Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.[NH:35]1[C:43]2[C:38](=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[O:20][C:16]3[CH:15]=[CH:14][C:13]([C:39]4[CH:40]=[CH:41][CH:42]=[C:43]5[C:38]=4[CH:37]=[CH:36][NH:35]5)=[CH:32][C:17]=3[C:18]=2[C:28]([NH:29][CH3:30])=[O:31])=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc4[nH]ccc34)cc12
Temperature: 90 °C
Yield: 47.8 %

Procedure:
Cesium carbonate (176 mg, 0.539 mmol) was added to Pd(Ph3P)4 (20.77 mg, 0.018 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (150 mg, 0.359 mmol), 1H-indol-4-ylboronic acid (87 mg, 0.539 mmol). Dioxane (3 mL) and water (600 μL) was added at rt. The reaction was degassed 3× and then heated to 90° C. overnight. It was allowed to cool. The mixture was diluted with ethyl acetate and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (66 mg, 46%). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.28 (1H, br. s.), 8.48-8.57 (1H, m), 7.98-8.07 (2H, m), 7.86 (1H, br. s.), 7.79 (1H, d, J=8.24 Hz), 7.69 (1H, d, J=7.93 Hz), 7.37-7.47 (4H, m), 7.21 (1H, t, J=7.63 Hz), 7.14 (1H, d, J=7.02 Hz), 6.60 (1H, br. s.), 2.84 (3H, d, J=4.27 Hz). LC-MS retention time: 1.53 min; m/z (MH+): 385. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=13.46 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=12.27 min, purity=97%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)([O-])=O.[H][H]>C(O)C.[Ni]>[C:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=2[C:16]([F:17])([F:18])[F:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(-c2ccccc2)c(C(F)(F)F)c1

Procedure:
Phenyl boronic acid (Aldrich, Buchs, Switzerland; 2.7 g, 22 mmol), Palladium II acetate (0.225 g, 1 mmol), tri-o-tolylphosphine (0.608 g, 2 mmol) and aqueous potassium carbonate solution (50 mL of 1 M) is added to a stirred solution of 2-bromo-5-nitrobenzotrifuoride (Lancaster Synthesis, GmbH; 5.4 g, 20 mmol) in dimethylformamide (200 mL) and heated at 120° C. under an argon atmosphere for 1 h. The mixture is then evaporated to dryness under reduced pressure and the residue is treated with water (100 mL) and extracted with ethyl acetate (3×80 mL). The combined extracts are washed (brine), dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to afford 4′-nitro-2′-(trifluoromethyl)-[1,1′-Biphenyl]. The biphenyl is dissolved in ethanol (200 mL) and hydrogenated at atmospheric pressure over Raney nickel (2 g) at 22° C. The calculated amount of hydrogen is taken up in 11 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatograghy (silica gel; eluent ethyl acetate) to give the title compound as a brown oil. 1H-NMR (400 MHz, DMSO-d6): 5.62 (br.s, 2H), 6.80 (dd, 1H), 6.96 (d, 1H), 6.99 (d, 1H), 7.19-7.23 (m, 2H), and 7.29-7.39 (m, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>N1C=CC=CC=1.CCOC(C)=O>[S:11]([O:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1CC(O)C1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1CC(OS(=O)(=O)c2ccc(C)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-hydroxycyclobutanecarboxylate (10.2 g, 78.4 mmol) in dry pyridine (56.5 mL) at 0° C., TsCl (14.9 g, 78.4 mml) was added portion-wise. The resulting mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue obtained was dissolved in EtOAc (100 mL) and sequentially washed with 2 N HCl (100 mL), saturated NaHCO3 (100 mL) and water (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to obtain ethyl 3-(tosyloxy)cyclobutanecarboxylate as a pale yellow oil, which was used in the next step without further purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH2:10]([P:17](=[O:22])([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N>>[N+:1]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][P:17](=[O:22])([CH2:18][CH3:19])[CH2:20][CH3:21])=[CH:12][CH:13]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCP(=O)(CC)Cc1ccccc1
Agent: N
Agent: O=S(=O)(O)O
Product: CCP(=O)(CC)Cc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of nitric acid (0.4 ml) and concentrated sulfuric acid (3 ml) was added benzyldiethylphosphine oxide (1.05 g) at 0° C., and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was added to ice-water, and ammonia solution was added to the solution to neutralize the solution, which was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethyl acetate/ethanol=3:2→1:1) to give 4-nitrobenzyldiethylphosphine oxide (518 mg) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH:33]=[CH2:34]>C(C(C)=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:11]([O:13][CH2:34][CH:33]=[CH2:32])=[O:12])=[CH:4][CH:3]=1
Reactant: C=CCI
Reactant: O=C(O)C(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: C=CCOC(=O)C(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Yield: 73.3 %

