Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].CC1C=CC=CC=1.[F:22][C:23]([F:28])([F:27])[CH:24]([OH:26])[CH3:25].[H-].[Na+]>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([O:26][CH:24]([CH3:25])[C:23]([F:28])([F:27])[F:22])(=[O:12])=[O:13]
Reactant: CC(O)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(OS(=O)(=O)c1ccc2ccccc2c1)C(F)(F)F
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a cooled (ice-bath) suspension of 41.7 parts of 2-naphthalenesulfonyl chloride in 174 parts of methylbenzene were added dropwise 20.0 parts of 1,1,1-trifluoro-2-propanol. After stirring for 1 hour, there was added dropwise a mixture of 9.6 parts of a dispersion of sodium hydride in mineral oil (50%) and some methylbenzene while cooling on ice. Subsequently, the whole was diluted dropwise with water. The organic layer was separated, dried, filtered and evaporated, yielding 53.2 parts (99.9%) of (2,2,2-trifluoro-1-methylethyl) 2-naphthalenesulfonate (interm. 28).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:23]2[CH2:24][CH2:25][O:26][CH2:27][CH:28]=2)O1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:23]2[CH2:28][CH2:27][O:26][CH2:25][CH:24]=2)[N:3]=1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Brc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Brc1cccc(C2=CCOCC2)n1
Temperature: 80 °C

Procedure:
2,6-Dibromopyridine (710 mg, 3.00 mmol), potassium carbonate (1184 mg, 8.57 mmol), PdCl2(dppf) (104 mg, 0.14 mmol) were placed in a flask and the flask was purged with argon. 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (600 mg, 2.86 mmol) was dissolved in degassed DMF (19 mL), added to the reaction mixture and 5 argon/vacuum purge cycles were performed. The reaction was heated at 80° C. overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered, and concentrated. The crude mixture was purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([CH3:30])[NH:25]1>C(=O)(O)[O-].[Na+]>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10]([N:25]3[CH:26]([CH3:30])[CH2:27][CH2:28][CH2:29][CH:24]3[CH3:23])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1CCCC(C)N1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1CCCC(C)N1C1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 0.1 %

Procedure:
1-Diphenylmethyl-3-methanesulphonyloxyazetidine (see Preparation 54) (2 g, 1 mol. equiv.) and 2,6-dimethylpiperidine (6.79 ml, 3 mol. equiv.) were heated together at 110° C. under nitrogen for six hours. Saturated aqueous sodium bicarbonate solution (60 ml) was added and the mixture extracted with ethyl acetate (3×40 ml). The combined organic extracts were dried using magnesium sulphate. The organic solvent was removed under reduced pressure and the residue purified by flash column chromatography on silica gel eluting with methanol:dichloromethane (1:9, by volume) to give the title compound (0.48 g). TLC Rf=0.39 (silica, methanol:dichloromethane, 1:9, by volume). LRMS m/z=335 (m+1)+. Found: C, 80.29; H, 9.00; N, 8.14. C23H30N2 0.125 CH2Cl2 requires C, 80.48; H, 8.84; N, 8.12%.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9](C(O)=O)=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[S:11][C:5]=2[N:4]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]1=[O:30].C([N:33](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.ClCCl.CCCC(C)C>C(O)(C)(C)C>[NH2:33][C:9]1[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:30])[N:4]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:5]=2[S:11][C:10]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:20])([F:21])[F:22]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3ccccc3C(F)(F)F)sc21
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCCC(C)C
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(N)c(Cc3ccccc3C(F)(F)F)sc21
Reaction time: 36 h

