Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(C)N([C@@H]2O[C@H](C[O:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H](O)[C@H]2O)N=1>C(O)(=O)C>[C:30]1([C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[OH:16])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cc(C)n([C@@H]2O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H](O)[C@H]2O)n1
Solvent: CC(=O)O
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
For splitting off the trityl group, in essence the method given by BREDERECK et al.(11) was carried out. 1.5 g (3.2 mmoles) of 3,5-dimethyl-1-(5' -O-trityl-β-D-ribofuranosyl)pyrazole are dissolved in 15 ml of 80% acetic acid and stirred for 10 minutes while being boiled under reflux. On cooling down the red solution, a white precipitate of triphenylcarbinol is produced. After the addition of 20 ml of water, the precipitate is filtered off and the filtrate, for neutralisation, is run over a column with an ion exchanger Amberlite IRA-402 in the OH⃝ form and the substance is eluted with methanol. After removal of the solvent from the yellow solution produced, the remaining yellow sirup is mixed for crystallisation with a few drops of 99% ethanol and allowed to stand for 24 hours at room temperature. Slightly yellow compact crystals are produced which are recrystallised for purification from absolute acetonenitrile. Yield: 480 mg (66%), melting point: 162° and 163° C.; [α] 57822 = 97.2° in methanol (C = 17.1 mg/ml).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH2:20][NH:21][CH2:22][CH3:23])[CH:8]=[C:9]([Cl:11])[CH:10]=1.[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](Cl)=[O:33])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH2:20][N:21]([C:32](=[O:33])[CH2:31][O:30][C:29]2[CH:35]=[CH:36][C:26]([Cl:25])=[CH:27][CH:28]=2)[CH2:22][CH3:23])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: CCNCc1ccc(OC)cc1-c1cc(Cl)cc(CC(=O)OC)c1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Product: CCN(Cc1ccc(OC)cc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)COc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (5-chloro-2′-ethylaminomethyl-5′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and 4-chlorophenoxyacetyl chloride.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:30]([OH:32])=[O:31])=[C:19]([C:20]3[NH:21][C:22](=[O:29])[C:23]([CH:26]([CH3:28])[CH3:27])([CH3:25])[N:24]=3)[C:14]=2[N:13]=[C:12]1[CH3:33])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC.CO>[CH2:4]([N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:30]([O:32][CH3:3])=[O:31])=[C:19]([C:20]3[NH:21][C:22](=[O:29])[C:23]([CH:26]([CH3:28])[CH3:27])([CH3:25])[N:24]=3)[C:14]=2[N:13]=[C:12]1[CH3:33])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=[N+]=[N-]
Reactant: Cc1nc2c(C3=NC(C)(C(C)C)C(=O)N3)c(C(=O)O)ccc2n1Cc1ccccc1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1ccc2c(nc(C)n2Cc2ccccc2)c1C1=NC(C)(C(C)C)C(=O)N1
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
A solution of diazomethane in ether is added to a suspension of 1-benzyl-4-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-2-methyl-5-benzimidazolecarboxylic acid (1.15 g, 2.84 mmol) in methanol until the yellow color persists. The reaction is stirred for 5 minutes, quenched with 2 drops of acetic acid and concentrated in vacuo. The resultant residue is purified by HPLC (silica gel, ethyl acetate eluent) to give the title product as a white powder (0.480 g, 40.3%), mp 194°-196° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1cccnc1)N1CCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1cccnc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and (2-morpholin-4-yl-2-pyridin-3-ylethyl)amine.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[N:8]=1)(=O)=O.[CH2:27]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:23][CH:22]([CH3:24])[CH2:21][NH:20][C:15]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[N:8]=[C:7]([N:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(C)CNc1c2c(nc(OS(=O)(=O)C(F)(F)F)c1[N+](=O)[O-])CCCC2
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)CNc1c2c(nc(N(Cc3ccccc3)Cc3ccccc3)c1[N+](=O)[O-])CCCC2
Yield: 92.2 %

