Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][N:25]=1.O>O1CCCC1>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][CH:9]=1)[CH2:2][O:1][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][N:25]=1
Reactant: CC(C)(C)c1ccc(C(CO)OC2CCCCO2)cc1
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(C(COc2ncnc3ccccc23)OC2CCCCO2)cc1

Procedure:
1-Hydroxy-2-tetrahydropyranyloxy-2-(4-tert-butylphenyl)ethane (0.3 g, 1.07 mmol) is dissolved in dry tetrahydrofuran (7 ml) and to it is added sodium hydride (30.96 mg, 1.29 mmol). The resulting solution is stirred at room temperature for 30 minutes after which 4-chloroquinazoline (0.175 g, 1.07 mmol) is added to the above solution. The solution is then stirred for 6 hours after which water is added to the mixture. The solution is then extracted in dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to give the product.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].[OH-].[Na+].[Cl:13][C:14]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18](Cl)=[O:19]>O.C(Cl)Cl>[Cl:13][C:14]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18]([NH:10][C:8](=[NH:9])[O:7][CH3:6])=[O:19]
Reactant: COC(=N)N
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=N)NC(=O)COc1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 3 h

Procedure:
13.5 g (0.11 mole) of O-methyl-isourea sulfate are dissolved in 50 ml of water and 100 ml of methylene chloride. 16 g of 50% strength aqueous sodium hydroxide solution (0.2 mole) and 24 g (0.1 mole) of 2,4-dichlorophenoxyacetyl chloride are simultaneously added dropwise from two separate vessels at 0° C., with vigorous stirring. The mixture is stirred at 0° C. for 1 hour and at 40° C. for 3 hours and the organic phase is separated off, washed twice with 100 ml of water and dried over sodium sulfate.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH:9](I)([CH3:11])[CH3:10]>>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH:9]([CH3:11])[CH3:10])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(I)cc[nH]1
Reactant: CC(C)I
Product: CC(C)n1ccc(I)cc1=O

Procedure:
4-iodo-1-isopropylpyridin-2(1H)-one was prepared from 4-iodopyridin-2(1H)-one and isopropyl iodide following a procedure analogous to that described in Example 628 Step 1.
Reaction SMILES: [I-].[C:2]([O:6][C:7]([NH:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([N:17]2[CH:21]=[CH:20][N+](C)=[CH:18]2)=[O:16])[CH2:11]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[N:27][C:28]2CCNC[C:33]=2[CH:34]=1.CCN(CC)CC>C(Cl)Cl>[C:2]([O:6][C:7](=[O:8])[NH:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([N:17]2[CH2:18][CH2:33][C:28]3[N:27]=[CH:26][C:25]([C:24]([F:36])([F:35])[F:23])=[CH:34][C:20]=3[CH2:21]2)=[O:16])[CH2:11]1)([CH3:3])([CH3:4])[CH3:5]
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Reactant: C[n+]1ccn(C(=O)N2CCC(NC(=O)OC(C)(C)C)C2)c1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a solution of 3-(3-tert-butoxycarbonylamino-pyrrolidine-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (preparation #4) (7.81 g, 18.5 mmol) in DCM (70 mL) was added 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine (3.74 g, 18.5 mmol) and Et3N (2.6 mL, 18.5 mmol) and the reaction mixture was stirred at ambient temperature for about 16 h. Additional Et3N (1.5 mL, 10.7 mmol) was added and the reaction mixture was stirred at ambient temperature for about 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using 5% MeOH/DCM as the mobile phase to give [1-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridine-6-carbonyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (4.91 g, 64%). RP-HPLC (Table 1, Method a) Rt 2.37 min; m/z: (M+H)+ 415.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[F:31]>C(COC)OC>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=2)=[C:25]([F:31])[CH:26]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc(N)cc1F
Temperature: 70 °C
Reaction time: 3 h

