Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.CN(C=O)C.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.O>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:9][CH:10]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: OB(O)c1cncnc1
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: CN(C)C=O
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1c(F)cc(O)cc12
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
A 25 ml RB flask was charged with (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (629 mg, 1.723 mmol), tetrakis(triphenylphosphine)palladium(0) (199 mg, 0.172 mmol), and pyrimidin-5-ylboronic acid (320 mg, 2.58 mmol). DMF (8613 μL) and sodium carbonate (2 M solution) (2584 μL, 5.17 mmol) were added and the mixture was stirred at 85° C. for 2.5 hrs The mixture was cooled to room temperature, water (˜5 ml) was added and stirring was continued for 10 min. The precipitate was filtered out, washed with water (3×5 mL), 1:1 i-PrOH/water to remove color and dried in vacuo to afford (S)-2-amino-4′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH2:10][OH:11]>ClCCl.[O-2].[Mn+4].[O-2]>[NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: Nc1c(Br)cc(F)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Nc1c(Br)cc(F)cc1C=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Manganese (IV) oxide (5 eq) was added to a 0.2M solution of (2-amino-3-bromo-5-fluorophenyl)methanol in dichloromethane. The suspension was stirred at ambient temperature under Argon for 12 h. The reaction mixture was filtered through celite and filter cake was washed with dichloromethane. The combined filtrate was concentrated to give brown color solid. ES/MS m/z 218/220 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:18])=[O:9])[CH:3]=1.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([N:20]([CH3:19])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[CH3:18])=[O:9])[CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CNC1CCCCC1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Product: Cc1cc(O)ccc1NC(=O)c1cc(N(C)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 8) and N-methylcyclohexylamine (Aldrich), the title compound was obtained as a yellow solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([NH:16][CH2:17][CH2:18][N:19]2[C:27]3[C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]5[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=5)=[C:31]([CH3:46])[CH:30]=4)=[N:25][CH:24]=[N:23][C:22]=3[CH:21]=[CH:20]2)=[O:15])[CH2:3]1.FC(F)(F)C(O)=O.[Cl:54]CCl>>[ClH:54].[ClH:54].[OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([NH:16][CH2:17][CH2:18][N:19]2[C:27]3[C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]5[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:43])([F:44])[F:45])[CH:37]=5)=[C:31]([CH3:46])[CH:30]=4)=[N:25][CH:24]=[N:23][C:22]=3[CH:21]=[CH:20]2)=[O:15])[CH2:3]1
Reactant: Cc1cc(Nc2ncnc3ccn(CCNC(=O)[C@@H]4C[C@@H](O)CN4C(=O)OC(C)(C)C)c23)ccc1Oc1cccc(C(F)(F)F)c1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2ncnc3ccn(CCNC(=O)[C@@H]4C[C@@H](O)CN4)c23)ccc1Oc1cccc(C(F)(F)F)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl (2S,4R)-4-hydroxy-2-[({2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}amino)carbonyl]pyrrolidine-1-carboxylate (230 mg) was dissolved in dichloromethane (2.39 mL), trifluoroacetic acid (1.79 mL) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate/tetrahydrofuran (1:1, 50 mL). The organic layer washed with saturated aqueous sodium hydrogen carbonate (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to basic silica gel chromatography (ethyl acetate/methanol=100/0→80/20). The fractions containing the title compound were collected and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, 4N hydrochloric acid (0.252 mL) was added, and the mixture was crystallized to give the title compound (136 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:15])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.CCN(CC)CC.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:15])=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: Nc1ncc(N2CCNCC2)nc1C(=O)Nc1ccccn1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)Nc3ccccn3)n2)CC1
Reaction time: 2 h
Yield: 100 %

