Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N+]([C:13]1[CH:14]=C(S([O-])(=O)=O)C=C[CH:18]=1)([O-])=O.[Na+].C(O)C(O)CO.S(=O)(=O)(O)O.[OH-].[Na+]>O.ClCCl.[Cl-].[Na+].O>[Br:1][C:2]1[C:3]([F:9])=[C:4]2[C:6]([CH:18]=[CH:13][CH:14]=[N:5]2)=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: Nc1cccc(Br)c1F
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: OCC(O)CO
Solvent: O
Solvent: ClCCl
Product: Fc1c(Br)ccc2cccnc12
Temperature: 150 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A 500 mL round bottom flask equipped with a stirbar and air-condenser was charged with 3-bromo-2-fluoroaniline (10.00 g, 52.6 mmol), sodium 3-nitrobenzenesulfonate (21.13 g, 94 mmol), and propane-1,2,3-triol (glycerol) (13.57 g, 147 mmol). The mixture was taken up in water (11.38 mL), carefully treated with conc. sulfuric acid (21.06 mL), and then heated to 150° C. with stirring for 2 h. The reaction was then cooled to room temperature and the flask fitted with an ice bath. The reaction mixture was carefully neutralized with 5N aq sodium hydroxide (˜180 mL). The mixture was then allowed to stir for 20 min, checked for neutral pH, and then diluted with dichloromethane (1000 mL). The entire mixture was transferred to a separatory funnel and the resulting emulsion was treated with ˜200 mL saturated brine and allowed to stand overnight to separate the layers. The organic layer was isolated and the aqueous layer was extracted with an additional quantity of dichloromethane (˜400 mL). The organics were then pooled, washed with 400 mL 1N aq sodium hydroxide solution, dried over sodium sulfate, filtered, and concentrated to a residue. The residue solidified under high vacuum to afford the title compound as a dark brown solid (9.16 g, 75% yield). MS(ES)+ m/e 225.9, 227.8 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:7][CH2:8][OH:9])=[N:4][O:5][CH:6]=1.CC(C)=[O:12].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.OS([O-])=O.[Na+].CCOC(C)=O>[CH3:1][C:2]1[C:3]([CH2:7][C:8]([OH:12])=[O:9])=[N:4][O:5][CH:6]=1
Reactant: Cc1conc1CCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: CCOC(C)=O
Product: Cc1conc1CC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a solution of 2-(4-methylisoxazol-3-yl)ethanol, Intermediate S7A, (7 mg, 0.055 mmol) in acetone (Volume: 0.5 mL) at room temperature was added 1.35M Jones reagent (0.082 mL, 0.110 mmol). The reaction mixture was stirred at room temperature for 5 h. The mixture was diluted with 2% NaHSO3 and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford 2-(4-methylisoxazol-3-yl)acetic acid, Intermediate S7B (6 mg, 0.043 mmol, 77% yield). 1H NMR (400 MHz, chloroform-d) δ 8.18 (s, 1H), 3.80 (s, 2H), 2.04 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][OH:19].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[CH:18]=[O:19]
Reactant: CCc1ccc(Cc2cc(Br)c(CO)cc2Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCc1ccc(Cc2cc(Br)c(C=O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution (−5° C.) of (2-bromo-5-chloro-4-(4-ethylbenzyl)phenyl)methanol (9.7 g, 29.4 mmol) in dry dichloromethane (100 mL), was added dropwise a solution of Dess-Martin reagent (18.7 g, 44 mmol) in 100 mL of dry dichloromethane. After it was stirred at room temperature for 2 h, TLC showed the reaction was complete. The reaction was quenched by addition of 10 mL of 1 M NaOH. The organic layer was washed 1× with NaHSO3, 2× with NaHCO3, 3× with brine, dried over anhydrous Na2SO4. Concentration under reduced pressure provided the pure product as a white solid. Yield: 9.3 g (96%). 1H NMR (CDCl3, 300 MHz) δ 10.24 (s, 1H), 7.91 (s, 1H), 7.40 (s, 1H), 7.18 (s, 1H), 7.15 (s, 1H), 7.11 (s, 1H), 7.09 (s, 1H), 4.08 (s, 2H), 4.02 (s, 2H), 2.63 (q, J=7.8 Hz, 2H), 1.23 (t, J=7.8 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11])([O-])=O>C(OCC)(=O)C.C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(O)cc1F
Yield: 980 %

