Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:28]([NH:30][CH2:31][C:32]([OH:42])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:33][CH2:34][CH3:35])=[O:29])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:17][N:16]=2)=[N:11][CH:10]=1.[CH3:43][N:44]([CH3:49])[CH2:45][C:46](O)=[O:47].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>CN1C(=O)CCC1>[CH3:43][N:44]([CH3:49])[CH2:45][C:46]([N:25]1[CH2:24][CH2:23][CH:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:12]3[S:13][C:9]([S:8][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([C:28]([NH:30][CH2:31][C:32]([OH:42])([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH2:33][CH2:34][CH3:35])=[O:29])[C:2]=4[F:1])=[CH:10][N:11]=3)=[N:16][CH:17]=2)[CH2:27][CH2:26]1)=[O:47]
Reactant: CN(C)CC(=O)O
Reactant: CCCC(O)(CNC(=O)c1nccc(Sc2cnc(Nc3ccc(NC4CCNCC4)cn3)s2)c1F)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: CCCC(O)(CNC(=O)c1nccc(Sc2cnc(Nc3ccc(NC4CCN(C(=O)CN(C)C)CC4)cn3)s2)c1F)c1ccccc1
Reaction time: 2 h

Procedure:
To a stirring suspension of 3-fluoro-N-(2-hydroxy-2-phenylpentyl)-4-(2-(5-(piperidin-4-ylamino)pyridin-2-ylamino)thiazol-5-ylthio)picolinamide (737 mg, 1.021 mmol), dimethylglycine (636 mg, 6.167 mmol), EDAC (590 mg, 3.078 mmol), HOBt (275 mg, 2.035 mmol) in NMP (10 mL) was added i-Pr2Net (1.8 ml, 10.3 mmol). After 2 h, the reaction was diluted with PrepLC solvent B (TFA):TFA (8 mL:2 mL), filtered into 14 prepLC vials, purified on PrepLC (YMC-Pack C18 30×100 mm, NH4Oac). The fractions containing the product were concentrated in SpeedVac overnight. The fractions were pooled together using MeOH and concentrated. The product was obtained (417 mg, 59%) as a solid, then converted to the HCl salt: 1H NMR (400 MHz, DMSO-d6) δ ppm: 11.52 (1H, s), 9.53 (1H, s), 8.23 (2H, t, J=5.81 Hz), 7.78 (1H, s), 7.72 (1H, s), 7.42 (2H, d, J=7.33 Hz), 7.29 (2H, t, J=7.58 Hz), 7.18 (2H, t, J=7.33 Hz), 7.03 (1H, t, J=5.31 Hz), 6.96 (1H, d, J=8.84 Hz), 4.29 (2H, m), 3.61 (3H, d, J=5.81 Hz), 3.15 (1H, m), 2.93 (1H, t, J=11.62 Hz), 2.75-2.82 (6H, m), 1.95 (3H, t, J=9.98 Hz), 1.65-1.78 (2H, m), 1.33 (2H, s), 1.17-1.26 (2H, m), 0.88 (1H, m), 0.74 (3H, t, J=7.20 Hz); LC/MS (M+H)+: 693. HPLC ret. time (Condition M): 1.40 min.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.C[Si](C)(C)Cl.[CH3:25][CH:26]([CH:28]([Cl:33])[O:29][C:30](Cl)=[O:31])[CH3:27]>ClCCl>[Cl:33][CH:28]([O:29][C:30]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:31])[CH:26]([CH3:27])[CH3:25]
Reactant: CC(C)C(Cl)OC(=O)Cl
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Reaction time: 0.33 h
Yield: 77.5 %

Procedure:
To a mixture containing gabapentin (1.71 g, 10 mmol) and triethylamine (3.06 mL, 22 mmol) in dichloromethane (150 mL) was added trimethylchlorosilane (1.4 mL, 11 mmol) and the resulting mixture was stirred until clear (about 20 min). A solution containing 1-chloro-2-methylpropylchloroformate (1.27 mL, 11 mmol) in dichloromethane (10 mL) was then added at 0° C. and stirred at room temperature for 60 min. The reaction mixture was washed with 10% citric acid (30 mL) and the organic layer separated. The aqueous layer was further extracted with ether (3×20 mL) and the combined organic phases were dried over MgSO4 and then concentrated in vacuo. Chromatography of the residue on silica gel, eluting with hexane:ethyl acetate (1:4) gave 2.37 g (77%) of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][N:6]=1)[CH2:2][CH:3]=C.[O:14]1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O.C(OCC)(=O)C>[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:5]([CH2:1][CH2:2][CH:3]=[O:14])=[N:6]1
Reactant: C1COCCO1
Reactant: C=CCCc1noc2ccccc12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=CCCc1noc2ccccc12
Reaction time: 1 h

