Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:7][O:8][P:9](=[O:12])([OH:11])[OH:10].[OH-].[Na+].C(=O)(O)[O-].[Na+].O=C1CCC(=O)N1[O:42][C:43](=O)[CH:44]([NH:58][C:59]([O:61][CH3:62])=[O:60])[CH:45]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CC(C)=O>[CH3:62][O:61][C:59](=[O:60])[NH:58][CH:44]([C:43](=[O:42])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:7][O:8][P:9]([OH:10])([OH:11])=[O:12])[CH:45]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)NC(C(=O)ON1C(=O)CCC1=O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)CN(C(CCCCN)COP(=O)(O)O)S(=O)(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC(=O)NC(C(=O)NCCCCC(COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 66 %

Procedure:
57 mL (or approximately 26 mmol) of the aqueous solution of phosphoric acid mono-{6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl}ester (XIX) was neutralized with 40 mL of 1N sodium hydroxide. The pH of the solution (pH˜4-5) was then adjusted to pH=8 by adding 150 mL solution of saturated of sodium bicarbonate. To this well stirred solution was added a freshly prepared solution, in 130 mL of acetone, of methoxycarbonylamino-3,3-diphenyl-propionic acid 2,5-dioxo-pyrrolidin-1-yl ester (13.34 g, 34 mmol) prepared according to Anderson et al J. Am. Chem. Soc. 1964, 1839. The resulting clear solution was stirred for 12 h. The reaction mixture was concentrated and the remaining aqueous phase extracted twice with ethyl acetate. The aqueous phase was then acidified with 1N hydrochloric acid and the resulting suspension extracted with ethyl acetate. The organic phase was washed with water then dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The solid residue was again suspended in ethyl acetate and acidified with HCl (g). The resulting beige precipitate was collected by filtration to give 12.5 g (66%) of the title product. Purity was determined by LC_MS and is greater than 97%.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[C:26]([F:29])[C:27]=1[F:28])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([NH2:24])=[N:20]1>>[F:29][C:26]1[CH:25]=[C:17]([CH:16]=[C:15]([F:14])[C:27]=1[F:28])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([NH:24][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:8][CH2:9]2)=[N:20]1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1ccn(Cc2cc(F)c(F)c(F)c2)n1
Product: Cc1nsc(N2CCC(Nc3ccn(Cc4cc(F)c(F)c(F)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3,4,5-trifluoro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a colorless oil (yield=42%).
Reaction SMILES: CS(O[CH2:6][C@H:7]([CH3:15])[CH2:8][CH2:9]OS(C)(=O)=O)(=O)=O.[NH2:16][CH2:17][CH2:18][OH:19].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C(#N)C.O>[CH3:15][C@@H:7]1[CH2:8][CH2:9][N:16]([CH2:17][CH2:18][OH:19])[CH2:6]1
Reactant: C[C@H](CCOS(C)(=O)=O)COS(C)(=O)=O
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CCN(CCO)C1
Temperature: 25 °C
Yield: 28.2 %

Procedure:
A mixture of (R)-2-methylbutane-1,4-diyl dimethanesulfonate (30 g, 0.115 mol), 2-aminoethanol (7.0 g, 0.115 mol), and K2CO3 (31.7 g, 0.23 mol) in acetonitrile (0.9 L) was refluxed for 20 h. The mixture was cooled to room temperature and concentrated under vacuum to afford a residue (a mixture of oil and solid). DCM (300 mL) and sat'd K2CO3 solution (300 mL) were added and just enough water was added to dissolve all solid. The organic layer was separated, and aqueous phase was further extracted with DCM (2×300 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography [EA/Hex/MeOH/TEA=10:7:2:1] gave (R)-2-(3-methylpyrrolidin-1-yl)ethanol (4.19 g, 28%). 1H NMR (CDCl3): δ 3.61 (t, 2H), 2.84 (dd, 1H), 2.70 (m, 1H), 2.65 (m, 1H), 2.62 (m, 1H), 2.54 (m, 1H), 2.25 (m, 1H), 2.11 (dd, 1H), 2.03 (m, 1H), 1.36 (m, 1H), 1.03 (d, 3H); MS: 130.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]([OH:7])[CH3:14])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: C[Mg]Br
Reactant: COc1cc(C=O)cc(OC)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(C)O)cc(OC)c1Cl
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-3,5-dimethoxybenzaldehyde (1.0 g) in tetrahydrofuran (20 mL) was added dropwise a 3M solution of methylmagnesium bromide in diethyl ether (1.83 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Then, thereto was added aqueous ammonium chloride solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, and then dried over magnesium sulfate and concentrated under reduced pressure to give a crude product of 1-(4-chloro-3,5-dimethoxyphenyl)ethanol [REx(22-2)] (1.23 g) as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Cl)([O-:3])=[O:2].[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>O>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:19][CH2:15][CH2:16][CH2:17][CH3:18])([O-:3])=[O:2]
Reactant: CCCCN
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: O
Product: CCCCNc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]