Procedure:
To a 250 mL flask stirring under nitrogen was charged 3.55 g (0.010 mole) of a 4-(4-chlorophenyl)-2-phenyl-2-[(1,2,4-triazol-1-yl)methyl]butanoic acid in 40 mL of methyl ethyl ketone and 10 mL of dimethyl formamide. To the mixture was added 2.07 g (0.015 mole) of potassium carbonate and 1.85 g (0.011 mole) of allyl iodide. The reaction was stirred for 16 hours at 45° C. The reaction was quenched by adding 150 mL of ether and 25 mL of water. The organic phase was washed with 50 mL of saturated sodium bicarbonate and 20 mL of 10% sodium hydroxide, then 50 mL of water. After decolorizing with charcoal, the solvent was filtered and concentrated and gave 2.9 g (79.4% yield) of a solid, Example 137 of Table 1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11](N)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[I:10].CI.[CH3:17][N:18]([CH:20]=O)C>>[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:18]([CH3:20])[CH3:17])(=[O:12])=[O:13])[CH:7]=[CH:8][C:9]=1[I:10]
Reactant: NS(=O)(=O)c1ccc(I)c(Cl)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)S(=O)(=O)c1ccc(I)c(Cl)c1
Reaction time: 0.33 h

Procedure:
Sodium hydride (0.33 g) was added to a solution of the product from step (i) (1.2 g) in DMF (25 ml) and stirred for 20 min. Methyl iodide (0.5 ml) was added dropwise and then stirred for a further 1 h. The reaction mixture was quenched with water, extracted with EtOAc, dried (MgSO4) and evaporated. The residue was treated with ether to give to give the subtitle compound as a white solid. Yield 0.45 g.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH2:19]([C:21]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH:40][C:41](=O)[O:42]C3C=CC=CC=3)=[CH:34][CH:33]=2)[C:24]2=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]2[N:22]=1)[CH3:20].O>CN(C=O)C>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:41]([NH:40][CH2:39][CH2:38][C:35]2[CH:36]=[CH:37][C:32]([N:31]3[C:24]4=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]4[N:22]=[C:21]3[CH2:19][CH3:20])=[CH:33][CH:34]=2)=[O:42])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Reaction time: 0.08 h
Yield: 49.7 %

