Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].NO.CC(O)=O.CO[CH:38](OC)[N:39](C)C>O1CCOCC1>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]4[O:26][N:39]=[CH:38][N:27]=4)=[CH:28][CH:29]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C(N)=O)cc3)CC2)nc1
Agent: NO
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(-c4ncno4)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the product of step B (80 mg, 0.203 mmol) in N,N-dimethylformamide dimethyl acetal (2 mL) was stirred at 120° C. for 4 h. Upon cooling to RT, the solvent was removed under vacuum to leave a residue. The resulting residue was dissolved in 1,4-dioxane (1 mL) followed by the addition of NH2OH (0.016 mL of 50% solution in H2O, 0.243 mmol) and HOAc (0.5 mL). The reaction was stirred at 90° C. for 4 h before being cooled to RT. The reaction was quenched with a saturated aqueous solution of NaHCO3 and the layer was extracted with EtOAc (×3). The combined organic layers were washed with brine (1×), dried over MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by silica gel column chromatography (elution with 5:1 hexane:ethyl acetate) to give the title compound. MS (ESI) m/z 420 [M+H]+. GPR119 Human EC50: 5.5 nM
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:21]([F:24])([F:23])[F:22])([OH:20])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[F:1][C:2]([F:25])([F:26])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:16]([F:17])([F:18])[F:19])([O:20][S:35]([CH3:34])(=[O:37])=[O:36])[C:21]([F:23])([F:22])[F:24])=[CH:11][CH:10]=1)([O:8][S:35]([CH3:34])(=[O:37])=[O:36])[C:4]([F:7])([F:6])[F:5]
Reactant: CS(=O)(=O)Cl
Reactant: OC(c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(c1ccc(C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.5 %

Procedure:
4.1 g (10 mmol) of 1,4-bis-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-benzene were dissolved in 50 ml of methylene chloride, and 2.5 g (25 mmol) of triethylamine were added. 2.86 g (25 mmol) of methanesulfonyl chloride were added dropwise at 5° to 10° C. The mixture was stirred for 48 hours at room temperature, separated off from the precipitated salt, washed with water, dried and evaporated down. The residue was chromatographed over a silica gel column with methylene chloride/n-hexane (1:1). 3.2 g of 1,4-bis-(2,2,2-trifluoro-1-methanesulfonyloxy-1-trifluoromethylethyl)-benzene were obtained (colorless crystals, m.p.: 151° C. [from diisopropyl ether]).
Reaction SMILES: [C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCCCC.[Al+3].[C:22]([O-])(=[O:40])[CH2:23]CCCCCCCCCCCCCCCC.C([O-])(=[O:60])CCCCCCCCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCCCCCCCC.[Li+]>>[C:13]1(=[O:60])[O:40][CH2:22][CH2:23][O:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Al+3]
Agent: [Li+]
Product: O=C1CCCCCCCCCCCC(=O)OCCO1
Temperature: 314 °C
Yield: 88.9 %

Procedure:
A mixed metal catalyst comprised of aluminum stearate and lithium stearate (molar ratio 1:1) was used for the depolymerization. For the reaction aluminum stearate (1.09 gram) and lithium stearate (0.36 gram) were blended in 70 grams poly(ethylene brassylate) at 200° C. The temperature was then raised to 314° C. while maintaining a vacuum of 0.05-0.1 mm Hg. Ethylene brassylate was obtained (40 mls during the first hour) in an 88.9 percent yield. Of the ethylene brassylate recovered, 90 percent of the product was obtained after 2 hours.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:16]=[C:17]([CH2:22]O)[CH:18]=[CH:19][C:20]=3[CH3:21])=[CH:12][CH:13]=2)[N:8]([CH3:24])[S:7]1(=[O:26])=[O:25].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[N:40]1([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[F:27][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=3[CH3:21])[CH2:22][N:43]3[CH2:44][CH2:45][N:40]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41][CH2:42]3)=[CH:12][CH:13]=2)[N:8]([CH3:24])[S:7]1(=[O:25])=[O:26]
Reactant: Cc1ccc(CO)cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
(3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylphenyl)methanol (39-1) (1.5 g, 3.8 mmol, 1.0 eq) was dissolved in NMP (19 mL) and triethylamine (1.6 mL, 11.4 mmol, 3.0 eq) was added followed by mesyl chloride (0.59 mL, 7.6 mmol, 2.0 eq). After 20 minutes, tert-butyl piperazine-1-carboxylate (1.8 g, 9.7 mmol, 3.0 eq) and DIPEA (2.8 mL, 16.2 mmol, 5.0 eq) were added. The resulting mixture stirred at 80° C. for 2 hours minutes. The mixture was cooled, diluted with EtOAc (200 mL), washed with sodium bicarbonate (50 mL), water (6×50 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (330 g SiO2, 0-80% EtOAc in hexanes) to afford tert-butyl 4-(3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylbenzyl)piperazine-1-carboxylate (43-1) as a tan solid. HRMS m/z (M+H) 564.2446 found, 564.2451 required.
