Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH:17]([CH2:19][CH3:20])[C:16](=O)[CH:15]([CH2:22][CH3:23])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:25].[Na+]>CO>[NH2:25][CH:16]1[CH:17]([CH2:19][CH3:20])[CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][CH:15]1[CH2:22][CH3:23]
Reactant: [BH3-]C#N
Reactant: CCC1CN(Cc2ccccc2)CC(CC)C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC1CN(Cc2ccccc2)CC(CC)C1N
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Ammonium acetate (10 g, 130 mmol) was added to the stirred solution of 1-benzyl-3,5-diethyl-4-piperidone (3.5 g, 14.3 mmol) in methanol (50 ml) and stirring was continued for 4 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.45 g, 7.14 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 10 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 2) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1M sodium hydroxide solution (pH 10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-benzyl-3,5-diethylpiperidine.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 166–168° C.; 1H NMR (300 MHz, CDCl3): δ 7.15 (s, 1 H), 7.09 (s, 1 H), 6.99 (s, 1 H), 4.34–4.24 (m, 2 H), 4.08–3.99 (m, 1 H), 3.11 (t, J=8.1 Hz, 2 H), 2.12–2.05 (m, 1 H), 1.92–1.76 (m, 1 H), 1.05–1.00 (m, 1 H), 0.94–0.86 (m, 3 H), 0.80–0.71 (m, 1 H), 0.53–0.46 (m, 2 H), 0.33–0.21 (m, 1 H); HRMS (ESI) calcd for C18H19N3OCl3 (M+H)+: 398.0594; found m/z 398.0575.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[CH2:7][C@@H:6]1[C:8]([O:10]C(C)(C)C)=[O:9]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[CH2:7][C@@H:6]1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C[C@H]1C[C@@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C[C@H]1C[C@@H]1C(=O)O

Procedure:
Tert-butyl (1S,2R)-2-(2-methoxy-2-oxoethyl)cyclopropanecarboxylate was dissolved in a mixture of trifluoroacetic acid:methylene chloride (7:3) and stirred at room temperature until the t-butyl ester was removed. The solvent was removed under reduced pressure to give product. 1H NMR (CDCl3) δ 3.70 (s, 3H), 2.35 (d, J=7.5 Hz, 2H), 1.85-1.70 (m, 1H), 1.52-1.49 (m, 1H), 1.39-1.30 (m, 1H), 0.93-0.87 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[CH:7]=[CH:6]2)=[O:2].C(=O)([O-])[O-:22].[K+].[K+].CS(C)=O.OO>O>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:22])=[CH:15][CH:14]=1)[CH:7]=[CH:6]2)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Cn2ccc3cc(C=O)ccc32)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(Cn2ccc3cc(C=O)ccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 169.4 %

Procedure:
Mix 4-(5-Formyl-indol-1-ylmethyl)-benzonitrile (0.73 g, 2.8 mmol), potassium carbonate (0.19 g, 1.4 mmol), and dimethylsulfoxide (14 mL) in a flask. Cool 10 minutes in an ice bath and add hydrogen peroxide (0.95 mL, 30% wt in water) dropwise. Remove ice bath and stir at rt for 4 hrs. Pour into water (30 mL). After trituration, filter the solid formed and dry on a vacuum pump to obtain the product as a white solid (0.66 g, 88%). 1H NMR (DMSO-d6) 9.95 (s, 1H), 8.17 (s, 1H), 7.89 (bs, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.69 (d, J=3.1 Hz, 1H), 7.63-7.60 (m, 2H), 7.32 (bs, 1H), 7.23 (d, J=8.1 Hz, 2H), 6.73 (d, J=3.1 Hz, 1H), 5.54 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH3:13][S:14][CH3:15].ClN1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([CH2:13][S:14][CH3:15])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1c(N)c([N+](=O)[O-])cc(F)c1F
Yield: 34.9 %

