Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].BrCC.[OH:5][C:6]1[CH:23]=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([O:24][CH3:25])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]=2[CH:7]=1.CN(C)P(=O)(N(C)C)N(C)C.[CH2:37]=[O:38].Cl>C1COCC1.C1C=CC=CC=1>[OH:5][C:6]1[C:23]([CH:37]=[O:38])=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([O:24][CH3:25])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]=2[CH:7]=1
Reactant: C=O
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Agent: Cl
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCBr
Product: CO[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)c(C=O)cc4[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a suspension of magnesium (0.110 g 4.5 mmol) in THF (1.0 mL) was added bromoethane (0.50 mL, 6.6 mmol) dissolved in THF (1.0 mL) at room temperature. 3-Hydroxy-17β-methoxyestra-1,3,5(10)-triene (41, 0.258 g, 0.90 mmol; synthesized by the method of Coombs et al., Steroids 6(6):841-844 (1965)), dissolved in THF (3.0 mL) was added to the reaction mixture, and stirring continued for 30 min. The solvent was removed at reduced pressure, and to the residue were added benzene (10 mL, hexamethylphosphoric triamide (0.40 mL, 2.1 mmol) and paraformaldehyde (0.370 g). Stirring was continued for 2 h at 80° C. After the reaction mixture was cooled to room temperature, 5N HCl (5.0 mL) was added and the mixture extracted with EtOAc. The combined organic layers were washed with H2O, then with saturated aqueous NaCl, and dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:AcOEt (10:1→8:1, v/v) to afford 0.221 g of 42 (78% yield), m.p. 120°-121° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([O:12]CC)=[O:11])[CH:5]=1.[Li+].[OH-]>CO>[CH3:1][O:2][CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([OH:12])=[O:11])[CH:5]=1
Reactant: CCOC(=O)c1cc(COC)n(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COCc1cc(C(=O)O)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 5-(methoxymethyl)-1-methyl-1H-pyrazole-3-carboxylate (WO9743277) (177 mg, 0.893 mmol) in MeOH, a 0.5 M solution of LiOH was added (5.3 mL, 2.68 mmol). The reaction was stirred at room temperature overnight. The solution was evaporated to dryness and the residue was adjusted to pH5 with a 2 N HCl solution. The aqueous solution was extracted with EtOAc and the organic layer was dried over Na2SO4 and evaporated in vacuo to give the title compound as a white solid 95%, 145 mg.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH:12]([CH3:16])[C:13](O)=[O:14])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.Cl.C([N:20]=C=NCCCN(C)C)C.CN(C=O)C>O>[NH2:20][C:13](=[O:14])[CH:12]([CH3:16])[O:11][C:3]1[C:2]([Br:1])=[CH:6][S:5][C:4]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)c1scc(Br)c1OC(C)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1scc(Br)c1OC(C)C(N)=O
Yield: 88.9 %

