Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:15]#[N:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C#N)Cc1ccc(F)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CC(C#N)(Cc1ccc(F)cc1)C(=O)OCC

Procedure:
In the same manner as Example 1-(b), 100 g of ethyl 3-(4-fluorophenyl)-2-cyanopropionate was reacted with ethyl bromoacetate to obtain ethyl 4-(4-fluorophenyl)-3-cyano-3-ethoxycarbonylbutyrate.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([C:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28][CH3:29])=[O:27])[CH:20]=3)[N:15]=2)[CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2]>CO.[Pd]>[CH:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28][CH3:29])=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC(C)C)c1)=N2
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC(C)C)c1)N2
Yield: 48.8 %

Procedure:
To a stirred solution of methyl 2-(3-(N-isopropylsulfamoyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (245 mg, 0.59 mmol) in methanol (5 mL) was added 10% Pd/C (130 mg). The mixture was hydrogenated by a H2 balloon. After filtration, the filtrated was concentrated and purified on preparative Thin layer chromatography to afford 120 mg of methyl 2-(3-(N-isopropylsulfamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as syrup. (Yield: 28%, three steps.)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[OH:24])=[CH:12][CH:11]=1>CO>[Cl:9][C:10]1[CH:11]=[CH:12][C:13](/[C:16](=[N:1]\[CH2:2][CH2:3][CH2:4][S:5]([NH2:8])(=[O:7])=[O:6])/[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[OH:24])=[CH:14][CH:15]=1
Reactant: NCCCS(N)(=O)=O
Reactant: O=C(c1ccc(Cl)cc1)c1cc(F)ccc1O
Solvent: CO
Product: NS(=O)(=O)CCC/N=C(\c1ccc(Cl)cc1)c1cc(F)ccc1O
Yield: 50.6 %

Procedure:
3-Amino-1-propanesulfonamide (0.55 g, 4 mmol; from step 4) was added to a solution of 4′-chloro-5-fluoro-2-hydroxy-benzophenone (1 g, 4 mmol) in methanol (50 mL). The reaction mixture was stirred under reflux for 5 h then concentrated under reduced pressure. The residual material was purified by column chromatography (silica gel, dichloromethane:methanol 90:10 then 80:20). The corresponding solid (after removal of solvent) was recrystallized in diethyl ether to afford 3-{[(1E)-(4-chlorophenyl)(5-fluoro-2-hydroxyphenyl)methylene]amino}propane-1-sulfonamide (0.75 g, 51%). 1H NMR (CDCl3, 500 MHz) δ 2.21 (m, 2H), 3.24 (t, J=7.0 Hz, 2H), 3.47 (t, J=7.0H, 2H), 4.63 (bs, 2H), 6.93 (m, 1H), 6.95 (m, 1H), 7.04 (m, 1H), 7.13 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 14.71 (s, 1H). ES-MS (369 M-1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33]I)[N:32]=2)=[CH:24][CH:23]=1>>[CH3:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:10]([CH2:9][O:8][CH:4]2[CH2:5][CH2:6][CH2:7][CH:2]([O:1][CH2:33][C:31]3[N:32]=[C:28]([C:25]4[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=4)[O:29][C:30]=3[CH3:35])[CH2:3]2)[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: Cc1ccc(-c2nc(CI)c(C)o2)cc1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Product: Cc1ccc(-c2nc(COC3CCCC(OCc4cccc(C)c4C(=O)O)C3)c(C)o2)cc1

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(4-methylphenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 70 of molecular weight 449.55 (C27H31NO5), MS(ESI): 450.36 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([NH:15][CH3:16])=[C:11]([CH:17]=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:21]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:22][C:23]([O:25]CC)=O.N1CCCCC1>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]3[N:15]([CH3:16])[C:23](=[O:25])[C:22]([C:21]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][C:11]=3[CH:10]=[N:9]2)=[CH:19][CH:20]=1
Reactant: CNc1c(C=O)cnn(Cc2ccc(OC)cc2)c1=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cnn(Cc3ccc(OC)cc3)c(=O)c2n(C)c1=O
Reaction time: 18 h

