Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([OH:13])([C:9]([F:12])([F:11])[F:10])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[C:16]1([S+:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:35]12([CH2:45][C:46](Cl)=[O:47])[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)[CH2:36]1)[CH2:42]2.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:35]12([CH2:45][C:46]([O:13][C:3]([C:2]([F:1])([F:14])[F:15])([C:9]([F:12])([F:10])[F:11])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6])=[O:47])[CH2:42][CH:41]3[CH2:40][CH:39]([CH2:38][CH:37]([CH2:43]3)[CH2:36]1)[CH2:44]2.[C:29]1([S+:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=S(=O)([O-])CC(O)(C(F)(F)F)C(F)(F)F
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CC12CC3CC(CC(C3)C1)C2)OC(CS(=O)(=O)[O-])(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h
Yield: 48.5 %

Procedure:
Into a mixture solution of 2.6 g (5 mmoles) of triphenylsulfonium 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropane-1-sulfonate prepared in Synthesis Example 1-9, 1.3 g (6 mmoles) of 1-adamantaneacetyl chloride, and 15 g of methylene chloride was added a mixture solution of 0.63 g (6 mmoles) of triethylamine, 0.12 g (1 mmole) of 4-dimethylaminopyridine, and 5 g of methylene chloride, and they were stirred at room temperature for 5 days. Thereafter, the reaction was terminated by adding 7 g of 5% hydrochloric acid, and then the organic layer was separated, washed by water, and concentrated under reduced pressure. Into the concentrated solution was added methyl isobutyl ketone, and the resulted mixture was concentrated again under reduced pressure to distil the remaining water out. The obtained residue was recrystallized by adding diisopropyl ether, and then the crystals were recovered and dried to obtain the intended triphenylsulfonium 2-(2-adamantane-1-yl-acetoxy)-3,3,3-trifluoro-2-trifluoromethylpropane-1-sulfonate (1.7 g of white crystals (yield 48%)). The structure of the intended product is shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:17]2C=C[C:20]([O:23]C)=[C:19](OC)[CH:18]=2)=[CH:12][C:13](OC)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C(C=CC=1OC)C(C1OC=CC=1)=O.C(OP(CC#[N:54])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:17]2[O:23][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:13]#[N:54])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1ccc(C(=O)c2ccco2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccco2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(2-furyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3',4'-dimethoxyphenyl)acrylate using 2-(3,4-dimethoxybenzoyl)furane (0.87 g, 4 mmol), diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithium hexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 3 hours at room temperature. The crude product was purified by chromatography (silica gel, 2% ethyl acetate/methylene chloride) to afford 0.78 g (76%) of a mixture of the E and Z isomers as an off white solid: mp 78-82° C.; 1H NMR (CDCl3) δ 7.68-7.73 (m, 2H), 7.16-6.75 (m, 7H), 6.54-6.39 (m, 3H), 5.87 (s, 1H), 5.30 (s, 1H), 3.93 (s, 3H), 3.93 (s, 3H), 3.91 (s, 3H), 3.88 (s, 3H); 13C NMR (CDCl3) δ 152.0, 150.7, 150.5, 150.4, 149.3, 148.8, 148.7, 148.7, 145.2, 145.0, 129.6, 126.7, 122.1, 121.6, 118.1, 118.0, 116.5, 115.6, 112.5, 112.1, 112.0, 111.5, 110.9, 110.8, 90.5, 90.2, 55.9, 55.9, 55.9, 55.8; Anal. Calcd for C15H13NO3. Theoretical: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.61; H, 5.09; N, 5.18.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:24]([O:28][C:29](Cl)=[O:30])[CH2:25][CH2:26][CH3:27]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:29]([O:28][CH2:24][CH2:25][CH2:26][CH3:27])=[O:30])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCN(C(=O)OCc2ccccc2)C1
Reactant: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)NC1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 12 h

