Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH3:13].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[N:28]1.C1(C)C=CC=CC=1>CO.N1CCCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:7]2\[O:8][C:4]3[C:3]([CH:12]([N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]4)[CH3:13])=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:28]1
Reactant: CC(c1c(O)ccc2c1OCC2=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(c1c(O)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
A solution of tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperazine-1-carboxylate (0.11 g, 0.30 mmol) in methanol (5.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.040 g, 0.27 mmol). Then, the mixture was added with 7 drops of piperidine, and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was added with toluene, then the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (95:5)) to obtain tert-butyl (Z)-4-{1-[2-(1H-indazol-3-yl)methylene-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl]ethyl}piperazine-1-carboxylate (0.075 g, 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1.C([BH3-])#N.[Na+].C(O)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:23]=1
Reactant: COC(=O)CCc1ccc(N)cc1
Reactant: Cc1cccc(C)c1-c1cccc(C=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc(NCc2cccc(-c3c(C)cccc3C)c2)cc1
Temperature: 25 °C
Reaction time: 55 h
Yield: 61 %

Procedure:
To a solution of methyl 3-(4-aminophenyl)propanoate (3.33 g, 18.6 mmol) and 2′,6′-dimethylbiphenyl-3-carbaldehyde (3.91 g, 18.6 mmol) in toluene (40 mL) were added molecular sieves (0.4 nm, beads, 7.2 g), and the mixture was stirred at room temperature for 55 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (100 mL). Sodium cyanoborohydride (2.53 g, 40.3 mmol) and acetic acid (2.31 mL, 40.3 mmol) were successively added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 3 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-40% ethyl acetate/hexane) to give the title compound (4.24 g, yield 61%) as a colorless oil.
Reaction SMILES: O([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([CH2:17][CH2:18][CH3:19])=[CH:11][C:10]=1[F:20])S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH3:28][OH:29].CN([CH:33]=[O:34])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][C:10]1[CH:11]=[C:12]([CH2:17][CH2:18][CH3:19])[C:13]([O:15][CH3:16])=[CH:14][C:9]=1[C:28]([O:34][CH3:33])=[O:29]
Reactant: CCCc1cc(F)c(OS(=O)(=O)C(F)(F)F)cc1OC
Reactant: CN(C)C=O
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCc1cc(F)c(C(=O)OC)cc1OC
Temperature: 70 °C
Reaction time: 4.5 h

Procedure:
2-Fluoro-5-methoxy-4-propylphenyl triflate (3.00 g, 9.5 mmol), triethylamine (2.91 mL, 20.9 mmol) and methanol (7.0 mL, 173 mmol) were dissolved in DMF (30 mL) and the solution was flushed with CO. 1,3-Bis(diphenylphosphino)propane (151 mg, 0.37 mmol) and palladiumacetate (84 mg, 0.37 mmol) were added and the reaction was stirred at 70° C. and atmospheric pressure for 4.5 h. Evaporation of the solvent and co-evaporation with xylene gave a residue which was extracted between Et2O and 2M NaOH and the organic phase was washed brine, dryed over MgSO4 and evaporated to give 2.3 g of crude product. Purification by flash chromatography (SiO2, CH2Cl2 -hexane 1:2) gave methyl 2-fluoro-5-methoxy-4-propylbenzoate (1.46 g) as an oil. 1H NMR (DMSO-d6): δ7.28 (d, J=6.0 Hz, 1H), 7.12 (d, J=11.4 Hz, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 2.54 (t, J=7.6 Hz, 2H), 1.53 (m, J=7.6 Hz, 2H), 0.87 (t, J=7.4 Hz, 3H). 13C NMR (DMSO-d6): δ164.01 (d, J=4 Hz), 155.21 (d, J=251 Hz), 152.95, 138.30 (d, J=8 Hz), 117.93 (d, J=24 Hz), 115.26 (d, J=11 Hz), 111.75, 55.88, 52.20, 31.32, 21.83, 13.66. MS (EI, 70 eV): m/z (rel. int) 226 (M+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C.O>CO.C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(F)cc1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
2-Amino-4-fluorobenzoic acid (10.0 g, 64.5 mmol) was dissolved in methanol (50 mL) and toluene (150 mL). (Trimethylsilyl)diazomethane (2M in diethyl ether, 48.3 mL, 96.7 mmol) was added over 10 minutes at RT. Stirring was continued for 2 h at RT. Water (300 mL) was added to the mixture and the volatiles were removed in vacuo. The remaining aqueous phase was cooled to 0° C. for 30 minutes and the formed precipitate was collected by filtration, washed with water and dried to give pure title compound (10.4 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[CH:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[CH:11]=[C:10]([C:20]([NH:34][C@@H:32]([C:29]3[CH:30]=[N:31][C:26]([CH3:25])=[CH:27][CH:28]=3)[CH3:33])=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(OC3CCOC3)cc(C(=O)O)c2)cc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(OC3CCOC3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(tetrahydrofuran-3-yloxy)biphenyl-3-carboxylic acid (40 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: C([N:8]([C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20])[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)(C(OCC)=O)=O.[N+:26]([O-:29])(O)=[O:27]>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:19]([NH:8][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[N+:26]([O-:29])=[O:27])[CH:17]=[CH:18][C:9]=1[NH:8][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20])([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)N(C(=O)C(=O)OCC)c1ccc2ccccc2c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=O)Nc1ccc2cccc([N+](=O)[O-])c2c1NC(=O)C(=O)OCC
Temperature: 0 °C