Procedure:
Compound 26 (549 mg, 3.2 mmol), water (5 mL), 1,4-dioxane (15 mL) and osmium tetroxide (15 mg, 0.06 mmol) were stirred for 5 min. in a small flask. Sodium metaperiodate (1.56 g, 7.3 mmol) was added over 30 min. and the suspension was then stirred for 1 hour. Ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate and dichloromethane. The combined organic phases were dried over magnesium sulphate and evaporated to dryness to produce 784 mg of crude 27, which was used directly without further purification in the synthesis compound 28.
Reaction SMILES: Cl[C:2]1[C:3](=[O:27])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH3:24])=[CH:18][C:17]=2[O:25][CH3:26])([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2C=CC(OC)=C(Cl)C=2)(C2CCCC2)CC=1O.[Cl:53][C:54]1[CH:64]=[CH:63][C:57]2[N:58]([CH3:62])[C:59]([SH:61])=[N:60][C:56]=2[CH:55]=1.ClC1C=CC2N(C(C)C)C(S)=NC=2C=1>>[Cl:22][C:20]1[C:19]([O:23][CH3:24])=[CH:18][C:17]([O:25][CH3:26])=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:27])[C:2]([S:61][C:59]3[N:58]([CH3:62])[C:57]4[CH:63]=[CH:64][C:54]([Cl:53])=[CH:55][C:56]=4[N:60]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=1
Reactant: Cn1c(S)nc2cc(Cl)ccc21
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Agent: CC(C)n1c(S)nc2cc(Cl)ccc21
Agent: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Sc3nc4cc(Cl)ccc4n3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example C(40), where 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one was substituted in place of 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one and 5-chloro-1-methyl-1H-benzimidazole-2-thiol was substituted in place of 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol. 1H NMR (300 MHz, DMSO-D6) δ: 1.37-1.71 (m, 8H), 2.07-2.19 (m, 2H), 2.35-2.42 (m, 1H), 2.57-2.72 (m, 3H), 2.83-2.88 (m, 1H), 3.71 (s, 3H), 3.75 (s, 3H), 3.86 (s, 3H), 6.71 (s, 1H), 7.01 (d, J=1.70 Hz, 1H), 7.13 (s, 1H), 7.16 (d, J=2.07 Hz, 1H), 7.45 (d, J=8.67 Hz, 1H). ESI-MS calcd for C28H30Cl2N2O5S: 576.1. Found (M+H+): 577.1. Anal. Calcd. For C28H30Cl2N2O5S.1.0H2O: C, 56.47; H, 5.42; N, 4.70; S, 5.38. Found: C, 56.86; H, 5.24; N, 5.05; S, 5.20.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([OH:11])(=O)[CH2:8][CH3:9].O1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCC)C>[CH:13]1[C:15]2[CH2:16][CH2:13][C:14]3[CH:16]=[CH:15][CH:14]=[CH:13][C:15]=3[CH:16]=[C:13]([CH2:9][CH2:8][CH2:7][OH:11])[C:14]=2[CH:16]=[CH:15][CH:14]=1
Reactant: C1CCOC1
Reactant: CCC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCCC1=Cc2ccccc2CCc2ccccc21
Yield: 100 %

