Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.C(O)(=O)C.[Cl:8][C:9]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[CH2:31][CH2:30]2)[C:26]([N+:43]([O-])=O)=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:16]=1)=[O:12]>[Fe]>[NH2:43][C:26]1[C:27]([N:29]2[CH2:30][CH2:31][N:32]([C:35]3[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[CH2:33][CH2:34]2)=[CH:28][C:9]([Cl:8])=[C:10]([CH:25]=1)[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:16]=1)=[O:12]
Reactant: Cc1ccc(C)c(N2CCN(c3cc(Cl)c(C(=O)NCc4cccc(CN(C)C)c4)cc3[N+](=O)[O-])CC2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C)c(N2CCN(c3cc(Cl)c(C(=O)NCc4cccc(CN(C)C)c4)cc3N)CC2)c1
Temperature: 75 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stir bar and a septum with a nitrogen inlet, the iron powder (557.40 mg, 9.98 mmol) was suspended in clean, dry, reagent-grade ethanol (50.00 ml, 856.34 mmol) and the mixture was stirred together vigorously under nitrogen at room temperature as the acetic acid (5.00 ml, 87.34 mmol) was added. The reaction continued to stir at room temperature as the 2-chloro-N-(3-dimethylaminomethyl-benzyl)-4-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-5-nitro-benzamide 13a (214.40 mg, 0.40 mmol) was added in one portion. The reaction mixture was then warmed to 75° C. and the reaction stirred for 4 h. After 4 h, the reaction was cooled to room temperature and filtered through Celite, washing with methanol. The solvent was then removed from the filtrate under reduced pressure. The ruby red oil was then taken back up in 100 ml of ethyl acetate; an equivalent amount of saturated aqueous NaHCO3 solution was added to the organic solution. The layers were then separated and the aqueous layer was extracted with ethyl acetate (2×75 ml). The organic phases were combined and dried over Na2SO4. The product solution was then decanted and the solvent was removed under reduced pressure. The crude product, 5-amino-2-chloro-N-(3-dimethylaminomethyl-benzyl)-4-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-benzamide 13b (142.50 mg, 0.28 mmol), was isolated as a brown solid and was carried on without further purification. LCMS (m/e)=507 (M+H).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[N:5]([C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)[N:4]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[F:25][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:15])=[O:34])=[CH:10][CH:9]=2)[N:5]([C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)[N:4]=1
Reactant: CSc1ccc(-c2cc(C(F)F)nn2-c2ccc3c(c2)OCO3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2cc(C(F)F)nn2-c2ccc3c(c2)OCO3)cc1
Temperature: 5 °C
Reaction time: 4 h
Yield: 30.1 %

Procedure:
A mixture of 3-(difluoromethyl)-1-[3,4-(methylenedioxy)phenyl]-5-[4-(methylthio)phenyl]pyrazole (2.7 g) and m-chloroperbenzoic acid (1.8 g) in dichloromethane (80 ml) was stirred at 5° C. for 4 hours. The mixture was washed with an aqueous solution of sodium bicarbonate, dried, and concentrated. The residue (2.9 g) was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (25:1). The purified product (1.3 g) was recrystallized from isopropanol to give 3-(difluoromethyl)-1-[3,4-(methylenedioxy)phenyl]-5-[4-(methylsulfinyl)phenyl]pyrazole (0.85 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](B(O)O)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:20]1[S:21][C:22]2[C:28]([N+:29]([O-:31])=[O:30])=[C:27]([O:32][CH3:33])[CH:26]=[CH:25][C:23]=2[N:24]=1>O.COCCOC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:20]3[S:21][C:22]4[C:28]([N+:29]([O-:31])=[O:30])=[C:27]([O:32][CH3:33])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: COc1ccc2nc(Br)sc2c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc2nc(-c3ccc4c(c3)OCO4)sc2c1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
0.697 g (4.2 mmol; 1.1 equivalent) of 1,3-benzodioxol-5-yl boronic acid as well as a solution of 1.2 g (11.35 mmol; 3 equivalents) of sodium carbonate in 15 ml of water are added to a suspension of 1.1 g (3.82 mmol) of 2-bromo-6-methoxy-7-nitro-1,3-benzothiazole and 133 mg (0.115 mmol; 0.03 equivalent) of palladium tetrakis-triphenylphosphine in 30 ml of 1,2-dimethoxyethane. The reaction mixture is maintained under stirring at 90° C. for 4 hours, then after concentration under reduced pressure, 100 ml of ethyl acetate is added to the medium which is then washed with twice 75 ml of a solution of water saturated with sodium chloride. The organic phase is dried over sodium sulphate then the solvents are evaporated off under reduced pressure and the residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane mixture 1:2). 0.960 g (yield of 76%) of 2-(1,3-benzodioxol-5-yl)-6-methoxy-7-nitro-1,3-benzothiazole is obtained in the form of beige powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]([NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[C:17]([N+:27]([O-])=O)=[CH:16][CH:15]=2)=[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:10]=1.[BH4-].[Na+]>CO.[Pd]>[NH2:27][C:17]1[C:18]([NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[N:19][C:14]([C:12]2[NH:13][C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])=[N:10][C:11]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:15][CH:16]=1
Reactant: CC(C)S(=O)(=O)Nc1nc(-c2[nH]c(-c3c(F)cccc3F)nc2-c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)S(=O)(=O)Nc1nc(-c2[nH]c(-c3c(F)cccc3F)nc2-c2ccccc2)ccc1N
Yield: 96.8 %