Procedure:
A partial suspension of 1 2-diethoxalylaminonaphthalene (1,79 g, 5 mmol) in 7 ml of acetic acid and 7 ml of acetic anhydride was treated dropwise with a solution of nitric acid (1.8 ml, 43 mmol, d 1.52) in 7 ml of acetic acid, with stirring at 0° C. The resulting solution was stirred at 0° C. for 11/2 h and then poured on 150 ml of ice/water. The yellow precipitate was isolated, dried and recrystallized from ethanol with decolourising carbon giving 0.67 g (33%) of the required compound, m.p. 173-175° C.,1H-NMR (CDCl3 +DMSO-d6), 1,43 (t,J=7 Hz, 6H,2 CH3), 4.40 (q,J=7Hz, 2H, CH2), 4.42 (q,J=7Hz, 2H, CH2), 7.3-8.4 (m, 5H, ArH).
Reaction SMILES: [N+:1]([C:4]1[NH:8][C:7](C(=O)C(Cl)(Cl)Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][O-:16].[Na+].[CH3:18][OH:19]>>[N+:1]([C:4]1[NH:8][C:7]([C:15]([O:19][CH3:18])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(c1ccc([N+](=O)[O-])[nH]1)C(Cl)(Cl)Cl
Reactant: C[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([N+](=O)[O-])[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.5 g (21.3 mmol) of 5-nitro-2-trichloroacetylpyrrole and 100 ml of methanol were introduced into a round-bottomed flask and 3.6 g of sodium methoxide were added in small quantities. The mixture was stirred at room temperature for 2 hours, the reaction medium was evaporated, the residue was triturated in water, the solid filtered and dried. 3 g (83%) of the expected methyl ester of melting point 178°-179° C. were recovered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH2:6][CH:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19](=[O:22])([O-])[O-].[K+].[K+].[I-].[Na+].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO.CC(C)=O>[CH3:19][O:22][C:7](=[O:12])[CH2:6][CH:5]([C:4]1[CH:3]=[C:2]([Br:1])[CH:11]=[CH:10][C:9]=1[O:8][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: O=C1CC(c2ccccc2)c2cc(Br)ccc2O1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)CC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1

