Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)[C:5]([OH:7])=O)=[N+]=[N-].[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:8]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=2)[C@@H:4]([C:5]([NH:23][C:24]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=2[CH2:26][CH2:27][C@H:28]2[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:40])([F:42])[F:41])[NH:30][CH2:29]2)=[O:7])[NH:1][C:36]([O:35][CH3:34])=[O:43])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)cc1)c1cncc(F)c1
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)cc1)c1cncc(F)c1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 2 and 3 of Example 93 and steps 1 and 2 of Example 91. MS (ES) m/z=714 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH:27](=[C:7]1[C:8](=[O:10])[O:9][C:4]([C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[Cl:1])=[N:6]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)CNC(=O)c1ccccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2ccccc2Cl)=NC1=Cc1ccccc1
Temperature: 60 °C
Yield: 90 %

Procedure:
To the stirred mixture of (2-chloro-benzoylamino)-acetic acid 21 (23.41 mmol), anhydrous sodium acetate (70.23 mmol), acetic anhydride (7 ml), and benzaldehyde (25.75 mmol) were added dropwise at 30° C. This mixture was then heated to 60° C. for 1 hr. The reaction mixture was poured into an ice-water solution and the resulting solids were filtered, washed with ethanol and dried on vacuum. The desired compound was obtained with a 90% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[C:18]1(C)C=CC=C[CH:19]=1>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>[CH:18]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)=[CH2:19]
Reactant: Cc1ccccc1
Reactant: O=C1CCc2cc(Br)ccc21
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: [K+]
Product: C=Cc1ccc2c(c1)CCC2=O
Temperature: 25 °C
Yield: 48 %

Procedure:
To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.7 mmol) in toluene were added vinylboronic anhydride pyridine complex (8.55 g, 35.54 mmol), Pd(PPh3)4 (0.1 g, 0.094 mmol), K2CO3 (22.88 g, 165.83 mmol). The resultant reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with H2O and brine. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (SiO2, 5% EtOAc in petroleum ether) afforded the title compound as a solid (1.8 g, 48%): 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=7.2 Hz, 1H), 7.49 (br s, 1H), 7.44 (d, J=7.2 Hz, 1H), 6.82 (m, 1H), 5.90 (d, J=7.4 Hz, 1H), 5.42 (d, J=6.4 Hz, 1H), 3.20 (m, 2H), 2.70 (m, 2H); ESIMS m/z 159.06 ([M+H]−).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3C=CC=CC=3)=[CH:11][CH:10]=[CH:9][C:8]=2O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([OH:26])C=CC=CC=1>>[CH:6]1[C:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][O:26][C:2]=2[CH:3]=[CH:4][CH:5]=1
Reactant: Oc1cccc(-c2ccccc2)c1-c1ccccc1
Reactant: Oc1ccccc1
Product: c1ccc2c(c1)COc1ccccc1-2

Procedure:
2,3-diphenylphenol is a typical example of a phenol which will form a dibenzopyran but cannot isomerize to the fluorenol because the meta position involved in the isomerization reaction is already substituted with a phenyl group. A solution of 1.0 g. of 2,3-diphenylphenol, 1.0 g. of acetone, 25 ml of trifluoroacetic acid and 1.5 ml of trifluoroacetic anhydride were heated at reflux in dry air for 3.25 hours by which time a sample which was worked up with hexane in water to remove the acidic materials was shown by vpc to be free of the starting phenol. Approximately 98 percent of the material was insoluble in Claisen's alkali and 2 percent of the material was soluble in Claisen's alkali. Apparently the latter was the trifluoroacetic of 2,3-diphenylphenol. Heating of the reaction mixture at reflux was continued for 18 hours, but caused no detectable change in the reaction mixture. Extraction with hexane and washing with water of the reaction mixture and evaporation of the solvent isolated 0.99 g. of 1-phenyl-6,6-dimethyl- 6H-dibenzo[b,d]pyran, corresponding to formula A where X is oxygen, R1 and R2 are each methyl, R3 is phenyl and R4, R5 and R6 are each hydrogen, as a viscous liquid which on standing in hexane for several days was isolated as a white crystalline compound. Its structure was confirmed by nmr spectroscopy. A sample of this material dissolved in anhydrous trifluoroacetic acid and refluxed for 23 hours did not produce any rearranged product. The phenyl substituent in the meta position of the initial phenyl had effectively prevented any rearrangement of the dibenzopyran to the fluorenol.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=O)C1C=CC=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1)[NH2:29].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[Cl:25][C:26]1[CH:27]=[C:28]([NH:29][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: OCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 63.1 %

