Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.Br[CH2:33][C:34](Br)=[O:35].[C:37]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:40]([O:39][C:37]([N:44]1[CH2:45][CH2:46][N:47]([CH2:33][C:34]([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:6]=[CH:5][C:4]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:3][C:2]=3[F:1])[CH2:9][CH2:10]2)=[O:35])[CH2:48][CH2:49]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CN4CCN(C(=O)OC(C)(C)C)CC4)CC3)c(F)c2)C(=O)O1
Temperature: 60 °C

Procedure:
To a stirred suspension of 672 mg of N-[(5S)-3-(3-fluoro-4-piperazine-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (2 mmol) and 0.42 ml of triethylamine (3 mmol) in 30 ml dichloromethane was added at rt. a solution of 484 mg bromoacetylbromide (2.4 mmol) in 2 ml of dichloromethane. The reaction was monitored by TLC. The reaction solution was washed with water and brine, the dichloromethane layer dried over Mg sulfate, filtered and the filtrate evaporated to dryness. The residue was digested in 20 ml ether, the solid filtered and dried. The colorless solid was dissolved in 10 ml DMF, 372 mg N-Boc piperazine 2 mmol) and 276 mg of potassium carbonate (2 mmol) were added. The reaction was stirred over night at 60° C. and monitored by TLC. The DMF was evaporated to dryness, the residue purified by chromatography, using a 19/1 dichloromethane/methanol mixture as eluent.
Reaction SMILES: [NH2:1][C:2]([CH2:9][C:10](=[O:12])[O-:11])([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[C:16]([F:23])[C:15]=1[F:24]>>[C:10]([O-:12])(=[O:11])[CH3:9].[C:10]([CH2:9][C@@H:2]([NH:1][C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([F:13])=[C:15]([F:24])[C:16]=1[F:23])=[O:22])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])([OH:11])=[O:12]
Reactant: O=C=Nc1ccc(F)c(F)c1F
Reactant: C[N+](C)(C)CC(N)(O)CC(=O)[O-]
Product: CC(=O)[O-]
Product: C[N+](C)(C)C[C@@H](CC(=O)O)NC(=O)Nc1ccc(F)c(F)c1F

Procedure:
According to the method described in example S11, aminocarnitine (41 mg) was reacted with 1,2,3-trifluoro-4-isocyanatobenzene to yield the title compound as a white solid (2.3 mg). 1H NMR (400 MHz, CD3OD): δ=7.70-7.60 (m, 1H), 7.10-7.00 (m, 1H), 4.61 (br s, 1H), 3.80-45 (m, 2H), 3.22 (s, 9H), 2.40-2.60 (m, 2H), 1.97 (s, 3H); MS ESI [M+H]+, calcd for [C14H18F3N3O3+H]+ 334.3 found m/z 334.1 (100)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:17])[C:3]=1[C:18]#[N:19])=[CH:13][CH:12]=[C:11]([OH:16])[CH:10]=3.Br[CH2:21][CH2:22][NH2:23].BrCCOCC>>[NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:17])[C:3]=1[C:18]#[N:19])=[CH:13][CH:12]=[C:11]([O:16][CH2:21][CH2:22][NH2:23])[CH:10]=3
Reactant: N#Cc1c(N)nc2c(c1N)Cc1ccc(O)cc1O2
Reactant: NCCBr
Agent: CCOCCBr
Product: N#Cc1c(N)nc2c(c1N)Cc1ccc(OCCN)cc1O2

