Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][C:10]=2[N+:24]([O-])=O)=[CH:4][CH:3]=1>CCO.CC(O)=O.[Fe]>[NH2:24][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(NC(=O)c2ccccc2)ccc1Sc1ccc(O)cc1
Temperature: 80 °C
Yield: 87.5 %

Procedure:
A suspension of the product from Example 220b (0.67 g, 1.8 mmol) and Fe powder (0.31 g, 5.5 mmol) in a mixture of EtOH (6.7 mL) and HOAc (6.7 mL) was gradually heated to 80° C. and heated at 80° C. for 3 hours. The reaction mixture was evaporated. The residue was portioned between EtOAc and 10% NaHCO3 and then filtered (through celite). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum giving the crude title compound, which was purified by washing with i-Pr2O to give the desired compound as pale brown crystals (0.53 g, 86%).
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>[C].[Pd].C(O)C>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1nccc1-c1ccc(C2=CCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cn1nccc1-c1ccc(C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
10% palladium carbon (20 mg) was added to an ethanol (2.4 mL) solution of 5-[4-(cyclopenta-1-ene-1-yl)phenyl]-1-methyl-1H-pyrazole (133 mg), and the obtained solution was then stirred under a hydrogen atmosphere at a room temperature overnight. Thereafter, the reaction solution was filtrated with Celite, and the filtrate was then concentrated under a reduced pressure, so as to obtain the title compound (140 mg) in the form of a light yellow oily substance.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+].Br[C:55]1[NH:56][C:57]2[C:62]([N:63]=1)=[C:61]([N:64]1[CH2:69][CH2:68][O:67][CH2:66][C@H:65]1[CH3:70])[N:60]=[C:59]([N:71]1[CH2:76][CH2:75][O:74][CH2:73][C@@H:72]1[CH3:77])[N:58]=2.[F-].[Cs+]>O1CCOCC1.CCOC(C)=O>[F:11][C:9]1[CH:8]=[C:7]2[C:3]([CH:4]=[CH:5][NH:6]2)=[C:2]([C:55]2[NH:56][C:57]3[C:62]([N:63]=2)=[C:61]([N:64]2[CH2:69][CH2:68][O:67][CH2:66][C@H:65]2[CH3:70])[N:60]=[C:59]([N:71]2[CH2:76][CH2:75][O:74][CH2:73][C@@H:72]2[CH3:77])[N:58]=3)[CH:10]=1
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@@H]2C)nc2[nH]c(Br)nc12
Reactant: Fc1cc(Cl)c2cc[nH]c2c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@@H]2C)nc2[nH]c(-c3cc(F)cc4[nH]ccc34)nc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 52.1 %

Procedure:
4-Chloro-6-fluoro-1H-indole (72 mg, 0.42 mmol) was dissolved in 4 mL of dioxane under argon. Bis(pinacolato)diboron (198 mg, 778 μmol), tricyclohexylphospine (19.8 mg, 71 μmol), bis(dibenzylidenacetone)palladium (20.3 mg, 35 μmol), and potassium acetate (104 mg, 1.06 mmol) were added under argon. The reaction was stirred for 24 hours at 80° C. The reaction mixture was cooled to room temperature and diluted with 30 mL of EtOAc. The organic layer was washed with 20 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was filtered through a column (40 g SiO2; EtOAc/heptane in a gradient from 0/100 to 12/88) to yield a mixture, which was concentrated under reduced pressure, and then dissolved in 2 mL of acetonitrile and 0.2 mL of water under argon. 8-Bromo-2-((S)-3-methylmorpholin-4-yl-)-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (100 mg, 153 μmol) was added, followed by cesium fluoride (25.8 mg, 170 μmol) and tetrakis(triphenylphospine)palladium (26 mg, 23 μmol). The reaction mixture was stirred at 135° C. for 2 hours in a sealed vial. The reaction mixture was cooled to room temperature and diluted with 40 mL of EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (10 g SiO2; tertbutylmethylether) to give the title compound as a foam (36 mg, 19% over 2 steps).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([C:11]2[S:15][C:14]([C:16](Cl)=[O:17])=[CH:13][CH:12]=2)=[N:3]1.ClCCl.[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C(=O)(O)[O-].[Na+]>O>[CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([C:11]2[S:15][C:14]([C:16]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:17])=[CH:13][CH:12]=2)=[N:3]1
Reactant: Cn1nc(-c2ccc(C(=O)Cl)s2)cc1C(F)(F)F
Reactant: Nc1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cn1nc(-c2ccc(C(=O)Nc3nccs3)s2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.9 %

