Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][C:12]3[N:13]([CH3:18])[C:14]([NH:16][CH3:17])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][S:23]([CH2:26][C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:24]>>[CH3:22][S:23]([CH2:26][C:27]1[CH:28]=[C:29]([NH:33][C:2]2[N:7]=[C:6]([N:8]([CH3:21])[C:9]3[CH:20]=[CH:19][C:12]4[N:13]([CH3:18])[C:14]([NH:16][CH3:17])=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:30]=[CH:31][CH:32]=1)(=[O:24])=[O:25]
Reactant: CNc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Reactant: CS(=O)(=O)Cc1cccc(N)c1
Product: CNc1nc2cc(N(C)c3ccnc(Nc4cccc(CS(C)(=O)=O)c4)n3)ccc2n1C

Procedure:
The title compound was prepared following the procedure of Example 1 with N5-(2-chloropyrimidin-4-yl)-N2,N5,1-trimethyl-1H-benzimidazole-2,5-diamine (48 mg, 0.16 mmol) and 3-methanesulfonylmethyl-phenylamine (30 mg, 0.16 mmol) as a white solid (75 mg, 83%). 1H NMR (300 MHz, d6-DMSO) δ 9.23 (s, 1H), 7.89 (s, 1H), 7.79 (d, J=6.0 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.19-7.27 (m, 3H), 7.13 (s, 1H), 6.87-6.93 (m, 2H), 5.66 (d, J=6.0 Hz, 1H), 4.33 (s, 2H), 3.54 (s, 3H), 3.43 (s, 3H), 2.93 (d, J=4.5 Hz, 3H), 2.89 (s, 3H). MS (ESI) m/z=452 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=2)=O)[CH2:3][CH2:2]1.[NH3:16]>>[CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=2)[NH2:16])[CH2:3][CH2:2]1
Reactant: N
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C1CC1
Product: NC(c1ccc(C(F)(F)F)cc1)C1CC1

Procedure:
The title compound was prepared using the product from Example 141B and the procedures described in Examples 136A and 136B. 1H NMR (300 MHz, d6-DMSO) 7.92 (m, 4H), 3.24 (d, 1H), 1.92 (broad s, 2H), 0.93 (m, 1H), 0.50-0.27 (m, 4H); MS (DCI/NH3) m/e. 216 (M+H)+.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:12])/[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][CH:5]=1.[C:13]1([C:19]2[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28](F)=O)[O:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:13]1([C:19]2[C:23]([C:24]([F:26])([F:27])[F:25])=[C:22]([C:28]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][CH:5]=4)[N:12]=3)[O:21][N:20]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=Cc1ccc(/C(N)=N/O)cc1
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 62 °C
Reaction time: 3 h
Yield: 61.8 %

Procedure:
To a mixture of (Z)—N′-hydroxy-4-vinylbenzimidamide (1.439 g, 8.87 mmol) and 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (2.300 g, 8.87 mmol) in acetonitrile was added DIEA (1.860 mL, 10.65 mmol). The reaction mixture was heated to 62° C. After 3 hours, the reaction mixture was cooled and a white solid precipitate formed. The solid was filtered and washed with ethyl acetate, then dried to give about 2.1 g of 5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-3-(4-vinylphenyl)-1,2,4-oxadiazole. MS (m+1)=384. HPLC Peak RT=1.24 minutes (Analytical Method B).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[S:15][C:14]3[C:13]([NH:16][NH2:17])=[N:12][CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:3]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1>C(O)C>[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[S:15][C:14]3[C:13]([NH:16][N:17]=[CH:24][C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)=[N:12][CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:3]1
Reactant: NNc1ncnc2cc(-c3ccsc3)sc12
Reactant: O=Cc1cccnc1
Agent: Cl
Solvent: CCO
Product: C(=NNc1ncnc2cc(-c3ccsc3)sc12)c1cccnc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A suspension of (6-(3-thienyl)thieno[3,2-d]pyrimidin-4-yl)hydrazine hydrochloride (222, 39 mg, 0.14 mmol) and 3-pyridinecarboxaldehyde (20 mg, 0.19 mmol) in ethanol (2 mL) was heated at reflux for 4 hours. After cooling to room temperature, the solid product was collected by vacuum filtration to yield 3-pyridinecarboxaldehyde(6-(3-thienyl)thieno[3,2-d]pyrimidin-4-yl)hydrazone (40 mg, 87% yield) as a yellow solid.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].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>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1cc(Br)oc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2cccc(F)c2)oc1C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 3-fluorophenylboronic acid (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.1 g, 92%) as a white solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[C:9]([CH3:12])[C:10]=1F)(=[O:4])=[O:3].[CH3:16][O-:17].[Na+]>>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[C:9]([CH3:12])[C:10]=1[O:17][CH3:16])(=[O:4])=[O:3]
Reactant: Cc1cc([N+](=O)[O-])cc(S(N)(=O)=O)c1F
Reactant: C[O-]
Agent: [Na+]
Product: COc1c(C)cc([N+](=O)[O-])cc1S(N)(=O)=O

