Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.C=O.[CH3:23][N:24]([CH2:26]N(C)C)[CH3:25].Cl>CCO.C1C=CC=CC=1>[CH3:23][N:24]([CH2:26][C:8]1[C:9]([OH:20])=[CH:10][C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:5]([C:6]=2[CH:7]=1)[CH2:4][CH2:3][C@@:2]1([CH3:1])[C@H:15]3[CH2:16][CH2:17][C:18]1=[O:19])[CH3:25]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CN(C)CN(C)C
Agent: C=O
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Product: CN(C)Cc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 80 °C
Reaction time: 20 h
Yield: 66.7 %

Procedure:
To a suspension of estrone (11, 5.40 g, 20 mmol) in EtOH (100 mL) and benzene (60 mL) were added paraformaldehyde (0.600 g, 20 mmol) and N,N,N',N'-tetramethyldiaminomethane (5.5 mL, 40 mmol), and stirred for 20 h at 80° C. After the reaction mixture was cooled to 0° C., 5 N HCl was added. The aqueous layer was washed with Et2O, and basified with aqueous NH4OH. The precipitate was collected by filtration and washed with H2O, and recrystallized from EtOH to afford 4.37 g of 72 (67% yield) mp: 172-173° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.[CH2:18]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=2)[N:27]([CH3:37])[CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH2:18]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([N:1]3[CH2:2][CH:3]([N:5]4[CH2:6][CH2:7][N:8]([C:11]([C:13]5[S:14][CH:15]=[CH:16][N:17]=5)=[O:12])[CH2:9][CH2:10]4)[CH2:4]3)=[O:35])=[CH:31][CH:32]=2)[N:27]([CH3:37])[CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cn1cc(Cc2ccccc2)c2ccc(C(=O)O)cc21
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cn1cc(Cc2ccccc2)c2ccc(C(=O)N3CC(N4CCN(C(=O)c5nccs5)CC4)C3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
To a mixture of compound 5e (71.6 mg, 0.22 mmol), compound 56d (53.1 mg, 0.2 mmol), and Et3N (0.14 mL, 1.0 mmol) in CH2Cl2 (1 mL) at room temperature was added HATU (106.5 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and H2O, washed with aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash column chromatography (silica gel, 2-4% MeOH/EtOAc) gave compound Cpd 753 (20.8 mg). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J=2.4 Hz, 1H), 7.74 (s, 1H), 7.55 (d, J=2.7 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.15-7.35 (m, 6H), 6.89 (s, 1H), 4.06-4.60 (m, 8H), 3.79-3.98 (m, 2H), 3.78 (s, 3H), 3.17-3.31 (m, 1H), 2.35-2.64 (m, 4H). MS m/z (M+H+) 500.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Product: CC(=O)N1CCC(Oc2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1

Procedure:
The title compound was prepared by using Mitsunobu condition from 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 1-(4-Hydroxy-piperidin-1-yl)-ethanone.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2.CS([Cl:17])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:17][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc2cnccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 0.1212 g (0.76 mmol) 15 in 8 mL CH2Cl2 at 0° C. was added 64.8 μL (0.84 mmol) methanesulfonyl chloride and 84.7 μL (0.61 mmol) triethylamine. After 3 h at 0° C., the reaction mixture was warmed to room temperature and 32.0 μL (0.23 mmol) triethylamine added. The reaction was recooled to 0° C., and 14.7 μL (0.19 mmol) methanesulfonyl chloride and 26.5 μL (0.19 mmol) triethylamine were added. After 62 h at room temperature, the reaction mixture was diluted with 25 mL CH2Cl2 and washed with 10 mL saturated NaHCO3 solution. The aqueous layer was extracted with 10 mL CH2Cl2, and the combined organic layers were washed with 10 mL brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography (15×140 mm silica gel, 2% (10% NH40H:MeOH):CH2Cl2). Mixed fraction repurified by flash chromatography (12×75 mm silica gel, 1% (10% NH40H:MeOH):CH2Cl2) to give 16. 1H NMR (CDCl3, 400 MHz) δ 9.305 (s, 1H, ArH); 8.653 (d, 1H, J=5.85 Hz, ArH); 7.992 (d, 1H, J=8.23 Hz, ArH); 7.927 (d, 1H, J=5.94 Hz, ArH); 7.753 (d, 1H, J=7.04 Hz, ArH); 7.583 (dd, 1H, J=7.14, 8.14 Hz, ArH); 5.020 (s, 1H, ArCH2); MS (Electrospray): m/z 177.9, 179.9 (M+H, 35Cl, 37Cl).
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([NH:22][S:23]([CH2:26][C:27]#[N:28])(=[O:25])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][S:23](/[C:26](=[CH:13]/[C:9]1[S:10][CH:11]=[CH:12][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)/[C:27]#[N:28])(=[O:25])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1sccc1Oc1ccccc1
Reactant: N#CCS(=O)(=O)NCc1ccccc1
Product: N#C/C(=C\c1sccc1Oc1ccccc1)S(=O)(=O)NCc1ccccc1

