Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([N:16]=[C:17]=[O:18])[CH2:14][CH3:15]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][NH:10][C:17]([NH:16][CH2:13][CH2:14][CH3:15])=[O:18])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: CCCN=C=O
Solvent: Cc1ccccc1
Product: CCCNC(=O)NCCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
4-Nitrophenethylamine (127 g, 0.767 mol) [J. Org. Chem., 43, 31 (1978)] was dissolved in 2.5 liters of toluene, and propyl isocyanate (72 ml, 0.764 mol) was slowly added dropwise at room temperature. The mixture was stirred for two hours, and the crystals formed were collected by filtration and dried under reduced pressure to give 171.5 g (yield: 89.8%) of 1-(4-nitrophenethyl)-3propylurea (Compound a).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:17]=1)=[CH:7][CH:8]=[C:9](/[CH:11]=[C:12](\[CH3:16])/[C:13]([OH:15])=[O:14])[CH:10]=2.[CH:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20](O)[CH:19]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CC=CN=1)C.ClCCl>[N+:24]([C:23]1[CH:18]=[CH:19][C:20]([O:14][C:13](=[O:15])[C:12]([CH3:16])=[CH:11][C:9]2[CH:10]=[C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[CH:17][C:6]3=[CH:7][CH:8]=2)=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: C/C(=C\c1ccc2cc(N)ccc2c1)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC(=Cc1ccc2cc(N)ccc2c1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 79.2 %

Procedure:
Into 20 ml of dichloromethane, 0.57 g (2.5 mmol) of (E)3-(2-amino-benzo[d]phenyl)-2-methyl-2-propenoic acid and 0.52 g (3.8 mmol) of p-nitrophenol (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved; and 20 mg of dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.) were added thereto. Thereafter, while the mixture was stirred under cooling with ice, 0.71 g (3.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC-HCl) (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto in portions. The liquid was returned to room temperature and then was stirred for 20 hours. After the end point of this reaction was verified by TLC, the reaction liquid was concentrated under a reduced pressure and then was dissolved in 100 ml of ethyl acetate. This solution was washed several times with a 5% aqueous sodium hydrogencarbonate solution and then with a saturated aqueous sodium chloride solution, and was dried with magnesium sulfate anhydride. Thereafter, the solvent was evaporated, whereby a crude product was obtained. This product was recrystallized from ethanol, whereby 0.69 g of the aimed product was obtained as a crystal (yield: 80%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](F)=[C:11]([F:33])[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])=[C:13]([CH:24]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+].O>CN(C=O)C>[N:35]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:24][C:13]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:11]=1[F:33])=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1c(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c(Nc2ccccc2Cl)c1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
To a solution of benzyl 5-(benzyloxy)-2-((2-chlorophenyl)amino)-3,4-difluorobenzoate (27.82 g, 57.97 mmol) in DMF (250 mL) was added NaN3 (4.52 g, 69.56 mmol). The mixture was stirred at 90° C. for 3 h. Then water (400 mL) was added. The solution was extracted with ethyl acetate (150 mL×3). The combined organic extracts were washed with water (150 mL) and brine (150 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) and gave the desired product (pale yellow solid, 22.97 g, 78.8% yield). 1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H), 7.40 (m, 12H), 7.13 (m, 1H), 6.87 (m, 1H), 6.69 (m, 1H), 5.34 (s, 2H), 5.17 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=2)=[CH:4][CH:3]=1.Cl.[CH3:30][NH:31][CH3:32].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:31]([CH3:32])[CH3:30])=[O:17])=[N:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CNC
Reactant: Cc1cc(C(=O)O)ncc1C(Sc1ccc(F)cc1)c1c(F)ccc(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N(C)C)ncc1C(Sc1ccc(F)cc1)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.5 %

Procedure:
To a solution of 5-[[(4-fluorophenyl)thio](2,3,6-trifluorophenyl)methyl]-4-m ethylpyridine-2-carboxylic acid (383 mg, 0.94 mmol) in methylene chloride (10 ml), dimethylamine hydrochloride (85 mg, 1.03 mmol), 1-hydroxybenzotriazole (140 mg, 1.03 mmol), 4-methylmorpholine (0.227 ml, 2.07 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) were added at room temperature. After stirring for 17 hours at room temperature, the reaction mixture was washed with 0.5 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure to obtain the title compound (373 mg, 0.86 mmol, 91%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[Cl-].[Ca+2].[Cl-].N1C=CC=CC=1.[S:22](Cl)(Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][N:4]1[CH2:3][CH2:2][O:1][S:22]1(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)Cl
Reactant: OCCNCc1ccccc1Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S1(=O)OCCN1Cc1ccccc1Cl
Temperature: -50 °C
Yield: 18.5 %

