Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(=O)(O)(O)O.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][CH2:12][N:13]=[C:14]=[S:15].[I:16][CH3:17]>CC(C)=O>[IH:16].[CH3:17][S:15][C:14]1[C:8]2[CH:9]=[CH:10][S:6][C:7]=2[CH2:11][CH2:12][N:13]=1
Reactant: S=C=NCCc1cccs1
Reactant: CI
Agent: O=P(O)(O)O
Solvent: CC(C)=O
Product: CSC1=NCCc2sccc21
Product: I
Reaction time: 1 h

Procedure:
To a stirred solution of phosphoric acid (205 g) at 175° C. was added dropwise 2-(2-thienyl)ethylisothiocyanate (R. V. Davies et al., J. Chem. Soc., Perkin l, 1976, 138). The solution was stirred for 1 h, poured onto ice/water (3 L), the mixture stirred for 3 h to decompose the phosphoric acid, extracted with chloroform, dried over magnesium sulphate and evaporated to give a dark oil which solidified on standing. This solid was taken up in acetone (250 ml) and iodomethane (12 ml) was added. The reaction mixture was stirred for 4 h and the solid was collected to give the title compound as a yellow solid (26 g), m.p. 184-187° C.
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[CH:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(C)C=CC=CC=1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.[CH3:44][OH:45]>C(Cl)(Cl)(Cl)Cl>[CH3:44][O:45][C:11]([C@@H:6]1[C@H:5]2[CH2:1][C@H:2]([CH:3]=[CH:4]2)[C@@H:7]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: O=C1OC(=O)C2C1[C@@H]1C=C[C@H]2C1
Reactant: CO
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H]1[C@@H](C(=O)O)[C@H]2C=C[C@@H]1C2
Temperature: -55 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
The starting material (a) was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-5-Norbornene-endo-2,3-dicarboxylic anhydride (4.104 g, 25 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (500 mL). The mixture was stirred for 20 min. Quinine (8.92 g, 27.5 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stirring, methanol (3.04 mL, 75 mmol) was added. The mixture was stirred at −55° C. for 20 h. Upon warming to 25° C., the mixture was concentrated in vacuo to a thick oil. The oil was dissolved in ethyl acetate (400 mL), washed with 1.0M aqueous hydrochloric acid solution (2×400 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1R,2S,3R,4S)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (4.8 g, 24.5 mmol, 98%), as a clear waxy solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (1H, d, J=8.5 Hz), 1.33 (1H, d, J=8.8 Hz), 3.00 (1H, s), 3.03 (1H, s), 3.21-3.30 (2H, m), 3.45 (3H, s), 6.02-6.04 (1H, m), 6.14-6.16 (1H, m), 11.86 (1H, s).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26]([N:32]=[C:33]=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH2:26]([NH:32][C:33](=[O:34])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: CCCCCCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) and triethylamine (0.4 mL) in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, n-hexyl isocyanate (457 mg/ml, 3.14 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere a RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 ml) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8g as solid. Yield: 0.619 g, 81%.
Reaction SMILES: [OH-].[K+].[N:3]#[C:4][NH2:5].[F:6][C:7]([F:28])([F:27])[C:8]1[CH:26]=[CH:25][C:11]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.Cl>O.CC(C)=O>[C:4]([NH:5][C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:11]2[CH:25]=[CH:26][C:8]([C:7]([F:28])([F:6])[F:27])=[CH:9][CH:10]=2)=[CH:24][CH:23]=1)[CH3:22])#[N:3]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Reactant: N#CN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)NC#N
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
10.4 g (0.1575 mole) of 85% potassium hydroxide are dissolved in 75 ml of water. 3.5 g (0.0825 mole) of cyanamide are added at 20° C. and the clear, colourless solution is cooled to 10° C. Then a solution of 25.8 g (0.075 mole) of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl chloride in 15 ml of acetone is added dropwise such that the temperature does not exceed 15° C. After the reaction mixture has been stirred for 45 minutes at this temperature, 9 g (0.09 mole) of 37% aqueous hydrochloric acid are added dropwise at 5° C. The product precipitates as an oil which crystallises on standing over 30 minutes. The colourless crystals are isolated by filtration, washed with water, dried over phosphorous pentoxide, affording 24.9 g (95.0% of theory) of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid N-cyanamide with a melting point of 125°-127° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].Cl[CH:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)C>[CH3:15][C:14]1[N:6]=[C:2]2[N:3]([C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:5][S:1]2
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1nccs1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2sccn12
Temperature: 80 °C
Reaction time: 24 h
Yield: 26.2 %