Procedure:
A solution of 2-{[4-bromo-2-(methoxycarbonyl)thiophen-3-yl]oxy}propanoic acid (220 mg), 1H-benzotriazol-1-ol 1 ammonium salt (162 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (205 mg) and DMF (4 mL) was stirred at room temperature for 1.5 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of Et2O and hexane to give the title compound (195 mg, 89%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]3[CH:40]=[CH:39][C:25]([C:26]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([C:34]([O:36]CC)=[O:35])[CH2:29]4)=[O:27])=[CH:24][CH:23]=3)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:10]([CH3:41])[CH:9]=2)=[N:6][CH:7]=1.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]3[CH:40]=[CH:39][C:25]([C:26]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([C:34]([OH:36])=[O:35])[CH2:29]4)=[O:27])=[CH:24][CH:23]=3)[CH2:15][CH2:16][C:17]([F:19])([F:18])[F:20])=[C:10]([CH3:41])[CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ncc(Cl)cn4)cc3C)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(-c2ncc(Cl)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To a reaction mixture of ethyl (3R)-1-(4-((1-(4-(5-chloropyrimidin-2-yl)-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoyl)piperidine-3-carboxylate (0.414 g), ethanol (1.4 mL) and tetrahydrofuran (1.4 mL) was added 1M aqueous sodium hydroxide solution (1.4 mL) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.348 g).
Reaction SMILES: Br[C:2]1[C:3]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2.[CH3:29][B-](F)(F)F.[K+].C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+].Cl>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:29][C:2]1[C:3]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=1)(=[O:12])=[O:13])[CH:6]=[CH:5]2
Reactant: C[B-](F)(F)F
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC(=O)OC(C)(C)C)c(Br)ccc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC(=O)OC(C)(C)C)c(C)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (5-bromo-1-tosyl-1H-indol-4-yl)carbamate (9.95 g, 21.38 mmol) in toluene (194 mL) was added potassium methyltrifluoroborate (13 g, 107 mmol) and PdCl2(dppf).CH2Cl2 adduct (1.75 g, 2.138 mmol) and Cs2CO3 (20.90 g, 64.1 mmol) and finally water (19.44 mL), and the mixture was stirred at 100° C. After stirring overnight the reaction was cooled to room temperature and 1N HCl (100 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc, washed with 1N HCl, dried over MgSO4, filtered and concentrated to provide the title compound, which was used in the next reaction without any further purification. MS (ESI−) m/z 399.2 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][N:15]([CH3:29])[C:16]([C:18]1[C:19]2[CH2:20][CH2:21][NH:22][CH:23]([CH3:28])[C:24]=2[CH:25]=[CH:26][CH:27]=1)=[O:17]>>[CH3:14][N:15]([CH3:29])[C:16]([C:18]1[C:19]2[CH2:20][CH2:21][N:22]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:23]([CH3:28])[C:24]=2[CH:25]=[CH:26][CH:27]=1)=[O:17]
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2c(C(=O)N(C)C)cccc21
Product: CC1c2cccc(C(=O)N(C)C)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid dimethylamide to provide the title compound in moderate yield.
Reaction SMILES: CS([O:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=3)[NH:18][C:17](=[O:38])[NH:16]2)=[CH:8][C:7]=1[O:39][CH2:40][CH3:41])(=O)=O.[OH-].[Na+].Cl.O>C(O)C>[CH2:40]([O:39][C:7]1[CH:8]=[C:9]([CH:15]2[NH:16][C:17](=[O:38])[NH:18][C:19]([C:27]3[CH:28]=[CH:29][C:30]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])=[CH:31][CH:32]=3)=[C:20]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[OH:5])[CH3:41]
Reactant: CCOc1cc(C2NC(=O)NC(c3ccc(NS(C)(=O)=O)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1OS(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(NS(C)(=O)=O)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 80 °C
Yield: 68.6 %

Procedure:
To a mixture of 2-ethoxy-4-(6-(4-(methylsulfonamido)phenyl)-2-oxo-5-phenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenyl methanesulfonate (60 mg, 0.10 mmol) in ethanol (2 mL) was added sodium hydroxide aqueous solution (2 mL, 1.25 mol/L) at 0° C. The mixture was heated at 80° C. for 5 h, cooled down to room temperature, adjusted to pH=5 with diluted hydrochloric acid, poured into water (20 mL), and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and evaporated. The residue was purified by preparative HPLC to give Compound 101 (36.0 mg, yield 68.9%). HNMR (DMSO-d6 300 MHz): δ 10.34 (s, 1H), 9.91 (s, 1H), 8.73 (s, 1H), 7.59 (s, 1H), 7.49 (s, 1H), 7.23 (d, J=9.0 Hz, 3H), 7.12-7.06 (m, 5H), 6.90 (d, J=6.9 Hz, 2H), 5.24 (d, J=2.7 Hz, 1H), 4.12-4.08 (m, 2H), 3.04 (s, 3H), 1.42-1.37 (m, 3H); MS (ESI): m/z 525.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C=O)C.C1COCC1>[Cl:21][C:6]1([C:5]2[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:12])[O:11]1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1OC(Cl)(c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
THF (25 mL) was added to 2-(4-fluorobenzoyl)benzoic acid (5 g, 20.4 mmol) followed by thionyl chloride (2.97 mL, 40.9 mmol) and a catalytic amount of DMF (3 drops). The system was stirred under nitrogen for 4 h at room temperature. Removal of the solvent gave 3-chloro-3-(4-fluorophenyl)-3H-isobenzofuran-1-one as a colourless oil (5.35 g, 20.4 mmol, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=O)[S:7][CH:8]=[C:4]2[CH2:3]1.[CH2:15](O)C>C(OCC)C.C1COCC1.C[Li].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:14][C:2]1([CH3:1])[CH2:13][CH2:12][C:5]2=[C:6]([C:9](=[O:11])[CH3:15])[S:7][CH:8]=[C:4]2[CH2:3]1
Reactant: CCO
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1scc2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (1051 mg, 5.0 mmol) in diethyl ether (15 mL) and THF (8 mL), methyllithium (7 mL of a 1.6 M solution in diethyl ether) is added. The mixture is stirred at rt for 15 min before the reaction is queched with ethanol. The mixture is diluted with 10% aq. citric acid and extracted with TBME. The organic extract is washed three times with sat. aq. NaHCO3, dried over Na2SO4 and evaporated to give crude 1-(5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (1.0 g) as a brownish oil; LC-MS: tR=1.03 min, [M+1]=209.07.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].N([O-])=O.[I-:19].[K+]>Cl.O>[I:19][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: [I-]
Reactant: COC(=O)c1cc(N)c(C)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cc(I)c(C)c([N+](=O)[O-])c1
Yield: 73.6 %