Procedure:
To a solution of N-hydroxyethyl-2-chlorobenzylamine (1.86 g, 10.0 mmole) in dry methylene chloride (6 ml) in a reaction vessel fitted with a calcium chloride (CaCl2) drying tube was added dry pyridine (1.66 ml, 20.5 mmole). The solution was stirred and cooled to -50° C. Sulfuryl chloride (1.35 g, 10.0 mmole) dissolved in dry methylene chloride (4 ml) was added dropwise over 20 minutes while the temperature of the solution was maintained between -45° C. and -50° C. The solution was stirred at -50° C. for 90 minutes and then allowed to warm to 8° C. over 90 minutes. The entire reaction mixture was poured onto a silica gel bed (30 g), slurry-packed in a 60 ml Type "C" sintered glass funnel. The bed was eluted with methylene chloride while collecting 40 ml fractions. Fractions containing the product were combined and the solvent removed by evaporation under vacuum at 40° C. yielding N-(2-chlorobenzyl)-2,2-dioxo-1,2,3-oxathiazolidine as a clear oil (0.40 g, 1.85 mmole), which crystallized. Characteristic analytical data are mp. 61°-62.5° C.; and NMR spectra similar to those of Example 2A (above).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]1[C:34](B(O)O)=[CH:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[C:34]2[C:33]([F:32])=[CH:38][N:37]=[C:36]([O:39][CH3:40])[CH:35]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1
Reactant: COc1cc(B(O)O)c(F)cn1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C2=CCCC2(C)C)c1
Temperature: 87 °C
Reaction time: 8 h

Procedure:
To a flask with methyl 3-(5,5-dimethylcyclopent-1-enyl)-4-(trifluoromethylsulfonyloxy)benzoate T3.5 (404 mg, 1068 μmol) was added Pd(PPh3)4 (123 mg, 107 μmol), potassium carbonate (443 mg, 3203 μmol), 5-fluoro-2-methoxypyridin-4-ylboronic acid T19.1 (456 mg, 2669 μmol, commercially available from Asymchem). The mixture was then degassed, and DMF (3 mL) was added. The reaction was stirred overnight at 87° C. and worked up with EtOAc and water. Silica gel chromatography (0-50% EtOAc/Hexanes) afforded methyl 3-(5,5-dimethylcyclopent-1-enyl)-4-(5-fluoro-2-methoxypyridin-4-yl)benzoate T19.2 (295 mg. 78%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>C(O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(Cl)cc(Nc2ccccc2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol) in ethanol (EtOH) (10 mL) was added aniline (0.3 mL, 3.3 mmol) and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto ethyl acetate (EtOAc) and saturated aqueous NaHCO3. The layers were separated and the aqueous layer was further extracted with more EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to provide the crude title compound (620 mg) as a yellow solid. Product contains ˜25% of bis-addition product. LC-MS (ES) m/z=221 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH3:25][C:26]1([CH3:36])[CH2:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([OH:35])[C:28]=2[O:27]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:34]3[C:28]4[O:27][C:26]([CH3:36])([CH3:25])[CH2:30][C:29]=4[CH:31]=[CH:32][CH:33]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cccc3c2OC(C)(C)C3)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 89.6 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.11 mmol) was reacted with 2,3-dihydro-2,2-dimethyl-7-benzofuranol (22 mg, 0.13 mmol) to give the title compound (50 mg, 94%) after purification by flash chromatography on silica gel (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [As:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12]SCCC(N[C@H](C(O)=O)CCC(O)=O)=O)=[O:11])=[CH:5][CH:4]=1)=[O:2].[SH:28][CH2:29][CH2:30][C:31]([NH:33][C@@H:34]1[C@@H:40]([OH:41])[C@H:39]([OH:42])[C@@H:38]([CH2:43][OH:44])[O:37][CH:35]1[OH:36])=[O:32].[Na].[Na].C(=O)(O)[O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O>[As:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH2:12][S:28][CH2:29][CH2:30][C:31]([NH:33][C@@H:34]2[C@@H:40]([OH:41])[C@H:39]([OH:42])[C@@H:38]([CH2:43][OH:44])[O:37][CH:35]2[OH:36])=[O:32])=[O:11])=[CH:7][CH:8]=1)=[O:2]
Reactant: O=C(CCS)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=[As]c1ccc(NC(=O)CSCCC(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: O=[As]c1ccc(NC(=O)CSCCC(=O)N[C@H]2C(O)O[C@H](CO)[C@@H](O)[C@@H]2O)cc1

