Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1c(F)cc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2c(F)cc(Cl)cc2F)cc1
Temperature: 100 °C
Yield: 69.6 %

Procedure:
To a solution of 4-chloro-2,6-difluorophenol (5.0 g, 30.4 mmol), 4-fluorobenzaldehyde (3.1 mL, 28.9 mmol) in DMF (30 mL), was added K2CO3 (5.0 g, 36.2 mmol). The mixture was heated at 100° C. overnight. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated, purified by flash chromatography to afford the title compound (5.4 g, 20.10 mmol, 66.1% yield) as a colorless oil. LCMS: rt=3.52 min, [M+H+]=269
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([N:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:13])[CH3:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(C(C)=O)C(C)C>[C:33]1([CH2:32][CH2:31][N:7]2[CH2:8][CH2:9][C:4]([CH2:3][O:2][CH3:1])([N:10]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:13])[CH3:12])[CH2:5][CH2:6]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COCC1(N(OCc2ccccc2)C(C)=O)CCNCC1
Reactant: ClCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: COCC1(N(OCc2ccccc2)C(C)=O)CCN(CCc2ccccc2)CC1
Yield: 46.2 %

Procedure:
A mixture of 0.67 g of 4-methoxymethyl-4-(N-phenylmethoxyacetamido)piperidine, 0.1 g of sodium iodide, 2.4 g of sodium carbonate, 3.9 g of (2-chloroethyl)benzene and 75 ml of methyl isobutyl ketone is heated to and maintained at a reflux for four days. The reaction mixture is cooled and filtered. The filtrate is evaporated and the resulting oil is purified using a Waters Associates Prep LC/System 500 and a PrepPAK-500/SILICA column. The mobile phase is 5% methanol in ethyl acetate. The eluent is flash evaporated to give 0.42 g of 1-(2-phenylethyl)-4-methoxymethyl-4-(N-phenylmethoxyacetamido)piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[C:7](=[CH:20][NH:21][CH:22]=3)[CH:8]([O:18][CH3:19])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH3:25]C(C)([O-])C.[K+].CI>CN(C)C=O.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[C:7](=[CH:20][N:21]([CH3:25])[CH:22]=3)[CH:8]([O:18][CH3:19])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: COC1N=C(c2ccccc2Cl)c2cc(Cl)ccc2-c2c[nH]cc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC1N=C(c2ccccc2Cl)c2cc(Cl)ccc2-c2cn(C)cc21
Reaction time: 0.25 h

Procedure:
In one portion 1.0 g (2.8 mmol) of 8-chloro-6-(2-chlorophenyl)-4-methoxy-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.35 g (3.0 mmol) of potassium t-butoxide in 20 ml of dimethylformamide which was cooled to 0°. After stirring for 15 min, 0.3 ml (4.8 mmol) of methyl iodide was added. The mixture was stirred for 5 min, diluted with water and extracted with ether. The ether solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a pale yellow oil. Purification by column chromatography (silica gel, 25 g; 5% ether in methylene chloride, eluent) gave an off-white solid, mp 128°-130°. Recrystallization from a mixture of ether and petroleum ether gave off-white prisms, 128°-130°.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([NH2:19])[CH2:11][CH2:10]1.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>ClCCl>[CH3:20][N:21]([CH3:25])[C:22]([NH:19][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:8])[CH2:10][CH2:11]1)=[O:23]
Reactant: CN(C)C(=O)Cl
Reactant: NC1CCC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NC1CCC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
In 25 ml of dichloromethane containing 2.8 ml of triethyl amine, 2,32 g of 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine are added followed by 2.16 g of dimethylcarbamoyl chloride. The mixture is heated at reflux for 3 hours, cooled to room temperature, washed successively with 50 ml of H2O, 50 ml of 3N NaOH, 50 ml of 3N HCl and 50 ml of H2O. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is recrystallized from toluene to give the title compound, melting point 157° C. to 162° C.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH:5]1[CH2:10][CH2:9][C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)=O.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[C:44]3([CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[C:43](=[O:50])[NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[F:39].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:7][CH2:6][CH:5]([N:47]3[CH2:46][CH2:45][C:44]4([N:40]([C:35]5[CH:36]=[CH:37][C:38]([F:39])=[C:33]([Cl:32])[CH:34]=5)[CH2:41][NH:42][C:43]4=[O:50])[CH2:49][CH2:48]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: O=C1NCN(c2ccc(F)c(Cl)c2)C12CCNCC2
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCN(c2ccc(F)c(Cl)c2)C12CCN(C1CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC1)CC2
Reaction time: 5 h