Procedure:
To a stirred solution of 4-biphenylsulfonamide (Greenlee, W. J.; Walsh, T. F.; et al. Eur. Pat. Appl., EP 617001 (1994)., 56 mg, 0.24 mmol) in DMF (3 mL) was added NaH (60% oil dispersion, 20 mg, 0.5 mmol) at room temperature. After 5 min, phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1, 100 mg, 0.24 mmol) was added, and the mixture was stirred for an additional 1 h. The mixture was poured into water (50 mL) and extracted with diethyl ether (2×50 mL). The combined extracts were washed with water (50 mL), brine (50 mL) and dried (MgSO4). Removal of solvent gave white oily solids. Purification by preparative TLC (ethyl acetate) gave 66 mg (50%) of the title compound as a colorless oil: MS (ESI) m/z 554 (M+H)+; 1H-NMR (CDCl3) δ 8.06 (2H, d, J=8.6 Hz), 7.13 (2H, d, J=8.6 Hz), 7.60–7.53 (2H, m), 7.48–7.36 (3H, m), 7.21 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.3 Hz), 6.92 (1H, s), 6.11 (1H, br.t, J=5.5 Hz), 3.54 (2H, dt, J=5.9, 6.0 Hz), 2.89 (2H, J=6.0 Hz), 2.64 (2H, q, J=7.5 Hz), 2.66 (3H, s), 2.40 (3H, s), 1.18 (3H, t, J=7.5 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22]CC2C=CC=CC=2)=[C:18]([CH3:30])[CH:17]=1)=O.[NH2:32][C:33]([NH2:35])=[O:34].[ClH:36].O1CCOCC1>C(O)C>[ClH:36].[OH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[CH:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:4][CH2:3][O:2][CH3:1])[NH:35][C:33](=[O:34])[N:32]=2)=[CH:17][C:18]=1[CH3:30]
Reactant: COCCOc1ccccc1C(=O)CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Reactant: NC(N)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COCCOc1ccccc1-c1cc(-c2ccc(O)c(C)c2)nc(=O)[nH]1
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of 1-(2-{[2-(methyloxy)ethyl]oxy}phenyl)-3-{3-methyl-4-[(phenylmethyl)oxy]phenyl}propane-1,3-dione (0.24 g, 0.56 mmol), urea (0.34 g, 5.6 mmol), 4.0M hydrochloric acid in dioxane (1.4 mL, 5.6 mmol) in ethanol (2 mL) was heated in a 110° C. oil bath for 12 h. The solution was allowed to cool to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate (10% methanol) and aqueous saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This crude mixture was taken up in 2.0 mL trifluoroacetic acid and heated in an 80° C. oil bath for 1 hour then concentrated. Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% trifluoroacetic acid), followed by concentration in vacuo, treatment with methanol and 4.0 M hydrochloric acid in dioxane, and lyophilization gave the title compound 4-(4-hydroxy-3-methylphenyl)-6-(2-{[2-(methyloxy)ethyl]oxy}phenyl)pyrimidin-2(1H)-one hydrochloride (0.037 g, 19%). 1H NMR (400 MHz, d6-DMSO): 11.07 (s, 1H), 8.01 (d, 1H), 7.92 (dd, 1H), 7.74 (dd, 1H), 7.63 (dt, 1H), 7.47 (s, 1H), 7.29 (d, 1H), 7.19 (dt, 1H), 7.10 (d, 1H), 4.29 (m, 2H), 3.71 (m, 2H), 3.27 (s, 3H), 2.20 (s, 3H). MS (EI) for C20H20N2O4: 352 (MH+).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8]1([P:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(C)=O>[C:21]1([P:14](=[C:2]2[CH2:3][C:4](=[O:6])[NH:5][C:1]2=[O:7])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1C=CC(=O)N1
Solvent: CC(C)=O
Product: O=C1CC(=P(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1
Yield: 92 %