Procedure:
A mixture of 1,3-thiazol-2-amine (10 g, 100 mmol), ethyl 2-chloro-3-oxobutanoate (16 g, 100 mmol) and ethanol (100 mL) was stirred at 80° C. for 1 day. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→50/50) and washed with diisopropyl ether to give the title compound (5.5 g, 26%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.O.[NH2:11][NH2:12]>O1CCOCC1.O>[C:8]([C:4]1[CH:3]=[C:2]([NH:11][NH2:12])[CH:7]=[CH:6][N:5]=1)#[N:9]
Reactant: N#Cc1cc(Cl)ccn1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(NN)ccn1

Procedure:
4-Chloro-2-cyanopyridine (1 g) was dissolved in hydrazine monohydrate (1 ml) and 1,4-dioxane (10 ml), and stirred overnight under reflux. The reaction solution was diluted with water (30 ml) and extracted repeatedly with ethyl acetate. The organic layer was concentrated to obtain the title compound as a crude product, which was used for the next step without further purification.
Reaction SMILES: OOS([O-])=O.[K+].[CH3:7][O:8][C:9](=[O:24])[C:10]([CH3:23])([CH3:22])[CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([CH:19]=O)=[C:14]([CH3:21])[CH:13]=1.ClC1C=C(N[C:33]2[O:37][C:36]([C:38]3[CH:39]=[CH:40][C:41]4[N:45]=C(C5C(C)=CC(CCC(O)=O)=CC=5C)[NH:43][C:42]=4[CH:59]=3)=[N:35][N:34]=2)C=CC=1.CN([CH:63]=[O:64])C>O>[CH3:7][O:8][C:9](=[O:24])[C:10]([CH3:23])([CH3:22])[CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([C:19]2[NH:45][C:41]3[CH:40]=[CH:39][C:38]([C:36]4[O:37][C:33]([C:12]5[CH:17]=[CH:16][C:15]([O:64][CH3:63])=[CH:14][CH:13]=5)=[N:34][N:35]=4)=[CH:59][C:42]=3[N:43]=2)=[C:14]([CH3:21])[CH:13]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Reactant: Cc1cc(CCC(=O)O)cc(C)c1-c1nc2ccc(-c3nnc(Nc4cccc(Cl)c4)o3)cc2[nH]1
Reactant: CN(C)C=O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: COC(=O)C(C)(C)Cc1cc(C)c(-c2nc3cc(-c4nnc(-c5ccc(OC)cc5)o4)ccc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxone (420 mg, 0.683 mmol) was added to a mixture of 3-(4-formyl-3,5-dimethyl-phenyl)-2,2-dimethyl-propionic acid methyl ester (250 mg, 1.00 mmol) and 4-[5-(4-Methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diamine (prepared as described in Example 1-59, 300 mg, 1.06 mmol) in DMF (8 mL) and water (0.8 mL), and the mixture was stirred at room temperature for 18 h. The mixture was partitioned between EtOAc and water. The EtOAc extract was washed with brine, dried over Na2SO4, concentrated and chromatographed to give the title compound. m/z 511.3 (MH+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:13][C:14]([S:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8](/[CH:11]=[N:19]/[S:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: O=CC1CCC2(CC1)OCCO2
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)/N=C/C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (6.68 g, 39.2 mmol, prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292), racemic 2-methylpropane-2-sulfinamide (3.50 g, 28.0 mmol), tech grade titanium (IV) ethoxide (14 mL, 67.5 mmol) were dissolved in dry THF (100 mL), placed under an argon atmosphere and stirred at ambient temperature for 16 hours. The next day the reaction mixture was diluted with ethyl acetate and poured onto rapidly stirred ice cold brine. The copious white precipitate was removed by filtration through celite and the organic layer removed. After drying over Na2SO4 and concentration the residue was purified by flash chromatography (silica gel, 0-100% ether/DCM) to afford the product.
Reaction SMILES: CS([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)=O.[F:28][C:29]([F:33])([F:32])[CH2:30][OH:31].[H-].[Na+].Cl>O1CCCC1>[F:28][C:29]([F:33])([F:32])[CH2:30][O:31][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1
Reactant: OCC(F)(F)F
Reactant: CS(=O)c1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(OCC(F)(F)F)nc2[nH]1
Reaction time: 0.17 h

Procedure:
2-(Methylsulfinyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (150 mg) was suspended in tetrahydrofuran (5 ml), 2,2,2-trifluoroethanol (108 μl) was added thereto, and then sodium hydride (60% in oil, 37.6 mg) was added thereto under ice-cooling, and the mixture was stirred for 10 min. To the reaction mixture was added 0.5M hydrochloric acid (4 ml), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained white residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (128 mg) as a white solid.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Br[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[N:7]=1>C1(C)C=CC=CC=1.O>[Br:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:1][CH2:2][CH3:3])[N:7]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1cccc(Br)n1