Procedure:
A mixture of 10.6 g of 4,4-bis(p-fluorophenyl)cyclohexyl tosylate, 5.7 g of 1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (m.p. 194.5°-196.5° C), 3.3 g of potassium carbonate, 4 g of potassium iodide and 50 ml of dimethylformamide is stirred at 75°-80° C for 5 hours. The reaction mixture is poured into water, and the precipitated crystals are collected by filtration, dried in a desiccator and dissolved in a mixture of chloroform and methanol (9:1). The solution is concentrated to some degree and cooled. The precipitated crystals are collected by filtration and purified in the same manner to give 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one as white crystals, melting at 201°-203° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[C:9]#N)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:14].[CH2:18]([OH:20])[CH3:19]>O>[CH2:18]([O:20][C:9](=[O:14])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:12])[CH3:11])[CH3:19]
Reactant: CC(C)(C#N)c1cccc(Br)c1
Reactant: O=S(=O)(O)O
Reactant: CCO
Solvent: O
Product: CCOC(=O)C(C)(C)c1cccc(Br)c1
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of 2-(3-bromo-phenyl)-2-methyl-propionitrile (prepared as described by Barlaam et al. J. Med. Chem., 1999, 42, 23, 4890-4908 incorporated herein by reference; 1.4 g, 6.24 mmol) was dissolved in ethanol (40 mL), treated with concentrated sulfuric acid (1 mL) and the resulting reaction mixture was refluxed for 36 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title product as an orange oil (0.77 g, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[H][H].[NH3:21]>[Ni]>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH2:21])[CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc(C(C)=O)cc2)cc1
Reactant: [H][H]
Reactant: N
Agent: [Ni]
Product: COc1ccc(Oc2ccc(C(C)N)cc2)cc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
78 mg (0.32 mmol) of 1-[4-(4-methoxy-phenoxy)-phenyl]-ethanone were dissolved in 10 ml of 7M methanolic ammonia and combined with 50 mg of Raney nickel. The mixture was shaken for 6 h at 50° C. and 3 bar hydrogen pressure. Raney nickel was added twice more and hydrogenation was continued for 2 h and 6 h under the same conditions. The catalyst was removed by suction filtering and the residue was evaporated down.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])=[O:11])[CH:7]=[CH:6][CH:5]=1.C[C:14]([OH:16])=[O:15].[C:17]1(C)C=CC=C[CH:18]=1>>[CH3:3][C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][CH:5]=1)[C:10]([CH2:12][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11]
Reactant: CC(=O)c1cccc(C)c1
Reactant: CC(=O)O
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
To a vigorously stirred suspension of NaH (564 mg, 48.5 mmol) and CO(OEt)2 (5.73 g, 48.5 mmol) in anhydrous toluene (50 ml) was added dropwise a solution of 3-methylacetophenone (4.33 g, 32.3 mmole) in toluene under reflux. The mixture was allowed to reflux and was stirred for 30 min after the addition was complete. When cooled to room temperature, the mixture was acidified with glacial AcOH. After ice-cold water was added, the mixture was extracted with toluene. The organic layer was dried over MgSO4, and evaporated. The residue was further chromatographed over silica gel by elution with CH2Cl2-n-haxane (3:2) to afford I-10-b as light-yellow liquid (3.13 g, 46.9%)
Reaction SMILES: O[C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](OC)[C:3]=1[C:12](=[O:22])[CH2:13][C:14](C1C=CN=CC=1)=[O:15].C(O)(=O)C.[ClH:27].C([O-])(O)=O.[Na+]>O>[ClH:27].[O:15]1[C:4]2[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=2)[C:12](=[O:22])[CH:13]=[CH:14]1
Reactant: COc1cc(O)c(C(=O)CC(=O)c2ccncc2)c(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccoc2ccccc12
Temperature: 100 °C
Yield: 13 %