Procedure:
The resulting 3-aminosulfonyl-4-fluoro-5-methylnitrobenzene (0.940 g, 4 mmol) was stirred with 25% methanolic NaOMe (1.00 mL) at 60° C. for overnight. The resulting solution was then filtered through a pad of Celite, washed with methanol and the methanolic solution was concentrated to give 3-aminosulfonyl-4-methoxy-5-methylnitrobenzene. LCMS: purity: 100%, MS (m/e): 247 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)#[N:27]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:26]#[N:27])=[CH:29][CH:30]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C#N)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.80 mmol) in methylene chloride (25 mL) was added dropwise 4-cyanobenzoyl chloride (92 mg, 0.56 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (61%) of the title compound as white crystals: mp 184-186° C.; [α]21D -47° (c 1.0, CHCL3); EIMS (70 eV) m/z (relative intensity) 374 (54, M+).
Reaction SMILES: ClC1C=CC=CC=1[C:8]1[S:9][C:10](C2C=CC(SC)=CC=2)=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:12]=1.C(O)C.OOS([O-])=O.[K+]>O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[CH:8][S:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: CSc1ccc(-c2sc(-c3ccccc3Cl)nc2-c2ccc(C)cc2)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2cscn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 225.9 %

Procedure:
A 100 mL one-neck round-bottom flask, equipped with provisions for magnetic stirring, was charged with 2-(2-chlorophenyl)-4-(4-methylphenyl)-5-(4-methylthiophenyl)thiazole from Step 4 (0.243 g, 0.596 mmol) and aqueous ethanol (25 mL). Oxone®(1.10 g, 1.787 mmol) was added, and the suspension was stirred at room temperature for 16 hours. Water (25 mL) was added, and the product precipitated. The suspension was cooled to 0° C. and held for one hour. The product was filtered, washed with water (25 mL), and dried to yield 2-(2-chlorophenyl)-5-methylsulfonylphenyl)-4-(4-methylphenyl)thiazole (0.236 g, 90%) as a white solid: mp 185°-187 ° C. 1H NMR (CDCl3) 300 MHz 8.40(m, 1H), 7.89(d, J=8.26 Hz, 2H), 7.61 (d, J=8.46 Hz, 2H), 7.54-7.37 (m, 5H), 7.16 (d, J=7.85 Hz, 2H), 3.09(s, 3H), 2.38(s, 3H). Mass spectrum: MH+ =439.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[S:16](=[O:28])(=[O:27])[NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:10].CI>>[CH3:7][O:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[S:16](=[O:27])(=[O:28])[N:17]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH3:1])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sccc1S(=O)(=O)NCCc1ccc(F)cc1
Agent: [K+]
Solvent: CI
Product: COC(=O)c1sccc1S(=O)(=O)N(C)CCc1ccc(F)cc1