Procedure:
Sodium ethoxide (1.5 g, 63 mmol sodium, in ethanol (30 ml)) was added to 2,6-dibromopyridine (15 g, 63 mmol) in toluene (150 ml) at ambient temperature under nitrogen, and the reaction heated under reflux for 5 hours. The cooled mixture was diluted with water (100 ml), and extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel using pentane/ethyl acetate (100:0 to 95:5) as eluant to give the title compound as a yellow oil, (quantitative).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)=[O:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 3 h
Yield: 196.8 %

Procedure:
To a mixture of 3-hydroxy-4-methylbenzoic acid (2.00 g) and potassium carbonate (5.40 g) in DMF (20 mL) was added dropwise benzyl bromide (4.50 g) at room temperature, and the mixture was stirred for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (4.30 g) as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][S:9]([N:12]2[CH2:17][C@H:16]([CH3:18])[NH:15][C@H:14]([CH3:19])[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH2:20].CCO.C([O-])([O-])=O.[Na+].[Na+].[C:30]1(B(O)O)[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1>C1(C)C=CC=CC=1.CCOC(C)=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:30]1([C:2]2[CH:7]=[C:6]([CH2:8][S:9]([N:12]3[CH2:17][C@H:16]([CH3:18])[NH:15][C@H:14]([CH3:19])[CH2:13]3)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=2[NH2:20])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: OB(O)C1=CCCCC1
Reactant: C[C@@H]1CN(S(=O)(=O)Cc2ccc(N)c(Br)c2)C[C@H](C)N1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@@H]1CN(S(=O)(=O)Cc2ccc(N)c(C3=CCCCC3)c2)C[C@H](C)N1
Temperature: 80 °C
Yield: 85.9 %

Procedure:
A solution of 356 mg (0.983 mmol) of 2-bromo-4-(cis-3,5-dimethyl-piperazine-1-sulfonylmethyl)-phenylamine (as prepared in the previous step) in toluene (8 mL) and EtOH (4 mL) was treated with 3.93 mL (7.86 mmol) of 2.0 M aqueous Na2CO3 and 186 mg (1.47 mmol) of cyclohex-1-enylboronic acid. The mixture was degassed via sonication, placed under Ar, treated with 170 mg (0.147 mmol) of Pd(PPh3)4, and heated to 80° C. for 4.3 h. The mixture was cooled to RT, diluted with EtOAc (10 mL), and washed with saturated aqueous NaHCO3 (1×10 mL) and brine (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with 0-4% MeOH—CH2Cl2 afforded 307 mg (86%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 7.01 (dd, 1H, J=8.0, 2.0 Hz), 6.99 (d, 1H, J=2.0 Hz), 6.57 (d, 1H, J=8.0 Hz), 5.77-5.72 (m, 1H), 4.07 (s, 2H), 3.85 (br s, 2H), 3.55-3.47 (m, 2H), 2.88-2.77 (m, 2H), 2.26-2.13 (m, 6H), 1.81-1.73 (m, 2H), 1.72-1.64 (m, 2H), 0.99 (d, 6H, J=6.0 Hz).
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([CH2:18][N:19]1[C:24](=[O:25])[CH:23]=[CH:22][C:21]([CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:20]1)[CH2:13]2)=[O:5])C.[OH-].[Na+]>COCCOC>[C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([CH2:18][N:19]1[C:24](=[O:25])[CH:23]=[CH:22][C:21]([CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:20]1)[CH2:13]2)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1cccc2c1CCC(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C(O)COc1cccc2c1CCC(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)C2
Yield: 81.2 %

Procedure:
A solution of 2-[(1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.43 g) in 1,2-dimethoxyethane (9.0 ml) and 1.0N aqueous solution of sodium hydroxide (0.85 ml) was stirred at room temperature for 5 hours. The solution was evaporated in vacuo and extracted with ethyl acetate and 1N hydrochloric acid. The organic layer was separated and washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was crystallized from n-hexane, ethyl acetate and ether to give 2-[(1,2,3,4-tetrahydro-5-carboxymethoxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (330 mg) as a white powder. mp: 176°-178° C.
Reaction SMILES: [C:1]1([CH:7]([NH:22][C:23]([C:36]2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:8][NH:9][C:10](=O)[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=CC=2OC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:42](O)=[O:43]>C(Cl)Cl>[CH3:42][O:43][C:16]1[CH:17]=[CH:18][CH:13]=[CH:12][C:11]=1[CH2:10][N:9]1[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:22]=[C:23]1[CH3:36]
Reactant: O=CO
Reactant: COc1ccccc1CCC(=O)NCC(NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COc1ccccc1CN1CC(c2ccccc2)N=C1C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
The 1-phenyl-1-(tritylamino)-2-[N-(2-methoxybenzyl)acetylamino]ethane, prepared as described in Preparation 1, supra, was detritylated and cyclized by dissolving the intermediate (8.0 g, 14.8 mmol) in 250 ml of methylene chloride and cooling this solution to 0° C. under a nitrogen atmosphere. Formic acid (5.7 ml, 148 mmol) was then added and the reaction mixture was warmed to room temperature and then stirred for 2.5 hours. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: C(C1C=CC(S(Cl)(=O)=O)=CC=1)(C)C.C1(C(C)C)C=CC=CC=1.Cl[C:24]1[C:29]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[C:28]([Cl:38])[N:27]=[CH:26][N:25]=1.[K].[CH:40]([C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH2:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1)([CH3:42])[CH3:41]>>[Cl:38][C:28]1[N:27]=[CH:26][N:25]=[C:24]([NH:52][S:49]([C:46]2[CH:47]=[CH:48][C:43]([CH:40]([CH3:42])[CH3:41])=[CH:44][CH:45]=2)(=[O:50])=[O:51])[C:29]=1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(-c2c(Cl)ncnc2Cl)cc1
Agent: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [K]
Solvent: CC(C)c1ccccc1
Product: COc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)C)cc2)cc1
Yield: 57.5 %

