Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14]C(=O)O[C:10]2=[O:11]>C(O)C>[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=1[C:10]([NH:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)=[O:11]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCc1c[nH]cn1
Solvent: CCO
Product: Nc1ccccc1C(=O)NCCc1c[nH]cn1
Yield: 14.3 %

Procedure:
The subtitled compound was prepared substantially in accordance with the method detailed in Example 6A using 5.55 g (0.05 mol) of 4-(2-aminoethyl)imidazole in 40 ml ethanol and 8.31 g (0.05 mol) of isatoic anhydride with the exception that after removing ethanol from the reaction solution the product was purified using column chromatography (500 ml dichloromethane; 2000 ml 9% methanol in dichloromethane, isocratic eluent). The fractions containing the desired product were combined and reduced to dryness under reduced pressure to provide a solid. This solid was recrystallized from diethyl ether to provide 1.65 g of the desired subtitled compound (m.p. 85°-87° C.).
Reaction SMILES: Br[CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[N-:15]=[N+:16]=[N-:17].[Na+]>CC(C)=O.O>[N:15]([CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N+:16]=[N-:17]
Reactant: BrC1c2ccccc2-c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NC1c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 87.5 %

Procedure:
9-Bromo-9H-fluorene (1.00 g, 4.08 mmol) was dissolved in acetone (7 mL). To this was added a solution of NaN3 (1.33 g, 20.4 mmol) in H2O (3 mL). The resulting solution was stirred overnight. Acetone was removed by concentration under reduced pressure. The resulting aqueous mixture was extracted with CH2Cl2 (2×15 mL), and the organic layers were combined, dried over Na2SO4(s), filtered, and concentrated under reduced pressure. The resulting solid residue was purified by silica gel flash chromatography, eluting with hexanes, to give azide 2j as a white solid (0.74 g, 3.57 mmol, 87% yield).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3]I.[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[OH:18])[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH2:3][C:2]([F:6])([F:5])[F:1])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(F)(F)F)c(Cl)c1
Reaction time: 16 h

Procedure:
1,1,1-Trifluoro-2-iodoethane (1.162 ml, 11.80 mmol) was added to methyl 3-chloro-4-hydroxybenzoate (Alfa Aesar; 1.0 g, 5.36 mmol) and anhydrous potassium carbonate (0.889 g, 6.43 mmol) in N,N-dimethylformamide (DMF) (30.0 ml), and the mixture was heated under reflux with stirring under nitrogen for 16 h.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: Brc1cccc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Temperature: 0 °C
Yield: 90.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 4-bromo-1H-indole (200 g) in tetrahydrofuran (2.0 L) was ice-cooled to 0° C., and sodium hydride (49 g) was added thereto, followed by stirring under ice-cooling for 1 hour. Benzenesulfonyl chloride (200 g) was added dropwise under ice-cooling to the reaction mixture, and the ice bath was removed, followed by stirring at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by ethyl acetate extraction. The organic layer was washed with brine and dried over magnesium sulfate, followed by filteration. The resulting residue was washed with isopropylether-hexane (1:1, 1.0 L), and then dried to obtain the title compound (310 g) having the following physical properties.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23]O)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:44]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:44][CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[O:16])[CH2:18][CH2:19]1
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(CO)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 210.1 %

