Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[N:4]=[C:5]([S:29][CH3:30])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]#[N:41].O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:31])[N:4]=[C:5]([S:29][CH3:30])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:39][C:40]#[N:41])=[C:22]([O:27][CH3:28])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(O)c(OC)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OCC#N)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
After dissolving 520 mg of {2-(4-hydroxy-3-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (18d)) in 5 ml of DMF, 262 mg of potassium carbonate and 107 μl of bromoacetonitrile were added and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (514 mg, isomeric mixture) as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CCOCC>CO.O>[C:18]([O:17][C:15]([NH:14][CH2:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[C:3]([OH:22])=[O:2])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1c(CNC(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc([N+](=O)[O-])c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid methyl ester (38.96 g, 126 mmol) lithium hydroxide (3.61 g, 151 mmol) in methanol (450 mL) and water (225 mL) was stirred with a mechanical stirrer at room temp overnight. The methanol was evaporated and to the aqueous solution, was added 1 N HCl (200 mL) to form the precipitate. Ether (300 mL) was added, and the mixture was stirred at 0° C. for 2 hours. The suspension was filtered, washed with water (100 mL) and ether (100 mL), and suction dried in hood overnight to give 2-(tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid as a yellow solid (22.4 g, 60% yield). The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8](OCC)=O)=[N:4][NH:5][C:6]=1C.C[C:14]1NN=[C:16]([N:19](CCC)[CH2:20][CH2:21][CH3:22])[CH:15]=1>>[Cl:1][C:2]1[C:6]([N:19]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15][CH3:14])=[N:5][NH:4][C:3]=1[CH3:8]
Reactant: CCOC(=O)c1n[nH]c(C)c1Cl
Reactant: CCCN(CCC)c1cc(C)[nH]n1
Product: CCCN(CCC)c1n[nH]c(C)c1Cl
Yield: 61 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1A, 5-methyl-N,N-dipropyl-1H-pyrazol-3-amine (400 mg, 2.21 mmol) was converted to the title compound (290 mg, 61%). 1H NMR (CDCl3) δ 3.20-3.16 (m, 4H), 2.18 (s, 3H), 1.55 (sxt, J=7.5 Hz, 4H), 0.88 (t, J=7.4 Hz, 6H); MS(ESI+) m/z 216.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4].C(N(CC)CC)C.O>CS(C)=O>[CH:2]([C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4])=[O:1]
Reactant: CC(C)(CO)NC(=O)c1ccc(F)cc1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C=O)NC(=O)c1ccc(F)cc1F
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of N-(2-hydroxy-1,1-dimethylethyl)-2,4-difluorobenzamide obtained in Example 27 (6.2 g, 27 mmol) and triethylamine (8.2 g, 81 mmol) in DMSO (60 ml) was added a solution of pyridine sulfur trioxide complex (12.9 g, 81 mmol) in DMSO (60 ml) dropwise with cooling in an ice-bath and stirred for 2 hours. The reaction mixture was poured over a mixture of ice and water, and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous NaHCO3 and brine, successively dried over Na2SO4, concentrated under a reduced pressure and the residue was crystallized from hexane/ethyl acetate to give the title compound (5.05 g; 82%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([NH2:48])=[S:47])=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>ClCCl>[F:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([NH:48][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])=[S:47])=[CH:44][CH:43]=1
Reactant: NC(=S)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC(=S)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1-tert-Butoxycarbonylpiperidine-4-carboxylic acid (0.70 g, 3.05 mmol, Aldrich) and HATU (1.74 g, 4.58 mmol) were suspended in dichloromethane (10.0 ml) at room temperature for 20 minutes, followed by addition of 4-fluorothiobenzamide (0.47 g, 3.05 mmol) in one portion. The mixture was stirred at room temperature for 40 minutes, and DIEA (1.18 g, 9.16 mmol) was added. After stirring at room temperature overnight, the solvent was removed under reduced pressure. The residue was passed through a silica gel cartridge using a gradient of 0˜50% ethyl acetate in hexanes to give the title compound as a bright yellow solid.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.C=O.C([O-])([O-])=O.[K+].[K+]>O1CCCC1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 40 °C