Procedure:
2,4-diamino-8-(2-aminoethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile was prepared from 2,4-diamino-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile in the same manner as described in Example 10 using 2-bromoethylamine in lieu of 2-bromoethyl-ethylether. The product was isolated as a tan solid (167 mg, 51% yield). 1H NMR (400 MHz, DMSO) δ 8.180 (bs, 2H), 7.100 (d, 1H), 6.762 (d, 1H), 6.646 (bs, 1H), 4.154 (t, 2H), 3.573 (s, 2H), 3.155 (t, 2H); m/z 398 (M+H). TNFα release assay IC50: 6.9 μM; Rat LPS Assay 88% inhibition at 20 mpk (IP).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].Cl.[CH2:38]([O:40][C:41](=[O:44])[CH2:42][NH2:43])[CH3:39]>>[CH2:38]([O:40][C:41](=[O:44])[CH2:42][NH:43][C:23](=[O:24])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:39]
Reactant: CCOC(=O)CN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Agent: Cl
Product: CCOC(=O)CNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with glycine ethyl ester hydrochloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[S:19][C:18]3[N:20]=[CH:21][CH:22]=[N:23][C:17]=3[N:16](COC)[C:15]=2[CH:27]=1)=O.S(Cl)(Cl)=O.ClCCl>C(Cl)(Cl)(Cl)Cl>[N:7]1[CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:19][C:18]4[N:20]=[CH:21][CH:22]=[N:23][C:17]=4[NH:16][C:15]=3[CH:27]=2)[N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=12
Reactant: COCN1c2cc(C(=O)CNc3ccccn3)ccc2Sc2nccnc21
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: c1ccn2c(-c3ccc4c(c3)Nc3nccnc3S4)cnc2c1
Yield: 61.6 %

Procedure:
10 ml of a solution of 200 mg of [N-(2-pyridyl)aminometyl](10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ketone in carbon tetrachloride was stirred at room temperature and 240 mg of thionyl chloride was dropped thereinto. The reaction mixture was distributed into dichloromethane and an aqueous solution of sodium bicarbonate and the organic layer was separated. To the organic layer were added methanol and tetrahydrofuran to give a homogeneous solution. After adding silica gel and distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 103 mg of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:13])=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22]C(=O)OC(C)(C)C)=[C:18]([O:30][CH3:31])[CH:17]=1)=O.N1CCCCC1>CCO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16](/[CH:14]=[CH:13]/[C:4]2[O:3][C:2]([CH3:1])=[CH:7][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:5]=2)=[CH:17][C:18]=1[O:30][CH3:31]
Reactant: CC1=CC(=C(C#N)C#N)C=C(C)O1
Reactant: COc1cc(C=O)ccc1NC(=O)OC(C)(C)C
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C2=CC(=C(C#N)C#N)C=C(C)O2)ccc1N
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture of 2-(2,6-dimethyl-4H-pyran-4-ylidene)malononitrile (1, 20.7 mg, 0.12 mmol) and aldehyde 2c (25.1 mg, 0.1 mmol) were dissolved in anhydrous EtOH (0.67 ml) at 65° C. Piperidine (0.5 μl) was added and the mixture was stirred at 80° C. for 7 hours. The solvent was removed with a stream of N2, the crude mixture was dissolved in EtOAc at 5 mg/ml and purified by normal phase preparative HPLC using hexanes/ethyl acetate as eluent. Yield: 10.6 mg (26%). LCMS ESI+m/z 406 (M+H+) H-NMR (400 MHz, CD2Cl2): 8.16 (1H, d, J=8 Hz) 7.47 (1H, d, J=16 Hz) 7.29 (1H, s) 7.19 (1h, dd, J=8 Hz, 0.4 Hz) 7.1 (1H, d, J=0.4 Hz) 6.67-6.74 (2H, m) 6.56 (1H, m) 3.97 (3H, s) 2.43 (3H, s) 1.55 (9H, s). C-NMR (400 MHz, CD2Cl2) 163.02, 160.11, 157.01, 152.81, 148.32, 138.31, 131.33, 129.29, 122.99, 118.01, 116.81, 115.74, 108.45, 107.26, 106.77, 81.27, 56.35, 28.56, 20.31. This compound was treated with a 4N HCl solution in dioxane (4 N, 1.3 ml) for 3 hrs. The mixture was diluted with hexanes, the precipitate centrifuged, re-suspended and washed with hexanes, then dried under vacuum. LCMS ESI+ m/z: 306 (M+H+). H-NMR (400 MHz, CD2Cl2) 7.37 (1H, d, J=16 hz) 7.12 (1H, dd, J=16 Hz, 0.4 Hz) 7.02 (1H, d, J=0.4 Hz) 6.56-6.63 (3H, m) 6.12 (1H, m) 3.97 (3H, s) 2.42 (3H, s). C-NMR (400 MHz, CD2Cl2) 164.58, 156.12, 151.52, 140.90, 139.05, 129.73, 127.19, 121.74, 115.48, 110.73, 109.95, 102.81, 101.68, 100.79, 90.2, 55.89, 21.02.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(CN)CCCCC1.[O:15]=[C:16]1[C:24]2([CH2:28][O:27][C:26]3[CH:29]=[C:30]4[C:34](=[CH:35][C:25]2=3)[CH2:33][CH2:32][O:31]4)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]1[CH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[N:1]1([C:41]([C:40]2[CH:39]=[CH:38][C:37]([CH2:36][N:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:24]4([CH2:28][O:27][C:26]5[CH:29]=[C:30]6[C:34](=[CH:35][C:25]4=5)[CH2:33][CH2:32][O:31]6)[C:16]3=[O:15])=[CH:45][CH:44]=2)=[O:42])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1)N1CCOCC1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using morpholine to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 1′-[4-(morpholin-4-ylcarbonyl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (58%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.44-7.35 (m, 4H), 7.24-7.15 (m, 2H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.76 (d, J=7.5 Hz, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 4.98 (ABq, 2H), 4.85 (ABq, 2H), 4.55 (t, J=8.6 Hz, 2H), 3.87-3.40 (m, 8H), 3.08-2.93 (m, 2H); MS (ES+) m/z 483.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[CH2:19]([O:26][C:27]1[C:32]([CH2:33]Cl)=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O>O1CCOCC1>[CH2:19]([O:26][C:27]1[C:32]([CH2:33][N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([Cl:1])[C:3]([C:13]4[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=4)=[CH:4][CH:5]=3)[C:10]2=[O:12])=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Reactant: Cn1nccc1-c1ccc2c(c1Cl)C(=O)NCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CN2CCc3ccc(-c4ccnn4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Yield: 68.4 %

