Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].N1C=CC=CC=1.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28]>O1CCCC1>[C:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:30])[C:27]([CH3:29])=[CH2:28]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCCCCCCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
16-Hydroxyhexadecanoic acid (6.81 g, 25.0 mmol) was dissolved in tetrahydrofuran (150 ml) and the solution was cooled to 0° C. before adding pyridine (2.73 g, 34.5 mmol). Methacryloyl chloride (2.61 g, 25.0 mmol) was dissolved in tetrahydrofuran (75 ml) and added dropwise. The mixture was stirred for 1 hour at 0° C., and then at room temperature for 24 hours. The solvent was removed under reduced pressure (room temperature), the residue suspended in ether (100 ml) and the mixture washed with distilled water. The ether layer was dried (MgSO4) and the ether evaporated. Chromatographic purification on a silica gel column (1:2 ethyl acetate/hexane) afforded 5.0 g (64%) of the title compound. 1H NMR (60 MHz, CDCl3): δ1.3 (br s, 26H, (CH2)13), 1.95 (m, 3H, C=CCH3), 2.1-2.6 (m, 2H, CH2COO), 4.0-4.4 (m, 2H, COOCH2), 5.52 (m, 1H, vinyl), 6.10 (m, 1H, vinyl).
Reaction SMILES: [NH2:1][CH:2]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH2:3][CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC>Cl>[NH2:1][CH:2]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH2:3][CH2:4][P:5]([OH:9])[OH:6]
Reactant: CCOC(OCC)P(=O)(CCC(N)c1ccc(Cl)cc1)OCC
Agent: Cl
Product: NC(CCP(O)O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 10.5 g of ethyl 3-amino-3-(4-chlorophenyl)propyl(diethoxymethyl)phosphinate in 100 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 2 hours. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure, and co-evaporated twice with 25 ml of water under reduced pressure. The crude product is then dissolved in 20 ml of water, washed twice with 20 ml of diethyl ether and the aqueous layer is then separated and evaporated under reduced pressure. The crude product is dissolved in 50 ml of ethanol and 5 ml of propylene oxide is added dropwise. The precipitated solid is collected by filtration and dried to give 3-amino-3-(4-chlorophenyl)propylphosphonous acid, m.p. 284°-286° C., 31P=+27.2 ppm (D2O).
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[C:28]([O:35][CH3:36])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl.[NH4+].[OH-].O>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[C:28]([O:35][CH3:36])[N:27]=3)[CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: COc1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1C(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)ccc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
To a solution of tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (141 mg, 281 μmol) in dichloromethane (4.3 mL) was added trifluoroacetic acid (641 mg, 433 μL, 5.62 mmol) and the mixture stirred at room temperature for 16 h. The mixture was diluted with 25% aqueous NH4OH, dichloromethane, and water. The organic phase was separated and washed with water (2×), then concentrated in vacuo and purified by chromatography (silica, 3 to 10% of a 99.5:0.5 methanol:NH4OH solution in dichloromethane) to give 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazine-3-carboxamide (35 mg, 87 μmol, 31%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (s, 1H), 8.37 (s, 1H), 7.70 (s, 1H), 7.62 (s, 1H), 7.54 (d, J=8.1 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 4.05 (br. s, 1H), 3.81 (d, J=11.9 Hz, 1H), 3.67 (dd, J=10.9, 3.5 Hz, 1H), 3.49 (dd, J=11.1. 1.9 Hz, 1H), 3.37 (m, 2H), 3.08 (m, 1H), 2.97 (s, 1H), 1.81 (m, 1H), 1.65 (m, 1H), 1.16 (d, J=6.8 Hz, 6H); MS (EI/CI) m/z: 402.3 [M+H].
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ClCI.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]=[CH2:25])=[CH:19][CH:18]=1.Cl>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:1][CH2:25]2)=[CH:19][CH:18]=1
Reactant: CC[Zn]CC
Reactant: C=COc1ccc(Br)cc1
Agent: Cl
Agent: ClCI
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccc(OC2CC2)cc1
Reaction time: 1 h
Yield: 102.4 %

