Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C)C=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:21]=[C:22]([C:24](O)=[O:25])[N:23]=2)=[CH:15][CH:14]=1.[CH3:37][NH:38][O:39][CH3:40].Cl.N1C=CC=CC=1>C(#N)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=3)[CH:21]=[C:22]([C:24]([N:38]([O:39][CH3:40])[CH3:37])=[O:25])[N:23]=2)=[CH:15][CH:14]=1
Reactant: CNOC
Reactant: CS(=O)(=O)c1ccc(-n2cc(C(=O)O)nc2-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (0.34 g, 2.65 mmole) in 5 ml acetonitrile was added to 16 ml acetonitrile containing dimethylformamide (0.25 g, 3.46 mmole) cooled to 0° C. After 15 minutes, 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-carboxylic acid from step 1 (1.0 g, 2.65 mmole) was added with 20 ml acetonitrile. After warming to room temperature N,0-dimethylhydroxylamine HCl (0.28 g, 2.92 mmole) and pyridine (0.42 g, 5.31 mmole) were added and the mixture was stirred at room temperature for three days. The reaction mixture was concentrated to give an oily solid. The amide was purified by silica gel chromatography: Anal. Calc'd. C19H15N3O4SCl (419.89); C, 54.35; H. 4.32; N, 10 10.01. Found: C, 53.96; H, 4.30; N, 9.68.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]([C:7]1[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[C:9]([Cl:17])[CH:8]=1)[CH:5]=[O:6].CO.[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C.O>[Cl:17][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH:14]([F:15])[F:16])[CH:10]=1)[CH:4]([CH2:5][OH:6])[C:3]([OH:18])=[O:2]
Reactant: COC(=O)C(C=O)c1cc(Cl)cc(OC(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C(O)C(CO)c1cc(Cl)cc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
α-Formyl(3-chloro-5-difluoromethoxyphenyl)acetic acid methyl ester (400 mg, 1.4 mmol; see step (vii) above) was dissolved in THF:methanol (50 mL, 9:1). Sodium borohydride was added and the mixture was stirred at ambient temperature for 30 minutes. Water was added and the mixture was concentrated to produce an aqueous suspension, which was taken up in ethyl acetate and water. The phases were separated and the organic phase was washed with sodium chloride (15% in water), dried over sodium sulphate, filtered and concentrated at reduced pressure. The residue was dissolved in methanol (30 μL) and hydrolyzed with sodium hydroxide (1 mL, 10 M) at ambient temperature for 10 minutes. Extractive work up gave 180 mg, 0.68 mmol (yield: 48%) of the sub-title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1>C1COCC1.CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]2=[O:8])=[CH:16][CH:17]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COC(=O)c1cc(Br)c[nH]c1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cn(Cc2ccc(Cl)cc2)c1=O
Yield: 90 %

Procedure:
According to Scheme 1 Step 2: The title compound was prepared from methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (1 eq, 10.0 mmol, 3.00 g) and 1-(bromomethyl)-4-chlorobenzene (1.5 eq, 20.0 mmol, 4.00 g) according to the procedure described for Example 1 Step 2. Reaction conditions: 3 hours at 50° C. in THF/DMF (2:1, 300 mL). The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked 130 g column SiO2) using CH2Cl2/AcOEt 85/15 as the eluent and recrystallized from Et2O to afford the title compound (9.00 mmol, 4.17 g, 90%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:18]([O:13][CH2:12][C@H:11]1[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([F:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:8][C@@H:9]1[OH:10])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Temperature: 0 °C
Yield: 56.4 %