Procedure:
Reaction of 3-phenoxythiophen-2-carboxaldehyde and benzylaminosulfonylacetonitrile as in Example 1 gave (E)-2-(benzylaminosulfonyl)-3-(3-phenoxythien-2-yl)acrylonitrile
Reaction SMILES: [OH:1][C:2]([C@H:5]1[S:10][C:9]([NH:11]C(=O)OC(C)(C)C)=[N:8][C@:7]([CH3:31])([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)[CH:20]=2)[CH2:6]1)([CH3:4])[CH3:3].CO.[F:34]C(F)(F)C(O)=O>>[NH2:11][C:9]1[S:10][C@H:5]([C:2]([OH:1])([CH3:4])[CH3:3])[CH2:6][C@:7]([C:19]2[CH:24]=[CH:23][C:22]([F:34])=[C:21]([C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)[CH:20]=2)([CH3:31])[N:8]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(-c3cncnc3)c2)C[C@@H](C(C)(C)O)S1
Reactant: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(O)[C@@H]1C[C@@](C)(c2ccc(F)c(-c3cncnc3)c2)N=C(N)S1
Yield: 67.5 %

Procedure:
A solution of tert-butyl (4S,6S)-6-(2-hydroxypropan-2-yl)-4-methyl-4-(3-(pyrimidin-5-yl)phenyl)-5,6-dihydro-4H-1,3-thiazin-2-ylcarbamate (221 mg, 0.50 mmol) in trifluoroacetic acid (2 mL) is stirred at room temperature for 80 min. The mixture is added directly to a MeOH-equilibrated SCX column. The column is washed with MeOH (100 mL) and the product is eluted with 7N NH3 in MeOH (100 mL). The solution is concentrated under reduced pressure. The residue is diluted with CH2Cl2 and HCl (g) is bubbled through for 5 min. The reaction mixture is concentrated to give the title compound (67.5% yield): MS (m/z): 343 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]([NH:31][C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[S:30])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH3:23])=[C:12]([C:15]([O:17]C(C)(C)C)=[O:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[ClH:41].O1CCOCC1>>[ClH:41].[F:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]([NH:31][C:32](=[O:40])[CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[S:30])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH3:23])=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)O
Temperature: 70 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Compound 1d (88.0 mg) was dissolved in 4N HCl-dioxane solution, followed by stirring at 70° C. for 1 hour. The precipitate in the reaction mixture was filtrated, to thereby yield compound 1e (67.1 mg, yield: 79%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.[NH2:13][C:14]1[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:17]>CCO>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C:16](=[O:17])[C:15]3[C:14](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=[C:11]2[C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:20][CH:21]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Reactant: O=Cc1cnc2ccccc2c1
Solvent: CCO
Product: O=c1c2ccccc2nc(-c2cnc3ccccc3c2)n1-c1ccc(Cl)cc1
Yield: 14 %

Procedure:
3-Quinoline carboxaldehyde (0.41 mmol) and anhydrous CuCl2 (0.110 g, 0.82 mmol) were added to a solution of 2-amino-N-(4-chlorophenyl)benzamide (0.100 g, 0.41 mmol) in anhydrous EtOH (10 mL). The mixture was heated at reflux temperature for 4 hours and concentrated in vacuo. The residue was dissolved in EtOAc and washed with H2O and brine, dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography on silica gel, eluting with 5% to 50% EtOAc in heptane, afforded the title compound as a white solid (14%). 1H-NMR (300 MHz, DMSO-d6): δ 8.83 (d, J=2.1 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.88-8.03 (m, 3H), 7.74-7.88 (m, 2H), 7.56-7.73 (m, 2H), 7.52 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.7 Hz, 2H). MS (APCI) m/z: 384 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[CH:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]23[CH2:31][CH:26]4[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]4)[CH2:23]2)[CH2:29]3)=[CH:17][CH:16]=1)=O.[OH-].[Na+]>O>[CH3:12][NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]23[CH2:31][CH:26]4[CH2:25][CH:24]([CH2:30][CH:28]([CH2:27]4)[CH2:29]2)[CH2:23]3)=[CH:19][CH:20]=1
Reactant: O=CNc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 8 h