Procedure:
5,7,6,8-tetrahydro-4-[(2-methylpropyl)amino]-3-nitroquinolin-2-yl trifluoromethanesulfonate (4.0 g, 0.01 mole), dibenzylamine (1.9 mL, 0.01 mole), triethylamine (1.4 mL, 0.01 mole) and benzene (100 mL) were combined and heated at reflux for 36 hours. The benzene was evaporated under vacuum and the residue purified by silica gel chromatography eluting with hexane:ethyl acetate 70:30 to provide 4.1 g of the desired product as a viscous orange oil.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:2]1.[Mg].I[CH2:14][CH3:15].[Cl-].[NH4+]>C(OCC)C.O>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:14][CH3:15])=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CCI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCC(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3,4-methylenedioxybenzaldehyde (4.5 g, 30 mmol) of formula 2 prepared in dry diethyl ether is slowly added to an ethereal solution of Grignard reagent prepared from magnesium metal (0.84 g, 35 mmol) and iodoethane (3.0 ml, 40 mmol) and the contents stirred for 1 hour at room temperature. After the completion of the reaction, the mixture is processed by adding saturated aqueous solution of ammonium chloride (10 ml) followed by dilution with water (100 ml), separating the organic layer and extracting the aqueous layer with solvent ether (2×100 ml). The combined organic layer washed with water (2×20 ml) dried over anhydrous sodium sulfate and concentrated in vacuo to yield 1-(3,4-methylenedioxyphenyl) propan-1-ol, a semisolid of formula 3(5.3 g, 97.5%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:32][C:31]4[CH2:30][CH2:29][NH:28][CH2:27][C:26]=4[CH:25]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[CH2:33]([N:35](CC)CC)C.C([O-])(=O)C.[Na+].[Br-]>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([C:24]3[S:32][C:31]4[CH2:30][CH2:29][N:28]([C:33]#[N:35])[CH2:27][C:26]=4[CH:25]=3)=[O:23])[CH2:20][CH2:21]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2
Reactant: O=C(c1cc2c(s1)CCNC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: CCN(CC)CC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Br-]
Solvent: CCO
Product: N#CN1CCc2sc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In ethanol, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (195 mg), triethylamine (0.2 ml) and sodium acetate (118 mg) were suspended, followed by the addition of cyan bromide (114 mg). The resulting mixture was stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was added with dichloromethane, followed by washing with water. After drying over anhydrous sodium sulfate, the residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane:methanol=100:1), whereby the title compound (51 mg, 28%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:40]=[CH:39][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:34][CH2:33][CH:32]([C:35]([OH:38])([CH3:37])[CH3:36])[CH2:31][CH2:30]4)=[CH:24][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22]C)=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:40]=[CH:39][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:30][CH2:31][CH:32]([C:35]([OH:38])([CH3:36])[CH3:37])[CH2:33][CH2:34]4)=[CH:24][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C(C)(C)O)CC4)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)O)CC4)c3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (1.05 g, 1.907 mmol) in MeOH (20 mL) was added 1 N aqueous NaOH (19.07 mL, 19.07 mmol). The solution was stirred overnight at RT. After 2 days, the reaction solution was concentrated, the pH was adjusted to 4 with 2 N aqueous HCl, and the mixture was extracted with 9:1 DCM/2-propanol. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to generate cis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (1.01 g, 1.882 mmol, 99% yield) as a white powder. MS, m/z (C30H37PN4O4): calcd, 536.3. found, 537.0 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[C:27](OC=C)(=O)[CH3:28].C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:26][CH:27]=[CH2:28])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: C=COC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: C=COC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (329 mg, 0.800 mmol), vinyl acetate (148 μL, 1.60 mmol), di-μ-chlorobis[(η-cycloocta-1,5-diene)iridium (I)] (26.9 mg, 0.0400 mmol) and sodium carbonate (50.9 mg, 0.480 mmol) in o-dichlorobenzene (1.6 mL) was stirred for 3 h at 100° C. After vinyl acetate (148 μL, 1.60 mmol) was added, the reaction mixture was purified by flash column chromatography on silica gel eluting with a 20% ethyl acetate/n-hexane to give the title compound as a pale yellow amorphous (279 mg, 0.638 mmol, 80%).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:5][NH:4][C:3]1=[O:15].[C:16]1([C:22]2[N:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH2:7][N:2]([NH:1][C:28]([C:25]3[CH:24]=[N:23][C:22]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:27][CH:26]=3)=[O:29])[C:3](=[O:15])[NH:4][N:5]=2)=[CH:13][CH:12]=1
Reactant: NN1CC(c2ccc(F)cc2)=NNC1=O
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NN1CC(c2ccc(F)cc2)=NNC1=O)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 49 h
Yield: 25 %

