Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:29](N1CCOCC1)=[O:30].C(OCC)C>O1CCCC1>[CH:29]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:10]=1)=[O:30]
Reactant: O=CN1CCOCC1
Reactant: Fc1ccc(-c2ocnc2-c2ccncc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1nc(-c2ccncc2)c(-c2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 4-[5-(4-fluoro-phenyl)-oxazol-4-yl]-pyridine (1.5 g, Reference Example 6) in dry tetrahydrofuran (50 ml), under an inert atmosphere and at −10° C., was treated with a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (12.5 ml, 1M). After 0.5 hour the mixture was treated with N-formylmorpholine (1.5 ml). This mixture was stirred at room temperature for 16 hours then treated with diethyl ether (50 ml) and then filtered. The solid was suspended in 10% aqueous ammonium chloride solution (50 ml) and the resulting yellow solid filtered to give the title compound. MS: 269 [MH+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](O)([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[CH2:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(O)c1ccc(Cl)nc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C(=O)OCC)c1ccc(Cl)nc1OC
Yield: 179.8 %

Procedure:
A mixture of ethyl 2-(6-chloro-2-methoxypyridin-3-yl)-2-hydroxypropanoate (220 g, 847 mmol) and TsOH·H2O (80.5 g, 423 mmol) in dry toluene (1.5 L) was heated at reflux azeotropically with a Dean-Stark trap for 5 h. All of reaction solutions were combined together for work up. After being cooled, the combined reaction mixtures were washed with 10% Na2CO3 aq., and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to afford ethyl 2-(6-chloro-2-methoxypyridin-3-yl)acrylate (368 g 90%) as a black oil, which was used for next step without any further purifications.
Reaction SMILES: N[CH2:2][C:3]1[C:4]([CH3:25])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O.CCN(CC)CC>C1COCC1>[C:30]([O:29][C:27]([CH2:2][C:3]1[C:4]([CH3:25])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:26])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CN)c(C)nc2n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CC(=O)OC(C)(C)C)c(C)nc2n1
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To a stirred solution of ethyl 6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (Example 54, Step 10, 200 mg, 0.53 mmol) in THF (5 mL) at room temperature was added (BOC)2O (1.0 M in THF, 1.05 mL, 1.05 mmol) and Et3N (0.37 mL, 2.65 mmol). After 2 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with NH4Cl and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography gave ethyl 6-((tert-butoxycarbonyl)methyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (100 mg, 40%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16]>O.CCOC(C)=O.[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[O:9][CH:10]([CH2:11][CH2:12]2)[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]3[C:19]([O:21][CH3:22])=[O:20])=[CH:6][CH:7]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Clc1ccc(-c2ccco2)cc1
Agent: [Pt]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C(=O)OC)C2(c3ccc(Cl)cc3)CCC1O2

Procedure:
2-(4-Chlorophenylfuran (2.3 g) and dimethyl acetylenedicarboxylate (1.54 ml) were subjected to Diels-Alder reaction in water (5.48 ml) as described in Example 53. The resulting adduct was dissolved in EtOAc (140 ml) and hydrogenated over Adam's platinum catalyst (100 mg) at room temperature and atmospheric pressure. The uptake of one equivalent of H2 required about 3 hours. The catalyst was removed by filtration and the solvent removed in-vacuo to provide a gummy product which was chromatographed over silica gel column. Elution of column with 10% acetone in n-hexane gave fractions containing the pure title compound (3.25 g) as colorless crystals:m.p. 90°-91° C.; PMR δH (CDCl3): 1.55-1.7 (n,1H), 2-2.3 (m,3H), 3.62 (s,3H), 3.79(s,3H), 5.37 (d, 1H, J=4.2 Hz), 7.3-7.44 (m,4H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[S:19][CH:18]=[N:17][CH:16]=2)[CH:12]=[CH:11][C:10]=1[N:20]1[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]1)C1C=CC=CC=1>CCO.O.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([C:15]2[S:19][CH:18]=[N:17][CH:16]=2)[CH:12]=[CH:11][C:10]=1[N:20]1[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]1
Reactant: O=C1CN(c2ccc(-c3cncs3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: O=C1CN(c2ccc(-c3cncs3)cc2O)S(=O)(=O)N1
Reaction time: 2.5 h