Procedure:
A mixture of 4-nitro-3-fluorophenol (0.314 g, 2 mmol) and iron (0.56 g, 10 mmol) in ethyl acetate (4 ml) and acetic acid (2 ml) was refluxed for 3 hour. The solid particles were filtered off. The filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated to yield 4-amino-3-fluorophenol (53a) (0.25 g, 19.6 mmol, 98%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]#[C:13][CH2:14][O:15][CH3:16])[C:10]=1[CH3:11])[C:5]([OH:7])=O.C([N:20](CC)[CH:21]([CH3:23])[CH3:22])(C)C.C1(N)CC1.[NH4+].[Cl-].C(OC(C)C)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]#[C:13][CH2:14][O:15][CH3:16])[C:10]=1[CH3:11])[C:5]([NH:20][CH:21]1[CH2:23][CH2:22]1)=[O:7]
Reactant: COCC#Cc1cc(C(=O)O)cc(Br)c1C
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)C
Product: COCC#Cc1cc(C(=O)NC2CC2)cc(Br)c1C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To 3-bromo-5-(3-methoxy-prop-1-ynyl)-4-methyl-benzoic acid (0.38 M solution in THF) was added N,N-diisopropylethylamine (1.8 equiv.) and cyclopropylamine (1.35 equiv.) maintaining the internal temperature below 25° C. The mixture was cooled to 5° C. and 2-propanephosphoric acid anhydride (50 wt % in EtOAc, 1.5 equiv.) was added whilst maintaining the internal temperature below 25° C. The reaction mixture was aged for 1 h at ˜20° C. then cooled to 2° C. and 10 wt % aq. NH4Cl solution added, maintaining the internal temperature <30° C. Isopropyl acetate was added and the layers were allowed to settle. The lower aqueous layer removed. The organics were then washed with 1M HCl, followed by 10% NaHCO3 solution and finally 10% NaCl solution. The organic layer was concentrated to ˜1 M followed by the addition of toluene. The batch was then reconcentrated to ˜2 M and the resultant slurry aged for 18 h. Heptane was then added and the solids were filtered, washed with a mixture of 1:1 toluene/heptane and dried to give the title compound as an off-white solid. 1H NMR (500 MHz, Acetone-d6): δ 8.01 (s, 1 H), 7.92 (s, 1 H), 7.86 (s, 1 H), 4.37 (s, 2 H), 3.39 (s, 3 H), 2.95-2.89 (m, 1 H), 2.53 (s, 3 H), 0.76-0.67 (m, 2 H), 0.68-0.60 (m, 2 H). HRMS (ES, M+H) Calcd 322.0443. Found 322.0457.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:21]=[C:20]([CH3:22])[C:12]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])=[C:11]([CH3:23])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[OH-].[Na+].Cl>>[F:1][C:2]([F:24])([F:25])[C:3]([C:9]1[CH:21]=[C:20]([CH3:22])[C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:11]([CH3:23])[CH:10]=1)([OH:8])[C:4]([F:5])([F:7])[F:6]
Reactant: CCOC(=O)COc1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1OCC(=O)O
Reaction time: 16 h

Procedure:
Stir together for 16 hours a mixture of ethyl 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetate (7.1 g=19 mmol) and 125 ml 1.0 N NaOH. Acidify with concentrated HCl and extract with ether. Dry and concentrate the ether. Recrystallize from ether-hexane to obtain, as white crystals, 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetic acid, m.p. 118°-120° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[C@H:22]3[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[C:16](=[O:23])[NH:15][N:14]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].I[CH3:25]>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[C@H:22]3[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[C:16](=[O:23])[N:15]([CH3:25])[N:14]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reaction time: 0.5 h

Procedure:
6 mmol of a 60% suspension of sodium hydride in mineral oil was added to a suspension of 5 mmol of compound 1 in about 40 ml of dimethylformamide, under a flow of nitrogen at room temperature. After stirring this mixture for 30 minutes, 7 mmol of iodomethane was added and the resulting mixture was stirred for another 4 hours, after which the solvent was evaporated. The residue was partitioned between ethyl acetate and water, the organic layer was dried over magnesium sulfate and evaporated. The residue was purified by chromatography (dichloromethane). Crystallized from petroleum ether (60-95° C.). M.p. 110-112° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([NH:17][CH3:18])[C:9]2=O.Cl>[Pd].C(O)C>[ClH:1].[CH3:2][O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([NH:17][CH3:18])[CH2:9]2
Reactant: CNC1CCc2c(ccc(OC)c2OC)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNC1CCc2c(ccc(OC)c2OC)C1
Reaction time: 24 h

