Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[CH:30]=[O:31])=[CH:24][CH:23]=1>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:30](=[O:31])[CH:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Reactant: Cc1ccc(/C=C/C=O)cc1
Product: Cc1ccc(CC2C(=O)Oc3[nH]c(-c4cc(F)ccc4F)nc3C2c2ccccc2)cc1
Yield: 82 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(p-tolyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 7 as an off-white solid (106 mg, 82%). Analytical data for 7: 1H NMR (500 MHz, CDCl3) δ 9.35 (d, J=8.1 Hz, 1H), 7.89 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.38-7.29 (m, 3H), 7.13 (d, J=7.7 Hz, 2H), 7.05 (ddd, J=11.4, 8.9, 4.1 Hz, 1H), 7.02-6.94 (m, 5H), 4.08 (d, J=6.8 Hz, 1H), 3.58 (ddd, J=10.2, 6.8, 4.5 Hz, 1H), 3.32 (dd, J=14.8, 4.5 Hz, 1H), 2.39 (dd, J=14.9, 10.2 Hz, 1H), 2.35 (s, 3H); 13C NMR (CDCl3, 126 MHz) δ 169.0, 159.1 (d, JCF=243.8 Hz), 155.4 (d, JCF=240.9 Hz), 148.9, 137.1, 136.34, 136.30, 134.7, 129.3, 129.2, 128.9, 128.3, 128.0, 118.4 (dd, JCF=12.8, 9.1 Hz), 117.1 (dd, JCF=25.7, 8.8 Hz), 116.5 (dd, JCF=24.7, 9.6 Hz), 114.5 (dd, JCF=26.8, 3.7 Hz), 111.1 (d, JCF=4.0 Hz), 47.4, 38.3, 32.2, 21.1; IR (film) cm−1 3029, 2923, 1768, 1618, 1529, 1482, 1463, 1452, 1351, 1240, 1172, 1118, 1102, 811, 766, 736, 700; LRMS (ESI): Mass calcd for [M+H]+ C26H21F2N2O2: 431.2. found 431.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 4% IPA/2% MeOH/hexanes; 0.7 mL/min, 280 nm), Rt1 (major)=34.4, Rt2 (minor)=43.7 min; er=99:1.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])=[CH:8][N:7]=1.S(=O)(=O)(O)[OH:20]>O>[F:17][C:13]([F:18])([O:12][C:9]1[CH:10]=[CH:11][C:6]([OH:20])=[N:7][CH:8]=1)[CH:14]([F:16])[F:15]
Reactant: Nc1ccc(OC(F)(F)C(F)F)cn1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(OC(F)(F)C(F)F)cn1
Reaction time: 3 h

Procedure:
A solution of 10.3 g (149 mmol) of sodium nitrite in 16.5 ml of water was added dropwise with stirring to a solution of 23 g (109 mmol) of 2-amino-5-(1,1,2,2-tetrafluoroethoxy)pyridine in 103 ml of water and 21.9 g of concentrated sulfuric acid at 0° C. The mixture was stirred for 3 hours at 20°-25° C., and the colorless solid was filtered off under suction and washed with water until free of acid.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[NH:13][C:14](=[O:21])[C:15](=[CH:19][CH:20]=3)[C:16](O)=O)[CH:9]=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:24])=O>>[ClH:24].[N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[NH:13][C:14](=[O:21])[C:15](=[CH:19][CH:20]=3)[CH2:16][Cl:24])[CH:9]=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2cccc(N3CCCC3)c2)[nH]c1=O
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=c1[nH]c(-c2cccc(N3CCCC3)c2)ccc1CCl

Procedure:
The 6-[m-(1-Pyrrolidinyl)phenyl]-1,2-dihydro-2-oxonicotinic acid (1.9 g.) is suspended in 40 ml. thionyl chloride and stirred at room temperature for 4 hours. A trace of undissolved solid is removed by filtration and the filtrate is diluted with 500 ml. of hexane. A gum which forms at first changes to a tan solid on continued stirring. The solid 6-[m-(1-pyrrdidinyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride hydrochloride is collected quickly by filtration and dried over phosphorus pentoxide overnight in vacuo. The 1.8 g. of product so obtained is taken on the the next step without further purification.
Reaction SMILES: Br[CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[Cl:9][C:10]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=1[NH2:12].O(C1C=C(C=CC=1)CBr)C1C=CC=CC=1>>[Cl:9][C:10]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=1[NH:12][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(Br)C(=O)O
Reactant: Cc1ccc(N)c(Cl)c1
Agent: BrCc1cccc(Oc2ccccc2)c1
Product: Cc1ccc(N[C@H](C(=O)O)C(C)C)c(Cl)c1

