Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@H:4]([CH2:5][C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[CH2:8]2)[CH2:3][NH:2]1.Br[CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[C:19]1(=[O:28])[N:18]([CH2:17][CH2:16][CH2:15][N:2]2[CH2:3][CH:4]3[CH:9]([CH2:8][C:7]4[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=4[CH2:5]3)[CH2:1]2)[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc2c(c1)C[C@@H]1CNC[C@H]1C2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CC2Cc3ccccc3CC2C1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A mixture of trans-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole (200 mg, 1.15 mmol), N-(3-bromopropyl)-phthalimide (309 mg, 1.15 mmol), potassium iodide (192 mg, 1.15 mmol), and potassium carbonate (320 mg, 2.31 mmol) in 10 mL of methylethyl ketone was heated at reflux for 8 hours. The mixture was cooled to room temperature, the solids were filtered, and the filtrate was concentrated in-vacuo. The residue was dry-loaded onto a 1×5 cm silica column, and eluted with ethyl acetate followed by 20% methanol/chloroform. Obtained 200 mg of an amber oil. Yield=48%. NMR (300 MHz, CDCl3) δ 7.87-7.83 (m, 2H), 7.76-7.70 (m, 2H), 7.15-7.07 (m, 4H), 3.80 (t, 2H, J=7 Hz), 3.22 (m, 2H), 3.01-2.87 (m, 4H), 2.76-2.56 (m, 4H), 2.11-1.96 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6](=[O:13])[C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:16])C>[O-2].[Cr+6].[O-2].[O-2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:13])[O:12][C:7](=[O:16])[NH:8][C:9]=2[C:10]=1[Cl:11]
Reactant: O=C1Nc2c(ccc(Cl)c2Cl)C1=O
Reactant: CC(=O)OC(C)=O
Agent: [Cr+6]
Agent: [O-2]
Product: O=c1[nH]c2c(Cl)c(Cl)ccc2c(=O)o1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6,7-dichloro-1H-indole-2,3-dione (4.95 g) in 25 mL glacial acid and 25 mL acetic anhydride was added chromium (VI) oxide (3.9 g, 39 mmol) portionwise at 85° C. After addition, the mixture was stirred at 90° C. for 30 min. and cooled down to room temperature. Filtration provided a small amount of 7,8-dichloro-1H-benzo[d][1,3]oxazine-2,4-dione. Evaporation of the filtrate gave the majority of the product as a green solid containing chromium (III) oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39]2)[C:34]([F:50])=[CH:33][N:32]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:39]4)[C:34]([F:50])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCN(C(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 90 °C
Yield: 42 %

Procedure:
A solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (2.41 g, 5.60 mmol) and tert-butyl (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]pyrrolidine-1-carboxylate, 7a, (1.69 g, 5.30 mmol) in DME (34 mL) and 2M Na2CO3 (8.5 mL) was degassed with nitrogen (5 min) then treated with Pd(PPh3)4 (0.31 g, 0.27 mmol) then heated at 90° C. overnight. The resulting dark solution was filtered through florisil, washed with EtOAc then concentrated in vacuo. The resulting residue was purified by silica-gel chromatography (0-100%) petroleum ether: EtOAc gradient. Removal of the solvent under reduced pressure afforded 1.33 g (42% yield) of a white solid after vacuum drying.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:40][CH3:41])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4OC)[C:22]4[S:23][C:24]([F:27])=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:11](=[O:39])[NH:10][N:9]=2)[CH:7]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:40][CH3:41])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:23][C:24]([F:27])=[CH:25][N:26]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[C:11](=[O:39])[NH:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(CN(c2ncc(F)s2)S(=O)(=O)c2ccc3c(-c4cc(Cl)ccc4OC)n[nH]c(=O)c3c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Nc3ncc(F)s3)ccc12
Reaction time: 0.5 h
Yield: 2.7 %