Procedure:
A suspension consisting of (±)-6-bromo-4-phenylchroman-2-one (85.0 g), anhydrous potassium carbonate (46.7 g), sodium iodide (20.5 g) and benzyl chloride (40.6 g) in methanol (350 ml) and acetone (350 ml) was refluxed for 3 hrs. After evaporation of the solvents the residue was extracted with diethyl ether (2×300 ml) and the extract was washed with water (2×200 ml) and aqueous sodium carbonate. Drying (Na2SO4) and rotoevaporation left 121.8 g (102.1% crude yield) of (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid methyl ester as a light yellow oil, tlc: (1) 0.77; NMR (CDCl3): 39.22, 40.53, 51.63, 70.16, 113.10, 113.77, 126.46, 126.92, 127.88, 128.08, 128.34, 128.45, 130.31, 130.55, 134.41, 136.44, 142.37, 154.94, 172.08.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18]([OH:20])=O)[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[CH:4][CH:3]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN1C(=O)CCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)=[O:20])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:34])[F:32])[CH:25]=2)=[CH:35][CH:36]=1
Reactant: CN1CCNCC1
Reactant: Cn1c(=O)n(CC(=O)O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)Cn2c(=O)c3c(nc(Oc4cccc(OC(F)(F)F)c4)n3Cc3ccc(Cl)cc3)n(C)c2=O)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 27.1 %

Procedure:
To a solution of 2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetic acid (80 mg, 0.152 mmol, example 9) in NMP (2 mL) was added TEA (0.1 mL, 0.614 mmol), 1-methylpiperazine (0.07 mL, 0.614 mmol) and O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (87 mg, 0.231 mmol); then the mixture was stirred at 60° C. for 16 h. Then the mixture was diluted with ethyl acetate and water, the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product. This crude material was purified by recrystallization from methanol to give 7-(4-chlorobenzyl)-3-methyl-1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (25 mg, 27.5% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.62-7.59(t, 1H), 7.55(s, 1H), 7.49-7.39(m, 5H), 7.36-7.34(d, 1H), 5.43(s, 2H), 4.71(s, 2H), 3.55-3.48(m, 4H), 3.30(s, 3H), 2.46-2.36(m, 4H), 2.21(s, 3H). LCMS retention time 2.298 min; LCMS MH+ 607.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH:3]1[CH2:33][CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[H-].[Na+].[CH3:44]I>CN(C=O)C>[CH:19]([N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[C:3]([CH3:44])([CH2:33][CH:34]=[CH:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:4](=[O:32])[N:5]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:6]2[CH:25]=[CH:24][CH:23]=[CH:22][C:7]1=2)([CH3:21])[CH3:20]
Reactant: CC(C)N(C(=O)CN1C(=O)C(CC=Cc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)C(C)(CC=Cc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 0.08 h
Yield: 51.9 %

Procedure:
To a stirring solution of 200 mg (0.37 mmol) of 2-[2,4-Dioxo-5-phenyl-3-(3-phenyl-allyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 41, in 3 mL of DMF at 0° C. is added 16 mg (0.41 mmol, 1.1 equiv) of sodium hydride (60% dispersion in mineral oil). The resulting solution is stirred 5 min, then 25 mL (0.41 mmol, 1.1 equiv) of methyl iodide is added. The reaction mixture is stirred 30 min at 0° C. then 19 h at RT and quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL EtOAc and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. Purification of the resulting oil via reverse phase MPLC using a C-18 column and 70% acetonitrile/30% H2O with 0.1% TFA as eluent followed by lyophilization afforded 107 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.53-7.05 (m, 18H), 6.79 (m, 1H), 6.15 (m, 1H), 5.97 (d, 1H, J=15.7), 5.09 (m, 1H), 4.44 (d, 1H, J=16.4), 3.95 (d, 1H, J=16.4), 3.07 (m, 2H), 2.28 (d, 1H, J=7.1), 1.61 (s, 3H), 1.14 (m, 6H); low resolution MS (FAB)m/e 558 (MH+), 423, 223.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)(=O)[CH3:2].Cl.[O:25]([NH2:27])[CH3:26].N1C=CC=CC=1>C(O)C>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[NH:15][C:6]1[CH:5]=[C:4]([C:1](=[N:27][O:25][CH3:26])[CH3:2])[CH:14]=[CH:13][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Nc2ccc(F)cc2F)c1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(C)c1ccc(NS(C)(=O)=O)c(Nc2ccc(F)cc2F)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
A mixture of 4'-acetyl-2'-(2,4-difluorophenylamino)methanesulfonanilide (1.5 g), methoxylamine hydrochloride (0.4 g) and pyridine (0.43 ml) in ethanol (15 ml) was refluxed for 3 hours. The mixture was cooled to room temperature. Precipitates were filtered, washed with water, and recrystallized from ethanol to give colorless needles of 2'-(2,4-difluorophenylamino)-4'-[1-(methoxyimino)ethyl]methanesulfonanilide (1.4 g).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:19]1[CH2:21][CH2:20]1.B(Br)(Br)Br.C(Cl)Cl>>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:19]1[CH2:21][CH2:20]1
Reactant: COc1cccc2c1cc(C1CC1)n2Cc1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc2c1cc(C1CC1)n2Cc1ccccc1-c1ccccc1
Yield: 29.2 %

