Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8](=[O:33])[CH2:9][N:10]([CH3:32])[C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]([S:29]([CH3:31])=[O:30])=[CH:18][N:19]2[C:22]2[N:27]=[CH:26][C:25](Br)=[CH:24][N:23]=2)=[CH:15][CH:14]=1)=[O:12].[F:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=1B(O)O>C(O)(CC)(C)C.O>[NH2:7][C:8](=[O:33])[CH2:9][N:10]([CH3:32])[C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]([S:29]([CH3:31])=[O:30])=[CH:18][N:19]2[C:22]2[N:27]=[CH:26][C:25]([C:36]3[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:35]=3[F:34])=[CH:24][N:23]=2)=[CH:15][CH:14]=1)=[O:12]
Reactant: CN(CC(N)=O)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(Br)cn3)c2c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Solvent: O
Product: COc1ccc(F)c(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N(C)CC(N)=O)cc43)nc2)c1
Temperature: 95 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (110 mg, 0.79 mmol) and (Ataphos)2PdCl2 (19 mg, 0.026 mmol) were added under an inert atmosphere to a solution of 279a) (120 mg, 0.26 mmol) and 2-fluoro-5-methoxyphenylboronic acid (91 mg, 0.53 mmol) in tert-amylalcohol (4.0 mL) and water (0.4 mL). The reaction mixture was stirred for 4 h at 95° C., then cooled to ambient temperature and filtered over celite. The filtrate was evaporated to dryness and the residue was purified by flash column chromatography [silica; methanol/dichloromethane=4:96]. White solid. Yield: 35 mg (27% of theory)
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37](=O)[CH3:38])=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:40][O:41][C:42](=[O:44])[CH3:43])[CH2:7][O:8]2)(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.[CH3:52][O:53][NH2:54].O>C(O)C>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:36][C:37](=[N:54][O:53][CH3:52])[CH3:38])=[CH:33][CH:34]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:40][O:41][C:42](=[O:44])[CH3:43])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)COc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(C)COc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Yield: 64.7 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-(2-oxopropoxy)benzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (180 mg, 0.28 mmol), in ethanol (8 mL) under nitrogen atmosphere, were added pyridine (0.114 mL, 1.42 mmol) and O-methylhydroxylamine hydrochloride (72 mg, 0.85 mmol). The reaction mixture was refluxed for 2 h. After completion of the reaction as confirmed by TLC, water (10 mL) was added to the reaction mixture and the crude compound was extracted with ethyl acetate (3×25 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1.5:8.5 Acetone:Pet. Ether) to afford the title compound (120 mg, 63.8%).
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[S:10][C:9]([CH:11]=[CH:12][C:13](=[O:17])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1>CO>[CH3:1][O:15][C:14](=[O:16])[C:13](=[O:17])[CH:12]=[CH:11][C:9]1[S:10][C:6]([Br:5])=[CH:7][CH:8]=1
Reactant: O=C(O)C(=O)C=Cc1ccc(Br)s1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)C(=O)C=Cc1ccc(Br)s1
Yield: 81.5 %

Procedure:
Acetyl chloride (36.4 mL, 515.7 mmol) was slowly added at 0° C. to methanol (200.0 mL) under stirring. A solution of 4-(5-bromo-thiophen-2-yl)-2-oxo-3-butenoic acid (39.6 g, 151.7 mmol) prepared in Step 1 in methanol (20.0 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 80° C. for 18 hours and then filtered to give 34.0 g of the titled compound as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17]2[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:11][CH2:10]1)(C)(C)C.Cl.N1C=CC=CC=1.[F:38][C:39]([F:52])([F:51])[O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47](Cl)(=[O:49])=[O:48]>CCOC(C)=O.C(Cl)Cl>[CH3:28][N:27]([CH3:29])[C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([NH:16][CH2:15][C@H:12]2[CH2:11][CH2:10][C@H:9]([CH2:8][NH:7][S:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[O:40][C:39]([F:38])([F:51])[F:52])(=[O:49])=[O:48])[CH2:14][CH2:13]2)[N:26]=1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)nc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CNS(=O)(=O)c3ccccc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]cyclohexylmethyl}-carbamic acid tert-butyl ester obtained in step G of example 1 (500 mg, 1.21 mmol) in EtOAc (8 mL) was added 4 M hydrogen chloride in EtOAc (7 mL). The mixture was stirred at ambient temperature for 40 min and concentrated to give a white solid. To a suspension of the solid in CH2Cl2 (7 mL) was added pyridine (215 μL, 2.66 mmol). The mixture was cooled at 4° C. and a solution of 2-trifluoromethoxy-benzenesulfonyl chloride (331 mg, 1.27 mmol) in CH2Cl2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 2 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 20% EtOAc in hexane) to give trans-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide (231 mg, 36%) as a pale yellow solid.