Procedure:
To a suspension of methyl 3-amino-4-methyl-5-nitrobenzoate (36.0 g) in 6-normal hydrochloric acid (276 mL) was added dropwise a solution nitrite (13.0 g) in water (35 mL) under ice-salt-cooling over 20 minutes, and the mixture was stirred under ice-cooling for 1 hour. Then, thereto was added dropwise a solution of potassium iodide (34.1 g) in water (280 mL) under ice-cooling over 20 minutes, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with chloroform. The organic layer was sequentially washed with aqueous saturated sodium thiosulfate solution and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=50/1) to give methyl 3-iodo-4-methyl-5-nitrobenzoate [REx(14-1)] (40.5 g) as a yellow powder.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][CH2:10][C@@H:11]3[C@@H:20]([C:21]=2[CH:22]=1)[C@H:19]([O:23]C(=O)C(C)(C)C)[CH2:18][C@@:16]1([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]1[O:30]C(=O)C(C)(C)C)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.Cl>CCOCC>[CH3:17][C@:16]12[CH2:18][C@@H:19]([OH:23])[C@H:20]3[C@@H:11]([CH2:10][CH2:9][C:8]4[CH:7]=[CH:6][C:5]([OH:4])=[CH:22][C:21]=43)[C@@H:12]1[CH2:13][CH2:14][C@@H:15]2[OH:30]
Reactant: CC(=O)Oc1ccc2c(c1)[C@@H]1[C@@H](CC2)[C@@H]2CC[C@H](OC(=O)C(C)(C)C)[C@@]2(C)C[C@H]1OC(=O)C(C)(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[C@]12C[C@@H](O)[C@@H]3c4cc(O)ccc4CC[C@H]3[C@@H]1CC[C@@H]2O
Yield: 91.3 %

Procedure:
A solution of the triester (28) (150 mg, 0.30 mmol) in dry ether (3 ml) was treated with lithium aluminium hydride (46 mg, 1.41 mmol) at room temperature. After 5 min ethyl acetate (1 ml) and then dilute hydrochloric acid (1 ml) was added, and the mixture was worked up with ether in the usual manner. Chromatography of the crude product on silica (2 g) eluted with ethyl acetate gave the product (6D) (79 mg, 91%), m.p. 229°-232° C. (from acetone), νmax (KBr disc) 3500 cm-1 (OH), δ (MeOH) (250 MHz) 7.41 (1 H, dd, J 2.5 and 1 Hz, 1-proton), 7.39 (1 H, d, J 8 Hz, 4-proton), 6.86 (1 H, ddd, J 8, 2.5, and 1 Hz, 3-proton), 4.11 (1 H, dt, J 10.5 and 5 Hz, 11-proton), 3.67 (1 H, t, J 8.5 Hz, 17-proton), 3.68 (2 H, t, J 9 Hz, 6-protons), 2.21 (1 H, A part of ABX system, JAX =5 Hz, JAX =12 Hz), 2.20-1.20 (13 H, m), 0.74 (3 H, s, 18-CH3),
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH2:5]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[C:24]2[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:19][CH:18]=1.[OH-].[Na+]>ClCCl>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[C:24]2[N:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH:4]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6](=[O:14])[CH2:5]3)[CH2:31][CH2:32]2)=[CH:19][CH:18]=1
Reactant: O=C1CC(CCCl)c2ccccc2N1
Reactant: COc1ccc2cccc(N3CCNCC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2cccc(N3CCN(CCC4CC(=O)Nc5ccccc54)CC3)c2c1
Temperature: 130 °C
Yield: 87.5 %