Procedure:
By the method used in Example 1, Part D, 1.25 g (3.7 mmol) of 1-([1,1'-biphenyl]-2-ylmethyl)-2-cyclopropyl-4-methoxyl-1H-indole was O-demethylated by treating it with 15 mL of 1M BBr3 /CH2Cl2. The crude product was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 367 mg (29% yield) of 1-([1,1'-biphenyl]-2-ylmethyl)-2-cyclopropyl-4-hydroxy-1H-indole as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][S:16]([CH3:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1.C(OCC)C.C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][S:16]([CH3:18])(=[O:36])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(CCCS(C)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(CCCS(C)(=O)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
The 2-[1-[(4-chlorophenyl)sulfonyl]-2-methyl-5-(methylsulfinyl)pentyl]-1,4-difluorobenzene (76 mg, 0.18 mmol) obtained in Example 44 was dissolved in methylene chloride (5 ml). Under ice cooling, 3-chloroperbenzoic acid (36 mg, 0.21 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction mixture was purified by silica gel chromatography (methylene chloride:methanol=100:1) to yield a pale yellowish brown oil. The resulting pale yellowish brown oil was solidified with diethyl ether/methylene chloride, whereby the title compound (61 mg, 77%) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](OC)([O:6][CH3:7])[O:4][CH3:5].[C:10]([O:18][CH3:19])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:20][N+](CCCC)(CCCC)CCCC>CO>[CH3:1][O:2][CH:3]([O:6][CH3:7])[O:4][CH3:5].[CH3:19][O:18][CH:10]([O:17][CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccccc1
Reactant: COC(OC)(OC)OC
Reactant: CCCC[N+](C)(CCCC)CCCC
Solvent: CO
Product: COC(OC)OC
Product: COC(OC)c1ccccc1

Procedure:
1062 g of tetramethoxymethane, 303 g of methyl benzoate, 225 g of 60% methyltributylammonium methosulfate solution and 910 g of methanol were electrolyzed at 3 A. The voltage per gap was kept below 5 V, the temperature was 30° C., and the pumping rate was 190 l/h. After the electrolysis had ended, 10.0 GC area % of trimethoxymethane and 13.2 GC area % of benzaldehyde dimethyl acetal had formed in the electrolyte; tetramethoxyethane had been degraded from 42.5% to 25.6 GC area %, and methyl benzoate was down to 0.4 GC area %, having been converted to more than 95%. Low-boiling byproducts included methyl formate at 2.2 GC area % in the electrolyte.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH:12]([N:15]=[C:16]=S)([CH3:14])[CH3:13].N=C=N.CC1C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[CH:12]([NH:15][C:16]1[NH:10][C:4]2[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[C:3]=2[N:11]=1)([CH3:14])[CH3:13]
Reactant: CC(C)N=C=S
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N=C=N
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(Cl)c(Cl)c(Cl)cc2[nH]1
Yield: 70.3 %