Procedure:
To a stirred suspension of 1.30 g. LiAlH4 in 20 ml. THF there was added 9.17 g. (0.034 mole) of N-formyl-p-(1-adamantyloxy)aniline in 200 ml. THF. Following 8 hours heating at reflux the mixture was cooled in ice and treated in turn with 1.3 ml. each of H2O and 15% NaOH and 4.9 ml. H2O. The inorganic gel was removed on a filter and the filtrate taken to dryness. The residue was recrystallized from Me2CO:SSB to give 5.96 g. (79%) of amine, N-methyl-p(1-adamantyloxy)aniline m.p. 134°-136°.
Reaction SMILES: C(=[O:5])C(C)C.[C:6](N)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(NC=C(C)C)(=O)C1C=CC=CC=1.[CH3:28][C@H:29]1[CH2:34][C@@H:33]([OH:35])[C@H:32]([CH:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]1.N1C=CC=CC=1>C1COCC1>[C:6]([OH:13])(=[O:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:28][C@H:29]1[CH2:34][C@@H:33]([OH:35])[C@H:32]([CH:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]1
Reactant: CC(C)C=O
Reactant: NC(=O)c1ccccc1
Agent: CC(C)=CNC(=O)c1ccccc1
Agent: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1
Temperature: 250 °C

Procedure:
0.10 mol of isobutyraldehyde and 0.20 mol of benzamide are heated together at 100° C. with stirring, and the product solid is heated in a sublimator at 250° C. and 1 mm Hg until formation of the enamide 1-benzoylamino-2-methylpropene is complete. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), L-menthol (0.5 mmol), Co2 (CO)8 (0.05 mmol), pyridine (0.25 mmol), and 1-benzoylamino-2-methylpropene (0.5 mmol). The reactor is sealed, pressurized to 1500 psig with 15:1 CO:H2 and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a mixture of two diastereomeric valine derivatives, N-benzoyl-L-valine L-menthyl ester and N-benzoyl-D-valine L-menthyl ester. These diastereomers are separated by column chromatography on silica gel with benzene-ethyl acetate eluent and are separately hydrolyzed by heating to 100° C. in 1N HCl for 2 hours to give pure L- and D-valine, benzoic acid, and L-menthol, which is thereafter recycled to a repeat of the foregoing hydrocarboxylation reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[O:34][C@@H:35]1[CH2:39][NH:38][C@H:37]([CH2:40][O:41][C:42]2[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=2)[CH2:36]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:38]2[CH2:39][C@@H:35]([O:34][C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:24]=3)[CH2:36][C@H:37]2[CH2:40][O:41][C:42]2[CH:43]=[CH:44][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:50][CH:51]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 728.1 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (333 mg, 0.106 mmol), methyl 4-[(2S, 4S)4-(2-naphthyloxy)-2-pyrrolidinyl]methoxybenzoate (400 mg, 1.06 mmol), EDC.HCl (305 mg, 1.59 mmol) and DMAP (194 mg, 1.59 mmol) in DMF (10 ml) was stirred at room temperature for 3 days. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [100 g, n-hexane/EtOAc(1/1)CHCl3/MeOH(50/1)], to give methyl 4-[(2S, 4S)-1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxybenzoate (520 mg, 73%) as a pale brown amorphous. 1H-NMR (CDCl3) δ 2.28 (s, 3H), 2.29 (m, 1H), 2.55 (d, J=14.2 Hz, 1H), 3.60 (d, J=3.4 Hz, 2H), 3.66 (d, J=3.7 Hz, 3H), 3.68–4.00 (m, 5H), 4.05–4.67 (m, 3H), 5.09 (br, 1H), 6.61 (s, 1H), 6.77 (m, 2H), 6.87 (d, J=8.8 Hz, 1H), 6.94–7.54 (m, 8H), 7.68–8.09 (m, 8H); MS (ESI) m/z 674 (M++1).
Reaction SMILES: Br[C:2]1[C:3]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[N:19]=1.[CH3:25]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:25][C:2]1[C:3]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[N:19]=1
Reactant: CC(C)N(C)c1nc2c(nc1Br)CN(C(=O)OC(C)(C)C)CCO2
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1nc2c(nc1N(C)C(C)C)OCCN(C(=O)OC(C)(C)C)C2
Temperature: 90 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A mixture of tert-butyl 2-bromo-3-[methyl(1-methylethyl)amino]-6,7-dihydropyrazino[2,3-f][1,4]oxazepine-8(9H)-carboxylate (200 mg), methylboronic acid (119 mg), tetrakis(triphenylphosphine)palladium(0) (58 mg), tripotassium phosphate (423 mg) and DME (3 mL) was stirred under an argon atmosphere at 90° C. for 16 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient: 3→40% ethyl acetate/hexane) to give the title compound (109 mg, 65%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH:8](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:9].[CH3:23][N:24]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][C:27](=[O:34])[N:26]([C:35]2[CH:40]=[C:39]([NH2:41])[C:38]([Cl:42])=[CH:37][C:36]=2[F:43])[C:25]1=[O:44].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH:8]([NH:41][C:39]1[CH:40]=[C:35]([N:26]2[C:27](=[O:34])[CH:28]=[C:29]([C:30]([F:32])([F:33])[F:31])[N:24]([CH3:23])[C:25]2=[O:44])[C:36]([F:43])=[CH:37][C:38]=1[Cl:42])[CH3:9]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Reactant: COC(=O)CCNC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CCNC(=O)C(C)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 38.7 %