Procedure:
5-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carbonyl chloride (100 mg) and dichloromethane (2 ml) were added to a mixture of 2-aminothiazole (68 mg), saturated sodium bicarbonate aqueous solution (1 ml) and dichloromethane (1 ml), followed by stirring at room temperature for 5 hours. Water was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=4:1-2:1) and then washed with diethyl ether to give 5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-N-(2-thiazolyl)thiophene-2-carboxamide (68 mg) as colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CS(C)=O>[C:11]([C:7]1[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
8.40 g (40.7 mmol) 2,6-di-tert-butylphenol was dissolved in 100 ml dried DMSO. 8 g (58 mmol) potassium carbonate and 7.6 g (54 mmol) p-fluoronitrobenzene were added into the DMSO solution. The DMSO solution was heated to 100˜120° C. for 12 hrs with stirring. Then the reaction mixture was allowed to cool to room temperature and poured into distilled water. The aqueous solution was acidified to pH 2˜4 and yellow precipitate was collected by filtration. The yellow precipitate was washed with water and dried. The crude yield was 75%. The yellow precipitate was purified by recrystallizing in cyanomethane, mp 157˜160° C.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:31][C:32]1[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=1>>[CH2:19]([O:18][C:16]([C:15]1[CH:21]=[CH:22][C:12]([NH:11][C:9](=[N:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:41][CH:42]=2)[C:8]2[CH:23]=[CH:24][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:13][CH:14]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(N=C(Nc2ccc(C(=O)OCC)cc2)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
N,N'-Bis(4-ethoxycarbonylphenyl)-4-t-butylbenzamidine (14) was prepared from ethyl 4-[N-(4-t-butylbenzoyl)]aminobenzoate, phosphorus pentachloride, and ethyl 4-aminobenzoate; yellow solid: mp 212°-219° C. 1H-NMR (CDCl3) 8.0-7.0 (m, 12H), 6.0 (br s, 1H), 4.3 (q, 4H, J=7 Hz), 1.4 (t, 6H, J=7 Hz), 1.3 (s, 9H); IR (Nujol) 3330, 1710, 1590; MS (m/e) 472 (M+), 308 (base).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]#[C:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=1[CH:13]=O.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH3:20][O:19][C:16]1[CH:15]=[C:12]2[C:11]([CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N+:22]([O-:23])=[CH:13]2)=[CH:18][CH:17]=1
Reactant: NO
Reactant: COc1ccc(C#Cc2ccccc2OC)c(C=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: COc1ccc2cc(-c3ccccc3OC)[n+]([O-])cc2c1
Yield: 59.8 %

