Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([CH2:16][CH:17]1[CH2:22][NH:21][C:20](=[O:23])[CH2:19][O:18]1)CC1C=CC=CC=1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[NH2:8][CH2:16][CH:17]1[CH2:22][NH:21][C:20](=[O:23])[CH2:19][O:18]1
Reactant: O=C1COC(CN(Cc2ccccc2)Cc2ccccc2)CN1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NCC1CNC(=O)CO1

Procedure:
A solution of 6-((dibenzylamino)methyl)morpholin-3-one (340 mg, 1.09 mmol), Pd(OH)2/C (170 mg) in EtOH (30 mL) was stirred equipped under H2 balloon overnight. The solution was filtered and concentrated to give white oil. The crude product was used directly for next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH2:18][CH2:17]2)=[CH:3][C:2]=1[NH:1][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1OCc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCN(c2ccc(OCc3ccccc3)c(Nc3ccccc3)c2)CC1
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To a stirred solution of (4-(3-amino-4-(benzyloxy)phenyl)piperazin-1-yl)(phenyl) methanone (1 g, 2.58 mmol) and phenylboronic acid (0.94 g, 7.74 mmol) in DCM (100 mL) was added triethylamine (1.0 mL, 7.74 mmol) and Cu(OAc)2 (0.7 g, 3.87 mmol). The mixture was stirred for 12 h. It was then filtered through celite, evaporated under vacuum. Flash column chromatography gave (4-(4-(benzyloxy)-3-(phenylamino) phenyl) piperazin-1-yl) (phenyl)methanone (0.87 g), 82% yield. 1H NMR (500 MHz, DMSO): δ 3.01 (bs, 2H), 3.16 (bs, 2H), 3.59 (bs, 2H), 3.95 (bs, 2H), 5.10 (s, 2H), 6.20 (s, 1H), 6.42 (dd, J=2.5, 3 Hz 1H), 6.91 (d, J=8.5 Hz, 1H), 7.01 (m, 2H), 7.17 (d, J=8.0 Hz, 2H), 7.32 (m, 2H), 7.37 (m, 10H). HRMS (ESI) calculated for C30H30N3O2: 464.2333, Found: 464.2338.
Reaction SMILES: [CH:1]1([C:4](=[O:7])[CH:5]=[CH2:6])[CH2:3][CH2:2]1.C(O[CH2:13][N:14]([CH2:23][Si](C)(C)C)[C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])CCC.FC(F)(F)C(O)=O>ClC(Cl)C>[CH:1]1([C:4]([CH:5]2[CH2:6][CH2:13][N:14]([C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:23]2)=[O:7])[CH2:3][CH2:2]1
Reactant: C=CC(=O)C1CC1
Reactant: CCCCOCN(C[Si](C)(C)C)[C@H](C)c1ccccc1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccccc1)N1CCC(C(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.6 %

Procedure:
The product (8.01 g) containing 1-cyclopropyl-2-propen-1-one described in Reference Example 1 and N-(n-butoxymethyl)-N-[1-(R)-phenylethyl]trimethylsilylmethylamine (23.2 g, 79.9 mmol) were dissolved in dry dichloroethane (350 ml), and trifluoroacetic acid (500 μl) was added dropwise thereto. After 12 hours of stirring at room temperature, the reaction solution was washed with saturated sodium bicarbonate aqueous solution (100 ml) and then with saturated brine (100 ml). After drying over anhydrous magnesium sulfate and subsequent filtration, the filtrate was concentrated under a reduced pressure. The thus obtained residue was subjected to a flash silica gel chromatography, and 9.08 g (49.6%) of the title compound was obtained from an eluate of n-hexane:ethyl acetate=2:1 as a colorless oil component. In this case, this product was obtained as a diastereomer mixture of 1:1.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=2)[S:7][CH:8]=1)[CH3:3].[C:18]1(=[O:29])[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]2[CH2:19]1>C1(C)C=CC=CC=1>[CH3:3][CH:2]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:29])[CH2:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])[CH:14]=[CH:15][CH:16]=2)[S:7][CH:8]=1)[CH3:1]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: CC(C)c1csc(/C=C/c2cccc(N)c2)n1
Solvent: Cc1ccccc1
Product: CC(C)c1csc(/C=C/c2cccc(NC(=O)Cc3ccccc3C(=O)O)c2)n1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A mixture of 1.2 g of (E)-3-[2-[4-(1-methylethyl)-2-thiazolyl]ethenyl]benzeneamine, 0.8 g of homophthalic anhydride and 25 ml of toluene was heated to reflux for 0.5 hr. Upon cooling to room temperature, the solid reaction product was filtered and washed with ethyl ether to yield 1.7 g of (E)-2-[2-[3-[2-[4-(1-methylethyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid. Recrystallization from ethyl alcohol yielded off-white solid material; m.p. 203°-204° C.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:2]2[C:3]([F:23])=[CH:4][C:5]3[C:6]4[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=4[N:8]([CH3:11])[C:9]=3[CH:10]=2)[C:34](=[O:38])[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cn1c2c(c3cc(F)c(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3cc(F)c(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 133 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