Procedure:
In an anhydrous acetone (60 mL), a solution including maleimide (6 g, 61.81 mmol) and triphenylphosphine (16.2 g, 61.76 mmol) was refluxed for 1 hour. After cooling, a precipitate was filtered, and a filter cake was washed with cold acetone (20 mL). Under reduced pressure, the washed filter cake was dried to obtain a white solid Compound 36a (20.428 g, 92%). The solid was used in following steps without further purification.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[CH2:7][C:8]1[C:16]2[S:15][N:14]=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>CS(C)=O>[C:1]([S:3][CH2:7][C:8]1[C:16]2[S:15][N:14]=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: ClCc1cccc2nnsc12
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)SCc1cccc2nnsc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 2.2 g of potassium thioacetate in 20 ml of absolute dimethyl sulfoxide, stirred at 20° C., is treated dropwise with stirring with a solution of 2.8 g of 7-chloromethylbenzo-1,2,3-thiadiazole in 10 ml of dimethyl sulfoxide, during which process the internal temperature rises to 37° C. The mixture is subsequently stirred overnight at room temperature and, on the following day, poured into ice-water and extracted using ethyl acetate. The extracts are washed five times with water, dried over sodium sulfate and evaporated. The residue which remains is distilled in vacuo, resulting in an oil of refractive index nd27 -1.6478.
Reaction SMILES: [CH:1]([O:3][CH2:4]C)=C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(N(CC)CC)C.[C:28]([O:31][CH2:32][CH3:33])(=[O:30])[CH3:29]>>[CH3:33][CH:32]([O:31][C:28]([CH3:29])=[O:30])[CH2:1][O:3][CH3:4]
Reactant: CCOC(C)=O
Reactant: C=COCC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(CC)CC
Product: COCC(C)OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
To the reaction solution above, 1.68 g of ethyl vinyl ether and 0.48 g of 2% camphorsulfonic acid (PGMEA solution) were added, and the mixture was stirred at room temperature for 4 hours. Thereafter, 0.35 g of 6% triethylamine (PGMEA solution) was added and after stirring for a while, and the reaction solution was transferred to a separating funnel containing 55 mL of ethyl acetate. The organic layer was washed with 50 mL of distilled water three times and then concentrated by an evaporator, and ethyl acetate was removed. This reaction solution was added dropwise in 800 mL of hexane. A part of the obtained precipitate was sampled for NMR measurement, and the remaining was dissolved in 25 g of PGMEA. From the obtained solution, the low boiling point solvent was removed by an evaporator to obtain 36.1 g of a PGMEA solution (28.9%) of Resin (R-3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH2:5][C:6]([C:8]1[S:9][C:10]([Br:13])=[CH:11][CH:12]=1)=O.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25]>CO>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:8]2[S:9][C:10]([Br:13])=[CH:11][CH:12]=2)[N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])[N:25]=1)=[O:15]
Reactant: NNc1ccccc1Cl
Reactant: COC(=O)C(=O)CC(=O)c1ccc(Br)s1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(Br)s2)n(-c2ccccc2Cl)n1
Temperature: 20 °C
Yield: 100.6 %

Procedure:
A solution of 4-(5-bromo-thiophen-2-yl)-2,4-dioxo-butyric acid methyl ester (15 g, 50 mmol) and 2-chlorophenylhydrazine hydrochloride (10.75 g, 60 mmol) in dry MeOH (200 mL) was heated to reflux for 6 h. After cooling to 20° C., a white solid precipitated and was collected by filtration, washed with a small volume of cold MeOH and dried under high vacuum to afford 5-(5-bromo-thiophen-2-yl)-1-(2-chloro-phenyl)-1H-pyrazole-3-carboxylic acid methyl ester (20 g, 100%). 1H-NMR (CDCl3): δ 7.48-7.55 (m, 3H), 7.43 (m, 1H), 7.11 (s, 1H), 6.90 (d, 2H), 6.65 (s, 1H), 3.95 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[CH2:26]Br>CC#N>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[CH2:26][NH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(N)Cc1ccc([N+](=O)[O-])cc1
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of methyl 2-amino-3-(4-nitrophenyl)propanoate 2 (6 g) in CH3CN (30 ml) is added, pulverized K2CO3 (11.095 g), 2,6-dichlorobenzyl bromide (6.42 g). The mixture is stirred at RT for 6 h then filtrated on decalite and evaporated. The residue is placed in CH2Cl2 (100 ml) and washed three time with water (100 ml) dried over MgSO4 and evaporated. The residue is purified by silica gel chromatography using AcOEt/hexane 10/90 as eluent.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Br:15][C:16]1[S:20][C:19]([C:21](O)=[O:22])=[CH:18][C:17]=1[CH3:24]>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:21]([C:19]2[S:20][C:16]([Br:15])=[C:17]([CH3:24])[CH:18]=2)=[O:22])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1cc(C(=O)O)sc1Br
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: Cc1cc(C(=O)NC[C@H]2CCN(C(=O)OC(C)(C)C)C2)sc1Br