Procedure:
2-[2-(2-Methoxyphenyl)ethynyl]-5-methoxybenzaldehyde (0.95 g), hydroxylamine hydrochloride (0.25 g) and sodium acetate (0.32 g) were reacted in ethanol (20 ml) at 60° C. for 2 hr. Potassium carbonate (0.6 g) and water (2 ml) were added to the reaction mixture, and the mixture was heated under reflux for 12 hr. The reaction solution was evaporated, and then the resulting residue was extracted with methylene chloride, washed with brine and dried. The solvent was removed, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 0.60 g of the title compound as a yellowish brown amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][O:15][C:16](=[O:27])[C@H:17]([CH:19]([CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:18]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:18][CH:17]([CH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:26])[C:16]([O:15][CH3:14])=[O:27])=[O:13])=[CH:5]2
Reactant: COC(=O)[C@@H](N)C(C)c1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: COC(=O)C(NC(=O)c1cc2cc(Cl)ccc2[nH]1)C(C)c1ccccc1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and DL-β-methylphenylalanine methyl ester. mp 135-136° C.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42]([CH:47]=O)=[CH:41]2>C1COCC1>[Cl:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42]([CH:47]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:41]2
Reactant: O=Cc1cc2cc(Cl)ccc2[nH]1
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC=Cc1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To the cold suspension of hexyl-triphenyl-phosphonium bromide in THF was added LiHMDS in THF and the mixture was stirred for 30 minutes and then the solution of 5-chloro-1H-indole-2-carbaldehyde was added to the reaction mixture and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product, 5-chloro-2-hept-1-enyl-1H-indole was purified by column chromatography.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:22][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:10][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[NH:22][N:21]([C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:20][N:19]=2)=[C:4]([Cl:3])[CH:9]=1
Reactant: BrBr
Reactant: OCc1ccc(-c2ccccc2C2=NNN(C(c3ccccc3)(c3ccccc3)c3ccccc3)N2)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(CBr)ccc1-c1ccccc1C1=NNN(C(c2ccccc2)(c2ccccc2)c2ccccc2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
First 6.79 g of bromine (42.5 mmol) and then 20.4 g of the compound from Example XXXV in 300 ml of methylene chloride are added dropwise to a solution of 11.2 g of triphenylphosphine (42.5 mmol) in 100 ml of methylene chloride under argon in an ice-bath. After the reaction mixture has been stirred at room temperature for 1 hour, it is filtered through silica gel and eluted with methylene chloride. Concentration of the filtrate and digestion of the residue with hexane gives 15.8 g of white crystals [68.9% of theory; melting point 15°-60° C.; Rf 0.40 (hexane/ethyl acetate=3:1)].
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:21])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH3:20])=[CH:5][CH:4]=[N:3]1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]=1[CH3:32].C(N(CC)CC)C>C1COCC1>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:21][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[CH3:20])=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[CH:8]=2)=[O:28])=[CH:25][C:24]=1[CH3:32]
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: CN1CCCC1COc1ccc(N)cc1-c1ccnn1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(OC[C@@H]3CCCN3C)c(-c3ccnn3C)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
A mixture of 3-(2-Methyl-2H-pyrazol-3-yl)-4-(1-methyl-pyrrolidin-2-ylmethoxy)-phenylamine (64 mg, 0.23 mmole), 4-fluoro-3-methyl-benzoyl chloride (60 mg, 0.35 mmole), and triethylamine (63.4 μL, 0.46 mmole) in 1 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 92 mg, 95% yield). Exact mass calculated for C24H27FN4O2 422.2, found 423.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH3:55][O:56][C:57]1[CH:61]=[C:60]([CH2:62][NH2:63])[O:59][N:58]=1>CN(C)C=O>[CH3:55][O:56][C:57]1[CH:61]=[C:60]([CH2:62][NH:63][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:12][N:11]=2)=[O:22])[O:59][N:58]=1
Reactant: COc1cc(CN)on1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.1 %

Procedure:
4-(4-Chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (100 mg, 0.3 mmol, example D) was dissolved in dimethylformamide (4 mL). To this stirred solution under argon was added in sequence 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (107 mg, 0.3 mmol), N,N-diisopropyl ethyl amine (0.26 mL, 1.5 mmol) and 3-methoxy-5-isoxazolemethanamine hydrochloride (55 mg, 0.3 mmol). The mixture was shaken for 16 h at room temperature, solvent was removed in vacuo (45° C.) and the residue was digested with dichloromethane (5 mL) and 2N NaOH (1.5 mL) for 5 min. The mixture was absorbed onto 10 g ChemElut (Varian) and eluted with dichloromethane (70 mL). Solvent was evaporated and the brown, oily residue (160 mg) was purified by gradient chromatography on silica with ethyl acetate/n-heptane to give the title compound as a white solid (122 mg, 92%), LC-MS (UV peak area/ESI) 93%, 442.0769 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:38])[N:24]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[O:21])=[C:14]([F:39])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[C:40]([O-])([O-])=O.[K+].[K+]>C(O)(C)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:38])[N:24]([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH:25]=[CH:26][C:27]=3[O:28][CH:29]([CH3:40])[CH3:30])=[O:21])=[C:14]([F:39])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(C)=O)c2)cc1F
Agent: [K+]
Solvent: CC(C)O
Product: CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)c3c(OC(C)C)ccn(-c4ccc(F)cc4)c3=O)cc2F)ccn1
Yield: 71.9 %