Procedure:
A solution of 8-chloro-7-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (66b, 48.0, 0.180 mmol), 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 71.7 mg, 0.274 mmol), and KHMDS (182 mg, 0.915 mmol) in 1,4-dioxane (5 mL) was heated at 80° C. overnight. To the reaction mixture was added H2O (10 mL), the solution was extracted with EtOAc (10 mL), the organic layer concentrated under vacuum, and the residue purified by prep chromatography to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (66c, 60 mg, 67%) as a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[C:12]1([CH3:18])[CH:17]=C[CH:15]=[CH:14][CH:13]=1>CO>[CH2:13]([C:12]1[CH:17]=[N:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([F:2])=[CH:4][CH:5]=2)=[N:9][CH:18]=1)[CH2:14][CH3:15]
Reactant: Cc1ccccc1
Reactant: N=C(N)c1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: CCCc1cnc(-c2ccc(F)cc2)nc1
Yield: 55 %

Procedure:
To a sodium methylate solution under agitation obtained by dissolving Na (2.8 g, 0.12 mol) in anhydrous methanol (20 c.c.) was added 4-fluorobenzamidine hydrochloride (10.5 g, 0.06 mol), followed by adding α-propyl-β-dimethylaminoacrolein (9.2 g, 0.06 mol), thereafter refluxing on heating for 3 hours with stirring, distilling off methanol under the atmospheric pressure after completion of the reaction, adding toluene (20cc) to the reaction residue to extract the resulting product, washing the extraction liquid with water, drying with anhydrous sodium sulfate, distilling off toluene and recrystallizing the remaining oily substance from ethanol (20 c.c.) to obtain the objective 5-propyl-2-(4-fluorophenyl)pyrimidine (7.0 g). Yield: 55%. M.P. 52.7° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[I-].[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26])[C:19]([CH2:27][O:28][CH2:29][CH3:30])=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1>CN(C=O)C>[ClH:26].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:3][C:2](=[NH:4])[NH2:1])[C:19]([CH2:27][O:28][CH2:29][CH3:30])=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCCCCl
Reactant: NC(N)=S
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCCCSC(=N)N
Product: Cl
Temperature: 110 °C
Yield: 95.6 %