Reaction SMILES: ClCl.[C:3]([C:7]1[O:8][C:9]2[C:15]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]3=[O:28])=[CH:14][CH:13]=[C:12]([Cl:29])[C:10]=2[N:11]=1)([CH3:6])([CH3:5])[CH3:4].[Cl:30]N(Cl)C(OCC)=O>>[C:3]([C:7]1[O:8][C:9]2[C:15]([N:16]3[C:21](=[O:22])[C:20]([Cl:30])=[C:19]([C:23]([F:25])([F:24])[F:26])[N:18]([CH3:27])[C:17]3=[O:28])=[CH:14][CH:13]=[C:12]([Cl:29])[C:10]=2[N:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)N(Cl)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3nc(C(C)(C)C)oc23)c1=O
Agent: ClCl
Product: Cn1c(C(F)(F)F)c(Cl)c(=O)n(-c2ccc(Cl)c3nc(C(C)(C)C)oc23)c1=O

Procedure:
At this point additional substituents may be optionally added to the pyrimidinedione ring. For example, a chlorine moiety was added to the 3-(2-t-butyl-4-chlorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione molecule (I) by treating it with N,N-dichlorourethane under acidic conditions, affording 3-(2-t-butyl-4-chlorobenzoxazol-7-yl)-1-methyl-5-chloro-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (III). In addition, the 3-[2-(substituted-methoxyalkyl)-substituted-benzoxazol-7-yl]-1-alkyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (I), for example 3-[2-(1-methoxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, can be hydrogenated under basic conditions, yielding the targeted 3-[2-(substituted-hydroxyalkyl)-substituted-benzoxazol-7-yl)-1-alkyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (IV), for example 3-[2-(1-hydroxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione. Examples 3 and 15 provide the detailed procedures for these methods.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:31])([F:19])[F:32])[CH:22]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Product: O=C(Cc1cccc(C(F)(F)F)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-[3-(trifluoromethyl)phenyl]acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 7.97-8.05 (m, 2H), 12.84-3.14 (m, 4H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 7.75-7.76 (bs, 1H), 7.60-7.70 (m, 3H), 3.80-3.86 (m, 6H); MS (ESI+) M/Z 433 (M+H)+.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[C:10]3[CH:17]=[CH:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[C:11]=3[N:12]=[CH:13][CH:14]=2)C=CC=CC=1.Cl>C1COCC1>[N:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:15]2[C:11]3=[N:12][CH:13]=[CH:14][C:9]([NH2:8])=[C:10]3[CH:17]=[CH:16]2)=[CH:20][CH:21]=1
Reactant: c1ccc(C(=Nc2ccnc3c2ccn3Cc2ccncc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ccnc2c1ccn2Cc1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 25-mL round-bottomed flask equipped with magnetic stirrer is charged with Compound 1c (0.580 g, 1.49 mmol), THF (10 mL) and 2N hydrochloric acid (2.0 mL). The reaction is then stirred at room temperature for 1 h. After such time, the reaction is partitioned between ethyl acetate (15 mL) and water (15 mL). The aqueous layer is separated and washed with ethyl acetate (2×25 mL). After basifying to pH 9 with solid potassium carbonate in order to liberate the free base of Compound 1d, the aqueous layer is extracted with ethyl acetate (2×25 mL). The extracts are then combined and dried over sodium sulfate. The sodium sulfate is removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is then purified by column chromatography to afford Compound 1d as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:14])[C@@H:4]([CH3:13])[CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[Mg]Br.[Cl-].[NH4+].O>C1COCC1>[Cl:1][CH2:2][C:3]([C:20]1[CH:21]=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[F:22])([OH:14])[CH:4]([CH3:13])[CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: C[C@@H](COC(=O)C(C)(C)C)C(=O)CCl
Reactant: Fc1ccc(F)c([Mg]Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(COC(=O)C(C)(C)C)C(O)(CCl)c1cc(F)ccc1F