Procedure:
57.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 5-bromo-4-methyl-thiophene-2-carboxylic acid (prepared according to M. Nemec et al., Collection of Czechoslovak Chemical Communications, 1974, 39, 3527) to give (R)-3-{[(5-bromo-4-methyl-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. White solid. MS 403.3 ([M−H]−)
Reaction SMILES: Cl[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:29])[CH2:19]C(C2C=CC(Cl)=CC=2)=O)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:29])[CH2:19][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:14][CH:13]=1
Reactant: O=C(CC(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccncc1Cl
Product: O=C(Cc1cnccc1C(=O)O)c1ccc(Cl)cc1

Procedure:
3-[2-(4-Chlorophenyl)-2-oxoethyl]-isonicotinic acid (above) was prepared by Method H using 3-chloro-isonicotinic acid and 1,3-bis-(4-chlorophenyl)-propane-1,3-dione.
Reaction SMILES: [C:1](=[O:11])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:2][CH3:3].[C:12]1(O)[CH:17]=[CH:16]C=[CH:14][CH:13]=1>>[C:1](=[O:11])([O:2][C:3]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1)[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)Oc1ccccc1
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
A mixture of 75 g/h of methyl phenyl carbonate, 175 g/h of phenol and 3 g/h of octylstannonic acid was continuously fed into this reactor at the feeding point above the sieve-point column. At the same time, a gentle nitrogen stream of 2 [1.h-1 ] from the spiral tube evaporator was passed in the opposite direction to this starting material stream. After establishment of constant conditions, at the head of the apparatus, 195 g/h of a mixture of 2.2% by weight of methanol, 13.7% by weight of dimethyl carbonate and 84.1% by weight of phenol were continuously withdrawn, and at the foot of the column, 61 g/h of a mixture of 1.5% by weight of phenol, 0.9% by weight of methyl phenyl carbonate and 97.6% by weight of diphenyl carbonate were continuously withdrawn. This represented a space-time yield for the formation of diphenyl carbonate of 0.06 g/mlh, based on the reactor volume. 18.6% of the methyl phenyl carbonate used reacted with phenol, transesterifying to form diphenyl carbonate. The selectivity of the formation of diphenyl carbonate was >99.9%, that is no by-products could be detected.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[CH:21]=[CH2:22])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH2:21][CH3:22])[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1cc(OCc2ccccc2)ccc1OCC(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1ccc(O)cc1CC
Yield: 78.1 %

Procedure:
A solution of (4-benzyloxy-2-vinylphenoxy)acetic acid ethyl ester (0.55 g, 1.77 mmol) in ethanol (15 mL) was treated with 5% Pd/C (70 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give a tan oil (0.31 g, 77%): 1H NMR (400 MHz, CDCl3) δ 6.68 (d, J=2.9 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 6.57 (dd, J=8.8, 2.9 Hz, 1H), 4.62 (s, 1H), 4.57 (s, 2H), 4.25 (q, J=7.2 Hz, 2H), 3.73 (q, J=7.0 Hz, 2H), 2.66 (q, J=7.7 Hz, 2H), 1.34-0.92 (m, 6H); MS (FIA) m/e 225 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[O:32]=[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][NH:34]1>>[CH3:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:36]3[CH:37]=[CH:38][C:33](=[O:32])[NH:34][CH:35]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)NS(C)(=O)=O)(c2ccccc2)OC1=O
Reactant: O=c1ccc(B(O)O)c[nH]1
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)NS(C)(=O)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from N-(1-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2-methylpropan-2-yl)methanesulfonamide and 2-oxo-1,2-dihydropyridin-5-ylboronic acid following a procedure analogous to that described in Example 4. LC-MS Method 1 tR=1.3 min, m/z=524 (M+1); 1H NMR (CDCl3) 7.81 (d, 1H, J=9 Hz), 7.63 (br s, 1H), 7.39-7.31 (m, 5H), 7.18 (d, 2H, J=8Hz), 7.03 (d, 2H, J=7Hz), 6.79 (d, 1H, J=9Hz), 5.67 (q, 1H, J=6Hz), 2.93 (s, 3H), 2.90 (m, 1H), 2.49 (d, 1H, J=15 Hz), 2.32 (d, 1H, J=15 Hz), 2.28-2.18 (m, 3H), 1.54 (d, 3H, J=7Hz), 1.36 (s, 3H), 1.25 (s, 3H).