Procedure:
To a solution of isonicotinic acid-2-acetyl-3,5-dimethoxyphenyl ester (2.72 g, 9.03 mmol) in anhydrous THF (50 mL) was added potassium tert-butoxide (1.21 g, 10.8 mmol) in small portions. The reaction mixture was stirred at room temperature for 24 hours. A sat. NH4Cl solution (20 mL) was added. The organic layer was separated and aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phase were washed with water, brine and dried over anhydrous Na2SO4. Removal of solvent gave 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-pyridin-4-yl-propane-1,3-dione (2.4 g, 88%). To a mixture of 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-pyridin-4-yl-propane-1,3-dione (2.4 g, 7.96° mmol) acetic acid (10 mL) and conc. HCl (1 mL) was heated at 100° C. for 1 hours. The reaction mixture was cooled to room temperature, diluted with water, neutralized with a sat. aqueous NaHCO3 solution. The solid was filtered off and dissolved in CH2Cl2 (120 mL) and hydrogen chloride in ether (5 mL, 2.0M solution) was added. The formed solid was isolated by filtration, washed with 10% methanol in ether and ether to give 5,7-dimethoxy-2-(pyridin-4-yl))-4H-chromen-4-one hydrochloride (0.335 g, 13%) as a yellow solid; MS (ES) m/z: 283.94 (M); MP 234-235° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.[C:11](Cl)(Cl)=[O:12].Cl.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[C:27]([C:29]3[CH:38]=[C:37]4[C:32]([CH2:33][CH2:34][NH:35][CH2:36]4)=[CH:31][CH:30]=3)[N:26]=[C:25]([NH2:39])[N:24]=2)[CH2:19][CH2:18]1>>[NH2:39][C:25]1[N:26]=[C:27]([C:29]2[CH:38]=[C:37]3[C:32]([CH2:33][CH2:34][N:35]([C:11]([NH:8][C:5]4[S:6][CH:7]=[C:3]([C:2]([F:10])([F:9])[F:1])[N:4]=4)=[O:12])[CH2:36]3)=[CH:31][CH:30]=2)[CH:28]=[C:23]([N:20]2[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]2)[N:24]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: O=C(Cl)Cl
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3nc(C(F)(F)F)cs3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 4-(trifluoromethyl)-1,3-thiazol-2-amine (Oakwood, Cat. #009875), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=519.2.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][C@:6]1([CH3:28])[C:10](=[O:11])[O:9][C@@H](C2C=CC=CC=2)[N:7]1C(OCC1C=CC=CC=1)=O.C[Si](C)(C)[O-].[K+].CO>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][C@:6]([CH3:28])([C:10]([OH:11])=[O:9])[NH2:7]
Reactant: C[C@@]1(Cc2cccc(I)c2)C(=O)O[C@@H](c2ccccc2)N1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@](N)(Cc1cccc(I)c1)C(=O)O
Temperature: 75 °C
Yield: 107 %

Procedure:
A mixture of benzyl (2S,4R)-4-(3-iodobenzyl)-4-methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate (1.47 g) and potassium trimethylsilanolate (1.2 g) was suspended in THF (50 ml) and heated to 75° C. for 2.5 h. MeOH (10 ml) was added and the solvents were removed under reduced pressure. The residue was dissolved in MeOH and applied to two 10 g SCX-2 cartridges eluting with MeOH and then with 0.2M ammonia in MeOH. The ammoniacal solutions were evaporated to dryness to give the title compound (910 mg) LCMS RT=1.93 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=O)[C:4]=12)=[O:7].C([NH2:16])=O>O>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([NH:16][C:9](=[O:8])[C:4]=12)=[O:7]
Reactant: NC=O
Reactant: COc1cccc2c1C(=O)OC2=O
Solvent: O
Product: COc1cccc2c1C(=O)NC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
A mixture of 3-methoxyphthalic anhydride (24.0 g, 134.8 mmol) and formamide (120 ml) was stirred and held at 210° C. for 5 hours and was then allowed to cool to room temperature overnight. Water (100 ml) was added and the solid material filtered off under reduced pressure. The crude product was washed sequentially with 50% aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford 3-methoxyphthalimide (8.95 g, 37%) as an off-white solid. 1H NMR (DMSO-d6) 11.08 (1H, br s), 7.78 (1H, dd), 7.45 (1H, d), 7.36 (1H, d), 3.93 (3H, s). MS: [M+H]+ 178.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[N:29]12[CH2:37][CH2:36][CH:33]([CH2:34][CH2:35]1)[NH:32][CH2:31][CH2:30]2>C(#N)C>[N:29]12[CH2:37][CH2:36][CH:33]([CH2:34][CH2:35]1)[N:32]([C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[O:8])[CH2:31][CH2:30]2
Reactant: CC(C)NC(=O)CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CN2CCC(CC2)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NC(=O)CNC(=O)c1cc(N2CCN3CCC2CC3)ccc1[N+](=O)[O-]
Temperature: 96 °C
Yield: 69 %