Procedure:
To a solution of 5-(2-benzyloxy-4-thiazol-5-yl-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (87 mg, 0.217 mmol) in EtOH (2.5 mL) and water (22.5 mL) is added 10% Pd/C (100 mg) and the mixture is stirred under an atmosphere of H2 for 2.5 h. The mixture is filtered through Celite and the filtrate evaporated. The residue is purified by reverse phase HPLC (CH3CN/water/0.1% TFA) to afford the title compound as a light yellow solid: 1H NMR (CD3O4.37 (s, 1H), 7.04 (d, J=8 Hz, 1H), 7.08 (s, 1H), 7.35 (d, J=8 Hz, 1H), 7.97 (s, 1H), 8.79 (s, 1H); (M−1)−=310.
Reaction SMILES: [I-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].ICCCC=C>CC(C)=O>[CH2:11]([O:10][P:9]([CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])(=[O:16])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: C=CCCCBr
Reactant: CCOP(OCC)OCC
Agent: C=CCCCI
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCCCP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium iodide (100.6 g, 0.66 mol, 1.1 eq.) was added to a solution of 1-bromo-4-pentene (100 g, 0.67 mol) in acetone (250 mL) and the mixture was stirred at room temperature overnight. The mixture was filtered and the solid was washed with acetone. The acetone filtrate and the acetone wash were combined. The acetone was then removed by distillation, revealing 1-iodo-4-pentene, which was used in the next step. 1H NMR (CDCl3) δ=5.8 (m, 1H), 5.0 (m, 2H), 3.2 (t, 2H), 2.2 (sq, 2H), 1.8 (sq, 2H). Triethyl phosphite (400 mL, 2.3 mol, 3.5 eq.) was added to the 1-iodo-4-pentene, and the mixture was heated to 130° C. for three hours. Diethyl ethyl phosphonate was removed by fractional vacuum distillation, revealing the desired 4-pentenyl phosphonic acid diethyl ester which was used without further purification. 1H NMR (CDCl3) δ=5.7 (m, 1H), 4.8 (m, 2H), 4.0 (m, 4H), 2.0 (sq, 2H), 1.7 (m, 4H), 1.2 (t, 6H). 31P NMR (CDCl3) δ=33.3.
Reaction SMILES: [CH:1]1([CH:7]([NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[C:8]2[CH:12]=[C:11]([CH3:13])[S:10][C:9]=2[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][NH:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([N:26]([CH3:25])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:22])=[CH:23][CH:24]=2)[C:8]2[CH:12]=[C:11]([CH3:13])[S:10][C:9]=2[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1cc(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)c(C)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)c(C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.9 %

Procedure:
To a mixture of 4-{[cyclohexyl(2,5-dimethylthiophen-3-yl)methyl]amino}benzoic acid (250 mg) synthesized in Example 270 (4), ethyl 3-(methylamino)propanoate (115 mg), 1-hydroxybenzotriazole monohydrate (134 mg) and triethylamine (122 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (168 mg), and the mixture was stirred at room temperature for 2 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate) to give a colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 2.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give a white solid. The obtained solid was purified by silica gel column chromatography (60% ethyl acetate/hexane) to give colorless oil. The obtained oil was crystallized from hexane to give the title compound (15.4 mg, 5%) as a white solid.
Reaction SMILES: N(C[C@@H](C1C=CC(OCC2C=CC=CC=2)=C2C=1C=CC(=O)N2)O)=[N+]=[N-].[Si]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]([C:49]2[CH:50]=[C:51]([S:55]([C:58]3[CH:59]=[C:60]4[C:65](=[C:66]([CH3:68])[CH:67]=3)[N:64]=[CH:63][C:62]([C:69]([NH2:71])=[O:70])=[C:61]4[NH:72][C:73]3[CH:78]=[CH:77][CH:76]=[C:75]([O:79][CH3:80])[CH:74]=3)(=[O:57])=[O:56])[CH:52]=[CH:53][CH:54]=2)=[O:48])[CH2:43][CH2:42]1)(C(C)(C)C)(C)C>>[OH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]([C:49]2[CH:50]=[C:51]([S:55]([C:58]3[CH:59]=[C:60]4[C:65](=[C:66]([CH3:68])[CH:67]=3)[N:64]=[CH:63][C:62]([C:69]([NH2:71])=[O:70])=[C:61]4[NH:72][C:73]3[CH:78]=[CH:77][CH:76]=[C:75]([O:79][CH3:80])[CH:74]=3)(=[O:57])=[O:56])[CH:52]=[CH:53][CH:54]=2)=[O:48])[CH2:43][CH2:42]1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCC(OCCCCCCO[Si](C)(C)C(C)(C)C)CC5)c4)cc23)c1
Agent: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCC(OCCCCCCO)CC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 5, using Intermediate 84 as a substrate. ES/MS calcd. for C36H43N4O7S+ 675.3. Found m/z=675.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][C:16]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH2:20][O:19]3)[CH2:15][CH2:14]1)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:29]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:11]([N:13]2[CH2:14][CH2:15][C:16]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH2:20][O:19]3)[CH2:17][CH2:18]2)=[O:12])=[C:2]1[CH3:1])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1[nH]c2ccccc2c1C(=O)N1CCC2(CC1)OCc1ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCC3(CC2)OCc2ccccc23)c2ccccc2n1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.9 %