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (1.0 g, 2.2 mmol) is dissolved in 5 mL of anhydrous tetrahydrofuran, add 37% formaldehyde aqueous solution (0.36 mL, 4.4 mmol), 1 M K2CO3 aqueous solution (4.4 mL, 4.4 mmol) and n-Bu4NOH (12 mg, 0.05 mmol), heat to 40° C. for 2 h. The reaction mixture is cooled to room temperature, extract with ethyl acetate, the extracts are washed with saturated Na2CO3 aqueous solution and brine, dry over anhydrous Na2SO4 and concentrate under vacuum, the residue is purified by column chromatography to obtain (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl). Spectroscopic data as Example 23, Method 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:22])[C@@H:12]([NH2:21])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].[C:23]([O:27][C:28]([NH:30][C@H:31]([C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[CH:36]=1)[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:22])[C@@H:12]([NH:21][C:32](=[O:33])[C@H:31]([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[C:35]2[CH:44]=[CH:43][C:38]3[O:39][CH2:40][CH2:41][O:42][C:37]=3[CH:36]=2)[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc2c(c1)OCCO2
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)[C@@H](C)c2ccccc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc3c(c2)OCCO3)[C@@H](C)c2ccccc2)n1
Reaction time: 0.5 h

Procedure:
2-((2S,3S)-2-Amino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid methyl ester (0.255 g, 0.80 mmol), (2R)-tert-butoxycarbonylamino-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acetic acid (prepared according to the procedure of Bohme, E. H. W. et al., J. Med. Chem. 1980, 23,405-412), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexaflurorophosphate (0.364 g, 0.96 mmol) and diisopropylethyl amine (0.56 mol, 3.2 mmol) were dissolved in N,N-dimethylformamide (3 mL) in an ice bath. 1-Hydroxybenzotriazole (0.13 g, 9.6 mmol) in N,N-dimethylformamide (1 mL) was added dropwise. Stirring was continued for 30 min at 0° C. The reaction mixture was diluted with ethyl acetate and the mixture was washed with water and brine. The organic layer was diluted with an equal volume of dichloromethane, filtered through a pad of silica gel with a layer of sodium sulfate on the top and eluted with 1:1 ethyl acetate/dichloromethane. Evaporation of the solvents gave a white solid which was triturated with ether/hexane to give crude 2-{(2S,3S)-2-[(R)-2-tert-butoxycarbonylamino-2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (0.49 g).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)[C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.S(OCC)(O[CH2:33][CH3:34])(=O)=O>O.CS(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16]/[C:17](/[N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[C:18](/[O:23][CH2:33][CH3:34])\[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)C(Oc1ccc(-c2ccc(Cl)cc2)cc1)n1ccnc1
Reactant: CCOS(=O)(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCO/C(=C(/Oc1ccc(-c2ccc(Cl)cc2)cc1)n1ccnc1)C(C)(C)C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
6 g of potassium hydroxide, dissolved in a little water, are added dropwise to 36.85 g (0.1 mole) of 1-(4'-chloro-4-biphenylyloxy)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one in 50 ml of dimethylsulphoxide. The mixture is subsequently stirred for a short time and 16 g (0.11 mole) of diethyl sulphate are then added dropwise. During this addition, the temperature of the reaction mixture is kept at about 40° C. and thereafter it was kept at 80° C. for 1/2 hour. It was allowed to cool, water is added and the crystalline precipitate is filtered off and recrystallised from petroleum ether. 22 g (50% of theory) of (E)-1-(4'-chloro-4-biphenylyloxy)-3,3-dimethyl-2-ethoxy-1-(imidazol-1-yl)-1-butene of melting point of 112°-113° C. are obtained.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([NH:6][C@@H:7]([CH:40]([CH3:42])[CH3:41])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH+:31]=[C:32]([C@@H:35]5[CH2:39][CH2:38][CH2:37][NH2+:36]5)[NH:33][CH:34]=4)=[CH:26][CH:25]=3)=[CH:23][C:17]=2[N:16]=1)=[O:9])=[O:5].[Cl-].[CH3:44][O:45][C:46]([NH:48][C@@H:49]([CH:53]([CH3:55])[CH3:54])[C:50](O)=[O:51])=[O:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:2][O:3][C:4]([NH:6][C@@H:7]([CH:40]([CH3:42])[CH3:41])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4[N:31]=[C:32]([C@@H:35]5[CH2:39][CH2:38][CH2:37][N:36]5[C:50]([C@@H:49]([NH:48][C:46](=[O:47])[O:45][CH3:44])[CH:53]([CH3:55])[CH3:54])=[O:51])[NH:33][CH:34]=4)=[CH:28][CH:29]=3)=[CH:23][C:17]=2[N:16]=1)=[O:9])=[O:5]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(-c3ccc(-c4c[nH]c([C@@H]5CCC[NH2+]5)[nH+]4)cc3)ccc2[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc4[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)nc4c3)cc2)c[nH]1)C(C)C
Temperature: 2 °C
Yield: 40 %

