Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](SC)[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:7]2=[O:20].ClC1C=C(C=CC=1)C(OO)=O.[CH:32]([NH2:35])([CH3:34])[CH3:33]>C(Cl)Cl.C([O-])(O)=O.[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:35][CH:32]([CH3:34])[CH3:33])[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:7]2=[O:20]
Reactant: CSc1nc2c(Br)cccc2c(=O)n1-c1ccccn1
Reactant: CC(C)N
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)Nc1nc2c(Br)cccc2c(=O)n1-c1ccccn1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 8-bromo-2-(methylthio)-3-(pyridin-2-yl)quinazolin-4(3H)-one (179 mg, 0.514 mmol, 415c) in DCM (5.1 mL) was set stirring and 3-chloroperoxybenzoic acid (127 mg, 0.565 mmol, 77% max.; Sigma Aldrich) was added. The mixture was stirred for 4 h to give a mixture of sulfone and sulfoxide. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow residue. The residue and isopropylamine (1.7 mL, 19.73 mmol) was set stirring at 80° C. for 30 min. The reaction was cooled to RT and diluted with water. The mixture was extracted with DCM and dried over Na2SO4. Silica was added, and the material was adsorbed under reduced pressure. It was purified on 12 g SiO2 (eluent: 0-100% EtOAc/hexanes over 25 min, RediSep Gold). The product fractions were combined and concentrated under reduced pressure to give 8-bromo-2-(isopropylamino)-3-(pyridin-2-yl)quinazolin-4(3H)-one (71 mg, 30% for 2 steps). 1H NMR (400 MHz, DMSO-d6) ppm 8.69 (1H, dd, J=4.79, 1.08 Hz) 8.08 (1H, td, J=7.73, 1.76 Hz) 7.97 (1H, dd, J=7.63, 1.37 Hz) 7.88 (1H, dd, J=7.92, 1.47 Hz) 7.55-7.63 (2H, m) 7.03 (1H, t, J=7.73 Hz) 5.90 (1H, d, J=7.63 Hz) 1.15 (6H, d, J=6.65 Hz). m/z (ESI, +ve) 360.8 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[Cl:9].C[Si](C)(C)[C:12]#[C:13][CH3:14].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(NC(C)C)(C)C>[Cu](I)I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CN(C=O)C>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:12]#[C:13][CH3:14])[C:3]=1[Cl:9]
Reactant: Clc1c(Br)cccc1Br
Reactant: CC#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: [Fe+2]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC#Cc1cccc(Br)c1Cl
Yield: 22 %