Procedure:
To a solution of 2-nitro-4,5-difluoroaniline (1.0 g) and dimethylsulfide (1.79 g) in dichloromethane (40 ml) is added gradually N-chlorosuccinimide (3.82 g) with stirring at below 15° C. The mixture is stirred for 30 minutes, and thereto is added triethylamine (2.89 g), and the mixture is refluxed for 21 hours. After allowing to cool, the reaction mixture is washed with 10% aqueous sodium hydroxide, water and aqueous sodium chloride in this order and dried. The solvent is removed by concentration, and the resulting residue is purified by silica gel column chromatography (solvent, n-hexane:ethyl acetate=30:1) and then recrystallized from n-hexane to give 2-nitro-4,5-difluoro-6-methylthiomethylaniline (0.47 g) as yellow needles, m.p. 110°-111.5° C.
Reaction SMILES: C1COCC1.[CH2:6]([Si:9]([CH2:24][CH:25]=[CH2:26])([CH2:21][CH:22]=[CH2:23])[CH2:10][CH2:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)[CH:7]=[CH2:8].[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO>[CH2:24]([Si:9]([CH2:6][CH:7]=[CH2:8])([CH2:21][CH:22]=[CH2:23])[CH2:10][CH2:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1)[CH:25]=[CH2:26]
Reactant: C=CC[Si](CC=C)(CC=C)CCCc1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=CC[Si](CC=C)(CC=C)CCCc1ccc(CO)cc1
Reaction time: 3 h
Yield: 83 %

Procedure:
THF (25 ml) and methanol (MeOH) (25 ml) were added to 4-{3-(triallylsilyl)propyl}benzaldehyde (4) (11.0 g, 36.9 mmol) under a nitrogen atmosphere, the mixture was cooled to around 0° C. with ice, NaBH4 (2.8 g, 73.8 mmol) was added thereto, and the mixture was stirred for 3 hours. An aqueous solution of saturated sodium hydrogen carbonate was added to the reaction mixture. The aqueous layer was extracted with diethyl ether, and the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under a reduced pressure to give a crude product. The crude product was purified by separating by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=5/1) to give 4-{3-(triallylsilyl)propyl}benzyl alcohol (5) (yield amount: 9.2 g, yield: 84%), as shown in the following chemical reaction formula.
Reaction SMILES: C(=O)(O)[O-].[Na+].C(O[CH2:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:21]([NH2:22])[C:20](=[O:23])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])(=O)C.[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([SH:32])[N:26]=1>O.CC(C)=O>[NH2:22][CH:21]1[C:20](=[O:23])[N:15]2[C:16]([C:17]([OH:19])=[O:18])=[C:11]([CH2:10][S:32][C:27]3[N:28]=[C:29]([CH3:31])[CH:30]=[C:25]([CH3:24])[N:26]=3)[CH2:12][S:13][C@H:14]12
Reactant: Cc1cc(C)nc(S)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C)nc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n1
Reaction time: 23 h