Procedure:
To a stirred solution of 40 mg (0.11 mmol) of 1′-[(2-methyl-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (the preparation of which has been described in example 43) in 3 ml DMF was added 5 mg (0.11 mmol) NaH (60% in oil). The mixture was stirred at RT for 30 min. and then 19 mg (0.13 mmol) of benzoyl chloride was added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Re-crystallization in Et2O afforded 51 mg (98%) of 1′-[(1-benzoyl-2-methyl-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Yield: 105.3 %

Procedure:
A mixture of 5.0 g (15 mmol) of 4-(4'-nitrophenyl)-2,6-di-tert-butylphenol, 0.5 g of 5% palladium on carbon, and 250 mL of absolute ethanol was hydrogenated for one hour under 50 psig of hydrogen, filtered, and concentrated to give 4.7 g (quantitative yield) of 4-(4'-aminophenyl)-2,6-di-tert-butylphenol as a foam: 1H NMR (CDC13) 1.48 (s, 18H), 3.25 (broad s, 2H), 5.20 (broad s, 1H), 6.67 (d, 2H, J=9Hz), 7.36 (s, 2H), 7.36 (d, 2H, J=9Hz). This compound may also be named 3,5-bis(1,1-dimethylethyl)-4'-amino-(1,1'-biphenyl)-4-ol.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]([Cl:15])[CH:2]=1.C([Li])CCC.[Cl:21][CH2:22][CH2:23][CH2:24]I>O1CCCC1>[Cl:21][CH2:22][CH2:23][CH2:24][CH:7]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:6]1[CH:1]=[CH:2][C:3]([Cl:15])=[CH:4][CH:5]=1
Reactant: ClCCCI
Reactant: Clc1ccc(Cc2ccc(Cl)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: ClCCCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 44 %

Procedure:
A solution of 4,4′-dichlorodiphenylmethane (4.37 g, 18.4 mmol) (Blackwell, J. et all, J. Chem. Soc., 1961, 1405) in dry tetrahydrofuran (50 ml) was treated at 0° C. with butyllithium (12.1 ml of 1.6 M, 19.36 mmol) added dropwise over 15 min. After 15 min, the red solution was then added dropwise to a cold (−78° C.) solution of 1-chloro-3-iodopropane (15.0 g, 73.4 mmol) in dry tetrahydrofuran (120 ml). After 20 min at −78° C., the reaction mixture was quenched by the addition of saturated ammonium chloride (100 ml) and diluted with toluene. The organic phase was washed with brine and dried. The oil obtained after evaporation of the solvent was purified on silica gel (elution hexane-toluene 85:15) and distilled under vacuum to give 2.54 g (44%) of the title material as a clear oil: bp 110-130° C./1.5 torr (air bath temperature).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O>>[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1
Reactant: OB(O)c1ccc[nH]1
Reactant: O=Cc1cnc2ccc(Br)cn12
Product: O=Cc1cnc2ccc(-c3ccc[nH]3)cn12
Yield: 21 %