tert-Butyl 7-bromo-8-fluoro-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (720 mg, 1.88 mmol), 4-benzyloxypyridone (380 mg, 1.9 mmol) and Cs2CO3 (680 mg, 2.1 mmol) were suspended in DMSO (8.0 mL) and the resulting suspension was degassed for 15 min. The system was flushed with Ar. Then 8-hydroxyquinoline (87 mg, 0.60 mmol) and copper iodide (114 mg, 0.599 mmol) were added. The degassing/Ar flushing process was repeated twice more, and the reaction mixture was heated at 133° C. for 18 h under argon. The reaction mixture was cooled, diluted with 15% solution of concentrated ammonium hydroxide in methanol (25 mL) and stirred at ambient temperature for 30 min. The reaction was further diluted with dichloromethane (75 mL). The solution was filtered through silica gel and concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with H2O (25 mL) and brine (3×50 mL). The combined organics were dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, (1:1 hexanes/EtOAc)/(10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide), 1:0 to 0:1) to afford crude tert-butyl 7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-8-fluoro-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (280 mg) as a yellow oil. This oil was dissolved in dichloromethane (3 mL) and TFA (1 mL) was added. The reaction mixture was stirred at ambient temperature for 1 h, concentrated and dried under vacuum overnight to provide the title compound (200 mg), which was used in the next step without further purification: ESI MS m/z 404 [M+H]+.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: C1CCNC1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COc1cccc(-c2c(N3CCCC3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 70 °C
Yield: 8 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (50 mg, 0.095 mmol) (Example 33), pyrrolidine (0.039 mL, 0.477 mmol), Pd2(dba)3 (8.74 mg, 9.54 μmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (8.11 mg, 0.019 mmol) and Cs2CO3 (93 mg, 0.286 mmol) in THF (1 mL) was heated at 70° C. for 19 h. The mixture was then filtered through celite and the filtrate concentrated. Purification by chromatography on silica gel, eluting with a gradient of 20-50% ethyl acetate in DCM was followed by further purification by MDAP (acidic conditions), to give the title compound (3.9 mg). LCMS (A) m/z: 514 [M+1]+, Rt 1.56 min (acidic), Rt 1.09 min (basic).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:27]=2[NH2:28])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:27]=2[NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:3]=2[CH3:19])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2cccnc2)nc2ccc(F)cc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2cccnc2)nc2ccc(F)cc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-6-fluoro-3-methyl-2-(pyridin-3-yl)quinoline (140 mg, 0.51 mmol), 2,5-dimorpholinoaniline (135 mg, 0.51 mmol) and a 4.0M solution of HCl in dioxane (0.13 mL, 0.51 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-6-fluoro-3-methyl-2-(3-pyridinyl)-4-quinolinamine was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.88 (1H, d, J=2.3 Hz), 8.72 (1H, dd, J=5.1, 2.0 Hz), 8.16 (1H, dd, J=9.0, 5.5 Hz), 7.99 (1H, dt, J=7.8, 2.2 Hz), 7.43-7.57 (3H, m), 7.16-7.20 (1H, m), 7.13 (1H, d, J=8.6 Hz), 6.46 (1H, dd, J=8.6, 2.7 Hz), 5.97 (1H, d, J=2.7 Hz), 3.87-3.99 (4H, m), 3.67-3.80 (4H, m), 3.01-3.13 (4H, m), 2.83-2.98 (4H, m), 2.33 (3H, s). Mass Spectrum (ESI) m/e=500.0 (M+1).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[Si:7]([CH:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([CH3:9])[CH3:8].C1CC=CC=1>C1COCC1>[C:1]([NH:5][Si:7]([CH:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(Cl)C1C=CC=C1
Reactant: CC(C)(C)N
Agent: C1=CCC=C1
Solvent: C1CCOC1
Product: CC(C)(C)N[Si](C)(C)C1C=CC=C1

Procedure:
To a solution of 3.69 g (50.4 mmol) tert-butyl amine in 45 mL THF was added 2.00 g (12.6 mmol) (chloro)(cyclopentadienyl)(dimethyl)silane. Precipitate formed quickly. The slurry was stirred for several days, then the amine hydrochloride was filtered off and the solvent was removed under reduced pressure to give the product as a very pale yellowish oil. The yield was 2.069 g (84.2%). Mass spec: m/e 195 (6%). 1H and 13C NMR show the presence of several cyclopentadiene isomers.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[CH:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#Cc1cccc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: CCc1cccc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)OC(C)(C)C)c1
Yield: 48.4 %

Procedure:
A solution of (4-tert-butyl-benzyl)-[2-(3-ethynyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (149 mg, 0.381 mmol) in methanol (12 ml) was stirred at RT under an atmosphere of hydrogen in the presence of a catalytic amount of palladium on charcoal (5%) for 2 days. The reaction mixture was then filtered and evaporated and the remaining residue was purified by chromatography (heptane/EtOAc 100:0 to 95:5) to obtain the title compound as a colorless oil (73 mg, 48%). MS (ISP) 396.4 (M+H)+.