Procedure:
1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-5-carboxylic acid made by the method of Example 8a) (3.316 g), triethylamine (1.38 ml) and diphenylphosphoryl azide (2.26 ml) were heated at 90° C. under an atmosphere of nitrogen in tert-butanol for 18 hrs. The reaction was concentrated in vacuo and the residue redissolved in dichloromethane (50 ml) and trifluoroacetic acid (30 ml). The mixture was allowed to stir for 36 hrs before being concentrated in vacuo, and residual acid was removed by azeotroping with toluene. The residue was partitioned between half saturated sodium hydrogen carbonate and dichloromethane. The organics were collected, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by chromatography, eluting with 2:1 isohexane:diethyl ether to yield a highly crystalline solid which was recystallised from dichloromethane/isohexane to yield the subtitle compound (1.553 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:32][C:33]1[CH:34]=[C:35]([CH:49]=[C:50]([CH3:52])[CH:51]=1)[C:36]([C:38]1[NH:43][C:42](=[O:44])[NH:41][C:40](=[O:45])[C:39]=1[CH:46]([CH3:48])[CH3:47])=[O:37].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.CN(C=O)C>[CH3:52][C:50]1[CH:49]=[C:35]([CH:34]=[C:33]([CH3:32])[CH:51]=1)[C:36]([C:38]1[N:43]([CH2:8][C:6]2[CH:5]=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:3]=[C:2]([F:1])[CH:7]=2)[C:42](=[O:44])[NH:41][C:40](=[O:45])[C:39]=1[CH:46]([CH3:48])[CH3:47])=[O:37]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COc1ccc(CNc2cc(CO)cc(F)n2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2cc(Cn3c(C(=O)c4cc(C)cc(C)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Yield: 56.2 %

Procedure:
[2-Fluoro-6-(4-methoxy-benzylamino)-pyridin-4-yl]-methanol (262 mg, 1 mmol) was dissolved in chloroform (10 ml) and cooled in an ice bath under nitrogen atmosphere. With stirring, triethylamine (210 μl, 1.5 mmol) was added and methanesulfonyl chloride (90 μl, 1.2 mmol) was added dropwise. After stirring for 1.1 hr., the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo for ca. 20 min. and mixed with (20) (286 mg, 1 mmol), powdered anhydrous potassium carbonate (138 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol). DMF (5 ml) was then added to the mixture at room temperature and stirred for ca. 4 hr. After evaporation of DMF, the residue was dissolved in methanol-chloroform (1:9) and filtered through celite pad. The filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2)) to afford 298 mg (56%) of a white solid. m.p. 120-122° C.; 1H-NMR (200 MHz, CDCl3) δ 1.11 (3H, d, J=6.9 Hz), 1.23 (3H, d, J=6.9 Hz), 2.31-2.33 (7H, m), 3.79 (3H, s), 4.25-4.27 (2H, m), 4.38 (1H, d, J=16.2 Hz), 4.85 (1H, d, J=16.2 Hz), 4.94 (1H, t, J=5.4 Hz), 5.76 (1H, s), 5.89 (1H, s), 6.84-6.87 (2H, m), 7.19-7.26 (3H, m), 7.34 (2H, s), 9.34 (1H, s).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([O:16][C:17]([NH:19][N:20]=[C:21]([CH3:42])[C:22](=[N:39][O:40][CH3:41])[C:23]([NH:25][CH:26]1[C:37](=[O:38])[N:28]2[CH:29]([C:34]([OH:36])=[O:35])[CH:30](O)[CH2:31][S:32][C@H:27]12)=[O:24])=[O:18])[CH3:15].[Cl-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:14]([O:16][C:17]([NH:19][N:20]=[C:21]([CH3:42])[C:22](=[N:39][O:40][CH3:41])[C:23]([NH:25][CH:26]1[C:37](=[O:38])[N:28]2[C:29]([C:34]([OH:36])=[O:35])=[CH:30][CH2:31][S:32][C@H:27]12)=[O:24])=[O:18])[CH3:15]
Reactant: CCOC(=O)NN=C(C)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)NN=C(C)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Yield: 93.4 %