Procedure:
With reference to the document (Tetrahedron Lett., (1998), 39, 8621-8624), the following cyclopropanization was conducted. Diethyl zinc (1.0 M hexane solution, 250 mL, 250 mmol) was added to dichloromethane (250 mL), and a solution of dichloromethane (120 mL) containing trifluoroacetic acid (19.2 mL, 249 mmol) was added thereto under ice-cooling over 100 minutes. The mixture was further stirred for 1 hour. Then, a solution of dichloromethane (100 mL) containing chloroiodomethane (20.1 mL, 250 mmol) was added thereto under ice-cooling over 40 minutes, and a solution of dichloromethane (120 mL) containing 1-bromo-4-(vinyloxy)benzene (32.8 g, 165 mmol) prepared in Example 6 (6b) was further added thereto at the same temperature over 20 minutes. The mixture was stirred at room temperature for 1.5 hours. Then, 0.1 N hydrochloric acid (400 mL) was added to the reaction solution. The mixture was stirred for 30 minutes, filtered through Celite, and washed with hexane (200 mL). The filtrate and the hexane washing solution were combined. The organic layer was washed with 0.1N hydrochloric acid (100 mL) and then with saturated brine (100 mL) containing about 1 g of sodium sulfite twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give 36.0 g of 1-bromo-4-(cyclopropyloxy)benzene (yellow oil).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13].Br[CH2:18]/[CH:19]=[CH:20]/[Sn:21]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:30]([Sn:21]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])/[CH:20]=[CH:19]/[CH2:18][N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13])[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn](/C=C/CBr)(CCCC)CCCC
Reactant: OCCNCCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[Sn](/C=C/CN(CCO)CCO)(CCCC)CCCC
Temperature: 20 °C
Reaction time: 15 h

Procedure:
N-Ethyl-N,N-diisopropylamine (315 mg) was added to a solution of diethanolamine (256 mg) in dry DMF (5 mL) at 0° C. [(1E)-3-bromoprop-1-enyl](tributyl)stannane (600 mg) was added to the reaction after 10 min. The reaction mixture was stirred for 15 h at 20° C. and then quenched with saturated NH4Cl (aq.). Extraction with Et2O and drying (MgSO4) of the organic phase gave, after concentration in vacuo, the crude product. Purification was done by chromatography eluting with Et2O/MeOH 100:4 to afford the title compound as a liquid.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][CH2:7][O:8][C:9]2[CH:22]=[CH:21][C:12]([CH:13]=[C:14]3[S:18][C:17](=[O:19])[NH:16][C:15]3=[O:20])=[CH:11][CH:10]=2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12>O1CCOCC1.[Pd]>[C:4]1(=[O:23])[N:5]([CH2:6][CH2:7][O:8][C:9]2[CH:22]=[CH:21][C:12]([CH2:13][CH:14]3[S:18][C:17](=[O:19])[NH:16][C:15]3=[O:20])=[CH:11][CH:10]=2)[C:1](=[O:28])[C:2]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:3]12
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCN3C(=O)c4ccccc4C3=O)cc2)S1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1NC(=O)C(Cc2ccc(OCCN3C(=O)c4ccccc4C3=O)cc2)S1

Procedure:
A suspension of 5-(4-(2-phthalimidoethoxy)benzylidene)-2,4-thiazolidinedione (3.25 g) in dioxan (100 ml)was hydrogenated at room temperature and pressure in the presence of 10% palladium-charcoal (5 g) for 18 hours. A further portion of catalyst (5 g) was added, and the reaction continued for a total of 23 hours. The reaction mixture was filtered through diatomaceous earth, and the solvent evaporated. The resulting gum was crystallised from methanol-dioxan to afford the title compound, mp 192°-4° C.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C@@H:8]1[O:12]C(C)(C)[O:10][C@@H:9]1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[C:32](=[O:33])[C:31]3[C:30]4[N:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:24][C:23]=3[C:22]([CH3:35])([CH3:34])[C:21]=2[CH:36]=1)(C)(C)C.CO.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:34][C:22]1([CH3:35])[C:23]2[O:24][C:25]3[CH:26]=[CH:27][CH:28]=[N:29][C:30]=3[C:31]=2[C:32](=[O:33])[C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][C@@H:9]([OH:10])[C@H:8]([OH:12])[CH2:7][OH:6])=[CH:36][C:21]1=2
Reactant: CC1(C)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)[C@@H](COc2ccc3c(c2)C(C)(C)c2oc4cccnc4c2C3=O)O1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)c2cc(OC[C@@H](O)[C@H](O)CO)ccc2C(=O)c2c1oc1cccnc21
Temperature: 57.5 °C
Yield: 28.1 %

