Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([N:10]2[CH:19]([C:20]([OH:22])=O)[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:40][NH2:41].Cl>C1COCC1.O>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([N:10]2[CH:19]([C:20]([NH:41][OH:40])=[O:22])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: O=C(O)C1Cc2ccccc2CN1S(=O)(=O)N1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NO)C1Cc2ccccc2CN1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.3 g (7.5 mmol) of the carboxylic acid 26b are dissolved in 40 ml of absolute THF and, at −20° C., admixed successively with 1.2 g (12 mmol) of N-methylmorpholine and 1.1 g (7.5 mmol) of isobutyl chloroformate. After 30 min, the mixture is admixed with 3.9 g (37.5 mmol) of O-trimethylsilylhydroxylamine and stirred at RT for a further 5 h. 200 ml of water are added and the mixture is acidified with dilute HCl and extracted repeatedly with dichloromethane. The pooled organic phases are dried over Na2SO4 and concentrated under reduced pressure. The resulting oil is chromatographed under pressure over silica gel 60 using ethyl acetate/dichloromethane (1:1) as mobile phase. Recrystallization of the product fractions from ethyl acetate gave crystalline hydroxamic acid 26c.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][C:14]1([CH3:29])[O:19][CH2:18][CH:17]([NH:20]C2COC(C)(C)OC2)[CH2:16][O:15]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.ClCCl.C(OCC)(=O)C>[CH3:13][C:14]1([CH3:29])[O:19][CH2:18][CH:17]([NH:20][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:16][O:15]1
Reactant: CC1(C)OCC(NC2COC(C)(C)OC2)CO1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)OCC(NC(=O)c2ccc([N+](=O)[O-])cc2)CO1
Temperature: 60 °C
Reaction time: 5 h
Yield: 100.8 %

Procedure:
4-Dimethylaminopyridine (20 mg, 0.164 mmol) and 4-nitrobenzoyl chloride (9) (276 mg, 1.49 mmol) were added to a solution of bis-(2,2-dimethyl-1,3-dioxane-5-yl)-amine (4) (79 mg, 0.322 mmol) in pyridine (2.5 ml) and dichloromethane (5 ml). The mixture was stirred for 5 hours at 60° C. before being diluted with ethyl acetate (80 ml) and successively washed with saturated sodium bicarbonate solution (2×25 ml) and brine (25 ml). Drying over magnesium sulfate, concentration and purification by flash chromatography (hexane/ethyl acetate, 1.5:1) gave bis-N-(2,2-dimethyl-1,3-dioxane-5-yl)-p-nitrobenzamide (10) (91 mg, 72%) as colourless crystals; mp.: 211° C. (needles, from hexane/acetone); m/z (CI, NH3) 337 (M+H+-acetone, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:14](=O)[CH2:15][CH3:16])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:18][NH2:19].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>C(O)C>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[CH2:15]([C:14]1[C:11]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=3[C:25]([C:24]3[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=3)=[N:13][C:12]=2[NH:19][N:18]=1)[CH3:16]
Reactant: NN
Reactant: CCC(=O)C(C#N)c1ccc(OC)c(OC)c1
Reactant: O=Cc1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCc1n[nH]c2nc(-c3ccc(O)cc3)c3cc(OC)c(OC)cc3c12
Temperature: 70 °C
Yield: 28 %

Procedure:
2-[3,4-bis(methyloxy)phenyl]-3-oxopentanenitrile (100 mg, 0.43 mmol) was dissolved in ethanol (1 mL), and anhydrous hydrazine (98%, 16 μL, 0.52 mmol) was added. The resulting mixture was heated at reflux for 1 hour. It was cooled, concentrated, and the residue was dried in vacuum for one hour. To this residue was added of 4-hydroxybenzaldehyde (79 mg, 0.64 mmol) and trifluoroacetic acid (1 mL), and the mixture was heated at 70° C. for 18 hours. Then the reaction mixture was concentrated, dissolved in 10 mL of N,N-dimethylformamide and purified by preparatory HPLC (Shimadzu LC-8A HPLC, Waters Xterra C18 30 mm×100 mm column, acetonitrile-water-trifluoroacetic eluent). After concentration then lyophillization of the pure fractions 4-[1-ethyl-7,8-bis(methyloxy)-3H-pyrazolo[3,4-c]isoquinolin-5-yl]phenol trifluoroacetic acid salt (55 mg, 0.12 mmol, 28% yield) was obtained. 