Procedure:
N-(2-chloro-4-methylphenyl)valine is prepared as above from α-bromoisovaleric acid and 2-chloro-4-methylaniline and then reacted with m-phenoxybenzyl bromide, as above, to yield the m-phenoxybenzyl ester of N-(2-chloro-4-methylphenyl)valine. MS m/e 423 (M+, 4), 196 (100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]3[CH2:10][C:9](=[O:11])[NH:8][C:5]3=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C1Cc2cc(Br)cnc2N1
Product: O=C1Cc2cc(-c3cccc(F)c3)cnc2N1
Yield: 32 %

Procedure:
The title compound was prepared in 32% yield according to the procedure described in Example 2, starting from 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (prepared according to the procedure described in WO2003082868, Page 33) and 3-fluoro-phenyl boronic acid. 1H NMR is the same as the one reported in WO2003082868, page 34.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:28](=[O:29])[N:13]3[CH:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[C:15]([CH3:19])([CH3:18])[S:16](=[O:17])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:30]N1C(=O)CCC1=O>C1(C)C=CC=CC=1>[CH3:18][C:15](=[CH2:19])[CH:14]([N:13]1[C:28](=[O:29])[CH:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]1[S:16]([Cl:30])=[O:17])[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]
Reactant: CC1(C)C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: Cc1ccccc1
Product: C=C(C)C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc2ccccc2)C1S(=O)Cl