Procedure:
1.6 g of 1-(t-butoxycarbonyl)pyrrole-2-boronic acid, 200 mg of tetrakistriphenylphosphine palladium, 5 ml of aqueous saturated sodium carbonate solution and 5 ml of water were added in order to a dimethoxyethane (10 ml) solution of 1 g of 4-bromo-3-fluoro-phenylamine, and the reaction liquid was stirred in a nitrogen atmosphere at 70° C. for 3 hours. After cooled, the reaction liquid was filtered through Celite, and the filtrate was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1) to obtain the entitled compound as a pale brown solid.
Reaction SMILES: C(O)C.[C:4]([C:8]1[C:9](=[O:28])[C:10]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:11][C:12](=[N:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)[CH:13]=1)([CH3:7])([CH3:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+]>[Pd].O>[C:4]([C:8]1[CH:13]=[C:12]([CH:11]=[C:10]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]=1[OH:28])[NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][CH:20]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C1=CC(=Nc2ccc(C(=O)O)cc2)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(Nc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O

Procedure:
To a mixture of 200 ml of ethanol and 25.0g (0.0736 mole) of 2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexadien-1-one and 12 g (0.087 mole) of potassium carbonate warmed on a steam bath was added 1.0g of palladium on charcoal. The mixture was reduced using a Paar apparatus for 2 hours. The mixture was diluted with 300 ml of water, filtered through celite, and the filtrate acidified with 6N hydrochloric acid. The yellow solid precipitate was collected by filtration to provide 4-[3,5-di(tertiary-butyl)-4-hydroxyanilino]benzoic acid, m.p. 241°-242° C.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([OH:14])[CH2:7][NH:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH:2]=[CH2:3].[CH3:15][Si:16]([CH3:30])([CH3:29])[O:17][SiH:18]([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[O:19][Si:20]([CH3:23])([CH3:22])[CH3:21].[Cl-]>C1(C)C=CC=CC=1>[OH:14][CH:6]([CH2:5][O:4][CH2:1][CH2:2][CH2:3][Si:18]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[O:17][Si:16]([CH3:29])([CH3:30])[CH3:15])[CH2:7][NH:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C[Si](C)(C)O[SiH](O[Si](C)(C)C)O[Si](C)(C)C
Reactant: C=CCOCC(O)CNC(=O)C(=C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)NCC(O)COCCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 96 °C
Reaction time: 16 h

Procedure:
N-(3-Allyloxy-2-hydroxy-propyl)-2-methyl acrylamide made according to Example 9 (18 g, 0.09 mol), platinic chloride (4 mg, 100 ppm), BHT (36 mg, 2000 ppm) and toluene (90 mL) were charged into a 500 mL three-neck flask, equipped with a condenser with a nitrogen inlet and outlet, and a thermocouple connected to a temperature controller. Tris(trimethylsiloxy)silane (26.8 g, 0.09 mol) was added dropwise to the above mixture at 96–97° C. After stirred at about 96° C. for 16 hours, additional platonic chloride (4 mg, 100 ppm) was added to the reaction solution. The reaction was monitored by gas chromatography. After stirred for 47 hours, the reaction solution was washed with 0.5 N aqueous sodium hydroxide solution and twice with 2.5% aqueous sodium chloride solution. This was followed by washing with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and filtered. The filtrate, inhibited with 4-methoxyphenol (0.02 g), was concentrated under reduced pressure at 30° C.–40° C. to give an oil (˜36 g). N-(2-hydroxy-3-(3-(tris(trimethylsilyloxy)silyl)propyloxy)propyl)-2-methyl acrylamide was purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH2:13]O)[CH:10]=[CH:11][CH:12]=2)=[N:4][CH:3]=1.P(Br)(Br)([Br:17])=O.C([O-])(O)=O.[Na+]>C1COCC1>[Br:17][CH2:13][C:9]1[CH:8]=[C:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][N:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cnc(-c2cccc(CO)c2)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(-c2cccc(CBr)c2)o1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
To a stirred solution of (3-(5-methyloxazol-2-yl)phenyl)methanol (0.79 g, 4.13 mmol) in THF (15 mL), POBr3 (1.93 g, 6.61 mmol) was added in portions at 5° C. The reaction mixture was allowed to warm to rt and then heated at 60° C. for 4 h. The mixture was cooled to rt, poured into saturated aqueous NaHCO3 solution and extracted with TBME (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash-column chromatography over silicagel (eluent: gradient 5%-40% ethyl acetate/heptane) to yield the title compound (0.88 g, 84%). [1H NMR (400 MHz, CHLOROFORM-d) ♀ ppm 8.01-8.07 (m, 1H), 7.93 (ddd, J=6.7, 2.1, 1.9 Hz, 1H), 7.39-7.47 (m, 2H), 6.85 (d, J=1.3 Hz, 1H), 4.53 (s, 2H), 2.41 (d, J=1.3 Hz, 3H); LCMS RtA=1.10, [M+H]+=252.1/254.1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-:18].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][F:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COS(C)(=O)=O
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(C)(C)OC(=O)N1CC[C@H]1CF
Temperature: 25 °C