Procedure:
Trifluoroacetic anhydride (6.8 ml.) and triethylamine (4.2 ml.) were added to a solution of 7-(3-ethoxycarbonylhydrazono-2-methoxyiminobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 4.3 g.) in dry tetrahydrofuran (215 ml.) under ice cooling and stirred at the same temperature for an hour. To the resultant solution were added ethyl acetate (200 ml.) and a sodium chloride saturated aqueous solution (100 ml.), and adjusted to pH 2.0 with 6N hydrochloric acid. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 ml.). The organic layer and the extract were combined; washed with a sodium chloride saturated aqueous solution and dried over magnesium sulfate. The solution was evaporated in vacuo, and diisopropyl ether (50 ml.) was added to the residue. The precipitates were collected by filtration and washed with diisopropyl ether to give 7-(3-ethoxycarbonylhydrazono-2-methoxyiminobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 3.85 g.).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](Cl)=[O:21].[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.CN1CCOCC1>ClCCl>[O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([NH:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:32])([F:23])[F:33])=[CH:30][N:29]=1)=[O:21]
Reactant: O=C(Cl)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)Nc1ccc(C(F)(F)F)cn1
Reaction time: 18 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetyl chloride (Example 246A, 0.157 g, 0.5 mmol) dissolved in dichloromethane (5 mL) was added 5-(trifluoromethyl)pyridin-2-amine (0.081 g, 0.5 mmol) and N-methylmorpholine (0.085 mL, 0.75 mmol) under nitrogen. After stirring for 18 hours, the reaction mixture was concentrated, loaded onto silica gel column (Analogix®, Burlington, Wis.) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes (Flow=30 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.70 (s, 1H), 8.53 (s, 1H), 8.24 (d, J=8.7, 1H), 7.90 (dd, J=2.3, 8.8, 1H), 7.44-7.18 (m, 10H), 4.21 (s, 2H), 3.55 (t, J=6.5, 2H), 2.88 (t, J=6.5, 2H); MS (DCI) m/z 440.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].N1C=CC=CC=1C1C=CC=CN=1.[CH3:22][O:23][C:24]([C:26]1[C:35]2[C:30](=[CH:31][C:32]([CH2:36]C(Cl)=O)=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25].Cl>C1COCC1.CCOCC>[CH3:22][O:23][C:24]([C:26]1[C:35]2[C:30](=[CH:31][C:32]([CH2:36][C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: CCOC(=O)CC(=O)O
Reactant: COC(=O)c1cccc2cc(CC(=O)Cl)ccc12
Agent: Cl
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Cc1ccc2c(C(=O)OC)cccc2c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 8.56 g (64.8 mMol) of malonic acid monoethyl ester and 112 mg (0.72 mMol) 2,2′-bipyridine in 200 ml THF is cooled to −78° C. Then 60 ml of a 1.6 M solution of nbutyllithium in THF are added dropwise (color changes from yellow to red!). Warming the mixture up to −10° C., renders the mixture turn to yellow again. Addition of another 10 ml of a 1.6 M solution of nbutyllithium in THF results in a persistent red color of the mixture. After cooling to −78° C., a suspension of 36 mMol 6-chlorocarbonylmethyl-naphthalene-1-carboxylic acid methyl ester in 250 ml THF is added during 40 min and then stirring is continued for 1 h. The dark mixture is poured into 200 ml of 1 N HCl and 400 ml ether, the aq. phase separated off and extracted with 2 portions of EtOAc. The organic layers are washed with brine, dried (Na2SO4) and concentrated to the title compound which can be used in the Step 3.6 as such. Pure product can be obtained by chromatography (Combi Flash; hexane/EtOAc 85:15): MS: [M−1]=313; HPLC: tRet=15.5.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20](O)[CH2:19][CH2:18]1)=[O:16])[CH3:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:12]([O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@@H:20]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=3[C:10]([I:11])=[CH:9]2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@@H](n2cc(I)c3c(Cl)ncnc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into the THF (5 mL) solution of 8-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (140 mg, 0.500 mmol), 4-hydroxycyclohexanecarboxylic acid ethyl ester (104 mg, 0.600 mmol; Aldrich, cis/trans mixture), and PPh3 (263 mg, 1.00 mmol) was added DIAD (203 mg, 1.00 mmol) dropwise at 0° C. under N2 over 5 min. The reaction was then stirred at rt for 2 days. After that time, the solvent was evaporated, and the residue was purified by chromatography on silica gel, eluting with 200 mL of 5%, 10%, 20% and 30% EtOAc/hexane to obtain cis-4-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclohexanecarboxylic acid ethyl ester as a white solid, which was further purified by HPLC. 1H NMR (CDCl3, 400 MHz): δ=1.32 (t, 3H, J=7.2 Hz), 1.74-1.78 (m, 2H), 1.88-1.98 (m, 4H), 2.33-2.36 (m, 2H), 2.75-2.77 (m, 1H), 4.23 (q, 2H, J=7.2 Hz), 4.73-4.81 (m, 1H), 7.45 (s, 1H), 8.60 (s, 1 H). MS (ES+): 433.9/435.9 [MH+]. HPLC: tR=4.0 min (polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:4]=1.[C:16](Cl)(Cl)=[S:17]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([N:7]=[C:16]=[S:17])=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:4]=1
Reactant: COc1ccc(N)c(N2CCOCC2)c1
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(N=C=S)c(N2CCOCC2)c1