Procedure:
The ester produced in Example 56 (5.0 g, 15 mmol) and triphenylphosphine (4.0 g, 15 mmol) were dissolved in 100 ml of benzene and the resulting solution put under a nitrogen atmosphere. N-Bromosuccinimide (2.7 g, 15 mmol) was added in portions to the above solution and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure to give 12.3 g of a brown oil. Purification of this oil by chromatography on 600 g of silica gel (230-400 mesh) using ethyl acetate-hexane as the eluent gave 4.52 g of a white solid. Recrystallization of this solid from diisopropyl ether gave the title compound as a white crystalline solid (4.12 g, 68%), mp 76°-78° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31](O)=[O:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][CH:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]4)=[O:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[N:6]=1)[CH2:2][CH3:3].C(=O)(O)[O-:23].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[O:23])[N:6]=1)[CH2:2][CH3:3]
Reactant: O=C([O-])O
Reactant: CCCOc1ccnc(Sc2cccc3cccnc23)n1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCCOc1ccnc(S(=O)c2cccc3cccnc23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 710 mg. (2.38 m mole) of 8-(4-n-propoxy-2-pyrimidylthio)quinoline and 999 mg. of sodium bicarbonate (11.9 m mole) in 40 ml. of methylene chloride cooled to 0° C. was added dropwise over a period of 15 minutes 574 mg. (3.33 m mole) of m-chloroperbenzoic acid in 15 ml. of the same solvent. The reaction mixture was stirred for 30 minutes and was then allowed to warm to room temperature and stirred overnight. The reaction was diluted with methylene chloride and the organic layer washed successively with a saturated sodium bicarbonate solution, water and a saturated brine solution. The organic phase was separated, dried over magnesium sulfate and concentrated to give 745 mg. of crude product which was purified by chromatographing on silica gel, 367 mg.
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].[CH2:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].OO>C(O)C.S(=O)(=O)(O)O>[CH2:6]([PH:2](=[O:4])[OH:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: C=CCCCCCC
Reactant: O=[PH2][O-]
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCC[PH](=O)O
Yield: 84.8 %

Procedure:
To a mixture of 95.1 g (0.897 mol) of sodium hypophosphite hydrate in 600 mL 95% ethanol, 23.8 mL of concentrated sulfuric acid was added. 1-Octene (33.6 g, 0.299 mol) was added to the stirred mixture followed by 1.69 g (0.0149 mol) of 30% hydrogen peroxide. The resulting mixture was refluxed for 8 hs, and then another 1.15 g (0.010 mol) of hydrogen peroxide was added and the reaction mixture was continued to reflux for another 8 hs. The resulting mixture was cooled, filtered, and then the ethanol was removed using a rotary evaporator. To the resulting residue, 200 mL water was added and then 50% sodium hydroxide solution was added until the solution became alkaline. The mixture was extracted twice with 200 mL diethyl ether, and the aqueous phase was then acidified with concentrated sulfuric acid. The aqueous layer was extracted with 200 mL ethyl acetate, and the organic layer was washed with saturated sodium chloride and then dried over anhydrous magnesium sulfate. The organic layer was decanted and the drying agent was washed with another 50 mL ethyl acetate. The combined organic layers were evaporated on a rotary evaporator. 45.2 g of n-octylphosphinic acid (84.8% yield) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28](=O)[CH2:29][CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH2:17]2)[CH2:28][CH2:29][CH3:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC=O
Reactant: COc1ccc2c(c1)CC(NCC1CCN(C(=O)OC(C)(C)C)CC1)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.9 %

Procedure:
To a solution of 4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (2.1 g, 5.6 mmol) and propionaldehyde (0.45 mL, 6.23 mmol) in dichloroethane (20 mL) under a nitrogen atmosphere was added sodium triacetoxyborohydride (3.09 g, 14.15 mmol, 2.5 eq.) in a single portion. The reaction was stirred at room temperature for 24 h then concentrated in vacuo. The residue was partitioned between EtOAc (75 mL) and 5% aq. KOH (50 mL). The aqueous phase was extracted twice more with EtOAc (2×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated onto silica (10 kg). This was placed on top of a flash column and eluted with 20% acetone in hexanes. The fractions containing product were pooled and concentrated to afford 4-{[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (2.4 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][C:15]12[CH2:22][CH2:21][CH2:20][N:19]1[CH2:18][CH2:17][CH2:16]2>>[N:19]12[CH2:20][CH2:21][CH2:22][C:15]1([CH2:14][CH2:13][N:12]([CH3:11])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:16][CH2:17][CH2:18]2
Reactant: CNCCC12CCCN1CCC2
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Product: CN(CCC12CCCN1CCC2)c1ccc([N+](=O)[O-])cc1