Procedure:
To a cold (0-4° C.) stirred light suspension of 4-(4-(2-((S)-1-((S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)phenyl)-2-((S)-pyrrolidin-1-ium-2-yl)-1H-imidazol-3-ium chloride (98.09 mg, 0.15 mmol) and (2S)-2-(methoxycarbonylamino)-3-methyl-butanoic acid (28.91 mg, 0.1650 mmol) in DMF (1.5 mL) is sequentially added HATU (85.55 mg, 0.2250 mmol) and DIPEA (116.3 mg, 156.7 μL, 0.9000 mmol). The resulting mixture is slowly warmed up to rt, stirred overnight, then diluted with water (5 mL), extracted with ethyl acetate (3×6 mL). The combined extracts are washed with saturated bicarbonate solution, brine, dried (Na2SO4) and concentrated. Residue purified on 25+M biotage SiO2 cartridge using MeOH-EtOAc (0:100, 15:85) as eluent to afford methyl N-[(1S)-1-[(2S)-2-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (45.8 mg, 0.06007 mmol, 37.45%) as white solid. This product is repurified by reverse phase HPLC to give methyl N-[(1S)-1-[(2S)-2-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (29.6 mg) as white solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[N:13]=[C:12]([Cl:18])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:10]2[Cl:25].[C:26]([CH:34]1[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[Cl:18][C:12]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:10]([Cl:25])[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]([C:26]([OH:33])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:34]3[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]3)[CH:8]=2)[N:13]=1
Reactant: Cc1cc(Br)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Reactant: CC(=O)N1CCC(C(=O)c2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(O)(c2ccccc2)c2cc(C)c3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)CC1
Reaction time: 0.03 h

Procedure:
A solution of n-butyllithium (1.6 M in hexanes, 0.5 mL, 0.8 mmol) was added dropwise by syringe to a solution of 6-bromo-2,4-dichloro-8-methyl-3-phenylquinoline (0.32 g, 0.88 mmol, Intermediate 3) in dry deoxygenated THF (10 mL) at −78° C. After 2 minutes, a solution of 1-(4-benzoylpiperidin-1-yl)ethanone (0.203 g, 0.88 mmol, Intermediate 4) in dry THF (4 mL) was added dropwise by syringe. An additional 2 mL of THF was used to complete the quantitative addition. After 10 minutes, the flask was removed from the dry-ice bath and placed into an ice-water bath. After 1 hour, the reaction was quenched with saturated aqueous ammonium chloride solution and the mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was further extracted with EtOAc and washed with saturated aqueous NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 0-100% EtOAc-DCM) to provide the title compound. MS m/e 519.1 (M+H)+.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([O-:22])=[O:21])[CH:16]=[C:11]3[C:10]([CH3:26])=[N:9]2)=CC=1.F[C:30](F)(F)[C:31](O)=O>C(Cl)(Cl)Cl>[CH3:26][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([O:22][CH2:30][CH3:31])=[O:21])[CH:16]=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4cccc(C(=O)[O-])c4)cnc32)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cccc(-c2cnc3[nH]nc(C)c3c2)c1
Temperature: 50 °C

Procedure:
To a solution of 3-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoate (118) (70 mg, 0.74 mmol) dissolved in chloroform (5 mL) was added trifluoroacetic acid (8 mL) and the reaction mixture was heated at 50° C. for 12 h. After completion of the reaction the solvents were removed and diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with chloroform two times. The organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed. The crude was passed through 100-200 mesh silica gel eluting the compound at 40% ethyl acetate in hexane as pale yellow solid of ethyl 3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoate 119 obtained in 10 mg quantity. MS m/z 281.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([NH2:21])[CH:15]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)(O)[O-].[Na+].O.Cl[CH2:29][C:30](Cl)=[O:31].[CH3:33][C:34](CC(C)C)=[O:35]>>[O:8]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:33][C:34](=[O:35])[NH:21][C:16]=4[CH:15]=3)=[CH:3][C:2]=2[NH:1][C:30](=[O:31])[CH2:29]1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(CCCCCc2ccc(O)c(N)c2)ccc1O
Reactant: CC(=O)CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1COc2ccc(CCCCCc3ccc4c(c3)NC(=O)CO4)cc2N1