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2([CH3:27])[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:18]2)=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[NH2:28][C:29](N)=[S:30].S1(CCCC1)(=O)=[O:33].Cl>O.COCCO>[CH3:27][C:17]1([CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH:2]3[S:30][C:29](=[O:33])[NH:28][C:3]3=[O:4])=[CH:14][CH:13]=2)[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:18]1
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3ccccc3O2)cc1
Reactant: NC(N)=S
Reactant: O=S1(=O)CCCC1
Agent: Cl
Solvent: O
Solvent: COCCO
Product: CC1(COc2ccc(CC3SC(=O)NC3=O)cc2)CCc2ccccc2O1
Temperature: 130 °C

Procedure:
A mixture of 330 mg of ethyl 2-chloro-3-[4-(2-methylchroman-2-ylmethoxy)phenyl]propionate (prepared as described in Preparation 5), 100 mg of thiourea and 1 ml of sulfolane was heated at 130° C. for 5 hours. At the end of this time, 2 ml of ethylene glycol monomethyl ether and 1.5 ml of 2N aqueous hydrochloric acid were added to the reaction mixture, which was then heated under reflux for 4.5 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography eluted with a 2:1 by volume mixture of hexane and ethyl acetate. The oily substance thereby obtained was washed with warm water and dried, to give 230 mg of the title compound as a pale yellow glass, softening at 42°-50° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C(Cl)Cl>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a mixture of N-methylpiperizine (1.00 g, 10 mmol) and Et3N (2.1 mL, 15 mmol) in CH2Cl2 (50 mL) at rt was added 4-bromobenzoyl chloride (2.195 g, 10 mmol) in one portion. The reaction was heated to reflux briefly and cooled. The resulting mixture was stirred O/N at rt. The reaction was quenched with H2O (30 mL) and sat. NaHCO3 (10 mL), separated and dried (Na2SO4). Evaporation of solvents afforded the title compound as a pale yellowish white solid (2.69 g, 95%). 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 3.70-3.20 (m, 4H), 2.40-2.15 (m, 7H; s, 3H at 2.18 ppm and m, 4H overlapping); MS ESI 283.0 [M+H]+, calcd. for [C12H15BrN2O+H]+ 283.0.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[Cl:45][C:46]1[C:51]([Br:52])=[CH:50][C:49](O)=[CH:48][N:47]=1>C1COCC1>[Cl:45][C:46]1[C:51]([Br:52])=[CH:50][C:49]([O:44][C@@H:41]2[CH2:42][CH2:43][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:38])[CH2:40]2)=[CH:48][N:47]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Oc1cnc(Cl)c(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cnc(Cl)c(Br)c2)C1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
To 3.15 gm (12 mmol) of PPh3 in 100 mL of dry THF at −20° C. was added 1.89 mL (12 mmol) of DEAD dropwise. The solution was allowed to stir 10 min. at −20° C. After 10 min, a solution containing 1.87 gm (10 mmol) of 1-t-butoxycarbonyl-3-(R)-hydroxypyrrolidine in 20 mL of dry THF was added dropwise. The solution was again allowed to stir 10 min at −20° C. After 10 min, to the solution was added 2.08 gm (10 mmol) of 2-chloro-3-bromo-5-hydroxypyridine at once. The solution was allowed to stir at room temperature overnight. Next day, solvent was removed under reduced pressure. The crude product was purified by flash chromatography (3:1, hexane:ethyl acetate) to obtain 3.65 gm (65%) of a foamy residue: 1H NMR (300 MHz, CD3OD) δ8.05 (1H, d, J=2.5 Hz), 7.78 (1H, d, J=2.5 Hz), 5.09 (1H, s), 3.66-3.32 (4H, m), 2.18 (2H, m), 1.46 (9H, s).