Procedure:
14.0 g of 5,6-dimethoxy-2-methylamino-1-tetralone hydrochloride (0.051 mole), 400 ml of absolute ethanol, 10 ml of 1M methanolic HCl and 4.0 g of 5% Pd/C are placed into an autoclave (50% humidity), then the mixture is hydrogenated (P about 7 atm., T=80° C.) with stirring for 24 hours. The mixture is filtered, washing thoroughly the filtration cake with hot methanol, then the alcoholic solution is evaporated to dryness. The resulting solid is taken up into 150 ml of acetone, then the precipitate is filtered and dried under vacuum at 60° C. Yield: 10.8 g, 82% (moles), 77% (weight);
Reaction SMILES: [OH:1][C:2]1C(=O)N2C(C3(CCCC3)OCC2)=N[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH2:22](O)CO>C1C=CC=CC=1.CCOCC.CC1C=CC(S(O)(=O)=O)=CC=1.O>[O:18]1[C:17]2([CH2:3][CH2:2][O:1][CH2:22]2)[O:19][CH2:20][CH2:21]1
Reactant: OCCO
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCOC21CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: C1CC2(CO1)OCCO2
Reaction time: 17 h
Yield: 80.1 %

Procedure:
A mixture of ethyl 3′-hydroxy-4′-oxo-6′,7′-dihydro-4′H-spiro[cyclopentane-1,9′-pyrimido[2,1-c][1,4]oxazine]-2′-carboxylate (15.79 g, 183.5 mmol), ethylene glycol (16.7 mL, 300 mmol) and cat. TsOH.H2O (100 mg) in benzene (100 mL) was heated at reflux using Dean-Stark trap. After 17 h, the reaction mixture was cooled, diluted with ether (150 mL), washed with sat. Na2CO3 and brine (50 mL each), dried (Na2SO4), filtered and concentrated to give yellow liquid. Distillation under reduced pressure afforded the title compound as a yellow liquid (19.13 g, 80%). 1H NMR (500 MHz, CDCl3) δ: 3.9.4 (2H, t, J=7.0 Hz), 3.94-3.90 (4H, m), 3.68 (2H, s), 2.09 (2H, t, J=7.0 Hz).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].CC(N(C)C)=O.C(=O)([O-])[O-].[K+].[K+].Br[C:22]1[CH:29]=[CH:28][CH:27]=[C:24]2[CH2:25][CH2:26][C:23]=12>C1(C)C=CC=CC=1>[OH:2][C:1]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[O:5][C:22]1[CH:29]=[CH:28][CH:27]=[C:24]2[CH2:25][CH2:26][C:23]=12
Reactant: Brc1cccc2c1CC2
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: Oc1cccc(Oc2cccc3c2CC3)c1
Temperature: 25 °C

Procedure:
Resorcinol (176.2 g, 1.60 moles), dimethylacetamide (DMAC) (550 mL), toluene (75 mL), potassium carbonate (55.2 g, 0.40 moles), 4-bromobenzocyclobutene (73.2 g, 0.40 moles), and cuprous chloride (3.96 g, 0.040 moles) are placed in a 1000 mL 3-necked flask. The flask is equipped with a water separating trap, reflux condenser, nitrogen inlet, and thermometer. The system is purged with nitrogen. The mixture is then heated to reflux, and water and toluene are collected in the trap. Toluene (about 25 mL) is distilled out of the reaction mixture and removed from the trap, until the temperature in the flask reaches 153° C. A sample, removed from the reaction after 5 hours of reflux and analyzed by gas chromatography (GC), shows little bromobenzocyclobutene remaining. The reaction is allowed to cool to room temperature after 6 hours of reflux. During the reaction, the temperature in the flask rises slightly to 156° C. by the end of the reaction.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH:13]1[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH:14]1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1.C(N(CC)CC)C.O>C1COCC1>[Cl:34][C:29]1[CH:28]=[C:27]([CH:14]2[CH:13]([CH2:12][NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C(c2ccc(Cl)c(Cl)c2)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(CNS(=O)(=O)c2ccccc2)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
Benzenesulfonyl chloride (130 mg) was added dropwise to a solution of tert-butyl (6SR,7RS)-7-(aminomethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (280 mg) and triethylamine (0.14 mL) in THF (5 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (195 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[C:12]([CH3:23])[C:11]([C:24](O)=[O:25])=[N:10]1.[OH:27][C:28]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=2)=[C:12]([CH3:23])[C:11]([C:24]([N:31]2[CH2:30][CH2:29][C:28]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([OH:27])[CH2:33][CH2:32]2)=[O:25])=[N:10]1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(N(C)C)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C(=O)N2CCC(O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(N(C)C)cc1
Yield: 49 %

