Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1>>[C:14]([Si:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[C:30][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1)([CH3:15])([CH3:16])[CH3:17]
Reactant: BrCCCCOC1CCCCO1
Reactant: C#CCCCCCCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Product: CC(C)(C)[Si](OCCCCCCCCCCC#CCCCCOC1CCCCO1)(c1ccccc1)c1ccccc1
Yield: 66 %

Procedure:
Alkylation of 12-(tert-butyldiphenylsilyloxy)dodec-1-yne with 2-(4-bromobutoxy)tetrahydropyran as described above gave tert-butyldiphenyl-[16-(tetrahydropyran-2-yloxy)hexadec-11-ynyloxy]silane (66%) as a colorless oil which was used in the next reaction without further purification. TLC: 10% EtOAc/hexane, Rf≈0.5.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1Cl)[C:5](Cl)=[O:6].CC[N:14](CC)CC.[OH-].[Na+]>C1COCC1>[C:5]([NH2:14])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCN(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3,4-dichlorobenzoyl chloride Compound 1e (0.25 mmol, 0.06 g) in THF (1 mL) was added dropwise over 2 min to a solution of Compound 2c (0.2 mmol, 0.05 g) and Et3N (0.4 mmol, 0.06 mL) in THF (4 mL) at 0° C. The resulting suspension was allowed to warm to r.t. overnight, then made basic with a 2N NaOH-solution and extracted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were washed with brine, then dried over Na2SO4 and filtered. The solvent was removed in vacuo to yield 3,4-dichloro-N-(4-{2-[methyl-(tetrahydro-pyran-4-yl)-amino]-ethyl)}-phenyl)-benzamide Compound 2d as a yellow solid. The product was purified by preparative TLC (10:1 EtOAc:MeOH) (0.06 g, 73%). MS m/e 407 (M+H, 100%);
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([O:24]C)=[O:23])=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([OH:24])=[O:23])=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccccc1-c1cnc(C(=O)CCCCCCc2ccccc2)o1
Solvent: CCOC(C)=O
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2ccccc2C(=O)O)o1
Yield: 81.5 %

Procedure:
The title compound was prepared from methyl 2-(2-(7-phenylheptanoyl)oxazol-5-yl)benzoate (10 mg, 0.026 mmol) following General Procedure E. Preparative thin layer chromatography (EtOAc) yielded the title compound as a white solid (8 mg, 80%): 1H NMR (CD3OD, 600 MHz) δ 7.62 (s, 1H), 7.22-7.19 (m, 2H), 7.14-7.09 (m, 3H), 3.04 (t, 2H, J=7.5 Hz), 2.58 (t, 2H, J=7.5 Hz), 1.71-1.68 (m, 2H), 1.62-1.59 (m, 2H), 1.41-1.32 (m, 4H); 13C NMR (CD3OD, 150 MHz) δ 189.0, 159.4, 159.4, 143.3, 143.3, 134.6, 128.9, 128.7, 126.1, 39.6, 36.3, 32.0, 29.5, 29.4, 23.9; MALDI-FTMS m/z 378.1705 (M+H+, C23H24NO4, requires 378.1700).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.I[C:21]1[CH:22]=[C:23]([C:27]2[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[CH:29]=[CH:30][N:31]=2)[CH:24]=[CH:25][CH:26]=1.N1C=CC=CC=1C(O)=O.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.CS(C)=O>[O:18]([C:25]1[CH:24]=[C:23]([C:27]2[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[CH:29]=[CH:30][N:31]=2)[CH:22]=[CH:21][CH:26]=1)[C:14]1[CH:13]=[C:12]([C:8]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:19])[CH:11]=[CH:10][N:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccccc1-n1ccnc1-c1cccc(O)c1
Reactant: Cc1ccccc1-n1ccnc1-c1cccc(I)c1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccccc1-n1ccnc1-c1cccc(Oc2cccc(-c3nccn3-c3ccccc3C)c2)c1
Temperature: 150 °C

