Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:13][O:14][C:15]=2[CH3:16])[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:33].[Mg+2].O>ClCCl.CO>[F:10][C:6]1[CH:5]=[C:4]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:13][O:14][C:15]=2[CH3:16])[CH:3]=[C:2]([F:1])[C:7]=1[S:8]([CH3:9])=[O:33]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CSc1c(F)cc(-c2c(-c3ccccc3)noc2C)cc1F
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1onc(-c2ccccc2)c1-c1cc(F)c(S(C)=O)c(F)c1
Reaction time: 1.5 h

Procedure:
To a solution of 4-[3,5-difluoro-4-(methylthio)phenyl]-5-methyl-3-phenylisoxazole in dichloromethane (75 mL) and methanol (15 mL) cooled in an ice bath was added magnesium monoperoxyphthalate hexahydrate (4.4 g 80%, 7.1 mmol) in portions over 5 minutes. The reaction mixture was stirred for 90 minutes, then poured into water and extracted with dichloromethane (1×250 mL, 1×75 mL). The combined extracts were washed with dilute ammonium chloride, dried with magnesium sulfate, and concentrated. Purification by silica gel chromatography using 25% ethyl acetate/25% hexanes/50% dichloromethane gave 4-[3,5-difluoro-4-(methylsulfinyl)phenyl]-5-methyl-3-phenylisoxazole as a white solid. 1H NMR (CDCl3/400 MHz) 7.37-7.44 (m, 5H), 6.77-6.81 (m, 2H), 3.13 (s, 3H) 2.50 (s, 3H). HRMS m/z 334.0698 (M+H+, calcd 334.0713). Anal. Calcd for C17H13F2NO2S: C, 61.25; H, 3.93; N, 4.20. Found: C, 61.22; H, 4.00; N, 4.02.
Reaction SMILES: C([NH:4][C:5]1[S:9][N:8]([C@@H:10]2[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]2[O:12]C(=O)C)[C:7](=[O:28])[N:6]=1)(=O)C.C(NC1SN([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C(=O)N=1)(=O)C.[Na]>CO>[NH2:4][C:5]1[S:9][N:8]([C@@H:10]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([OH:17])[C@H:11]2[OH:12])[C:7](=[O:28])[N:6]=1
Reactant: CC(=O)Nc1nc(=O)n([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)s1
Agent: CC(=O)Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)s1
Agent: [Na]
Solvent: CO
Product: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)s1

Procedure:
To a solution of 5-acetamido-2-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,2,4-thiadiazol-3-one (4,1.0 g) or 5-acetamido-2-(β-D-ribofuranosyl)-1,2,4-thiadiazol-3-one (7) in anhydrous methanol (50 ml) was added 1N sodium methozide in methanol, till the pH of the solution was 9.0 and the solution was stirred at 30° for several days. After the reaction was complete, the solution was neutralized by stirring for 15 min with Amberlite IRC-50 (H+) resin. The resin was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column (2.5 × 45 cms) using ethylacetate:water:n-propanol (4:2:1), v/v, upper phase). The appropriate fractions were pooled, solvent evaporated and the reisdue crystallized from aaueous ethanol to yield 0.24 g (40.2%), m.p. > 240° (dec.); 1H nmr (Me2SO-d6) δ5.63 (d, J=4.5 Hz, C1'H); uv λmax (pH 1) 220 nm (ε 14,950), 273 (5000); λmax (pH 7) 220 nm (ε 13,950), 255 (6250); λmax (pH 11) 230 nm (ε 1,200), 278 sh (7500).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].[C:15]([O:34][CH2:35][C@@H:36]1[NH:40][C:39](=[O:41])[CH2:38][CH2:37]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:14][C:3]1[C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([CH:8]=[CH:9][C:2]=1[N:40]1[C@@H:36]([CH2:35][O:34][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:37][CH2:38][C:39]1=[O:41])[C:6]#[N:7]
Reactant: O=C1CC[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)N1
Reactant: Cc1c(Br)ccc(C#N)c1C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(N2C(=O)CC[C@@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)ccc(C#N)c1C(F)(F)F
Temperature: 80 °C
Yield: 31.9 %