Reaction SMILES: Br[N:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][NH:3]1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(OC(C)(C)C)(C)(C)C.[Na]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][N:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[CH:4][NH:3]2)=[CH:19][CH:18]=1
Reactant: BrN1C=CC(OCc2ccncc2)=CN1
Reactant: Nc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)OC(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1ccc(NN2C=CC(OCc3ccncc3)=CN2)cc1
Temperature: 80 °C
Yield: 10 %

Procedure:
To 1-bromo-4-(4-pyridylmethoxy)pyridazine (50 mg, 0.19 mmol) in toluene (3 mL) was added 4-chloroaniline (29 mg, 0.22 mmol), catalytical amount of (R)-(+)2,2′-bis(diphenyl phosphino)-1,1′-binaphthyl (1 mg), tris(dibenzylideneacetone)-dipalladium(0) (0.6 mg) and sodium t-butyloxide (26 mg, 0.27 mmol). The reaction mixture was heated at 80° C. for 12 h under argon. The reaction mixture became deep brown upon heating. The mixture was cooled to RT, diluted with ethyl acetate (10 mL), washed by brine and the organic layer was dried over Na2SO4, and the solvent was evaporated in vacuo. The crude mixture was purified by preparative thin layer plate to afford the title compound (6 mg, yield 10%). 1H-NMR (MeOH-4), 8.51 (d, 2H), 7.61(d, 2H) 7.52(dd, 2H), 7.15-7.25(m, 4H), 5.49(s, 2H); MS ES 313 (M+H)+, 315 (M+3H)+, 316 (M+4H)+, calc. 312; TLC (5:95 v/v methanol-methylene chloride) Rf=0.2.
Reaction SMILES: [Cl-].C[SiH](C)C.[F:6][C:7]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:16][C:17]1[CH:22]=[C:21]([CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:7]=2[F:6])[N:20]=[CH:19][N:18]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Fc1cccc(CBr)c1F
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(Cc2cc(Cl)ncn2)c1F
Reaction time: 0.33 h
Yield: 38.4 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 2.1 g of 2,3-difluorobenzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution G). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution G was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.93 g of 4-chloro-6-(2,3-difluorobenzyl)pyrimidine.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O.[CH3:34][O:35][CH2:36]/[CH:37]=[CH:38]/B1OC(C)(C)C(C)(C)O1>O1CCOCC1.CCOC(C)=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>[OH:26][C:6]1[C:5]2[C:10](=[CH:11][C:2](/[CH:38]=[CH:37]/[CH2:36][O:35][CH3:34])=[CH:3][CH:4]=2)[C:9]([CH3:13])([CH3:12])[C:8](=[O:14])[C:7]=1[C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[O:16]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC/C=C/c1ccc2c(c1)C(C)(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 80 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
1,1-Dimethylethyl N-((7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (500 mg, 1178 μmol, see Example 53) was dissolved in 1,4-dioxane (11785 μL). 2M K2CO3 in water (2357 μL, 4714 μmol), Pd(Ph3P)4 (136 mg, 118 μmol), and (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 μL, 1414 μmol) were added, and the reaction was stirred at 80° C. for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (385 mg) after flash chromatography. MS m/e=438 (M+Na)+.