Procedure:
3-amino-6-piperazin-1-yl-N-(2-pyridyl)pyrazine-2-carboxamide (100 mg, 0.1896 mmol) was dissolved in DCM (5 mL) and treated with Et3N (57.56 mg, 79.28 μL, 0.5688 mmol) followed by ethanesulfonyl chloride (26.82 mg, 19.76 μL, 0.2086 mmol). The reaction mixture was allowed to stir for 2 hours and then diluted with dichloromethane and washed with water. The aqueous layer was extracted further with dichloromethane and the organics washed with saturated aqueous NaHCO3, dried and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (0-5% MeOH/DCM) to afford the title compound (74.2 mg, 37% Yield). 1H NMR (400.0 MHz, DMSO) d 1.24 (t, J=7.3 Hz, 3H), 3.13 (q, J=7.4 Hz, 2H), 3.34-3.38 (m, 4H), 3.52-3.54 (m, 4H), 7.04 (s, 2H), 7.18-7.21 (m, 1H), 7.88 (s, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.38 (d, J=3.2 Hz, 2H) and 10.08 (s, 1H) ppm; MS (ES+) 392.0
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([N+:17]([O-:19])=[O:18])([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])([OH:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH2:26]([O:10][C:9]([CH2:8][CH2:7][C:6]([CH2:5][CH2:4][C:1]([O:3][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:2])([N+:17]([O-:19])=[O:18])[CH2:12][CH2:13][C:14]([O:16][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15])=[O:11])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)CCC(CCC(=O)O)(CCC(=O)O)[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CCC(CCC(=O)OCc1ccccc1)(CCC(=O)OCc1ccccc1)[N+](=O)[O-])OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
To a mixture of [3-(2-carboxyethyl)]-3-nitropentane-1,5-dicarboxylic acid (2.8 g, 0.01 mole) (prepared as described by James K. Young et al., Macromolecules, 1994, 27, 3464-34-71) and cesium carbonate (3.25 g, 0.025 mol) in acetonitrile (20.0 mL) was added benzylbromide (8.55 g, 6.0 mL, 0.05 mole) and the mixture stirred at RT for 24 h. Inorganic salts were filtered and the salts washed with acetonitrile. The filtrate and the washings were combined and evaporated to obtain an oil. Purification by chromatography over silica gel (hexane:ethyl acetate, 7:3) afforded the benzyl ester (40) as colorless viscous oil (4.5 g, yield: 82%). Mass Spectrum (M+H)+=548.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[CH2:9][CH2:10][CH:11]1[CH2:16][N:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:14](=[O:25])[CH2:13][NH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28]>>[CH2:1]([N:8]([CH3:26])[CH2:9][CH2:10][CH:11]1[CH2:16][N:15]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:14](=[O:25])[CH2:13][N:12]1[C:31]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N=C=O
Reactant: CN(CCC1CN(Cc2ccc(F)cc2)C(=O)CN1)Cc1ccccc1
Product: CC(C)NC(=O)N1CC(=O)N(Cc2ccc(F)cc2)CC1CCN(C)Cc1ccccc1
Reaction time: 0.25 h

Procedure:
The title compound was prepared from 5-{2-[benzyl(methyl)amino]-ethyl}-1-(4-fluorobenzyl)piperazine-2-one (1.15 g, 3.23 mmol) and isopropyl isocyanate (0.412 g, 4.84 mmol) essentially according to the procedure described in Example 6, Step 8. The crude product was purified by silica gel chromatography (120 g RediSep column, 85 mL/min, gradient elution with EtOAc for 4 min, then with 0-10% MeOH-EtOAc over 15 min, then with 10% MeOH-EtOAc for 11 min) to afford the title compound as a viscous, light orange oil. 1H NMR (400 MHz, CDCl3): δ 7.34-7.19 (br m, 7 H), 7.03-6.98 (m, 2 H), 5.59 (m, 1 H), 4.75 (d, J=11.6 Hz, 1 H), 4.58 (d, J=14.8 Hz, 1 H), 4.28 (d, J=11.6 Hz, 1 H), 4.18 (m, 1 H), 4.12 (d, J=6.0 Hz, 1 H), 3.93-3.87 (m, 1 H), 3.70 (d, J=14.8 Hz, 1 H), 3.54 (d, J=10.4 Hz, 1 H), 3.49-3.46 (br m, 1 H), 3.24 (d, J=10.4 Hz, 1 H), 2.83 (dd, J=1.2, 10.0 Hz, 1 H), 2.34-2.29 (m, 1 H), 2.18-2.14 (m, 4 H), 1.71-1.65 (m, 1 H), 1.47-1.42 (m, 1 H), 1.08 and 1.05 (d, J=5.2 Hz, rotamers, 6 H). ES MS (M+1)=441.6.
Reaction SMILES: ClC1C=C(C=CC=1)O[C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[CH:13][C:14]([CH:15]=O)=[C:8]2[N:7]=1.[NH:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.O>CN(C=O)C>[N:27]1([C:6]2[CH:11]=[CH:10][N:9]3[N:12]=[CH:13][C:14]([CH:15]=[C:26]4[NH:20][C:21](=[O:22])[NH:23][C:24]4=[O:25])=[C:8]3[N:7]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2ccc(Oc3cccc(Cl)c3)nc12
Reactant: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(=Cc2cnn3ccc(N4CCCCC4)nc23)N1
Temperature: 70 °C