Procedure:
A solution of 500 mg. of 2,2,2-trichloroethyl 6β-phenylacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 134 mg. of N-chlorosuccinimide in 40 ml. of dry toluene was refluxed for 90 minutes. The mixture was cooled, washed with H2O and brine, dried over MgSO4, and the solvent was evaporated on a rotavapor. The title compound was recovered as a colorless foam.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=2[O:6][CH:5]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>ClCCl>[CH3:26][S:27]([O:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=2[O:6][CH:5]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)COc1cccc2c(CCO)coc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)COc1cccc2c(CCOS(C)(=O)=O)coc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
Methyl (3-(2-hydroxyethyl)benzofuran-7-yloxy)acetate (4.12 g) was dissolved in dichloromethane (120 ml) and triethylamine (3 ml) and methanesulfonyl chloride (1.35 ml) were added to the solution, followed by stirring the resulting solution at 0° C. for 1.5 hours. The reaction mixture was then poured into 1N hydrochloric acid and the resultant was extracted with dichloromethane. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, water, and with saturated saline, and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure. The residue was recrystallized from n-hexane/ethyl acetate to obtain the desired compound (5.25 g, yield: 97%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][C:8]([CH3:20])([O:10][CH2:11][CH:12](O)[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH3:9].[ClH:21]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:21][CH:12]([CH2:11][O:10][C:8]([CH3:20])([CH3:9])[CH3:7])[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OCC(O)CN1CCCC1
Reactant: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OCC(Cl)CN1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred, cooled suspension of 34.7 g (0.167 ml) of phosphorous pentachloride in 20 ml of dry toluene (argon atmosphere) was added a solution of 31.93 g (0.159 m) of 1-[3-(1,1-dimethylethoxy)-2-hydroxypropyl]pyrrolidine (the product of Example 13a) and excess hydrogen chloride (gas) in 46 ml of dry toluene and 50 ml of dry tetrahydrofuran at a rate to keep the reaction temperature at 10°-25° C. When the addition was completed, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 1.5 hr. The reaction mixture was added portionwise, with stirring to a cooled solution of 122 ml of 45% potassium hydroxide and 230 g of ice at a rate to keep the reaction temperature at 25°-35° C. The reaction mixture was partitioned between ether and water. The ether portion was dried and concentrated in vacuo to give 31.69 g of oily title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([N+:14]([O-])=O)[CH:13]=[C:7]2[CH2:6]1>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([NH2:14])[CH:13]=[C:7]2[CH2:6]1
Reactant: COCCN1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: COCCN1CCn2nc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of 327a (286 mg, 1.26 mmol) in methanol (10 mL) was added Pd/C (28.6 mg). The system was evacuated and then refilled with H2. After stirring at room temperature for 2 h, the mixture was filtered. The filtrate was concentrated under reduced pressure to afford 327b as a yellow solid (240 mg, 97%), which was used in the next step without further purification. MS-ESI: [M+H]+ 197.0
Reaction SMILES: [CH:1]([C:3]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:5]([O:6][C:7]3=O)[CH2:4]1)[CH2:11]2)=[CH2:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:24]2)=CC=1>C1(C)C=CC=CC=1>[CH:1]([C:3]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:5]([O:6][C:7]3=[S:24])[CH2:4]1)[CH2:11]2)=[CH2:2]
Reactant: C=CC12CC3CC(C1)OC(=O)C(C3)C2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: C=CC12CC3CC(C1)OC(=S)C(C3)C2
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a mixture of 6-vinyl-3-oxatricyclo[4.3.1.14,8]undecan-2-one (10 mmol) obtained by the procedure of Example 3 and toluene (50 ml) was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide [(p-MeO-C6H4P(═S)—S—)2)] (10 mmol), and the resulting mixture was stirred at 110° C. for 24 hours. The reaction mixture was concentrated, the concentrate was subjected to silica gel column chromatography and thereby yielded the title compound 6-vinyl-3-oxatricyclo[4.3.1.14,8]undecane-2-thione in a yield of 75%.
Reaction SMILES: NC1C=CC([Cl:11])=C(C=1)C(O)=O.Cl.C(Cl)(=O)C1C=CC=NC=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=2)=[CH:28][C:24]=1[C:25](O)=[O:26].S(Cl)(Cl)=O>C1COCC1.ClCCl>[Cl:22][C:23]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=2)=[CH:28][C:24]=1[C:25]([Cl:11])=[O:26]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccnc1
Agent: Cl
Agent: O=C(Cl)c1cccnc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(=O)Cl)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-amino-2-chlorobenzoic acid (1.71 g, 10 mmol) and TEA (6.96 mL, 50 mmol) in THF (50 mL) was added nicotinoyl chloride hydrochloride (1.78 g, 10 mmol) solid portion-wise. After 1 h stirring at room temperature, product was isolated through filtration as a white solid. The solid was washed with water and dried (1.85 g, 67%). The solid, 2-chloro-5-(nicotinamido)benzoic acid (1.0 g, 3.62 mmol) was suspended in dichloromethane (50 mL) and treated with thionyl chloride (1.57 mL, 36.2 mmol) at reflux for 6 hr. The reaction mixture was evaporated, and the residue was dissolved in hexane-ethyl acetate mixture (100 mL, 6:4) and quickly filtered through a short silica plug. On evaporation of solvent, the title compound was obtained as a white solid (873 mg, 82%).
Reaction SMILES: CON(C)[C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5].[CH2:17]([Mg]Br)[CH:18]([CH3:20])[CH3:19].O1CCCC1.C([Mg]Br)C(C)C.[Cl-].[NH4+]>O1CCCC1>[CH3:17][CH:18]([CH3:20])[CH2:19][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5]
Reactant: CC(C)C[Mg]Br
Reactant: CON(C)C(=O)c1oc2ccccc2c1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)CC(C)C)oc2ccccc12
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution (20 mL) of N-methoxy-N,3-dimethyl-1-benzofuran-2-carboxamide (1.00 g) synthesized above in tetrahydrofuran was added dropwise a 1.0M solution (6.84 mL) of isobutylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. In addition, 1.0M isobutylmagnesium bromide tetrahydrofuran solution (6.84 mL) was added, and the mixture was stirred at 0° C. for 1 hr then at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, volume ratio) to give the title object compound (873 mg, 89%) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[S:6][CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]=2[CH:3]=1.[F:18][C:19]([F:24])([F:23])C([O-])=O.[K+]>CN(C)C=O.C1(C)C=CC=CC=1.[Cu]I>[F:18][C:19]([F:24])([F:23])[C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[S:6][CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]=2[CH:3]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: CCOC(=O)c1csc2cc(OC)c(Br)cc12
Agent: [Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc2cc(OC)c(C(F)(F)F)cc12
Yield: 54.8 %