Procedure:
To a suspension of 1.5 g of 1,5-bis(3-amino-4-hydroxyphenyl)pentane (0.0052 mol) in 7 ml of isobutyl methyl ketone was added 1.05 g (0.0125 mole) of sodium bicarbonate and 5 ml of water. The suspension was stirred in an ice bath and 1.4 g (0.0124 mole) of chloroacetyl chloride was added dropwise. After addition, the mixture was allowed to come to room temperature and then was refluxed for 4 hours. After cooling, the resulting crystalline solid was filtered and washed with acetone to yield 0.4 g of off-white product of m.p. 189°-190° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][C@H:8]3[C:7](=[O:15])[NH:6][C:5]=2[CH:4]=1.[N:16]1([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC.CO>[O:15]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:19]3[CH2:18][CH2:17][N:16]([C:22]4[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=4)[CH2:21][CH2:20]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][C@@H:8]12
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCC#N
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCN43)CC2)cc1
Temperature: 90 °C
Yield: 6.2 %

Procedure:
(S)-3-(hydroxymethyl)-7,8-dihydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (103 mg, 0.5 mmol), 4-(piperazin-1-yl)benzonitrile (108 mg, 0.575 mmol), (cyanomethyl)trimethylphosphonium iodide (207 mg, 0.850 mmol) and N,N-diisopropylethylamine (0.437 ml, 2.500 mmol) were suspended in Propiononitrile (Volume: 1.502 ml) and heated in a closed vial at 90° C. for 23 h. The reaction mixture was cooled, diluted with MeOH (2 mL) and purified using preparative HPLC (basic phase). The fractions containing product were concentrated in vacuo and crystallized from water-methanol (3 mL, ˜5:1) The precipitate was filtered and dried in vacuum to afford (S)-4-(4-((6-oxo-6,6a,7,8-tetrahydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile (11.7 mg, 0.031 mmol, 6.25% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37-2.47 (m, 4H) 2.68-2.80 (m, 1H) 2.94 (tt, J=10.67, 7.26 Hz, 1H) 3.30 (d, J=4.80 Hz, 4H) 3.36 (s, 2H) 3.87-4.00 (m, 1H) 4.21 (q, J=7.66 Hz, 1H) 4.93 (t, 1H) 6.98 (d, J=1.77 Hz, 1H) 7.00 (d, J=9.09 Hz, 2H) 7.57 (d, J=9.09 Hz, 2H) 7.65 (d, J=1.77 Hz, 1H) 10.34 (s, 1H). [M+H] calc'd for C21H22N6O, 374. found, 374.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.F[B-](F)(F)F.[CH3:19][O+](C)C>CC(C)=O>[CH3:19][N:3]1[C:2]([CH3:1])=[C:10]2[C:5]([CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:9]2)=[N:4]1
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)=O
Product: Cc1c2ccc([N+](=O)[O-])cc2nn1C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro-1H-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetrafluoroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHCO3 (600 ml) and a 4:1 mixture of chloroform-isopropanol (200 ml), and the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4×200 ml) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 ml) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73%). 1H NMR (300 MHz, d6DMSO) δ 8.51 (s, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([NH2:22])=[O:21])[C:15](=[O:23])[CH2:14]2.BrC1OC(C(Cl)=O)=CC=1.Cl>S(Cl)(Cl)=O.CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([NH2:22])=[O:21])[C:15](=[O:23])[CH:14]2[C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)c1ccc(Br)o1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)N1C(=O)C(C(=O)c2ccc(Br)o2)c2cc(Cl)ccc21

Procedure:
Using the procedure of Example 32, 1.91 g (10.0 mmoless) of commercially available 5-bromo-2-furancarboxylic acid was dissolved in 10 ml of thionyl chloride and heated to reflux under nitrogen for 1 hour and the acid chloride product was recovered. A 40 ml N,N-dimethylformamide solution of 1.75 g (8.3 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 3.05 g (25 mmoles) of 4-(N,N-dimethylamino)pyridine was reacted with 2.09 g (10 mmoles) of 5-bromo-2-furan carbonyl chloride in 10 ml of N,N-dimethylformamide. After a reaction time of about 45 minutes, the mixture was acidified by pouring into 250 ml of 1N HCl. The product was recrystallized from acetic acid, washed with acetic acid, then hexane and dried overnight in vacuo at room temperature. The resulting product then was dried over refluxing isopropanol under high vacuum to yield 1.37 g of the title compound.