Procedure:
A vial was charged with 5-fluoro-N-(4-methoxybenzyl)thiazol-2-amine (67.1 mg, 0.282 mmol), perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (100 mg, 0.188 mmol), and THF (938 μl). The resulting solution was cooled to 0° C. for 10 min. Then lithium bis(trimethylsilyl)amide (1M in THF) (413 μl, 0.413 mmol) was added drop wise. LCMS after 15 min showed incomplete conversion of SM. Additional LHMDS (400 μL, 1M in THF) was added. After 15 min, TLC showed complete conversion of PFP-sulfonate to a lower spot. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(5-chloro-2-methoxyphenyl)-N-(5-fluorothiazol-2-yl)-N-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (65 mg, 59.0% yield) as a brown solid. m/z (ESI) 587.0 (M+H)+, 609.0 (M+Na)+. 1-(5-Chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(5-fluorothiazol-2-yl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (65 mg, 0.105 mmol) was dissolved in DCM (1053 μl, 0.105 mmol) and then TFA (40.6 μl, 0.527 mmol) was added. After 30 min at rt, LCMS showed a complete conversion of SM to product. Purification was done with 0.1% NH4OH in ACN and water as mobile phase to afford impure product. The product was purified further by RPLC on the acidic Gilson. Fractions containing the product were combined and washed with sat. NaHCO3. The product was extracted with DCM. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated to afford 1-(5-chloro-2-methoxyphenyl)-N-(5-fluorothiazol-2-yl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (1.3 mg, 2.64% yield) as off-white solid. m/z (ESI) 467.0 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1.F.F.F.C(N(CC)CC)C.[F:23]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1.C(N(CC)CC)C>[F:23][CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: COC(=O)c1cnc(CO)cn1
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(CF)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
To a solution of methyl 5-(hydroxymethyl)pyrazine-2-carboxylate (0.64 g) in THF (20 mL) was added triethylamine (2.30 g) and the solution was cooled to 0° C. Triethylamine trihydrofluoride (1.22 g) was then added followed by nonafluorobutanesulfonyl fluoride (2.28 g) dropwise over 5 mins. After warming to RT and stirring for 2 h, NaHCO3 (sat., aq., 100 mL) was added, and the mixture was extracted with EtOAc (2×50 mL). The combined organic portions were dried over MgSO4, evaporated, and purified by silica gel chromatography (5% to 50% EtOAc in hexane) to afford the title compound (94 mg). 1H NMR (400 MHz, CDCl3) δ ppm 4.07 (s, 3H), 5.67 (d, J=46.5 Hz, 2H), 8.89 (s, 1H), 9.28 (s, 1H)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]2[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:16]=[CH:17][C:3]=12.Cl.[CH:25]12[NH:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][O:27][CH2:26]2.C(N(CC)CC)C>C(O)C>[CH:29]12[N:32]([C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=4)[N:5]=[C:4]4[N:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:16]=[CH:17][C:3]=34)[CH:25]([CH2:31][CH2:30]1)[CH2:26][O:27][CH2:28]2
Reactant: Oc1cccc(-c2nc(Br)c3cnn(-c4ccccc4)c3n2)c1
Reactant: C1CC2COCC1N2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1cccc(-c2nc(N3C4CCC3COC4)c3cnn(-c4ccccc4)c3n2)c1
Temperature: 130 °C

Procedure:
A Smith process vial was charged with a suspension of 3-(4-bromo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (0.18 g, 0.49 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (approximately 100 mg, 0.67 mmol) in ethanol (4 mL). The suspension was treated with triethylamine (750 μL, 5.7 mmol) and was then heated in the microwave reactor for 10 minutes at 130° C. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 20% acetonitrile/80% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol. MS (ES+): 400.3 (M+H)+
Reaction SMILES: [Br:1]CCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:24]1>>[Br:1][CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:24]1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCO)C1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCBr
Product: O=C(OCc1ccccc1)N1CCCC(CCBr)C1