Procedure:
To a slurry of 4-amino-6-(4-fluoro-phenyl)-4,5-dihydro-2H-1,2,4-triazin-3-one (0.26 g, 1.23 mmol), 2-phenyl-pyrimidine-5-carboxylic acid (0.25 g, 1.23 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.37 g, 1.94 mmol) in DMF (12 mL) is added Et3N (0.2 mL, 1.435 mmol) under N2 and the reaction mixture is stirred at rt for 49 h. The mixture is diluted with EtOAc (120 mL), and washed successively with saturated aqueous NH4Cl (2×50 mL), water (2×50 mL), and saturated aqueous NaCl (50 mL). The organic phase is dried (MgSO4), filtered, and concentrated in vacuo. The residue is triturated with EtOH (30 mL) to afford 2-phenyl-pyrimidine-5-carboxylic acid [6-(4-fluoro-phenyl)-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl]-amide (0.12 g, 25%). MS: 391 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 11.25 (s, 1H), 10.58 (s, 1H), 9.31 (s, 2H), 8.47 (dd, J=7.7, 1.8 Hz, 2 H), 7.70-7.86 (m, 2 H), 7.49-7.67 (m, 3H), 7.18-7.34 (m, 2H), 4.77.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH:14]1(C(O)=O)[CH2:17][CH2:16][CH2:15]1>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[CH:14]1[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)C1CCC1
Reactant: Clc1ccc(Cl)nn1
Agent: O=S(=O)(O)O
Solvent: O
Product: Clc1cc(C2CCC2)c(Cl)nn1
Temperature: 70 °C
Yield: 98.3 %

Procedure:
3,6-Dichloropyridazine (10 g) was suspended in water (200 ml), H2SO4 (19.7 g) and cyclobutane carboxylic acid (32.7 g) were added and the reaction degassed under N2 at 70° C. Silver nitrate (2.28 g) was added followed by dropwise addition of ammonium persulfate (45.9 g) in water (120 ml). After an additional 1 hour heating at 70° C., the reaction was poured onto ice, basified to pH 8-9 with aqueous ammonium hydroxide and extracted into ethyl acetate (3×500 ml), dried (MgSO4) and evaporated to dryness. Purified with hexane-ethyl acetate mixtures to obtain pure product (13.4 g). 1H NMR (360 MHz , CDCl3) δ 1.57 (2H, m), 1.82 (4H, m), 2.20 (1H, m), 3.30 (1H, m), 7.38 (1H, s); MS (ES+) m/e 217 [MH]+.
Reaction SMILES: O[CH2:2][CH:3]([C:13]1[C:18]([OH:19])=[C:17]([CH3:20])[C:16]([CH3:21])=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1>CO>[CH:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:3]2[C:13]3[CH:14]=[CH:15][C:16]([CH3:21])=[C:17]([CH3:20])[C:18]=3[O:19][CH2:2]2)=[CH:5][CH:6]=1)([CH3:12])[CH3:11]
Reactant: Cc1ccc(C(CO)c2ccc(C(C)C)cc2)c(O)c1C
Solvent: CO
Product: Cc1ccc2c(c1C)OCC2c1ccc(C(C)C)cc1
Yield: 80 %