Procedure:
A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (1.037 g), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (863 mg) and 1-methyl-2-pyrrolidone (10 mL) was stirred at 120° C. for 1.5 hrs. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=50:50→100:0). The object fraction was concentrated under reduced pressure. To a solution of the residue (1.420 g) in methanol (30 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→5:95). The object fraction was concentrated under reduced pressure. The precipitated crystals were collected by filtration, and washed with diethyl ether. The crude crystals were recrystallized from ethyl acetate-diisopropyl ether to give the title compound (933 mg) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[C:14](Cl)(=[O:18])[C:15]([Cl:17])=[O:16]>C(OCC)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14](=[O:18])[C:15]([Cl:17])=[O:16])=[CH:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ccc2ccc([N+](=O)[O-])cc21
Solvent: CCOCC
Product: Cn1cc(C(=O)C(=O)Cl)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A stirred solution of 1-methyl-6-nitro-1H-indole in diethyl ether (Et2O) (5 mL) was cooled to 0° C., and treated with oxalyl chloride (0.15 mL, 1.7 mm). After stirring at room temperature overnight, solids were collected, washed with ether and dried to afford (255 mg, 96%) (1-methyl-6-nitro-1H-indol-3-yl)-oxo-acetyl chloride.
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[C:10]([OH:26])=[C:11]([C:23](=[O:25])[CH3:24])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1>[C:23]([C:11]1[C:10]([OH:26])=[C:9]([NH:8][C:3](=[O:4])[C:2]([Br:1])([CH3:7])[CH3:6])[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=1)(=[O:25])[CH3:24]
Reactant: CC(C)(Br)C(=O)Cl
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(N)c1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)c1cc(OCc2ccccc2)cc(NC(=O)C(C)(C)Br)c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4.64 g (25 mmol) 2-bromo-2-methyl-propionyl chloride are added dropwise at 5 to 20° C. to a solution of 5.15 g (20 mmol) 1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone in 20 mL pyridine. After the addition has ended the mixture is stirred for 15 minutes, combined with ice water and 100 mL ethyl acetate and acidified with conc. hydrochloric acid. The organic phase is separated off, washed with water and dried with sodium sulphate. After the solvent has been distilled off the residue is crystallised from a diethyl ether/petroleum ether mixture.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32]([C:34]2[CH:35]=[CH:36][C:37]3C=CS[C:38]=3[CH:42]=2)=[O:33])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:43][O:44]C1C=C(C=CC=1)C(O)=O>>[CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32](=[O:33])[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([O:44][CH3:43])[CH:42]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Reactant: COc1cccc(C(=O)O)c1
Product: COc1cccc(C(=O)/N=c2\[nH]c3cnc(OCCN4CCCCC4)cc3n2[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c1

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 3-methoxybenzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-N(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-methoxy-benzamide (42.5% yield). MS m/z=563.4 [M+H], calc 562.71 for C31H42N6O4.
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:9]1([C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][O:11]1)=[O:10].O>C(O)C>[C:1]([NH:5][NH:6][C:9](=[O:10])[C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:12][OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NN
Reactant: O=C1OCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NNC(=O)c1ccccc1CO
Yield: 13.5 %

Procedure:
t-Butylhydrazine (0.1 mol) in 75 ml ethanol was treated with 50% aqueous sodium hydroxide (0.11 mol). Phthalide (0.1 mol) was added and the mixture was refluxed for 5 days. After cooling, water was added and the crude product was isolated by filtration. Filtration through silica gel afforded N'-t-butyl-N-(2-hydroxymethylbenzoyl)hydrazine (3.0 g). m.p. 116-118° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[C:10]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]([CH3:16])=[CH:12][C:13]=2[CH3:15])[NH:8][CH2:7]1)([OH:3])=[O:2].[CH3:24]COC(C)=O>CCOCC>[CH3:24][O:2][C:1]([CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[C:10]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[C:11]([CH3:16])=[CH:12][C:13]=2[CH3:15])[NH:8][CH2:7]1)=[O:3]
Reactant: CCOC(C)=O
Reactant: Cc1cc(C)c2c(c1NC(=O)C(C)(C)C)NCC2CCC(=O)O
Solvent: CCOCC
Product: COC(=O)CCC1CNc2c(NC(=O)C(C)(C)C)c(C)cc(C)c21