Procedure:
3-[2-(Toluene-4-sulfonyloxy)-propionylamino]propionic acid methyl ester (307 mg) was dissolved in acetonitrile (5 mL). After addition of 1-methyl-3-(5-amino-4-chloro-2-fluorophenyl)-6-trifluoromethyl-1H-pyrimidin-2,4-dione (300 mg) and potassium carbonate (135 mg), the reaction mixture was heated for 6 hours under reflux without cooling. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). Thus obtained organic layer was dried with magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography to give the target compound (170 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14](C(N[C@@H](C3C=CC=CC=3)C)=O)[C:13]([O:26][CH3:27])=[N:12][C:11]([CH2:28][CH3:29])=[C:10]2[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:5]=[CH:6][C:7]=1[F:8].N12CCCN=C1CCCCC2>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][C:13]([O:26][CH3:27])=[N:12][C:11]([CH2:28][CH3:29])=[C:10]2[C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)N[C@H](C)c2ccccc2)C(OC)=N1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Reaction time: 16 h
Yield: 79.8 %

Procedure:
Into a stirred solution of (+)-benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1-({[(1R)-1-phenylethyl]amino}carbonyl)-1,6-dihydro-5-pyrimidinecarboxylate (17.1 mmol, 9.35 g) in CH2Cl2 was added 1,8-diazabicyclo[5,4,0]-undec-7-ene (17.1 mmol, 2.56 mL) and stirring was continued for 16 h at room temperature. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 3:1 EtOAc/Hexanes as the eluting system. 5.27 g of the (+)-benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate was obtained (77% yield).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[C:7]([O:9]C)=[O:8].Cl.C1C=CC=CC=1>O>[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CON=C(C(=O)OC)c1cccc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CON=C(C(=O)O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
A 2 N aqueous solution of sodium hydroxide (40 ml.) was added with stirring at ambient temperature to a suspension of methyl 2-methoxyimino-2-(3-hydroxyphenyl)acetate (syn isomer) (7.55 g.) in water (70 ml.) and the mixture was stirred for 1 hour at ambient temperature. The reaction mixture was adjusted to pH 6.5 with 10% hydrochloric acid, subjected to salting-out and washed with ether (60 ml.). The aqueous layer was adjusted to pH 1 with conc. hydrochloric acid and extracted once with 100 ml. of and twice with 60 ml. of ether. The extract was washed twice with a saturated sodium chloride aqueous solution (60 ml.) and dried over magnesium sulfate. Ether was distilled off to give oil. Benzene was added thereto and removed (twice) to give crystals of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (6.44 g.), mp 98° to 101° C. (dec.).
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([NH:10][C@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22]C)=[O:21])[CH:18]=2)[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO.C1COCC1>[C:3]([O:7][C:8]([NH:10][C@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[CH:18]=2)[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2ccc(C(=O)O)cc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