Procedure:
The title compound was prepared by following the procedure as described for Intermediate 1 using 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and 1H-pyrrol-2-ylboronic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:13]12([CH2:23][N:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:27](=[O:41])[CH:26]([NH2:42])[C:25]3=[O:43])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>C(#N)C.ClCCl>[C:13]12([CH2:23][N:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:27](=[O:41])[CH:26]([NH:42][C:11]([NH:10][C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[O:12])[C:25]3=[O:43])[CH2:22][CH:17]3[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]3)[CH2:20]1)[CH2:14]2
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: NC1C(=O)N(CC23CC4CC(CC(C4)C2)C3)c2ccccc2N(c2ccccc2)C1=O
Solvent: CC#N
Solvent: ClCCl
Product: O=C(Nc1cccc([N+](=O)[O-])c1)NC1C(=O)N(CC23CC4CC(CC(C4)C2)C3)c2ccccc2N(c2ccccc2)C1=O
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A solution of 3-nitrophenyl isocyanate (0.082 g) in dry acetonitrile (8 ml) was added to a solution of the 1-(1-Adamantylmethyl-3-amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.2 g) in dry acetonitrile (10 ml) under a nitrogen atmosphere. The mixture was stirred at 23° for 2 h, then diluted with dichloromethane (15 ml) and washed with brine (15 ml). The organic solution was dried, concentrated in vacuo and the residue was triturated with diethyl ether to give the title compound as a white solid (0.229 g). M.p. 213°-5°. T.I.c. CH-EA (2:1), Rf0.33.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:19][S:20]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:22])=[O:21]
Reactant: OCCOCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCc1ccccc1
Reaction time: 3 h
Yield: 96.4 %

Procedure:
2-Benzyloxyethanol (85.0 g) and triethylamine (73.5 g) were dissolved in THF (500 mL) and methanesulfonyl chloride (76.8 g) was added dropwise at from 0° C. to 10° C. The mixture was stirred for 3 hr. 10% Aqueous sodium bicarbonate (300 mL) was poured into the reaction mixture, the mixture was partitioned and combined with an extract of the aqueous layer with MTBE (300 mL), and the mixture was washed with 10% aqueous sodium bicarbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 2-benzyloxyethyl methanesulfonate (124.0 g). The 2-benzyloxyethyl methanesulfonate (124.0 g) was dissolved in acetone (500 mL), and sodium iodide (130.0 g) was added. The mixture was stirred at from 50° C. to 60° C. for 3 hr. The reaction mixture was filtered and the solvent was evaporated. Water (300 mL) was added, and the mixture was extracted twice with toluene (300 mL). The toluene layer was washed successively with aqueous sodium hydrogen sulfite solution, water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (127.0 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[C@H:28]([CH3:29])[CH2:27][CH2:26][S:25]2(=[O:31])=[O:30])[CH:3]=1.[O:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH2:35][CH2:36][O:32][C:33]4=[O:37])=[CH:3][C:4]=3[N:24]3[C@H:28]([CH3:29])[CH2:27][CH2:26][S:25]3(=[O:31])=[O:30])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3[C@H](C)CCS3(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3[C@H](C)CCS3(=O)=O)CC2)c(C)c1
Yield: 15.1 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using (R)-[4-chloro-2-(3-methyl-1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (95.1 mg) described in Preparation Example 125 and oxazolidin-2-one (17.9 mg), the title compound (15.9 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][C:14]([Br:20])=[CH:13][N:12]=1>C(#N)C.[F-].[K+]>[Br:20][C:14]1[CH:15]=[C:16]([C:4]2[CH:3]=[C:2]([F:1])[N:7]=[CH:6][C:5]=2[NH2:8])[C:11]([F:10])=[N:12][CH:13]=1
Reactant: Nc1cnc(F)cc1I
Reactant: OB(O)c1cc(Br)cnc1F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Nc1cnc(F)cc1-c1cc(Br)cnc1F
Temperature: 80 °C
Yield: 28.6 %