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.Cl.O.C(OCC)(=O)C>O1CCCC1>[C:10]1([CH:7]2[CH2:8][CH2:9][CH:4]([CH:3]=[O:2])[CH2:5][CH2:6]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC=C1CCC(c2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=CC1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a solution in tetrahydrofuran (10.0 mL) of the compound (3.59 g) obtained in step (1) above, 3 mol/L hydrochloric acid was added and the mixture was refluxed for 4 hours. After cooling the reaction mixture to room temperature, water was added to it and three extractions were conducted with ethyl acetate. The combined organic layers were washed with water and then concentrated under reduced pressure to give the titled compound as a colorless oil (2.75 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([CH:21]([NH2:23])[CH3:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[C:27]([O:29][CH3:30])=[O:28]>O1CCCC1.C(N(CC)CC)C.ClCCl>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([CH:21]([NH:23][C:27](=[O:28])[O:29][CH3:30])[CH3:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)Cl
Reactant: CC(C)Oc1ccc(Oc2ccc(-c3cc(C(C)N)on3)cc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)NC(C)c1cc(-c2ccc(Oc3ccc(OC(C)C)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A solution of Example 17F (340 mg, 1.00 mmol) in tetrahydrofuran (5 mL) and triethyl amine (1.0 mL) was cooled to 0° C. To this was added methyl chloroformate (200 μL, 2.59 mmol) at 0° C. The mixture was stirred at room temperature for 30 minutes. The reaction was diluted with dichloromethane, which was washed with water (1×) and concentrated. The residue was purified on silica gel eluting with hexane and ethyl acetate gradient to give the desired product as a white solid (234 mg, 59%). MS (DCI): m/z 397 (M+H); 1H NMR (300 MHz, CDCl3) δ ppm 7.65-7.77 (m, 2H), 6.94-7.07 (m, 4H), 6.85-6.93 (m, 2H), 6.40 (s, 1H), 5.01-5.16 (m, 1H), 4.44-4.58 (m, 1H), 3.71 (s, 3H), 1.58 (d, J=6.99 Hz, 3H), 1.35 (d, J=6.25 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:13])=[C:5]([CH:11]=[O:12])[C:6]=1[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(O)C>C1COCC1.O>[CH:11]([C:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([CH3:1])[N:3]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:4]=1[CH3:13])=[O:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1c(C)[nH]c(C)c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(C=O)c(C)n(C(=O)OCc2ccccc2)c1C
Temperature: 10 °C
Reaction time: 4 h

Procedure:
Methyl 2,5-dimethyl-4-formyl-pyrrole-3-carboxylate (500 mg) in THF (5 ml) under nitrogen was added to a suspension of sodium hydride (120 mg of 60% oil dispersion) in dry THF (10 ml). When effervescence had ceased the suspension was cooled to 10° C., and benzyl chloroformate (0.437 ml) was added. After stirring at room temperature for 4 h, ethanol (0.5 ml) was added and then the reaction was poured into water. Extraction into ethyl acetate, washing the extracts with brine, drying and evaporation gave the crude product. Purification by chromatography (SiO2/30%-50% ethyl acetate in isohexane) afforded the subtitle compound (0.6 g).
Reaction SMILES: C(O[C:4](=[O:32])[C:5]1[CH:10]=[C:9](C2C=CC=C(C(F)(F)F)C=2)[C:8]([OH:21])=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:6]=1)C.S(Cl)(Cl)=O.[C:37]1(NCCCCCCCC)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([N:54]([CH2:57][CH3:58])CC)C.Cl>>[C:7]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:58][CH2:57][NH:54][C:4]([C:5]2[CH:10]=[C:9]([C:41]3[CH:40]=[CH:39][CH:38]=[C:37]([C:28]([F:29])([F:30])[F:31])[CH:42]=3)[C:8]([OH:21])=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)[CH:6]=2)=[O:32])[CH:8]=[CH:9][CH:10]=[CH:5][CH:6]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: CCCCCCCCNc1ccccc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 173.1 %

Procedure:
To 3,5-bis-(m-trifluoromethylphenyl)-4-hydroxy-benzoic acid ethyl ester (0.315 g, 0.74 mmol, 1 eq) was added thionyl chloride (2 mL) and the reaction was stirred overnight at rt and concentrated in vacuo. It was then added to a solution of phenyl octyl amine (0.222 mL, 1.12 mmol, 1.51 eq) and triethylamine (0.470 mL, 3.37 mmol, 4.6 eq). The reaction was stirred at rt 1 h, poured into 0.1 N HCl solution and extracted with Et2O. The combined organics were washed with 1N HCl (×3), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc:hexane) to afford title compound (0.393 g, 86%) as a colorless oil. 1H NMR (DMSO-d6) δ 9.30 (s, 1H); 8.42 (t, 1H); 7.91–7.85 (m, 4H); 7.82 (s, 2H); 7.75–7.65 (m, 4H); 7.26–7.10 (m, 5H); 3.23 (dd, 2H); 2.52 (t, 2H); 1.52 (m, 4H); 1.27 (m, 8H); IR (film) 3330, 2980, 2840, 1640, 1600, 1550, 1470, 1320, 1180, 1120, 1080, 900, 805 cm−1; mass spectrum [(+)APCI], m/z 614 (M+H)+; Anal. Calcd. for C35H33F6NO2: C, 68.51; H, 5.42; N, 2.28. Found: C, 66.76; H, 5.46; N, 2.18.
