Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[NH:12][CH2:11][CH2:10]2)(=O)=O.[C:20](=[N:33][NH2:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1(C)C=CC=CC=1.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.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[C:21]1([C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:33][NH:34][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[NH:12][CH2:11][CH2:10]3)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: O=C1NCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NCCc2cc(NN=C(c3ccccc3)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a suspension of 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate (1.70 g, 5.76 mmol), benzophenone hydrazone (1.36 g, 6.91 mmol), Cs2CO3 (2.81 g, 8.64 mmol) and DPPF (0.048 g, 0.086 mmol) in degassed PhMe (40 mL) was added Pd(OAc)2 (0.013 g, 0.058 mmol) and the resulting mixture was stirred at RT for 30 min and then heated at 90° C. After 16 h, the mixture was cooled to RT, H2O (50 mL) was added and the mixture was extracted with EtOAc (3×50 mL), dried (MgSO4), concentrated and purified via column chromatography to yield 6-(2-(diphenylmethylene)hydrazinyl)-3,4-dihydroisoquinolin-1(2H)-one (980 mg, 50% yield). 1H NMR (400 MHz, acetone-d6): δ 8.69 (brs, 1H), 7.79 (d, J=9.2 Hz, 1H), 7.63-7.54 (m, 5H), 7.37-7.31 (m, 5H), 7.11-7.08 (m, 2H), 6.67 (brS, 1H), 3.47 (dt, J=7.2, and 3.2 Hz, 2H), 2.90 (t, J=6.6 Hz, 2H); MS (ESI) m/z: 342.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12>C(O)(=O)C>[C:14]1(=[O:19])[N:1]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([CH3:13])=[CH:7][C:8]([CH3:12])=[N:9]3)=[CH:4][CH:3]=2)[C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12
Reactant: Cc1cc(C)c2ccc(N)cc2n1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: Cc1cc(C)c2ccc(N3C(=O)c4ccccc4C3=O)cc2n1

Procedure:
6.90 g (40 mmol) of 7-amino-2,4-dimethyl-quinoline, 5.95 g (42 mmol) of phthalic acid anhydride and 100 ml of glacial acetic acid are refluxed for 2 hours. After cooling the reaction mixture is poured onto ice water, the precipitated product is suction filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[N:4]1[C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]2[C:10]1=[O:15]
Reactant: Nc1ccc(I)cc1Cl
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1c1ccc(I)cc1Cl

