Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH2:23])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1.[CH3:31][C:32]1[CH:36]=[C:35]([C:37](O)=[O:38])[O:34][N:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH:23][C:37]([C:35]5[O:34][N:33]=[C:32]([CH3:31])[CH:36]=5)=[O:38])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)n1
Reactant: Cc1cc(C(=O)O)on1
Product: Cc1cc(C(=O)NC2(C(=O)NC3CCc4cc(-c5cc(Cl)cc(F)c5-c5nnn(C)n5)cnc43)CC2)on1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-3-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide (example 55) was coupled with 3-methyl-isoxazole-5-carboxylic acid to yield the title compound as light yellow solid. MS: 537.2 (MH+, 1Cl).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=1.[C:20](OCC)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:19][S:18][C:14]1[N:13]=[C:12]([CH2:11][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])[CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)c1ccccc1
Reactant: CSc1nccc(C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nccc(CC(=O)c2ccccc2)n1
Yield: 99.5 %

Procedure:
86 ml (86 mmoles) of 1.0 M sodium bis(trimethylsilyl)amide in tetrahydrofuran was added drop-wise by addition funnel to a solution of 6.03 g (43 mmoles) 4-methyl-2-(methylthio)pyrimidine and 6.46 g (43 mmoles) ethyl benzoate in 86 ml tetrahydrofuran under a nitrogen atmosphere. After 2 hours the reaction was quenched with saturated ammonium chloride solution. Most of the tetrahydrofuran was removed in vacuo. The residue was diluted with 400 ml ethyl acetate and 200 ml water. The organic layer was separated and washed 2×100 ml saturated sodium chloride solution, separated, dried over Na2SO4, filtered, and concentrated in vacuo to give 10.45 g (42.77 mmoles) of 2-[2-(methyl thio)pyrimidin-4-yl]-1-phenyle thanone as a viscous red-brown oil that solidified upon standing. MH+=244.9.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:29])[CH:5]([CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[NH:6][C:7](=[O:21])[CH2:8][N:9]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:10].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[BH3-]C#N.[Na+].Cl>CO.C1COCC1.C([O-])(O)=O.[Na+].C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:29])[CH:5]([CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:25][CH2:24]1)[NH:6][C:7](=[O:21])[CH2:8][N:9]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:10]
Reactant: COC(=O)C(CC1CCNCC1)NC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(CC1CCN(Cc2ccccc2)CC1)NC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 5 h
Yield: 52.1 %

Procedure:
N-(Toluene-4-sulfonyl)sarcosyl-β-(piperidin-4-yl)-D,L-alanine methyl ester hydrochloride (180 mg, 0.402 mmol) was dissolved in MeOH (3 mL). Triethylamine (56 μL), benzaldehyde (53 mg, 0.502 mmol) and 1.0 M NaBH3CN in THF (400 μL) were added and the mixture was stirred for 5 hr. 1N HCl (3 mL) was added and the mixture was stirred for 5 minutes before diluting with saturated aqueous NaHCO3 (30 mL). The mixture was extracted with EtOAc (3×25 mL) and the combined extracts were dried (Na2SO4), filtered and evaporated in vacuo to give a residue which was purified by silica gel flash chromatography (95:5:0.5 CH2Cl2/MeOH/NH4OH) to give N-(toluene-4-sulfonyl)sarcosyl-β-(N-benzylpiperidin-4-yl)-D,L-alanine methyl ester (105 mg, 52%). The title compound was prepared via hydrolysis of the methyl ester using 0.5 N aqueous NaOH in THF/water as a very hygroscopic solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]([C:15](=[O:28])[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH3:27])=[O:26])=[CH:20][CH:19]=2)[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.C(O)(=O)C>CN(C)C=O.C1C=CC=CC=1>[NH:24]([C:21]1[CH:22]=[CH:23][C:18]([C:17]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]([C:15](=[O:28])[CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:19][CH:20]=1)[C:25]([CH3:27])=[O:26]
Reactant: COC(=O)C(=CNc1ccc(F)cc1)C(=O)C=Cc1ccc(NC(C)=O)cc1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
In 25 ml of N,N-dimethylformamide was dissolved 2.9 g of methyl 2-(4-fluorophenylaminomethylene)-5-(4-acetaminophenyl)-3-oxo-4-pentenoate, and they are reacted at 140° C. for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform) to obtain an oily substance. This oily sugstance was dissolved in 30 ml of benzene, followed by dropwise addition thereto of a solution of 2.06 g of 2,3,5,6-tetrachloro-p-benzoquinone in 18 ml of benzene at 80° C. After completion of this dropwise addition, the reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration and washed with 30 ml of benzene. These crystals were then dissolved in a mixed solution of 20 ml of methanol and 20 ml of a 1N aqueous sodium hydroxide solution, and they were reacted at room temperature for 30 minutes. The reaction solution was adjusted to a pH of 6.0 with acetic acid and the precipitated crystals were collected by filtration, washed with water and dried to obtain 2.3 g of 6-(4-acetaminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 249°-250° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[N:9]=[C:8]1[CH2:22][CH2:23][CH3:24])[CH3:2].[CH2:29]([NH2:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:1]([C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:35][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:18])=[CH:15][CH:14]=2)[N:9]=[C:8]1[CH2:22][CH2:23][CH3:24])[CH3:2]
Reactant: CCCCCCN
Reactant: CCCC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=CNc1ccccc1CC
Product: CCCCCCNC(=O)c1ccc(N2N=C(CCC)C(=CNc3ccccc3CC)C2=O)cc1