Procedure:
Add 10% Pd/C (0.033 g) to a stirring solution of propane-2-sulfonic acid {6-[2-(2,6-difluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-nitropyridin-2-yl}amide (0.33 g, 0.66 mmol) in MeOH (10 mL). Add sodium borohydride (0.124 g, 3.3 mmol) in portions and with stirring under nitrogen for 15 min. Filter the catalyst and concentrate. Dilute with EtOAc (20 mL) and extract successively with saturated NaHCO3 and saturated aqueous NaCl. Dry the organic layer over Na2SO4 and concentrate to give the title compound (0.3 g, 98%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([CH:22]=O)[N:6]=1)([CH3:4])[CH3:3].NCCC(O)=O.[S:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36]>>[CH3:3][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:19])([CH3:21])[CH3:20])[N:8]=[C:7]([CH:22]=[C:34]2[S:30][C:31](=[O:36])[NH:32][C:33]2=[O:35])[N:6]=1)([CH3:1])[CH3:4]
Reactant: O=C1CSC(=O)N1
Reactant: COCCOCOc1c(C(C)(C)C)nc(C=O)nc1C(C)(C)C
Agent: NCCC(=O)O
Product: CC(C)(C)c1nc(C=C2SC(=O)NC2=O)nc(C(C)(C)C)c1O
Yield: 23.9 %

Procedure:
4,6-Bis-(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-pyrimidine carboxaldehyde (0.5 g, 1.5 mmoles) is treated with β-alanine (0.27 g, 3.1 mmoles) and 2,4-thiazolidinedione (0.22 g, 1.8 mmoles) according to the procedure of Example 6 to give 0.12 g (25%) of 5-[[4,6-bis-(1,1-dimethylethyl]-5-hydroxy-2-pyrimidinyl]methylene]-2,4-thiazolidinedione. MP=229°-232° C. dec.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.O(C(C)(C)C)[Na]>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].C1(C)C=CC=CC=1>[CH3:18][C@@H:19]1[NH:20][CH2:21][CH2:22][N:23]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:24]1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc(Br)cc1
Reactant: C[C@H]1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: C[C@H]1CN(c2ccc(S(=O)(=O)Nc3ccncn3)cc2)CCN1
Yield: 37.5 %

Procedure:
Synthesized according to general procedure 8. The reaction was set up with 4-bromo-N-(pyrimidin-4-yl)benzenesulfonamide (2.4 mmol), (S)-2-methylpiperazine (4.7 mmol), Pd2(dba)3 (0.12 mmol), 2-(di-t-butylphosphino)biphenyl (0.50 mmol), NaO-tBu (10 mmol), and toluene (12 mL). For the purification, 10% MeOH in CH2Cl2 with the addition of 1% triethylamine was used as a solvent system to obtain the desired amine as a white solid (300 mg, 38% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=334.3; tR=0.39 min.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:7]=[N:8][C:9]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=O>Cl>[CH3:25][N:22]1[CH2:21][CH2:20][N:19]([C:9]2[N:8]=[CH:7][C:6]([NH2:5])=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:10]=2)[CH2:24][CH2:23]1
Reactant: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1NC(=O)C(C)(C)C
Agent: Cl
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1N
Temperature: 92.5 °C
Yield: 81.5 %