1H NMR (400 MHz, d6-DMSO): 7.77 (s, 1H), 7.71-7.69 (d, 2H), 7.51 (s, 1H), 7.01-6.98 (d, 2H), 4.05 (s, 3H), 3.76 (s, 3H), 3.26-3.21 (q, 2H), 1.44-1.40 (t, 3H); MS (EI) for C20H19N3O3: 349 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:16]2[C:11](=[C:12]([NH:17][C:18](OCC)=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]>[Zn].O>[CH:14]1[CH:13]=[C:12]([N:17]=[C:18]=[O:19])[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([N:6]=[C:4]=[O:3])[C:16]=2[CH:15]=1.[NH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)Nc1cccc2c(NC(=O)OCC)cccc12
Agent: [Zn]
Solvent: O
Product: CCOC(N)=O
Product: O=C=Nc1cccc2c(N=C=O)cccc12
Temperature: 350 °C

Procedure:
Via a powder metering device, 25 parts of 1,5-bis(ethoxycarbonylamino)naphthalene were fed at a rate of 450 liters per liter of reaction volume an hour into a tube reactor filled with zinc shavings and heated to 350° C. A pressure of 1 millibar to 3 millibars was maintained in the separating reactor. The escaping decomposition gases were fractionally condensed. In a first water-cooled vessel, 14 parts of 1,5-naphthalene diisocyanate (NDI) were obtained (80.5 theoretical percent relative to feed urethane). The melting point was 129° C. to 132° C.
Reaction SMILES: [C:1]1([OH:13])[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[CH:2]=1.[C:14](=[O:16])=[O:15]>OCC(CO)O>[OH:13][C:1]1[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[C:2]=1[C:14]([OH:16])=[O:15]
Reactant: O=C=O
Reactant: CCCCCc1cc(O)cc(O)c1
Solvent: OCC(O)CO
Product: CCCCCc1cc(O)c(C(=O)O)c(O)c1

Procedure:
A mixture of olivetol (2.1 g, 12 mM), KHCO3 (4.9 g, 39 mM), and solid CO2 (1.95 g, 44.3 mM) in glycerol (5.1 mL) was heated in a stainless steel bomb to 145° C. at 220 psi for 5 hours. The reaction was cooled and removed from the reaction vessel using water to transfer. The aqueous solution was carefully acidified to a pH=3 with 1 N HCl to give a precipitate. The solids were filtered, washed with water and dried to give the desired product. MS (ESI(−)) m/e 223 (M−H)+; 1H NMR (300 MHz, CDCl3) δ 9.40 (bs, 2H), 6.37 (s, 2H), 2.52 (t, 2H), 1.66-1.57 (m, 2H), 1.37-1.29 (m, 4H), 0.93-0.87 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH3:36].CO>C(Cl)Cl>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Temperature: 90 °C

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (196 mg, 0.364 mmol) and ammonia in methanol 7M (8 ml, 56.0 mmol) was heated in a sealed tube to 90° C. for 24 h. The reaction was diluted with DCM and added silica gel and concentrated. The crude product was chromatographed on silica gel eluting with 100% DCM to 1:1 [DCM:(9:1 EtOAc:MeOH)]. The clean fractions were concentrated to yield the crude product. The crude product was repurified by reverse phase HPLC (a gradient of acetonitrile:water with 0.1% TFA in both). The combined clean fractions were concentrated then partitioned between DCM and saturated NaHCO3. The DCM layer was separated and dried over Na2SO4. The title compound, N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide was obtained (94 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1 H), 7.93 (d, J=5.2 Hz, 1 H), 7.55-7.70 (m, 1 H), 7.35-7.43 (m, 1 H), 7.31 (t, J=6.3 Hz, 1 H), 7.14-7.27 (m, 3 H), 6.70 (s, 2 H), 5.79 (d, J=5.13 Hz, 1 H), 1.35 (s, 9 H). MS (ESI): 519.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>ClCCl>[Br:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(CCBr)cc1
Reactant: Cc1cccnc1N
Agent: Cl
Solvent: ClCCl
Product: Cc1cccnc1NS(=O)(=O)c1ccc(CCBr)cc1
Temperature: 35 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
