Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[O:20]1C[CH2:23][CH2:22][CH2:21]1.C(Cl)(=O)C=C>O>[C:21]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:20])[CH:22]=[CH2:23]
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a mixture of 10 mmole of 1,3-adamantanediol, 15 mmole of triethylamine, and 100 ml of tetrahydrofuran, 13 mmole of acrylic chloride was added drop wise over about 30 minutes. After the completion of addition, the resulting mixture was stirred at 50° C for 1.5 hours. Water was added to the reaction mixture; the mixture was then extracted with ethyl acetate; the organic layer was concentrated; and the concentrate was subjected to column chromatography on a silica gel to yield the title compound in a yield of 63%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH3:11]CCCCCCCC.CNC(=NC)C1C=CC=CC=1.C(=O)(OC)OC>CO>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: CCCCCCCCC
Reactant: O=[N+]([O-])c1ccccc1O
Agent: CN=C(NC)c1ccccc1
Solvent: CO
Solvent: COC(=O)OC
Product: COc1ccccc1[N+](=O)[O-]

Procedure:
10 mol of 2-nitrophenol was charged into a stirred, heated reactor, along with 800 ml of nonane and 5% N,N'-dimethylbenzoamidine, and the mixture was heated to 150° C. Then 12 mol of dimethyl carbonate was added portionwise over 5 hr. The methanol produced by the reaction was removed by distillation over a distillation column. After completion of the reaction, the reaction mixture was refined by distillation. 2-Nitroanisole was obtained in the amount of about 9 mol, corresponding to a yield of c. 90%, based on the starting amount of 2-nitrophenol.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([OH:23])[CH:12]=[C:13]([C:15]2([O:21][CH3:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([C:15]2([O:21][CH3:22])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:14]=1)[O:23][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(F)cc(C2(OC)CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
A mixture of ethyl bromoacetate (0.5 g, 3 mmol), 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol (Example 8, Step 4) (0.3 g, 1.3 mmol) and K2CO3 (0.11 g, 0.8 mmol) in dimethylformamide (5.0 mL) was stirred at room temperature for 16 h under an argon atmosphere. The reaction mixture was partitioned between 5% citric acid (25 mL) and EtOAc (25 mL). The organic phase was washed with water, dried (Na2SO4), filtered and concentrated. The resulting syrup was purified by flash column chromatography on silica gel, eluting with 25% EtOAc in hexane, to give 0.3 g (73%) of ethyl 3-fluoro-5(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxyacetate as a colorless viscous liquid: 1H NMR (CDCl3/300 MHz) δ 6.77 (d,2H, J=10.5 Hz), 6.52 (d, 1H, J=10.5 Hz), 4.61 (s, 2H), 4.28 (q, 2H, J=6.9 Hz), 3.82 (m, 4H), 2.99 (s, 3H), 1.92 (m, 4H), 1.31 (t, 3H, J=6.9 Hz). FABMS m/z=313 (M+H). HRMS calcd for C16H22FO5313.1451, found 313.1399.
Reaction SMILES: [C:1]([N:5]1[CH2:27][CH2:26][CH2:25][CH2:24][C:8]2[C:9]([Cl:23])=[C:10]3[C:19]4[CH:18]=[C:17](Br)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>O.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>[C:1]([N:5]1[CH2:27][CH2:26][CH2:25][CH2:24][C:8]2[C:9]([Cl:23])=[C:10]3[C:19]4[CH:18]=[C:17]([C:31]5[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=5)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2c(cc1Br)-c1c(Cl)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
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+]
Solvent: COCCOC
Solvent: O
Product: COc1cc2c(cc1-c1cccnc1)-c1c(Cl)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 90 °C