Procedure:
In 2.5 ml of pyridine were dissolved 0.25 g of 2'-deoxy-5-fluorouridine and 0.34 g of trityl chloride, and the solution was reacted at 60° C. for 4 hours under stirring. After completion of the reaction, the reaction mixture was poured into 80 ml of ice-cold water and precipitated crystals were collected by filtration. These crystals were dissolved in 30 ml of ethyl acetate, washed with saturated saline solution, dried over anhydrous magensium sulfate and condensed under reduced pressure. The residue obtained was applied to silica gel column chromatography to give 0.28 g (Yield: 56%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[ClH:14].[CH3:15]O>>[ClH:14].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: CO
Reactant: Nc1ccc(CCCC(=O)O)cc1
Agent: Cl
Product: COC(=O)CCCc1ccc(N)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
4-(4-Aminophenyl)butyric acid (5 g) was dissolved in 40 ml methanol. The solution was refluxed at 80-90° C. with stirring for 4 h while hydrogen chloride gas was bubbled through the solution. After the reaction mixture was cooled to room temperature, ethyl ether (100 ml.) was added. The mixture, which separated into two layers, was refrigerated overnight. The crystalline product was collected by filtration and dried thoroughly. The filtrate was evaporated to dryness and the residue was recrystallized from MeOH/benzene. The total amount of the product methyl 4-(4-aminophenyl)butyrate hydrogen chloride obtained was 5.6 g (87.5%), m.p. 143-145° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([Cl:13])=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>CN(C)C=O>[Cl:13][C:5]1[C:4]([Cl:3])=[CH:9][N:8]=[C:7]2[N:10]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[CH:11]=[CH:12][C:6]=12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1cnc2[nH]ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) suspension of sodium hydride (60% dispersion in mineral oil, 0.556 g, 13.9 mmol) in N,N-dimethylformamide (20 mL) was added a solution of the 5-chloro-4-chloro-1H-pyrrolo[2,3-b]pyridine (2 g, 10.69 mmol) in N,N-dimethylformamide (10 mL) slowly over 5 minutes. The reaction was allowed to stir at ambient temperature for 0.5 hours, and was again cooled to 0° C. A solution of para-toluenesulfonyl chloride (2.14 g, 11.23 mmol) in N,N-dimethylformamide (5 mL) was added, and the reaction was stirred at ambient temperature for 1.5 hours. The reaction was poured into 60 mL water cooled in an ice bath. The suspension was filtered. The solid was collected and purified by flash chromatography on a silica gel, eluting with a gradient of 30% to 100% dichloromethane in hexane, to provide the title compound. MS ESI(+) m/z 340.8 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CCOCC>CN(C=O)C.O>[CH2:32]([CH:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[C:3]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CC(C)(C)OC(=O)CC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 71 %

Procedure:
To a suspension of NaH (160 mg, 4.0 mmol) in DMF (8 mL) at 0° C. under N2, was added benzyl tert-butyl malonate (1.0 g, 4.0 mmol) in DMF (2 mL). The mixture was stirred for 50 min after which 1-bromoundecane in DMF (2 mL) was added. After an additional hour of stirring the reaction was allowed to warm to room temperature. The reaction was maintained overnight. Et2O (100 mL) and water (20 mL) were added to partition the reaction. The aqueous phase was extracted with Et2O (100 mL), and the combined organics dried over Na2SO4. The solvent was evaporated and the residue purified by flash column (C18 12 g, 40-100% ACN/water+0.1% TFA) to yield the title compound as a colorless oil (1.14 g, 2.82 mmol, 71%): LCMS Method F Rt=1.58 min, M+Na 427.4; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.84-0.96 (m, 3H) 1.28 (br. s, 12H) 1.31 (m, J=3.90 Hz, 6H) 1.41 (s, 9H) 1.88 (q, J=7.38 Hz, 2H) 3.29 (t, J=7.58 Hz, 1H) 5.19 (q, J=12.27 Hz, 2H) 7.30-7.42 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH2:29]>ClCCCl>[C:20]1([NH:11][C:12](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][CH:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:12]3)(=[O:10])=[O:9])=[CH:6][CH:7]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2N(S(=O)(=O)c2ccc(N)cc2)C1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(S(=O)(=O)c2ccc(NC(=O)Nc3ccccc3)cc2)C1