Procedure:
To a solution of lithiumaluminum hydride (0.7 g, 18 mmol) in dry tetrahydrofuran (30 ml) the above propionic acid (2.6 g, 9.3 mmol) in dry diethyl ether (30 ml) was added. The reaction mixture was stirred at reflux temperature for 1.5 hour. The reaction was cooled on a ice bath and quenched by addition of water (0.7 ml), and 20% sodium hydroxide (0.7 ml), successively. The resulting mixture was filtered and the filtercake was washed with diethyl ether (2×100 ml). The phases were separated and the organic phase was evaporated in vacuo affording 2.6 g (100%) of 3-(11,12-dihydro-dibenz[a,e]cycloocten-5-yl)-1-propanol as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:14][C:13]2[C:8](=[N:9][C:10]([Cl:15])=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+].C(O)(=O)C>C(O)C.ClCCl>[Cl:15][C:10]1[N:9]=[C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:14][C:13]2=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2nc(Cl)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)c1cc2nc(Cl)ccc2[nH]1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester (Preparation 5, 151 mg, 0.67 mmol) in ethanol (10 mL) was added sodium hydroxide (0.35 mL, 2M) and the stirred solution was heated at 70° C. for 2 h. The reaction mixture was then allowed to cool to rt and left to stand for 16 h. The pH was adjusted to 4 by addition of glacial acetic acid, the solvents removed in vacuo to give a white solid, which was suspended in dichloromethane and filtered through a sinter, washing with additional dichloromethane. The filter cake was washed with ethyl acetate (3×30 mL) and dried to give the title compound as a white solid. δH (CD3OD): 6.97 (1H, s), 7.17 (1H, d, 8.35 Hz), 7.83 (1H, d, 8.35 Hz); m/z (ES+)=197 [M+H]+; RT=2.82 min.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>C(#N)CC>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:44][CH2:45][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:47][CH2:48]2)=[CH:39][CH:38]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CCC(c4ccc(Cl)cc4)CC3)cnc2N2CCCC[C@@H]12
Temperature: 90 °C
Reaction time: 16 h
Yield: 12.5 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.429 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (125.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (225 ul, 1.3 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)piperidine hydrochloride (109 mg, 0.472 mmol). The reaction was heated to 90° C. with stirring for 16 h. The crude reaction was cooled to room temperature and concentrated to a residue, then taken up in 3 mL DMSO and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (22.1 mg, 12.5%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.46 (s, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.29-7.37 (m, 2H), 7.21-7.28 (m, 2H), 6.96 (d, J=2.0 Hz, 1H), 4.42-4.58 (m, 1H), 3.83 (dd, J=11.4, 2.8 Hz, 1H), 3.32 (s, 2H), 2.80-2.95 (m, 2H), 2.54-2.66 (m, 1H), 1.92-2.08 (m, 3H), 1.83 (br. s., 1H), 1.66-1.77 (m, 2H), 1.33-1.66 (m, 6H). [M+H] calc'd for C, 23; H, 27; ClN, 4; O, , 411; found, 411.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Sn](C)(C)C>CN1CCCC1=O.C(OCC)(=O)C.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:19])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Cu]I