Procedure:
2-(S)-Methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester (5.62 g, 21.2 mmol) was treated with tetrabutylammonium fluoride (1 M solution in THF, 191 mL) under N2, heated to reflux for 1 hour, cooled to ambient temperature, concentrated to 50 mL, treated with water (100 mL) and extracted with ethyl acetate (2×250 mL). The combined ethyl acetate layers were washed with 0.25 M HCl (100 mL), washed with NaHCO3 solution, washed with brine, dried (MgSO4), filtered, concentrated and chromatographed (10:1 and then 5:1 hexane:ethyl acetate) to provide 2.9 g (72%). 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9 H) 2.26 (m, 2 H) 3.84 (t, J=7.46 Hz, 2 H) 4.35 (m, 1 H) 4.42 (ddd, J=46.36, 9.92, 2.71 Hz, 1 H) 4.72 (ddd, J=48.31, 10.00, 3.05 Hz, 1 H).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[CH:20][S:21][CH:22]=1)=[O:17].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[N+:1]([O:4][CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[CH:20][S:21][CH:22]=1)=[O:17])([O-:3])=[O:2]
Reactant: O=C(NCCO)c1cscn1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: O=C(NCCO[N+](=O)[O-])c1cscn1
Temperature: 5 °C

Procedure:
Fuming nitric acid (12.8 ml) was added dropwise to acetic anhydride (27.4 ml) with stirring and ice-sodium chloride cooling at 10° C. for 1 minute, and the mixture was stirred for 10 minutes at the same temperature. Continuously, a solution of N-(2-hydroxyethyl)-4-thiazolecarboxamide (25.0 g) in dry chloroform (35 ml) was added dropwise thereto with stirring and cooling at 5° C. for 10 minutes and the mixture was stirred for hour at the same temperature. The reaction mixture was poured into a mixture of sodium bicarbonate (100 g) and ice-water (1.0 kg) and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residual solid was recrystallized from a mixture of diisopropyl ether and methanol (3:2) to give colorless crystals of N-(2-nitrooxyethyl)-4-thiazolecarboxamide (10.17 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[N+]1([O-])CC[O:24]CC1.O>C(#N)C>[CH:2]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:24]
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(CBr)c1
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccccc2)c(C=O)c1
Reaction time: 4 h
Yield: 66.7 %