Procedure:
To 5-(3-chlorophenoxy)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (30 mg, 0.109 mmol) in DMF was added hydantoin (10.9 mg, 0.109 mmol) and piperidine (21.8 μL, 0.218 mmol). The mixture was heated at 70° C. Added water, and the solid formed was isolated by filtration to yield 5-((5-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=313)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[C:7]=1[C:8](=[CH2:12])C(Cl)=O)#[N:2].[C:25]1([CH2:31][S:32]([NH2:35])(=[O:34])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+].[O:38]1CCC[CH2:39]1>>[C:25]1([CH2:31][S:32]([NH:35][C:39](=[O:38])[CH:12]=[CH:8][C:7]2[N:6]([C:13]3[C:14]([Cl:24])=[CH:15][C:16]([C:20]([F:23])([F:21])[F:22])=[CH:17][C:18]=3[Cl:19])[N:5]=[CH:4][C:3]=2[C:1]#[N:2])(=[O:33])=[O:34])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C1CCOC1
Reactant: NS(=O)(=O)Cc1ccccc1
Reactant: C=C(C(=O)Cl)c1c(C#N)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C=CC(=O)NS(=O)(=O)Cc1ccccc1

Procedure:
By the method of Example 10, 0.49 g (0.0012 mole) of 3-[[4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazol-5-yl]acrylic acid chloride, 0.25 g (0.0015 mole) of phenylmethanesulfonamide, and 0.038 g (0.0016 mole) of sodium hydride were reacted in 10 mL of tetrahydrofuran, yielding 0.35 g of N-phenylmethanesulfonyl-3-[4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazol-5-yl]acrylamide as a solid; m.p. 178°-183° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[C:11]([OH:20])=[C:12]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[CH2:15][CH2:14][CH2:13]2)=[O:9])([CH3:6])[CH3:5].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>>[CH3:6][C:4]([NH:7][C:8]([C:10]1[C:11]([O:20][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)=[C:12]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[CH2:15][CH2:14][CH2:13]2)=[O:9])([CH3:5])[C:3]([OH:2])=[O:21]
Reactant: COC(=O)C(C)(C)NC(=O)c1cc(C)c2c(c1O)CCC2
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1cc(C(=O)NC(C)(C)C(=O)O)c(OCc2ccc(C(F)(F)F)cc2)c2c1CCC2