Agent: C[Sn](C)(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Lit. Tetrahedron Lett. 1999, 40, 2719-2722. To a stirred suspension of 1.58 mmol 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) in 3 ml N-methylpyrolidone were added 0.05 mmol tris(dibenzylideneacetone)dipalladium chloroform complex and 0.32 mmol triphenylphosphine and the mixture was stirred at 50° C. for 10 min. 0.16 mmol copper(I) iodide was then added and the mixture stirred at 50° C. for a further 10 min. Finally, 3.48 mmol tetramethyl tin was added and the reaction mixture was stirred at 80° C. for 16 h. The mixture was then cooled to room temperature, diluted with ethyl acetate and washed twice with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a yellow solid. MS (m/e): 214.1 ({37Cl}[M+H-Me2C═CH2]+, 35%), 212.0 ({35Cl}[M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([C:9]([O:11]CC)=O)[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[C:24]1(C)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.C1([Mg]Br)CCCCC1.O1CCCC1.[Cl-].[NH4+]>O1CCCC1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([CH:9]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[OH:11])[CH:3]=1
Reactant: CCOC(=O)c1cc(Br)sc1CC
Reactant: Cc1ccccc1
Agent: [Mn+4]
Agent: Br[Mg]C1CCCCC1
Agent: CC(C)C[Al+]CC(C)C
Solvent: C1CCOC1
Product: CCc1sc(Br)cc1C(O)C1CCCCC1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution (40 mL) of ethyl 5-bromo-2-ethylthiophene-3-carboxylate (3.69 g) synthesized in Example 69 (4) in tetrahydrofuran was added 1.5M diisobutylaluminum hydride-toluene solution (26.4 mL) at 0° C., and the mixture was stirred for 1 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a pale-yellow oil. To a solution of the obtained oil in tetrahydrofuran (30 mL) was added activated manganese dioxide (15.8 g), and the mixture was stirred at room temperature overnight and at 50° C. for 2 hr. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure to give a brown oil. To a solution of the obtained oil in tetrahydrofuran (60 mL) was added dropwise 1.0M cyclohexylmagnesium bromide-tetrahydrofuran solution (39.6 mL) at −78° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio) to give the title compound (2.53 g, 60%) as a yellow oil.
Reaction SMILES: [H-].[Na+].F[C:4]1[C:28]([F:29])=[CH:27][C:26]([I:30])=[CH:25][C:5]=1[C:6]([C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9][NH:10][N:11]([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7]>CN(C)C=O.[Cl-].[Na+].O>[C:15]([O:14][C:12]([N:11]([CH3:19])[N:10]1[C:4]2[C:5](=[CH:25][C:26]([I:30])=[CH:27][C:28]=2[F:29])[C:6](=[O:7])[C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C(=CNN(C)C(=O)OC(C)(C)C)C(=O)c1cc(I)cc(F)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N(C)C(=O)OC(C)(C)C)c2c(F)cc(I)cc2c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Sodium hydride (0.256 g, 60% oil dispersion) is added to a solution of tert-butyl 2-(2-(2,3-difluoro-5-iodobenzoyl)-3-ethoxy-3-oxoprop-1-enyl)-1-methylhydrazinecarboxylate (Preparation 33, 3.20 g) in N,N-dimethylformamide (18 mL) at room temperature, and the mixture is stirred for 2 h. The reaction mixture is poured into a mixture of 100 mL of ice water and 100 mL of saturated brine. The mixture is extracted 3 times with ethyl acetate. The combined organic layers are dried (Na2SO4) and concentrated under a nitrogen stream overnight. The crude product is purified by chromatography, using 200 g of silica gel packed and eluted with acetone/CH2Cl2/heptane (1/3/6), provided 2.76 g (90%) of the title compound as a white foam. Physical characteristics: 1H NMR (CDCl3) δ8.50, 8.31, 7.67, 4.32, 3.37, 1.49, 1.34, 1.25; 13C NMR (CDCl3) δ168.87, 163.97, 160.01, 155.50, 141.76, 131.84, 131.37, 128.46, 127.24, 110.98, 86.73, 78.64, 61.47, 36.09, 28.00, 14.64; MS (ESI+) m/z 491 (M+H)+; TLC (silica gel GF): Rf=0.44 acetone/CH2Cl2/hexane (1/1/3).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([N:12]([CH2:24][CH3:25])[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=1)=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:30]>ClCCl>[CH2:1]([O:8][CH2:9][C:10]1[N:12]([CH2:24][CH3:25])[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=2)[N:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC(=O)c1ccc(F)c(C)c1)C(=O)COCc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCn1cc(-c2ccc(F)c(C)c2)nc1COCc1ccccc1
Yield: 74.8 %

