solid was produced. The solid was taken up in chloroform and this was washed with sodium bicarbonate solution, then water and then brine until the aqueous layer was neutral. The chloroform extract was dried with magnesium sulphate, filtered and evaporated to give a solid. Microanalysis showed this to be impure and the bicarbonate washing was repeated as outlined above. The dried chloroform extract was evaporated off and the residue treated with ether to give 2.5 grams of the title compound as a yellow solid, m.p. 153°-155°.
Reaction SMILES: [CH2:1]([C@H:5]1[O:7][C@@H:6]1[C:8]([OH:10])=O)[CH2:2][CH2:3][CH3:4].CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]1O.C1CCC(NC2CCCCC2)CC1.C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C.Cl.[CH3:66][O:67][C:68](=[O:78])[C@H:69]([CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[NH2:70]>O1CCCC1>[CH3:66][O:67][C:68](=[O:78])[C@@H:69]([NH:70][C:8]([C@@H:6]1[C@@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[O:7]1)=[O:10])[CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCCC[C@H]1O[C@@H]1C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
Under ice-cooling, to 10 ml of an anhydrous tetrahydrofuran solution containing 299 mg (1.84 mmol) of (2S-trans)-3-butyl-oxirane carboxylic acid.dicyclohexylammonium salt was added 2 ml of an anhydrous tetrahydrofuran solution containing 222 mg (1.84 mmol) of pivaloyl chloride, and the resulting mixture was stirred at the same temperature for 15 minutes. Moreover, the temperature of the reaction mixture was returned to room temperature and the mixture was stirred for 2 hours. After filtering off insoluble materials in the reaction mixture, 187 mg (1.84 mmol) of triethylamine was added to the filtrate under ice-cooling, and then, 397 mg (1.84 mmol) of L-phenylalanine methyl ester hydrochloride was added to the mixture, and the resulting mixture was stirred at room temperature for 2 hours. Under reduced pressure, the reaction mixture was concentrated and ethyl acetate was added to the concentrate, and the resulting mixture was washed successively with a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and then a saturated NaCl solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 558 mg (Yield: 100%) of the title compound.