Procedure:
0.05 mol (10.8 g) of 2,6-dinitro-4-methylchlorobenzene is added gradually, in the course of 10 minutes, whilst stirring, to 25 ml of butylamine, the reaction medium being cooled as necessary so as not to exceed 50° C. When the addition has ended, stirring is maintained for 5 minutes and the reaction medium is then poured into 100 ml of iced water. The expected product precipitates and is filtered off, washed with water and recrystallised from ethanol. After drying in vacuo, it melts at 52° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14]>C(OC)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)([C:12]2[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=2[F:10])[OH:14])=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C(c1ccc(F)cc1)c1ccccc1F
Solvent: COC(C)(C)C
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)c1ccccc1F
Temperature: 25 °C

Procedure:
p-Fluorophenylmagnesium bromide (124 mL, 0.12 mol) was added dropwise to a stirring solution of 2,4′-difluorobenzophenone (24.5 g, 0.11 mol) in t-butylmethyl ether (100 mL) at rt. After the addition was complete the reaction was heated at reflux for 3 h. The solution was then cooled to rt and was poured in to ice cold 1.0 M HCl (aq) (100 mL). The organics were extracted with EtOAc (3×70 mL) and dried (Na2SO4). Concentration under reduced pressure gave the desired product bis(4-fluorophenyl)-2-fluorophenylmethanol as a pale yellow oil which was used in the next reaction without any further purification.
Reaction SMILES: [CH2:1](Cl)[C:2](=[CH2:4])[CH3:3].[CH2:6]([NH:13][CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:6]([N:13]([CH2:3][C:2]([CH3:4])=[CH2:1])[CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=C(C)CCl
Reactant: OCCNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=C(C)CN(CCO)Cc1ccccc1
Temperature: 62 °C
Yield: 96.2 %

Procedure:
Add methallyl chloride (68.8 g, 0.760 mol, Aldrich) to a mixture of N-benzylethanolamine (100 g, 0.663 mol) and potassium carbonate (139 g, 1.00 mol) in water (600 mL). Heat the mixture to 62° C. for 23 h and then transfer to a separatory funnel. Extract the product with tert-butyl methyl ether (500 mL). Dry, filter, and concentrate the organic solution to give the title compound (131 g, 96%) as a colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.20-7.33 (5H, m), 4.92 (1H, br s), 4.83 (1H, br s), 4.35 (1H, t), 3.53 (2H, s), 3.44-3.50 (2H, m), 2.94 (1H, s), 2.42 (2H, t), 1.69 (1H, s).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:10][CH3:11].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.O>C1COCC1>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][CH:10]([CH3:11])[C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:19][CH:18]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)CC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the LDA solution at -78° C., was added dropwise a solution of 5 mL (44 mmoles) of ethyl propionate in 20 mL of THF. Stirring was continued at —78° C. for 1 hour, after which a solution of 10 g (40 mmoles) of p-bromo benzylbromide in 25 mL of THF was added dropwise. Stirring was continued at −78° C. for 2 hours. Water was then added dropwise and the reaction was allowed to warm to room temperature.
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4]C.C[C:9]1([CH3:17])[O:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])O1>>[O:16]=[C:11]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:12][C:13]([O:14][CH2:9][CH3:17])=[O:15]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)CC(=O)OCC

Procedure:
The title compound was prepared in a manner analogous to Intermediate 123 from valeryl chloride and 2,2-dimethyl-1,3-dioxane-4,6-dione (both commercially available).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[Cl:6][C:7]1[C:12]2[C:13](=[O:24])[N:14]([CH3:23])[CH2:15][C:16]3[N:17]([CH:18]=[N:19][C:20]=3[CH:21]=O)[C:11]=2[CH:10]=[CH:9][CH:8]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1.CCCCCC>[Cl:6][C:7]1[C:12]2[C:13](=[O:24])[N:14]([CH3:23])[CH2:15][C:16]3[N:17]([CH:18]=[N:19][C:20]=3/[CH:21]=[CH:1]\[CH3:2])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Cl:6][C:7]1[C:12]2[C:13](=[O:24])[N:14]([CH3:23])[CH2:15][C:16]3[N:17]([CH:18]=[N:19][C:20]=3/[CH:21]=[CH:1]/[CH3:2])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: CN1Cc2c(C=O)ncn2-c2cccc(Cl)c2C1=O
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C/C=C/c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Product: C/C=C\c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reaction time: 0.33 h