Procedure:
1.5 g (7.15 mmol) of (±)-4-(2-chloroethyl)-3,4-dihydro-2(1H)-quinolinone are mixed intimately with 3.65 g (15 mmol) of 1-(7-methoxy-1-naphthyl)piperazine and the mixture is heated to 130° C. for 1 h while stirring. The cooled residue is taken up between 25 ml of 2N sodium hydroxide and twice 50 ml of dichloromethane. The organic extract is washed with water, dried over magnesium sulphate and concentrated. The residue is purified by elution with a dichloromethane/methanol (95:5) mixture on a silica column. The purified fraction is crystallized in ether and this solid is drained and dried. 2.6 g (87.5%) of (±)-4-{2-[4-(7-methoxy-1-naphthyl)-1-piperazinyl]ethyl}-3,4-dihydro-2(1H)-quinolinone, melting point 177°-178° C., are obtained.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl>C(O)C>[CH2:11]([O:10][C:2]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:9])[CH3:12]
Reactant: ClCCOCCCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.2 %

Procedure:
Sodium (10 g) was dissolved in dry ethanol (300 cm3) and then diethyl malonate (30 g) was added slowly. After stirring for 15 minutes, bis(2-chloroethyl)ether (35 g) was added dropwise. The mixture was heated under reflux for 72 hours and then cooled to room temperature. After filtering the solvent was removed from the reaction mixture under reduced pressure to give the crude product. An initial purification was achieved by chromatography on alumina (activity 4) using ethyl acetate/petroleum ether mixtures as eluants. The pure product (11.3 g) was isolated by distillation under reduced pressure as an oil (b.p. 106°-108° C. at 0.03 mmHg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1)([O-:15])=[O:14].C(OC(=O)C)(=O)C.[H-].[Na+]>C(O)(=O)C.O>[N+:10]([C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[O:1][C:23](=[O:24])[C:22]([C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=1)=[CH:4]2)([O-:12])=[O:11]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=c1oc2ccc([N+](=O)[O-])cc2cc1-c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 70 %

Procedure:
2-Hydroxy-5-nitrobenzaldehyde (250 mg, 1.50 mmol) and p-nitrophenylacetic acid (271 mg, 1.50 mmol) were placed in a dry 25-mL round bottom flask. Acetic anhydride (2.8 mL, 30 mmol) was then added with stirring. To this suspension sodium hydride (60 mg, 1.50 mmol) was then added in small aliquots (60% oil suspension) and the reaction mixture was heated to 100° C. for 3 h. Then, 100 μL of water and 3 mL of acetic acid were added. The mixture was cooled to 4° C. for one hour and then filtered. The solid was rinsed with cold glacial acetic acid and placed in a 100-mL flask, to which was added 30 mL of toluene, which was then removed by rotary evaporation. This addition and removal of toluene was repeated two more times to remove the last traces of acetic acid. The resulting solid was then dried under vacuum to give a beige powder (11) in 70% yield (325 mg, 1.05 mmol). mp: 250° C. (dec). FTIR (KBr) (cm−1): 1620, 1480, 1750, 1540, 1350. 1H-NMR (DMSO-d6): δ (ppm) 8.80 (d, J=2.6 Hz, 1H), 8.62 (s, 1H), 8.47 (dd, J=9.1 Hz, J=2.7 Hz, 1H), 8.37 (dd, J=8.9 Hz, J=2.0 Hz, 1H), 8.02 (dd, J=8.9 Hz, J=2.0 Hz, 2H), 7.71 (d, J=9.1 Hz, 1H). 13C-NMR (DMSO-d6): δ (ppm) 159.43, 157.87, 148.46, 144.68, 142.30, 141.50, 130.85, 127.92, 125.77, 124.51, 120.53, 118.64. HRMS: expected, 312.038236; found, 312.039100. Elemental analysis for C15H8N2O6: expected: C, 57.70; H, 2.58; N, 8.97; found: C, 57.37; H, 2.62; N, 8.78.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][C:7]=1[CH3:15].[CH3:20][C:21]([S@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH:26][S@@:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])[CH3:13])=[CH:8][C:7]=1[CH3:15]
Reactant: CC(=O)c1cnc(Oc2ccc(F)c(F)c2)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1Oc1ccc(F)c(F)c1
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (2.03 g, white solid) from 1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanone (2.00 g, 7.60 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.38 g, 11.4 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])(O)[CH2:10][CH2:9]1)=O)(C)(C)C.S(=O)(=O)(O)O.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(F)c2F)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cccc(C2=CCNCC2)c1F
Yield: 53.6 %