Reaction SMILES: [CH2:1]([S:7][C:8]1[S:20][C:11]2=[N:12][C:13]([C:17]#[C:18][CH3:19])=[CH:14][C:15](=[O:16])[N:10]2[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:21]OS([O-])=O.[K+].[OH2:27]>CO>[CH2:1]([S:7]([C:8]1[S:20][C:11]2=[N:12][C:13]([C:17]#[C:18][CH3:19])=[CH:14][C:15](=[O:16])[N:10]2[N:9]=1)(=[O:21])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O
Reactant: CC#Cc1cc(=O)n2nc(SCCCCCC)sc2n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: CC#Cc1cc(=O)n2nc(S(=O)(=O)CCCCCC)sc2n1
Reaction time: 0.83 h
Yield: 41 %

Procedure:
In 225 ml of methanol, 6.6 g of 2-hexylthio-7-(1-propynyl)-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved. A dispersion of 51.2 g of OXONE® suspended in 180 ml of water was added to the methanol solution, and the resulting mixture was warmed to 60°~65° C. and stirred for 50 minutes. After cooling, the mixture was extracted with chloroform, and the organic layer was washed with a sodium thiosulfate aqueous solution and water respectively, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography using an ethyl acetate/toluene mixture as an eluent, and was recrystallized from ethanol. Thus 2.6 g of 2-hexanesulfonyl-7-(1-propynyl)-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 122°~125° C. Yield 41%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].N1C=CC=CC=1.[Cl-].[F:29][C:30]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:31]=1[C:32]([O-])=[O:33].O>CN(C)C=O>[CH:19]([O:18][CH:12]([CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([CH2:2][NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:37]([C:39]([F:40])([F:41])[F:42])=[CH:38][C:30]=2[F:29])[CH:4]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:20])[CH3:21]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Reactant: O=C([O-])c1ccc(C(F)(F)F)cc1F
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)c2ccc(C(F)(F)F)cc2F)c1)OC(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.1 %

Procedure:
0.15 g of ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate was dissolved in 5 ml N,N-dimethylformamide, and 0.2 ml pyridine and 0.24 g of 2-fluoro-4-(trifluoromethyl)benzoate chloride were added, followed by stirring at room temperature for 12 hours. Water was added to the reaction solution, followed by extracting with ethyl acetate The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with ethyl acetate-hexane (1:2), 0.2 g of ethyl 2-isopropoxy-3-[4-methoxy-3-({[2-fluoro-4-(trifluoromethyl)benzoyl]amino}methyl)phenyl]propanoate was obtained as a pale yellow oil. This product was treated in the same manner as in Example 1d), to give 0.15 g of 2-isopropoxy-3-[4-methoxy-3-{[2-fluoro-4-(trifluoromethyl)benzoyl]amino}methyl)phenyl]propanoic acid as a pale yellow solid.