Procedure:
To a solution of 3.00 g 3-amino-pyrrolidine-1-carboxylic acid benzyl ester hydrotrifluoroacetate in 50 ml dichloromethane were added dropwise 3.7 ml triethylamine and 1.3 ml butylchloroformate at 0° C. After stirring for 12 h the reaction mixture was diluted with dichloromethane, washed with 0.1 M HCl, saturated aqueous NaHCO3 and brine. The crude product thus obtained was purified by flash chromatography on silica using ethyl acetate/heptane 2:3 as eluent. Yield: 648 mg.
Reaction SMILES: [H-].[Na+].CS(C)=O.[C:7]([O:11][C:12](=[O:51])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[C:41]=2[Cl:50])[CH2:25][CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=1)([CH3:10])([CH3:9])[CH3:8].[CH3:52][O:53][C:54](=[O:57])[CH2:55]Br>CN(C=O)C>[CH3:52][O:53][C:54](=[O:57])[CH2:55][N:13]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:51])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:48])([F:49])[F:47])[C:41]=2[Cl:50])[CH2:25][CH:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of sodium hydride (18.8 mg, 0.47 mmol, 60% in mineral oil) in anhydrous DMF (10 mL) at 0° C. and DMSO (10 ml) was added dropwise a solution of (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-carbamic acid tert-butyl ester (150 mg, 0.235 mmol) in DMF (5 ml). The solution was stirred at 0° C. for 20 minutes and was then treated with bromo-acetic acid methyl ester (72 mg 0.47 mmol). The resulting solution was warmed to room temperature and stirred for 6 hours. The reaction mixture was poured into ice water (30 ml). The mixture was extracted with EtOAC (3×) and the combine organic layers were washed with saturated aqueous sodium bicarbonate (2×), brine (×), dried over sodium sulphate, and filtered. The ethyl acetate filtrate was concentrated to afford the title compound as an oil. MS(ES) m/e 711.2 (M+).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](=[O:9])[N:6]([CH3:10])[C:5]=1[CH3:11])(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[S:8][C:7](=[O:9])[N:6]([CH3:10])[C:5]=1[CH3:11])=[O:3]
Reactant: CC(=O)c1sc(=O)n(C)c1C
Reactant: COC(OC)N(C)C
Product: Cc1c(C(=O)C=CN(C)C)sc(=O)n1C
Temperature: 100 °C
Yield: 44.5 %

Procedure:
5-Acetyl-3,4-dimethyl-3H-thiazol-2-one (4.64 g, 27.10 mmol) and dimethylformamide dimethyl acetal (8.4 mL, 59.62 mmol) were mixed in a dry, argon-flushed flask, and heated at 100° C. for 3 h. The mixture was cooled, producing some precipitation, which was enhanced by the addition of an equal volume of Et2O. The resulting orange solid was filtered and washed with Et2O to give 2.73 g of the title product. 1H-NMR (d6-DMSO): δ2.52 (s, 3H), 2.82 (bs, 3H), 3.11 (bs, 3H), 3.22 (s, 3H), 5.10 (d, 1H, J=12.2 Hz), 7.61 (d, 1H, J=11.7 Hz). IR (ATR): 1669 and 1630 cm−1 (CO str).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([F:12])([F:23])[F:24])=[O:22]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1C(F)(F)F
Yield: 52.7 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2-trifluoromethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-trifluoromethyl phenyl isocyanate (1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (180 mg, 52%). EI-MS m/z 342 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([NH2:10])(=[O:9])=[O:8].[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1.Cl>CC(C)=O>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([NH:10][C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:22])(=[O:9])=[O:8]
Reactant: Cc1ccsc1S(N)(=O)=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccsc1S(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Yield: 57.1 %

Procedure:
The procedure of Example 4B was followed with the 3-methyl-2-thiophenesulfonamide (1.6 g, 9.0 mmole), 1N NaOH (9.0 ml), acetone (10 ml), 4-chlorophenyl isocyanate (1.4 g, 9.2 mmole), 1N HCl (9.5 ml) to provide the named product (1.7 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)N)=[CH:5][CH:4]=1.O=[C:21]([CH2:29][CH3:30])[CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:12]3[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:29]([CH3:30])=[C:21]2[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:5][CH:4]=1
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: CCC(=O)CCCC(=O)OC
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)c(C)c(CCCC(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-methoxyphenyl)hydrazine hydrochloride and methyl 5-oxoheptanoate as the starting materials and ethanol as the solvent, the title compound was prepared.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:13]([CH2:27][CH2:28][CH3:29])[C:14]([C:16]1[CH:17]=[C:18]([CH:23]=[C:24](I)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:15])[CH3:12]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:11]([N:13]([CH2:27][CH2:28][CH3:29])[C:14]([C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:15])[CH3:12]
Reactant: CCCN(CC)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: c1cocn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of oxazole (106 mg, 1.5 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 1.0 mL, 1.7 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 4.6 mL, 4.6 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-{[ethyl(propyl)amino]carbonyl}-5-iodobenzoate (535 mg, 1.45 mmol) in anhydrous tetrahydrofuran (1.8 mL) followed by palladium(0)tetrakis(triphenylphosphine) (120 mg, 0.10 mmol). The reaction mixture is heated at reflux for 2 h. The reaction mixture is cooled, diluted with ethyl acetate, washed with water, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides the title compound. ESI MS m/z 317.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:5]=1[CH2:6][N:7]([CH2:15][CH2:16][OH:17])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:23][C:24]1[CH:25]=[C:26]([N+:31]([O-:33])=[O:32])[CH:27]=[CH:28][C:29]=1F.O>CN(C)C=O>[Cl:23][C:24]1[CH:25]=[C:26]([N+:31]([O-:33])=[O:32])[CH:27]=[CH:28][C:29]=1[O:17][CH2:16][CH2:15][N:7]([CH2:6][C:5]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:4]=1[F:3])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1ccc([N+](=O)[O-])cc1Cl)Cc1ccc(F)cc1F
Temperature: -2.5 °C
Reaction time: 0.17 h
Yield: 106.1 %