Procedure:
To a microwave vial were added 1,3-dibromo-2-chlorobenzene (780 mg, 2.89 mmol), trimethyl(prop-1-ynyl)silane (0.645 mL, 4.33 mmol), copper iodide (28 mg, 0.14 mmol), PdCl2(dppf) CH2Cl2 (118 mg, 0.14 mmol), tetrabutylammonium fluoride (1 M in THF, 8.66 mL, 8.66 mmol), diisopropylamine (1.23 mL, 8.66 mmol) and anhydrous DMF (5 mL). The vial was capped and purged with argon and the mixture was irradiated at 100° C. for 1 h in a microwave reactor. The mixture was diluted with water and extracted with DCM three times, dried through a phase separator and concentrated in vacuo. The product was purified by flash chromatography (100% heptanes as eluent) to give 146 mg (22% yield) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.13 (s, 3 H) 7.24 (t, J=7.88 Hz, 1 H) 7.53 (dd, J=7.57, 1.26 Hz, 1 H) 7.74 (dd, J=8.04, 1.42 Hz, 1 H); MS (CI) m/z 231 [M+H]1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]3[NH:15][CH2:14][C:13]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[N:11][CH:12]=2)[CH2:3][CH2:2]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C:34]2=[O:39])[C:23]=1[CH3:40].CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([N:15]3[C:9]4[C:10](=[N:11][CH:12]=[C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[CH:8]=4)[C:13]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:23]([CH3:40])[C:24]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][C:34]3=[O:39])=[N:25]2)=[CH:30][CH:29]=1
Reactant: Cc1c(N2CCCCC2=O)nc2cc(F)ccc2c1Cl
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCCC2=O)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by stirring 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (56.4 mg, 0.20 mmol), 1-(4-chloro-7-fluoro-3-methylquinolin-2-yl)piperidin-2-one (60 mg, 0.20 mmol), sodium tert-butoxide (39.4 mg, 0.41 mmol) and XPhos precatalyst (15.1 mg, 0.020 mmol) in toluene (1.5 mL) at 130° C. for 1 h and 15 min in a microwave reactor. Purification by column chromatography (DCM: (DCM:MeOH:NH4OH, 9:1:0.4) from 1:0 to 7:3) gave the desired product. Further purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1-(7-fluoro-3-methyl-4-(6′-(4-morpholinyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-1′(2′H)-yl)-2-quinolinyl)-2-piperidinone. 1H NMR (500 MHz, chloroform-d) δ ppm 7.59-7.84 (3H, m), 7.20-7.33 (1H, m), 6.02-5.69 (1H, m), 4.10-4.34 (3H, m), 3.88-4.08 (1H, m), 3.71-3.82 (4H, m), 3.41-3.64 (4H, m), 2.91-3.15 (4H, m), 2.53-2.68 (2H, m), 2.28-2.41 (2H, m), 1.98-2.18 (7H, m), 1.78-1.87 (2H, m). Mass Spectrum (ESI) m/e=532.2 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:9][CH:8]=1.CCN(CC)CC.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CC#N>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][N:15]1[CH2:16][CH2:17][O:18][CH:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]3[C:3]([Cl:2])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:23])=[CH:12][CH:11]=2)[CH2:14]1)[CH3:37]
Reactant: Clc1cccc(Cl)c1COc1ccc(C2CNCCO2)cc1
Reactant: CCOC(=O)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN1CCOC(c2ccc(OCc3c(Cl)cccc3Cl)cc2)C1
Temperature: 85 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine hydrochloride (0.65 g; 1.68 mmol), Et3N (0.58 mL; 4.2 mmol), and ethyl bromoacetate (0.24 ml; 2.19 mmol) in CH3CN (65 mL) was stirred at 85° C., overnight. After cooling to RT the mixture was concentrated in vacuo and the residue partitioned between water and CH2Cl2. The layers were separated and aqueous layer was extracted once more with CH2Cl2. The combined organic layers were concentrated in vacuo and the residue was purified by column chromatography (SiO2, Et2O:hexanes 2:1) to afford {2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-acetic acid ethyl ester (0.62 g).
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>O1CCCC1>[CH3:3][C:2]1([C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:4][CH:12]2[S:11][CH:15]1[CH:14]=[CH:13]2
Reactant: c1ccsc1
Reactant: C=C(C)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(C)CC2C=CC1S2
Temperature: 700 °C
Reaction time: 24 h

Procedure:
In tetrahydrofuran solvent (500 g), tert-butyl methacrylate (1.2 mole) of Chemical Formula 3d below and thiophene (1.0 mole) are dissolved, and the solution is introduced into a 2-liter flask. After stirring at 700° C., 10 atm for 24 hours, the solvent and excess amount of tert-butyl methacrylate are removed by using a rotary evaporator. The residue is distilled in vacuo to obtain pure 1,1-dimethylethyl 2-methyl-7-thiabicyclo[2.2.1]hept-5-ene-2-carboxylate of Chemical Formula 125 (yield: 50%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([NH:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:17]=1[N+:24]([O-])=O)[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O>[NH2:24][C:17]1[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=1[NH:15][C@@H:13]([CH3:14])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: C[C@H](Nc1cc(C#N)ccc1[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(C#N)ccc1N)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 4 h
Yield: 99.7 %