3-Methyl-2-pyridinamine (431 g, 4.0 mol) was dissolved in dichloromethane (700 ml) and 4-(2-bromoethyl)benzenesulfonyl chloride (340 g, 1.33 mol) was added at room temperature. After 1 h at 20° C., the solution was heated to 35° C. for 2 h. Excess dilute hydrochloric acid was added and the phases separate& After washing once with water, the organic phase was dried with MgSO4 and treated with decolorizing carbon. The solvent was evaporated and warm methanol added to the residue, which crystallized. The material was collected and recrystallized from toluene. Yield 178 g. A further crop of 36 g was obtained by workup of the mother liquor. Total yield 45%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:11])=[C:7]([NH:9][CH3:10])[CH:8]=1.CO[C:14]([CH2:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:20][CH:19]=1)=O.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[C:14]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:30][CH:31]=3)[N:9]([CH3:10])[C:7]=2[CH:8]=1
Reactant: CNc1cc(OC)ccc1N
Reactant: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
A mixture of 21.8 g of 5-methoxy-N-methyl-1,2-phenylenediamine (see Referential Example 9, Japanese Patent Application Publication No. Hei-9 (1997)-295970), 63.4 g of 5-(4-methoxycarbonylmethoxybenzyl)thiazolidin-2,4-dione (see Referential Example 21, Japanese Patent Application Publication No. Hei9-(1997)-295970), 250 ml of 1,4-dioxane and 750 ml of conc. hydrochloric acid was heated under reflux for 60 hours. The reaction mixture was cooled with ice, and the precipitate was filtered. The precipitate was mixed with 800 ml of 5% aqueous sodium hydrogencarbonate solution and stirred at room temperature for 2 hours. The insoluble material was filtered, dissolved in a mixture of 1000 ml of N,N-dimethylformamide and 200 ml of methanol and treated with activated charcoal. The activated charcoal was filtered off, and the filtrate was concentrated to about 50 ml by evaporating the solvents. To the residue was added 750 ml of diethyl ether and this was then allowed to stand at room temperature for 2 days. The precipitate was filtered to give 20.1 g of the desired compound having a melting point of 267-271° C. having an Rf=0.68 (thin layer chromatography on silica gel; 5% ethanol-methylene chloride solution).
Reaction SMILES: [C:1]([O:5][C:6](=[O:8])[NH2:7])([CH3:4])([CH3:3])[CH3:2].[NH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[C:24](Br)[CH:25]=1)(=[O:15])=[O:14].[C:27]1(B2OCCCO2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CO.CCOC(C)=O>[C:1]([O:5][C:6](=[O:8])[NH2:7])([CH3:4])([CH3:3])[CH3:2].[NH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=1)(=[O:15])=[O:14]
Reactant: c1ccc(B2OCCCO2)cc1
Reactant: NCCNS(=O)(=O)c1cc(Br)cc2cnccc12
Agent: CC(C)(C)OC(N)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CO
Product: NCCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A mixture of 7-bromo-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide carbamic acid t-butyl ester (1.50 g, 3.49 mmol), 2-phenyl-1,3,2-dioxaborinane (1.129 g, 6.98 mmol), Pd(dppb)Cl2 (211 mg, 0.0349 mmol) and Na2CO3 (2.0M, 12 mL) in ethylene glycol dimethyl ether (60 mL) and CH3OH (15 mL) is heated to 80° C. (oil bath) with stirring overnight. After cooling to room temperature, the mixture is diluted with EtOAc, filtered and concentrated. The residue is dissolved in EtOAc, washed with brine and dried over Na2SO4. The crude material is chromatographed on silica gel (gradient 50% EtOAc in hexane) to give 1.45 g (97% yield) 7-phenyl-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide carbamic acid