Procedure:
A mixture of 1-(4-methoxybenzyl)-5-(methylamino)-6-oxo-1,6-dihydropyridazine-4-carbaldehyde (4) (3.78 g, 13.8 mmol), diethyl malonate (4.20 mL, 27.7 mmol), piperidine (1.44 mL, 14.5 mmol), and EtOH (100 mL) was stirred at reflux in an oil bath for 5 h. The reaction mixture was allowed to stand at RT for 18 h to afford a suspension. The solid was collected by suction filtration, washed with EtOH (10 mL), and dried in vacuo to afford ethyl 7-(4-methoxybenzyl)-1-methyl-2,8-dioxo-1,2,7,8-tetrahydropyrido[2,3-d]pyridazine-3-carboxylate as a tan solid. MS (ESI, pos. ion) m/z: 370 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(CC(=O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)Nc1cccc(CC(=O)O)c1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
Methanesulphonylchloride (1.70 ml) was added to a stirred mixture of 3-aminophenylacetic acid (3.2 g) and sodium carbonate (5.44 g) in water (36 ml), and the mixture was heated at 85° C. with stirring for 4 h, allowed to cool and acidified with conc. hydrochloric acid to pH 2. After leaving to stand at approximately 4° C. for 18 h, a solid was filtered off, and the residue washed with water and ether. The aqueous and ether filtrates were combined and evaporated in vacuo to give a solid, which was dissolved in hot water, the solution was filtered whilst still hot and the filtrate left to cool before standing at 4° C. for 18 h. The precipitated solid was filtered, washed with a small quantity of cold water and dried in vacuo to give the title compound as a pale yellow solid (0.417 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])O)O)=O.CN1[C:18](=[O:19])[CH2:17]CC1.C(OC(=O)C)(=O)C>CN(C1C=CN=CC=1)C.O>[C:18]([O:12][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1)(=[O:19])[CH3:17]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CN1CCCC1=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1ccc(C=O)o1
Temperature: 110 °C

Procedure:
39.4 kg (219 mol) of D-fructose and 5.9 kg of dried acidic Dowex® 50WX8-200 ion exchanger (styrene-divinylbenzene copolymer resin with SO3H groups, obtainable from The Dow Chemical Company, Midland, U.S.A.) in the H form were introduced with stirring into 90 l of NMP and heated to 110° C. for 6 h. After cooling, the reaction mixture was filtered and washed with 8 l of NMP. The filtrate was admixed with stirring with 390 g (3.2 mol) of 4-(N,N-dimethylamino)pyridine and 20.5 1 (217 mol) of acetic anhydride at 20-25° C. within 1 h. After continuing the reaction for 1 h, the brown reaction mixture was freed of the solvent at 90-100° C. under reduced pressure (of 50-10 mbar). After cooling, the residue was admixed with 160 l of MtBE, 60 1 of water and 4 kg of activated carbon. The suspension was filtered though Celite®. After the phase separation, the solvent of the filtrate was distilled off at 50° C. under reduced pressure (20 mbar) and the residue was fractionally distilled under reduced pressure at 106-110° C./5 mbar.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH:21]([CH3:23])[CH3:22])=[O:5].[CH3:25][Mg]Br>O1CCCC1>[CH:21]([C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=2)[S:10][C:6]=1[C:4](=[O:5])[CH3:25])([CH3:22])[CH3:23]
Reactant: CON(C)C(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Temperature: 0 °C
Yield: 81.7 %