Procedure:
Prepared similarly to Intermediate 26 from phenylmethyl 3-(2-hydroxyethyl)-1-piperidinecarboxylate
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[O:13]=[C:14]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=3)[CH:27]=2)[O:22][C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15]1.[CH2:38]([O:40][C:41]1[CH:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[C:43]([O:50][CH2:51][CH3:52])[C:42]=1[C:53]1[CH:58]=[CH:57][C:56]([C:59]([O:61][CH3:62])=[O:60])=[CH:55][CH:54]=1)[CH3:39].O>CN(C=O)C>[C:33]([C:32]1[CH:36]=[CH:37][C:29]([C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[O:22][C:16]2([CH2:21][CH2:20][N:19]([C:47]([C:45]4[CH:44]=[C:43]([O:50][CH2:51][CH3:52])[C:42]([C:53]5[CH:58]=[CH:57][C:56]([C:59]([O:61][CH3:62])=[O:60])=[CH:55][CH:54]=5)=[C:41]([O:40][CH2:38][CH3:39])[CH:46]=4)=[O:48])[CH2:18][CH2:17]2)[CH2:15][C:14]3=[O:13])=[N:30][CH:31]=1)(=[O:34])[NH2:35]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1ccc(C(=O)OC)cc1
Reactant: NC(=O)c1ccc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)nc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4ccc(C(N)=O)cn4)ccc2O3)cc(OCC)c1-c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
TEA (0.657 ml, 4.71 mmol) was added to a stirred mixture of HOBT (313 mg, 2.04 mmol), WSCDI (361 mg, 1.89 mmol), 6-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)nicotinamide dihydrochloride (2.61 g, 6.97 mmol) and 2,6-diethoxy-4′-(methoxycarbonyl)biphenyl-4-carboxylic acid (2.00 g, 5.81 mmol) in DMF (30 ml) and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water (600 ml) and stirred for 30 min. The resulted precipitate was filtered, washed with water and the solid was dried in vacuo at 70° C. The crude product was purified by silicagel column chromatography (CHCl3/Acetone) to give intended compound (3.85 g, quantitative) as a colorless solid.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(OCC)(=O)C>[CH3:18][S:19]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Methyl anthranilate (11.73 g, 77.6 mmol) was dissolved in pyridine (25 mL, 309 mmol). Mixture was cooled to 0° C. Methanesulfonyl chloride (6.60 mL, 85.3 mmol) was added to the mixture drop-wise. Reaction mixture was warmed to room temperature and held with stirring overnight. Mixture was diluted with ethyl acetate. Material was washed twice with water and three times with 1N hydrochloric acid. Organic layer was dried (magnesium sulfate), filtered and then concentrated. Residue was triturated with 50% diethyl ether in hexanes. Solids were filtered off, washed with 50% diethyl ether-hexanes, washed with hexanes and then dried under high vacuum. Title compound was obtained as an off-white solid in 88% yield. MS m/e (M−H)−=227.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([OH:18])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirred solution of Intermediate 57 (300 mg) in a mixture of methanol (2.5 mL) and dichloromethane (2.5 mL) at ambient temperature was added sodium borohydride (75.0 mg) in one charge. The reaction was stirred at ambient temperature under an atmosphere of nitrogen for 1 hr (incomplete). Stirring continued for 16 hr. The reaction was partitioned between ethyl acetate (40 mL) and water (40 mL). The organic was dried (hydrophobic frit) and concentrated in vacuo to give the title compound (166 mg). LC/MS MH+ 305, 307, Rt 1.38 min (5 min run).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([CH3:15])[NH:12][C:9]2=[N:10][CH:11]=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>ClCCl>[Br:5][C:6]1[CH:7]=[C:8]2[C:14]([C:18](=[O:19])[CH2:17][Cl:16])=[C:13]([CH3:15])[NH:12][C:9]2=[N:10][CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cc2cc(Br)cnc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1[nH]c2ncc(Br)cc2c1C(=O)CCl
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a suspension of AlCl3 (1.57 g, 11.84 mmol) in dichloromethane (50 mL) was added 5-Bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine. After stirring for 30 min, chloroacetyl chloride (1.33 g, 11.84 mmol) was added and the reaction mixture was stirred for 2 hours at room temperature. On completion, solvents were evaporated and quenched with aq. NaHCO3 solution at 0° C. Resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and filtered through a plug of silica gel. Solvent was evaporated to dryness to give 1-(5-Bromo-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-chloro-ethanone (0.650 g, 95% yield).
Reaction SMILES: C(O)(=O)C(O)=[O:3].C([O:15][CH2:16][CH2:17][CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH2:30][C@H:31]([NH:33][CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH2:44][C:45]([F:48])([F:47])[F:46])[CH3:32])=[CH:25][C:26]=2[C:28]#[N:29])[CH2:21][CH2:20]1)(=O)C1C=CC=CC=1.[OH-].[K+:50].O>CO>[OH-:3].[K+:50].[OH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH2:30][C@H:31]([NH:33][CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH2:44][C:45]([F:48])([F:46])[F:47])[CH3:32])=[CH:25][C:26]=2[C:28]#[N:29])[CH2:21][CH2:20]1
Reactant: C[C@H](Cc1cc(C#N)c2c(c1)CCN2CCCOC(=O)c1ccccc1)NCCOc1ccccc1OCC(F)(F)F
Reactant: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](Cc1cc(C#N)c2c(c1)CCN2CCCO)NCCOc1ccccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.6 %