Procedure:
p-Isopropylbenzenesulfonyl chloride, boiling point 105° C./0.25 Torr, was prepared from cumene and converted into the corresponding sulfonamide, melting point 104°-105° C. Reaction of 765 mg of 4,6-dichloro-5-(p-methoxyphenyl)-pyrimidine and 925 mg of p-isopropylbenzenesulfonamide potassium yielded 720 mg of N-[6-chloro-5-(p-methoxyphenyl)-4-pyrimidinyl]-p-isopropylbenzenesulfonamide, melting point 181°-182° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>C1(C)C=CC=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:30](=[O:31])[NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:22])[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1N=C=O
Reactant: O=C1CN(C(=O)OCc2ccccc2)OC1CCCCO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccccc1NC(=O)OCCCCC1ON(C(=O)OCc2ccccc2)CC1=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a solution of N-benzyloxycarbonyl-5-(4-hydroxybutyl)-4-oxo-isoxazole (170 mg, 0.58 mmol) in dry toluene was added 2-methylphenyl isocyanate (76 μL, 0.61 mmol). The reaction mixture was heated at approximately 80° C. under nitrogen for 0.5 hour. One drop of pyridine was added and heating was continued for an additional 1.5 hours. A second portion (25 μL) of 2-methylphenyl isocyanate was added and the reaction mixture was heated for another 2 hours. The reaction mixture was then allowed to cool to ambient temperature and diluted with ethyl acetate and extracted with water. The aqueous layer was acidified with potassium hydrogen sulfate and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 240 mg of the title compound. MS (FAB+) m/e 427 (M+H)+.
Reaction SMILES: [O:1]1C=CC=[CH:2]1.[CH3:6][O:7][C:8]1[O:12][CH2:11][CH2:10][C:9]=1OC>>[CH3:2][O:1][CH:11]1[CH2:10][CH2:9][CH:8]([O:7][CH3:6])[O:12]1
Reactant: c1ccoc1
Reactant: COC1=C(OC)OCC1
Product: COC1CCC(OC)O1
Yield: 0.7 %

Procedure:
After 1 F/mol of furan, the proportion of furan in GC-percent by area had dropped from 22.8% to 18.0%, while the proportion of dimethoxydihydrofuran had increased from 30.7% to 30.9%. At the same time, 0.7% of 2,5-dimethoxytetrahydrofuran were formed.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]([CH2:40][CH3:41])[CH2:37][CH2:38][OH:39]>>[CH2:40]([N:36]([CH2:37][CH2:38][OH:39])[CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29])[CH3:41]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CCN(CCO)CCCCN
Product: CCN(CCO)CCCCNC(=O)Nc1snc(OCc2c(F)cc(C)c(F)c2F)c1C(N)=O

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[(4-amino-butyl)-ethyl-amino]-ethanol by the procedure analogous to Example 1. MS (APCI, m/z): 504 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[NH:6]1[CH2:14][CH2:13][CH2:12][CH:8]([C:9]([NH2:11])=[O:10])[CH2:7]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>>[C:15]([N:6]1[CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]([NH2:11])=[O:10])[CH2:7]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)C1CCCNC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)[C@@H]1CCCN(C(=O)c2ccccc2)C1
Temperature: 15 °C
Reaction time: 3 h
Yield: 27.7 %

Procedure:
Concentrated sulfuric acid is added to the reaction mixture obtained in Example 4 (amount: 10 g, net weight of (R)-nipecotamide: 1 g) to adjust the pH to 9. Benzoyl chloride (3.5 g, 2.5 equivalents) was slowly added dropwise, and the pH of the reaction mixture was kept from 7 to 9 by a 30% aqueous sodium hydroxide solution. After completion of the dropwise addition, the solution was stirred at 15° C. for 3 hours to obtain a solution containing the title compound (1.6 g, yield: 88%).