Procedure:
To the mixture of 8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy]-10,10-dimethyl-10H-11-oxa-4-aza-benzo[b] fluoren-5-one (Compound GT15-6, 27 mg), MeOH (0.1 ml) and THF (0.3 ml), 0.5 N sulfuric acid (0.1 ml) was added, and the mixture was stirred and heated at 55 to 60° C. for 4 hrs. The reaction mixture was neutralized with saturated aqueous solution of sodium bicarbonate. The resulting solid was filtered and washed with diethyl ether. The filtrate was extracted with the mixture solution of DCM and MeOH (DCM:MeOH=10:1). The organic layer was washed with saturated brine, and dried over magnesium sulfate. The filtered solid and the residues obtained after concentration under reduced pressure were combined and purified by silica gel column (DCM/MeOH) to obtain the title compound (5.4 mg, 28%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:26])[CH:11]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:15]([F:25])[CH:14]=2)[CH3:12])=[CH:6][CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[N:3]=1.[C:31]1(C)[C:32](CCO)=[CH:33][CH:34]=[CH:35][CH:36]=1.C1(B(CO)CO)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].O=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>[F:25][C:15]1[CH:14]=[C:13]([CH:11]([CH3:12])[C:10]([NH:9][CH2:8][C:7]2[C:2]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:3][C:4]([C:27]([F:30])([F:29])[F:28])=[CH:5][CH:6]=2)=[O:26])[CH:18]=[CH:17][C:16]=1[CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: Cc1ccccc1CCO
Reactant: CC(C(=O)NCc1ccc(C(F)(F)F)nc1Cl)c1ccc(CNS(C)(=O)=O)c(F)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: O=O
Product: CC(C(=O)NCc1ccc(C(F)(F)F)nc1-c1ccccc1)c1ccc(CNS(C)(=O)=O)c(F)c1
Temperature: 100 °C
Yield: 84 %

Procedure:
The N-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanamide (100 mg, 0.214 mmol) was added to a mixture of 1.2 mL toluene-ethanol (8:2). After addition of (phenylboranediyl)dimethanol (39 mg, 0.324 mmol), 0.2 mL 2 M aqueous sodium carbonate solution and tetrakis(triphenylphosphine)palladium (0) (25 mg) the mixture was heated at 100° C. for 1 h in a microwave. The reaction mixture was free from oxygen by evacuating and flushing with nitrogen. After cooling to room temperature the reaction mixture was diluted with 15 mL water, extracted with ethyl acetate (2×15 mL), dried over magnesium sulfate and concentrated under reduced pressure. The solid obtained was purified by column chromatography (silica gel: 100-200 mesh, eluent: cyclohexane/ethyl acetate 2:3) to afford 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)-N-((2-phenyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 5) (92 mg, 84%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][N:3]=1.Cl[Sn]Cl.O>CCO>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2[nH]nc(Br)c2c1

Procedure:
The product of Step (a) (10.0 g, 41.3 mmol, 1.00 equiv) was suspended in EtOH (120 mL). SnCl2.H2O (46.6 g, 206 mmol, 5.00 equiv) was added and the mixture was refluxed for 18 hours. The reaction mixture was concentrated en vacuo and water was added to the residue. The mixture was basified to pH 8 with satd. NaHCO3 and extracted with EtOAc (3×). The combined organic extracts were washed with satd. NaCl, dried over MgSO4, filtered and concentrated en vacuo. 8.10 g (92%) of the title compound was iolated as a purple solid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:57]=[CH:56][C:17]([C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][N:27](C)[CH2:28]C4CCN(C(=O)C5C=CC(C6C=C(OC)C(OC)=C(OC)C=6)=CC=5)CC4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][CH:15]=2)[CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11]>C(O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:57]=[CH:56][C:17]([C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][NH:27][CH3:28])[CH2:22][CH2:21]3)=[O:19])=[CH:16][CH:15]=2)[CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(-c2ccc(C(=O)N3CCC(CN(C)CC4CCN(C(=O)c5ccc(-c6cc(OC)c(OC)c(OC)c6)cc5)CC4)CC3)cc2)cc(OC)c1OC
Agent: Cl
Solvent: CCO
Product: CNCC1CCN(C(=O)c2ccc(-c3cc(OC)c(OC)c(OC)c3)cc2)CC1