t-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]([C:15](=[O:29])[C@@H:16]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17]([CH3:19])[CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](N)[CH:9]=1)[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1.CCOC(C)=O.Cl>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]([C:15](=[O:29])[C@@H:16]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17]([CH3:19])[CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:32]([CH3:31])(=[O:34])=[O:33])[CH:9]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CN(Cc1cccc(N)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CN(Cc1cccc(S(C)(=O)=O)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 735 (476.0 mg, 1.16 mmol) in pyridine (3.0 mL) was added methanesulfonyl chloride (135 μL, 1.75 mmol), and the reaction allowed to stir overnight. The reaction was diluted with EtOAc and 1N HCl. The layers were separated and the organic phase washed with brine, dried over MgSO4, filtered and concentrated to provide 550 mg of 744. ##STR123##
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[N+:19]([C:13]1[CH:12]=[C:11]([C:10]2[O:22][C:2]3[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=3[N:9]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18])([O-:21])=[O:20]
Reactant: COc1ccc(C(=O)Nc2cc(Br)ccc2O)cc1[N+](=O)[O-]
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Yield: 91 %

Procedure:
A suspension of N-(2-hydroxy-5-bromophenyl)-3-nitro-4-methoxybenzamide (5.24 g, 14.2 mmol) and toluenesulfonic acid monohydrate (5.36 g, 31.2 mmol) in toluene (100 ml) was heated to reflux overnight. The cooled reaction mixture was washed with saturated sodium hydrogen carbonate solution (care foaming) and the organic layer separated. The aqueous layer was extracted with ethyl acetate (2×50 ml) and the combined organic layers dried over sodium sulfate and the solvent removed under reduced pressure. The residue was triturated with ether, filtered and dried under vacuum to give the subtitle compound as a pale pink solid (4.51 g, 93%). 1H NMR (DMSO) δ 8.61(d, 1H), 8.42(dd, 1H), 8.05(d, 1H), 7.79(d, 1H), 7.61(m, 2H), 4.05(s, 3H). MS m/z 349.0 (M+H)+.
Reaction SMILES: C12CC(CC1)C[CH2:3][O:2]2.[CH3:9][C:10]1[CH2:14][CH2:13][CH:12]([C:15](O)=O)[CH:11]=1.S(Cl)(Cl)=[O:19]>>[CH3:9][C:10]1[CH2:14][CH2:13][CH:12]([CH2:15][C:3]([OH:2])=[O:19])[CH:11]=1
Reactant: CC1=CC(C(=O)O)CC1
Reactant: O=S(Cl)Cl
Reactant: C1CC2CCC(C2)O1
Product: CC1=CC(CC(=O)O)CC1

Procedure:
When m is 0, n is 2 and p is 2, the ring system is a 2-oxabicyclo[3.2.1]octane, another subclass of this invention. For example, compound XIp, ##STR26## in which R2, R5 and R6 are methyl, can be prepared by conversion of 3-methylcyclopent-2-ene-1-carboxylic acid described in IV to the corresponding acid chloride with thionyl chloride. The resulting carboxylic acid chloride is subjected to a modified Arndt-Eistert homologation, as described by G. P. Kugatova-Sheinyakina and R. A. Poskiene, Zh. Organ. Khim., 2(5), 844 (1966) (CA 65 10504c) to produce 3-methyl-2-cyclopentene-1-acetic acid, which is treated similarly to the acid of Subclass IX to yield the desired 2-oxabicyclo[3.2.1]octan-8-ol. The octanol is treated with WCH2X in which X is halogen to yield the desired ether, XIp.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[C:28]([O:32][C:33]([NH:35][C:36]1[CH:44]=[C:43]2[C:39]([CH2:40][N:41]([CH2:46][C:47](O)=[O:48])[C:42]2=[O:45])=[CH:38][CH:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:28]([O:32][C:33]([NH:35][C:36]1[CH:44]=[C:43]2[C:39]([CH2:40][N:41]([CH2:46][C:47]([O:10][C@H:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]4[CH2:25][CH2:24]4)[CH:12]=3)[CH2:8][C:7]3[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=3[Cl:1])=[O:48])[C:42]2=[O:45])=[CH:38][CH:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=O)N(CC(=O)O)C2