Procedure:
From the reaction of 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzoic acid and hexylamine, 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-N-hexylbenzamide is obtained, Mp 46.7° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][CH2:11][C:12]([O:14]CC)=[O:13].[OH-].[K+]>CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CN=c1sc2ccccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN=c1sc2ccccc2s1
Yield: 58.5 %

Procedure:
A solution of [(1,3-benzodithiol-2-ylidene)amino]acetic acid ethyl ester (2.5g, prepared as described in Example 1) and potassium hydroxide (550 mg) in 500 ml of anhydrous methyl alcohol is stirred at room temperature for 120 hours. The reaction mixture is then concentrated in vacuo. The resultant solid residue is triturated with diethyl ether to remove unreacted starting material. The undissolved residue is then dissolved in 50 ml of water and filtered through Celite. The aqueous solution is treated with 10% hydrochloric acid until the pH is 5. The resultant precipitate is collected by filtration and dried in vacuo over phosphorous pentoxide at 60° C for about 16 hours. The dried solid is recrystallized twice from ethyl acetate to yield 1.3g of the title compound, melting point 195°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[S:16][CH2:17][C:18]2[C:23](F)=[CH:22]C=[C:20](F)[C:19]=2F)=[CH:4][CH:3]=1.[NH:27]1C(C([O-])=O)=CN=C1.[Li+].[OH-]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[S:16][CH2:17][C:18]2[CH:19]=[CH:20][N:27]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])c1cnc[nH]1
Reactant: O=C(O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(SCc2ccncc2)n1-c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-2-((pyridin-4-ylmethyl)thio)-1H-imidazole-5-carboxylic acid (51) was prepared in a similar manner as that described for the synthesis of compound 11 using ethyl 1-(4-fluorophenyl)-2-(pyridine-4-ylmethyl)thio)-1H-imidazole-5-carboxylate (50) (390 mg, 1.09 mmol), 1N LiOH (5 mL) in THF (5 mL) and MeOH (5 mL).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH2:25][CH3:26])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:27].Cl[CH2:29][C@@H:30]([OH:33])[CH2:31][OH:32]>C(O)(C)C.[OH-].[Na+]>[OH:33][C@@H:30]([CH2:31][OH:32])[CH2:29][O:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH2:25][CH3:26])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:27]
Reactant: OC[C@H](O)CCl
Reactant: CCCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCc1sc(C(=O)CCc2cc(C)c(OC[C@@H](O)CO)c(C)c2)cc1-c1ccccc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 26.5 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(4-phenyl-5-propyl-thiophen-2-yl)-propan-1-one (47 mg, 125 μmol) in isopropanol (2 mL) and 3 N aq. NaOH (0.5 mL) is treated with (S)-3-chloro-propane-1,2-diol (55 mg, 0.50 mmol) and the mixture is stirred at 70° C. for 14 h. Another portion of (S)-3-chloro-propane-1,2-diol (55 mg, 0.50 mmol) is added and stirring is continued at 70° C. for 24 h. The solvent is removed in vacuo and the residue is separated on prep. TLC plates with heptane:EA 2:1 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(4-phenyl-5-propyl-thiophen-2-yl)-propan-1-one (15 mg) as a colourless resin; LC-MS: tR=1.05 min, [M+1]+=453.18.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([O:30][CH:31]([CH3:33])[CH3:32])[C:15]([N:17]2[CH:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][O:19][C:18]2=[O:29])=[O:16])[CH:8]=1)(=O)=O.[CH2:36]([OH:39])[C:37]#[CH:38].C(N(CC)CC)C>CN(C)C=O.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:22]([CH:21]1[CH2:20][O:19][C:18](=[O:29])[N:17]1[C:15](=[O:16])[CH:14]([O:30][CH:31]([CH3:32])[CH3:33])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:38]#[C:37][CH2:36][OH:39])[CH:8]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C#CCO