Procedure:
Concentrated hydrochloric acid (0.045 ml; 0.54 mmol) was added to a solution of N,N-bis[[1-[4-(3,4,5-trimethoxyphenyl)benzoyl]-4-piperidinyl]methyl]methylamine (142 mg; 0.18 mmol) in ethanol (5 ml) and the reaction mixture was concentrated under reduced pressure. A process of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure was performed twice to obtain the title compound as a colorless amorphous powder.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[O:3]1.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CN(C)C=O>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:6]1([CH2:7][CH2:8][CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[O:3][C:2]1=[O:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCCC1C(=O)Oc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC1(CC(=O)OCc2ccccc2)C(=O)Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A solution of 0.204 mol of 2,3-dihydro-2-oxo-3-propylbenzofuran in 200 ml of anhydrous dimethylformamide is added to a suspension of 0.204 mol of sodium hydride in 100 ml of anhydrous dimethylformamide. The medium is maintained with stirring at room temperature for one hour, 0.224 mol of benzyl bromoacetate is then added and the medium is left for 12 hours at room temperature. The reaction mixture is concentrated under vacuum and hydrolyzed using one liter of water, the aqueous phase is extracted with twice 250 ml of benzene, the organic phase dried over anhydrous sodium sulfate and the solvent evaporated off. The crystallized residue is washed with isopropyl ether and filtered, yielding 0.173 mol of a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15]CC)=O.[C:18]([O:21][CH2:22][C:23]1[C:28]([Br:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=1Br)(=[O:20])[CH3:19].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+]>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].O1CCOCC1>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:1]2[CH2:2][CH2:3][N:4]3[C:12]4[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=4[CH:6]=[C:5]3[C:13]2=[O:15])=[CH:25][C:26]([F:30])=[CH:27][C:28]=1[Br:29])(=[O:20])[CH3:19]
Reactant: CCOC(=O)c1cc2c(n1CCN)CCCC2
Reactant: CC(=O)OCc1c(Br)cc(F)cc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Yield: 60 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with ethyl 1-(2-aminoethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101k (3.8 g, 20 mmol), 197c (20 g, 60 mmol), Xantphos (1.2 g, 2 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.8 g, 2 mmol), Cs2CO3 (16 g, 50 mmol), and 1,4-dioxane (120 mL). The system was evacuated and then refilled with N2. A reflux condenser was attached to the flask, and the reaction mixture was heated at 100° C. for 16 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography eluting with 5:1 petroleum ether/ethyl acetate to afford 197d in 60% yield (5.2 g) as a white solid. MS: [M+H]+ 435. 1H NMR (500 MHz, DMSO) δ 7.70 (dd, J=3, 1H), 7.48 (dd, J=3, 1H), 6.52 (s, 1H), 5.01 (m, 2H), 4.18 (m, 2H), 4.02 (m, 1H), 3.73 (m, 1H), 2.60 (m, 2H), 2.45 (m, 2H), 1.98 (s, 3H), 1.77 (m, 2H), 1.68 (m, 2H)
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH:18][CH:19]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]([CH3:33])[CH2:20]1.C(N(CC)CC)C>ClCCl.O>[CH3:33][CH:21]1[CH2:20][C:19](=[O:18])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22]1
Reactant: CC1CC(O)CCN(C(=O)OC(C)(C)C)C1
Solvent: CS(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: CC1CC(=O)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
A mixture of 46 mL DMSO and 500 mL dichlormethane was cooled to −78° C. and a solution of 68 mL, trifluoroacetic anhydride in 200 mL dichlormethane was added. Then, a solution of 50.6 g tert-butyl 5-hydroxy-3-methylazepane-1-carboxylat in 500 mL dichlormethane was added. The mixture was stirred at −78° C. for 1 h, 128 mL triethylamine was added and the mixture was warmed to RT. 1 L water was added and the layers were separated. The aqueous fraction was extracted two times with 500 mL dichlormethane. The combined organic fractions were dried, filtered and concentrated. Column chromatography on silica with ethyl acetate/heptane (1:4) yielded 13.7 g of the desired product. (M+H)+: 228
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.[OH:18][CH2:19][C:20]([CH2:22][OH:23])=[O:21]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH:19]([OH:18])[C:20](=[O:21])[CH2:22][OH:23])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O=C(CO)CO
Product: O=C(CO)C(O)C(O)c1ccc(-c2nc3ccccc3o2)cc1