Procedure:
To a solution of tert-butyl-4-(2,3-difluorophenyl)-4-hydroxypiperidine-1-carboxylate (7.48 g, 23.9 mmol) in toluene (50 ml) was added sulfuric acid (18 M, 1.33 ml, 23.9 mmol) and the mixture was refluxed under a Dean-Stark water separator. The mixture was poured on to ice and was basified with aqueous sodium hydroxide solution (15%). The mixture was extracted with ethylacetate (3×50 ml) and the combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash column chromatography (MeOH) to give the title compound (2.5 g). MS m/z (rel. intensity, 70 eV) 195 (M+, bp), 194 (42), 166 (30), 151 (33), 127 (35).
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([NH2:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][N:21]=[C:22]=[O:23]>C1(C)C=CC=CC=1>[CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([NH:11][C:22]([NH:21][CH3:20])=[O:23])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN=C=O
Reactant: NC(=O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Yield: 87.3 %

Procedure:
A solution of rac-2-cyclohexyloxy-2-(3,4-dichloro-phenyl)-acetamide (291 mg, 0.96 mmol) in toluene (10 mL) was treated with methyl isocyanate (0.09 mL, 1.44 mmol). The resulting solution was heated at reflux for 24 h and then the cooled reaction was concentrated in vacuo. The reaction product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) to give 1-[cyclohexyloxy-(3,4-dichloro-phenyl)-acetyl]-3-methyl-urea (301 mg, 87% yield) as a colorless oil: EI-HRMS m/e calcd for C16H20N2Cl2O3 (M+H)+359.0929, found 359.0922.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C[C:19]([N:21]([CH3:23])[CH3:22])=O>CN(C=O)C>[N+:15]([C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=1/[CH:1]=[CH:19]/[N:21]([CH3:23])[CH3:22])([O-:17])=[O:16]
Reactant: Cc1cc(C(F)(F)F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc(C(F)(F)F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A mixture of 1-methyl-2,4-dinitro-5-trifluoromethyl-benzene (2.0 g, 8.0 mmol) and DMA (1.0 g, 8.2 mmol) in DMF (20 mL) was stirred at 100° C. for 30 min. The mixture was poured into ice-water and stirred for 1 h. The precipitate was filtered and washed with water to give (E)-2-(2,4-dinitro-5-(trifluoromethyl)phenyl)-N,N-dimethylethenamine (2.1 g, 86%).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[S:22][CH:21]=[CH:20][C:19]=2[CH:23]=1.S1C2C=CC(CO)=CC=2C=C1.S(Cl)(Cl)=O>>[S:22]1[C:18]2[CH:17]=[CH:16][C:15]([CH2:14][O:8][C:7]3[C:2]([F:1])=[C:3]([C:10]([NH2:12])=[O:11])[C:4]([F:9])=[CH:5][CH:6]=3)=[CH:23][C:19]=2[CH:20]=[CH:21]1
Reactant: ClCc1ccc2sccc2c1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: OCc1ccc2sccc2c1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1c(F)ccc(OCc2ccc3sccc3c2)c1F
Yield: 10 %

Procedure:
Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. The required building block, 5-(chloromethyl)-1-benzothiophene, was synthesised by chlorination of commercially available 1-benzothiophen-5-ylmethanol with thionyl chloride. Yield 10%, mp 146-148° C., HPLC-MS (method 1): m/z 320 [M+H]+, Rt=3.95 min.