Procedure:
In the presence of potassium carbonate (2.58 g), 3-[2-(4-fluorophenyl)-ethylsulfamoyl]-thiophene-2-carboxylic acid methylester (3.2 g) was reacted with methyl iodide (0.69 mL), and an oily substance (3.38 g) was obtained, in the same way as Preparation Example 52.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7](OC(=O)C)(=[O:9])[CH3:8]>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[NH:4]1[CH:5]=[CH:6][C:2]([NH:1][C:7](=[O:9])[CH3:8])=[N:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc[nH]n1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc[nH]n1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a 2 L glass flask was charged with 200 g (2.36 mol) of 3-aminopyrazole and 900 g of ethyl acetate. The mixture was agitated at 45° C. for 30 min to form a homogeneous solution. To the mixture was added 245 g (2.36 mol) of acetic anhydride over 1.2 h. The mixture was stirred at 60° C. for 3 h. HPLC analysis of reaction mixture indicated the presence of 3-aminopyrazole. Another 9.7 g (0.09 mol) of acetic anhydride was added into the mixture over 15 min at ca. 60° C. The resulting suspension was agitated for another 2 h at ca. 60° C. The mixture was cooled to 20-25° C. and stirred at that temperature for 15 h. The solids were collected by filtration and washed with 630 g of ethyl acetate. The solids were dried in a vacuum oven (45-50° C./P≦−0.1 MPa) for ca. 24 h to afford 295.2 g (94% yield) of N-(1H-pyrazol-3-yl)-acetamide as off-white solid. 1H-NMR (400 MHz, d6-DMSO): δ 12.26 (s, 1H), 10.33 (s, 1H), 7.57 (s, 1H), 6.47 (s, 1H), 1.99 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[C:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])[CH3:34]>>[C:33]([N:36]1[CH2:41][CH2:40][N:39]([C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:6]3[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]4[S:12][CH:13]=[C:14]([C:16]5[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=5)[N:15]=4)=[CH:8][CH:7]=3)=[CH:29][CH:28]=2)=[O:32])[CH2:38][CH2:37]1)(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCNCC1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: CC(=O)N1CCN(C(=O)c2ccc(-c3ccc(-c4nc(-c5ccc(Cl)c(Cl)c5)cs4)cc3C(=O)O)cc2)CC1
Yield: 66.4 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 1-acetylpiperazine (available from Aldrich Chemical Company, Inc.; 79 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4′-(4-acetyl-piperazine-1-carbonyl)-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (81 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.24 (br s, 1H), 8.48 (s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (dd, J=8.3, 2.0 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.45-7.53 (m, 4H), 3.46-3.59 (br s, 6H), 3.32-3.36 (s, 6H), 2.03 (s, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[O:9])[CH2:3]1.[Br:22][C:23]1[CH:24]=[C:25]([C:29](O)=[O:30])[O:26][C:27]=1[Br:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:23]1[CH:24]=[C:25]([C:29]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([C:10]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)[N:11]=3)=[O:9])[CH2:3][C@@H:2]2[CH3:1])=[O:30])[O:26][C:27]=1[Br:28]
Reactant: Cc1cccc(-n2cnc(C(=O)N3CCN[C@@H](C)C3)n2)c1
Reactant: O=C(O)c1cc(Br)c(Br)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-n2cnc(C(=O)N3CCN(C(=O)c4cc(Br)c(Br)o4)[C@@H](C)C3)n2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 86 mg (0.30 mmol) ((S)-3-methyl-piperazin-1-yl)-(1-m-tolyl-1H-[1,2,4]triazol-3-yl)-methanone, 84 mg (0.30 mmol) 4,5-dibromo-2-furoic acid, 0.11 g (0.33 mmol) TBTU and 80 μL (0.45 mmol) DIPEA in 5.0 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC.
Reaction SMILES: C[C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.[CH3:11][O:12][CH2:13]C(Cl)=O>>[CH3:11][O:12][CH2:13][C:4](=[O:9])[CH2:5][C:6]([O:7][CH2:2][CH3:10])=[O:8]
Reactant: COCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: CCOC(=O)CC(=O)COC

Procedure:
The title compound was prepared in a manner analogous to Intermediate 123 starting from 2,2-dimethyl-1,3-dioxane-4,6-dione and methoxyacetyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:30][CH:31]=O)[CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:30][CH2:31][N:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:13](=[O:18])[CH2:14]2)[CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28]
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(CC=O)ccc1[N+](=O)[O-]
Product: COc1cc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)C(=O)C2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 1-[2-(4-Nitrophenyl)ethyl]piperazin-2-one and (3-Methoxy-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 429 [M+1]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].[C:21]12([CH2:31][CH2:32]I)[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.C(N(CC)CC)C>ClCCl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[S:7][CH2:32][CH2:31][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2)(=[O:3])[CH3:2]
Reactant: ICCC12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](S)[C@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](SCCC23CC4CC(CC(C4)C2)C3)[C@H]1OC(C)=O
Reaction time: 72 h
Yield: 54.9 %

Procedure:
A solution of 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranose (2.14 g, 7 mmol) and 2-(1-adamantyl)ethyl iodide (2.03 g, 7 mmol) in dichloromethane (40 ml) containing triethylamine (0.71 g) is kept under nitrogen for 3 days. The reaction mixture is washed successively with N hydrochloric acid, aqueous sodium bicarbonate and water. The dried solution is concentrated to a residue which is taken up in ethanol to remove crystals (0.3 g, 2-(1-adamantyl)ethyl iodide). The mother liquor is put on a silica gel column and eluted with 1% methanol in chloroform. The desired fractions are pooled and evaporated to give 2-(1-adamantyl)ethyl 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranoside (1.8 g, 66%), [α]D +18° (c, 1.5, chloroform). Deblocking of this material with sodium methoxide in methanol affords the title compound, m.p. 130°-131°, [α]D +31° (c, 1.07, chloroform).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=2)[OH:9])[CH:5]=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][CH2:21][CH2:20]2.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.[Cu]I>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[N:22]([C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=3)=[O:9])[CH:3]=1)[CH2:21][CH2:20]2
Reactant: O=C1NCCc2cc(Cl)ccc21
Reactant: Cn1ccnc1C(O)c1cncc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1ccnc1C(=O)c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 150 °C
Yield: 2.5 %