Procedure:
Thiourea (0.29 g, 3.8 mmol) and potassium iodide (0.052 g, 3.1 mmol) were sequentially added to a suspension of 7-bromo-1-(5-chloropentyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (1.3 g, 3.2 mmol) in DMF (15 mL), and the reaction was heated at 110° C. for 24 hours. The DMF was removed under reduced pressure, and the residue was partitioned between saturated aqueous sodium bicarbonate (40 mL) and dichloromethane (50 mL). The mixture was adjusted to pH 7 with the addition of 10% hydrochloric acid. Product remained on the walls of the reaction flask and was dissolved with methanol. The resulting solution was concentrated under reduced pressure to provide a solid. The aqueous layer was concentrated under reduced pressure, and the resulting solid was triturated with methanol and isolated by filtration. The filtrate was concentrated under reduced pressure, and the residue was triturated and isolated as described above. The isolated solids were combined and dried under high vacuum to provide 1.49 g of 2-[5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentyl]isothiourea hydrochloride as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21]3)=[O:17])(=[O:12])=[O:11])[CH2:6][CH2:5]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][N:30]=1>CN(C)C=O.C(=O)([O-])O.[Na+]>[ClH:28].[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:21]2[C:20]3[C:24](=[CH:25][CH:26]=[C:18]([C:16]([NH:15][CH2:14][CH2:13][S:10]([N:7]4[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]4)(=[O:11])=[O:12])=[O:17])[CH:19]=3)[NH:23][C:22]=2[OH:27])=[N:30][CH:31]=1)#[N:36]
Reactant: CN1CCN(S(=O)(=O)CCNC(=O)c2ccc3c(c2)CC(=O)N3)CC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(S(=O)(=O)CCNC(=O)c2ccc3[nH]c(O)c(-c4ccc(C#N)cn4)c3c2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 11 %

Procedure:
Sodium hydride (0.026 g of 60% suspension in mineral oil, 0.65 mmol) was added to a cooled (0° C.) solution of N-{2-[(4-methylpiperazin-1-yl)sulfonyl]ethyl}-2-oxoindoline-5-carboxamide (0.120 g, 33 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 0° C. for 10 min under an N2 atmosphere, followed by the addition of 2-chloro-5-cyanopyridine (0.050 g, 0.36 mmol) in N,N-dimethylformamide (2 mL). The reaction vessel was closed, immediately warmed up to 100° C., and the reaction was stirred at this temperature for 1 h. The cooled mixture was diluted with a saturated sodium hydrogen carbonate solution (5 mL) and concentrated in vacuo. The residue was suspended in methanol/dichloromethane (1:1), silica gel (˜2 g) was added and mixture was re-concentrated in vacuo. The solid residue was purified on a silica gel column using dichloromethane/methanol/aqueous NH3, (60:10:1), as the eluent. Fractions containing product were concentrated, the resulting orange foam was suspended in ethyl acetate (3 mL), and filtered to give 0.020 g (13% yield) of the title compound as the base. This material was dissolved in chloroform/methanol, (1:1), and treated with HCl in diethyl ether followed by addition of diethyl ether. The resulting yellow crystals were collected by filtration and washed with diethyl ether to afford 0.014 g (60% yield) of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ 14.68 (br s, 1H), 10.94 (s, 1H), 10.55 (br s, 1H), 8.74 (br s, 1H), 8.59 (s, 1H), 8.00 (s, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.70 (d, J=9.0 Hz, 1-H), 7.60 (d, J=8.1 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 3.83-3.75 (m, 4H), 3.70-3.62 (m, 2H), 3.52-3.42 (m, 4H), 3.27-3.20 (m, 2H), 3.12-3.05 (m, 2H), 2.75 (s, 3H); MS (ES) m/z 469 (M++1).
Reaction SMILES: [OH-:1].[Na+].O[NH2:4].C[O:6][C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1)=O>C1COCC1.CO.O>[OH:1][NH:4][C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1)=[O:6]
Reactant: COC(=O)c1ccc2ccn(CC3CCCCC3)c2c1
Reactant: [OH-]
Reactant: NO
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(NO)c1ccc2ccn(CC3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 84 %