Procedure:
A suspension of 56 g (152 mmol) 2,2-dimethyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-propionamide in 1300 ml 3 N hydrochloric acid solution was heated to 90-95° C. overnight. The reaction mixture was cooled to room temperature, washed with three 500 ml portions diethyl ether and filtered over celite. The filtrate was diluted with 500 ml water and was adjusted to pH 7-8 by addition of 28% sodium hydroxide solution under ice cooling. The product was extracted with four 1000 ml portions of dichloromethane. The combined organic layers were washed with 500 ml brine, dried (magnesium sulfate) and evaporated to give 35 g (82%) of the title compound as a light brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:17]([C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH3:12])[CH:15]=1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: COc1cccc(C=O)c1
Solvent: O
Solvent: CCO
Product: COc1cccc(C2CC(=O)c3cc(Br)ccc3O2)c1
Yield: 35.7 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (18 g, 84.1 mmol), 3-methoxy-benzaldehyde (11.4 g, 84.1 mmol) and borax (32 g, 84.1 mmol) in ethanol (112 mL) and H2O (187 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ether. The ether was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(3-methoxyphenyl)chroman-4-one (10 g, 36%). 1H-NMR (CDCl3): 2.71 (d, 1H), 2.99 (t, 1H), 3.75 (s, 3H), 5.38 (d, 1H), 6.90 (m, 4H), 7.27 (t, 1H), 7.51 (d, 1H), 7.95 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].O.O1CCCC1.[C:15](Cl)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>[OH-].[Na+]>[C:15]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 10 °C