Procedure:
Ethyl-5-bromo-6-methoxybenzo[b]thiophene-3-carboxylate (D4) (0.81 g, 3 mmoles) in dry dimethylformamide (20 ml) and toluene (10 ml) was treated with potassium trifluoroacetate (0.78 g, 6 mmoles) and copper (I) iodide (0.98 g, 6 mmoles). The mixture was heated under reflux for 1 hr using a Dean-Stark trap to collect the toluene. The mixture was cooled and poured into water (150 ml) and extracted with diethyl ether. The resulting emulsion was filtered through kieselguhr. The combined organic extracts were washed several times with water then dried (Na2SO4). Flash chromatography on TLC silica gel eluting with dichloromethane/60-80 petrol ether 1:1 gave the title compound (D6) (0.5 g, 64%)
Reaction SMILES: [CH2:1]([C:3]([C:7]1[S:11][C:10]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=2[CH:8]=1)(O)[CH2:4][CH3:5])[CH3:2].[C:19]1([CH3:26])[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][CH:20]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([C:3]([C:7]1[S:11][C:10]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=2[CH:8]=1)([C:21]1[CH:22]=[CH:23][C:24]([OH:25])=[C:19]([CH3:26])[CH:20]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(O)(CC)c1cc2ccc(C(=O)O)cc2s1
Reactant: Cc1ccccc1O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(C(=O)O)cc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
A solution of 2-(1-ethyl-1-hydroxy-propyl)-benzo[b]thiophene-6-carboxylic acid (3.80 g, 14.4 mmol) and o-cresol (1.94 g, 18.0 mmol) in CH2Cl2 (100 mL) at −40° C. is added BF3-Et2O (1.02 g, 7.20 mol). After stirring for 10 min, the reaction mixture is allowed to warm up to 0° C. over 30 min. The reaction is quenched with water (15 mL) and the aqueous layer is extracted with EtOAc (50 mL). The organic layer is dried over Na2SO4, concentrated, and purified by silica gel column chromatography (2% HOAc in 50% EtOAc/Hex) to give the product (3.98 g, 78%).
Reaction SMILES: [N:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9])=[O:2].CS(O)(=O)=O.[OH2:15]>C(Cl)Cl>[CH3:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]([C:6]1[CH:7]=[CH:8][C:3]([N:1]=[O:15])=[C:4]([CH3:9])[CH:5]=1)[OH:2]
Reactant: O
Reactant: Cc1ccccc1N=O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: Cc1cc(N(O)c2ccccc2C)ccc1N=O

Procedure:
4.982 g of 97% ortho-nitrosotoluene (41.12 mmol) were dissolved in 20 ml of methylene chloride at room temperature and 5.93 g of 98% methane sulfonic acid (61.7 mmol = molar ratio of 1:1.5) added thereto in the course of 2 minutes. Stirring was continued for one-half hour at room temperature and subsequently the dark brown, clear solution sprayed into water of 30° C. under a vacuum, whereby the methylene chloride was distilled off simultaneously. By means of filtration, it was possible to obtain 4.85 g = 97% of theoretical, of N-(2-methylphenyl)-N-(3-methyl-4-nitrosophenyl)-hydroxylamine in the form of a light yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].NC1C=CC(O)=C([N+]([O-])=O)C=1.C(Cl)(Cl)=O.[CH3:29][NH:30][CH3:31]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:30]([CH3:31])[CH3:29])=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C=Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: CNC
Agent: Nc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Hydroxy-3-nitrophenylisocyanate (15.5 g), prepared as described by H. Ulrich et al., loc. cit., from 4-amino-2-nitrophenol and phosgene, is added to 100 g of a solution of 29% by weight of dimethylamine in toluene, and the mixture is stirred at room temperature for 2 hours. Evaporation under reduced pressure leaves a residue on recrystallization from water gives N-(4-hydroxy-3-nitrophenyl)-N',N'-dimethylurea, m.pt. 142° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:22][CH3:23])=[CH:7][C:8]([CH2:19][S:20][CH3:21])=[C:9]([C:11]2[C:12]([O:17]C)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br.CC(O)=O.C([O-])([O-])=O.[K+].[K+]>O>[C:1]([C:5]1[C:6]([O:22][CH3:23])=[CH:7][C:8]([CH2:19][S:20][CH3:21])=[C:9]([C:11]2[C:12](=[O:17])[NH:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(CSC)c(-c2cccnc2OC)cc1C(C)(C)C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(CSC)c(-c2ccc[nH]c2=O)cc1C(C)(C)C
Temperature: 70 °C
Yield: 20.9 %