Reactant: CC(C)OC(Cc1cccc(OS(=O)(=O)C(F)(F)F)c1)C(=O)N1C(=O)OCC1Cc1ccccc1
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)OC(Cc1cccc(C#CCO)c1)C(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
390 mg of 3-[3-(4-Benzyl-2-(oxo)-oxazolidin-3-yl)-2-isopropoxy-3-oxo-propyl]-phenyl trifluoromethanesulfonate was dissolved in 2 ml of N,N-dimethylformamide, 85 mg of propargyl alcohol, 8 mg of copper iodide, 45 mg of tetrakis (triphenylphosphine) palladium and 0.3 ml of triethylamine were added in succession, and the mixture was stirred overnight at 50° C. under a nitrogen atmosphere. The reaction solution was filtered through silica gel, and the filtrate was dissolved in ethyl acetate, washed with water, 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 207 mg of the title compound as a colorless oil in the 3:2 hexane-ethyl acetate fraction.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[CH:10]([N:25]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1.C(#N)C>O>[C:41]1([CH3:51])[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:48])=[O:49])=[CH:45][CH:46]=1.[CH2:1]([O:8][C:9](=[O:39])[CH:10]([NH2:25])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CC(N=C(c2ccccc2)c2ccccc2)C(=O)OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(CC(N)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
A solution of rac.-2-[(diphenylmethylene)amino]-3-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid benzyl ester (11.5 g. 22 mmol) and p-toluenesulfonic acid monohydrate (4.18 g. 22 mmol) in a 10/1 mixture of acetonitrile and water (640 ml) was stirred for 2 h at room temperature. Concentration provided a crude solid product which was recrystallized from ethanol-ether to give rac.-2-amino-3-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid benzyl ester p-toluenesulfonic acid salt, (8.1 g, 15 mmol) in 67% yield. mp. 154°-157° C. Following the previous procedure, the analogs listed below were prepared.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][C:8]#[N:9].C(C[C@H]1CCCN1C(OC(C)(C)C)=O)#N>>[ClH:1].[NH:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][C:8]#[N:9]
Reactant: N#CC[C@@H]1CCCN1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1CC#N
Agent: Cl
Product: N#CC[C@H]1CCCN1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 138, starting from tert-butyl (R)-2-cyanomethylpyrrolidine-1-carboxylate (Intermediate 144) and used without further characterisation.
Reaction SMILES: [H-].[Na+].C1(O)C=CC=CC=1.[C:10]([O:18][CH2:19][CH2:20]Cl)(=[O:17])[C:11]([O:13][CH2:14][CH2:15]Cl)=[O:12].FC(F)=C(F)F>COCCOCCOC.CCOCC.O>[CH2:14]1[O:13][CH:11]([CH:10]2[O:18][CH2:19][CH2:20][O:17]2)[O:12][CH2:15]1
Reactant: O=C(OCCCl)C(=O)OCCCl
Agent: FC(F)=C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Solvent: CCOCC
Product: C1COC(C2OCCO2)O1
Reaction time: 8 h
Yield: 161.8 %