Procedure:
4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid methoxy-methyl-amide (7.56 g, 21.09 mmol) is suspended in anhydrous tetrahydrofuran (100 mL), and cooled to 0° C. with stirring under nitrogen. Methyl magnesium bromide (28 mL, 3.0M in diethyl ether, 84.36 mmol) is slowly added to the reaction over 1 h. The reaction is allowed to warm slowly to room temperature and monitored by TLC. Upon complete consumption of starting material, the reaction is carefully neutralized with 1N hydrochloric acid, extracted with diethyl ether, washed, dried, and concentrated. The 1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanone (5.4 g, 17.23 mmol) 82% yield, is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][OH:7]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7]
Reactant: COc1cc(CO)c([N+](=O)[O-])c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C=O)c([N+](=O)[O-])c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Active manganese dioxide (8.0 g) was added to a solution of 3,4,5-trimethoxy-2-nitrobenzyl alcohol (1.01 g, 4.15 mmol), prepared in the step (a), in methylene chloride (15 ml), and the mixture was stirred at room temperature overnight. Further, active manganese dioxide (8.0 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was filtered through Celite, and the solvent was removed under reduced pressure to give 3,4,5-trimethoxy-2-nitrobenzaldehyde (300 mg, 30%) as colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1.Cl[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[C:11](=[O:23])[C:10]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1
Reactant: ClCC1CC1
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)n[nH]c1=O
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn(CC2CC2)c1=O
Yield: 89.1 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-ethoxycarbonyl-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedures of Example 19 were repeated likewise, whereby the title compound was obtained in a yield of 89.1%.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:15]2=[O:31])=[CH:9][C:8]=1[CH3:32])(C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:45][O:46][C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=1)[CH2:50]Br.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:10]2[CH:9]=[C:8]([CH3:32])[C:7]([OH:6])=[C:12]([CH3:13])[CH:11]=2)([CH2:50][C:49]2[CH:52]=[CH:53][CH:54]=[C:47]([O:46][CH3:45])[CH:48]=2)[C:15]1=[O:31]
Reactant: COc1cccc(CBr)c1
Reactant: Cc1cc(C2C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1cccc(CC2(c3cc(C)c(O)c(C)c3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)c1
Yield: 95.9 %

Procedure:
Using a method similar to Example 37, with 3-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1-(2-chloro-benzyl)-1,3-dihydro-indol-2-one (250 mg, 0.51 mmol), a 0.5M solution of potassium bis(trimethylsilyl)amide (1.04 mL, 0.52 mmol), and 3-methoxybenzyl bromide (0.073 mL, 0.31 mmol) in DMF (5 mL) followed by treatment with TBAF (0.56 mL, 0.56 mmol) gives a crude yellow solid. Purify by flash chromatography (gradient of 50% hexanes/CH2Cl2 to CH2Cl2) to give 148 mg (58%) of the title compound as a yellow powder. MS (ES): m/z=498 (M+1), 496 (M−1); 1H NMR(DMSO-d6); δ8.28 (s, 1H), 7.56 (m, 1H), 7.45 (dd, J=1.0 Hz, J=8.0 Hz, 1H), 7.24 (m, 1H), 7.14 (m, 2H), 7.00 (s, 2H), 6.85-6.76 (m, 3H), 6.64 (d, J=8.7 Hz, 2H), 6.50 (m, 1H), 5.68 (d, J=6.6 Hz, 1H), 4.79 (abq, J=17.1 Hz, 2H), 3.68 (s, 3H), 3.60 (d, J=12.7 Hz, 1H), 2.15 (s, 6H).
Reaction SMILES: O.Cl.[Cl:3][C:4]1[NH:9][C:8](=[O:10])[CH:7]=[C:6]([OH:11])[C:5]=1[CH3:12].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[Cl:3][C:4]1[NH:9][C:8](=[O:10])[C:7]([N+:13]([O-:15])=[O:14])=[C:6]([OH:11])[C:5]=1[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(O)cc(=O)[nH]c1Cl
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(Cl)[nH]c(=O)c([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 6-chloro-4-hydroxy-5-methylpyridin-2(1H)-one hydrochloride hydrate (67.0 g, 0.313 mmol) in concentrated sulfuric acid (335 mL) was cooled to ˜0° C.; nitric acid (19.6 mL of 16 M) was added dropwise over a period of ten minutes. The reaction was stirred for 20 minutes and then poured slowly into 2.5 L of ice water. A yellow precipitate formed, which was isolated by filtration and dried overnight in a vacuum oven at 60° C. to provide 39.7 g of 6-chloro-4-hydroxy-5-methyl-3-nitropyridin-2(1H)-one as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=O.[C:15]([NH2:18])(=[S:17])[CH3:16]>C(O)(=O)C>[CH3:16][C:15]1[S:17][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)[N:18]=1
Reactant: CC(N)=S
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Solvent: CC(=O)O
Product: Cc1nc(-c2ccc3c(c2)CC(=O)N3)cs1
Temperature: 80 °C
Yield: 91.1 %