Procedure:
1-(2,4-dichlorophenyl)-5-[4-(dimethylamino)phenyl]-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq, 10 mg, 0.026 mmol), 4-hydroxy-4-phenylpiperidine (1 eq, 4.5 mg, 0.026 mmol), benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1 eq., 11.3 mg, 0.026 mmol), and triethylamine (0.02 mL) were stirred in tetrahydrofuran (5 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 1-{[1-(2,4-dichlorophenyl)-5-[4-(dimethylamino)phenyl]-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-ol (7 mg, 50%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.73-1.95 (m, 2H) 2.09-2.29 (m, 5H) 2.85-3.04 (m, 3H) 3.34 (t, J=12.43 Hz, 1H) 3.66 (t, J=12.81 Hz, 1H) 4.34 (d, J=13.19 Hz, 1H) 4.74 (d, J=13.28 Hz, 1H) 6.61 (d, J=8.57 Hz, 2H) 6.99 (d, J=8.67 Hz, 2H) 7.09-7.57 (m, 8H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([OH:16])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[C:18]1([C:24]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:32]3[CH:28]([CH2:29][NH:30][CH2:31]3)[C:27](=[O:33])[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[C:34]1([C:24]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:32]3[CH:28]([CH2:29][N:30]([C:14](=[O:16])[CH2:13][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH2:31]3)[C:27](=[O:33])[CH2:26][CH2:25]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccccc1N1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3N3CCOCC3)CC12
Reaction time: 1.25 h
Yield: 25.2 %

Procedure:
N,N'-Carbonyldiimidazole (0.35 g) is added to a solution of 2-[2-(4-morpholinyl)phenyl]acetic acid (0.48 g) in dry dichloromethane (25 cc), cooled to +5° C. The mixture is stirred for 75 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (0.71 g) and triethylamine (0.6 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 1 hour at +5° C. and then for 8 hours at 20° C. It is washed with distilled water (3×100 cc) and with saturated sodium chloride solution (100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.063 mm, diameter 2.2 cm, height 12 cm), eluting with a mixture of ethyl acetate and cyclohexane (70/30 by volume) under a nitrogen pressure of 0.7 bar and collecting 50 cc fractions. Fractions 4 and 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from ethylene oxide (2 cc). The crystals are drained, washed with isopropyl ether (1 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-[2-(4-morpholinyl)phenyl]acetyl]-4-perhydroisoindolone (0.27 g) melting at 167° C. is obtained.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19]CC=C)=[CH:15][CH:14]=1)C=C>C1C2C(=CC=CC=2)CCC1>[CH2:10]([C:10]1[CH:9]=[C:8]([CH2:11][CH3:12])[CH:7]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[C:17]([CH2:9][CH:8]=[CH2:7])[CH:18]=2)[C:5]=1[OH:4])[CH:5]=[CH2:6]
Reactant: C=CCOc1ccc(-c2cc(CC)ccc2OCC=C)cc1
Solvent: c1ccc2c(c1)CCCC2
Product: C=CCc1cc(-c2cc(CC)cc(CC=C)c2O)ccc1O
Temperature: 200 °C
Reaction time: 8 h
Yield: 137 %

Procedure:
A solution was prepared by dissolving 58.4 g of 2,4'-diallyloxy-5-ethylbiphenyl into 200 ml of tetrahydronaphthalene. The solution was heated at 200° C. with nitrogen gas blowing for 8 hours with stirring, cooled, extracted with 10% sodium hydroxide and washed with n-hexane. The extract, which was acidified with hydrochloric acid, was extracted with diethylether. The extract was washed with an aqueous solution saturated with NaCl, and 10% water solution of sodium hydrogencarbonate, dried with sodium sulfate and concentrated. The concentrate was purified by a silica gel column-chromatography (n-hexane:ethylacetate=15:1) and recrystallized from n-hexane to yield white powder 40 g of 3,3'-diallyl-5-ethyl-2,4'-biphenyldiol having a m.p. of 47°-48° C.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)(=O)=O)=CC=1.[I:25][C:26]1[CH:31]=[CH:30][NH:29][C:28](=[O:32])[C:27]=1[CH3:33].C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC>[I:25][C:26]1[CH:31]=[CH:30][N:29]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]2)[C:28](=[O:32])[C:27]=1[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Cc1c(I)cc[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: Cc1c(I)ccn(C2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Reaction time: 22 h
Yield: 80.7 %