Procedure:
2-Methyl-2-{[7-methyl-4-(4-trifluoromethyl-benzyloxy)-indane-5-carbonyl]-amino}-propionic acid was prepared in analogy to example 1 via a sequence of an alkylation reaction of 2-[(4-Hydroxy-7-methyl-indane-5-carbonyl)-amino]-2-methyl-propionic acid methyl ester using 1-bromomethyl-4-trifluoromethyl-benzene and a basic hydrolysis of the amino acid ester to the free amino acid
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20]3[CH:19]=[CH:18][C:17]([C:21]4[CH:22]=[CH:23][C:24]5[N:25]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[C:26]6[C:31]([C:32]=5[CH:33]=4)=[CH:30][CH:29]=[CH:28][CH:27]=6)=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.[C:40]1([CH3:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:34]1([N:25]2[C:24]3[CH:23]=[CH:22][C:21]([C:17]4[CH:18]=[CH:19][C:20]5[N:8]([C:5]6[CH:6]=[CH:7][C:2]([C:12]7[CH:11]=[CH:10][C:9]8[N:8]([C:5]9[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=9)[C:45]9[C:40]([C:46]=8[CH:13]=7)=[CH:41][CH:42]=[CH:43][CH:44]=9)=[CH:3][CH:4]=6)[C:9]6[C:14]([C:15]=5[CH:16]=4)=[CH:13][CH:12]=[CH:11][CH:10]=6)=[CH:33][C:32]=3[C:31]3[C:26]2=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccccc1
Reactant: Brc1ccc(-n2c3ccccc3c3cc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)ccc32)cc1
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: CCO
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc(-n5c6ccccc6c6cc(-c7ccc8c(c7)c7ccccc7n8-c7ccccc7)ccc65)cc4)ccc32)cc1
Temperature: 72 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
The resulting 9-(4-bromophenyl)-9′-phenyl-9H,9′H-[3,3′]bicarbazolyl (17.00 g), 9-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabororan-2-yl)-9H-carbazole (12.25 g), toluene (160 ml), ethanol (40 ml), and a 2 M potassium carbonate aqueous solution (23 ml) were added to a nitrogen-substituted reaction vessel, and aerated with nitrogen gas for 30 minutes under ultrasonic waves. After adding tetrakis(triphenylphosphine)palladium (1.74 g), the mixture was heated, and stirred at 72° C. for 12.5 hours. The mixture was allowed to cool to room temperature, and extraction was performed by adding toluene (100 ml) and water (150 ml) thereto. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to obtain a black crude product. The crude product was purified by column chromatography (carrier: silica gel; eluent: hexane/toluene) to obtain a pale yellowish white powder of 9′-phenyl-9-[4-(9-phenyl-9H-carbazol-3-yl)-phenyl]-9H,9′H-[3,3′]bicarbazolyl (10.44 g; yield 48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:10]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:11](=O)[CH3:12]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([C:10]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([CH3:12])[N:8]=2)[CH:7]=1
Reactant: COCCCC(Cl)C(C)=O
Reactant: Nc1ncc(Br)cn1
Product: COCCCc1c(C)nc2ncc(Br)cn12

Procedure:
0.85 mmol of 5-bromopyrimidin-2-ylamine [7752-82-1] and 1.7 mmol of 3-chloro-6-methoxyhexan-2-one are reacted in analogy to building block 35. The title compound is identified by means of the Rf.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[N:11](C3CCCCO3)[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.Cl>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[NH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc2c(c1)c(/C=C/c1ccccc1)nn2C1CCCCO1
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]nc(/C=C/c3ccccc3)c2c1

Procedure:
The title compound was prepared by hydrolyzing 3-((1E)-2-phenylvinyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.268 g, 0.815 mmol) in a mixture of 6 mL of tetrahydrofuran and 6 mL of aqueous hydrogen chloride (6.0 N) at room temperature for 12 hours, and reflux temperature for 6 hours. The compound was used without further purification. ES-MS (m/z) 246 [M+1]+.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(O[C:9](=O)[CH3:10])(=O)C.[NH2:12][CH:13](O)[CH2:14]CC>C(#N)C>[N+:1]([O-:4])([OH:3])=[O:2].[N+:1]([O:4][CH2:14][C@H:13]([NH2:12])[CH2:9][CH3:10])([O-:3])=[O:2]
Reactant: CCCC(N)O
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Solvent: O=[N+]([O-])O
Product: CC[C@@H](N)CO[N+](=O)[O-]
Reaction time: 1 h
Yield: 93 %