Procedure:
In 100 ml of acetonitrile was dissolved 9.3 g of ethyl 2-(bromomethyl)biphenyl-4-carboxylate, and 7.0 g of N-methylmorpholine-N-oxide was added thereto at room temperature, followed by 4 hours of stirring. Water was added to the reaction solution, which was then extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate. After the solvent was removed by evaporation, the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 4.94 g of ethyl 2-formylbiphenyl-4-carboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.C(Cl)CCl.[CH:16](O)=[O:17]>C(Cl)Cl>[O:11]=[C:8]1[CH2:7][C:6]2[C:10](=[C:2]([NH:1][CH:16]=[O:17])[CH:3]=[CH:4][CH:5]=2)[NH:9]1
Reactant: O=CO
Reactant: Nc1cccc2c1NC(=O)C2
Solvent: ClCCl
Solvent: ClCCCl
Product: O=CNc1cccc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a suspension of 7-aminooxindole (32 mg, 0.22 mmol) in CH2Cl2 (1 mL) was added EDC (83 mg, 0.43 mmol) and formic acid (12 mg, 0.26 mmol). The reaction mixture was stirred at rt for 2 h and then filtered. The filter cake was washed with diethyl ether to give the title compound as a grey solid (27 mg, 71%). 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 7.20 (d, 1H, J=8 Hz), 7.15 (d, 1H, J=8 Hz), 7.02 (t, 1H, J=8 Hz), 3.59 (s, 2H); MS ESI [M+H]+, calcd for [C9H8N2O2+H]+ 177.07. found m/z 177.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.ClC1C=C(C=CC=1)C(OO)=[O:15].CCOC(C)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N+:7]([O-:15])[CH:8]=1
Reactant: COc1ccc(C)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-methoxy-2-methylpyridine (15 g, 0.121 mol) in DCM (200 mL) was added 3-chloro peroxybenzoic acid (23.14 g, 0.134 mol, Aldrich). The reaction was stirred at rt for 3 h. Reaction progress was monitored by TLC (50% EtOAc in petroleum ether). After completion of reaction, the reaction mixture was concentrated under reduced pressure providing the product as a yellow oil. The oil was dissolved in EtOAc (50 mL) and passed through a silica gel plug (60-120 mesh) and the plug eluted with 10% MeOH in CHCl3 to give the title compound as a colorless liquid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (d, J=2.4 Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 6.98 (dd, J=2.7 and 8.7 Hz, 1H), 3.78 (s, 3H), 2.26 (s, 3H). MS (ESI, positive ion) m/z: 140.0 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](Br)[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1[O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].[CH2:21]=[O:22]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1[O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:21]=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O[Si](C)(C)C
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O[Si](C)(C)C
Yield: 45 %

Procedure:
By proceeding as indicated in the procedure of Preparation VII above, starting with 10 mmol of 3,5-di-t-butyl-4-trimethylsilyloxy-bromobenzene and 15 mmol of HCHO (in the protected form of H2C(OCH3)2), one obtains (yield: 45%) 3,5-di-t-butyl-4-trimethylsilyloxy-benzaldehyde, followed by the expected product, 3,5-di-t-butyl-4-hydroxybenzaldehyde.
Reaction SMILES: Cl[CH2:2][CH:3]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4]Cl.[CH3:20][NH2:21]>>[C:8]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:6][CH:3]2[CH2:4][N:21]([CH3:20])[CH2:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCC(CCl)OC(c1ccccc1)c1ccccc1
Reactant: CN
Product: CN1CC(OC(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 244. g (0.83 mole) of 1,3-dichloro-2-diphenylmethoxypropane in 300 ml of methylamine was heated in a steel bomb to 100° for 18 hours. The mixture was concentrated, and the residue partitioned between chloroform and dilute hydrochloric acid. The acid solution was washed twice with chloroform, and the chloroform solutions combined. The chloroform was extracted with dilute sodium hydroxide, dried with sodium sulfate, and concentrated. The residue was distilled (b.p. 125°-130°/0.1 mm) to yield 104 g (40%). The distillate crystallizes on standing and can be recrystallized from isooctane, mp 44°-48°.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]2[N:6]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:21])[C:7](=[O:18])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:64]=[N+:65]=[N-:66])(=O)=O)(C)C.C(O)(=O)C>O1CCCC1>[N:64]([CH:8]1[C:7](=[O:18])[N:6]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:21])[C:5]2[CH:34]=[CH:35][C:2]([F:1])=[CH:3][C:4]=2[N:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:9]1=[O:17])=[N+:65]=[N-:66]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(N(C(=O)CN2C(=O)C(N=[N+]=[N-])C(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
A solution of 262 mg of 2-(7-Fluoro-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (0.550 mmol) in 5 mL of anhydrous tetrahydrofuran at -78° C. under nitrogen was treated dropwise with 1.54 mL of potassium bis(trimethylsilyl)amide (0.5M in toluene, 0.770 mmol, 1.4 eq). After stirring 15 min., 212 mg of 2,4,6-triisopropylbenzenesulfonyl azide (0.687 mmol, 1.25 eq, J. Org. Chem. 1984, 49, 1430-1434) was added. After stirring 4 min., the reaction mixture was quenched by addition of 78.6 mL of glacial acetic acid (1.38 mmol, 2.5 eq) and allowed to warm to ambient temperature. The reaction mixture was evaportated in vacuo to a residue and purified on flash grade silica with 1:1 ethyl acetate / hexane. The appropriate fractions were combined, evaporated in vacuo and dried under high vacuum to provide 170 mg of the title compound as an amorphous solid. Low resolution MS (FAB)m/e 518 (MH+); TLC (silica) 3:1 Ethyl acetate: hexane Rf=0.68.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10](S(C)=O)SC)[CH:7]=[C:6]([F:16])[C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:18].O>C1COCC1>[F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:18])[CH:7]=[C:6]([F:16])[C:3]=1[C:4]#[N:5]
Reactant: O=S(=O)(O)O
Reactant: CSC(c1cc(F)c(C#N)c(F)c1)S(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(F)cc(C=O)cc1F
Reaction time: 72 h