Procedure:
To a solution of 5-fluoro-N-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide (Intermediate 2A) (7.39 g, 26.1 mmol) in acetonitrile (240 mL) was added potassium carbonate (14.6 g, 104 mmol) followed by 1,4-diazabicyclo[3.2.2]nonane dihydrochloride (5.45 g, 27.4 mmol). The resulting suspension was heated to reflux at 96° C. overnight. The reaction mixture was filtered and concentrated. Sample was diluted in methanol (100 mL) and split between two 20 g SCX cartridges. Purification by SCX and evaporation to dryness afforded 5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide (7.0 g, 18.0 mmol).
Reaction SMILES: [C:1]1(=[O:14])[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:15]>>[Br:15][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:13])=[O:14]
Reactant: O=C1CCCCCCCCCCCO1
Reactant: Br
Product: O=C(O)CCCCCCCCCCCBr
Reaction time: 16 h
Yield: 86 %

Procedure:
11.9 g (60.0 mmol) of 12-dodecanolide and 24.3 g (96.0 mmol, 1.6 equivalents) of a 32% (hydrogen bromide)/(acetic acid) solution were introduced into a 100-mL autoclave protected with Teflon (registered trademark), and the autoclave was purged with nitrogen and then sealed. The content in the autoclave was stirred with a magnetic stirrer for 16 hours by using an oil bath at 60° C. After cooling the mixture, 14 mL of water was added thereto, and the mixture was transferred into a separatory funnel by using 200 mL of hot hexane. The mixture was washed with ion-exchanged water, dried over magnesium sulfate, filtered, and crystallized from n-hexane. Thus, 14.4 g (yield: 86%) of 12-bromododecanoic acid was obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[CH:6]=1)([CH3:3])[CH3:2].[CH2:18](O)[CH2:19][OH:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]2([CH3:15])[O:20][CH2:19][CH2:18][O:16]2)=[C:7]([CH3:17])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(OC(C)C)cc1C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(OC(C)C)c([N+](=O)[O-])cc1C1(C)OCCO1

Procedure:
A mixture of 1-(4-Isopropoxy-2-methyl-5-nitro-phenyl)-ethanone (0.788 g, 3.32 mmol), ethyleneglycol (1.8 mL), and p-toluenesulfonic acid monohydrate (6.3 mg) in 60 mL of benzene is heated at reflux with a Dean-Stark trap for 18 hrs. The reaction mixture is diluted with 100 mL of ethyl acetate and successively washed with 100 mL each of aqueous saturated NaHCO3, H2O, and saturated brine. The organic phase is dried over anhydrous Na2SO4, filtered and concentrated in vacuo, affording 2-(4-Isopropoxy-2-methyl-5-nitro-phenyl)-2-methyl-[1,3]dioxolane as yellow crystals. MS (ES+): 282.2 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH:30]4[CH2:32][CH2:31]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[CH3:33][CH:34]1[NH:38][C:37](=[O:39])[CH2:36][CH2:35]1>>[CH:30]1([C:26]2[CH:27]=[C:28]([CH3:29])[C:23]([N:20]3[CH2:21][CH2:22][N:17]([C:15]([C:5]4[CH:4]=[CH:3][C:2]([N:38]5[C:37](=[O:39])[CH2:36][CH2:35][CH:34]5[CH3:33])=[CH:7][C:6]=4[N:8]4[CH2:12][CH2:11][N:10]([CH3:13])[C:9]4=[O:14])=[O:16])[CH2:18][CH2:19]3)=[N:24][CH:25]=2)[CH2:32][CH2:31]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)cc2N2CCN(C)C2=O)CC1
Reactant: CC1CCC(=O)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)CCC3C)cc2N2CCN(C)C2=O)CC1
Yield: 8.4 %