Procedure:
N-[3-(2-Carboxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (1.5 g) was dissolved in AcOEt (10 ml) and a solution of CH2N2 in ether was added. AcOEt (100 ml) was added, and after washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=50/1-10/1) to give 1.0 g of N-[3-(2-methoxycarbonylethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:20]([CH2:21][C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[CH2:21][N:20]1[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccco2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1nc2ccccc2n1Cc1ccco1)C1CCNCC1
Reaction time: 0.25 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (1.16 mmol), furfuryl alcohol (0.10 mL, 1.16 mmol), and triphenylphosphine (0.33 g, 1.28 mmol) in tetrahydrofuran (5 mL). Add diethyl azodicarboxylate (0.20 mL, 1.28 mmol). After 18 hours, evaporate the reaction mixture in vacuo to give a residue. Partition the residue between ethyl acetate and water. Separate the organic layer and extract with water and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate invacuo to give the title compound. Chromatograph the residue on silica gel eluting with 5% acetone/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine. Cool 1-(t-butoxycarbonyl)-4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine (1.0 mmol), and dichloromethane (5 mL). Slowly add a cold solution of trifluoroacetic acid (1 mmol) in dichloromethane (2 mL). After 15 minutes, partition the reaction mixture between dichloromethane and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate invacuo to give the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[Br:8][C:9]1[CH:14]=[C:13]([Br:15])[N:12]=[C:11]([Cl:16])[C:10]=1[OH:17].Cl[C:19]([F:29])([F:28])C(C1C=CC=CC=1)=O>CC#N>[Br:8][C:9]1[CH:14]=[C:13]([Br:15])[N:12]=[C:11]([Cl:16])[C:10]=1[O:17][CH:19]([F:29])[F:28]
Reactant: Oc1c(Br)cc(Br)nc1Cl
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: FC(F)Oc1c(Br)cc(Br)nc1Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Potassium carbonate (K2CO3; 5.01 g, 36.3 mmol) and H2O (4 mL) were added to a microwave reaction vessel. 4,6-Dibromo-2-chloropyridin-3-ol (0.359 g, 1.25 mmol) was dissolved in CH3CN (4 mL) and added to the microwave reaction vessel. 2-Chloro-2,2-difluoro-1-phenylethanone (0.953 g, 5.00 mmol) was then added, and the microwave reaction vessel was sealed. The reaction mixture was heated with vigorous stirring with a large stir bar in a Biotage microwave reactor at 100° C. for 4 h. (The reaction mixture is biphasic, and the reaction will not proceed to completion without vigorous stirring.) The reaction mixture was then partitioned between EtOAc and H2O. The organic phase was washed once more with H2O, dried and concentrated. The product was redissolved in CH2Cl2 and filtered through short plug of silica gel utilizing CH2Cl2 as the eluting solvent. The eluent was concentrated to provide the title compound as a light yellow low-melting solid (0.325 g, 0.963 mmol, 77%): 1H NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 6.63 (t, J=73.1, 1H); EIMS m/z 337.
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C@@H:17]([C:29]([OH:31])=[O:30])[C:18]([S:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)([CH3:20])[CH3:19])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[O:34]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35]1>C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].CCO.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:34]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([S:13]([NH:16][C@@H:17]([C:29]([OH:31])=[O:30])[C:18]([S:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)([CH3:20])[CH3:19])(=[O:14])=[O:15])=[CH:11][CH:12]=3)=[CH:32][CH:33]=2)=[CH:35]1
Reactant: OB(O)c1ccoc1
Reactant: CC(C)(SCc1ccccn1)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1)C(=O)O
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: c1ccccc1
Solvent: CCO
Product: CC(C)(SCc1ccccn1)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1)C(=O)O
Temperature: 80 °C
Reaction time: 72 h
Yield: 77.1 %