Reaction time: 0.08 h

Procedure:
A solution of 0.66 g (3.0 mmol) of (S)-1-chloro-3-methyl-4-pivaloyloxybutan-2-one in 4 mL of THF was cooled to 0° C., and 3.9 mL (3.3 mmol) of a 0.86 M solution of 2,5-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise thereto over a period of 5 minutes. After the completion of the dropwise addition, stirring was continued for another 1 hour, 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The resulting product was purified by column on silica gel to obtain 0.50 g of 1-chloro-2-(2,5-difluorophenyl)-3-methyl-4-pivaloyloxybutan-2-ol as a diastereomeric mixture (yield: 50%) ((2S,3S):(2R,3S)=72:28) (HPLC, column: YMC-A302 manufactured by YMC Co. Ltd., mobile phase: acetonitrile/20 mM (potassium) phosphate buffer solution (pH=2.5)=6/4, flow rate: 1.0 mL/min, column temperature: 30° C., detector: UV 210 nm, retention time: 18 minutes (2S,3S), 20 minutes (2R,3S)). The resulting compound was dissolved in 10 mL of THF, and 1.02 g (5.25 mmol) of a 28% solution of NaOMe in methanol was added thereto under ice cooling. The reaction was performed for 5 hours. A reaction product was extracted with ethyl acetate (10 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The resulting product was purified by column on silica gel to obtain 0.28 g of the title compound (yield: 88%) (HPLC, column: YMC-A302 manufactured by YMC Co. Ltd., mobile phase: acetonitrile/20 mM (potassium) phosphate buffer solution (pH=2.5)=3/7, flow rate: 1.0 mL/min, column temperature: 30° C., detector: UV 210 nm, retention time: 17 minutes (2R,3S), 18 minutes (2S,3S)). 1H-NMR (400 MHz, CDCl3) (2R,3S) δ: 0.97 (d, 3H, J=6.6 Hz), 2.25 (q, 1H, J=6.6 Hz), 2.88 (d, 1H, J=4.4 Hz), 3.21 (d, 1H, J=4.4 Hz), 3.51 (d, 2H, J=6.1 Hz), 6.99-7.01 (m, 2H), 7.13-7.17 (m, 1H); (2S,3S) δ: 1.27 (d, 3H, J=6.6 Hz), 2.14 (q, 1H, J=6.6 Hz), 2.83 (d, 2H, J=4.4 Hz), 3.17 (d, 1H, J=4.4 Hz), 3.60 (d, 2H, J=5.9 Hz), 6.99-7.01 (m, 2H), 7.13-7.17 (m, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][Si:11]([CH3:15])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:16].C(OCC)C>C(O)C>[ClH:16].[CH3:14][Si:11]1([CH3:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: C[Si]1(C)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: C[Si]1(C)CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.6 %

Procedure:
To a solution of 3 (2.3 g, 10.5 mmol) in ethanol (EtOH), 6 N HCl (10.5 mmol) is added and the solvent is removed under reduced pressure. The reaction mixture is co-evaporated with EtOH (2×10 mL) and recrystallized from EtOH-diethyl ether. To a slurry of Pd/C in EtOH, an ethanolic solution of the HCl salt is added dropwise and stirred at 25° C. under hydrogen atmosphere for 20 h. The reaction mixture is filtered through celite, washed with 2×20 mL of Methanol. The filtrate is concentrated under reduced pressure to give a viscous oil which is titrated with diethyl ether to obtain the product 4 as a white solid (950 mg) in 70% yield. This compound was previously documented in WO 2006/066872.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[N:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: COc1ccc(N)cc1
Solvent: CO
Product: COc1ccc(N=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Reaction time: 8 h

Procedure:
3,5-di(Tert-butyl)-4-hydroxybenzaldehyde (1 g, 4.11 mmol) was dissolved in methanol (30 ml). To this solution was added p-anisidine (0.51 g, 4.11 mmol). The resultant reaction solution was stirred at room temperature under nitrogen for two (2) hours and the solution was taken to dryness in vacuo. The resultant oil was azeotroped with methanol (2x), ether (1x), a mixture of ethyl acetate/hexane (1x), and methanol (1x). The oil was left in vacuo overnight which began crystallization of the oil. The crystals were then dissolved in a mixture of ether and hexane. Dark flakes of p-anisidine were filtered out of the solution, the mother liquor was reduced with low heat, resulting in crystals of the title product which were collected by filtration: 1H NMR (300 MHz, CDCl3) ; δ 8.38 (S, 1H) , 7.72 (S, 2H), 7.19 (d, J=9 Hz, 1H), 6.90 (d, J=9 Hz, 2H), 5.58 (S, 1H), 3.83 (S, 3H).
Reaction SMILES: C1([Li])C=CC=CC=1.[Br:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>CCOCC.O1CCCC1>[Br:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:20]([C:19]1[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)=[O:21]
Reactant: Brc1ccsc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C(=O)c2sccc2Br)cc1
Reaction time: 8 h

Procedure:
A solution of phenyllithium (67 ml, 1.65M in ether/benzene) was added dropwise to a solution of 16.3 g of 3-bromothiophene in 100 ml of dry ether at room temperature under nitrogen. After the addition, the solution was stirred overnight under nitrogen. The resultant solution was then added dropwise to a solution of p-methoxybenzoyl chloride (20.5 g) in 80 ml of tetrahydrofuran at -70° C. over two hours and stirring was further continued for two hours at the same temperature. The reaction was then quenched with water, the organics were extracted into ether, and the ether phase was washed with 10% aqueous sodium hydroxide solution and water and dried over anhydrous magnesium sulfate. Upon evaporation of the solvent, oily liquid was obtained which was chromatographed by high performance liquid chromatography with 5% ethyl acetate/hexane used as an eluent. Appropriate fractions were combined and evaporated to give crystals which were recrystallized from ether/hexane (yield 11.9 g).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]2Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]2[CH2:1][NH2:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1Cl
Reactant: CN
Solvent: O
Product: NCc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Methylamine (available as a 40% solution in water, 24 mL, 0.28 mol) was added to a solution of 6-benzyloxy-4-chloro-3-nitroquinoline (15.0 g, 48.5 mmol), prepared as described in Parts A-D of Example 2, in distilled water (300 mL), and the reaction was stirred at 100° C. for 1.5 hours. The reaction was allowed to cool to ambient temperature and stirred for four hours. A precipitate formed, which was isolated by filtration and washed with distilled water (3×60 mL). The solid was combined with material from another run and recrystallized from 2-propanol. The crystals were isolated by filtration, washed twice with cold hexanes, and dried for three days under high vacuum to provide 24.10 g of (6-benzyloxy-3-nitroquinolin-4-yl)methylamine as yellow crystals.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][C:10]([C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:15]2[S:27][C:28]([CH3:30])=[CH:29][C:14]=2[C:13]=1O)=[O:11])[CH3:8]>CN(C=O)C>[CH2:7]([O:9][C:10]([C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:15]2[S:27][C:28]([CH3:30])=[CH:29][C:14]=2[C:13]=1[Cl:4])=[O:11])[CH3:8]
Reactant: CCOC(=O)c1c(O)c2cc(C)sc2n(Cc2cccc(F)c2)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)c2cc(C)sc2n(Cc2cccc(F)c2)c1=O
Temperature: 75 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