Procedure:
The procedures described in Example 12 were repeated except that 1-chloro-4-nitrobenzene (1.87 g, 11.9 mmol) and 5-(2-methylaminoethyl)-1-azabicyclo[3.3.0]octane (4.00 g, 23.8 mmol) were employed. In this case, the desired compound was obtained as yellow solids (2.15 g, 62.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:21][C:22](N(OC)C)=[O:23])=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C@H:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:21][C:22](=[O:23])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:18][CH:19]=1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Reactant: Cc1ccncc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1[C@H](CC(=O)Cc1ccncc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 4-methylpyridine (308 mg, 3.31 mmol) in tetrahydrofuran at −78° C. was added dropwise n-butyllithium solution (1.6 M in hexane, 2.07 mL, 3.31 mmol). The reaction mixture was stirred for 1 hour at room temperature and cooled down again to −78° C. (R)-3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 142, step 1; 400 mg, 1.1 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. A saturated solution of sodium hydrogencarbonate and ethyl acetate were added, the phases were separated and the inorganic one was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% methanol in dichloromethane) to yield the title compound as a yellow oil (51%), MS (ESI+): m/z=394.0 ([M+H]+).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[O:19])[N:10]=[N:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)=[O:19])[N:10]=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)CCCCCc2cn(Cc3ccccc3)nn2)CC1
Reactant: [H][H]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CCCCCc2c[nH]nn2)CC1

Procedure:
Tert-butyl 4-(6-(1-benzyl-1H-1,2,3-triazol-4-yl)hexanamido)piperidine-1-carboxylate (187 mg, 0.410 mmol) was dissolved in ethanol (10 ml) to give a yellow solution. The solution was then submitted to continuous flow hydrogenation using H-cube hydrogenation apparatus, at 70° C. and 30 bar hydrogen pressure for 2 hours. The resultant solution was concentrated under reduced pressure to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([NH:10][C:11]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=2)=[CH:29][C:30]=1[CH3:35])=[S:12])=[O:9]
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 50%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][N+:10]([O-])=[C:9]([CH3:14])[C:8]=1[CH3:15])[CH2:2][CH2:3][CH2:4][CH3:5].[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17]>>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:14][O:19][C:16](=[O:18])[CH3:17])[C:8]=1[CH3:15])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1cc[n+]([O-])c(C)c1C
Reactant: CC(=O)OC(C)=O
Product: CCCCCOc1ccnc(COC(C)=O)c1C
Yield: 79.6 %

Procedure:
To 26.7 g (0.11 mol, 1.0 eq.) of 4-pentyloxy-2,3-dimethylpyridine-N-oxide, 44.0 g (0.43 mol, 4.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 7 hours at 90 to 100° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 22.0 g of 4-pentyloxy-2-acetoxymethyl-3-methylpyridine as an oily matter (yield 79.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:19]=[CH:18][C:10]([C:11]([O:13]C(C)(C)C)=[O:12])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O>C(O)(C)(C)C>[C:1]([O:5][C:6](=[O:20])[C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:18][CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1
Temperature: 60 °C
Yield: 96.1 %

Procedure:
A slurry of terephthalic acid di-tert-butyl ester (6.1 g, 0.022 mole) in tert-butanol (30 mL) was added to 1N KOH (22 mL, 0.022 mole). The mixture was heated to 60° C. for 7-8 hours. After cooling the mixture was treated with water and extracted 3 times with ethyl acetate. The aqueous layer was acidified with dilute HCL and the product was extracted into ethyl acetate. After washing of the organic layer with a saturated aqueous NaCl solution and drying over MgSO4, the solvent was filtered and concentrated to yield terephthalic acid mono tert butyl ester as a white solid (4.7 g, 96%) melting at 100°-102° C.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:1][C:2]2[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=2[CH3:9])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1occc(=O)c1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2c(C)occc2=O)cc1
Yield: 64 %

Procedure:
3-Hydroxy-2-methyl-4H-pyran-4-one (0.5 g, 4.0 mmol) was reacted with p-toluenesulfonyl chloride (2.27 g, 11.9 mmol) in 40 mL of pyridine to afford PZBG-2b in 64% yield (0.71 g, 2.5 mmol). 1H NMR (500 MHz, CDCl3) δ=7.99 (d, J=8 Hz, 2H), 7.64 (d, J=5.8 Hz, 1H), 7.37 (d, J=8 Hz, 2H), 6.34 (d, J=5.8 Hz, 1H), 2.46 (s, 3H, CH3), 2.45 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ=127.2, 163.2, 154.2, 145.8, 138.4, 133.6, 129.8, 129.0, 117.7, 22.0, 16.3. ESI-MS(+): m/z 281.01 [M+H]+, 303.03 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2O)=[O:10])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:20]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]=[CH:12][C:11]=1[C:9](=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(Nc1ccc(Cl)cc1)c1cnc2c(c1O)CCCC2
Product: O=C(Nc1ccc(Cl)cc1)c1cnc2c(c1Cl)CCCC2