Procedure:
The procedure used was the same as for N-(3-(4-arsenosophenylcarbamoylmethylthio)propanoyl)-L-glutamic acid, using 3.00 mL (210 μmol) of 70.0 mM BRAO in DMSO, the disulfide of disodium N-(3-mercaptopropanoyl)-D-glucosamine (0.67 g), 0.5 M bicarbonate buffer, pH 9 (11.96 mL, 6.0 mmol), and 0.69 M triphenylphosphine in DMSO (1.9 mL, 1.3 mmol). The active concentration of trivalent arsenic was found to be 13.5 mM (11.0 mL of solution).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CCN(CC)CC.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(N)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(C)(C)C)nc1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a stirred solution of 5-methylpyridin-2-amine (200 g, 1.85 mol) in anhydrous CH2Cl2 (1000 mL) was added dropwise a solution of Et3N (513 mL, 3.70 mol) and 2,2-dimethyl-propionyl chloride (274 mL, 2.22 mol) at 0° C. under N2. The ice bath was removed and stirring was continued at room temperature for 2 hours. The reaction was poured into ice (2000 g). The organic layer was separated and the remaining aqueous layer was extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4 and evaporated to afford 2,2-dimethyl-N-(5-methyl-pyridin-2-yl)-propionamide (350 g), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=8.4 Hz, 1 H), 8.06 (d, J=1.2 Hz, 1 H), 7.96 (s, 1 H), 7.49 (dd, J=1.6, 8.4 Hz, 1 H), 2.27 (s, 1 H), 1.30 (s, 9 H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:15])=O>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A mixture of p-nitrobenzoic acid (500 g, 3.0 moles, 1 equiv) and thionyl chloride (600 mL, 8.2 moles, 2.73 equiv) was heated to reflux for 6-7 hours until a clear solution was obtained. Excess of thionyl chloride was removed by distillation followed by co-distillation with toluene (300 mL). The reaction mass was cooled to room temperature, and hexane (1.5 L) was added, forming a precipitate, which was then filtered and dried under vacuum, yielding 4-nitrobenzoyl chloride as a yellow solid (530 g, approximately 100% yield), which was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:27]=[CH:26][C:19]2[N:20]([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:18]=2[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1F)[C:33]#[N:34].C([O-])([O-])=O.[Cs+].[Cs+].C(O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:27]=[CH:26][C:19]2[N:20]([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:18]=2[CH:17]=1)([OH:15])[C:11]([F:12])([F:13])[F:14])[O:8][C:37]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[F:29]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=CO
Solvent: CN(C)C=O
Product: CC(c1ccc(Oc2ccc(C#N)cc2F)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F

Procedure:
A mixture of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (Example 85, 25 mg), 3,4-difluorobenzonitrile (CAS Reg. No. 64248-62-0, 10 mg), and Cs2CO3 (59 mg) in DMF (1 ml) was heated in a microwave oven at 120° C. for 30 min. The mixture was acidified with HCOOH and then purified by prep. HPLC (C18-column, solvent gradient 30-98%) to give the title compound (19 mg) as a colorless oil. MS (m/e)=534.1 [M+H+].
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH:20]([OH:36])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]2.[H-].[Na+].O>CN(C=O)C>[F:8][C:6]1[CH:5]=[C:4]2[C:3](=[CH:2][CH:7]=1)[C:9]1[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)[CH:20]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:25][CH:26]=1)[O:36]2
Reactant: Oc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2c3c(ccc2c1)-c1ccc(F)cc1OC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
Dissolve 6-(2,4-difluoro-phenyl)-5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-naphthalen-2-ol (3.4 g, 7.0 mmol) in dry DMF (70 mL). Slowly add sodium hydride (440 mg, 18 mmol) and plunge into a 140° C. oil bath for 30 minutes. Cool to room temperature and pour into water. Adjust the pH to 7 and extract three times with methylene chloride. Wash combined organic layers with water, dry with sodium sulfate, filter and concentrate. Triturate with ether to yield 2.2 g (69%) of the title compound: mass spectrum (ion spray) m/z=470.3 (M+H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C@H:17]([CH3:26])[CH2:18][NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)#[N:28]>ClCCl>[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:19]([CH2:18][C@H:17]([N:14]2[CH2:15][CH2:16][N:11]([C:10]3[C:5]4[O:4][CH2:3][CH2:2][O:1][C:6]=4[CH:7]=[CH:8][CH:9]=3)[CH2:12][CH2:13]2)[CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[O:34])=[CH:31][CH:30]=1)#[N:28]
Reactant: C[C@H](CNc1ccccn1)N1CCN(c2cccc3c2OCCO3)CC1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: C[C@H](CN(C(=O)c1ccc(C#N)cc1)c1ccccn1)N1CCN(c2cccc3c2OCCO3)CC1
Reaction time: 16 h