Procedure:
29 g of L-valine is dissolved in 250 ml of 1N aqueous NaOH, and to the solution is added water so that 400 ml of the solution is obtained. To the solution is added 150 ml of tetrahydrofuran. Then, while vigorously stirring at 10° C., to the solution are added 100 ml of Boc-Cl by 1/5 amounts at intervals of ten minutes, while 2N aqueous NaOH is added after every addition of Boc-Cl in such amount as will provide a pH value of about 8 to 9. Two hours later, the mixture is extracted with diethyl ether. The aqueous layer is acidified with an aqueous solution of 0.5 M aqueous citric acid, whereby an oily substance is precipitated. The precipitate is extracted with ethyl acetate. The extract is washed with a small amount of water, dried over Na2SP4, and concentrated under reduced pressure. To the concentrated extract is added petroleum ether, and the mixture is allowed to stand in a refrigerator, whereby a crystal is formed. The crystal is filtered off and dried. Thus, there is obtained 30 g of Boc-valine having a melting point of 78° C. The yield of the product is 55%.
Reaction SMILES: Cl[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[C:3]#[N:4].[CH2:14]([N:20]1[C:24](=[O:25])[CH:23]=[CH:22][C:21]1=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O>[CH2:14]([N:20]1[C:21](=[O:26])[CH:22]2[CH:23]([C:2]2([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:3]#[N:4])[C:24]1=[O:25])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: N#CC(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCN1C(=O)C=CC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN1C(=O)C2C(C1=O)C2(C#N)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
A solution of 2-chloro-2-(3-nitrophenyl)acetonitrile (Preparation 112, 103 mg, 0.524 mmol) and 1-hexyl-1H-pyrrole-2,5-dione (Preparation 56, 79 mg, 0.436 mmol) in N,N-dimethylformamide (2 ml) was added dropwise over 30 min to a stirred slurry of potassium carbonate (120 mg, 0.868 mmol) and sodium iodide (33 mg, 0.22 mmol) in N,N-dimethylformamide (4 ml) and water (0.1 ml) at 0° C. The reaction mixture was stirred for 30 min at 0° C. and then allowed to warm to room temperature. After stirring at room temperature for 2 h the mixture was diluted with water (10 ml) and extracted with ethyl acetate (3×5 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give a residue which was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (5:1 and then 3:1). This gave the title compound as brown needles (47 mg, 32%).
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:30]1[CH:31]=[C:32]([C:40]2[CH:41]=[C:42]([CH3:48])[C:43](=[O:47])[N:44]([CH3:46])[CH:45]=2)[CH:33]=[C:34]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:35]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:46][N:44]1[CH:45]=[C:40]([C:32]2[CH:31]=[C:30]([O:9][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[CH:35]=[C:34]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:33]=2)[CH:41]=[C:42]([CH3:48])[C:43]1=[O:47]
Reactant: Cc1cc(-c2cc(O)cc(S(C)(=O)=O)c2)cn(C)c1=O
Reactant: C[C@H](O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(O[C@H](C)c3ccccc3)cc(S(C)(=O)=O)c2)cn(C)c1=O
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of (1S)-1-phenylethan-1-ol (14 mg, 0.11 mmol) in THF (1 mL) stirred at rt under an atmosphere of nitrogen was treated with triphenylphosphine (38 mg, 0.15 mmol) and 5-(3-hydroxy-5-methylsulfonylphenyl)-1,3-dimethylpyridin-2-one (33 mg, 0.11 mmol). After 30 min, the reaction mixture was treated with DIAD (29 mg, 0.15 mmol). The nitrogen inlet was removed and the mixture was stirred (closed system) for 18 h. After the reaction mixture was diluted with EtOAc (10 ml), it was washed with water, saturated sodium bicarbonate solution (aq), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was diluted with ACN (1 mL) and was purified by prep-HPLC to afford the title compound (21 mg, 48%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (d. J=6.4, 3 H) 2.08 (s, 3H) 3.20 (s, 3H) 3.52 (s, 3H) 5.70-5.80 (q. J=6.4, 1 H) 7.23-7.31 (m, 2H) 7.35-7.41 (m, 2H) 7.44-7.51 (m, 3H) 7.56-7.63 (m, 1H) 7.73-7.80 (m, 1H) 8.08-8.15 (m, 1H). LCMS (M+H)+=398.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13]([OH:21])=[CH:14][C:15](=[O:20])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13]([OH:21])=[C:14]([C:30](=[O:31])[NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([Br:22])[CH:24]=3)[C:15](=[O:20])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(OCc2ccccc2)ccc2c(O)cc(=O)oc12
Reactant: O=C=Nc1cccc(Br)c1
Solvent: CCN(CC)CC
Product: Cc1c(OCc2ccccc2)ccc2c(O)c(C(=O)Nc3cccc(Br)c3)c(=O)oc12
Yield: 15.2 %

Procedure:
According to the procedure of example 2, 7-benzyloxy-4-hydroxy-8-methylcoumarin (0.813 g, 2.88 mmol) and 3-bromophenylisocyanate (0.39 ml, 3.12 mmol) were reacted in the presence of triethylamine (0.1 ml) to generate the title compound as an off-white solid, mp 229-231° C., (0.211 g, 0.44 mmol, yield 15.2%). Analysis: Calculated for C24H18NO5Br: C, 601.13; H, 3.76; N, 2.92. Found: C, 60.04; H, 3.51; N, 2.89. 1H NMR (CDCl3): 7.94 (br s, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.41 (m, 5H), 7.24 (m, 2H), 6.97 (d, J=9.0 Hz, 1H), 5.21 (s, 2H), 2.36 (s, 3H).
Reaction SMILES: Cl[CH:2]([N:7]=[C:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:3]([F:6])([F:5])[F:4].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[NH:7][C:2]([C:3]([F:6])([F:5])[F:4])=[CH:19][C:18]=2[C:17]([O:21][CH3:22])=[O:20])=[CH:10][CH:11]=1
Reactant: C=CC(=O)OC
Reactant: FC(F)(F)C(Cl)N=C(Cl)c1ccc(Cl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 26.1 %