Procedure:
A mixture of 1.0 g of 3-(N-p-chlorophenylcarbamoyl)-4-hydroxy-5,6,7,8-tetrahydroquinoline (Example 17a) and 25 mL of phosphorous oxychloride is heated at 80° for 3 hours to obtain a clear solution, and evaporated to dryness. The residue is treated with 400 mL of a 1:1 mixture of ice cold 2N aqueous sodium hydroxide and dichloromethane. The organic phase is separated, dried and evaporated to yield the 4-chloro-3-(N-p-chlorophenylcarbamoyl)-5,6,7,8-tetrahydroquinoline. The mixture of 0.6 g thereof, 1.0 g of O-methylhydroxylamine hydrochloride and 1.65 g of diisopropylethylamine is heated to 100° in a small pressure vessel for 18 hours. The cooled mixture is then triturated with water, dissolved in tetrahydrofuran, dried and evaporated to yield the 4-(O-methylhydroxylamino)-3-(N-p-chlorophenylcarbamoyl)-5,6,7,8-tetrahydroquinoline.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[Na+].Cl[C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16].O>CS(C)=O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:13]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=2[C:15]#[N:16])=[CH:5][CH:4]=1
Reactant: CSc1ccc(O)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 60 °C
Yield: 97.1 %

Procedure:
To a solution of 11.55 g (0.0824 moles) of 4-(methylthio)phenol dissolved in 150 ml of DMSO was added 3.3 g (0.0824 moles) of NaOH. The slurry was heated to 60° C. and 13.7 g (0.0730 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture heated at 75° C. for 21/2 hrs. The mixture was cooled and poured into a solution of 200 ml of 5 N aqueous NaOH and 500 ml of water. The product was collected by filtration, washed well with water and dried, to obtain 20.3 g of product (94.6% yield). Recrystallization from methanol afforded purified 2-(4-(methylthio)phenoxy)-5-nitrobenzonitrile, mp 124°-126° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[CH:28]=[C:29]([CH3:35])[C:30]([O:33][CH3:34])=[N:31][CH:32]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:27]3[CH:32]=[N:31][C:30]([O:33][CH3:34])=[C:29]([CH3:35])[CH:28]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ncc(I)cc1C
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ncc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 164 mg (0.66 mmol) of 5-iodo-2-methoxy-3-methyl-pyridine in 1 mL THF with 0.34 mL 2M isopropylmagnesium chloride. Yield: 40 mg of a white powder. LC-MSD, m/z for C23H18BrN3O3 [M+H]+=464.0, 466.0; HPLC retention time: 2.4 min.
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([CH3:24])([CH3:23])[CH2:7]1)[CH2:2][CH2:3][CH3:4].Cl[P:26]1[O:31][CH2:30][C:29]2([CH2:36][O:35][P:34](Cl)[O:33][CH2:32]2)[CH2:28][O:27]1>>[CH3:22][CH:15]([O:14][N:9]1[C:8]([CH3:23])([CH3:24])[CH2:7][CH:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[P:26]2[O:31][CH2:30][C:29]3([CH2:36][O:35][P:34]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]4[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([O:14][CH:15]([CH3:22])[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:8]([CH3:24])([CH3:23])[CH2:7]4)[O:33][CH2:32]3)[CH2:28][O:27]2)[CH2:11][C:10]1([CH3:13])[CH3:12])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClP1OCC2(CO1)COP(Cl)OC2
Reactant: CCCCNC1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1
Product: CCCCN(C1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1)P1OCC2(CO1)COP(N(CCCC)C1CC(C)(C)N(OC(C)c3ccccc3)C(C)(C)C1)OC2

Procedure:
The title compound is prepared as a viscous syrup from 4-n-butylamino-1-alpha-methylbenzyloxy-2,2,6,6-tetramethylpiperidine (made in Example 13A) and 3,9-dichloro-2,4,8,10-tetraoxa-3, 9-diphosphaspiro[5.5]undecane according to the procedure of Example 14.