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (Compound 7, 60 mg, 0.143 mmol), 2-(6-(tert-butoxycarbonylamino)-1-oxoisoindolin-2-yl)acetic acid (65.6 mg, 0.214 mmol), DMAP (20.93 mg, 0.171 mmol), and EDC (82 mg, 0.428 mmol) were dissolved in DMF (5 ml). The reaction was stirred at RT overnight. The reaction mixture was diluted with water, and the precipitate was washed with water, dissolved in EtOAc and extracted with HCl 1N, Na2CO3 sat. sol. and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum to give (S)-4-(2-(2-(6-(tert-butoxycarbonylamino)-1-oxoisoindolin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (70 mg, 0.099 mmol, 69% yield). MS/ESI+ 306.12 [MH]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[C:13]([O:16]C(=O)C)(=O)[CH3:14].[N+:20]([O-])([OH:22])=[O:21]>O>[C:13]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][C:7]=1[N+:20]([O-:22])=[O:21])(=[O:16])[CH3:14]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1ccc(N)cc1
Solvent: O
Product: COC(=O)Cc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Methyl 4-aminophenylacetate (110 g, 0.667 mol) was added dropwise to acetic anhydride (600 ml), maintaining the temperature of the reaction mixture below 30° C. by external cooling. Once the addition was complete the mixture was cooled to below 10° C. and concentrated nitric acid (85 ml) was added dropwise. Once the addition of the acid was complete, the mixture was allowed to warm to room temperature and poured onto a mixture of ice and water. The precipitated solid was collected by filtration and dried to give methyl 4-acetamido-3-nitrophenylacetate (120 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:17])[CH2:14][CH2:15]Cl)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4].[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+].CC(C)=O.[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41]>CC(C)=O.CN(C)C=O.N1C=CC=CC=1>[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41].[CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:17])[CH2:14][CH2:15][N:27]3[CH2:28][CH2:29][N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4]
Reactant: CN1C(=O)CCc2cc(C(=O)CCCl)ccc21
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN1C(=O)CCc2cc(C(=O)CCN3CCN(c4ccccc4)CC3)ccc21
Reaction time: 7 h

Procedure:
2.6 Grams of 1-methyl-6-(1-oxo-3-chloropropyl)-3,4-dihydrocarbostyril, 1.2 g of pyridine and 2.0 g of 4-phenylpiperizine were mixed into 30 ml of dimethylformamide and the mixture was stirred at 70°-80° C. for 7 hours. The reaction mixture was poured into 100 ml of 5%-sodium hydrogencarbonate solution and was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue thus obtained was dissolved with acetone and the pH of the solution was adjusted to pH 4 by adding 5%-oxalic acid acetone solution to form crystalline precipitates. The precipitates were collected by filtration and recrystallized from ethanol-water to obtain 2.8 g of 1-methyl-6-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril monooxalate in colorless flake-like crystals.
Reaction SMILES: [C:1](ONS(C)(=O)=O)(=O)[CH2:2]CCCCC.CS(NCCCCCCC(OCC)=O)=[O:17].[C:30]([O:33][CH:34]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:35][CH2:36][CH2:37][N:38]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50]CC)=[O:49])[S:39]([CH3:41])=[O:40])(=[O:32])[CH3:31]>>[CH2:1]([CH:47]([CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][N:38]([CH2:37]/[CH:36]=[CH:35]/[CH:34]([O:33][C:30](=[O:32])[CH3:31])[CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[S:39]([CH3:41])(=[O:40])=[O:17])[C:48]([OH:50])=[O:49])[CH3:2]
Reactant: CCOC(=O)CCCCCCNS(C)=O
Reactant: CCCCCCC(=O)ONS(C)(=O)=O
Reactant: CCCCCC(CCCN(CCCCCCC(=O)OCC)S(C)=O)OC(C)=O
Product: CCCCCC(/C=C/CN(CCCCCC(CC)C(=O)O)S(C)(=O)=O)OC(C)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the ethyl 7-(methanesulfonamido heptanoate is replaced by an equimolar amount of ethyl 7-(methanesulfinamido)heptanoate (Example T). The product of Step A is thus ethyl 7-[N-(4-acetoxynonyl)methanesulfinamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxynonyl)methanesulfinamido]heptanoic acid (B).