Procedure:
15 g (40.4 mmol) of ethyltriphenylphosphonium bromide was placed in 60 ml of tetrahydrofuran and treated dropwise at -40° with 28 ml (45 mmol) of 1.6 molar butyllithium solution in n-hexane. The orange suspension obtained was stirred at -40° for a further 20 minutes and subsequently a solution of 10 g (36 mmol) of 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde in 250 ml of tetrahydrofuran was added dropwise thereto within 50 minutes at -40° to -50°. The mixture was stirred at room temperature for a further 2 hours and subsequently filtered. The filtrate was evaporated and chromatographed on silica gel while eluting with cyclohexane/ether/isopropanol (3:3:1). There was obtained 7-chloro-4,5-dihydro-5-methyl-3-[(Z)-propenyl]-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 169.5°-170.5° (from ethyl acetate/hexane) and 7-chloro-4,5-dihydro-5-methyl-3-[(E)-propenyl]-6H-imidazo[1,5-a][1,4] benzodiazepin-6-one of melting point 200°-201° (from acetonitrile).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[CH:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[O:53]1[CH2:58][CH2:57][CH:56]([CH2:59][CH:60]=[O:61])[CH2:55][CH2:54]1>O1CCCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([CH:60]([OH:61])[CH2:59][CH:56]3[CH2:57][CH2:58][O:53][CH2:54][CH2:55]3)[N:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[N:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CCC1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Nc1cnc2c(c1)cc(C(O)CC1CCOCC1)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 32.9 %

Procedure:
To a suspension of (1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-carbamic acid tert-butyl ester (prepared as in Example 107, 3.4 g, 9.1 mmol) in dry tetrahydrofuran (120 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (17.1 mL, 27.3 mmol) to a 0° C. solution of diisopropylamine (2.76 g, 27.3 mmol) in dry tetrahydrofuran (20 mL)] dropwise. The mixture was stirred at −78° C. for 5 min and then treated with (tetrahydro-pyran-4-yl)-acetaldehyde (2.91 g, 22.75 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 75% ethyl acetate/hexanes) afforded {1-benzenesulfonyl-2-[1-hydroxy-2-(tetrahydro-pyran-4-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (1.5 g, 33%) as a white solid: LC/MS m/e calcd for C25H31N3O6S [M+H]+ 502.61, observed 502.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.Cl.[OH-:11].[Na+].[CH3:13]S(C)=O>>[NH2:8][C:4]1[CH:5]=[CH:6][C:7]([CH:13]=[O:11])=[C:2]([Br:1])[C:3]=1[CH3:9]
Reactant: CS(C)=O
Reactant: [OH-]
Reactant: Cc1c(N)cccc1Br
Agent: Cl
Agent: [Na+]
Product: Cc1c(N)ccc(C=O)c1Br
Temperature: 90 °C
Yield: 31 %

Procedure:
To a solution of commercially available 3-bromo-2-methyl-phenylamine (1.86 g, 10 mmol) in DMSO (200 mL) was added concentrated HCl (10 mL), followed by CuCl2 (2.7 g, 20 mmol). The resulting suspension was heated to 90° C. for 6 h. After cooling to rt, the reaction mixture was poured into ice/water (600 mL) and adjusted to pH=8 by dropwise addition of 10% aqueous NaOH. The resulting greenish suspension was filtered through a pad of Celite®, and the filtrate extracted with ether (3×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica gel), eluting with 30-70% EtOAc/hexane to furnish the title compound (0.67 g, 31%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].[CH3:11][C:12](=O)[CH2:13][CH2:14][C:15](=O)[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([N:9]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:11])=[N:6][C:7]=1[CH3:8]
Reactant: CC(=O)CCC(C)=O
Reactant: Cc1nc(N)nc(Cl)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1nc(-n2c(C)ccc2C)nc(Cl)c1Br
Temperature: 25 °C
Yield: 15.3 %