Procedure:
To a 250 mL round bottom flask was added 3-(1-(o-tolyl)-1H-imidazol-2-yl)phenol (2.009 g, 8.03 mmol), 2-(3-iodophenyl)-1-(o-tolyl)-1H-imidazole (3.18 g, 8.83 mmol), picolinic acid (1.482 g, 12.04 mmol), copper(I) iodide (0.459 g, 2.408 mmol), potassium phosphate tribasic monohydrate (6.47 g, 28.1 mmol), and 80 mL DMSO. Nitrogen was bubbled directly into the mixture and then was heated to 150° C. overnight under nitrogen. The reaction mixture was cooled to room temperature, added water, extracted twice with ethyl acetate, dried extracts over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography eluting with 80% ethyl acetate/hexane (2.12 g, 55%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)=[N:7][CH:6]=[C:5]2[CH:24]=[O:25].C(=O)([O-])[O-].[K+].[K+].[Br:32][CH2:33][CH2:34][CH2:35]Br>CN(C)C=O>[Br:32][CH2:33][CH2:34][CH2:35][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)=[N:7][CH:6]=[C:5]2[CH:24]=[O:25]
Reactant: BrCCCBr
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(O)c(OC)cc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCCBr)c(OC)cc23)c1
Temperature: 85 °C
Yield: 63.6 %

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (86 g, 0.24 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (337 mg, 2.40 mmol) and 1,3-dibromopropane (0.124 mL, 1.22 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 6-(3-bromo-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde as a colorless oil (70 mg, 62% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.C(N=C=NC1CCCCC1)C1C=CC=CC=1.ON1C2C=CC=CC=2N=N1.[CH3:42][C@H:43]1[CH2:48][N:47]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([NH:56][CH3:57])=[CH:52][CH:51]=2)[CH2:46][CH2:45][N:44]1[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59]>CN(C=O)C.C(Cl)Cl>[CH3:42][C@H:43]1[CH2:48][N:47]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([N:56]([CH3:57])[C:11]([C:10]3[CH:9]=[CH:8][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:15][CH:14]=3)=[O:13])=[CH:52][CH:51]=2)[CH2:46][CH2:45][N:44]1[C:58]([O:60][C:61]([CH3:62])([CH3:64])[CH3:63])=[O:59]
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Agent: C(=NCc1ccccc1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(-c4ccccn4)cc3)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
To 4-(2-pyridinyl)benzoic acid (0.0624 g, 0.313 mmol) in DMF (3 mL) was added N-benzyl-N′-cyclohexylcarbodiimide resin (0.294 g, 1.6 mmol/g, 0.47 mmol), 1-hydroxybenzotriazole (0.064 g, 0.47 mmol) and DCM (1 mL) and the mixture was shaken for 30 minutes. 1,1-Dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazine-carboxylate (D3) (100 mg, 0.313 mmol), DMF (3 mL) and DCM (1 mL) were then added and the mixture was shaken for ˜2 days at room temperature The reaction mixture was filtered to remove the resin which was then washed with further DMF/DCM (3:1). The filtrate was concentrated to give the crude product which was purified by column chromatography. Elution with an ether/pentane gradient yielded the title compound (0.055 g). MS (ES): MH+ 501.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17])([O-:3])=[O:2].[CH:20](OCC)(OCC)[O:21][CH2:22][CH3:23].C(OC(=O)C)(=O)C>>[CH2:22]([O:21][CH:20]=[C:15]([C:16](=[O:18])[CH3:17])[C:14]([C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:19])[CH3:23]
Reactant: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(C)=O)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
A mixture of 1-(2-nitro-4-trifluoromethylphenyl)-butan-1,3-dione (-11.0 g), triethyl orthoformate (11.3 g) and acetic anhydride (12.3 g) was stirred and heated at reflux for 3 hours. After cooling, the mixture was evaporated to dryness. Toluene (50 ml) was added and the mixture was evaporated to dryness to give 2-ethoxymethylene-1-(2-nitro-4-trifluoromethylphenyl)-butan-1,3-dione as a crude brown oil which was not further purified.
Reaction SMILES: O=[C:2]1[CH:7]2[CH2:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH:3]1[CH2:4][N:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]2.C([BH3-])#N.[Na+]>C1COCC1>[CH:3]12[CH2:2][CH:7]([CH2:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:10]1)[CH2:6][N:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4]2
Reactant: COC(=O)C1CC2CN(C(=O)OC(C)(C)C)CC(C1)C2=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CC2CC(C1)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
To a solution of 3-tert-butyl 7-methyl 9-oxo-3-azabicyclo[3.3.1]nonane-3,7-dicarboxylate (22.1 g) in THF (372 mL) was added p-toluenesulfonylhydrazide (16.6 g). The reaction mixture was stirred at room temperature for 2 hr, sodium cyanoborohydride was added. The mixture was stirred at 65° C. for 16 hr, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (9.50 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:21]=2[N:20]=1>>[Cl:2][C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([C:19]2[NH:23][C:22]3[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:21]=3[N:20]=2)[CH2:11][CH2:10]1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: CC(=O)c1cnc(N2CCNCC2)c(Cl)c1
Agent: Cl
Product: CC(=O)c1cnc(N2CCN(c3nc4ccc(C(F)(F)F)cc4[nH]3)CC2)c(Cl)c1