Procedure:
Sodium hydride (0.101 g, 3.83 mmol, 95% in oil) was added to N,N-dimethyl formamide (20 mL) at −5 to 0° C. under nitrogen. The suspension was stirred for 10 minutes and to the resulting cooled mixture was added a solution of tert-butyl 2,4-difluorobenzyl(2-hydroxyethyl)carbamate (1.1 g, 4.21 mmol) in N,N-dimethylformamide (10 mL), maintaining the temperature at −5 to 0° C. during addition. The reaction mixture was stirred further for 20 minutes and then a solution of 3-chloro-4-fluoro-nitrobenzene (0.67 g, 3.83 mmol) in N,N-dimethyl formamide (10 mL), was added dropwise, maintaining the temperature in the range −5 to 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. Water (300 mL) was then added to the reaction mixture and the resulting mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (2×30 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 5-20% EtOAc in hexane to give the title compound (1.8 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]=1[N:16]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]=1[NH:16][S:24]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)(=[O:26])=[O:25]
Reactant: COC(=O)c1cccc(CN2CCCC2)c1N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(CN2CCCC2)c1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of the product of example 316 in 10 mL of dichloromethane was added 10.0 mL of trifluoroacetic acid. The resulting solution was stirred at room temperature for 1 h and then concentrated in vacuo. The resulting residue was diluted with ether washed with saturated sodium bicarbonate solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then triturated with ether to provide 0.93 g (57%) of the product as a pale yellow solid. Electrospray Mass Spec: 405.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]=1)[CH3:2].O[N:23]1[C:27]2C=CC=C[C:26]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N)C>CN(C=O)C.ClCCl>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8](=[O:10])[NH:23][CH2:27][CH3:26])[CH:6]=1)[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(C(=O)NCC)cc(C(=O)OCC)c1
Yield: 98 %

Procedure:
Stir a solution of 5-(methyl-propylcarbamoyl)-isophthalic acid monoethyl ester (146 mg, 0.5 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (110 mg, 0.55 mmol), ethylamine (2 N in THF, 0.275 mL, 0.55 mmol) in 0.75 mL DMF at room temperature overnight. Dilute with dichloromethane (15 mL) and wash with water (5 mL), 0.1 N aqueous citric acid (5 mL), saturated aqueous sodium bicarbonate (5 mL), and saturated aqueous sodium chloride (5 mL). Dry (magnesium sulfate) and concentrate to give the title compound (157 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.Br[CH2:15][C@@H:16]([CH3:26])[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>CCCCCCC.CCOC(C)=O>[Si:19]([O:18][CH2:17][C@@H:16]([CH3:26])[CH2:15][N:8]1[C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12])([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21]
Reactant: COc1ccc2c(c1)NC(=O)CO2
Reactant: C[C@H](CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)N(C[C@H](C)CO[Si](C)(C)C(C)(C)C)C(=O)CO2
Yield: 73 %

Procedure:
6-Methoxy-4H-benzo[1,4]oxazin-3-one (111MF24) (2.7 g, 15.1 mmol), (S)-3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.03 g, 15.1 mmol) and Cs2CO3 (12.3 g, 38 mmol) were mixed according to GP7. CC (SiO2; Heptane/EtOAc 9:1) to give the title compound (111MF32) (4.03 g, 80%). 1H NMR (CDCl3) δ 6.89 (d, J=8.8 Hz, 1H), 6.71 (d, J=2.8 Hz, 1H), 6.50 (dd, J=2.8 Hz, J=8.6 Hz, 1H), 4.53 (q, J=14.8 Hz, J=29.2 Hz, 2H), 3.98 (dd, J=8.8 Hz, J=14.0 Hz, 1H), 3.85 (dd, J=5.8 Hz, J=14.2 Hz, 1H), 3.77 (s, 3H), 3.57 (dd, J=9.2 Hz, J=10.0 Hz, 1H), 3.47 (dd, J=7.2 Hz, J=10.0 Hz, 1H), 2.20-2.12 (m, 1H), 0.91 (s, 12H), 0.05 (d, J=1.2 Hz, 6H); 13C NMR (CDCl3) δ 165.3, 155.6, 139.7, 129.8, 117.2, 107.4, 103.3, 68.0, 66.2, 55.9, 43.9, 34.3, 26.1, 18.5, 14.7, −5.3, −5.4.
Reaction SMILES: [O-]CC.[Na+].[Na].[O:6]([C:13]1[CH:14]=[C:15]([CH2:19][C:20]#[N:21])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:22](OCCC(C)C)=[O:23]>C(O)C.C(OCC)C>[OH:23][N:22]=[C:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)[C:20]#[N:21]
Reactant: CC(C)CCON=O
Reactant: N#CCc1cccc(Oc2ccccc2)c1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: N#CC(=NO)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45 %