Procedure:
Using 6-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-2,3-dimethylphenol synthesized in Reference Example 9, the title compound was synthesized in the same manner as in Reference Example 13. Yield 80%. Melting point: 50-51° C. (methanol).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:14]=[C:15]1[O:18][C:17](=[O:19])[CH2:16]1>ClCCCl>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:17](=[O:19])[CH2:16][C:15](=[O:18])[CH3:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Reactant: C=C1CC(=O)O1
Solvent: ClCCCl
Product: CC(=O)CC(=O)Nc1ccc(Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a stirred solution of 10 parts of 4-[(1H-imidazol-l-yl)methyl]benzenamine in 180 parts of 1,2-dichloroethane were added dropwise 3.9 parts of 4-methylene-2-oxetanone. After stirring for 1/2 hour at room temperature, the precipitate was filtered off, washed with 1,2-dichloroethane and dried, yielding 9.8 parts (74.8%) of N-[4-(1H-imidazol-1-ylmethyl)phenyl]-3-oxobutanamide; mp. 175° C. (interm. 57).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][C:3]=1[NH2:4].F[C:16]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:25][C:24]1[C:16]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([C:9]#[C:10][Si:11]([CH3:13])([CH3:12])[CH3:14])=[CH:8][C:2]=2[F:1])=[C:17]([CH:21]=[CH:22][C:23]=1[F:26])[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: C[Si](C)(C)C#Cc1ccc(N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Temperature: -78 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
A mixture of the product of Step A, 2-fluoro-4-[(trimethylsilyl)ethynyl]aniline (3.85 g, 18.6 mmol) and 2,3,4-trifluorobenzoic acid (3.27 g, 18.6 mmol) was dissolved in dry THF (25 mL). The flask was fitted with a pressure-equalising dropping funnel and the entire apparatus evacuated and flushed with N2. The solution was then cooled to −78° C. (acetone/dry ice) and a solution of 1.06 M LiHMDS (52.64 mL, 55.8 mmol) was added dropwise from the dropping funnel. Following this addition, the reaction mixture was allowed to warm to room temperature and stirred for a further 15 hours. The reaction solvent was removed under reduced pressure and the resulting residue partitioned between 1 M HCl (100 mL) and EtOAc (2×100 mL). The combined EtOAc fractions were then washed with water (100 mL) and saturated NaCl (100 mL), dried (Na2SO4), and the EtOAc removed under reduced pressure to afford a crude product which was purified by chromatography on flash silica (10% EtOAc/hexanes as eluant), giving the desired product as a pale yellow solid (3.99 g, 59%); m.p. (EtOAc/hexanes) 164–167° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.70 (br s, 1 H), 9.31 (br s, 1 H), 7.82 (ddd, J=9.1, 6.1, 2.0 Hz, 1 H), 7.34 (dd, J=12.0, 1.9 Hz, 1 H), 7.18 (ddd, J=8.3, 1.9, 0.8 Hz, 1 H), 7.16 (td, J=9.5, 7.3 Hz, 1 H), 6.93 (ddd, J=8.9, 8.3, 5.4 Hz, 1 H), 0.22 (s, 9 H). Anal. Calcd for C18H16F3NO2Si: C, 59.5; H, 4.4; N, 3.9. Found: C, 59.7; H, 4.7; N, 3.9.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9]([O:10][Si](C(C)(C)C)(C)C)[CH2:8][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:6]1)=[N+:2]=[N-:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[Cl-].[Na+].O>[N:1]([CH2:4][C@@H:5]1[C@@H:9]([OH:10])[CH2:8][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CN=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reaction time: 1 h
Yield: 93.2 %

Procedure:
(3R,4R)-3-Azidomethyl-1-benzyloxycarbonyl-4-- (tert-butyldimethylsilyl)oxypyrrolidine (3.05 g) was dissolved in tetrahydrofuran (50 mL). While this solution was chilled in an ice water bath, tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 13.3 mL) was added dropwise and the mixture was stirred for 1 hour, followed by addition of saturated brine (70 mL) and the mixture was extracted with ethyl acetate (150 mL, 100 mL). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate) to give (3R,4R)-3-azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine as a milky white syrup (2.01 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1.[CH3:10][O:11]C1C=CC(Br)=CN=1.C([Li])CCC>O1CCCC1>[CH3:10][O:11][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1
Reactant: CSc1ccc(Br)nc1
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(SC)cn1