Procedure:
A solution of sodium bicarbonate (9.45 g.) in water (100 ml.) was added in portions to a stirred suspension of 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid (13.5 g.) in water (100 ml.) and acetone (50 ml.). The solid dissolved with effervescence. To this solution under nitrogen at 55° was added rapidly, drop by drop, a solution of 4,6-dimethyl-2-mercaptopyrimidine (10.5 g.) in water (100 ml.) and acetone (100 ml.), the pH being maintained between 7.4 and 7.8 by addition of 6 NHCl or 5% w/v aqueous NaHCO3. After 23 hours at 55°, the reaction mixture was cooled to 0° and acidified to pH 4.0. The resulting precipitate was filtered, washed with water and acetone, and dried over P2O5 to give 7-amino-3-(4,6-dimethylpyrimid-2-yl)thiomethylceph-3-em-4-carboxylic acid. A mixture of this acid (3.52 g.) and O-t-butyl-1,3-diisopropylisourea (6.0 g.) in dry CH2Cl2 (60 ml.) was stirred under nitrogen for 20 hours. The reaction mixture was filtered, the filtrate evaporated and the residue purified by chromatography on silica gel (200 g.) at -40° using CH2Cl2 /ether 6:4 v/v as eluant to give the t-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][CH:14]3[NH:17][C:18]3[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=3)[O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C1C=CC=CN=1)C.[C:39](Cl)(=[O:41])[CH3:40].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][CH:14]3[N:17]([C:18]3[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=3)[O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:39](=[O:41])[CH3:40])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)COc1cccc(NC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1cccc(N(C(C)=O)C2CCc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of methyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetate (8 mg, 0.02 mmol) and dimethylaminopyridine (2 mg, 0.016 mmol) in dichloromethane (1 mL) at 0° C. was added acetyl chloride (12 mL, 0.173 mmol) and triethylamine (0.25 mL, 0.176 mmol). The reaction was warmed to room temperature and allowed to stir for approximately 2 hours. The resultant mixture was concentrated and the resulting crude residue was purified on a preparative TLC (1000 mm thickness) with a 1:1 ratio of ethyl acetate and hexane solution to afford 7 mg (94%) of methyl 2-(3-(N-(6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)acetamido)phenoxy)acetate.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[Cl:15])[CH:2]=[CH2:3].[CH:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18](O)[CH:17]=1.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.C(Cl)(Cl)Cl>[N+:22]([C:21]1[CH:16]=[CH:17][C:18]([O:13][C:12](=[O:14])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[C:6]([Cl:15])[CH:7]=2)=[CH:19][CH:20]=1)([O-:24])=[O:23]
Reactant: C=CCOc1ccc(CC(=O)O)cc1Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=CCOc1ccc(CC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Allyloxy-3-chloro-phenylacetic acid (4.3 g) was dissolved in dry tetrahydrofuran (20 ml). To the solution was added p-nitrophenol (2.28 g) in dry chloroform (30 ml). DCC (4.1 g) was then added and the whole was then stirred at room temperature overnight.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][O:17][C:18]3[CH:31]=[CH:30][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:20][CH:19]=3)[N:13]([CH3:32])[C:12]=2[CH:33]=1.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]=[C:46]=[O:47])[CH:40]=1.C(N(CC)CC)C>CN(C)C=O>[O:28]=[C:26]1[NH:25][C:24](=[O:29])[CH:23]([CH2:22][C:21]2[CH:30]=[CH:31][C:18]([O:17][CH2:16][C:14]3[N:13]([CH3:32])[C:12]4[CH:33]=[C:8]([O:7][C:6]5[CH:5]=[C:4]([NH:3][C:46]([NH:45][C:41]6[CH:42]=[CH:43][CH:44]=[C:39]([C:38]([F:37])([F:48])[F:49])[CH:40]=6)=[O:47])[CH:36]=[CH:35][CH:34]=5)[CH:9]=[CH:10][C:11]=4[N:15]=3)=[CH:19][CH:20]=2)[S:27]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(N)c3)cc21
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(NC(=O)Nc4cccc(C(F)(F)F)c4)c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
A mixture of 5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), α,α,α-trifluoro-m-tolyl isocyanate (149 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (4 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=2:1→ethyl acetate as the eluant and the product was recrystallized from a mixture of methanol and diisopropyl ether (1:3) to afford the title compound (239 mg, mp 161.8-163.4° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)[N:7]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1ccc(CCNc2ccnc(Cl)n2)cc1OC
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNc2nccc(NCCc3ccc(OC)c(OC)c3)n2)cc1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
In a sealed flask, a mixture of 7 (744 mg, 2.53 mmol), methyl 4-(aminomethyl)benzoate (628 mg, 3.80 mmol) and i-Pr2NEt (882 μl, 5.07 mmol) in isopropanol (50 mL) was heated to 120-125° C. for 7 days (during this period of time an excess of methyl 4-(aminomethyl)benzoate was added to the reaction mixture). The reaction mixture was allowed to cool to the room temperature, concentrated and purified by flash chromatography on silica gel (MeOH/CH2Cl2, 5/95→10/90 plus several drops of NH4OH) to afford the title compound 8 (671 mg, 1.59 mmol, 63% yield) as an orange sticky solid.
Reaction SMILES: [OH-].[Na+].[Br:3]Br.[C:5]1([C:11]#[CH:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[C:5]1([C:11]#[C:12][Br:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrBr
Reactant: C#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of sodium hydroxide (31.4 g) in water (160 ml) was cooled to 6° C. and bromine (18 ml) was added dropwise, the temperature being kept below 20° C. Phenylacetylene (20 g) in dimethoxethylene (80 ml) was added over 15 minutes and the mixture was stirred at room temperature for 5 hours. Water (200 ml) was added, and the mixture was extracted with ether (4×60 ml), dried (MgSO4) and the solvents removed at room temperature to yield phenylbromoacetylene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17](=[O:18])[CH:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[CH2:25]([SH:27])[CH3:26]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17](=[O:18])[C:16]([S:27][CH2:25][CH3:26])=[C:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCCC1=CC(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O
Reactant: CCS
Solvent: CO
Product: CCCC1=C(SCC)C(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O
Temperature: 0 °C