Procedure:
A mixture of (2S,3S)-2-(tert-butoxycarbonyl amino)-3-(5-cyano-2-nitrophenylamino)butanoic acid (5.35 g, 14.7 mmol) and PdC (10% dry basis, wet, 50% water) (535 mg, 251 μmol) in MeOH (60 ml) and EtOAc (60 ml) was shaken under H2 (50 PSI) for 4 h, then filtered through a bed of celite and concentrated to afford (2S,3S)-3-(2-amino-5-cyanophenylamino)-2-(tert-butoxycarbonylamino)butanoic acid (4.9 g, quant.) as a dark brown solid.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[NH:10][CH:9]([C:11]([OH:13])=O)[CH2:8][CH2:7]1.[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[O:23][C:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32])=[CH:21][C:20]2=[O:35].N1C=CC=CC=1>C1COCC1.CN(C=O)C>[O:5]=[C:6]1[NH:10][CH:9]([C:11]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:32])[F:33])=[CH:21][C:20]3=[O:35])=[O:13])[CH2:8][CH2:7]1
Reactant: Nc1cccc2c(=O)cc(-c3ccccc3C(F)(F)F)oc12
Reactant: O=C1CCC(C(=O)O)N1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C1CCC(C(=O)Nc2cccc3c(=O)cc(-c4ccccc4C(F)(F)F)oc23)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionylchloride (236 mg, 2.0 mmol) was added to a solution of 5-oxopyrrolidine-2-carboxylic acid 120 (170 mg, 1.32 mmol) in THF (5 mL) at 0° C. DMF (1 drop) was added and the solution was allowed to warm to room temperature for 2 h then cooled to 0° C. A solution of 8-amino-2-(2-(trifluoromethyl)phenyl)-4H-chromen-4-one 11 (100 mg, 0.33 mmol) and pyridine (0.5 mL) in THF (1 mL) was added and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated to dryness, dissolved in EtOAc, washed with sat. aq NaHCO3, brine, and dried (Na2SO4). The crude residue was purified by preparative TLC eluting with EtOAc to give Compound 313. MS (ESI) calcd for C21H15F3N2O4: 416.1. found: 417 [M+H].
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].[CH3:8][N:9]1[C@H:13]2[C:14]([C:17](OC)=O)=[CH:15][CH2:16][C@@H:10]1[CH2:11][CH2:12]2>C1COCC1>[CH3:2][C:1]1[N:3]=[C:17]([C:14]2[CH:13]3[N:9]([CH3:8])[CH:10]([CH2:16][CH:15]=2)[CH2:11][CH2:12]3)[O:5][N:4]=1
Reactant: COC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C2=CCC3CCC2N3C)n1

Procedure:
Acetamide oxime (500 mg, 6.75 mmol) suspended in THF (50 mL) under nitrogen was heated at 60° C. with NaH (132 mg, 5.5 mmol in oil dispersion) for 1 h. Anhydroecgonine methyl ester (2.76 mmol) and 4 Å° molecular sieves (2 g) were added and the reaction mixture heated under reflux for 3 h. After cooling, the reaction mixture was filtered and the solvent removed in vacuo. The residue was chromatographed on a silica gel column eluting with CHCl3 --CH3OH (95:5) to give the free base.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO>[C:10]1([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: c1ccc(-c2ccoc2)cc1
Temperature: 80 °C
Yield: 77.6 %

Procedure:
Furan-3-boronic acid (1.0 g, 8.93 mmol), bromo benzene (1.26 g, 8.04 mmol) and sodium carbonate (1.89 g, 17.86 mmol) were dissolved in a mixture of toluene (15 mL) and methanol (5 mL) and purged with argon for 15 min. Tetrakis palladium (0) (20 mg) was added and the mixture again degassed for 15 min. The reaction was heated at 80° C. for 4 h and the resultant solids which formed were filtered and the filtrate was concentrated in vacuo to give a crude residue. Purification by flash chromatography over silica gel (100-200 mesh) using 2% ethyl acetate/petroleum ether as eluent afforded 3-phenylfuran (0.9 g, 70%).
Reaction SMILES: [F:1][C:2]1([F:27])[CH:7]([NH:8][C:9]2[N:26]=[C:12]3[C:13]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=4[F:25])=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:29]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31][N:30]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[F:27][C:2]1([F:1])[CH:7]([NH:8][C:9]2[N:26]=[C:12]3[C:13]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=4[F:25])=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH2:6][CH2:5][N:4]([C:29]2[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31][N:30]=2)[CH2:3]1
Reactant: Fc1ccc(-c2cccn3nc(NC4CCNCC4(F)F)nc23)c(F)c1F
Reactant: Cc1cc(Cl)ncn1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCC(Nc3nc4c(-c5ccc(F)c(F)c5F)cccn4n3)C(F)(F)C2)ncn1
Temperature: 150 °C

Procedure:
A solution of N-(3,3-difluoropiperidin-4-yl)-8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (75 mg, 196 μmol), 4-chloro-6-methylpyrimidine (27.7 mg, 215 μmol) and N,N-diisopropylethylamine (37.9 mg, 49.9 μL, 293 μmol) in dioxane (4 mL) was heated to 150° C. in the microwave for 1 hour. Further 4-chloro-6-methylpyrimidine (27.7 mg, 215 μmol) and N,N-diisopropylethylamine (37.9 mg, 49.9 μL, 293 μmol) were added and heated to 150° C. in the microwave for another hour. Further 4-chloro-6-methylpyrimidine (27.7 mg, 215 μmol) and N,N-diisopropylethylamine (37.9 mg, 49.9 μL, 293 μmol) were added and heated to 110° C. for 12 hours. The crude material was directly purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as light yellow foam (25 mg, 22%). MS ISP (m/e): 476.1 (100) [(M+H)+].
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9]C(O)=O.Cl[O-].[Na+]>CO>[C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:13]([OH:15])=[O:14])=[CH2:9]
Reactant: Cc1ccccc1N[C@@H](CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: C=C(Nc1ccccc1C)C(=O)O
Yield: 33.4 %

Procedure:
10 g of N-(ortho-toluyl)aspartic acid are disolved in 20 ml of methanol in a 500 ml, three-necked, round-bottomed flask equipped with a thermometer, a dropping funnel and a reflux condenser. After having completely dissolved, 28.5 ml of an aqueous sodium hypochlorite solution, assaying at 1.40 mol/l, are added dropwise while maintaining the temperature below 20 °C. At the end of the addition, the mixture is diluted with 180 ml of methanol before being brought to reflux for 1 h 30 minutes. After concentrating under vacuum, the residue is taken up in ethyl acetate and extracted with an aqueous sodium bicarbonate solution. The aqeuous phase is acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with brine before being dried and concentrated under vacuum to provide an oil which crystallizes on addition of water. The precipitate formed is filtered and purified by recrystallization from water (a few drops of methanol are added, if necessary) to provide 2.65 g of N-(ortho-toluyl) dehydroalanine. (Nonoptimized yield 32%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].F[C:20]1[C:25]([C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3C2CCCCO2)=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(C(F)(F)F)=O.N>O.C(Cl)Cl.CO.CN(C=O)C>[N:34]1[C:26]([C:25]2[C:20]([O:18][C:15]3[CH:16]=[CH:17][C:12]([C:10]([C:2]4[NH:3][C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[N:1]=4)=[O:11])=[CH:13][CH:14]=3)=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:27]2[C:31]([NH:30][CH:29]=[N:28]2)=[N:32][CH:33]=1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Agent: N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(c1ccc(Oc2ncccc2-c2ncnc3[nH]cnc23)cc1)c1nc2ccccc2[nH]1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A screw cap heavy wall flask was charged with (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.350 g, 1.469 mmol), 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.440 g, 1.469 mmol), cesium carbonate (0.957 g, 2.94 mmol) and DMF (6 mL). The vial was capped and heated to 100° C. After 12 hours, the reaction was allowed to cool to RT and diluted with 20 ml of water. The mixture was extracted (3×) with 10 ml of ethyl acetate. The organic layers were combined and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 20 to 60% EtOAc in hexanes. The pure fractions were combined and reduced under vacuum to give an oily residue. The residue was dissolved in DCM (10 mL) and treated with 1 mL of TFA and a few drops of water. The mixture was allowed to stir at room temperature overnight. 10 ml of 2N ammonia in MeOH was added to the reaction with was reduced in vacuo. The residue was partitioned in water and EtOAc. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and reduced. The residue obtained was triturated in 1:1 ethyl acetate:ether and then dried in a vacuum oven to give product as solid. MS (ESI, pos. ion) m/z: 434.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [NH2:1]/[C:2](=[CH:7]\[C:8]([O:10][CH3:11])=[O:9])/[C:3]([O:5][CH3:6])=[O:4].[CH:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=O)=O>>[N:1]1[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=2[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]=1[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=CC1CCCCC1=O
Reactant: COC(=O)/C=C(\N)C(=O)OC
Product: COC(=O)c1cc2c(nc1C(=O)OC)CCCC2
Temperature: 150 °C
Yield: 18.9 %

Procedure:
A mixture of 10.04 g dimethyl aminofumarate and 8.0 g 2-formylcyclohexanone is heated at 150° C. under a reflux condenser for one hour. The condenser is removed, and the volatile components allowed to escape. Material volatile at 0.5 mm and 150° C. is then removed. The residue is purified by flash chromatography on silica gel using hexane-ethyl acetate (4:1) as eluant. Fractions containing the product are combined to give 2.97 g dimethyl 5,6,7,8-tetrahydroquinoline-2,3-dicarboxylate as an amber oil having the appropriate NMR and IR spectra.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.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>CN(C=O)C>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([O:1][C:2]2[CH:15]=[CH:14][C:13]3[S:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]=3[CH:3]=2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: Oc1ccc2c(c1)Nc1ccccc1S2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)Nc2ccccc2S3)cc1
Temperature: 70 °C
Yield: 83 %

Procedure:
1.1 g (5.11 mmol) of 2-hydroxy-10H-phenothiazine (J. Med. Chem. (1992) 35, 716), 1.34 g (9.71 mmol) of K2CO3 and 0.94 g (6.64 mmol) of 4-fluoro-1-nitrobenzene are mixed in 25 ml anhydrous DMF in a flask under argon atmosphere,. The reaction mixture is heated at 70° C. for 18 hours. The solvent is then evaporated off under vacuum and the residue is taken up in 50 ml of AcOEt and 50 ml of water. After agitation and decantation, the organic phase is washed with 50 ml of salt water. The organic solution is dried over MgSO4, filtered and concentrated under vacuum. The residue is crystallized from diisopropyl ether. After drying, a yellow solid is obtained with a yield of 83%. Melting point: 210–211° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[N:7]([N:8]=[C:9]([C:15]4[N:16]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:17]=[CH:18][N:19]=4)[CH:10]=3)[C:6]=2[CH:25]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:26]([O:30][C:31]([N:33]1[CH2:34][CH:35]=[C:36]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[N:7]([N:8]=[C:9]([C:15]5[N:16]([CH2:20][C:21]([F:24])([F:22])[F:23])[N:17]=[CH:18][N:19]=5)[CH:10]=4)[C:6]=3[CH:25]=2)[CH2:37][CH2:38]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(Br)ccc1OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Temperature: 80 °C
Yield: 89.8 %

Procedure:
9-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (207 mg, 0.5 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (232 mg, 0.75 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (10 mol %), and potassium carbonate (138 mg, 1.0 mmol) were charged to a reaction vial, the atmosphere evacuated and back-filled with nitrogen. DMF (1 mL) was added, degassing repeated, and the mixture heated at 80° C. for 18 h. The cooled reaction mixture was diluted with ethyl acetate and washed with water then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 20 to 60% ethyl acetate in cyclohexane) to give 4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert butyl ester as a white crystalline solid (232 mg, 90%). LCMS: RT=4.87 min, M+H+=517.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.[OH-].[Na+].C(OCC)(=O)C>C1C=CC=CC=1.O>[CH3:23][C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc(NC(=O)c2ccc(C)cc2)cc1
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
10 g of ethyl 4-aminophenylacetate was dissolved in 120 ml of benzene and to this was further added 25 ml of water. To this solution were added dropwise a solution of 8.6 g of p-toluoyl chloride dissolved in 20 ml of benzene and a solution of 2.4 g of 93% NaOH dissolved in 25 ml of water simultaneously under stirring over 15 minutes. After completion of the dropwise addition, the solution was stirred for 3 hours and allowed to stand overnight. After adding 200 ml of ethyl acetate, the oil layer was separated, washed with 1N-HCl solution and with a saturated solution of sodium chloride, and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was recrystallized from benzene-n-hexane to give 12 g of ethyl 4-(4-methylbenzoylamino)phenylacetate.