Reaction SMILES: [CH:1]1([C:9]([OH:11])=O)[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.C[O:26][C:27](=[O:30])[CH2:28][NH2:29].[OH-].[Na+].Cl>COCCOC.C(OCC)(=O)C.O>[CH:1]1([C:9]([NH:29][CH2:28][C:27]([OH:30])=[O:26])=[O:11])[C:3]2([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:2]1
Reactant: COC(=O)CN
Reactant: O=C(O)C1CC12CCCCC2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: O=C(O)CNC(=O)C1CC12CCCCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.8 %

Procedure:
The product from Example 1B (4.50 g, 29.2 mmol), and 1,1′-carbonyldiimidazole (5.0 g, 30.8 mmol, 1.06 equiv) were combined in 1,2-dimethoxyethane (50 mL) and stirred at room temperature for 1.5 hours. Glycine methyl ester hydrochloride (3.85 g, 30.8 mmol, 1.06 equiv, purchased from Aldrich) and water (0.2 mL) were added and the reaction mixture was heated at 65° C. for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (250 mL) and washed water (2×100 mL). The organic extract was concentrated and the residue was dissolved in ethanol (20 mL). An aqueous solution of NaOH (1.52 g, 38 mmol, 1.3 equiv) was added and the mixture was agitated at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (250 mL) and water (100 mL), which was acidified with to pH 3 by the addition of concentrated HCl. The organic extract was concentrated and the residue was crystallized from ethyl acetate (40 mL) to afford the title compound (4.0 g, 65%). 1H NMR (CDCl3, 400 MHz) δ 6.30 (m, 1H), 4.10 (d, 2H), 1.25-1.7 (m, 11H), 1.16 (dd, 1H), 0.81 (dd, 1H); MS, m/z, 212 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[O:11][C:10]([CH3:12])=[C:9]([C:13]([OH:15])=O)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:16]1([C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[N:16]1([C:22]2[N:27]=[CH:26][C:25]([NH:28][C:13]([C:9]3[CH:8]=[C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[O:11][C:10]=3[CH3:12])=[O:15])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: Cc1oc(C2CCCCC2)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1oc(C2CCCCC2)cc1C(=O)Nc1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
5-Cyclohexyl-2-methyl-furan-3-carboxylic acid (83 mg, 0.365 mmol), 6-morpholin-4-yl-pyridin-3-ylamine (83 mg, 0.4 mmol), and triethylamine (154 uL, 1.09 mmol) were dissolved in 5 mL of DMF and chilled in an ice bath. To this solution was added BOP (169 mg, 0.383 mmol) in one portion. The mixture was stirred at room temperature for one hour and then diluted with 30 mL ethyl acetate. The ethyl acetate solution was washed with saturated sodium bicarbonate (2×10 mL) and saturated sodium chloride (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to dryness under vacuum. The crude product was purified by flash chromatography using ethyl acetate/hexane to yield 5-cyclohexyl-2-methyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide as a light grey powder (87 mg, 64%). ES-MS calcd for C21H27N3O3 (m/e) 369.5, obsd 370.3 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=O)[O:13][C:14](=[O:21])[C:15]=2[C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:3]1.C[N:24](C=O)C.N>O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:13])[NH:24][C:14](=[O:21])[C:15]=2[C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:3]1
Reactant: CN(C)C=O
Reactant: Cn1cc(C2=C(c3ccsc3)C(=O)OC2=O)c2ccccc21
Agent: N
Solvent: O
Product: Cn1cc(C2=C(c3ccsc3)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
0.28 g of 3-(1-methyl-3-indolyl)-4-(3-thienyl)furan-2,5-dione was treated with 10 ml of DMF and 40 ml of 33% aqueous ammonia. The mixture was heated at 140° C. for 4 hours. The cooled solution was poured into 150 ml of water and the resulting precipitate was filtered off and dried to give 0.15 g of 3-(1-methyl-3-indolyl)-4-(3-thienyl)-1H-pyrrole-2,5-dione, m.p. 211°-212° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2.[I:12]I.[OH-].[K+].S([O-])(O)=O.[Na+]>CN(C)C=O>[I:12][C:8]1[C:7]2[C:11](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[NH:10][N:9]=1
Reactant: COc1cccc2cn[nH]c12
Reactant: II
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c(I)n[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
To a solution of 7-methoxy-1H-indazole (2.60 g, 17.5 mmol) in N,N-dimethylformamide (50 mL) are added iodine (6.68 g, 26.3 mmol) and potassium hydroxide (2.79 g, 49.7 mmol), and the mixture is stirred at room temperature for 0.5 hour. The reaction solution is poured into a 10% aqueous sodium hydrogen sulfite solution (200 mL), and the mixture is extracted with diethyl ether. The organic layer is washed with water and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the obtained residue is purified by silica gel column chromato-graphy (n-hexane/ethyl acetate=5/1) to give the title compound (3.97 g, yield: 83%).