Procedure:
Reaction of 4-methoxy-2-morpholinoaniline (4.7 g) and thiophosgene (2.9 ml) in dioxan (25 ml) and water (75 ml) for 30 minutes at 0° C. and 3 hours at room temperature yielded a residue which was extracted with dichloromethane to give 4-methoxy-2-morpholinophenyl isothiocyanate as an oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:24]([CH:26]=[CH2:27])=[O:25].O>O1CCCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:24]([OH:25])[CH:26]=[CH2:27])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 4 h

Procedure:
10.3 g (40 mmol) of 1-(phenylsulfonyl)indole (synthesized analogous to T. Sakamoto; Y. Kondo; N. Takazawa; H. Yamanaka; J.Chem.Soc.Perkin Trans.1; 16; 1996; 1927-1934) in 110 ml tetrahydrofuran were cooled to −20° C. To the stirred solution 30 ml of 1.6 M n-butyllithium were added at −20° C. within 20 min. The resulting suspension was warmed to 10° C. and stirred at 10° C. for 4 hours. The mixture was again cooled to −20° C. and a solution of 3.4 g acrolein (61 mmol) in 20 ml THF was added dropwise within 20 min at −20° C. The solution was stirred at 20° C. for 16 hours. 150 ml water was added dropwise, the mixture was vigorously stirred for 10 min. The phases were separated, and the water phase was extracted with 3×100 ml of methyl-t-butyl-ether. The combined organic phases were washed with 100 ml of brine, dried on sodium sulfate and rotary evaporated (35° C., 20 mbar). The residue was purified by liquid chromatography (eluent toluene/ethyl acetate 6:1), the pure fractions were collected and rotary evaporated (40° C./15 mbar).
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](O)(=[O:29])[CH2:27][CH3:28].N1C=CC=CC=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:29])[CH2:27][CH3:28]
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: CCC(=O)O
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC(=O)Oc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Reaction time: 1 h
Yield: 97 %

Procedure:
To the same flask as used in Example 1 were added 340.51 g (1.0 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 74.08 g (1.0 mole) of propionic acid, 500 g of toluene and 191.42 g (2.42 moles) of pyridine. After replacing the air in the container with nitrogen, 210.05 g (1.1 moles) of o-toluenesulfonyl chloride was added dropwise with stirring. After completion of the dropwise addition, the reaction solution was kept at 100° C. for 1 hour and then aftertreated in the same manner as in Example 2 to obtain 384.7 g of a white crystalline 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monopropionate having a melting point of 108° to 110° C. Yield, 97%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([F:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[OH:16])=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([F:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:16][CH2:31][C:30]1[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:34][CH:33]=1)=[O:4]
Reactant: COC(=O)c1cc(F)c2ccccc2c1O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.8 %