Procedure:
To a solution of sodium ethoxide prepared from sodium (1.09 g) and ethanol (20 ml), a solution of 3-phenoxyphenylacetonitrile (8.30 g) in ethanol (15 ml) was added dropwise at 0° C., and then isoamyl nitrite (7.99 ml) was added dropwise. After stirring for 15 hours at room temperature, diethyl ether was added and the mixture was washed sequentially with 1N HCl, aqueous sodium bicarbonate and then saturated aqueous sodium chloride. The diethyl ether layer was dried (MgSO4), concentrated, and the residue was subjected to column chromatography on silica gel. The crystals obtained from a fraction eluted with ethyl acetate-hexane (1:4, v/v) were recrystallized with ethyl acetate-hexane to obtain 2-hydroxyimino-2-(3-phenoxyphenyl)acetonitrile (4.25 g, yield: 45%) as pale-yellow crystals. A mixture of the E- form and the Z- form. m.p. 124-125° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[OH:30]>>[OH:30][C@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[CH2:28][NH:27][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(C(=O)O)cc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(NS(=O)(=O)c4ccc(C(=O)O)cc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-benzoic acid (which was obtained in Example 233) and N-[5-((1R)-2amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.35–1.50 (m, 2 H), 1.75–2.00 (m, 2 H), 2.50–2.95 (m, 5 H), 2.92 (s, 3 H), 3.45–3.60 (m, 2 H), 4.60–4.70 (m, 1 H), 6.77 (d, J=9.3 Hz, 2 H), 6.80–6.90 (m, 3 H), 7.02 (dd, J=8.4, 1.8 Hz, 1 H), 7.20 (d, J=1.8 Hz, 1 H), 7.60 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.4 Hz, 2 H); MS (ES) m/z: 603.2 (M−H)−; HRMS Calcd. for C27H31N4O8S2 (M−H)−: 603.1588. Found: 603.1572.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([F:34])[C:13]([N:21]3[CH2:25][CH2:24][C@H:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[C:14]([F:20])[C:15]=2F)[N:10]([CH:35]2[CH2:37][CH2:36]2)[C:9]1=[O:38])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:47]([NH2:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CS(C)=O>[C:1]([O:5][C:6](=[O:39])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([F:34])[C:13]([N:21]3[CH2:25][CH2:24][C@H:23]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:22]3)=[C:14]([F:20])[C:15]=2[NH:54][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:10]([CH:35]2[CH2:36][CH2:37]2)[C:9]1=[O:38])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(F)c3c(=O)n(NC(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2F)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(NCc3ccccc3)c3c(=O)n(NC(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2F)C1
Yield: 86.8 %

Procedure:
A solution of {7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-1,4-dihydro-2,4-dioxo-5,6,8-trifluoro-2H-quinazolin-3-yl}carbamic acid tert-butyl ester from Example 8 (0.51 g, 0.914 mmol), triethylamine (1.3 mL, 9.3 mmol), and benzylamine (0.50 mL, 4.6 mmol) in dimethyl sulfoxide (7.5 mL) is heated at 100° C. for 16 hours in a sealed glass tube. The mixture is concentrated under high vacuum and the residue purified by column chromatography (1:2 ethyl acetate/hexanes) to afford {7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-benzylamino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamic acid tert-butyl ester as a solid (0.51 g). 1H NMR (CDCl3): δ 8.50 (bs, 1H), 7.37-7.18 (m, 5H), 6.56 (bs, 1H), 4.76-4.62 (bd, 1H), 4.59-4.48 (m, 2H), 4.34-4.18 (m, 1H), 3.93-3.49 (m, 3H), 3.48-3.20 (m, 2H), 2.24-2.04 (m, 1H), 1.96-1.74 (m, 1H), 1.49 (s, 9H), 1.46 (s, 9H), 1.13-1.00 (m, 2H), 0.75-0.61 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([O:15]CC3C=CC=CC=3)=[O:14])=[CH:11][CH:10]=2)=[CH:6][C:5]=1[O:27]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:6][C:5]=1[OH:27]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc(C(=O)O)cc2)cc1O
Reaction time: 8 h
Yield: 93 %

Procedure:
46.6 g of the benzyl 4-(4-nitro-3-benzyloxyphenoxy)benzoate (0.11 mol) prepared as described in Example 4 are dissolved in 500 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 5 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated using hydrogen at a pressure of 1 bar at room temperature in an autoclave with vigorous stirring; the reaction is terminated after 3 days. The pale violet solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then separated off and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 93%).