Procedure:
A suspension of 24.0 g (0.50 mol) of 50% NaH in mineral oil in 100 mL of diglyme was treated with a solution of 47.0 g (0.50 mol) of phenol in 50 mL of diglyme. The resulting mixture was stirred overnight, and then charged into a 400 mL metal tube along with 53.8 g (0.25 mol) of bis(2-chloroethyl) oxalate and 50 g (0.50 mol) of tetrafluoroethylene. The resulting reaction mixture was agitated for 12 hr, and then shaken with 1 L of cold water, after which layers formed. The lower layer, which was a mixture of solid and oil, was dissolved in 900 mL of ether to give an ether solution which was dried over CaSO4, filtered, and concentrated to 200 mL. Addition of 50 mL of petroleum ether to the concentrated ether solution caused precipitation of a crystalline product which was filtered off and rinsed to give 59.1 g of crystalline 2,2'-bi(2-[ 2-phenoxytetrafluoroethyl[-1,3-dioxolane), m.p. 102°-103°. The filtrate was cooled to obtain a second crop of crystals, m.p. 92°-97°, to give a total of 64.5 g (49% yield) of the bisketal. An analytical sample , m.p. 102.5°-103.5°, was obtained by recrystallization of some of the product from tetrahydrofuran/petroleum ether mixed solvent. The IR (KBr) and NMR (acetone-d6) spectra of the product were consistent with the structure. Anal.: Calcd for C22H18F8O6 : C, 49.82; H, 3.42; F, 28.66. Found C, 50.02; H, 3.47; F, 28.68.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[S:8][C:7]1([CH2:16][CH2:15][CH2:14]1)[CH2:6][C:5]2=O.Cl.[CH3:20][O:21][NH2:22]>N1C=CC=CC=1>[CH3:20][O:21][N:22]=[C:5]1[C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[S:8][C:7]2([CH2:16][CH2:15][CH2:14]2)[CH2:6]1
Reactant: CON
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC1(CCC1)S2
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CC2(CCC2)Sc2c(C)c(C)c(O)c(C)c21
Reaction time: 8 h

Procedure:
To a solution of 6′-hydroxy-5′,7′,8′-trimethylspiro[cyclobutane-1,2′-thiochromen]-4′(3′H)-one prepared as described above (300 mg) in 2 mL of pyridine was added methoxyamine hydrochloride (192 mg, 2.3 mmol). The reaction mixture was allowed to stir overnight. The mixture was washed with water and extracted with ethyl acetate. After concentration in vacuo, the residue was purified by flash chromatography eluted with 20% ethyl acetate in hexane to give 150 mg of 6′-hydroxy-5′,7′,8′-trimethylspiro[cyclobutane-1,2′-thiochromen]-4′(3′H)-one O-methyloxime, as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[NH:7][C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:9])([O-])=O.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]2[NH:18][C:17]3[CH:16]=[CH:15][C:6]([NH:7][C:8]([C:10]4[S:11][CH:12]=[CH:13][CH:14]=4)=[O:9])=[CH:5][C:4]=3[N:1]=2)=[CH:25][CH:24]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1cccs1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(-c2nc3cc(NC(=O)c4cccs4)ccc3[nH]2)cc1

Procedure:
Compound 210 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(thien-2-oyl)aniline and 4-methoxybenzaldehyde. [M+H]+ calcd for C19H15N3O2S: 350.09; found: 349.89.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17]C)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]>C(O)(=O)C.Br>[OH:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[OH:17])[C:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: COc1cc(C(=O)c2ccccc2)cc([N+](=O)[O-])c1OC
Agent: Br
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
0.5 g of 3,4-dimethoxy-5-nitrobenzophenone is stirred at 110° for 30 hours in a mixture of 4 ml of acetic acid and 4 ml of 48 percent aqueous hydrobromic acid. The reaction mixture is subsequently evaporated to dryness. The residue is taken up in methylene chloride. It is washed with water, dried over sodium sulfate and evaporated. After recrystallization from methylene chloride/hexane there is obtained 3,4-dihydroxy-5-nitrobenzophenone of m.p. 132°.
Reaction SMILES: [OH:1][C:2]1[C:11]2[S:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Br:14][CH:15](Br)[CH3:16]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Br:14][CH2:15][CH2:16][O:1][C:2]1[C:11]2[S:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(Br)Br
Reactant: Oc1cccc2c1SCCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Product: BrCCOc1cccc2c1SCCC2
Reaction time: 24 h