Procedure:
Tert-butyl 4-(((4-methylphenyl)sulfonyl)oxy)piperidine-1-carboxylate (21.7 g) was added to a mixture of 4-iodo-3-methylpyridin-2(1H)-one (8.98 g) and potassium carbonate (21.1 g) in 1-methoxy-2-(2-methoxyethoxyl)ethane (160 mL) at room temperature. The mixture was stirred at 100 C under nitrogen atmosphere for 22 hours. The mixture was quenched with water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Toluene was added to the residue. The mixture was concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12.9 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCCCCCCCCCC>C1(C)C=CC=CC=1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(Br)c([N+](=O)[O-])c1
Reactant: OB(O)c1ccccc1
Solvent: CCCCCCCCCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Yield: 100.5 %

Procedure:
To a solution of commercially available 1-bromo-4-methyl-2-nitro-benzene (0.107 g, 0.49 mmol) in anhydrous toluene (3 mL) was added CsCO3 (0.305 g, 0.94 mmol) followed by phenylboronic acid (0.062 g, 0.49 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3.]undecane as a 0.1M solution in toluene (0.200 mL, 4 mole %). Nitrogen was bubbled through the resulting suspension for three minutes then palladium acetate (0.0043 g, 4 mole %) was added, the reaction vessel sealed and immersed in an 80° C. oil bath and heated for 22 hours. Subsequent filtration through celite and removal of volatiles under vacuum gave the crude product (0.105 g, 100%), which was sufficiently pure for use as isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:20])[C:18]=2[OH:19])=[CH:15][C:14]([CH3:21])=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=1[OH:8].[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[OH:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:20])[C:18]=2[OH:19])=[CH:15][C:14]([CH3:21])=[CH:13][CH:12]=3)=[CH:3][C:2]=1[NH:1][C:22](=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2oc(-c3ccc(O)c(N)c3)c(O)c(=O)c2c1
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2oc3ccc(C)cc3c(=O)c2O)ccc1O
Yield: 44 %

Procedure:
The compound prepared in Example 5 (10 mg, 35 μmol) was dissolved in dichloromethane (2 ml) and reacted with excess acetic anhydride for 1 hour at room temperature. The mixture was concentrated and the residue was purified by silica gel column chromatography (eluent: 50% ethylacetate/hexane) to give 5 mg (Yield 44%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:35][OH:36]>C(Cl)(=O)C1C=CC=CC=1>[OH:1][CH2:2][C@@H:3]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH2:30][CH2:31][N:32]([C:35]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:36])[CH2:33][CH2:34]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CO
Reactant: Cc1cc(N2CCNCC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Solvent: O=C(Cl)c1ccccc1
Product: Cc1cc(N2CCN(C(=O)c3ccccc3)CC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Reaction time: 0.08 h
Yield: 33 %

Procedure:
To a solution of (S)-4-(1-hydroxymethyl-2-phenyl-ethylamino)-3-(4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one (30 mg, 0.063 mmol) in methanol (2 mL) was added benzoyl chloride (1 drop). The reaction mixture was stirred for 5 min. and concentrated. The residue was purified by prep. HPLC to yield the title compound (11 mg, 33%). 1H NMR (400 MHz, CD3OD) δ 7.48–7.54 (5H, m), 7.37 (1H, s), 7.13–7.26 (7H, m), 6.08 (1H, d, J=7.7 Hz), 3.79–4.02 (5H, m), 3.76 (1H, dd, J=4.7, 11.2 Hz), 3.67 (1H, dd, J 5.7, 11.2 Hz), 3.54 (4H, m), 3.03 (1H, dd, J=5.7, 13.7 Hz), 2.89 (1H, dd, J=8.0, 13.7 Hz), 2.62 (3H, s). LCMS (M+H)+ m/z 563 (t=2.19 min.).