Procedure:
2-Chloro-4-iodoaniline (12.65 g) and phthalic anhydride (7.4 g) are dissolved in 30 mL of dimethylformamide. The solution is heated to reflux for 16 hours. The reaction mixture is diluted with diethyl ether and washed with brine to yield a precipitate which is filtered off and washed with water and diethyl ether to yield N-(2-chloro-4-iodophenyl)phthalimide as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].[OH-].[Na+].OS(O)(=O)=O>C1(C)C=CC=CC=1.O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: OCC(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Temperature: 47.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-difluoronitrobenzene (300.0 g, 1.89 mol) and 2,2,2-trifluoroethanol (245.0 g, 2.45 mol) in toluene (600 mL) was added sodium hydroxide (90.5 g, 2.26 mol) in portions over 30 min to keep the temperature between 30 and 40° C. After the temperature had dropped to 30° C., the reaction mixture was heated to 45-50° C. using an oil bath for additional 16 h. After cooling, water (500 mL) and 2.5 N H2SO4 (200-300 mL, for adjustment of pH to 5) were added and the organic layer was separated. The water layer was extracted with EtOAc (2×300 mL). The combined organic layers were washed with saturated sodium chloride solution (100 mL) and dried over magnesium sulfate. The solvent was evaporated to give a yellow oil, which solidified after 30 min to give a yellowish solid (450.0 g, quantitative). The crude product was used in the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.03-7.98 (m, 1H), 6.93-6.82 (m, 2H), 4.49 (q, J=7.7 Hz, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 165.0 (d, 1JCF=259.6 Hz), 152.3 (d, 3JCF=13.1 Hz), 128.2 (d, 3JCF=11.9 Hz), 122.4 (d, 1JCF=273.4 Hz), 110.1 (d, 2JCF=22.5 Hz), 105.9 (q, 1JCF=242.6 Hz), 104.3 (d, 2JCF=26.1 Hz), 67.6 (q, 1JCF=36.7 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:17]2[CH:16]=[CH:15][C:14]([S:28][C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)=[C:13]([NH:12][C:2]3[C:11]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)[CH:18]=2)=[CH:22][CH:23]=1
Reactant: Nc1cc(OCc2ccc(F)cc2)ccc1Sc1ccc(O)cc1
Reactant: Clc1ccnc2ncccc12
Product: Oc1ccc(Sc2ccc(OCc3ccc(F)cc3)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (50 mg, 0.30 mmol) was reacted with the product from 4-[2-amino-4-(4-fluoro-benzyloxy)-phenylsulfanyl]-phenol (102 mg, 0.30 mmol) for 20 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (99 mg, 56%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 5.11 (s, 2H) 6.31 (d, J=6.99 Hz, 1H) 6.64 (d, J=8.45 Hz, 2H) 7.08-7.27 (m, 6H) 7.50 (m, J=5.51 Hz, 2H) 7.91 (d, J=4.41 Hz, 1H) 8.47 (d, J=6.98 Hz, 1H) 9.13 (dd, J=1.47 Hz, J=8.45 Hz, 1H) 9.17 (dd, J=1.47 Hz, J=4.05 Hz, 1H) 9.79 (s, 1H) 11.14 (br s, 1H) 14.50 (br s, 1H); MS (ESI+) m/z, 470 (M+H−TFA)+; (ESI−) m/z, 468 (M−H−TFA)−.
Reaction SMILES: [Br-].[CH:2]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=O)[CH:33]=1>O1CCCC1>[C:2]1(=[CH:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCC2)cc1
Reactant: O=Cc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C(=C1CCCC1)c1cccnc1
Temperature: 5 °C
Reaction time: 1.33 h
Yield: 61.8 %

Procedure:
A suspension of cyclopentyltriphenylphosphonium bromide (226 g, 0.55 mol) in anhydrous tetrahydrofuran (1000 ml) at 2° C. was treated with vigorous stirring under an atmosphere of argon, with potassium t-butoxide (61.7 g, 0.55 mol). The dark red mixture was stirred at 5° C. for 80 minutes and then treated with pyridine-3-carbaldehyde (58.9 g, 0.55 mol) during a period of 20 minutes. The reaction mixture was stirred at 0° C. for 2 hours and then at 20° C. for 18 hours. The tetrahydrofuran was removed in vacuo (30° C.; 14 mmHg) and the residue extracted with pentane (2×500 ml) After treatment with decolourising charcoal (5 g), the mixture was filtered through a plug of flash silica gel (Merck 70-230 mesh; 13 cm×2 cm diameter). The filtrate was concentrated in vacuo (30° C., 14 mmHg; then 20° C., 0.01 mmHg) to afford 3-cyclopentylidenemethylpyridine (54 g, 0.34 mol) as an orange oil which was used without further purification;
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].B(F)(F)F.CCOCC.[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20]>>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:18](=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)C(=O)Cl
Agent: FB(F)F
Solvent: CCOCC
Product: CC(C)C(=O)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.5 %