LiOH (647 mg, 15.42 mmol, 3 eq), dissolved in water (8 ml), was added dropwise to an ice-cooled (0° C.) solution of (R)-methyl 3-(tert-butoxycarbonylamino)-2,3-dihydro-1H-indene-5-carboxylate (stage (ii) product of A-07) (1.5 g, 5.15 mmol, 1 eq) in MeOH:THF (1:1, 16 ml), and stirring was carried out for 6 h at RT. After monitoring by thin-layer chromatography, the reaction solution was concentrated and the residue was taken up in water (20 ml) and adjusted to pH 3 with NaHSO3. The acidic, aqueous phase was extracted with ethyl acetate (2×150 ml), washed with sat. NaCl solution (2×50 ml), dried over sodium sulfate and concentrated under reduced pressure. Yield: 70% (1.0 g, 3.61 mmol).
Reaction SMILES: [O:1]([C@H:13]1[C@@H:19]([OH:20])[C@@H:18]([CH2:21][OH:22])[O:17][C@H:15]([OH:16])[C@@H:14]1[NH:23][C:24]([CH3:26])=[O:25])[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1NC(C)=O.C1C=C2C(=C(S(NCCNC(N)=N)(=O)=O)C=1)C=CN=C2.C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP(O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=1.CC(N[C@H]1[C@@H](OP(OP(OC[C@H]2O[C@@H](N3C(=O)NC(=O)C=C3)[C@H](O)[C@@H]2O)(O)=O)(O)=O)O[C@H](CO)[C@@H](O)[C@@H]1O)=O.CCC(COC(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-].CCCC(NC1C2N=CN([C@@H]3O[C@@H]4COP(O)(O[C@H]4[C@H]3OC(CCC)=O)=O)C=2N=CN=1)=O.C1OP(O)(=O)O[C@H]2[C@@H](O)[C@H](N3C(Br)=NC4C(N)=NC=NC3=4)O[C@H]12.CCCCCCCCCCCCCC(O[C@H]1[C@@]2(OC(C)=O)C(C)(C)[C@H]2[C@@H]2C=C(CO)C[C@]3(O)C(=O)C(C)=C[C@H]3[C@@]2(O)[C@@H]1C)=O.OP([O-])(O)=O.[K+].C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP(O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=1.O=C[C@@H]([C@H]([C@H]([C@@H](CO)O)O)O)O>C(#N)C>[C:24]([NH:23][C@@H:14]1[C@@H:13]([OH:1])[C@H:19]([OH:20])[C@@H:18]([CH2:21][OH:22])[O:17][CH:15]1[OH:16])(=[O:25])[CH3:26]
Reactant: CC(=O)N[C@@H]1[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H](CO)O[C@@H]1O
Agent: CC(=O)N[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O
Agent: CC(=O)N[C@H]1[C@@H](OP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
Galβ1-3GalNAcα-pNp and GalNAcα-pNp, H-7, H-8 and H-1004 were purchased from Toronto Research Chemicals, Toronto, Canada, UDP-Gal, UDP-GlcNAc, bovine milk β1-4Gal-T (defined as 5-15 units/mg in the presence of lactalbumin), buffer salts and Triton X-100, cholera toxin, dibutyryl cAMP, 8-bromo-cAMP and phorbol 12-myristate 13-acetate (PMA) and TDA were obtained from Sigma. HPLC grade KH2PO4 and acetonitrile were obtained from Fisher Scientific. UDP-6- 3H!-galactose (18.9 Ci/mmol) and UDP-6- 3H!-N-acetylglucosamine (26.8 Ci/mmol) were provided by Amersham and NEN, respectively. C18 Sep-Pak were from Millipore-Waters. Actinomycin D and cycloheximide were purchased from Calbiochem. UDP-6- 3H!-galactose (18.9 Ci/mmole) was purchased from Amersham; dimethysulfoxide (DMSO) from BDH; all-trans-retinoic acid and sodium butyrate from Aldrich; α-modified Eagle's minimum essential medium (α-MEM) and fetal calf serum from Gibco.