Procedure:
3-{7-Cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}-propyl benzoate monooxalate(10.0 g) was dissolved. in methanol (40 mL), then an aqueous potassium hydroxide solution, which was prepared from potassium hydroxide (2.93 g) and water (10 mL) was added little by little, and the mixture was stirred at room temperature for overnight. To the reaction mixture, water (150 mL) was added and extracted with ethyl acetate (150 mL and 50 mL) successively. The combined ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (7.86 g).
Reaction SMILES: [CH3:1][C:2]1[N:31](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][N:14]=[C:13]4[N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23](=[O:30])[CH2:22][CH2:21]3)[CH:9]=[C:4]2[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[NH:31][C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][N:14]=[C:13]4[N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23](=[O:30])[CH2:22][CH2:21]3)[CH:9]=[C:4]2[N:3]=1
Reactant: Cc1nc2cc(-c3ccc4ncnc(N5CCC(=O)c6ccccc65)c4c3)cnc2n1COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2cc(-c3ccc4ncnc(N5CCC(=O)c6ccccc65)c4c3)cnc2[nH]1
Yield: 21.1 %

Procedure:
0.25 g of 1-{6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]-pyridin-6-yl]quinazolin-4-yl}-2,3-dihydro-1H-quinolin-4-one and 255 μl of trifluoroacetic acid in 2 ml of dichloromethane are stirred at 25° C. in a flask until the reaction is complete (HPLC check, about 72 hours). The cooled reaction solution is evaporated to dryness in a rotary evaporator. The residue is purified by means of preparative HPLC (gradient water:acetonitrile 1-50% in 16 min.), giving 0.04 g of 1-[6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-quinazolin-4-yl]-2,3-dihydro-1H-quinolin-4-one (“A13”) as white solid (yield 23%, content 99%); MS-FAB (M+H+)=407.1; Rf (polar method): 1.50 min;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:48]=[CH:47][C:28]([CH2:29][O:30][C:31]([NH:33][C:34]2[N:42]=[CH:41][N:40]=[C:39]3[C:35]=2[N:36]=[CH:37][N:38]3[CH2:43][C:44](O)=[O:45])=[O:32])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:44](=[O:45])[CH2:43][N:38]1[CH:37]=[N:36][C:35]2[C:39]1=[N:40][CH:41]=[N:42][C:34]=2[NH:33][C:31]([O:30][CH2:29][C:28]1[CH:47]=[CH:48][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)=[O:32])[CH3:2]
Reactant: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)O)cc1
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(NC(=O)OCc3ccc(OC)cc3)ncnc21
Yield: 102.5 %