Procedure:
A solution of N-[1-chloro-(2,2,2-trifluoroethyl)]-4-chlorobenzimidoyl chloride (3.40 g, 0.012 mol) and methyl acrylate (1.26 g, 0.015 mol) in N,N-dimethylformamide (10 mL) is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 5.0 g, 0.033 mol) over 1 hour. The reaction mixture is then held at 600° C. for 15 minutes, quenched with dilute HCl, and extracted with ethyl acetate. The organic extract is concentrated in vacuo to obtain a residue. Flash chromatography of the residue on silica gel, packed and eluted with 20% ethyl acetate in heptane, and crystallization from heptane gives the title product as a yellow solid (0.95 g, 26.0% yield) which is identified by 1H and 19F NMR spectral analyses.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.[H-].[Na+].O>O1CCOCC1>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:13][CH2:12]1
Reactant: N#Cc1ccccc1F
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCC(Oc2ccccc2C#N)CC1
Temperature: 50 °C
Yield: 30.5 %

Procedure:
To a mixture of 2-fluoro-benzonitrile (1.6 g, 13.2 mmol) and 1-methyl-piperidin-4-ol (1.52 g, 13.2 mmol) in dioxane (50 mL) was added NaH (60%) (634 mg, 15.8 mmol) in portion. The reaction was heated at 50° C. overnight. The mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographered using ethyl acetate/methanol (20:1-10:1) to give the title compound (870 mg, 31%). MS (DCI/NH3) m/z 217 (M+1)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.63 (m, 2H) 1.86 (m, 2H) 2.11 (s, 3H) 2.18 (m, 2H) 2.48 (m, 2H) 4.55 (m, 1H) 7.00 (td, J=7.67, 0.61 Hz, 1H) 7.23 (d, J=8.59 Hz, 1H) 7.56 (td, J=10.13, 7.36, 1.84 Hz, 1H) 7.63 (dd, J=7.67, 1.84 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35][OH:36])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46].O>CN(C)C=O>[F:1][C:2]1[C:3]([CH2:35][O:36][S:45]([CH3:44])(=[O:47])=[O:46])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:32])[CH3:31]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c3o2)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(COS(C)(=O)=O)c(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
3.30 g (6.55 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 118 (4) was dissolved in 70 mL of dimethylformamide, 4.6 mL of triethylamine and 1.0 mL of methanesulfonyl chloride were added under ice-cooling and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 3.57 g of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methanesulfonyloxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 94%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][CH:10]([C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[C:7]([CH2:26][CH2:27][CH3:28])[CH:6]=1)(=[O:4])=[O:3].[CH3:29][N:30]=[C:31]=[O:32].C(N(CC)CC)C.Cl>CN(C)C=O.CO.C(Cl)Cl>[CH3:29][NH:30][C:31]([NH:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][CH:10]([C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[C:7]([CH2:26][CH2:27][CH3:28])[CH:6]=1)(=[O:3])=[O:4])=[O:32]
Reactant: CN=C=O
Reactant: CCCc1cc(S(N)(=O)=O)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCc1cc(S(=O)(=O)NC(=O)NC)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a stirred solution of 500 mg (1.23 mmol) of methyl α-(4-aminosulfonyl-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetate (the product of Example 100, Step C) in dry dimethylformamide (2 mL) was added 80 μL (1.35 mmol) of methyl isocyanate followed by 6 mg (0.06 mmol) of cuprous chloride. The reaction mixture was stirred overnight, after which TLC analysis (5% methanol/methylene chloride) indicated the reaction had not proceeded to completion. Subsequently, an additional 80 μL (1.35 mmol) of methyl isocyanate, 6 mg (0.06 mmol) of cuprous chloride as well as 342 μL (2.46 mmol) of triethylamine was added and the reaction mixture was again stirred overnight. TLC analysis (5% methanol/methylene chloride) indicated the reaction had proceeded to completion. The reaction mixture was poured into 1N HCl and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo and dried to afford 570 mg (100%) of the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[Br:34][C:35]1[S:39][C:38]([C:40](Cl)=[O:41])=[CH:37][CH:36]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:40]([C:38]1[S:39][C:35]([Br:34])=[CH:36][CH:37]=1)=[O:41])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: O=C(Cl)c1ccc(Br)s1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(Br)s3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 23-(1) and 5-bromothiophene-2-carbonyl chloride were treated in a manner similar to Example 21-(1) to give 5-bromo-2-thienyl 4-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indol-3-yl ketone as a yellow powder. APCI-Mass m/Z 650/652 (M+H).