Procedure:
(5-Bromo-pyridin-3-yl)-(1-methyl-1H-imidazol-2-yl)-methanol (150 mg, 0.56 mmol), 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (90 mg, 0.49 mmol) (intermediate A-2), CuI (30 mg, 0.16 mmol), Cs2CO3 (330 mg, 1.0 mmol) and (+)-(1S,1S)-1,2-diaminocyclohexane (0.08 mL, 0.64 mmol) were dissolved in dioxane (4.0 mL). The resulting mixture was heated at 150° C. for 2 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×75 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give the title compound (4.5 mg, 2.5%) as light yellow oil. MS: 367.1 (M+H+).
Reaction SMILES: [F:1][C:2](=[CH:8][CH2:9][C:10]([F:23])=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH:6]=[O:7].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[F:1][C:2](=[CH:8][CH2:9][C:10]([F:23])=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][C:6]([OH:26])=[O:7]
Reactant: CCCCCC=CCCCCC=C(F)CC=C(F)CCCC=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCCCCC=CCCCCC=C(F)CC=C(F)CCCC(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a solution of the aldehyde prepared in 1I (0.2 g, 0.61 mmoles) in acetone (7 ml) cooled to 0° C. was added dropwise 2.67M Jones reagent until the orange color was stable. The mixture was stirred 15 min. at 0° C. The excess of Jones reagent was reacted with isopropanol. The acetone was evaporated under reduced pressure without heating. The residue was taken with water and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to leave an oil. Flash chromatography on silica gel and elution with a 25:75 mixture of ethyl acetate and hexane afforded the expected acid as an oil (0.125 g, 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])[O:8][CH:14]=1
Reactant: Cc1ccsc1C(N)=O
Reactant: O=C(CCl)CCl
Product: Cc1ccsc1-c1nc(CCl)co1
Yield: 61 %

Procedure:
In substantially the same manner as in Reference Example 47, 3-methyl-2-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(3-methyl-2-thienyl)oxazole. The yield was 61%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 95-96° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[O-:10][C:11]#[N:12].[Na+]>C(O)(=O)C.O>[CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]([NH2:12])=[O:10])=[CH:5][CH:4]=1
Reactant: CSc1ccc(N)cc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(NC(N)=O)cc1
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
A solution of 30 g (170 mmol) of 4-(methylmercapto)aniline dissolved in 83 ml of acetic acid and 165 ml of water was heated to 40° C. Once warmed to 40° C. a solution of sodium cyanate (22.2 g; 340 mmol) in 150 ml of water was slowly added. The resulting suspension was stirred for 15 minutes and then allowed to sit for 2 hours. Filtration of the suspension provided 29.98 g of title compound. m.p. 155°-159° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:13][CH:15]1[CH2:16][O:17]1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: ClCC1CO1
Product: FC(F)(F)Oc1cccc(OCC2CO2)c1

Procedure:
The title compound was prepared from 3-trifluoromethoxy-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH2:7][C@H:8]([NH:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:37])[CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O-:36])=[O:35])[CH2:30][CH2:29]2)[CH2:20]1)=[O:18])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([OH:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:45]1([CH3:68])[CH:50]=[CH:49][C:48]([S:51]([O:54][CH2:55][CH2:56]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:53])=[O:52])=[CH:47][CH:46]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:38])[CH2:7][C@H:8]([NH:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:37])[CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:35])[CH2:32][CH2:33]2)[CH2:20]1)=[O:18])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([O:15][CH2:56][CH2:55][O:54][S:51]([C:48]2[CH:49]=[CH:50][C:45]([CH3:68])=[CH:46][CH:47]=2)(=[O:53])=[O:52])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)[O-])CC2)C1)c1cncc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCOc2cncc([C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H]3CCCN(C(=O)CCC4CCN(C(=O)OC(C)(C)C)CC4)C3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 154.7 %

Procedure:
4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-hydroxypyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (200 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (39 mL). Cesium carbonate (277 mg, 0.85 mmol) and ethylene glycol bis-p-toluenesulfonate (188 mg, 0.51 mmol) were added. The mixture was stirred at room temperature for 4 hours, the addition of cesium carbonate (277 mg, 0.85 mmol) and ethylene glycol bis-p-toluenesulfonate (188 mg, 0.51 mmol) was repeated and stirring at 5° C. was continued for 17 hours. The mixture was quenched by addition of saturated aqueous ammonium chloride solution and extracted with diethyl ether and ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane 20% to 100% followed by dioxane in ethyl acetate 0 to 60%) to yield 207 mg of tert-butyl 4-{3-[(3R)-3-({(1S)-3-tert-butoxy-1-[5-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)pyridin-3-yl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylat.