Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[Br:16][C:17]1[C:18]([C:23]2[O:24][CH:25]=[CH:26][N:27]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[O:24][CH:25]=[CH:26][N:27]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:20][CH:21]=1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Reactant: Nc1scc(Br)c1-c1ncco1
Product: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Br)c1-c1ncco1

Procedure:
The title compound was prepared from 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (85 mg, 0.416 mmol) and 4-bromo-3-(oxazol-2-yl)thiophen-2-amine (51 mg, 0.208) mmol) according to protocol A. Retention time (min)=3.245, method [7], MS (ESI) 433.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.39 (dd, J=5.1, 1.0 Hz, 1H), 7.72 (s, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.45 (dd, J=8.4, 5.5 Hz, 1H), 7.17 (s, 1H), 6.94 (s, 1H), 4.93 (s, 2H), 3.51-3.46 (m, 2H), 3.05-3.00 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:36]>O1CCOCC1>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (100 mg, 0.192 mmol) and ammonium hydroxide (4 mL) and 1,4-Dioxane (1 mL), the title compound was obtained as an off-white solid (65 mg, 64% yield). MS (ESI): 503 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2.[CH3:18]I>CN(C)P(=O)(N(C)C)N(C)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:18])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.7 %

Procedure:
8.7 gm (0.2 mol) of a 55% dispersion of sodium hydride in oil were added over a period of 15 minutes at a temperature of 0° C. and in a nitrogen atmosphere to a solution of 40.0 gm (0.18 mol) of ethyl 5-chloro-indole-2-carboxylate in 150 ml of hexamethyl-phosphoric acid triamide. After stirring the resulting mixture for 2.5 hours at room temperature, 35.5 gm (0.25mol) of methyl iodide were added dropwise, while cooling. After stirring overnight, 1200 ml of ice water were added to the mixture, while externally cooling on an ice bath. The aqueous mixture was then extracted 5 times with 150 ml of ether each. The combined ether extracts were washed with water 5 times, dried over magnesium sulfate, and evaporated in vacuo. The raw product was then recrystallized from petroleum ether, yielding 35.8 gm (85% of theory) of ethyl 5-chloro-1-methyl-indole-2-carboxylate. M.p.: 81.5°-82° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[S:10](Cl)(Cl)=O.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][S:10][N:9]=[C:4]2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1ccc(Br)cc1N
Agent: O=S(=O)(O)O
Product: Brc1ccc2nsnc2c1

Procedure:
A mixture was prepared by mixing 4.0 g (21 mmol) of 4-bromo-o-phenylenediamine, 14 mL of thionyl chloride and 0.62 mL of concentrated sulfuric acid and was refluxed for one hour. This mixture was cooled and then poured onto ice, and a resulting precipitate was filtered and collected. This precipitate was washed with water till the waste water became neutral and then thoroughly dried to yield 4.5 g of 5-bromo-2,1,3-benzothiadiazole as a crude product (melting point, 48 to 50° C.; yield, 96.5%). This crude product was vacuum-distilled to yield a pure product of 5-bromo-2,1,3-benzothiadiazole (melting point, 50° C.; yield, 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:9]=[CH:10][CH:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CI.[CH2:35]1COC[CH2:36]1>>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH:13]([CH3:17])[C:14]([O:16][CH2:35][CH3:36])=[O:15])[CH:9]=[CH:10][CH:11]=1
Reactant: C1CCOC1
Reactant: Cc1cccc(C)c1COc1cccc(CC(C)C(=O)O)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Product: CCOC(=O)C(C)Cc1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of Ethyl 3-(2,6-dimethylbenzyloxy)phenylacetate (Step B, 4.53 g, 14.5 mmol) in dry THF (30 ml) at −68° C. under a dry argon atmosphere was added LiHMDS drop wise (1 M solution in THF, 21.77 ml, 21.77 mmol), and the resulting orange solution was stirred at low temperature for 30 minutes before CH3I (20.60 g, 145.2 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 15 hours. The reaction was quenched with ice, and the product was extracted with EtOAc (2×), the organic phase was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ether 5:1) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([O:15]CC2C=CC=CC=2)=[O:14])[CH2:11][C@@H:10]2[CH2:23][CH2:24][CH2:25][C@H:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][C@@H:10]2[CH2:23][CH2:24][CH2:25][C@H:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)O)C[C@@H]2CCC[C@@H]21
Yield: 97.1 %

Procedure:
56.5 g (0.163 mol) of benzyl N-tert.-butoxycarbonyl-(2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylate are hydrogenated in 400 ml of ethanol with 2 g of palladium on charcoal as catalyst at 20° C. and under 1.1 bar. 40.4 g of the title compound are obtained. Rf (SiO2, EtOAc/MeOH=20:1) 0.45.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1.C1(=O)O[CH2:18][CH2:17][O:16]1>CN(C=O)C>[CH3:3][C:4]1[N:8]([CH2:18][CH2:17][OH:16])[N:7]=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=1
Reactant: Cc1cc(-c2ccccc2)n[nH]1
Reactant: O=C1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2)nn1CCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
Sodium hydride (2.5 g, 1.5 g NaH, 62 mmol, 1.1 equiv) was added over a period of 3 min to a solution of 5-methyl-3-phenyl-1H-pyrazole (9.00 g, 56.9 mmol, 1 equiv) in DMF (90 mL) cooled to 0° C. in an ice bath. After stirring 15 min, ethylene carbonate (7.6 mL, 10 g, 110 mmol, 2.0 equiv) was added. The bath was removed, and the reaction mixture was stirred for 15 h. The mixture was treated with 4 M aq K2CO3 (90 mL), heated at reflux for 5 h, and diluted with H2O (200 mL). After allowing the hot mixture to cool for 15 min, more H2O (100 mL) and then hexanes (100 mL) were added. The mixture was shaken vigorously and then allowed to separate. Crystals formed and stayed with the top organic layer. The aqueous layer was separated, and the crystals were collected by vacuum filtration and washed with hexanes (2×50 mL). The crystals were dissolved in Et2O/EtOAc (1:1; 200 mL), and the solution was dried (Na2SO4), filtered, and concentrated (75° C.) to give the title compound as an off-white crystalline solid (6.86 g, 59.6%). HRMS Calculated for C12H15N2O: m/z 203.1184. Found: 203.1168.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=2[CH3:21])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH3:21])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(C)C(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1

Procedure:
An ethanol solution of 2.9 g. (0.0087 mole) of ethyl 5-(p-chlorobenzoyl)1,4,α-trimethylpyrrole-2-acetate is added to 17.5 ml. 0.5 N sodium hydroxide solution, and the mixture is heated under reflux for one hour. The ethanol is evaporated in vacuo, and the solution poured into dilute hydrochloric acid. The precipitated solid is collected by filtration and recrystallized from ether-cyclohexane to give 5-(p-chlorobenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid as a white solid, m.p. 153-154° C. Anal. Calcd. for C16H16ClNO3 : C, 62.85; H, 5.29; N, 4.58%. Found: C, 62.74; H, 5.22; N, 4.47%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:14]2=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].C(O)(=O)C(O)=O.CS(O[CH:40]1[CH2:43][N:42]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:41]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH:44]1([N:42]2[CH2:43][CH:40]([NH:1][C:2]3[CH:3]=[C:4]([N:13]4[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]5[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=5)[C:14]4=[O:28])[CH:5]=[CH:6][C:7]=3[O:8][C:9]([F:10])([F:11])[F:12])[CH2:41]2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(N)c2)C(=O)N1Cc1ccncc1
Reactant: CS(=O)(=O)OC1CN(C2CCCCC2)C1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC3CN(C4CCCCC4)C3)c2)C(=O)N1Cc1ccncc1

Procedure:
300 mg (0.76 mmol) of 3-(3-amino-4-trifluoromethoxyphenyl)5,5-dimethyl-1-pyridin-4-ylmethylimidazolidine-2,4-dione were dissolved in 15 ml of ethyl acetate, admixed with 492 mg (1.52 mmol) of 1-cyclohexylazetidin-3-yl methanesulphonate oxalate and 631 mg (4.56 mmol) of K2CO3, and heated under reflux for 4 h. To complete the reaction, a further 49 mg (0.15 mmol) of 1-cyclohexylazetidin-3-yl methanesulphonate oxalate and 63 mg (0.46 mmol) of K2CO3 were added, and the mixture was stirred under reflux once again for 2 h. Subsequently, the mixture was concentrated and the residue purified by flash chromatography (150 g of silica gel/95:5 CH2C12:CH3OH).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH2:40]>CN(C)C=O>[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH:40][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: COC(=O)CCN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.03 h

Procedure:
24.9 g of benzyloxycarbonyl-L-proline were dissolved in 200 ml of dimethylformamide, cooled to -20° C and treated with 11.1 ml of N-methylmorpholine and 13.0 ml of chloroformic acid isobutyl ester. The suspension was stirred for a further 2 minutes at -° C and then treated with a suspension, pre-cooled to -20° C, prepared from 14.0 g of β-alanine methyl ester hydrochloride and 11.1 ml of N-methylmorpholine in 100 ml of dimethylformamide. The mixture was stirred for 30 minutes at a temperature below -10° C and for a further 30 minutes at room temperature, filtered and the filtrate concentrated in vacuo. The oily residue was dissolved in 1.2 liters of ethyl acetate and washed three times, each time with 1-N hydrochloric acid, water, 10% sodium carbonate solution and saturated sodium chloride solution, and dried over sodium sulphate. The organic phase was concentrated in vacuo and the oily residue crystallised from ethyl acetate/hexane. Yield: 22.8 g; melting point 55° C; [α]D25 = -50.7° (c = 1 in methanol).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:4](=[O:19])[CH:3]=1.[N:20]([O-])=[O:21].[Na+]>O.C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:4](=[O:19])[C:3]=1[N:20]=[O:21]
Reactant: O=N[O-]
Reactant: COc1ccc(Cn2c(=O)cc(N)n(C)c2=O)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Cn2c(=O)c(N=O)c(N)n(C)c2=O)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
To a solution of 6-amino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (4.3 g, 16.45 mmol) in water (20 mL) and acetic acid (20 mL) was added sodium nitrite (3.4 g, 49.4 mmol) in small portions at 70° C. After addition, the mixture was stirred at 70° C. for 4 h. The reaction was cooled and concentrated. The solids were collected, washed with water and dried under vacuum to give 6-amino-3-(4-methoxybenzyl)-1-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione (4.1 g, 85.9% yield) as purple solid. LCMS retention time 0.885 min; LCMS MH+ 291.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2].[C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:37])[CH2:35][CH3:36]>>[CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:36]#[C:35][C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2]
Reactant: CCC(=O)OC(C)(C)C
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(I)cc2C(F)(F)F
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(C#CC(=O)OC(C)(C)C)cc2C(F)(F)F

Procedure:
The title compound (75.7 mg, quant.) was prepared from 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(2-naphthyl)oxindole of Example 48 (75.1 mg, 0.132 mmol) and t-butyl propionate by the procedure similar to that described in Reference Example 21.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[NH:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.Cl[CH2:23][C:24](OCC)=[O:25].O>CN(C)C=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[C:5]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:4]3[NH:3][C:24](=[O:25])[CH2:23][N:8]3[N:7]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCl
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Cn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
To a suspension of sodium hydride (288 mg) in N,N-dimethylformamide (20 ml) was added dropwise a solution of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (1,524 g) in N,N-dimethylformamide (5 ml) with ice cooling. The mixture was stirred for 30 minutes and to the mixture was added a solution of ethyl chloroacetate (883 mg) in N,N-dimethylformamide (5 ml). After stirring of the mixture for 1 hour at ambient temperature, the reaction mixture was poured into water and the separated oil was extracted with dichloromethane. The extract was washed with brine, dried and concentrated in vacuo. The residue was dissolved in a solution of sodium (138 mg) in ethanol (5 ml) and the solution was refluxed for 1 hour. The reaction mixture was cooled, poured into water and neutralized with diluted hydrochloric acid. The separated oil was extracted with dichloromethane and the extract was washed with brine, dried and concentrated in vacuo. The residue was crystallized from ethanol to yield 2,3-dihydro-6-(4-fluorophenyl)-2-oxo-7-(pyridin-4-yl)-1H-imidazo[1,2-b]pyrazole (178 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([N+:27]([O-:29])=[O:28])=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.[C:32]([NH:36][C:37]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[C:32]([NH:36][C:37]([C:39]1[CH:40]=[C:41]([C:7]2[C:8]([N+:27]([O-:29])=[O:28])=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=4)=[C:12]([C:22]([NH:23][CH3:24])=[O:25])[C:11]=3[CH:26]=2)[CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)NC(=O)c1cc(B(O)O)cc([N+](=O)[O-])c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)cc12
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cc(C(=O)NC(C)(C)C)cc([N+](=O)[O-])c3)cc12
Temperature: 99 °C
Yield: 75.7 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl trifluoromethanesulfonate (400 mg), (3-(tert-butylcarbamoyl)-5-nitrophenyl)boronic acid (345 mg) and Cs2CO3 (846 mg) in dioxane (8 mL) and water (1.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (150 mg). The mixture was flushed with nitrogen and then heated at 99° C. for 16 hours. The mixture was diluted with water and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column (hexanes/EtOAc=3:1) to give 5-(3-(tert-butylcarbamoyl)-5-nitrophenyl)-2-(4-fluorophenyl)-N-methyl-6-nitrobenzofuran-3-carboxamide 2 (350 mg).
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].Cl[C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([C:20]3[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[N:18]=[CH:19][C:12]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:26][C:25]1[C:20]([N:17]2[C:13]3=[N:14][CH:15]=[N:16][C:11]([O:3][C@H:4]4[CH2:8][CH2:7][O:6][C:5]4=[O:9])=[C:12]3[CH:19]=[N:18]2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Reactant: O=C1OCC[C@@H]1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OCC[C@@H]1Oc1ncnc2c1cnn2-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
60% Sodium hydride in mineral oil (0.470 g, 11.75 mmol) was added to (S)-3-hydroxydihydrofuran-2(3H)-one (0.764 mL, 9.80 mmol) in anhydrous THF (30 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (CAS no. 52079-23-9) (2.87 g, 10.77 mmol) was added portionwise maintaining the temperature below 5° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2×100 mL). The combined organics were washed with saturated brine (75 mL), water (75 mL) dried (MgSO4), filtered and evaporated. The residue was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane to afford the product (1.970 g, 61%). 1H NMR (400 MHz, CDCl3) 2.52-2.62 (1H, m), 2.92-3.00 (1H, m), 4.41-4.47 (1H, m), 4.59-4.64 (1H, m), 6.11-6.16 (1H, m), 7.46-7.49 (1H, m), 8.00-8.02 (1H, m), 8.37 (1H, s), 8.61-8.63 (1H, m), 8.64 (1H, s); m/z (ESI+) (M+H)+=332; HPLC tR=1.51 min.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:11]([C:12](=O)[CH3:13])=[CH:10][C:9]([N+:15]([O-])=O)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C([O:22][C:23]([C:25]1[CH:48]=[CH:47][C:28]2[N:29]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:30]([C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([CH:39]=O)[CH:33]=3)=[N:31][C:27]=2[CH:26]=1)=[O:24])C.[OH-].[K+].Cl>C(O)C>[NH2:15][C:9]1[CH:10]=[C:11]([C:12]2[CH:13]=[CH:39][C:34]3[C:35](=[CH:36][CH:37]=[C:32]([C:30]4[N:29]([CH:41]5[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]5)[C:28]5[CH:47]=[CH:48][C:25]([C:23]([OH:24])=[O:22])=[CH:26][C:27]=5[N:31]=4)[CH:33]=3)[N:38]=2)[C:6]([C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:7][CH:8]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1-c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)c(C=O)c1)n2C1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Temperature: 75 °C
Reaction time: 72 h
Yield: 12.6 %

Procedure:
1-(4′-Chloro-4-nitro-biphen-2-yl)-ethanone (69 mg, 0.25 mmol) and 2-(4-amino-3-formyl-phenyl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester (98 mg, 0.25 mmol) were dissolved in 500 μL ethanol and 500 μL 10% ethanolic KOH were added. The reaction was stirred at 75° C. for 3 days. The reaction was acidified with 4N hydrochloric acid, extracted three times with ethyl acetate, the organic extracts were dried with sodium sulfate and then evaporated. Purification via reverse-phase HPLC gave 18 mg product.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[N:3]=1.Cl.[CH3:26][C:27]1[N:28]=[C:29]([NH:32][C:33]([NH:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]2)=[O:34])[S:30][CH:31]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:4]3[N:3]=[C:2]([N:38]4[CH2:39][CH2:40][CH2:41][C@@H:36]([NH:35][C:33]([NH:32][C:29]5[S:30][CH:31]=[C:27]([CH3:26])[N:28]=5)=[O:34])[CH2:37]4)[CH:10]=[CH:9][C:5]=3[C:6]([NH2:8])=[O:7])=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: CN1CCN(c2ccc(Nc3nc(Cl)ccc3C(N)=O)cc2)CC1
Reactant: Cc1csc(NC(=O)N[C@@H]2CCCNC2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1csc(NC(=O)N[C@@H]2CCCN(c3ccc(C(N)=O)c(Nc4ccc(N5CCN(C)CC5)cc4)n3)C2)n1
Temperature: 120 °C
Yield: 23.1 %

Procedure:
A mixture of 6-chloro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide (60 mg, 0.173 mmol), (R)-1-(4-methylthiazol-2-yl)-3-(piperidin-3-yl)urea hydrochloride (96 mg, 0.347 mmol), and DIEA (0.182 mL, 1.041 mmol) in N-methyl-2-pyrrolidinone (2 mL) was heated at 120° C. overnight. The reaction mixture was quenched with water, resulting in the formation of light brown precipitate. The solid was filtered, washed with water, and dried under vacuum. The residue was purified by MPLC chromatography (ISCO, 7% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 22 mg of (R)-2-(4-(4-methylpiperazin-1-yl)phenylamino)-6-(3-(3-(4-methylthiazol-2-yl)ureido)piperidin-1-yl)nicotinamide as a yellow solid. LCMS: (M+H)+=550.08; 1H NMR (400 MHz, CDCl3) δ ppm 10.62 (1H, s), 7.47 (2H, d, J=9.23 Hz), 7.33 (1H, d, J=8.79 Hz), 6.85 (2H, d, J=9.23 Hz), 6.28 (1H, s), 5.91 (1H, d, J=8.79 Hz), 5.69 (2H, br. s.), 4.00 (1H, d, J=7.47 Hz), 3.65-3.79 (2H, m), 3.55-3.64 (1H, m), 3.40-3.50 (1H, m), 3.07-3.14 (4H, m), 2.52-2.58 (4H, m), 2.33 (3H, s), 2.19 (3H, s), 1.87-1.98 (1H, m), 1.55-1.82 (3H, m).