Procedure:
tert-butyl 1-(4-aminophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (60.5 mg, 0.15 mmol) and isocyantobenzene (17.8 mg, 0.15 mmol) in 1,2-dichloroethane (3 mL) were stirred at room temperature for 20 hours. Water (1.5 mL) was added and the mixture extracted with ethyl acetate (3×1.5 mL). The combined organics were dried over sodium sulfate and concentrated to give tert-butyl 1-(4-(3-phenylureido)phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:42][C:43]([F:60])([F:59])[C:44]1[CH:49]=[CH:48][C:47]([S:50]([N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)(=[O:52])=[O:51])=[CH:46][CH:45]=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:56]2[CH2:55][CH2:54][N:53]([S:50]([C:47]3[CH:46]=[CH:45][C:44]([C:43]([F:59])([F:60])[F:42])=[CH:49][CH:48]=3)(=[O:51])=[O:52])[CH2:58][CH2:57]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
To a suspension of 6-chloro nicotinic acid (1.76 g, 11.2 mmol) in DCM (50 ml) at 0° C. was added EDC.HCl (2.93 g, 15.3 mmol), HOBt (2.34 g, 15.3 mmol) and DIPEA (7.52 ml, 40.8 mmol) and the mixture stirred for 20 min. 1-{[4-(Trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 1) (3.00 g, 10.2 mmol) was added and the solution allowed to warm to room temperature, then stirred overnight. The mixture was diluted with DCM (20 ml), washed with water (5×20 ml), then the organic layers dried (Na2SO4) and concentrated under vacuum to leave the crude compound. Flash chromatography (silica; 60% EtOAc in pet. ether) gave the title compound as a white solid (2.20 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:13][C:14](OCC)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:29][OH:30].C[O-].[Na+]>CO>[OH:30][NH:29][C:14](=[O:15])[CH2:13][N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN(CC(=O)NO)S(=O)(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-[[4-methoxybenzenesulfonyl](4-methoxybenzyl)amino]acetate (0.90 g, 2.3 mmol) is dissolved in methanol (20 mL). To this solution is added hydroxylamine hydrochloride (0.80 g, 11.5 mmol), followed by the addition of sodium methoxide (5.2 mL of a 2.67M solution). The reaction is stirred overnight at room temperature. The reaction is worked up by partitioning between dilute hydrochloric acid (pH=~3) and ethyl acetate. The aqueous phase is extracted well with ethyl acetate, the combined organic layers are washed with brine, dried (Na2SO4), and the solvent is evaporated. The product is recrystallized from ether/ethyl acetate to give N-hydroxy-2-[[4-methoxybenzenesulfonyl]-(4-methoxybenzyl)amino]acetamide, m.p. 134°-135.5° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([O:14][C:15]3[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=3[F:25])(=[O:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH3:26])[CH:3]=1.[CH3:27][N:28]1[C:32]([C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=2B(O)O)=[CH:31][CH:30]=[N:29]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[CH3:26][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:11]([O:14][C:15]3[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=3[F:25])(=[O:13])=[O:12])[CH:6]=2)[C:2]([C:34]2[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:40])[F:41])=[CH:38][C:33]=2[C:32]2[N:28]([CH3:27])[N:29]=[CH:30][CH:31]=2)=[CH:3]1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1B(O)O
Reactant: Cn1cc(Br)c2ccc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cn(C)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Temperature: 90 °C
Yield: 364.9 %

Procedure:
The following reaction was conducted in two separate vials, and the reaction mixtures were combined before purification: A vial was charged with perfluorophenyl 3-bromo-1-methyl-1H-indole-6-sulfonate (52.1 mg, 0.114 mmol), (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (Intermediate G) (40.1 mg, 0.148 mmol), potassium phosphate (72.7 mg, 0.343 mmol), Pd(AmPhos)2Cl2 (4.04 mg, 5.71 μmol), 1,4-dioxane (428 μl), and water (143 μl). The vial was flushed with Ar, sealed, and heated in a microwave reactor to 90° C. for 30 min. A separate vial was charged with perfluorophenyl 3-bromo-1-methyl-1H-indole-6-sulfonate (180 mg, 0.395 mmol), (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (139 mg, 0.513 mmol), potassium phosphate (251 mg, 1.184 mmol), Pd(AmPhos)2Cl2 (13.97 mg, 0.020 mmol), 1,4-dioxane (1480 μl), and water (493 μl). The vial was flushed with Ar, sealed, and heated in a reactor to 90° C. for 30 min. The reaction mixtures from both vials were combined, and the combined mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (10 to 60% EtOAc/Heptane) to give perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonate (250.0 mg, 0.416 mmol, 82% yield) as a pink foam. 1H NMR (400 MHz, CDCl3) δ=8.09-8.01 (m, 1 H), 7.91-7.81 (m, 3 H), 7.76-7.67 (m, 2 H), 7.53 (d, J=2.0 Hz, 1 H), 6.79 (s, 1 H), 6.38 (d, J=1.9 Hz, 1 H), 3.81 (s, 3 H), 3.23 (s, 3 H). m/z (ESI) 602.0 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:3]=[C:4]([C:9]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:11][N:10]=3)[C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)nc1-c1noc(-c2ccccc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(-c3noc(-c4ccccc4)n3)n2)cc1
Temperature: 110 °C
Yield: 67 %