Procedure:
A suspension of 5-(chloroacetyl)-1,3-dihydro-2H-indol-2-one (1.5 g, 7.15 mmol) and thioacetamide (540 mg, 7.15 mmol) in acetic acid (18 mL) was heated at 80° C. for 3 h. The mixture was cooled to room temperature and the formed precipitate was filtered and washed with ethyl acetate two times and diethyl ether two times and the solid was dried under vacuo to give 1.5 gram (91% yield) of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ 10.49 (s, 1 H), 7.90-7.70 (m, 3 H), 6.85-6.75 (m, 1 H), 3.55 (s, 2 H), 2.70 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:14])[C:10](=[S:13])[NH:11][N:12]=1.[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:14])[C:10]([S:13][CH3:15])=[N:11][N:12]=1
Reactant: Cn1c(-c2ccccc2F)n[nH]c1=S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSc1nnc(-c2ccccc2F)n1C
Yield: 72.9 %

Procedure:
A mixture of 5-(2-fluorophenyl)-2 4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (4.56 g 2.18×10-2 mole), K2CO3 (3.01 g, 2.18×10-2 mole), methyl iodide (1 5 ml 2.4×10-2 mole), and acetone (65 ml) was stirred and warmed to reflux. After refluxing overnight, the solvent was evaporated and the concentrate was treated with water. The aqueous mixture was extracted three times with EtOAc. The EtOAc extracts were combined washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure affording a pale yellow oil which was purified by chromatography and kugel rohr distillation, affording a pale yellow oil 3.55 g (73%), bp=190°-197° C. (0.3 mm).
Reaction SMILES: [C:1]1([N:7]2[CH:11]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)[CH2:10][O:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC(N2C(COC3C=CC(C(OC)=O)=CC=3)COC2=O)=CC=1>>[C:1]1([N:7]2[CH:11]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=3)[CH2:10][O:9][C:8]2=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCC2COC(=O)N2c2ccccc2)cc1
Agent: COC(=O)c1ccc(OCC2COC(=O)N2c2ccc(Cl)cc2)cc1
Product: O=C(O)c1ccc(OCC2COC(=O)N2c2ccccc2)cc1
Yield: 61 %

Procedure:
The same procedure of Example 25 was repeated except that methyl 4-(3-phenyl-2-oxooxazolidin-4-yl)methoxybenzoate (compound 177) obtained in Example 23 was used in lieu of methyl 4-[3-(4-chlorophenyl)-2-oxooxazolidin-4-yl]methoxybenzoate to give the title compound (compound 180) in a yield of 61%.
Reaction SMILES: CN1[C@@H]([C@H:12]2[O:21][C:19](=[O:20])[C:18]3[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=[CH:14][C:13]2=3)C2C(OC)=C3OCOC3=CC=2CC1.[F-].FF>C1COCC1>[CH3:25][O:24][C:16]1[C:17]([O:22][CH3:23])=[C:18]2[C:13]([CH2:12][O:21][C:19]2=[O:20])=[CH:14][CH:15]=1
Reactant: COc1ccc2c(c1OC)C(=O)O[C@@H]2[C@H]1c2c(cc3c(c2OC)OCO3)CCN1C
Agent: FF
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1OC)C(=O)OC2
Yield: 74 %