Procedure:
Combine resorcinol (1010 g, 9.17 mol) in boron trifluoride etherate (1.9 L, 15.0 mol) and mechanically stir in a 12-L Morton flask at room temperature. Treat mixture with isobutyryl chloride (880 mL, 8.37 mol), neat, over a 3 hour period via addition funnel, then stir overnight at room temperature. Pour the cooled oil into ˜10 kg of cracked ice and extract twice with ethyl ether (5 L total). Wash organic layers with water, saturated sodium chloride solution, dry with magnesium sulfate, filter, and evaporate filtrate to provide the title compound (1636 g, quantitative yield) as a reddish oil. HPLC Rt=4.29 min; 1H NMR (CDCl3) δ 13.03 (s, 1H), 7.69 (d, J=12.0 Hz, 1H), 6.4 (m, 2H), 3.51 (hept, J=8.0 Hz, 1H), 1.23 (d, J=8.0 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:22]3[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]3)[CH:9]=[C:10]([C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][CH2:16][N:17]4[CH3:20])=[CH:13][C:12]=3[F:21])[C:3]=12.[C:33]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C.O>[F:21][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:11]=1[C:10]1[C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:42][S:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])[N:8]([CH:22]3[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:23]3)[CH:9]=1)[N:17]([CH3:20])[CH2:16][CH2:15]2
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CN1CCc2cc(F)c(-c3cn(C4CN(C(=O)OC(C)(C)C)C4)c4nccc(Br)c34)cc21
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCc2cc(F)c(-c3cn(C4CN(C(=O)OC(C)(C)C)C4)c4nccc(NS(=O)(=O)c5ccccc5)c34)cc21
Temperature: 120 °C
Yield: 85.3 %

Procedure:
A mixture of tert-butyl 3-(4-bromo-3-(5-fluoro-1-methylindolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)azetidine-1-carboxylate (D32) (420 mg, 0.838 mmol), benzene sulfonamide (158 mg, 1.005 mmol), xantphos (97 mg, 0.168 mmol), diacetoxypalladium (18.81 mg, 0.084 mmol), cesium carbonate (819 mg, 2.51 mmol) in 1,4-dioxane (7 mL) was refluxed at 120° C. for 3 hours. The mixture was cooled. Water (50 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated to give a residue which was purified on normal phase silica, eluting with ethyl acetate in cyclohexane (0-50%) to give the title compound (413 mg). LCMS (A): m/z (M+H)+ 578, C30H32FN5O4S requires 577 (acidic).
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:27])[C@@H:12]1[OH:28])([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:3])[OH:2].[Na].S(OC)(O[CH3:34])(=O)=O.[OH-].[Na+]>O.C(O)(=O)C>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]([CH3:34])[CH2:17]2)[C@H:13]([OH:27])[C@@H:12]1[OH:28])([O:4][P:5]([OH:7])([OH:8])=[O:6])(=[O:2])[OH:3]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN1CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c2nc(N)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a clean, dry 2000 mL round bottom flask equipped with a stifling bar and under a stream of argon slowly dissolve dry and finely powdered guanosine 5′-diphosphate (1), (10.0 g, 20.5 mmol), either in free acid or sodium as a counter ion form, in 200 mL water, adjusting pH to 4.0 with glacial acetic acid. Dimethyl sulfate (20 mL, 119.04 mmol) was then added over a period of one hour with constant stirring at room temperature and the reaction continued for an additional hour during which time a decrease in pH was observed but pH was kept between pH 3.8 to 4.0 by drop-wise addition of 10 mM NaOH and methylation was monitored by analytical HPLC for progress. Methylation was determined to be 98% complete within 2 hr. After 2 hr, the reaction mixture was extracted with CHCl3 (3×200 mL) to remove unreacted excess dimethyl sulfate.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[C:1]([NH:4][C:5](=[CH2:9])[C:6]([O:8][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: C=C(NC(C)=O)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(NC(C)=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-acetamidoacrylic acid (10.3 g, 80.0 mmol) and K2CO3 (10 g, 72.5 mmol) in N,N-dimethylformamide (50 mL) was added benzyl bromide (8.7 ml, 72.5 mmol) at room temperature then stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water (50 mL, 1:1), the aqueous layer was extracted with ethyl acetate (2×45 mL). The combined organic layers was washed with brine (2×25 mL), dried (MgSO4), filtered and concentrated under reduced pressure to provide titled compound. MS (ESI(+)) m/e 220(M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.43-7.30 (m, 5H), 6.13 (s, 1H), 5.70 (s, 1H), 5.23 (s, 2H), 2.01 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH3:37][C:38]([CH3:40])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH:38]([CH3:40])[CH3:37])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)=O
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(C)C)nc32)[C@H](O)[C@@H]1O
Yield: 59.1 %