Procedure:
A flask containing a mixture of 5-bromo-4-chloro-6-methylpyrimidin-2-amine (34.8 mmol), 2,5-hexanedione (6.15 mL, 52.2 mmol), and p-toluenesulfonic acid (330 mg, 1.74 mmol) in toluene (100 mL) was fitted with a Dean-stark apparatus and condenser and the mixture was heated to reflux. After refluxing overnight the solution was cooled to room temperature and concentrated. The residue was slurried in hexanes, filtered and the filtrate was concentrated. The precipitate was purified by flash chromatography eluting with hexanes/chloroform (0-50%) to afford the 5-bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine (1.60 g, 15%). The concentrated filtrate was purified by flash chromatography eluting with hexanes/chloroform (10-40%) to afford 5-bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine (5.22 g, 50%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=3)[CH:12]=[C:11]([CH2:25][OH:26])[CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)=O)(O)=[O:28]>C(O)CO>[Cl:44][C:41]1[CH:40]=[CH:39][C:38]([C:36]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27](=[O:28])[N:1]([C:3]3[CH:8]=[C:7]([C:9]4[C:18]5[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=5)[CH:12]=[C:11]([CH2:25][OH:26])[CH:10]=4)[CH:6]=[CH:5][N:4]=3)[N:2]=2)=[CH:43][CH:42]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: CCOc1cc2cc(CO)cc(-c3ccnc(NN)c3)c2cc1OCC
Solvent: OCCO
Product: CCOc1cc2cc(CO)cc(-c3ccnc(-n4nc(-c5ccc(Cl)cc5)c5ccccc5c4=O)c3)c2cc1OCC
Yield: 85.3 %

Procedure:
1-(2-Hydrazino-4-pyridyl)-3-hydroxymethyl-6,7-diethoxynaphthalene (177 mg), 1-carboxy-2-(4-chlorophenylcarbonyl)benzene (137 mg) and ethylene glycol (1 ml) are treated in the same manner as in Example 104-(3) to give 1-[2-{4-(4-chlorophenyl)-1(2H)-phthalazinon-2-yl}-4-pyridyl]-3-hydroxymethyl-6,7-diethoxynaphthalene (247 mg), which is listed in Table 14.
Reaction SMILES: C([Mg]Cl)#C.[CH2:5]1[CH2:9][O:8][CH2:7][CH2:6]1.[O:10]1CC[C:13](=O)[CH2:12][CH2:11]1.[Cl-].[NH4+]>C(OCC)C>[C:12]([C:11]1([OH:10])[CH2:6][CH2:7][O:8][CH2:9][CH2:5]1)#[CH:13]
Reactant: O=C1CCOCC1
Reactant: C1CCOC1
Agent: C#C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C#CC1(O)CCOCC1

Procedure:
A solution of ethynylmagnesium chloride in THF (0.5 M, 120 mL, 60 mmol) was added with cooling in an ice—water bath to a solution of tetrahydro-4H-pyran-4-one (4.96 g, 50 mmol) (Aldrich) in diethyl ether (300 mL) dropwise over 15 min. The mixture was stirred with cooling for 3 h. Aqueous ammonium chloride solution (100 mL, 15% W/V) was then added and mixture extracted with ether (2×200 mL). The ether layers were washed with saturated aqueous sodium chloride solution (200 mL), then combined, dried (MgSO4), filtered and concentrated to give 4-Ethynyl-tetrahydro-pyran-4-ol as a colorless oil that solidified on standing. (Yield 6.01 g, 96.2%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]1[C:23]([CH3:24])=[N:22][S:21][N:20]=1>CN(C)C=O>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH:5][CH2:18][C:19]1[C:23]([CH3:24])=[N:22][S:21][N:20]=1)[CH3:2]
Reactant: CCc1cccc(C)c1N
Reactant: Cc1nsnc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(C)c1NCc1nsnc1C
Temperature: 100 °C
Yield: 73.7 %