Procedure:
A mixture of 5-bromo-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyrazin-2-amine (100 mg, 0.3143 mmol), (4-methylsulfonylphenyl)boronic acid (94.29 mg, 0.4714 mmol) and PdCl2(PPh3)2 (11.03 mg, 0.01572 mmol) in DMF (2 mL) was treated with Na2CO3 (471.4 μL of 2 M, 0.9429 mmol) and the reaction placed under an atmosphere of nitrogen and heated at 110° C. in a sealed tube for 16 hours. The resultant precipitate was filtered, washed with water and dried under vacuum (83 mg, 67% Yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([OH:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4][C:3]1=2.[Br:19]Br>CC(O)=O>[Br:19][C:7]1[C:8]2[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:18])([CH3:1])[C:3]=2[CH:4]=[C:5]([C:15]([OH:17])=[O:16])[C:6]=1[OH:14]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)c(O)cc21
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2c1cc(C(=O)O)c(O)c2Br

Procedure:
3-Hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl acid (Compound L, 155 mg, 0.62 mmol) was dissolved in 1 ml of HOAc. To this solution was added Br2 (0.033 ml, 0.62 mmol). The reaction mixture was left at room temperature for over night. A stream of air was passed through the reaction mixture to remove the unreacted Br2. The remaining solid was dissolved in small amount of THF and purified by column chromatography (ethyl acetate/hexane 1/1) to yield the desired product as a cream colored solid.
Reaction SMILES: [N:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]=[O:10])=[N+:2]=[N-:3].S(=O)(=O)([OH:13])N.Cl([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[N:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([OH:13])=[O:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccsc1C=O
Reactant: NS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1ccsc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
3-Azidothiophene-2-carbaldehyde (1.22 g, 8.0 mmol) was dissolved in 30 mL of acetone:H2O (2:1) and treated with sulfamic acid (1.16 g, 12.0 mmol). Sodium chlorite (1.27 g, 17.1 mmol) was added and stirred at 0° C. for 30 min. The mixture was alkalinized to pH 9 with sodium carbonate, and the product was washed with diethyl ether (10 mL). The aqueous layer was carefully treated with aqueous concentrated HCl to pH 1. The product was extracted with diethyl ether (3×10 mL), dried over Na2SO4, and concentrated in vacuo to give 13a (1.01 g, 75% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:10]([OH:12])=O)=[CH:7][NH:8][CH:9]=1)=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CN(C=O)C.C(Cl)Cl.[OH-].[Na+]>[N:46]1([C:10]([C:6]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:9][NH:8][CH:7]=2)=[O:12])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1
Reactant: C1COCCN1
Reactant: COC(=O)c1c[nH]cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c[nH]cc1C(=O)N1CCOCC1
Reaction time: 0.25 h