Procedure:
The bromo-compound 3f (0.5 g, 1.89 mmol) was dissolved in 1,4-dioxane (10 mL) and (R)-5-((trityloxy)methyl)pyrrolidin-2-one (3g) (0.54 g, 1.51 mmol) was added followed by Cs2CO3 (1.2 g, 3.78 mmol) at room temperature. The reaction mixture was degassed with Argon gas for 30 min, Pd2(dba)3 (0.17 g, 0.18 mmol) and Xanthphos (0.21 g, 0.37 mmol) were added and heated to 80° C. for 12 h. After completion of reaction (by TLC), the reaction mixture was diluted with water (20 mL), filtered through celite bed and the filtrate was washed with water (2×20 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography to afford (R)-3-methyl-4-(2-oxo-5-((trityloxy)methyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (3h) (0.26 g, 26%) as a brown solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([CH:9]1[O:13][N:12]=[C:11]([C:14]([OH:16])=O)[CH2:10]1)([OH:8])[C:4]([F:7])([F:6])[F:5].[NH2:19][CH:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:21].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH3:21][CH:20]([NH:19][C:14]([C:11]1[CH2:10][CH:9]([C:3]([OH:8])([C:2]([F:18])([F:1])[F:17])[C:4]([F:5])([F:6])[F:7])[O:13][N:12]=1)=[O:16])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCC(C)N
Reactant: O=C(O)C1=NOC(C(O)(C(F)(F)F)C(F)(F)F)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCCCCC(C)NC(=O)C1=NOC(C(O)(C(F)(F)F)C(F)(F)F)C1
Yield: 65.2 %

Procedure:
A solution of 5-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-4,5-dihydroisoxazole-3-carboxylic acid from example 8-2 (84 mg, 0.3 mmol), 2-aminoheptane (69 mg, 0.6 mmol), 4-methylmorpholine (121 mg, 1.2 mmol), and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (265 mg, 0.6 mmol) in DMF (0.5 ml) was stirred at r.t. for 17 h. The reaction mixture was diluted with EtOAc, washed with water, 1 M citric acid and brine, then dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (EtOAc:Haxanes, 2:1) to afford the title compound as a clear oil (74 mg, 65%). 1H NMR δ 0.86 (t, 3H), 1.16 (d, 3H), 1.27-1.45 (m, 8H), 3.39 (dd, 1H), 3.65 (dd, 1H), 3.99 (m, 1H), 5.11 (t, 1H), 6.36 (d, 1H). ESIMS: m/z 377 (M−H).
Reaction SMILES: [Br:1][C:2]1[C:10]([CH2:11][CH3:12])=[C:9]2[C:5]([C:6]3[CH2:16][CH2:15][O:14][C:13]([CH2:19][C:20](O)=[O:21])([CH2:17][CH3:18])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1>C1COCC1>[Br:1][C:2]1[C:10]([CH2:11][CH3:12])=[C:9]2[C:5]([C:6]3[CH2:16][CH2:15][O:14][C:13]([CH2:19][CH2:20][OH:21])([CH2:17][CH3:18])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCc1c(Br)ccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3
Solvent: C1CCOC1
Product: CCc1c(Br)ccc2c3c([nH]c12)C(CC)(CCO)OCC3
Temperature: 90 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a stirred solution of 2-(7-Bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid (0.87 g, 2.4 mmol) in THF (5 ml), was added dropwise via syringe borane-tetrahydrofuran complex, 1.0 M solution in tetrahydrofuran (3.6 ml, 3.6 mmol) during 30 min. The mixture was stirred at 90° C. for 8 hr, cooled, quenched with distilled water and 5% HCl, extracted with EtOAc. The organic phases collected, washed with brine, dried over MgSO4, and evaporated to give a residue which was chromatographed on silica gel. Elution with hexane-EtOAc (1:1) gave the product which was further recrystallized in hexane/dichloromethane to give the product (0.64 g, 76%). 1H NMR (300 MHz, CDCl3) δ 7.91 (b, NH), 7.28 (d, 1H), 7.20 (d, 1H), 4.02 (m, 2H), 3.71 (m, 2H), 2.95 (qrt, 1H), 2.81 (m, 1H), 2.75 (t, 1H), 2.69 (t, 1H), 2.58 (t, 1H), 2.19 (m, 1H), 2.04 (m, 2H), 1.26 (t, 3H), 0.93 (t, 3H).
Reaction SMILES: [C:1]([N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].FC(F)(F)S(O)(=O)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.COC1C=CC(N)=CC=1.[Cl-].[NH4+]>O1CCCC1>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH:3]([CH3:4])[CH2:2][C:1]([N:6]2[CH2:10][CH2:9][O:8][C:7]2=[O:11])=[O:5])=[CH:24][CH:23]=1
Reactant: C/C=C/C(=O)N1CCOC1=O
Reactant: COc1ccc(N)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(NC(C)CC(=O)N2CCOC2=O)cc1
Yield: 83 %