Procedure:
To a suspension of 2-(4-methoxybenzyl)-3-methyl-5-propyl-4,7-benzofurandione (from Preparation 28) (0.988 g, 3.05 mmol) in MeOH (23 mL) was added ethanethiol (2.5 mL). After a few minutes, the yellow quinone passed into solution giving a reddish colour. The reaction was cooled to 0° C. and solid FeCl3 (2.5 g) was added. The reaction was quenched 10% HCl and extraction with CH2Cl2 afforded the crude product which was chromatographed on silica gel (5% EtOAc/hexane) to yield the title compound.
Reaction SMILES: Br([O-])(=O)=O.[Na+].[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC[O:16]CC>C(#N)C.O>[C:6]([OH:16])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCc1ccccc1
Reactant: CCOCC
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccccc1
Temperature: 80 °C
Reaction time: 40 h
Yield: 90 %

Procedure:
A mixture of Ceiv catalyst from EXAMPLE 47 (0.08 g), sodium bromate (0.3 g) and benzyl alcohol (0.216 g, 2 mmol) in acetonitrile:water (5:7, 12 ml) was stirred at 80° C. for 40 h under an atmosphere of nitrogen. On cooling ether (70 ml) was added and the catalyst was filtered off. The organic layer was separated and the aqueous phase was extracted with ether (2×50 ml). The combined organic extracts were washed with water (25 ml), dried with anhydrous magnesium sulphate and concentrated to give benzoic acid as a white solid (0.22 g, 90%). M.p. 120° C., lit. 120–122° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:22](=[O:24])[NH:21][C:20]([CH3:25])=[N:19][C:18]=3[N:17]=[C:16]([S:26][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[O:31][CH:32]=3)[C:15]=2[C:40]#[N:41])=[CH:10][CH:9]=1)(=O)C.[OH-].[Li+].Cl>O1CCOCC1.O.O>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[O:31][CH:32]=[C:28]([CH2:27][S:26][C:16]3[C:15]([C:40]#[N:41])=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][OH:4])=[CH:9][CH:10]=4)[C:23]4[C:22](=[O:24])[NH:21][C:20]([CH3:25])=[N:19][C:18]=4[N:17]=3)[N:29]=2)=[CH:34][CH:35]=1
Reactant: CC(=O)OCCOc1ccc(-c2c(C#N)c(SCc3coc(-c4ccc(Cl)cc4)n3)nc3nc(C)[nH]c(=O)c23)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2nc(SCc3coc(-c4ccc(Cl)cc4)n3)c(C#N)c(-c3ccc(OCCO)cc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
95 mg (0.162 mmol) of 2-{4-[7-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfanyl)-6-cyano-2-methyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-5-yl]phenoxy}ethyl acetate were initially charged in 10 ml of a dioxane/water mixture 2:1, 7.7 mg (0.323 mmol) of lithium hydroxide were added and the mixture was stirred at RT for 5 h. The reaction mixture was then diluted with water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated. The residue was purified by preparative HPLC (mobile phase gradient: acetonitrile/water 10:90→95:5, with 0.1% TFA added). This gave 88 mg (99% of theory) of the target compound.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@H:3]([OH:5])[CH3:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.O>N1C=CC=CC=1>[OH:5][C@H:3]([CH3:4])[CH2:2][CH2:1][O:6][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: C[C@@H](O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC[C@@H](C)O)cc1
Temperature: -25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