Procedure:
Using 1-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (84 mg) described in Preparation Example 242 and 5-methylpyrrolidin-2-one (27.4 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (8 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1C(O)=O.[OH:13][C:14]1C2C(=C(C)C(OC)=CC=2)[N:17]=[C:16]([C:27]2[S:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[N:31]=2)[CH:15]=1>>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[N:17]=[C:16]([C:27]1[S:28][CH:29]=[C:30]([CH:32]([CH3:33])[CH3:34])[N:31]=1)[CH:15]=[C:14]2[OH:13]
Reactant: COc1cccc(C(=O)O)c1F
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C
Product: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1F

Procedure:
The title compound was prepared from 2-fluoro-3-methoxybenzoic acid following the procedure (steps 1-5) reported for the preparation of 4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinoline (36): m/z=319 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]([OH:15])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH2:2][CH3:3].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][CH:26]([CH2:29][N:4]([CH:5]2[CH2:6][CH2:7][C:8]3[C:13](=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=3)[CH2:14]2)[CH2:1][CH2:2][CH3:3])[CH2:27][CH2:28]1)=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCCNC1CCc2ccc(O)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
To a solution of 7-propylamino-5,6,7,8-tetrahydro-naphthalen-2-ol (937 mg, 4.6 mmol) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.46 g, 6.9 mmol) in dichloroethane (40 mL) was added sodium triacetoxyborohydride (2.1 g, 10.12 mmol) in a single portion. The reaction was allowed to stir at room temperature for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc (75 mL) and 5% aq. KOH (75 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford 4-{[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (1.37 g).
Reaction SMILES: BrBr.[C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])C.S([O-])([O-])=[O:21].[Na+].[Na+].Cl>O.O1CCOCC1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([OH:5])=[O:21])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: O=S([O-])[O-]
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2)cc1
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A solution of 64.7 g (1.61 mol) of soda in 560 ml water is prepared at 0° C. 69.9 g (0.44 mol) of bromine then 260 ml of 1,4-dioxane are added successively. A yellow solution is obtained which is cooled down to 0° C. and which is added over 10 minutes, without exceeding 10° C., to a suspension of 28 g (0.12 mol) of 4'-acetyl-4-methoxybiphenyl in a mixture of 750 ml of 1,4-dioxane and 510 ml water. The reaction medium is agitated for 1 hour at approximately 20° C., a solution of 15.5 g of sodium sulphite in 160 ml water is added and taken to reflux for 10 minutes. 76 ml of concentrated hydrochloric acid is added and the reaction medium is left under agitation whilst being cooled down, for 1 hour. After drying, washing with water and drying at 50° C., 25.5 g of 4'-methoxy-4-biphenyl carboxylic acid is obtained in the form of a white powder (yield: 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(Br)c1
Yield: 39 %

Procedure:
The title compound was synthesized from methyl 4-(3-bromobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.099 g, 0.30 mmol, 1 equiv) and lithium hydroxide (0.124 g, 2.96 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to the title compound: 37 mg, 39% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.03-2.11 (m, 1H), 2.48-2.57 (m, 1H), 2.60-2.64 (m, 2H), 2.75 (dd, J1=7.32 Hz, J2=3.71 Hz, 2H), 3.21-3.28 (m, 1H), 6.31 (s, 1H), 7.14-7.20 (m, 2H), 7.32-7.35 (m, 2H); LCMS-MS (ESI−) 318.0 (M−H); HPLC (UV=98.99%), (ELSD=100%).