Procedure:
(2R)-Aminobutan-1-ol (1.01 g, 11.3 mmol) was dissolved in anhydrous acetonitrile (50 mL) and the solution was cooled using an ice bath. To the solution, fuming nitric acid (0.5 mL) was added. A mixture of acetic anhydride (8.3 mL, 90 mmol) and fuming nitric acid (2.3 mL, 57 mmol) were cooled in an ice bath and then added slowly to the aminobutan-1-ol reaction mixture and stirred for 1 hour. Solvent was removed under reduced pressure and the residue obtained was dried overnight under high vacuum to yield the title compound (2.07 g, 10.5 mmol, 93% yield) as a light green solid. 1H NMR (300 MHz, CDCl3) δ 8.22 (s, 2H), 4.75 (dd, J=11.9 and 2.7 Hz, 1H), 4.60-4.53 (m, 1H), 3.46 (s, 1H), 1.61 (m, 2H), 0.92 (t, J=7.4 Hz, 3H). 13C NMR (CDCl3, 75.45 MHz) δ 72.1, 49.7, 22.5, 9.5. LRMS (APIMS) m/z 135 (M−HNO3+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[Cl:18][C:19]1[C:20]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:21][C:22]([O:26][CH3:27])=[C:23]([CH:25]=1)[NH2:24]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[C:19]([Cl:18])[C:20]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)[CH2:32][CH2:33]3)=[CH:21][C:22]=2[O:26][CH3:27])=[N:3][CH:4]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(Cl)cc1N
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(Cl)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and 5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 55).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[I:13]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[I:13]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of ethyl 4-aminobenzoate (13.0 g) in DMF (33 mL) is added a solution of N-iodosuccinimide (18.6 g) in DMF (39 mL). The reaction is stirred at room temperature overnight. The mixture is poured into 800 mL water. The resulting solid is collected and dried to yield 20.7 g (90%) of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]([OH:18])[C:13](OCC)=[O:14])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[OH-].[NH4+:20]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]([OH:18])[C:13]([NH2:20])=[O:14])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: [NH4+]
Reactant: CCOC(=O)C(O)c1cc(F)cc2cccnc12
Agent: [OH-]
Product: NC(=O)C(O)c1cc(F)cc2cccnc12

Procedure:
Ethyl 2-(6-fluoro-8-quinolyl)-2-hydroxyacetate (1.1 g.) was refluxed for 10 minutes in 300 ml. of conc. ammonium hydroxide. The reaction mixture was cooled slightly, clarified by filtration and evaporated to solids. Trituration of the residue with 25 ml. of toluene gave the title product (860 mg., m.p. 169°-171° C.).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CC(N(C)C)=O>[F:10][C:4]1[CH:3]=[C:2](/[CH:13]=[CH:12]/[C:11]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: C=CC(=O)OC
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C=O)c(F)c1
Temperature: 100 °C
Yield: 71 %

Procedure:
4-Bromo-2-fluorobenzaldehyde (20.88 g, 102.87 mmol) and methyl acrylate (13.98 ml, 154.30 mmol) were taken up in thoroughly degassed DMA (150 nil) and tri-o-tolylphosphine (3.13 g, 10.29 mmol), palladium(II) acetate (1.155 g, 5.14 mmol) and triethylamine (28.7 ml, 205.74 mmol) added. The reaction was stirred and heated to 100° C. for 16 hours. More tri-o-tolylphosphine (3.13 g, 10.29 mmol) and palladium(II) acetate (1.155 g, 5.14 mmol) were added and the reaction mixture was heated to 110° C. for a further 2 hours. Water (1 L) was added and the reaction mixture extracted with DCM (2×500 ml). Combined organics were dried (MgSO4), filtered and evaporated to give a brown solid. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(3-fluoro-4-formylphenyl)acrylate (15.20 g. 71.0%) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18](F)=[N:19][CH:20]=1>CC(=O)OCC.O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:19][CH:20]=1
Reactant: OCCC1CC1
Reactant: Fc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCCC2CC2)nc1
Reaction time: 4 h

Procedure:
A mixture of 2-cyclopropyl-ethanol (4.1 g) and DMF (15 mL) under argon was treated with NaH (60% in oil, 0.45 g). After 4 hours 5-bromo-2-fluoro-pyridine (3.0 g) was added at 0° C. After 4 hours at room temperature, the mixture was distributed between water and EA. The organic phase was washed twice (water), dried (Na2SO4) and concentrated. The residue was purified by chromatography (SiO2; EA/heptane 1:4) to provide the subtitle compound. MS ESI+: m/z=242 [M+H]+.