Procedure:
1-(5-Chloro-6-piperazin-1-yl-pyridin-3-yl)-ethanone, hydrochloride from step (d) above (0.6 g, 1.92 mmol) reacted with 2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.423 g, 1.92 mmol, Example 1c) under the conditions of Example 94d to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 424 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[C:34]([C:46]([F:49])([F:48])[F:47])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:59])=[C:34]([C:46]([F:49])([F:48])[F:47])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)c(C(F)(F)F)c2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)c(C(F)(F)F)c2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 27.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfanyl]-3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.36 g) in methylene chloride (10.8 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.11 g) in methylene chloride (7.2 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfinyl]-3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 236) (100 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[F:13].O1CCOCC1.CCN(C(C)C)C(C)C.[CH2:29]([SH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O.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].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>[CH2:29]([S:36][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[F:13])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Fc1cc2c(Cl)ccnc2cc1Br
Reactant: SCc1ccccc1
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
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2c(Cl)ccnc2cc1SCc1ccccc1
Reaction time: 0.17 h
Yield: 90 %

Procedure:
A vial was charged with 7-bromo-4-chloro-6-fluoroquinoline (0.141 g, 0.541 mmol), Xantphos (0.016 g, 0.027 mmol), and Pd2(dba)3 (0.012 g, 0.014 mmol) and after flushing with argon, dioxane (1.083 ml) and n,n-diisopropylethylamine (0.189 ml, 1.083 mmol) were added in sequence. The vial was sealed, and was placed in a heating bath at 80° C. for 10 minutes, after which benzylmercaptan (0.067 ml, 0.568 mmol) was added drop wise via syringe. The reaction was stirred for 30 minutes. The material was diluted with water, and washed with DCM (×3), and the combined organics were dried via phase separator and concentrated in vacuo. The material was purified via silica gel chromatography eluting with 0-50% ethyl acetate in heptane to yield 7-(benzylthio)-4-chloro-6-fluoroquinoline (0.148 g, 0.487 mmol, 90% yield) as a light yellow solid. m/z (ESI) 304.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([N:34]3[CH2:35][CH2:36][N:31]([C:28](=[O:30])[CH3:29])[CH2:32][CH2:33]3)=[O:21])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCNCC1
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1nccc(-c2ccc(C(=O)N3CCN(C(C)=O)CC3)c(F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 100 mg (0.28 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid (A-38) using 46 mg (0.36 mmoL) N-acetyl piperazine, 116 mg (0.30 mmol) HATU and 81 μL DIPEA in 1 mL DMF. After completion of the reaction, the reaction mixture is filtered and the product is isolated from the obtained solution by RP-HPLC using a H2O/ACN-gradient. Yield: 69 mg (53%).
Reaction SMILES: [CH2:1]([OH:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1>CC(C)=O.C(Cl)Cl.CCOC(C)=O.O>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH2:1][OH:11])[CH:10]=[CH:9][C:7]=1[O:8][CH2:14][CH:13]=[CH2:12]
Reactant: COc1cc(CO)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: C=CCOc1ccc(CO)cc1OC
Temperature: 60 °C
Yield: 94.8 %

Procedure:
Acetone (107.5 mL), vanillyl alcohol (25 g, 0.163 mol), and allyl bromide (15.8 mL, 0.183 mol) were added to a 250 mL, round-bottomed flask and stirred until homogeneous. Potassium carbonate (22.5 g, 0.163 mol) was then added slowly, which briefly gave a light pink color that indicated deprotonation of the phenol. The mixture was heated at 60° C. overnight. The reaction was monitored by TLC using 10% acetone in CH2Cl2 as eluent. Upon completion, the reaction mixture was allowed to cool to rt with stirring. The acetone was removed under vacuum, yielding a white residue. CH2Cl2 (200 mL) and H2O (200 mL) were added to redissolve the residue and transferred to a separatory funnel. The aqueous layer was removed and the organic layer was washed with 1 M NaOH (3×100 mL) and saturated NaCl (1×100 mL). The organic layer was then collected, dried over MgSO4. After filtration, the solvent was removed under vacuum to afford a yellow powder. The yellow powder was redissolved in EtOAc (250 mL), which was subsequently removed under vacuum (in order to remove excess allyl bromide) to afford the product as a fine, white powder (30.0 g, 93% yield). 1H NMR δ=6.94 (s, 1H), 6.86 (s, 2H), 6.09 (multi, 1H), 5.42 (dd, J1=20, J2=1.5, 1H), 5.30 (dd, J1=20, J2=1.5, 1H), 4.63 (d, J=3.6, 2H), 4.62 (d, J=5, 2H), 3.89 (s, 3H), 1.57 (t, J=6, 1H).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]2[CH:39]=[CH:40][N:41]=[C:34]2[CH:33]=[C:32]3[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:28])=[CH:23][CH:22]=1>C1COCC1.O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([C:11]2[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=2)([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]2[CH:39]=[CH:40][N:41]=[C:34]2[CH:33]=[C:32]3[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[OH:28])=[CH:25][CH:26]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1ccccc1)cc1nccn12
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1ccccc1)cc1nccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.1 %