Procedure:
A mixture of Example 1 (0.400 g, 0.743 mmol) and K2CO3 (0.400 g, 2.89 mmol) in isopropanol (10 mL) was heated at 120° C. for 1 h with microwave irradiation. The solids were removed by filtration and washed with THF. The filtrate was concentrated to dryness. The residue was stirred in water (15 mL) and the remaining solids were collected and crystallized from MeCN to provide N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide, (0.295 g, 71.9% yield) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1 H), 10.58 (s, 1 H), 8.29 (dd, J=12.6, 7.2 Hz, 1 H), 8.18 (d, J=5.7 Hz, 1 H), 7.87 (d, J=7.8 Hz, 1 H), 7.67 (s, 1 H), 7.50-7.49 (m, 3 H), 7.35 (t, J=8.7 Hz, 2 H), 6.71 (dd, J=5.7, 2.4 Hz, 1 H), 6.55 (d, J=7.9 Hz, 1 H), 4.85 (m, 1 H), 2.03 (s, 3 H), 1.31 (d, J=6.0 Hz, 6 H); MS (ESI) m/z: 553.1 (M+H+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]2=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[N:3]=1.[NH:25]1[CH:29]=[CH:28][C:27](B(O)O)=[N:26]1.C(=O)([O-])[O-].[K+].[K+].COCCOC.O>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.CN(C=O)C>[O:18]([C:15]1[CH:16]=[CH:17][C:12]([C:4]2[N:3]=[C:2]([C:29]3[CH:28]=[CH:27][NH:26][N:25]=3)[N:6]3[CH:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]=23)=[CH:13][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cc[nH]n1
Reactant: Nc1nccn2c(Br)nc(-c3ccc(Oc4ccccc4)cc3)c12
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+]
Solvent: COCCOC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nccn2c(-c3cc[nH]n3)nc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
A mixture of 3-bromo-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine (20.0 mg, 0.052 mmol), 1H-pyrazol-3-yl boronic acid (6.46 mg, 0.057 mmol), Pd(PPh3)4 (10 mg, 0.01 mmol), potassium carbonate (21.8 mg, 0.157 mmol) and DME/H2O (v:v=5:1, 2 mL) was microwaved at 300 watt, 100° C. for 30 min. The solution was transferred to a 20 mL vial, and 1 mL of DMF was added. The solution was concentrated in vacuo until only DMF remained. The mixture was passed through a syringe filter pad, and prepared for Gilson HPLC separation. The fractions containing the pure product were collected and concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=6.99 (d, J=2.5 Hz, I H), 7.07-7.13 (m, 3H), 7.13-7.20 (m, 3H), 7.37-7.45 (m, 2H), 7.63-7.69 (m, 2H), 7.76 (d, J=2.5 Hz, 1H), 8.65 (br. s., 1H). MS (ES+): m/z 369.10 (100) [MH+]. HPLC: tR=20.39 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@@H:42]([C:51]([O:53]C(C)(C)C)=[O:52])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=1>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:41][C@@H:42]([C:51]([OH:53])=[O:52])[CH2:43][C:44]3[CH:45]=[CH:46][C:47]([OH:50])=[CH:48][CH:49]=3)=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccc(O)cc1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@H](Cc3ccc(O)cc3)C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-D-Tyr-OtBu (47 mg, 0.2 mmole) were processed as in Example 213A-B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ11.78-13.25 (br.s, 1 H), 8.95 (s, 1 H), 8.64-9.80 (br.s, 1 H), 8.03 (d, 1 H), 7.26 (m, 6 H), 7.19 (m, 1 H), 7.12 (d, 2 H), 7.00 (m, 5 H), 6.88 (m, 4 H), 6.64 (d, 2 H), 4.35 (m, 1 H), 4.06 (s, 2 H), 4.02 (s, 2 H), 2.94 (d, 1 H), 2.91 (s, 3 H), 2.72 (dd, 1 H), 2.44 (t, 2 H), 2.39 (s, 3 H), 2.06 (m, 2 H), 1.69 (m, 2 H); MS (APCI+) m/z 723 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[CH2:25]([O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:37][C:36]2[CH:35]=[CH:34][C:33]([O:32][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:39][CH:38]=2)=[C:9]([NH:37][C:36]2[CH:35]=[CH:34][C:33]([O:32][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:39][CH:38]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ccc(OCc3ccccc3)cc2)c(Nc2ccc(OCc3ccccc3)cc2)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 4.8 g (24 mmol) of 4-benzyloxyaniline in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is dissolved while hot in ethyl acetate and filtered, then allowed to crystallize at 0°. The crystalline residue is chromatographed on silica gel with ethyl acetate/hexane 3:2 and the product fractions are concentrated by evaporation and recrystallized from ethyl acetate/hexane, yielding the title compound in the form of beige crystals, FAB-MS: 589 [M+ +H].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([O:12]CC)=[O:11])=[N:2]1.S(=O)(=O)(O)O>O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:12])=[O:11])=[N:2]1
Reactant: CCOC(=O)c1noc2ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1noc2ccccc12
Temperature: 80 °C

Procedure:
8.6 g of 3B was mixed with 175 ml of 70% sulfuric acid and the mixture was heated at 80° C. for 4 hours. The mixture was cooled, 200 ml of cold water was added, the mixture was extracted with ether, and the extract was dried (Na2SO4) and stripped of solvent. The residue was triturated with pentane, and the solid was collected and dried to give 3-benzisoxazolecarboxylic acid (3C), as a white solid, m.p.: 132°-134° C. (with decomposition).