Procedure:
In a stream of nitrogen, a solution of 3-crotonoyl-1,3-oxazolidin-2-one (776 mg, 5.0 mmol), anisidine trifluoromethanesulfonate (1.64 g, 6.0 mmol), anisidine (3.1 mg, 0.005 mmol) and Pd((R)-segphos)(H2O)2(OTf)2 (26.3 mg, 0.005 mmol) in tetrahydrofuran (5 ml) was stirred at room temperatures for 24 hours. When no starting material remained was noticed, a saturated aqueous solution of ammonium chloride was added to quench the reaction and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by a silica gel column chromatography (hexane: ethyl acetate=1:1) to give the objective 3-[3-(4-methoxyphenylamino)butyryl]-1,3-oxazolidin-2-one (1.16 g, in a yield of 83%). The enantiomeric excess ratio was determined to be 97% e.e. by a liquid chromatography with an optical isomer separating column (column: AD-H).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[O:28][C:29]=1[CH3:30]>>[CH3:30][C:29]1[O:28][C:27]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=2)=[N:26][C:25]=1[CH2:24][N:11]1[C:12]2[C:8](=[CH:7][C:6]([CH2:5][CH:4]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:3]([OH:2])=[O:22])=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: COC(=O)C(Cc1ccc2[nH]ccc2c1)Oc1ccccc1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1Cn1ccc2cc(CC(Oc3ccccc3)C(=O)O)ccc21

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-phenoxy-propionic acid methyl ester (preparation 7) was reacted with 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole to give rac-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl methyl]-1H-indol-5-yl}-2-phenoxy-propionic acid as colorless solid.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][N:11]=2)=[CH:6][CH:5]=1.Br[CH2:25][CH2:26][CH2:27][C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O>[CH3:35][C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26][CH2:25][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: CCCCCC[C@@H](C)CCCBr
Reactant: CCCCCCCCc1ccc(-c2ccc(O)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCc1ccc(-c2ccc(OCCC[C@H](C)CCCCCC)cc2)nc1
Yield: 47.1 %

Procedure:
20 ml of a 30% aqueous solution of sodium hydroxide was added dropwise to a mixture of 2 g (0.007 mol) of 2-(p-hydroxyphenyl)-5-octylpyridine and 1.65 g (0.007 mol) of (R)-1-bromo-(4-methyl)decane with stirring. The resulting solution was heated to a temperature between about 90° and 100° C. for 3 hours. 150 ml of water was added to the reaction solution and the organic layer was extracted with chloroform. After washing the extract three times with water, chloroform was removed by distillation. The residue was chromatographed over 2.5×100 (cm) of silica gel and developed with hexane and benzene. The effluent was repeatedly recrystallized from a mixture of methanol and acetone to yield 1.44 g (0.0033 mol) of (R)2-[p-(4-methyldecyloxy)phenyl]-5-octylpyridine.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH:31]([CH3:33])[CH3:32])[CH3:15])=[CH:8][C:7]=1[CH3:34].[OH-].[Na+].Cl>O1CCCC1.C(OCC)C>[CH:31]([C:17]1[N:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=2)[S:20][C:16]=1[CH:14]([CH3:15])[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]([CH3:34])[CH:8]=1)([CH3:32])[CH3:33]
Reactant: COC(=O)CCc1ccc(OCC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(OCC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)ccc1CCC(=O)O
Temperature: 25 °C