Procedure:
n-Butyllithium (0.0129 mol) was added slowly at −70° C. under N2 flow to a solution of 1-methylimidazole (0.0129 mol) in THF (25 ml). The mixture was stirred for 30 min. Chlorotriethylsilane (0.0129 mol) was added. The mixture was allowed to warm to room temperature and then cooled to −70° C. n-Butyllithium (0.0129 mol) was added. The mixture was stirred at −70° C. for 1 hour, then allowed to warm to −15° C. and cooled to −70° C. A solution of (±)-α-(4-chlorophenyl)-5-phenylimidazo[1,2-a]quinoline-7-methanone (0.0107 mol) in THF (12 ml) was added. The mixture was stirred at −70° C. for 1 hour. Water was added The mixture was extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel. The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 0.9 g (18%) of (±)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-phenylimidazo[1,2-a]quinoline-7-methanol (compound 11).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[C:13]([CH:23]([P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[OH:24])=[CH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH3:22])[CH:16]=2.C(N(CC)CC)C>C(Cl)Cl.O>[Br:11][C:12]1[C:13]([C:23]([P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[O:24])=[CH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH3:22])[CH:16]=2
Reactant: CCOP(=O)(OCC)C(O)c1cc2cc(C)ccc2cc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(=O)c1cc2cc(C)ccc2cc1Br
Temperature: 25 °C

Procedure:
To a solution of oxalyl chloride (0.15 mL) in 2.5 mL of CH2Cl2 at −78° C. was added DMSO (0.23 mL). The reaction was stirred for 10 minutes after which a solution of diethyl (3-bromo-7-methyl-2-naphthyl)(hydroxy)methylphosphonate (160 mg), in 2.5 mL CH2Cl2 was added dropwise. The reaction was stirred for 1 h at −78° C. after which triethylamine (0.66 mL) was added to the mixture and the temperature was raised to rt. Water (5 mL) was added and the mixture was extracted with CH2Cl2. The organic extracts were combined, dried over Na2SO4 and evaporated to dryness to afford the titled product which was used as such in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:43])[C:13]([S:16][C:17]3[CH:34]=[CH:33][C:20]([CH2:21][NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[C:19]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:18]=3)=[N:14][N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:44]1(O)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2N=N1.C(N)CCCCC.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:43])[C:13]([S:16][C:17]3[CH:34]=[CH:33][C:20]([CH2:21][NH:22][C:23]4[CH:24]=[CH:25][C:26]([CH2:29][C:30]([NH:44][CH2:48][CH2:47][CH2:52][CH2:51][CH2:50][CH3:49])=[O:32])=[CH:27][CH:28]=4)=[C:19]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:18]=3)=[N:14][N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCOc1cc(Sc2nnc(-c3ccc(C(C)(C)C)cc3)n2C)ccc1CNc1ccc(CC(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCCN
Product: CCCCCCCOc1cc(Sc2nnc(-c3ccc(C(C)(C)C)cc3)n2C)ccc1CNc1ccc(CC(=O)NCCCCCC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (4-{4-[5-(4-tert-butylphenyl)-4-methyl-4H-[1,2,4]-triazol-3-ylsulfanyl]-2-heptyloxybenzyl amino}phenyl)acetic acid (0.3 g, 0.5 mmol), benzotriazol-1-ol (0.074 g, 0.55 mmol) in dimethylformamide (10 ml) is stirred for 20 minutes. n-Hexylamine (0.066 ml, 0.5 mmol) and (3-dimethylaminopropyl)ethylcarbodiimide (0.105 g, 0.55 mmol) are added and then the medium is stirred for 24 hours at room temperature. The addition of water causes the formation of a precipitate which is dried before being purified by chromatography on a silica column, eluted with a heptane/ethyl acetate (3/7) mixture. After evaporation of the solvents, 0.205 g (60%) of the expected compound is recovered.