Procedure:
A mixture of 65 mg of 19e, 25 mg of 3-pyridine-boronic acid, 45 mg of K2CO3 and 12 mg of Pd(PPh3)4 in 3 ml of degassed 90% aq. dimethoxyethane was heated under a nitrogen atmosphere for 16 h at 90° C. The mixture was diluted with water, extracted with ethyl acetate, dried and concentrated. The residues were purified by chromatography over silica gel, using a gradient of heptane/ethyl acetate as eluent. The material thus obtained was triturated with pentane, to provide 45 mg of white crystalline 19f; Mp: 190-192° C. MS-ESI: [M+1] 464.17, 465.17 and 466.17. NMR (CDCl3) δ 1.58 (s, 3, tertC4H9), 1.62-1.77 (bm, 2, CH2), 1.80-2.05 (bm, 2, CH2), 2.60-2.77 (bm, 2, CH2), 2.970-3.18 (bm, 2, CH2), 3.50 bm, 1, CH), 3.76-3.92 (bm, 2, CH2), 3.86 (s, 3, OCH3), 4.50 (bm, 1, CH), 6.87 (s, 1, ArH), 8.20 (s, 1, ArH), 7.36, 7.89, 8.57, 8.83 (4×m, 4, pyridine-H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]3[C:21]([CH:22]4[CH2:32][CH:23]4[CH2:24][O:25]3)=[CH:20][CH:19]=2)(=[O:16])=[O:15])=[C:10]([CH2:33][N:34](C)[C:35](=O)C(F)(F)F)[CH:9]=1>O.CO>[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]3[C:21]([CH:22]4[CH2:32][CH:23]4[CH2:24][O:25]3)=[CH:20][CH:19]=2)(=[O:15])=[O:16])=[C:10]([CH2:33][NH:34][CH3:35])[CH:9]=1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CN(C)C(=O)C(F)(F)F)ccc2c1OCC1CC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Temperature: 45 °C
Yield: 74.6 %

Procedure:
A solution of potassium carbonate (0.345 g) in water (2 mL) was added to a solution of methyl (1aRS,7bSR)-5-(4-fluoro-2-[N-methyl-N-(2,2,2-trifluoroacetyl)-aminomethyl]-benzenesulfonyl-amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 157, 0.257 g) in methanol (12 mL) and the mixture was heated at 45° C. for 3 hours. After cooling, the volatiles were removed in vacuo and the residue was treated with water (30 mL) and saturated with sodium chloride and extracted with ethyl acetate (50 mL). The organic layer was dried (Na2SO4) and filtered and the filtrate was evaporated to dryness to give methyl (1aRS,7bSR)-5-(4-fluoro-2-methylaminomethylbenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.156 g) as a solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:13]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:14][CH2:15][OH:16])[CH3:12].C(N(CC)CC)C>ClCCl.O>[CH2:11]([C:13]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:14][CH:15]=[O:16])[CH3:12]
Reactant: CCC(CC)(CC)CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCC(CC)(CC)CC=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 78.1 %

Procedure:
Step E To a solution of oxalyl chloride (0.86 mL, 9.9 mmol) (Aldrich) in dichloromethane (20 mL) at −78° C. was added the solution of dimethyl sulfoxide (1.4 mL, 19.8 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3,3-diethyl-pentan-1-ol (1.3 g, 9 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (4.5 mL, 32 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3,3-diethyl-pentanal as a yellow oil (Yield: 1 g, 78%).
Reaction SMILES: CO[CH:3]=[CH:4][C:5]([O:7][Si](C)(C)C)=[CH2:6].[CH2:12]1[CH2:16]O[CH2:14][CH2:13]1>[Cl-].[Cl-].[Zn+2]>[C:5]1(=[O:6])[C:7]2[C:16]3=[C:16]4[C:4](=[CH:5][CH:6]=2)[CH:3]=[CH:14][CH:13]=[C:12]4[CH:14]=[CH:13][C:12]3=[CH:3][CH2:4]1
Reactant: C1CCOC1
Reactant: C=C(C=COC)O[Si](C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C1CC=c2ccc3cccc4ccc1c2c43

Procedure:
To the 7,24-bis-OSiMe3-protected 1″,2″-dihydro-3″-aldehyde (1″,2″-dihydro-Intermediate II, 30 mg) in THF (0.8 μL) at rt was added 1-methoxy-3-trimethylsilyloxy-butadiene (50 μL) followed by ZnCl2 (80 μL, 1M solution in Et2O) After 2 h at rt and 12 h at 0° C., bis-protected Diels-Alder adducts were obtained without workup by PTLC on silica gel (1×1000 μm plate) using 2/8 acetone/hexanes as eluant. The pure products (7 mg methoxy-substituted pyranone and 10 mg pyrenone) thus obtained were characterized by 1H NMR. Both products were deprotected separately as described previously (10 mg pyrenone yielded 9 mg deprotected product and 7 mg methoxypyranone yielded 6 mg deprotected product). The deprotected products were characterized by 1H NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[OH:28].CCN(C(C)C)C(C)C.COCCOCCOC>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:28][C:20]3[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=3[F:18])[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CNc2cc(Cl)ncn2)cc1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: CCOC(C)=O
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2cc(Oc3ccc([N+](=O)[O-])cc3F)ncn2)cc1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 51.4 %