Oxalyl chloride (4.83 mL, 0.055 mol) was added to a solution of 7-(3-fluoro-benzyl)-4-hydroxy-2-methyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester (69) (8 g, 0.022 mol) in DMF at −30° C. under argon. The temperature was raised gradually to 75° C. and stirred for 3 h. The solution was cooled and poured into ice water. The solids formed were filtered, washed by cold water and dried to yield 6.8 g (82%) of 4-chloro-7-(3-fluoro-benzyl)-2-methyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester. 1H-NMR (DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 2.45 (d, J=1.2 Hz, 3H), 4.33 (q, J=7.2 Hz, 2H), 5.31 (s, 2H), 7.05 (d, J=1.2 Hz, 1H), 7.09-7.17 (m, 3H), 7.40 (m, 1H) ppm, EIMS m/z 380 (M+1).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[OH:5][CH:6]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1.[OH-].[K+]>C1(C)C=CC=CC=1>[OH:5][CH:6]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:1]2=[O:2])[CH2:10][CH2:9]1
Reactant: O=C(Cl)Cl
Reactant: COc1ccccc1OCC(O)CN1CCC(NCCNc2ccc(Cl)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccccc1OCC(O)CN1CCC(N2CCN(c3ccc(Cl)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
With vigorous stirring, 630 ml of a 20% solution of phosgene in toluene are added dropwise at a reaction temperature of 5° to 10° C in the course of 13/4 hours to an emulsion of 56 g of 1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-[2-(4-chloroanilino)-ethylamino]-piperidine in 340 ml of toluene and 200 ml of a 3N potassium hydroxide solution. Thereafter 193 ml of a 6N aqueous potassium hydroxide solution are added dropwise at the same reaction temperature in the course of half an hour. The reaction mixture is further stirred for 1 hour at 5° to 10° C and for 20 hours at room temperature and then concentrated. The residue is made alkaline with a 2N aqueous sodium hydroxide solution and extracted with five 100 ml portions of methylene chloride. The extracts are dried over sodium sulphate and concentrated under reduced pressure. The residue is dissolved in methanol and boiled for 30 minutes with the addition of activated charcoal. The batch is filtered and the filtrate is concentrated under reduced pressure. The residue is treated with toluene and recrystallised from isopropanol to yield 1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-(4-chlorophenyl)-imidazolidin-2-one with a melting point of 136°-137° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].[C:17]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCCl>[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([C:20]2[CH:21]=[CH:22][C:17]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:12](=[O:13])[C:11]4[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:16][CH:15]=4)=[CH:28][CH:29]=3)=[CH:18][CH:19]=2)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccc(Cc2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 47 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
In a 10-liters three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 1300 g (9.75 mole) of aluminum chloride and 4.2 liters of 1,2-dichloroethane were mixed, and 1323 g (7.13 mole) of paranitrobenzoyl chloride was introduced with ice cooling to be dissolved. After warming the reaction solution to 47° C., a solution of 500 g (2.97 mole) of diphenylmethane in 500 milliliters of 1,2-dichloroethane was added dropwise for 3 hours and 30 minutes. After the dropwise addition was ended, the solution was stirred at 50° C. for 4 hours. After the end of the reaction was confirmed by a liquid chromatography, the reaction solution was poured in 7 liters of ice water, and then extracted with 7 liters of chloroform. The solution was washed with a 6N-HCl aqueous solution, an aqueous solution of sodium hydrogencarbonate, brine and water, and then dried with magnesium sulfate. After removing off chloroform by a rotary evaporator, filtration was carried out when crystals being deposited sufficiently. Filtered substances were treated with a silica gel column and recrystallized from chloroform/ethyl acetate, to obtain 867 g of 1,1-bis(4-(4-nitrobenzoyl)phenyl)methane as crystals.