Procedure:
To a solution of sodium hydroxide (0.1 g, 2.5 mmol) and 50% aqueous hydroxyl amine (1 mL) was added 1-cyclohexylmethyl-1H-indole-6-carboxylic acid methyl ester (0.2 g, 0.7 mmol) dissolved in THF/MeOH (2 mL, 1:1). After stirring 3.5 hr at room temperature, the solution was diluted with water (4 mL) and the volatile solvents were removed in vacuo. The solution was then neutralized to pH=7-8 with 1N HCl. The resulting precipitate was isolated by filtration to provide 1-cyclohexylmethyl-1H-indole-6-carboxylic acid hydroxyamide as a white solid (0.16 g, 84% yield). 1H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 8.92 (s, 1H), 7.92 (s, 1H), 7.55 (d, 1H, J=8.0 Hz), 7.47-7.42 (m, 2H), 6.45 (d, 1H, J=3.1 Hz), 4.03 (d, 2H, J=7.4 Hz), 1.84 (m, 1H), 1.66-1.57 (m 3H), 1.47 (m, 2H), 1.12 (m, 3H), 0.98 (m, 2H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:14]2[CH:15]=[C:16]([CH:18]=O)[S:17][C:13]=2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.NO.C([N:25](CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[Si:1]([O:8][CH:9]1[C:14]2[CH:15]=[C:16]([C:18]#[N:25])[S:17][C:13]=2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2sc(C=O)cc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NO
Product: CC(C)(C)[Si](C)(C)OC1CCCc2sc(C#N)cc21

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1c) using 4-{[t-butyl(dimethyl)silyl]oxy}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxaldehyde (4.4 g, 15.3 mmol) that was obtained in Example 8 (8c), hydroxylamine hydrochloride (1.1 g, 16 mmol), triethylamine (4.1 ml, 30 mmol), and N,N′-dicyclohexylcarbodiimide (3.4 g, 16 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (4.1 g) in a yield of 94% as a colourless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:27])[CH2:13][CH2:12][N:11]([CH:14]([F:26])[CH2:15][CH:16](F)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(C)C=CC=CC=1>O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:27])[CH2:13][CH2:12][N:11]([CH:14]([F:26])[CH2:15][CH:16]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)C(F)CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: C1CCNCC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(c1ccccc1)C(CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1)N1CCCCC1

Procedure:
A mixture of γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone (1.5 g), piperidine (15.0 g) and toluene (50 ml) was heated for 23 hours under refluxing. The reaction mixture was diluted with water and extracted with toluene. The extract was sufficiently washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was treated with hydrochloric acid in ethanol-ether, and the resulting product was recrystallized from isopropanol to yield γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-4-fluoro-2-piperidinobutyrophenone hydrochloride. M.P 218° - 220°C (decomposition).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>O1CCCC1>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[O:13][C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])=[CH:5][C:4]=1[C:16]([F:19])([F:17])[F:18])#[N:2]
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2OC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
A solution of 0.4 g (1.48 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline -2,3(1H,4H)-dione in 50 ml dry tetrahydrofuran was added 0.225 ml (1.63 mmol) dry triethylamine and 0.2 ml (1.58 mmol) phenyl chloroformate. The mixture was stirred at 25° C. for 30 min., and then filtered and evaporated in vacuo. The residue was stirred with ether to give 0.48 g (83%) of 7-cyano-1-phenoxycarbonyloxy-6-trifluoromethylquinoxaline-2,3-(1H,4H)-dione. M.p. 190° C. decomp. 1H-NMR (DMSO-d6): 8.43 (1H,s), 7.63 (1H, s), 7.3 (5H, broad s).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3Br)[CH2:5][C:4]=2[N:3]=1.NC1N=CC2C(=O)CC(C3C=CC(F)=CC=3[C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)CC=2N=1.N1C=CC=CC=1B(O)O>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:40]3[CH:39]=[CH:44][CH:43]=[CH:42][N:41]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Nc1ncc2c(n1)CC(c1ccccc1Br)CC2=O
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1-c1cccnc1)CC2=O
Agent: OB(O)c1ccccn1
Product: Nc1ncc2c(n1)CC(c1ccccc1-c1ccccn1)CC2=O

Procedure:
The title compound was prepared from 2-amino-7-(2-bromo-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 2/h stage 2), following the procedure describing the synthesis of 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 4/a stage 1) using 2-pyridyl boronic acid instead of 3-pyridyl boronic acid.