Procedure:
A mixture of N-(4-methoxybenzyl)-6-chloropyrimidin-4-amine (2.3 g, 9.2 mmol), 2-fluoro-4-nitrophenol (1.45 g, 9.2 mmol), DIPEA (15 mL), and 2-methoxyethyl ether (75 mL) was heated at 160° C. in a sealed pressure bottle for 50 h. The mixture was cooled, poured onto crushed ice (200 g), treated with EtOAc (200 mL). After vigorously stirring for 10 min, the insoluble material was filtered off. The EtOAc phase was washed with saturated aq. Na2CO3 solution (100 mL), brine (3×100 mL), dried (MgSO4) and concentrated in vacuo. The gummy solid obtained was triturated with isopropyl ether to give the title compound (1.75 g, 76%) as a brown solid. 1H NMR (DMSO-d6) δ 8.32 (dd, 1H, J=10.2, 2.0 Hz), 8.15 (d, 2H, J=9.2 Hz), 8.05 (br s, 1H), 7.61 (dd, 1H, J=8.4, 8.4 Hz), 7.26 (d, 2H, J=8.5 Hz), 6.91 (d, 2H, J=8.5 Hz), 6.14 (br s, 1H), 4.48 (br s, 2H), 3.74 (s, 3H).
Reaction SMILES: Cl.C([O:6][C:7]([NH:9][CH2:10][CH2:11][S:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[N:18]=1)=O)(C)(C)C.[O-]C#[N:24].[K+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C>[C:7]([NH:9][CH2:10][CH2:11][S:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[N:18]=1)(=[O:6])[NH2:24]
Reactant: N#C[O-]
Reactant: CC(C)(C)OC(=O)NCCSc1ccc2nccn2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)NCCSc1ccc2nccn2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
To 20 ml of 3 N-hydrochloric acid is added 2.94 g of 6-(2-tert-butoxycarbonylaminoethylthio)imidazo[1,2-b]pyridazine and the mixture is stirred at room temperature for 1.5 hours. Then, a solution of 4.06 g of potassium cyanate in 40 ml of water is added dropwise over 15 minutes with stirring at 35° C. and the mixture is further stirred at the same temperature for 1 hour and at 60° C. for 1 hour. To the reaction mixture are added 2.5 ml of acetic acid and 2.43 g of potassium cyanate and the mixture is stirred at 60° C. for 1 hour. Then, 20 ml of a saturated aqueous solution of sodium hydrogen carbonate and 20 ml of water are added and the mixture is cooled. The resulting crystals are collected by filtration, rinsed and dried to give 2.08 g of 6-(2-carbamoylaminoethylthio)imidazo[1,2-b]pyridazine as colorless crystals melting at 216° to 217° C.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:14](O)(=O)[C:15](C)([CH3:17])[CH3:16].S(O[O-])([O-])(=O)=O>C(#N)C.O.C(OCC)C.[N+]([O-])([O-])=O.[Ag+]>[C:15]([C:11]1[C:10](=[O:12])[C:9]2[C:4]([C:3](=[O:13])[C:2]=1[OH:1])=[CH:5][CH:6]=[CH:7][CH:8]=2)([CH3:17])([CH3:16])[CH3:14]
Reactant: CC(C)(C)C(=O)O
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [Ag+]
Agent: O=S(=O)([O-])O[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: CC(C)(C)C1=C(O)C(=O)c2ccccc2C1=O
Temperature: 20 °C
Yield: 34.4 %