Procedure:
To the mixture of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (172 mg, 0.5 mmol), [6-N-(4-methoxybenzyloxycarbonyl)-adenin-9-yl]-acetic acid (179 mg, 0.5 mmol), and HBTU (190 mg, 0.5 mmol) in DMF (2 ml) was added diisopropylethylamine (0.09 ml, 0.5 mmol) at ambient temperature. The resulting reaction mixture was stirred for 2 h at the same temperature and 1N HCl was added to the reaction mixture. The resulting precipitate product was filtered off, washed with water, and dried in vacuo to give the title compound as a white solid (0.35 g, 97%). 1H NMR (500 MHz; DMSO-d6) δ 8.97 (t, 0.6H) 8.76 (t, 0.4H) 8.64 (s, 0.4H) 8.60 (s, 0.6H) 8.53 (d, 1H) 8.28 (m, 1H) 8.17 (d, 1H) 7.66 (m, 2H) 7.40 (d, 2H) 6.95 (d, 2H) 5.41 (s, 1.2H), 5.20 (s, 0.8H) 5.18 (s, 2H) 4.46 (s, 0.8H) 4.18 (q, 0.8H) 4.08 (s, 1.2H) 4.03 (q, 1.2H) 3.75 (s, 3H) 3.70 (q, 1.2H) 3.48 (q, 1.2H) 3.42 (t, 0.8H) 3.22 (q, 0.8H) 1.24 (t, 1.2H) 1.13 (t, 1.8H)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:12]/[O:13][C:14]([CH3:43])([CH3:42])[C:15](=[O:41])[CH:16]2[CH2:21][NH:20][CH2:19][CH2:18][N:17]2[C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)/[C:8]([O:10]C)=[O:9])[N:6]=1.[OH-].[K+]>C(O)C.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:12]/[O:13][C:14]([CH3:43])([CH3:42])[C:15](=[O:41])[CH:16]2[CH2:21][NH:20][CH2:19][CH2:18][N:17]2[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: COC(=O)/C(=N\OC(C)(C)C(=O)C1CNCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(N)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)C1CNCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
(Z)-2-Amino-α-[[1,1-dimethyl-2-oxo-2-(N-tritylpiperazinyl)ethoxy]imino]-4-thiazoleacetic acid, methyl ester (4.03 g, 6.75 mmol) was suspended in a solution of 0.90 g of potassium hydroxide in ethanol (22.5 ml) and water (1.8 ml), and stirred overnight at room temperature. The reaction was then heated to 60° C. for 30 minutes. Upon cooling to room temperature, water (22.5 ml) was added, and the reaction mixture was filtered through Celite. The filtrate was then acidified to pH 3 with 1N hydrochloride acid while cooling in ice, and the precipitate that formed was isolated by filtration. The precipitate was washed with water, ether and acetonitrile to yield 1.71 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][N+:14]([O-])=O)[CH2:3][C:4]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)([OH:6])[CH3:5]>CCO>[NH2:14][CH2:13][CH:2]([CH3:1])[CH2:3][C:4]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)([OH:6])[CH3:5]
Reactant: CC(C[N+](=O)[O-])CC(C)(O)c1cccnc1
Solvent: CCO
Product: CC(CN)CC(C)(O)c1cccnc1
Yield: 84.4 %

Procedure:
Stir a mixture of 4-methyl-5-nitro-2-pyridin-3-yl-pentan-2-ol (860 mg, 3.84 mmol) and Pt—C(S) (200 mg) in EtOH (25 mL) at room temperature under hydrogen atmosphere (7 atm) for 24 h. Filter through a pad of Celite® and evaporate to obtain 630 mg (84%) of the title compound.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]([C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)[C:18]([NH2:20])=[NH:19]>C1C=CC=CC=1.N1C=CC=CC=1>[N:25]1[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[NH:22][C:21]=1[N:17]=[C:18]1[NH:20][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:20][C:18](=[N:17][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)[NH:19][C:9]2([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:19]1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: c1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccccc2)NC(=Nc2nc4ccccc4[nH]2)N3)cc1
Yield: 17.8 %

Procedure:
A mixture of benzil (1.05 g, 5.0 mmol) and 2-guanidinobenzimidazole (1.57 g, 9.0 mmol) in benzene (25 mL) was refluxed in pyridine (10 mL) for 1 h. After evaporating most of the pyridine under reduced pressure, the residue was treated with hot toluene and the resulting precipitate was filtered. The precipitate was then dissolved in 9:1 water:acetic acid (30 mL); the solution was filtered and the filtrate was neutralized to pH 7 with phosphate buffer. A precipitate formed, that was then collected and triturated with water to afford the title compound (0.42 g, 16%). 1H NMR (300 MHz, d6-DMSO) d 11.5 (br s, NH, 2 H), 10.0 (br s, NH, 2 H), 8.6 (br s, NH, 2 H), 7.28-7.10 (m, 14 H), 6.97 (dd, J=6.0, 3.0 Hz, 4 H); MS (ESI) m/z 525 [M+H]+; Anal. Calcd. for C30H24N10 . ½CH3CO2H ¾H2O: C, 65.37; H, 4.88; N, 24.65. Found: C, 65.36; H, 4.79; N, 24.48.