Procedure:
A mixture of 68 g (0.652 mol) of 2-ethyl-6-methylaniline, 45 g (0.326 mol) of powdered potassium carbonate and 30 ml of dimethylformamide was heated to 100° C. and 63 g (0.326 mol) of 3-bromomethyl-4-methyl-1,2,5-thiadiazole were added dropwise, while stirring. The mixture was stirred at 100° C. for a further 5 hours, the inorganic precipitate was filtered off and the filtrate was distilled. 59.4 g (77.4% of theory) of 2-ethyl-6-methyl-N-(4-methyl-1,2,5-thiadiazol-3-yl-methyl)-aniline of boiling point 160°-163° C./0.3 mm Hg were obtained. ##STR18##
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:30])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N:20]3[CH2:25][CH:24]([CH2:26][CH3:27])[O:23][CH:22]([OH:28])[CH2:21]3)[C:11]=2[Cl:29])[CH:5]=[N:4]1)[CH3:2].[C:31](Cl)(=O)C>CO.ClCCl>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:30])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N:20]3[CH2:25][CH:24]([CH2:26][CH3:27])[O:23][CH:22]([O:28][CH3:31])[CH2:21]3)[C:11]=2[Cl:29])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCC1CN(c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(CC)c3O)c2Cl)CC(O)O1
Reactant: CC(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: CCC1CN(c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(CC)c3O)c2Cl)CC(OC)O1
Reaction time: 1 h

Procedure:
A solution of 1.08 g (2.35 mmol) of 1-ethyl-4-(2-chloro-3-(2-hydroxy-6-ethylmorpholin-4-yl)-4-methylsulfonylbenzoyl)-5-hydroxypyrazole in 5 mL of methanol was added with stirring to a solution of 20 mL of methanol pre-treated with 2 mL of acetyl chloride. After 1 hour, the mixture was diluted with dichloromethane and the resulting solution was washed with water and concentrated by evaporation under reduced pressure. The two component mixture residue obtained was separated and purified by preparative reverse-phase HPLC eluting with 1:1 acetonitrile/water containing 0.1 percent phosphoric acid. The fractions containing each of the two products were combined separately, concentrated by evaporation under reduced pressure and extracted with dichloromethane. The dichloromethane solutions were dried over sodium sulfate and concentrated by evaporation under reduced pressure to obtain the title compound as cis and trans isomers, both as syrups. There was 294 mg (27 percent of theory) of the more polar cis compound and 548 mg (49 percent of theory) of the less polar trans compound. These syrups were separately crystallized from ethanol to obtain the cis and trans isomers of the title compound as brown and off-white crystals, respectively.
Reaction SMILES: C1(N(Cl)[C:7](=[O:8])N(Cl)C(=O)N1Cl)=O.F[C:14]1C=[CH:18][C:17]([CH3:20])=[C:16]([N+]([O-])=O)[CH:15]=1.CC(O)=[O:26].OS(O)(=O)=O>>[CH3:20][C:17]1[CH:18]=[C:7]([OH:8])[C:14](=[CH:15][CH:16]=1)[OH:26]
Reactant: CC(=O)O
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: O=S(=O)(O)O
Product: Cc1ccc(O)c(O)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
TCCA (16.7 g, 72 mmol) was added to a solution of 4-fluoro-1-methyl-2-nitrobenzene (12.4 g, 80 mmol) in CH3CO2H/H2SO4 (80 mL/80 mL). The mixture was heated to 70° C. and stirred overnight. After cooling to room temperature, the reaction mixture was poured into ice water (1000 mL) and extracted with DCM (2×200 mL). The combined organic phase was washed with brine and concentrated in vacuo. The residue was purified by column chromatography (PE: EA=50:1) to give compound 1 (5.0 g, 33.1%) as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[N:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)[NH:21][C:22]3=[O:25])=[CH:17][CH:16]=2)[CH2:10]1>ClCCl>[OH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[NH:21][C:22]3=[O:25])=[CH:17][CH:16]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2-c2cc3ccc(N4CCCC(O)C4)cc3c(=O)[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccccc2N2CCNCC2)cc2ccc(N3CCCC(O)C3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
Trifluoroacetic acid (0.2 ml) was added to a dichloromethane solution (0.3 ml) containing 11.5 mg (0.0227 mmol) of t-butyl 4-{2-[7-(3-hydroxypiperidin-1-yl)-1-oxo-1,2-dihydroisoquinolin-3-yl]phenyl}piperazin-1-carboxylate obtained in Example 101. The obtained mixture was stirred at a room temperature for 30 minutes. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was purified using BondElute NH2 (register trade mark; Varian; 1 g; dichloromethane:methanol=20:1), so as to obtain 8.9 mg (97%) of 7-(3-hydroxypiperidin-1-yl)-3-(2-piperazin-1-ylphenyl)-2H-isoquinolin-1-one in the form of a yellow solid.