Procedure:
3,4,5-Trichloro-1,2-phenylenediamine (3.12 g, 14.8 mmol), isopropyl isothiocyanate (1.62 g, 16.0 mmol), 1-cyclohexyl-3-2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (8.4 g, 19.9 mmol), and pyridine (50 mL) were used according to general procedure II. The product was recrystallized from 1,4-dioxane to give 2.9 g (72%) of a tan solid. MS (CI): m/z 276 (M+1). Anal. Calcd. for C10H10Cl3N3-(0.10 C4H8O2): C, 43.47; H, 3.79; N, 14.62. Found. C, 43.70; H, 3.89; N, 14.43.
Reaction SMILES: [C:1]12([NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([NH2:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.CCN(C(C)C)C(C)C.[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[N:24]1.[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]([NH:12][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][C:3]([NH:11][C:36]([C:32]5[S:31][CH:35]=[CH:34][N:33]=5)=[O:37])([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:29])=[N:24]1
Reactant: O=C(Cl)c1nccs1
Reactant: Cn1ccc(C(=O)Cl)n1
Reactant: NC12CC3CC(C1)CC(N)(C3)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ccc(C(=O)NC23CC4CC(C2)CC(NC(=O)c2nccs2)(C4)C3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.9 %

Procedure:
To a solution of adamantane-1,3-diamine (17 mg, 0.1 mmol, Zerenex Molecular Ltd., Greater Manchester, UK) in DCM (2 mL) was added DIEA (20 mg, 0.15 mmol), 1-methyl-1H-pyrazole-3-carbonyl chloride (16 mg, 0.11 mmol; Maybridge Chemical Co., Cornwall, UK) and thiazole-2-carbonyl chloride (16 mg, 0.11 mmol; Maybridge Chemical Co., Cornwall, UK). After stirring at room temperature for 3 h, the reaction mixture was partitioned into dichloromethane and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a RP-HPLC/MS purification system (Gradient; acetonitrile in water, 25-95%, in 3.9 minutes with a cycle time of 5 min. A shallow gradient between 27-53% of acetonitrile was used between 0.75-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 25 mM of ammonium formate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan)) to afford 15 mg (38%) of the title compound, thiazole-2-carboxylic acid {3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amide, as a colorless oil. 1H NMR (400 MHz, CDCl3) δ7.81 (d, J=3.2 Hz, 1H), 7.53 (d, J=3.2 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.14 (d, J=2.3 Hz, 1H), 6.74-6.71 (m, 2H), 3.89 (s, 3H), 2.55-2.51 (m, 2H), 2.35-2.29 (m, 2H), 2.19-2.11 (m, 8H), 1.71-1.67 (m, 2H), ESI-MS m/z: 386.0 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][N:9]2[CH:13]=[CH:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[C:10]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(OCC)(=O)C>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][N:9]([CH2:8][CH2:7][CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:10]2=[O:23])=[CH:19][CH:18]=1
Reactant: O=c1n(CCCC2CCCC2)ccn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCN(CCCC3CCCC3)C2=O)cc1
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A mixture of the product from Example 49 (3.7 g, 11.7 mmol) and 10% palladium on activated carbon (0.74 g) in ethyl acetate (200 mL) was placed under an atmosphere of hydrogen overnight. The mixture was filtered through a pad of Celite with excess ethyl acetate, and the filtrate was concentrated to a crude brown oil. The crude was purified by silica gel chromatography (gradient elution from 2:1 hexanes/ethyl acetate to 1:1 hexanes/ethyl acetate) to afford a pale orange solid (2.01 g, 60%). Mp 97-99° C.; Rf =0.1 (2:1 hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 7.20 (d, 2 H), 6.72 (d, 1 H), 6.63 (d, 1 H), 6.57 (d, 2 H), 5.09 (br s, 1 H), 3.50 (t, 2 H), 1.72 (m, 3 H), 1.59 (m, 6 H), 1.26 (m, 2 H), 1.03 (m, 2 H); MS (FAB) m/z 286 (MH+).