Procedure:
Compound B was prepared as a mixture of isomers in analogy to example 1 from 4-benzoxazol-2-yl-benzaldehyde and 1,3-dihydroxyacetone.
Reaction SMILES: Br[C:2]1[C:25](=[O:26])[N:24]([CH2:27][CH3:28])[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:8]=[CH:9][C:4]=2[CH:3]=1.[CH3:29][S:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:32])=[O:31].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:27]([N:24]1[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:8]=[CH:9][C:4]=2[CH:3]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:34][CH:35]=2)[C:25]1=[O:26])[CH3:28]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCn1c(=O)c(Br)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c(-c2ccc(S(C)(=O)=O)cc2)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 14.8 %

Procedure:
6-Bromo-8-ethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (5, 120 mg, 0.27 mmol), 4-methylsulfonylphenylboronic acid (60 mg, 0.30 mmol), K3PO4 (64 mg, 0.30 mmol) and PdCl2(dppf) (25 mg, 0.03 mmol) were mixed under argon in a degassed mixture of dimethylformamide and water (20:1, 4 mL). The resulting suspension was irradiated for 30 min at 140° C. in a microwave reactor. After completion, the reaction mixture was evaporated and the residue purified by ISCO eluting with chloroform:methanol (100:0→98:2). The partially purified product (50 mg) was recrystallized from ethyl acetate. The title compound (21 mg, 0.04 mmol, 15%) was obtained as a yellow solid. ESMS m/z 519 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.60 (s, 1H) 7.99 (d, J=8.3 Hz, 2H) 7.90 (d, J=8.3 Hz, 2H) 7.71 (s, 1H) 7.55 (d, J=8.8 Hz, 2H) 7.30 (br. s, 1H) 6.98 (d, J=8.8 Hz, 2H) 4.51 (q, J=7.0 Hz, 2H) 3.18-3.27 (m, 4H) 3.07 (s, 3H) 2.54-2.67 (m, 4H) 2.37 (s, 3H) 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:25])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[CH:26](OCC)(OCC)[O:27][CH2:28][CH3:29].C(OC(=O)C)(=O)C>>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:24])[C:18](=[CH:26][O:27][CH2:28][CH3:29])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:25])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(C2CCC(NC(C)=O)C2)cc1F
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2CCC(NC(C)=O)C2)cc1F

Procedure:
A solution of 17.7 g (50 mmol) of 4-[3-(acetylamino)cyclopentyl]-2,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester, 11.1 g (75 mmol) triethyl orthoformate and 75 ml of acetic anhydride was refluxed for 3 hours. The solvent was removed in vacuo and the residue triturated with toluene which was also removed in vacuo, then in high vacuo at 50°. The residue, 20.1 g, was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH3:10])=[C:6]([Cl:11])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[NH4+].[Cl-]>ClCCl>[Cl:11][C:6]1[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[N:3]=[C:2]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1c(Cl)nc(-c2ccc([N+](=O)[O-])cc2)nc1Cl
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCOc1c(Cl)nc(-c2ccc([N+](=O)[O-])cc2)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
4,6-dichloro-5-ethoxy-2-(4-nitro-phenyl)-pyrimidine (0.50 g, 1.0 eq) was stirred in dichloromethane (10 mL) and a solution of morpholine (0.21 mL, 1.5 eq) in dichloromethane (5 mL) was added dropwise at 0° C. After stirring the resulting solution overnight at r.t., NH4Cl (aq) was added to the solution and the solution was extracted with dichloromethane. The combined organic layers were washed with brine, dried and evaporated in vacuo. A product was obtained as a white solid (0.57 g, 81%).