Procedure:
To a suspension of 221 mg (0.40 mmol) of N-[4-(4-bromophenoxy) benzenesulfonyl]--S--[(pyrid-2-yl)methyl]-D-penicillamine (from example 3(d)) in 2 mL of benzene and 2 mL of 2M aqueous Na2CO3 solution was added a solution of 71 mg (0.48 mmol) of 3-furan boronic acid (J. Org. Chem. 1984, 49, 5237-5243) in 2 mL of EtOH. To the resulting mixture was added solid Pd(PPh3)4 (46 mg, 0.04 mmol) under a flow of Ar. The mixture was heated at 80° C. with vigorous stirring for 72 hours, cooled to room temperature, and partitioned between ehtyl acetate and AcOH/H2O buffer (pH 3). The aqueous layer was adjusted to pH of 3 by adding AcOH, then extracted with EtOAc (2×70 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residual yellow solid was chromatographed on silica gel, eluting first with CH2Cl2, then with 10% methanol in dichloromethane to elute the product fractions. After concentration of the product-containing fractions, the residue was triturated with hexane/t-butyl methyl ether, and the solid was collected by filtration. The solid was dried in high vacuum to give 166.1 mg (77%) of N-[4-(4-(furan-3-yl)phenoxy)benzenesulfonyl]--S--[(pyrid-2-yl)methyl]-D-penicillamine as a yellow solid: mp 185-189° C.; 1H--NMR (CDCl3) δ 1.40 (s, 3H) 1.44 (s, 3H), 3.32-4.01 (m, 3H), 6.83 (s, 1H), 7.10-7.13 (m, 4H), 7.22-7.23 (m, 2H), 7.57-7.92 (m, 8H), 8.42 (d, J=4 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[F:15][C:16]([F:31])([F:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=1>>[F:31][C:16]([F:15])([F:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:27][C:26]([CH:28]=[N:1][C:2]2[CH:3]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[OH:8])=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)o1
Reactant: Nc1cc(-c2ccccc2)ccc1O
Product: Oc1ccc(-c2ccccc2)cc1N=Cc1ccc(-c2ccccc2C(F)(F)F)o1

Procedure:
Using 3-aminobiphenyl-4-ol and 5-(2-(trifluoromethyl)phenyl)furan-2-carbaldehyde, 1.64 g of 3-{[5-(2-(trifluoromethyl)phenyl)furan-2-yl]methyleneamino}biphenyl-4-ol was obtained as an orange powder (yield 34%).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][NH2:29])[CH:22]=1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:29][CH2:28][CH2:27][C:23]4[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: NCCc1cccnc1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(NCCc4cccnc4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2-pyridin-3-yl-ethyl)-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (250 mg, 0.81 mmol) and 2-pyridin-3-yl-ethylamine (0.95 mL, 8.1 mmol) in a manner analogous to Example 406. Product isolated as a light yellow powder (98.5 mg, 31%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.71 (d, J=6.4 Hz, 1H), 8.51 (m, 1H), 8.39 (d, J=7.8 Hz, 2H), 8.03 (d, J=7.4 Hz, 2H), 7.86 (d, J=7.4 Hz, 1H), 7.70 (t, J=15.1, 7.6 Hz, 1H), 7.30 (m, 1H), 7.22 (m, 1H), 7.04 (t, J=13.9, 7.3 Hz, 1H), 6.86 (m, 1H), 3.62 (m, 2H), 3.28 (s, 3H), 3.06 (m, 2H). MS=394 (MH)+.
Reaction SMILES: [S:1]1[C:5]([CH:6]([O:11][CH3:12])[C:7](OC)=[O:8])=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.O.[NH2:18][NH2:19]>C(O)C>[S:1]1[C:5]([CH:6]([O:11][CH3:12])[C:7]([NH:18][NH2:19])=[O:8])=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: NN
Reactant: COC(=O)C(OC)c1cc2ccccc2s1
Solvent: O
Solvent: CCO
Product: COC(C(=O)NN)c1cc2ccccc2s1
Temperature: 50 °C
Yield: 104.1 %

Procedure:
To a solution of methyl 2-(benzo[b]thiophen-2-yl)-2-methoxyacetate (0.174 g, 0.74 mmol) in absolute ethanol (3 mL) was added hydrazine hydrate (0.14 mL, 2.87 mmol) and the mixture was heated at 50° C. for 20 hours. After cooling to room temperature, the solution was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give 2-(benzo[b]thiophen-2-yl)-2-methoxyacetohydrazide as a colorless oil (0.182 g, quantitative yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14](Br)[CH:15]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(Br)C=O)CC1
Reactant: Nc1ccccn1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cnc3ccccn23)CC1
Yield: 35.4 %

Procedure:
To a solution of 1.15 g of 1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)-piperidine (from Example 292, Step C) in 15 mL ethanol was added 388 mg of 2-aminopyridine. After refluxing for 18 hours, the solvent was evaporated. The mixture was partitioned between EtOAc and saturated sodium bicarbonate solution. Aqueous layer was extracted with EtOAc (3×). The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography with 50% EtOAc in hexanes, followed by 100% EtOAc to give 401 mg of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ1.48 (s, 9H), 1.70 (m, 2H), 2.06 (d, J=13 Hz, 2H), 2.93-3.02 (m, 3H), 4.26 (br, 2H), 6.87 (t, J=6.8 Hz, 1H). 7.21(m, 1H), 7.44(s, 1H), 7. 69(d, J=9.2 Hz,1H), 7.99 (d, J=6.9 Hz, 1H).