Procedure:
step 3—A mixture of 82 (30 mg), 48% HBr (50 μL) and HOAc (2 mL) in a sealed tube was heated overnight at 70° C. The reaction mixture was cooled to RT, carefully poured into water and neutralized with K2CO3 then extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on a preparative SiO2 TLC developed with 8% MeOH/DCM to afford 6 mg of 3-(5-tert-butyl-4-methoxy-2-methylsulfanylmethyl-phenyl)-1H-pyridin-2-one (84) as a white solid. The title compound can be prepared by oxidation of 84 with MCPBA which afford the sulfone I-15 directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=2)[C:16]([O:18]CC)=[O:17])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[K+]>C(O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=2)[C:16]([OH:18])=[O:17])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(-c2cc(C(=O)O)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 2-(3,4,5-trimethoxyphenyl)isonicotinate (3.17 g) in ethanol (40 mL) was added 10% potassium hydroxide (2.42 g). The mixture was stirred at room temperature for 5 hours and evaporated. Water was added to the residue and pH was adjusted to 7. White precipitates of the title compound were collected by filtration and the Compound was used for next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=O.[NH2:14][C@H:15]([C:17]([NH:19][CH:20]1[C:26](=[O:27])[N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]([CH3:38])[C:21]1=[O:39])=[O:18])[CH3:16]>>[F:13][C:11]1[CH:10]=[C:4]([CH:5]([OH:9])[C:6]([NH:14][C@H:15]([C:17]([NH:19][CH:20]2[C:26](=[O:27])[N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]([CH3:38])[C:21]2=[O:39])=[O:18])[CH3:16])=[O:8])[CH:3]=[C:2]([F:1])[CH:12]=1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(C)c2ccccc2N(c2ccccc2)C1=O
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Product: C[C@H](NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2N(c2ccccc2)C1=O

Procedure:
Following General Procedure D above using 3,5-difluoromandelic acid (Fluorochem) and 3-(L-alaninyl)amino-2,4-dioxo-1-phenyl-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (Example 8-N), the title compound was prepared as a solid. The product was purified by LC 2000 chromatography, eluting with hexanes/ethyl acetate (30:70).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:18])[CH:5]([NH:10][C:11](=[O:17])[CH:12]([NH3+:16])[CH2:13][C:14]#[CH:15])[CH2:6][CH:7]([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[CH2:28]([O:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([O:35][C:36]([NH:16][CH:12]([CH2:13][C:14]#[CH:15])[C:11]([NH:10][CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([O:3][CH3:2])=[O:18])=[O:17])=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C#CCC([NH3+])C(=O)NC(CC(C)C)C(=O)OC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a solution of compound 2 (8.5 g; 31 mmol) in dry THF (100 mL) was added DIEA (16.02 g; 124 mmol) and the reaction mixture was stirred for 30 min at room temperature. Benzylchloroformate (6.87 g; 40.3 mmol) was added and stirring was continued at room temperature for 16 h. The solvent was removed on the rotary evaporator and the residue was taken up in ethyl acetate (150 mL) and washed sequentially with water (50 mL), 5% HCl (2×50 mL), and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 3 as a white solid (10.46 g: 90% yield). 1H NMR (CDCl3) δ 7.3 (m, 5H), 6.7 (s, 1H), 5.6 (s, 1H), 5.1 (s, 2H), 4.6 (m, 1H), 4.4 (m, 1H), 3.7 (s, 3H), 2.6 (m, 2H), 2.8 (s, 1H), 2.6 (m, 1H), 1.6 (m, 2H), 1.5 (m, 1H), 0.9 (d, 6H).