Procedure:
A mixture of 6-fluoro-4-iodopyridin-3-ylamine (1.57 g, 6.59 mmol), 2-fluoro-5-bromopyridine-3-boronic acid (2.17 g, 9.89 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.43 g, 0.53 mmol) in acetonitrile (25 mL) and 1N aqueous potassium fluoride solution (25 mL) was degassed with nitrogen for 20 minutes. The reaction mixture was heated at 80° C. for 3 h, allowed to cool to ambient temperature and then partitioned between ethyl acetate (100 mL) and water (75 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica, 40 g column, ISCO, 0-50% ethyl acetate in cyclohexane) to afford the title compound as an brown solid (0.54 g, 29%). 1H NMR (CDCl3, 300 MHz): 8.37 (dd, J=2.5, 1.4 Hz, 1H), 7.99 (dd, J=8.1, 2.5 Hz, 1H), 7.79 (d, J=1.5 Hz, 1H), 6.74 (d, J=2.8 Hz, 1H), 3.62 (s, 2H). LCMS (Method B): RT=3.01 min, M+H+=286/288.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:16]=[CH2:17])=[C:9]([C:12]([NH:14][NH2:15])=[O:13])[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:21]=[O:22])C>C(OCC)(=O)C>[C:12]([C:9]1[CH:8]=[C:7]([CH:1]=[CH:2][C:21]=1[OH:22])[C:11]([NH:15][NH:14][C:12]([C:9]1[O:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]=1[CH:16]=[CH2:17])=[O:13])=[O:10])#[N:14]
Reactant: C=Cc1c(-c2ccccc2)coc1C(=O)NN
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1c(-c2ccccc2)coc1C(=O)NNC(=O)c1ccc(O)c(C#N)c1

Procedure:
A mixture of 4-phenyl-3-vinyl-2-furancarboxylic acid hydrazide (compound of Reference Example 39, 0.20 g) and the compound of Reference Example 63 (0.32 g) in DMF (5 ml) was stirred at 70° C. for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate, thereby giving 0.17 g of the desired compound. Melting point: 170-174° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([CH2:10][NH2:11])[OH:9]>O>[OH:9][CH2:8][CH2:10][NH:11][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: NCCO
Solvent: O
Product: OCCNc1cccnc1
Yield: 27.2 %

Procedure:
A mixture of 3-bromopyridine (25.10 g), ethanolamine (34.89 g) and cupric sulfate (2.90 g) in water (140 ml) was refluxed for 5 hours under stirring. The reaction mixture was washed with chloroform and the aqueous layer was separated out. To the aqueous solution was added an aqueous solution of potassium carbonate (22 g) and then the mixture was saturated with sodium chloride, and extracted with a mixed solvent of chloroform and ethanol (1:1). The extract was evaporated and the residue was subjected to column chromatography on silica gel (200 g) using a mixed solvent of chloroform and ethanol (5:1) as an eluent. The fractions containing an object compound were collected and evaporated to give 3-(2-hydroxyethyl)aminopyridine (5.96 g) as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]=2[CH:22]=O)[CH2:6][CH2:5]1.OC1CCN(CCCC2C3CCCCC=3NC=2C=O)CC1.[CH3:45][NH:46][S:47]([C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[NH:55][C:54](=[O:59])[CH2:53]2)(=[O:49])=[O:48]>>[CH3:45][NH:46][S:47]([C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[NH:55][C:54](=[O:59])/[C:53]/2=[CH:22]\[C:14]1[NH:15][C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=2[C:13]=1[CH2:12][CH2:11][CH2:10][N:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH2:9][CH2:8]1)(=[O:49])=[O:48]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1CCCN1CCN(CCO)CC1)CCCC2
Agent: O=Cc1[nH]c2c(c1CCCN1CCC(O)CC1)CCCC2
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(CCO)CC1)CCCC3)C(=O)N2
Yield: 62.5 %

Procedure:
3-{3-[4-(2-Hydroxyethyl)-piperazin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (64 mg, 0.2 mmol), prepared by following the procedure described for 3-[3-(4-hydroxy-piperidin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (Example 20), was condensed with 5-methylaminosulfonyloxindole (46 mg, 0.2 mmol) to give 66 mg of the desired product.