Procedure:
To a solution of 4-(methoxycarbonyl)-1H-pyrrole-3-carboxylic acid (2.35 g) in DMF (49 ml) there are added diisopropylethylamine (2.11 ml) and HATU (4.9 ml). After stiffing for 15 minutes at 40° C., morpholine (1.35 ml) is added. After stiffing for 9 hours at 60° C. and at ambient temperature over a weekend, the mixture is diluted with CH2Cl2 and 1N sodium hydroxide solution. The aqueous phase is extracted 3 times with CH2Cl2 and the organic phases are combined. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness to yield the title product, which is used directly in the next Step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:21][C:22]1([CH3:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24](=O)[O:23]1>C1COCC1>[CH3:21][C:22]1([CH3:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2/[C:24](=[C:3]2\[C:2](=[O:10])[NH:1][C:9]3[C:4]\2=[CH:5][CH:6]=[CH:7][CH:8]=3)/[O:23]1
Reactant: CC1(C)OC(=O)c2ccccc21
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)O/C(=C2/C(=O)Nc3ccccc32)c2ccccc21
Temperature: 0 °C
Reaction time: 0.07 h
Yield: 41.5 %

Procedure:
To a solution of oxindole (127 mg, 0.956 mmol) in THF (2.0 ml) cooled at 0° C. was added 1.0M LiHMDS in THF (1.91 ml). The mixture was stirred for 4 minutes at 0° C., then allowed to warm to room temperature for an additional 6 minutes. The solid 3,3-dimethyl-2-benzofuran-1(3H)-one (140 mg, 0.86 mmol) was added in one portion and the reaction rapidly stirred for 1.5 hours. The reaction was quenched into 30 ml 10% HCl aqueous solution. The resulting mixture was stirred 5 minutes, and then extracted into EtOAc. The combined organic layers were washed with water, brine, dried with anhydrous Na2SO4, and rotary evaporated to a yellow oil. The yellow oil was chromatographed through silica gel column (20% to 30% EtOAc/hexane gradient) to give (3E)-3-(3,3-dimethyl-2-benzofuran-1(3H)-ylidene)-1,3-dihydro-2H-indol-2-one as a yellow solid (99 mg, 41%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6]1[C:7]2[S:24][C:23](=[O:25])[NH:22][C:8]=2[N:9]=[C:10]([S:12]([CH2:15][C:16]2C=C[CH:19]=[CH:18][CH:17]=2)(=O)=O)[N:11]=1)[CH3:4].C(S)C1[O:31]C=CC=1>>[O:31]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:15][S:12][C:10]1[N:11]=[C:6]([NH:5][C@H:3]([CH3:4])[CH2:2][OH:1])[C:7]2[S:24][C:23](=[O:25])[NH:22][C:8]=2[N:9]=1
Reactant: SCc1ccco1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2ccccc2)nc2[nH]c(=O)sc12
Product: C[C@H](CO)Nc1nc(SCc2ccco2)nc2[nH]c(=O)sc12

Procedure:
The titled compound was prepared from the product of example 24 step (a), using the method of example 23, step (b) using furfuryl mercaptan
Reaction SMILES: [C:1]([O:4][CH:5]([C:15]1[CH:19]([OH:20])[O:18][C:17](=[O:21])[CH:16]=1)[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([O:4][CH:5]([C:15]1[CH:19]([O:20][CH3:22])[O:18][C:17](=[O:21])[CH:16]=1)[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)OC(CCCc1ccccc1)C1=CC(=O)OC1O
Solvent: CO
Product: COC1OC(=O)C=C1C(CCCc1ccccc1)OC(C)=O
Reaction time: 0.2 h

Procedure:
A solution of 4-(1-acetoxy-4-phenylbutyl)-5-hydroxy-2(5H)-furanone (0.020 g., 0.069 mmol) and p-toluene sulfonic acid (approx. 3 mg.) in 2.5 ml methanol was stirred for 72 hours at room temperature. The reaction mixture was concentrated and partitioned between ethyl ether and water. The organic portion was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give an oil (0.027 g.) This material was purified by flash chromatography (30% ethyl acetate/hexane) to give a diasteriomeric mixture of the two methoxybutenolides. The mixture was subsequently separated by semi-preparative HPLC on a Whatman Partisil M-9 silica column, with an elution rate of 4 ml/min with 20% ethyl acetate/hexane. One diasteriomer (A) was eluted at 11 minutes, followed by the other (B) at 12 minutes. Concentration gave the purified compounds.