Procedure:
5.8 g 2-benzyloxy-N-ethyl-N-[2-(4-fluoro-3-methyl-phenyl)-2-oxo-ethyl]-acetamide and 4 g ammonium acetate was melted at 200° C. for 30 min Dichlormethane was added and the mixture was washed with aqueous potassiumhydrogen carbonate solution. The organic layer was evaporated. The residue was purified by chromatographie on silica gel (cyclohexane/ethyl acetate 4:1) to yield 4.1 g of the desired product. Rt: 0.74 min (method J), (M+H)+: 325
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][C:8]([CH:11]([OH:13])[CH3:12])=[CH:9][N:10]=1.Cl.C(=O)([O-])O.[Na+]>CC(C)=O>[OH:13][CH:11]([C:8]1[S:7][C:6]([CH:2]=[O:1])=[N:10][CH:9]=1)[CH3:12]
Reactant: CC(O)c1cnc(C2OCCO2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(O)c1cnc(C=O)s1
Yield: 39.2 %

Procedure:
A mixture of 1-[2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl]ethanol (1.96 g), 1M hydrochloric acid (8 mL) and acetone (20 mL) was stirred with heating under reflux for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (0.60 g, yield 39%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 158 (MH+).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([Br:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:20][C:21]([OH:40])([CH2:26][C:27]([C:30]2[C:38]3[O:37][CH2:36][CH2:35][C:34]=3[CH:33]=[C:32]([Cl:39])[CH:31]=2)([CH3:29])[CH3:28])[C:22]([F:25])([F:24])[F:23])(=O)=O)C=CC=CC=1>CO.[OH-].[Na+].[Cl-].[Na+].O>[Br:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][C:11]([CH2:20][C:21]([OH:40])([CH2:26][C:27]([C:30]1[C:38]3[O:37][CH2:36][CH2:35][C:34]=3[CH:33]=[C:32]([Cl:39])[CH:31]=1)([CH3:29])[CH3:28])[C:22]([F:25])([F:23])[F:24])=[CH:12]2
Reactant: CC(C)(CC(O)(Cc1cc2cc(Br)ccc2n1S(=O)(=O)c1ccccc1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CC(O)(Cc1cc2cc(Br)ccc2[nH]1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Reaction time: 18 h
Yield: 63.1 %

Procedure:
A mixture of 2-(1-benzenesulfonyl-5-bromo-1H-indol-2-ylmethyl)-4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-ol (30 mg, 0.046 mmol) in 5 mL of methanol and 5 mL of 10% aqueous sodium hydroxide solution was warmed at reflux. After 18 hours, the mixture was diluted with brine and extracted with three 7 mL portions of ethyl acetate. The combined organic layers were washed with three 5 mL portions of brine, three 5 mL portions of saturated aqueous ammonium chloride solution, 5 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative TLC (1 mm, silica gel, ethyl acetate-hexanes (3:7)) to afford 15 mg (63% yield) of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[N:22]([CH2:25][CH3:26])[CH:21]=[C:20]([CH3:27])[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[CH2:25]([N:22]1[CH:21]=[C:20]([CH3:27])[C:18]2[N:19]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:15]=[CH:16][C:17]=2[C:23]1=[O:24])[CH3:26]
Reactant: [H][H]
Reactant: CCn1cc(C)c2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCn1cc(C)c2nc(N3CCNCC3)ncc2c1=O
Yield: 88.2 %

Procedure:
Added to 300 mg (0.83 mmol) of the 2-(4-benzylpiperazino)-6-ethyl-8-methylpyrido[4,3-d]pyrimidine-5(6H)-one obtained in Referential Example 11 were 6 ml of ethanol, 2 ml of acetic acid and 30 mg of 10% Pd-C. The resultant mixture was stirred at 45° C. for 3.5 hours in a hydrogen atmosphere. The Pd-C was removed from the reaction mixture, followed by concentration under reduced pressure. The concentrate was added with 20 ml of water, to which potassium carbonate was added until no foams were developed. The resultant mixture was extracted three times with 50 ml of chloroform. The chloroform layer was dried with sodium sulfate and then concentrated under reduced pressure, thereby obtaining 200 mg of 6-ethyl-8-methyl-2-piperazinopyrido[4,3-d]pyrimidine-5(6H)-one as colorless crystals (yield: 88%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([NH:28][C:29](=[O:37])[CH2:30][CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:20]([Cl:38])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:38][C:20]1[CH:19]=[C:18]([N:8]2[CH2:9][CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7]2)[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]=1[NH:28][C:29](=[O:37])[CH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(CCC1CCCC1)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Reactant: c1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CCC1CCCC1)Nc1c(Cl)cc(N2CCc3ccccc3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (150 mg, 1.34 mmol), 1,2,3,4-tetrahydroisoquinoline (107 mg, 0.8 mmol), and N-(4-bromo-2-chloro-6-trifluoromethyl phenyl)-3-cyclopentyl propionamide (200 mg, 0.5 mmol) were then added, and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:ethanol 5%) to afford the title compound as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11].[Cl:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([S:19]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]#[N:1])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: N#CCCCCCCCCN
Product: N#CCCCCCCCCNS(=O)(=O)c1cccc(Cl)c1
Yield: 5.1 %

Procedure:
9-Aminononanenitrile (4.0 g, 0.26 mol) was treated with 3-chlorobenzene sulphonyl chloride (5.5 g, 0.26 mol) by the method described in Example 6(i) to give the title compound (4.4 g, m.p. 42°-3° C.).