Procedure:
Aromatic fluorination of noscapine was achieved by employing the fluoride form of Amberlyst-A 26, a macroreticular anion-exchange resin containing quaternary ammonium groups. The method described [33] for Hal/F exchange may also be applied to other Hal/Hal′ exchange reactions. In Br/F exchange reactions, good yields were obtained only when a large molar ratio of the resin with respect to the substrate was employed. Thus, after refluxing a solution of bromonoscapine in anhydrous THF and an excess of Amberlyst-A 26 (fluorine, polymer-supported, 10 milliequivalents of dry resin; the average capacity of the resin is 4 milliequivalents per gram) for 12 hours, the resin was filtered off and the solvent was removed in vacuo to afford the desired compound (3) in 74% yield. The resin was recovered by washing with 1 N NaOH and then rinsing thoroughly with water until neutrality to generate the hydroxy-form of the resin. It was then stirred overnight with 1 N aqueous hydrofluoric acid, washed with acetone, ether and dried in a vacuum oven at 50° C. for 12 hours to afford the regenerated Amberlyst-A 26 (fluorine, polymer-supported), which can be reused.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH:32]=[N:31][CH:30]=[N:29]1>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:38][C:37]3[CH:39]=[CH:40][C:34]([CH2:33][N:28]4[CH:32]=[N:31][CH:30]=[N:29]4)=[CH:35][CH:36]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(Cn2cncn2)cc1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cn2cncn2)cc1)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 100 mg; 0.36 mmol) in DCM (4 ml) was treated with polymer-supported Mukaiyama reagent (400 mg) followed by triethylamine (100 mL; 0.73 mmol) and 4-((1H-1,2,4-triazol-1-yl)methyl)aniline (Maybridge, 63.2 mg; 0.36 mmol). After stirring at RT for 24 hours the mixture was filtered and washed with saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[C:25]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[N:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=2)=[O:29])[C:24]([O:39][CH3:40])=[CH:23][C:4]=1[CH2:5][CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)C(=O)OC(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[C:4]([CH2:5][CH2:6][NH:7][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:23][C:24]([O:39][CH3:40])=[C:25]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[N:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=2)=[O:29])[CH:26]=1
Reactant: COc1cc(CCN(Cc2ccc(F)cc2)C(=O)OC(C)(C)C)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(CCNCc2ccc(F)cc2)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 10 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
A solution of HCl in 1,4-dioxane (0.05 mL) was added to a solution of tert-butyl 2-chloro-4-(3-(5-cyanopyrazin-2-yl)ureido)-5-methoxyphenethyl(4-fluorobenzyl)-carbamate (0.03 g, 0.4 mmol) in DCM (5 mL) at 0° C. The solution was allowed to warm to 10° C. and stirred at this temperature for one hour. The solvents were removed under reduced pressure and the residue was washed with methanol (2×5 mL) to give the title compound (0.017 g, 68%) as a white solid.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Br[CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[I:1][C:2]1[C:3]([O:12][CH2:14][C:15]#[N:16])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Oc1cc2ccccc2cc1I
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: N#CCOc1cc2ccccc2cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
A mixture of 3-iodo-naphthalen-2-ol (2.0 g, 7.4 mmol), bromoacetonitrile (1.066 g, 8.88 mmol) and potassium carbonate (2.04 g, 14.81 mmol) in three mL of acetonitrile was stirred at room temperature for 16 hours. The reaction mixture was diluted with methylene chloride and filtered. The filtrate was washed with 2% aqueous NaOH solution, water, and saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from EtOAc/hexanes to give 2.07 g of (3-iodo-naphthalen-2-yloxy)-acetonitrile, MP=105-107° C., MS (M+H)=309.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:9]1[CH:10]=[C:11]([N+:20]([O-:22])=[O:21])[C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])([CH3:8])([CH3:7])[CH3:6].[CH3:23]O>>[C:5]([C:9]1[CH:10]=[C:11]([N+:20]([O-:22])=[O:21])[C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14]([O:16][CH3:23])=[O:15])([CH3:8])([CH3:6])[CH3:7]
Reactant: COc1c(C(=O)O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(C)(C)C)cc([N+](=O)[O-])c1OC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2.3 ml of thionyl chloride are added dropwise to an ice-cooled solution of 5.40 g 5-tert-butyl-2-methoxy-3-nitro-benzoic acid in 50 ml of methanol. The cooling bath is removed and the solution is heated to 60° C. The solution is stirred overnight at 60° C. and then cooled to ambient temperature. The solution is evaporated down completely and the residue is mixed with water. The aqueous mixture is extracted with ethyl acetate, and the combined extracts are dried (MgSO4). The solvent is removed, and the residue is chromatographed on silica gel with cyclohexane/ethyl acetate (98:260:40).
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:24]2[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][CH2:25]2)[C:17](=[O:23])[C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:32][NH:33][CH2:34][CH3:35]>>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:24]2[CH2:29][CH2:28][C:27]([CH3:30])([CH3:31])[CH2:26][CH2:25]2)[C:17](=[O:23])[C:18]([CH3:21])([CH3:22])[CH2:19][OH:20])[CH2:13][C@H:9]1[C:10]([N:33]([CH2:34][CH3:35])[CH3:32])=[O:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)CC1
Reactant: CCNC
Product: CCN(C)C(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)CO)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Step D of Example A1 using (4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-L-pr oline (0.85 g, 1.94 mmol) prepared in Step B and commercially available N-methylethylamine (0.86 g, 93%).