Procedure:
To 0.190 g of 4-fluoro-1-hydroxynaphthalene-2-carboxylic acid methyl ester in 4 ml of dry DMF 560 mg of Cesium carbonate and 31 mg of potassium iodide was added. The mixture was stirred at ambient temperature for 20 minutes after which was added a solution of 0.31 g of 4-(trifluoromethyl)benzyl bromide in 2 ml of DMF. The mixture was stirred at room temperature for 3 h, poured into saturated sodium bicarbonate, extracted with ethyl acetate, washed with water, brine, dried (sodium sulphate), filtered and concentrated to a white solid. The material was purified by flash chromatography on silica gel eluting with ethyl acetate/heptanes to provide 0.231 g of 4-fluoro-1-[4-(trifluoromethyl)benzyloxy]naphthalene-2-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:5][N:4]=[C:3]1[S:12][CH:13]([CH3:17])[C:14]([OH:16])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Cl:41][C:42]1[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=1)[C:45]([NH:47]O)=[NH:46]>C(OCC)(=O)C.CN(C=O)C>[Cl:41][C:42]1[CH:43]=[C:44]([C:45]2[N:47]=[C:14]([CH:13]([S:12][C:3]3[N:2]([CH3:1])[C:6]([C:7]4[S:8][CH:9]=[CH:10][CH:11]=4)=[N:5][N:4]=3)[CH3:17])[O:16][N:46]=2)[CH:49]=[CH:50][CH:51]=1
Reactant: CC(Sc1nnc(-c2cccs2)n1C)C(=O)O
Reactant: N=C(NO)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(Sc1nnc(-c2cccs2)n1C)c1nc(-c2cccc(Cl)c2)no1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
DMF was added to a mixture of 2-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-propionic acid (50 mg, 0.186 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (35.7 mg, 0.186 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (28.5 mg, 0.186 mmol) and 3-chloro-N-hydroxy-benzamidine (29.3 mg, 0.172 mmol) at room temperature and stirred overnight. The reaction mixture was diluted lo with ethyl acetate (75 ml), washed with water 3 times, once with 1.0 M HCl (30 ml), saturated NaHCO3 (30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. DMF (1 ml) was added to the residue and the resulting solution was heated at 135° C. for 3 h to effect cyclization to oxadiazole. After cooling the reaction mixture was diluted with ethyl acetate (75 ml), washed with water 3 times, once with 1.0 M HCl (30 ml), saturated NaHCO3 (30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The title compound (46.5 mg, 66.9%) was purified by SPE chromatography on silica gel using 50 ml 40%, 150 ml 50% ethyl acetate in hexanes. 1H NMR (CDCl3), a (ppm): 8.03 (s, 1H), 7.92 (m, 1H), 7.47 (m, 4H), 7.18 (dd, 1H), 4.99 (q, 1H), 3.64 (s, 3H), 1.97 (d, 3H).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=O.B.Cl>O1CCCC1>[CH3:1][NH:3][CH2:4][C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[C:6]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: O=CNCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CNCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 5-(N-formylaminomethyl)-4-(4-pyridyl)-3-(4-fluorophenyl)pyrazole (8.74 g, 29.5 mmol) in 90 mL anhydrous tetrahydrofuran was added a 1.0 M solution of borane in tetrahydrofuran (90 mL, 90 mmol) and the mixture was stirred at room temperature for 24 h. 1 N aqueous hydrochloric acid (100 mL) was then added to this mixture and the solution was refluxed for 5 hours and cooled to room temperature. The solution was extracted with ether (2×250 mL) and the pH of the aqueous layer adjusted to 9 by addition of concentrated ammonium hydroxide. The aqueous layers (pH —9) were then extracted with ethyl acetate (4×150 mL). The organic extracts were dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was triturated with acetonitrile and filtered to obtain the title compound as a white solid: MS (M+H): 283 (base peak).
Reaction SMILES: [Na].N.[NH2-].[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[CH:16]=3)=[CH:9][CH:8]=1.[CH3:24]I>O1CCCC1>[CH3:24][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[CH:16]=2)[CH:21]=[C:13]1[C:10]1[CH:11]=[CH:12][C:7]([O:6][CH3:5])=[CH:8][CH:9]=1
Reactant: CI
Reactant: COc1ccc(-c2cc3ccc(OC)cc3[nH]2)cc1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3ccc(OC)cc3n2C)cc1
Reaction time: 8 h

Procedure:
There were added in portions 0.06 gram atom of sodium to 200 ml of liquid ammonia. At -70° C. there were dropped into the sodamide solution a solution of 8.85 grams (35 mmol) of 2-(4-methoxy-phenyl)-6-methoxy-indole in 100 ml of absolute tetrahydrofuran, stirring continued for one-half hour and then there were dropped in 6 grams (42 mmol) of methyl iodide in 30 ml of absolute tetrahydrofuran. After a further 30 minutes there was removed the cold bath and the ammonia allowed to vaporize overnight. The residue was treated carefully with water and then extracted with ether. The organic phase was washed, dried, and the solvent removed on a rotary evaporator. The residue is recrystallized from ethanol. Yield: 8.63 grams, M.P. 163°-166° C.