Procedure:
2-Hydroxynaphthalene-1,4-dione (1.00 g, 5.68 mmol), pivalic acid (870 mg, 8.51 mmol) and silver nitrate (568 mg) were heated in a mixture of acetonitrile (20 ml) and water (20 ml) at 60-65° C. A solution of animonium peroxysulphate (1.94 g, 8.51 mmol) in water (10 ml) was added dropwise and the mixture heated for 1 hour. The mixture was then cooled to room temperature (about 20° C.), diluted with diethyl ether and extracted with 1% (w/v) aqueous sodium hydroxide solution (4×25 ml). The combined aqueous layers were then acidified with 2M hydrochloric acid and extracted with diethyl ether (3×25 ml). The combined ethereal extracts were then washed with water and saturated sodium chloride solution and dried over magnesium sulphate. Filtration and evaporation of the solvent under reduced pressure and purification by silica gel column chromatography yielded 2-(t-butyl)-3-hydroxynaphthalene-1,4-dione (450 mg) as a yellow crystalline solid, m.pt.: 89° C.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]([OH:7])[CH2:4][CH2:5]I.[N-:10]=[N+:11]=[N-:12].[Na+]>CS(C)=O.O>[N:10]([CH2:5][CH2:4][CH:3]([OH:7])[C:2]([F:9])([F:8])[F:1])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: OC(CCI)C(F)(F)F
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCC(O)C(F)(F)F
Temperature: 50 °C
Yield: 92.4 %

Procedure:
A solution of 1,1,1-trifluoro-4-iodo-2-butanol (0.604 g, 2.38 mmol) in DMSO (4 mL) was treated with sodium azide (0.178 g, 2.74 mmol) at ambient temperature, followed by heating at 50° C. for 21 h. The mixture was diluted with cold water and extracted with ethyl acetate. The combined organic extracts were washed (brine), dried, and evaporated to give the product as a pale yellow oil (0.372 g, 92%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=O.II.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C>[CH2:1]([N:8]1[C:9]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:10]=2[N:11]=[C:18]1[C:17]([O:21][CH2:22][CH3:23])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=O
Reactant: Nc1ccc(Cl)cc1NCc1ccccc1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 500 ml of ethanol solution containing 26 g of 2-benzylamino-4-chloroaniline was added 45.7 g of polymer form (45-50% toluene solution) of ethyl glyoxylate, further 28.4 g of iodine was added and the reaction mixture was stirred at room temperature for 20 minutes. Then 27.8 g of sodium thiosulfate aqueous solution was added thereto, the crystals being separated were collected by filtration, and washed with water and ethanol, then dried. There was obtained 26.1 g of ethyl 1-benzyl-6-chlorobenzimidazol-2-carboxylate as in the form of pale brown powdery product.
Reaction SMILES: [Si](OCC1N=CC2N(C3SC(C(OC)=O)=C(O)C=3)C=NC=2C=1)(C(C)(C)C)(C)C.[Si:29]([O:36][CH2:37][C:38]1[N:43]=[CH:42][C:41]2[N:44]=[CH:45][N:46]([C:47]3[S:51][C:50]([C:52]([O:54][CH3:55])=[O:53])=[C:49]([OH:56])[CH:48]=3)[C:40]=2[CH:39]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].Br[CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[C:71]([F:74])([F:73])[F:72]>CN(C)C=O>[Si:29]([O:36][CH2:37][C:38]1[N:43]=[CH:42][C:41]2[N:44]=[CH:45][N:46]([C:47]3[S:51][C:50]([C:52]([O:54][CH3:55])=[O:53])=[C:49]([O:56][CH2:64][C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=4[C:71]([F:72])([F:73])[F:74])[CH:48]=3)[C:40]=2[CH:39]=1)([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:30])[CH3:31]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B3, 2.08 g of an isomeric mixture of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-hydroxythiophene-2-carboxylate and methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate (example C3) and 0.82 g of K2CO3 and 1.42 g of 1-(bromomethyl)-2-(trifluoromethyl)benzene in 15 ml N,N-dimethylformamide yield compound B2a and compound B2b.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([NH:8][N:9]=[C:10]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1.[CH3:21]OC(OC)N(C)C>>[Br:1][C:2]1[C:3]([F:20])=[C:4]([N:8]2[CH:21]=[C:16]([O:17][CH3:18])[C:15](=[O:19])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1cccc(Br)c1F)C(=O)OC
Product: COC(=O)c1nn(-c2cccc(Br)c2F)cc(OC)c1=O
Temperature: 0 °C
Yield: 75 %