Procedure:
A solution of {(R)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]-propyl}-pyridin-2-ylamine (0.846 g, 2.38 mmol) in dichloromethane (20 mL) was treated at 0° C. with the dropwise addition of a dichloromethane solution of 4-cyanobenzoyl chloride (1.1 equivalents, 2.63 mmol in 5 mL). After stirring for 16 hours the mixture was poured onto hexane (100 mL) to precipitate the titled compound as its mono-hydrochloride salt (white solid, 1.2 g, 97% yield), which was recrystallized from dichloromethane/hexane.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5].Cl[C:24]1C=CC(C(C2N(C)C(CC(OCC)=O)=CC=2C)=O)=CC=1>>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH:12]([CH3:24])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2C)n1C
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccccc2C)n1C

Procedure:
The methylation procedure of Example 77A is repeated, except that an equivalent quantity of ethyl 5-(2′-methylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 92) is methylated instead of the ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A, to yield ethyl 5-(2′-methylbenzoyl)-1,4, α-trimethylpyrrole-2-acetate.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[CH2:7][OH:8])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OCC(CO)c1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(COS(=O)(=O)c1ccc(C)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of (−)-2-(4-bromophenyl)-3-hydroxypropyl acetate (5.88 g, 21.5 mmol) in dichloromethane (100 ml) was added triethylamine (5.45 g, 53.8 mmol), p-toluenesulfonyl chloride (4.93 g, 25.8 mmol) and 4-dimethylaminopyridine (0.263 g, 2.15 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours and partitioned between saturated ammonium chloride solution and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=4/1) to afford (+)-3-acetoxy-2-(4-bromophenyl)propyl 4-methyl-benzenesulfonate as colorless oil (8.32 g, 90%). [α]D=+1.63 (C=0.5, CHCl3).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:31]([NH:35][CH2:36][CH2:37]O)([CH3:34])([CH3:33])[CH3:32]>O1CCCC1>[C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH2:37][CH2:36][NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc2cc(-c3ccccc3)oc12
Reactant: CC(C)(C)NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)NCCOC(=O)c1cccc2cc(-c3ccccc3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
1.43 g of 2-phenylbenzofuran-7-carboxylic acid are dissolved in 10 ml of tetrahydrofuran, and 1.08 g of carbonyldiimidazole are added to the solution. The mixture is stirred at room temperature for 2 hours and a solution of 0.76 g of 2-(t-butylamino)ethanol in 4 ml of tetrahydrofuran is added thereto. The mixture is stirred at room temperature for 15 hours and evaporated to remove solvent. Water is added to the residue and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried, and evaporated to remove solvent to give 1.72 g of 2-(t-butylamino)ethyl 2-phenylbenzofuran-7-carboxylate as pale yellow oil.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([C:13]([C:15]1[S:27][C:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]([CH2:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:18](=[O:37])[C:17]=2[C:16]=1[O:38][CH3:39])=[O:14])[CH3:12])=[O:7])(=O)C.[OH-].[Na+].CO>C1COCC1.C(=O)([O-])O.[Na+]>[OH:4][CH2:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:12])[C:13]([C:15]1[S:27][C:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]([CH2:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:18](=[O:37])[C:17]=2[C:16]=1[O:38][CH3:39])=[O:14])=[O:7]
Reactant: COc1c(C(=O)N(C)CCNC(=O)COC(C)=O)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(=O)N(C)CCNC(=O)CO)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 58.2 %

Procedure:
A mixed solution of the compound of Example 504 (120 mg, 0.22 mmol) and 4N aqueous sodium hydroxide solution (2 mL) in THF (4 mL)-methanol (4 mL) was stirred at room temperature for 2 hr, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Recrystallization of the crude solid from ethyl acetate-hexane gave the title compound (65 mg, 58%) as white crystals.