After adding pyridine (100 ml) to (R)-1,3-butanediol (86.0 g), the solution was cooled to −25° C. under nitrogen atmosphere. A solution of p-toluenesulfonyl chloride (200 g) in pyridine (200 ml) was slowly added dropwise thereto at a temperature ranging from −20 to −10° C. The mixture was stirred for 1 hour at a temperature ranging from −20 to −10° C. A small amount of water was added to the reaction mixture to stop the reaction and the solution was extracted with toluene and water. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain (R)-3-hydroxy-1-(p-toluenesulfonyloxy)butane (209 g) as light brown oil. The oil thus obtained was used in the next step as such without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[CH2:11][CH2:12][CH:13]2[O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O.CC#[N:30].CCOCC>>[NH2:30][N:2]=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:20])[CH2:11][CH2:12][CH:13]2[O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14]2)=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(NC(=O)CCC2CCCC(=O)O2)cc1
Reactant: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: NN=Cc1ccc(NC(=O)CCC2CCCC(=O)O2)cc1

Procedure:
The title compound was prepared from the product of step B (770 mg, 2.83 mmol) in a manner similar to example 1, step G to give 430 mg (38%) of product as TFA salt after reverse phase chromatography and trituration with CH3CN/Et2O (m.p. 151°-153° C. dec.).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]([CH3:28])[CH2:26][NH2:27].CC1N(C(N(C)C)=O)C1>N1C=CC=CC=1>[CH3:24][CH:25]([CH3:28])[CH2:26][NH:27][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Reactant: CC(C)CN
Agent: CC1CN1C(=O)N(C)C
Solvent: c1ccncc1
Product: CC(C)CNc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 100 °C

Procedure:
A mixture of 0.16 g of 10-[(6-chloro-3-pyridinyl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c]-[1,4]benzodiazepine, 40 mg of pyridine and 2 ml of 2-methylpropylamine is stirred and heated at 100° C. in a sealed vessel for 1 hour. To the mixture is added 0.2 ml of N,N-dimethylpropyleneurea and the mixture is heated at 110° C. for 7 hours. The volatiles are removed under vacuum and 10 ml of 0.5N NaOH is added to the residue. The mixture is filtered and the solid washed with water and then hexane. The solid is dissolved in ethyl acetate and the solution washed with 0.5N NaOH, brine and dried (Na2 SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is triturated with diisopropylether-hexane to give 0.18 g of white solid; mass spectrum (CI) 361 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[N+:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)([O-:24])=[O:23].CO.[OH-].[Na+]>O>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol), 3-nitrobenzaldehyde (96 mg, 0.633 mmol), methanol (5 ml) and saturated NaOH (50 ul). The mixture was diluted with water (5 ml). The resulting yellow precipitate was collected by filtration, wash with water and dried under vacuum to give yellow solid (129 mg, 45%). 1H NMR (CDCl3): 8.48 (s, 1H), 8.28-8.24 (m, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.74 (d, J=15.9 Hz, 1H), 7.61 (d, J=16.2 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.36 (d, J=3.0 Hz, 1H), 7.18 (dd, J=3.3, 9.0 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 4.49-4.36 (m, 4H).