Procedure:
A mixture of methyl 2-[(3-bromo-2-fluorophenyl)hydrazono]-4-methoxy-3-oxobutanoate (5.36 g, 15.4 mmol) in N,N-dimethylformamide dimethyl acetal (54 mL) was heated to reflux for 2 h and cooled to 0° C. The precipitates were collected by filtration, washed with hexane and dried to yield the title compound (4.16 g, 75% yield) as a brown solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.80 (3H, s), 3.83 (3H, s), 7.40 (1H, td, J=8.1, 1.1 Hz), 7.75-7.84 (1H, m), 7.94 (1H, ddd, J=8.1, 6.4, 1.7 Hz), 8.60 (1H, d, J=1.9 Hz).
Reaction SMILES: C([C:4]([C:22](=O)[CH3:23])([CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH2:11][C:12]([O-:14])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)C.[C:25](=O)=O>C(O)C>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:10]1[CH2:11][C:12](=[O:14])[CH:25]=[C:22]([CH3:23])[CH:4]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C(C)=O)(C(C)=O)C(CC(=O)[O-])c1ccccc1F
Reactant: O=C=O
Solvent: CCO
Product: CCOC(=O)C1C(C)=CC(=O)CC1c1ccccc1F

Procedure:
The ethyl α,α-diacetyl-β-(2-fluorophenyl)glutarate was heated under vacuum at 160°-180°/10-15 mm for 1 hr, eliminating carbon dioxide and ethanol and producing 5-(2-fluorophenyl)-3-methyl-4-carbethoxy-2-cyclohexen-1-one. The crude product was distilled under reduced pressure to give 5-(2-fluorophenyl)-3-methyl-4-carbethoxy-2-cyclohexen-1-one (57.3 g); bp, 155°-162°/1.2 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:22])[C:12]([S:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[N:13][CH:14]=2)=[O:9])=[CH:4][CH:3]=1.[OH:23]O.O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:22])[C:12]([S:15]([CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[O:23])=[N:13][CH:14]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: OO
Reactant: CN(C)CCCSc1ncc(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CCCS(=O)c1ncc(C(=O)c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of (4-Chloro-phenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone (135 mg) in glacial acetic acid (4.00 mL) was added at rt H2O2 (82.0 μL; 30 wt. % in water). The reaction solution was stirred for 48 h at rt, and water (10.0 mL) was added. The solution was brought to pH=12 using NaOH (25% in water) and extracted with CH2Cl2 (250 mL, 2×50.0 mL). The combined organic layers were washed with water (3×20.0 mL) and were dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel (CHCl3/2 M NH3 in MeOH) to give the title compound (121 mg). M calc=353; M+H found=354; 1H NMR (400 MHz, CD3OD): δ 7.91-7.87 (m, 2H), 7.70 (s, 1H), 7.60-7.55 (m, 2H), 4.21 (s, 3H), 3.61-3.48 (m, 2H), 2.54-2.43 (m, 2H), 2.21 (s, 6H), 2.04-1.94 (m, 2H). The compound demonstrated useful biological activity when assessed with a [3H]-N-methylhistamine binding assay (see Table in Example XXV).
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].[CH2:25]([C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([CH2:25][CH3:26])[CH:28]=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: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CCc1cccc(O)c1
Product: CCc1cccc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 81 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-ethyl-phenol (32 mg, 0.26 mmol) to give the title compound (49 mg, 80%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:22])=O)=[CH:16][CH:15]=1.[C:23]1([C@@H:29]([NH2:31])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:23]1([C:29](=[N:31][C@H:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH3:22])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: C[C@H](N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=N[C@@H](C)c1ccc(C)cc1)c1ccccc1
Yield: 89 %

Procedure:
At first, 0.24 g (1.25 mmol) of p-toluenesulfonic acid monohydrate were added to a toluene solution (25 ml) containing 3.35 g (25 mmol) of 4-methylacetophenone (3c) as a ketone and 3.03 g (25 mmol) of (S)-1-phenylethylamine ((S)-2a) as an optically active primary amine, followed by heating under reflux for 24 hr and by removing water (formed as a by-product) with a Dean-Stark tube during the reaction, in order to conduct the reaction. Then, the reaction liquid after the reaction was washed with a saturated sodium hydrogencarbonate aqueous solution, followed by drying with sodium sulfate anhydride, then filtration, then concentration, and then vacuum drying, thereby obtaining as a crude product 5.66 g of (S)-N-(1-phenylethylidene)-1-(4-methylphenyl)-ethylamine ((S)-3ca, yield: 89%).