Procedure:
2,6-Difluoro-4[(methylsulfinyl)(methylthio)methyl]benzonitrile (2.17 g, 8.32 mmol; see step (i) above) was dissolved in 90 mL of THF and 3.5 mL of concentrated sulfuric acid was added. The mixture was left at room temperature for 3 days and subsequently poured into 450 mL of water. Extraction three times with EtOAc followed and the combined ethereal phase was washed twice with aqueous sodium bicarbonate and with brine, dried (Na2SO4) and evaporated. Yield: 1.36 g (98%). The position of the formyl group was established by 13C NMR. The signal from the fluorinated carbons at 162.7 ppm exhibited the expected coupling pattern with two coupling constants in the order of 260 Hz and 6.3 Hz respectively corresponding to an ipso and a meta coupling from the fluorine atoms.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([S:11][CH3:12])[NH:8]2)=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:15][CH2:14]2)[N:3]=1.[CH3:30]I>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([S:11][CH3:12])[N:8]2[CH3:30])=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:15][CH2:14]2)[N:3]=1
Reactant: CSc1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2[nH]1
Reactant: CI
Product: CSc1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2n1C
Yield: 97 %

Procedure:
This compound was synthesized from 2-amino-6-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-8-methylthio-9H-purine using methyl iodide, yielding the title compound in 97% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:38][C:39]1[C:44]([F:45])=[C:43]([F:46])[CH:42]=[CH:41][C:40]=1B(O)O.[F-].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:18][CH:19]=1)=[O:29])=[C:8]([C:42]1[CH:41]=[CH:40][C:39]([F:38])=[C:44]([F:45])[C:43]=1[F:46])[CH:7]=[CH:6]2
Reactant: OB(O)c1ccc(F)c(F)c1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)c(F)c3F)ccc2c1
Temperature: 80 °C

Procedure:
Charge a round bottom flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.13 g, 4.0 mmol), 2,3,4-trifluorophenyl boronic acid (1.0 g, 5.7 mmol), trans-dichlorobis(triphenylphosphine)palladium II, (561 mg, 0.8 mmol) and cesium fluoride (5.5 g, 36 mmol) and add 50 mL of acetonitrile. Heat the mixture at 80° C. for 4 hours. Cool and filter the mixture and purify on an SCX column, eluting with 2N ammonia/methanol. Purify further on a silica column eluting with 2% 2N ammonia/methanol/methylene chloride. The yield is 880 mg (43%): 1H-NMR (CD3OD, 400 MHz) δ7.93 (d, J=8.8 Hz, 1H); 7.50 (d, J=8.4 Hz, 3H); 7.39 (d, J=8.8 Hz, 1H); 7.35 (d, J=2.4 Hz, 1H); 7.07 (dd, J=9.2, 2.8 Hz, 1H); 6.96-6.87 (m, 2H); 6.80 (d, J=9.6 Hz, 2H); 4.10-4.07 (t, 2H); 3.91 (s, 3H); 2.72-2.69 (t, 2H); 2.48-2.48 (m, 4H); 1.61-1.55 (m, 4H); 1.46-1.43 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([Cl:19])=[O:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (1.5 g, 6.3 mmol) in thionyl chloride (18 mL) is warmed to reflux for 1 hour. After cooling to room temperature, the reaction mixture is concentrated in vacuo to afford 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl chloride as a tan solid (1.6 g, 100%) which is used without further purification.