Procedure:
3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionic acid methyl ester (239 mg, 0.4725 mmol) is dissolved in tetrahydrofuran (1 mL) and 5N NaOH (1 mL) is added. The mixture is heated to reflux until the conversion is complete. Upon complete conversion, the reaction is cooled to room temperature and 5N HCl (1 mL) is added. The mixture is diluted with diethyl ether and extracted with 1N HCl. The organic layer is washed with water and brine, then dried over anhydrous sodium sulfate. Concentration of the solvent reveals the pure 3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionic acid in near quantitative yield (221 mg, 0.4489 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[N:32]1([CH2:38][C:39]([NH2:41])=[O:40])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:35]5[CH2:36][CH2:37][N:32]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:33][CH2:34]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: NC(=O)CN1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: NC(=O)CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-acetamide was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-piperazin-1-yl-acetamide following General Procedure C.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>Br.CC(O)=O>[Br:16][CH2:2][C:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:5]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1cnc(NC(=O)C(C)(C)C)s1
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1ncc(C(=O)CBr)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 20z (0.26 g, 1.15 mmol) was dissolved in 33% HBr in HOAc (100 mL), pyridinium tribromide (0.37 g, 1.15 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction mixture was poured onto ice water and the solid was collected by filtration to yield 21z which was in the next step without purification (0.34 g, 97%). 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 4.27 (s, 2H), 1.36 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=1[CH3:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[I-].C[N+]1C2C=CC=CC=2N(C)C=1.[H-].[Na+]>C1COCC1>[CH2:9]([O:16][C:17]1[C:18]([CH3:26])=[CH:19][C:20]([C:21]([C:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=2)=[O:22])=[CH:23][C:24]=1[CH3:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(C=O)cc(C)c1OCc1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cn1c[n+](C)c2ccccc21
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc(C)c1OCc1ccccc1
Temperature: 0 °C

Procedure:
150 mg (1.00 mmol) 4,6-dichloropyrimidine, 367 mg (1.50 mmol) 4-benzyloxy-3,5-dimethylbenzaldehyde and 166 mg (0.600 mmol) 1,3-dimethyl-3H-benzimidazol-1-ium-iodide (Chem. Pharm. Bull. 1990, 1147-52) in 10.0 mL THF were stirred at RT. Then 73.0 mg (1.51 mmol) sodium hydride (50% in mineral oil) were added and the reaction mixture was refluxed for 2.5 h. The reaction mixture was added to ice water and extracted with DCM. The organic phase was dried and evaporated down.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH:10]([CH2:20][CH:21]=[CH2:22])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)C>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][CH:11]([CH3:19])[CH:10]([CH2:20][CH:21]=[CH2:22])[C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC1C(=O)N(Cc2ccccc2)c2ccccc2N=C1C
Solvent: CCOCC
Product: C=CCC1C(=O)N(Cc2ccccc2)c2ccccc2NC1C
Yield: 85 %

Procedure:
Using 1-benzyl-4-methyl-3-(2-propen-1-yl)-1,3-dihydro-1,5-benzodiazepin-2(2H)-one, the titled compound was synthesized in substantially the same manner as in Working Example 24 in a yield of 85%, m.p. 81°-83° C. (diethylether).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[N:7]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[N:6]=[C:5]([S:17][CH3:18])[C:4]=1[CH2:19][N:20]1[CH:29]([CH2:30][OH:31])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1.[H-].[Na+].[CH3:35]I>O1CCCC1>[CH3:35][O:31][CH2:30][CH:29]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][N:20]1[CH2:19][C:4]1[C:5]([S:17][CH3:18])=[N:6][N:7]([C:8]2[C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12][C:13]=2[Cl:14])[C:3]=1[N:2]([CH3:1])[CH3:32]
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N(C)C)c1CN1Cc2ccccc2CC1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1Cc2ccccc2CN1Cc1c(SC)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
To a solution of the racemic mixture of Example 7 (200 mg, 0.39 mmol) in anhydrous tetrahydrofuran (2.0 ml), sodium hydride (78 mg of 60% sodium hydride mineral oil dispersion; 46 mg, 2.0 mmol of sodium hydride) was added; and the resulting mixture was stirred for 15 minutes at ambient temperature. Methyl iodide (0.10 ml, 1.6 mmol) was added, and the mixture was stirred for 18 hours at ambient temperature. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate/water (20 ml of each). The aqueous phase was separated and extracted with three equal volumes of ethyl acetate. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to a yellow oil. Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with ethyl acetate/hexane=1:10 in volume) afforded the title compound (118 mg) as a light-yellow oil.
Reaction SMILES: FC(F)(F)S(O[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12]([O:36][CH3:37])=[CH:13][C:14]2[C:15]3[C:16]4[C:33](=[O:34])[NH:32][C:31](=[O:35])[C:17]=4[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])=[CH:19][C:20]=3[NH:21][C:22]=2[CH:23]=1)(=O)=O.[I-:40].[Na+]>C(OCC)(=O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:18]1[C:17]2[C:31](=[O:35])[NH:32][C:33](=[O:34])[C:16]=2[C:15]2[C:14]3[CH:13]=[C:12]([O:36][CH3:37])[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][I:40])=[CH:23][C:22]=3[NH:21][C:20]=2[CH:19]=1
Reactant: [I-]
Reactant: COc1cc2c(cc1CCCCOS(=O)(=O)C(F)(F)F)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1CCCCI)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O