Procedure:
The title compound was prepared by a similar method to example 6 from (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (100 mg, 0.20 mmol), acetone (12 mg, 0.21 mmol), sodium triacetoxyborohydride (70 mg, 0.33 mmol) and acetic acid (0.14 ml, 0.25 mmol) to afford the title compound (63 mg). MS: 533 (MH+).
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([CH3:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([CH3:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:2][CH3:1])[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1
Reactant: Cc1cc(F)c(N)cc1-n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(Cl)c21
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3C)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution (100 mg) of methylamine and 1-(5-amino-4-fluoro-2-methylphenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) were added to pyridine (2 ml), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, a mixed liquid of ethanol and diethyl ether was added to the residue, and the mixture was left to stand overnight. Solids deposited were collected by filtration to obtain the title compound (63 mg) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[NH2:20][C:21]1[O:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:25]=1>>[CH3:29][O:28][C:26]([C:23]1[O:22][C:21]([NH:20][C:16]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]2[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[CH3:19])[CH2:15][C:14]3=2)=[O:18])=[CH:25][CH:24]=1)=[O:27]
Reactant: COC(=O)c1ccc(N)o1
Reactant: CN(C)C1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Product: COC(=O)c1ccc(NC(=O)c2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)o1
Yield: 10 %

Procedure:
Beginning with 7.4 mg (0.029 mMol) 3-dimethylamino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid and 2-amino-5-methoxycarbonylfuran, 1.3 mg (10%) of the title compound were recovered.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[CH3:11])=[O:8])=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2ccc(F)cc2)cc1
Yield: 29.1 %

Procedure:
The title compound (D117) (20 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-piperidine-2-carboxamido)ethyl)benzoate (D86) (50 mg) and 4-fluorobenzyl bromide (0.043 ml, 0.34 mmol). (Na2CO3: 2.5 eq; reaction time: 4 hrs; 60° C.)
Reaction SMILES: [NH2:1][NH2:2].[NH2:3][C:4]1[C:16]([Br:17])=[CH:15][C:7]([C:8]([CH2:10][CH2:11][C:12](O)=[O:13])=O)=[CH:6][C:5]=1[Br:18]>C(O)C>[NH2:3][C:4]1[C:16]([Br:17])=[CH:15][C:7]([C:8]2[CH2:10][CH2:11][C:12](=[O:13])[NH:1][N:2]=2)=[CH:6][C:5]=1[Br:18]
Reactant: NN
Reactant: Nc1c(Br)cc(C(=O)CCC(=O)O)cc1Br
Solvent: CCO
Product: Nc1c(Br)cc(C2=NNC(=O)CC2)cc1Br

Procedure:
The title compound was prepared as described in Example 1 starting with hydrazine and 3-(4-amino-3,5-dibromobenzoyl)propionic acid in ethanol to give a solid: mp 212°-214° C.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[N:36]([CH3:37])[C:16]3=[N:17][CH:18]=[C:19]([C:21]([N:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:25][CH:24]4[C:32]([O:34]C)=[O:33])=[O:22])[CH:20]=[C:15]3[N:14]=2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[OH-].[Na+].C(OCC)(=O)C.C(O)C.N>>[ClH:1].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C:13]2[N:36]([CH3:37])[C:16]3=[N:17][CH:18]=[C:19]([C:21]([N:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:25][CH:24]4[C:32]([OH:34])=[O:33])=[O:22])[CH:20]=[C:15]3[N:14]=2)=[CH:9][CH:10]=1)(=[NH:3])[NH2:4]
Reactant: COC(=O)C1Cc2ccccc2N1C(=O)c1cnc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N3c4ccccc4CC3C(=O)O)cnc21
Yield: 90 %