Procedure:
Tetrabutylammonium bromide (1.94 g 6 mmol; 0.2 eq.), phase-transfer agent, is added to a heterogeneous mixture composed of 8-hydroxy-3,4-dihydro-2H-1-benzothiopyran (5 g; 30 mmol), acetonitrile (30 ml) and a 1.6N sodium hydroxide solution (28.3 ml; 45 mmol; 1.5 eq.). Dibromoethane (10 ml; 60 mmol; 1.5 eq.) is added after 30 minutes' stirring, the stirring being continued for 24 hours at 30° C. Concentration of the various phases under reduced pressure at 25° C. is followed by extraction of the products with dichloromethane. Washing with a 5% sodium hydroxide solution allows a first purification, which is followed by purification over a silica column eluted with a 3:7 AcOEt/PE mixture, yielding the brominated title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([O:13]C)=[O:12])=[CH:5][CH:4]=1.O1CCOCC1.[OH-].[K+]>O>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([OH:13])=[O:12])=[CH:19][CH:20]=1
Reactant: CCCC(CC(=O)OC)(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(CC(=O)O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Methyl 3,3-bis(4-methoxyphenyl)hexanoate (5.2 g, 15.2 mmol) was introduced into 20 ml of dioxane, KOH (1.05 g, 18.2 mmol) was added, and the mixture was boiled for about 1 h. It was subsequently diluted with water and washed with ethyl acetate, and the aqueous phase was then adjusted to pH 3 with dilute HCl and extracted with ethyl acetate. The organic phase was then washed with saturated NaCl solution, dried over MgSO4 and concentrated. Chromatography on silica gel (CH2Cl2 /methanol 3%) resulted in 4.1 g of a pale yellowish oil (84%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:10]([CH2:12][OH:13])[N:11]=1)=[O:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[C:10]([CH:12]=[O:13])[N:11]=1)=[O:5]
Reactant: O=C(Nc1nc(CO)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Into a solution of Compound 39 (100 mg, 0.24 mmol) in 2 mL of CH2Cl2 was added Dess-Martin periodinane (127 mg, 0.3 mmol) at 0° C. The solution was stirred at 0° C. for 1 hour and warmed to room temperature. The reaction was concentrated. The residue was purified by column chromatography on silica gel (1-5% MeOH in CH2Cl2) to give Compound 67 (93 mg, 94%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:24]=O.[NH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>ClCCl>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:24]=[N:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: Cc1c(C=O)oc2cccc(OCCCN(C)Cc3cccnc3)c12
Reactant: NN1CCOCC1
Solvent: ClCCl
Product: Cc1c(C=NN2CCOCC2)oc2cccc(OCCCN(C)Cc3cccnc3)c12
Reaction time: 8 h

Procedure:
To a solution of 3-methyl-4-[3-(methyl-pyridin-3-ylmethyl-amino)-propoxy]-benzofuran-2-carbaldehyde (the compound of Example 115-b) (420 mg) in dichloromethane (50 ml) was added 4-aminomorpholine (380 mg) at room temperature. After stirring overnight, the mixture was washed with water (20 ml), NH4Cl solution (20 ml) and dried over anhydrous sodium sulfate. The mixture was purified by silica gel column chromatography developed by dichloromethane and methanol to give the title compound as a colorless oil (340 mg). ESI-MS: m/z 423 (MH+); 1H-NMR (CDCl3): δ 1.98-2.07 (2H, m), 2.23 (3H, s), 2.30 (3H, s), 2.59 (2H, t, J=6.9 Hz), 3.21-3.26 (4H, m), 3.53 (2H, s), 3.88-3.92 (4H, m), 4.10 (2H, t, J=5.9 Hz), 6.58 (1H, d, J=7.6 Hz), 7.03-7.15 (3H, m), 7.58-7.63 (2H, m), 8.40-8.51 (2H, m).