Procedure:
A mixture of the mesylate (172) 0.12 g, 0.21 mmol) prepared as described in example 311 and sodium iodide (1 g) in ethyl acetate (50 mL) was refluxed for 4 h. The cooled solution was washed with water and worked up to give the iodide (173) which crystallised from tetrahydrofuran/petroleum ether as an orange powder (0.10 g, 85%), mp 142–144° C. 1H NMR δ [(CD3)2SO] 11.86 (s, 1H), 11.05 (s, 1H), 8.43 (s, 1H), 7.58 (m, 1H), 7.55 (s, 1H), 7.52–7.43 (m, 3H), 7.42 (s, 1H), 3.94 (s, 3H). EIMS found M+=558.0212, 560.0178. C25H20ClN2O3 requires 558.0207, 560.0178.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=C(C)C=1>[OH:15][C:11]1[CH:10]=[C:9]([N:8]2[C:1](=[O:7])[CH:2]=[CH:3][C:4]2=[O:6])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1cccc(C)c1
Product: O=C1C=CC(=O)N1c1cccc(O)c1
Reaction time: 8 h

Procedure:
A one-liter flask containing 52.8 grams (0.53 mole) of maleic anhydride dissolved in 200 ml of m-xylene was slowly charged with 55.0 grams (0.50 mole) of 3-aminophenol. The reaction temperature was maintained below 50° C. with cooling. Five grams of para-toluenesulfonic acid was then added to the flask and the reactor contents heated to reflux with a pot temperature of 148°-150° C. Water removal was complete after 8 hours of reflux under nitrogen with a Dean-Stark trap. The flask was cooled, xylene decanted, and the remaining product dried under reduced pressure. One hundred two grams of crude product containing N-(3-hydroxyphenyl) maleimide were recovered.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14](S(C2C=CC(C(C)(C)C)=CC=2)(=O)=O)[C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][CH3:25])[C:16]=2[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][CH3:25])[C:16]=2[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOc1nn(C)c(N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCOc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Yield: 82.2 %

Procedure:
4-(tert-butyl)-N-{[4-(tert-butyl)phenyl]sulfonyl}-N-[3-(2-methoxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (278 mg) (Preparation 36) was dissolved in dioxane, 1M sodium hydroxide solution (4 ml) was added and the reaction was stirred at reflux for 0.5 hours. The solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (25 ml) and 1M hydrochloric acid (25 ml). The organic phase was separated, dried over magnesium sulphate and thesolvent removed under reduced pressure. The product was purified on silica (10 g) eluting with a solvent gradient of pentane:ethyl acectate (1:0 to 6.4) to yield the title compound as a white solid (160 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11](=[CH:14]N(C)C)[CH:10]2[CH2:18][CH:19]=[CH:20][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[O:22]1CCOCC1>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][OH:22])[CH:10]2[CH2:18][CH:19]=[CH:20][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCO1
Reactant: CN(C)C=C1C(=O)N(C(=O)OC(C)(C)C)C2C=CCC12
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)C(=CO)C2CC=CC21
Yield: 93 %

Procedure:
A solution of tert-butyl-3-(dimethylaminomethylene)-2-oxo-4,6a-dihydro-3aH-cyclopenta[b]pyrrole-1-carboxylate III-1 (120 mg, 0.43 mmol) in dioxane (9 mL) was stirred with hydrochloric acid (2 M, 0.86 mL, 1.72 mmol) for 15 h at room temperature. The solution was diluted with ethyl acetate, washed with water and brine, dried, concentrated giving the desired compound as a colorless oil (101 mg, 93%); 1H NMR (400 MHz, CDCl3) 9.92 (1H, d), 7.05 (1H, d), 6.91 (1H, m), 5.71 (1H, m), 5.07 (1H, d), 3.46 (1H, dt), 2.87 (1H, dd), 2.31 (1H, m), 1.55 (9H, s). LCMS (Method A): 0.79 min; ES−250 (M−H+).