Procedure:
Prepared analogously to Example 2 from 2-[2-(4-amidinophenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-2,3-dihydroindol-1-yl-carbonyl)imidazo[4,5-b]pyridine hydrochloride and sodium hydroxide solution. Yield: 90% of theory, C26H24N6O3 (468.52); Rf value: 0.24 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5); EKA mass spectrum: (M+H)+=469; (M+Na)+=491.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13](=[O:14])[CH:12]=[C:11]([CH:15]=[CH:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[O:10]1
Reactant: O=Cc1ccsc1
Reactant: CC1=CC(=O)C(C)(c2ccccc2)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccccc2)OC(C=Cc2ccsc2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
To a solution of 3-thiophenecarboxaldehyde (1.07 g, 9.6 mM) and 2,5-dimethyl-2-phenyl-3(2H) -furanone (1.5 g, 8 mM) in ethanol (50 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). After the reaction solution was stirred at room temperature for one day, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with dichloromethane (3×100 ml). The combined dichloromethane extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow liquid. The liquid was purified by chromatography (silica gel,pet. ether-ethyl acetate) to afford a yellow solid (1.6 g, 71% yield), m.p. 75°-77° C.
Reaction SMILES: O[CH:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[C:11]([OH:12])[C:4]=2[CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[C:13]([C:10]1[CH:9]=[CH:8][C:5]2[O:6][CH2:7][CH:2]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:3][C:4]=2[C:11]=1[OH:12])(=[O:15])[CH3:14]
Reactant: CC(=O)c1ccc2c(c1O)CC(O)CO2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)c1ccc2c(c1O)CC(S(C)(=O)=O)CO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound of Example 8 (250 mg) was dissolved in dry pyridine (5 ml) and cooled to 0°. Methanesulfonylchloride (100 μl) was added to the stirred solution, which warmed to room temperature and stirred for 16 hours. The pyridine was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with dilute acid, water, dried and evaporated to afford the title compound, m.p. 158°-162°.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:3]=1.O1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH:23]1([O:24][CH2:25][C:26]2[CH:16]=[CH:15][CH:8]=[CH:9][C:10]=2[C:5]2([N:7]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:4][CH:3]=[CH:2][S:6]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:22]1
Reactant: C1COCCO1
Reactant: Brc1cnc(N=C(c2ccccc2)c2ccccc2)s1
Product: C1=CSC(N=C(c2ccccc2)c2ccccc2)(c2ccccc2COC2CCCCC2)N1
Reaction time: 18 h

Procedure:
24 g of tripotassium phosphate trihydrate, 16.7 g of 2-[(cyclohexyloxy)methyl]phenylboronic acid, obtained in step 1.2, and 2 g of tetrakis(triphenylphosphine)palladium(0) are successively introduced into 17 g of 5-bromo-N-(diphenylmethylene)-1,3-thiazol-2-amine, obtained in step 1.3, in suspension in 250 ml of 1,4-dioxane, and the mixture is kept at 60° C. for 18 hours. The reaction medium is evaporated to dryness, the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a silica gel column, eluting with dichloromethane to give 37.2 g of a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15][OH:16])[CH:7]=[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:9]=1)[CH3:2]>CN(C=O)C.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH:9]=1)[CH:15]=[O:16])[CH3:2]
Reactant: CCOc1cc(CO)cc(OCC(C)C)c1
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(OCC(C)C)c1
Temperature: 60 °C
Yield: 100.8 %

Procedure:
To a solution of (3-ethoxy-5-isobutoxy-phenyl)-methanol (0.28 g, 1.25 mmol, 1.0 equiv) in DMF (20 mL) was added activated MnO2 (1.09 g, 12.48 mmol, 10.0 equiv). The reaction mixture was heated to 60° C. for 2 h, filtered through Hyflo Super Cel and concentrated by evaporation under reduced pressure yielding 0.28 g (99% yield) of the title compound. MS (ISP): 223.0 [M+H]+.