Procedure:
For example, 2-bromo-5-methylthiopyridine may be prepared by the treatment of 2-methoxy-5-bromopyridine (Shiao. M. J. et. al. Syn. Comm. 20(19), 2971, 1990) with n-butyllithium in anhydrous tetrahydrofuran at -78° C., followed by quenching the reaction with dimethyldisulfide to afford 2-methoxy-5-methylthiopyridine. Demethylation provides 2-hydroxy-5-methylthiopyridine which upon reaction with phosphorousoxybromide yields the desired 2-bromo-5-methylthiopyridine starting material. (Scheme 7) ##STR19##
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:11])[CH2:8][CH2:9]Cl)=[CH:4][CH:3]=1.[CH3:12][C:13]([O-:15])=[O:14].[Na+]>C(O)(=O)C>[C:13]([O:15][CH2:9][CH2:8][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:11])(=[O:14])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: O=C(CCCl)c1ccc(Br)s1
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCCC(=O)c1ccc(Br)s1
Temperature: 130 °C
Reaction time: 8 h
Yield: 541.3 %

Procedure:
To the mixture of 1-(5-bromothiophen-2-yl)-3-chloropropan-1-one (2.8 g, 1.6 mmol, 1.0 eq), NaOAc (4.5 g, 55.3 mmol, 5 eq) and KI (200 mg) in acetic acid (16 mL) was stirred at 130° C. for overnight. The mixture was extracted with CH2Cl2 (3×40 ml). The combined organic layers were washed (brine), dried (Na2SO4), filtered and concentrated to give yellow oil 3-(5-bromothiophen-2-yl)-3-oxopropyl acetate (2.4 g, 76.2%). LC-MS (m/z)=278.1 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:15](Cl)(=[O:17])=[O:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>N1C=CC=CC=1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:7]1[CH:6]=[CH:5][C:4]([S:15](=[O:17])(=[O:16])[NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:3][C:2]=1[F:1])=[O:14]
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)cc1F)C(F)(F)F
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 54.2 %

Procedure:
Synthesized according to general procedure 70. Under an N2 atmosphere, a mixture of the 3-fluoro-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (5.0 g, 16.4 mmol) and 2-aminothiazole (1.64 g, 16.4 mmol), and pyridine (9.6 mL) was stirred at RT for 19 h. Purification via silica gel chromatography using 0-10% MeOH in CH2Cl2 gave 2,2,2-trifluoro-N-(2-fluoro-4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide (3.28 g, 54%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=370.1; tR=1.07 min.
Reaction SMILES: CO[C:3](=[O:17])[C@H:4]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH:5]([CH3:7])[CH3:6].[O-:18][C:19]#[N:20].[K+]>C(O)(=O)C>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C@H:4]([CH:5]([CH3:6])[CH3:7])[C:3](=[O:17])[NH:20][C:19]2=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)[C@H](NCc1ccc(Cl)cc1)C(C)C
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)[C@@H]1C(=O)NC(=O)N1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.3 %

Procedure:
To a solution of 1.68 g (6.59 mmoles) of (R)-2-(4-chloro-benzylamino)-3-methyl-butyric acid methyl ester in 20 ml of acetic acid, 0.64 g (7.91 mmoles) of potassium cyanate is added at ambient temperature under N2 atmosphere. The mixture is stirred for 15 hours at ambient temperature and heated for 3 hours at 100° C., and then the reaction mixture is concentrated under reduced pressure. The mixture is extracted with AcOEt, and the combined extracts are washed with sat. NaHCO3 and brine, dried over MgSO4 and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 1.57 g of desired (R)-1-(4-chloro-benzyl)-5-isopropyl-imidazolidine-2,4-dione in 77% yield.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:26])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:25])([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1)[CH2:6][CH2:5]2.[C:27](OC(=O)C)(=[O:29])[CH3:28].N1C=CC=CC=1>C1C=CC=CC=1>[C:27]([O:1][C:2]1[C:3]([CH3:26])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:25])([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1)[CH2:6][CH2:5]2)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc([N+](=O)[O-])cn1)O2
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc([N+](=O)[O-])cn1)O2

Procedure:
Following the same procedure as described in Preparation 16, 5.2 g of 6-hydroxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chroman (prepared as described in Preparation 35), 3 ml of acetic anhydride, 3 ml of pyridine and about 20 ml of benzene were reacted to give the title compound.