Reaction SMILES: N12[CH2:11][CH2:10][CH2:9][N:8]=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3]C2.[N+](C1CCCCC=1)([O-])=O.[CH2:21]([O:23][C:24](=[O:28])C[N+]#[C-])[CH3:22].Cl>CC(O)C.C1COCC1.CCOC(C)=O>[CH2:21]([O:23][C:24]([C:7]1[NH:8][CH:9]=[C:10]2[C:6]=1[CH2:5][CH2:4][CH2:3][CH2:11]2)=[O:28])[CH3:22]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Agent: O=[N+]([O-])C1=CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)c1[nH]cc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,8-Diazabicyclo[5.4.0]-undec-7-ene (6.2 mL, 41.5 mmol) in 2-propanol (45 mL) was added by addition funnel over ˜25 minutes to a stirring solution of 1-nitrocyclohexene (5.0441 g, 39.67 mmol) and ethylisocyanoacetate (4.3340 g, 37.16 mmol) in THF (45 mL). The reaction was judged complete after stirring overnight at room temperature. 2N HCl (˜100 mL) and EtOAc (˜50 mL) were added. The organic layer was removed, then washed with H2O, 5% NaHCO3, and H2O. The crude product was dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 100% CH2Cl2) to obtain 171 contaminated with a minor impurity. Attempts to recrystallize from hexanes were unsuccessful at removing the impurity, so the product was carried on to the next step with no further purification. 1H (CDCl3, 400 MHz): δ 9.01 (1H, broad s), 6.64 (1H, s), 4.31 (3H, q, J=7.2 Hz), 2.82 (2H, t, J=5.6 Hz), 2.55 (2H, t, J=5.6 Hz), 1.80-1.68 (4H, m), 1.36 (3H, t, J=7.2 Hz) ppm. 13C (CD3OD, 100 MHz): 6161.71, 128.06 and 127.84, 121.98 and 121.96, 118.74 and 118.55, 118.03 and 117.71, 59.62, 23.41 and 23.39, 23.36 and 23.33, 23.16 and 23.13, 21.88 and 21.86, 14.48 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 14.48; CH2 carbons: 59.62, 23.41 and 23.39, 23.36 and 23.33, 23.16 and 23.13, 21.88 and 21.86; CH carbons: 118.74 and 118.55 ppm. HPLC: 10.689 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH:11]=O)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][C:30](OCC)=[O:31])=[CH:22][CH:21]=1.[Li+].CC([N-]C(C)C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[C:10](=[CH:13][CH:14]=[CH:15][N:16]=3)[CH:11]=[C:29]([CH2:28][CH2:27][CH2:26][C:23]3[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=3)[C:30]2=[O:31])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: CCOC(=O)CCCCc1ccncc1
Reactant: O=Cc1cccnc1Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=c1c(CCCc2ccncc2)cc2cccnc2n1-c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 34 %

Procedure:
The procedure of Example 1 was repeated using 2-(4-chloro-3-nitrophenylamino)nicotinaldehyde (1.0 eq.; prepared in Synthetic Example 1d)), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq.; prepared in Synthetic Example 2) and LDA (1.5 eq.) to obtain 1-(4-chloro-3-nitrophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (yield 34%). The target product was purified through flash column chromatography and recrystallization, mp 136–137° C./DMF.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17]>O1CCCC1>[CH2:15]([NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH:16]([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)CN
Solvent: C1CCOC1
Product: CC(C)CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
To a stirred solution of 50.Og (0.24 mole) of 4-chloro-3-nitroquinoline in 300 ml of tetrahydrofuran was added, in small portions, 52.7g (0.72 mole) of isobutylamine. The mixture was heated at its reflux temperature for one hour, and was then evaporated in vacuo. Water was added to the residue and the solid was separated by filtration. The solid was suspended in one liter of water, and was dissolved by the gradual addition of concentrated hydrochloric acid (to pH 3 to 4), at which time the solution was filtered. The filtrate was basified (to pH 9 to 10) by the addition of concentrated ammonium hydroxide to provide bright yellow 4-(isobutylamino)-3-nitroquinoline, m.p. 119°-121° C. The structural assignment was supported by infrared spectral analysis.
Reaction SMILES: [CH2:1]1[C:3]2([C:8](=O)[NH:7][CH2:6][C:5](=O)[NH:4]2)[CH2:2]1.CO.[ClH:13].O1CCOCC1>O1CCCC1>[ClH:13].[CH2:2]1[C:3]2([CH2:8][NH:7][CH2:6][CH2:5][NH:4]2)[CH2:1]1
Reactant: O=C1CNC(=O)C2(CC2)N1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: C1CNC2(CC2)CN1

Procedure:
1.04M Borane-tetrahydrofuran complex in tetrahydrofuran (24.7 mL) was added dropwise to 4,7-diazaspiro[2.5]octane-5,8-dione (1.2 g) in tetrahydrofuran (30 mL) at 0° C. over a period of 30 minutes, and the resultant mixture was refluxed under heat for 13 hours. To the reaction mixture, methanol (4 mL) and 4N HCl-dioxane (8 mL) were added at 0° C., and the mixture was refluxed under heat for 1 hour, and then cooled in air. The precipitated solid was recovered by filtration, and washed with tetrahydrofuran, to thereby give a product mixture containing the title compound (1.86 g).