Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[F:11][C:12]([F:26])([F:25])[O:13][CH2:14][CH2:15][CH2:16]OS(C(F)(F)F)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH2:16][CH2:15][CH2:14][O:13][C:12]([F:26])([F:25])[F:11])[CH:7]=1
Reactant: O=S(=O)(OCCCOC(F)(F)F)C(F)(F)F
Reactant: COc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Br)cc1OCCCOC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-2-methoxy-phenol (1.20 g, 5.62 mmol), crude trifluoro-methanesulfonic acid 3-trifluoromethoxy-propyl ester (2.52 g, 6.74 mmol; purity of 74%) and anhydrous K2CO3 (1.18 g, 8.42 mmol) in MeCN (8 mL) is stirred in a sealed flask at room temperature overnight and then filtered. The combined filtrates are concentrated and the crude product is chromatographed over silica gel (eluent: toluene) to give the title compound as oil. TLC, Rf (toluene/AcOEt 10:1)=0.63. 1H-NMR (CDCl3): δ 2.25 (m, 2H), 3.87 (s, 3H), 4.13 (m, 2H), 4.23 (m, 2H), 6.79 (dd, 1H), 7.04 (d,1H), 7.09 (dd, 1H) ppm. 19F-NMR (CDCl3): zδ −60.7 ppm.
Reaction SMILES: COCCO[Li].[CH:7]([Li])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1C=CC=CC=1.C(=O)=O.[C:24]([O:28]CC(CC)CCCC)(=[O:27])[CH:25]=[CH2:26].[H-].[Ca+2].[H-]>C1COCC1.CC(C)=O>[C:24]([O:28][CH:14]([CH2:7][CH3:8])[CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])(=[O:27])[CH:25]=[CH2:26]
Reactant: [Li]C(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: O=C=O
Agent: [Ca+2]
Agent: [H-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C=CC(=O)OC(CC)CCCCC
Yield: 95 %

Procedure:
2.0×10-3 mol of CH3OCH2CH2OLi in solution in THF are introduced under nitrogen atmosphere into a predried round bottom flask. 100 ml of predried THF are added followed, with stirring, dropwise, by 1.0×10-3 mol of (Ph)2CHLi in 0.2-molar solution in THF. The mixture is cooled to a temperature of -78° C. with a mixture of acetone and solid carbon dioxide, followed by the addition, still at -78° C., of 0.048 mol of 2-ethylhexyl acrylate previously stirred for 48 hours over calcium hydride, distilled and then treated over fluorenyllithium until the appearance of a yellow colour and distilled over triethylaluminium immediately before the polymerisation. After 10 minutes the reaction is stopped by addition of 5 ml of acidified methanol and the solvent is then stripped off. An ethylhexyl acrylate polymer is obtained in a 95% yield. Analysis of the polymer by GPC shows the following characteristics:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]2[NH:12][C:10](=[O:11])[O:9][C@H:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:30](Cl)(=[O:32])[CH3:31]>C1COCC1.O>[C:30]([N:12]1[C@H:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]1=[O:11])(=[O:32])[CH3:31]
Reactant: O=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)O1
Reactant: CC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 1.13 h
Yield: 100.4 %

Procedure:
To a stirred suspension of 5.100 g (4R,5S)-(+)-cis-4,5-diphenyl-2-oxazolidinone (20.89 mmol) in 102 mL THF, were added 13.65 mL n-butyllithium in hexane (1.5 M, 20.47 mmol, 0.98 eq) at −78° C. during 6 min. The resulting dark red solution was stirred for additional 68 min at −78° C. During this period, the solution became colorless. Stirring was continued for 15 min at −25° C., before it was cooled again to −78° C. A solution of 1.536 mL acetyl chloride (21.31 mmol, 1.02 eq) in 15.3 mL THF was then added within 5 min. After 52 min, the mixture was poured on 510 mL water and the product was extracted three times with 305 mL, in total 915 mL dichloromethane. The combined organic phases were washed with 715 mL aqueous NaHCO3 and with 715 mL brine. The solution was dried over 25 g sodium sulfate (30 min) and filtered. The filter cake was washed with 50 mL dichloromethane. After removal of solvent in a rotary evaporator (40° C., 30 mbar), the crude product (5.899 g, 100% by weight) was obtained as a white solid. Purification was accomplished by recrystallization from 13 mL toluene. The heterogeneous mixture was heated to reflux until a clear solution was obtained, which was then allowed to slowly cool down to room temperature. After two days, the title compound was collected by filtration as white crystals (5.157 g, 18.332 mmol, 88% by weight).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCCBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCC(=O)c2ccccc2)CC1
Yield: 48.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.3 g) as starting compound, potassium carbonate (2.1 g) and 7-bromo-1-phenyl-1-heptanone (0.92 g) were reacted and treated in the same manner as in Example 172 to give 0.80 g of 4-amino-5-chloro-2-methoxy-N-((1-(7-oxo-7-phenylheptyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:12])=[C:7]2[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C[O:21][C:22](=[O:33])[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:12])=[C:7]2[C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C@@H:23]([CH3:24])[C:22]([OH:33])=[O:21])=[CH:30][CH:29]=1
Reactant: COC(=O)C(C)c1ccc(CBr)cc1
Reactant: Cc1cnc2c(Cl)cccc2c1-c1cccc(O)c1
Product: Cc1cnc2c(Cl)cccc2c1-c1cccc(OCc2ccc([C@@H](C)C(=O)O)cc2)c1

Procedure:
This compound was prepared according to the procedure of example 41, substituting 3-(8-chloro-3-methyl-quinolin-4-yl)-phenol and 2-(4-bromomethyl-phenyl)-propionic acid methyl ester. Purification by supercritical fluid chromatography (MeOH/CO2). Electronic circular dichroism CD λmax=+6 mdeg @ 226 nm (EtOH). MS (ESI) m/z 432.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([C:9]#[C:10][CH:11]([CH3:13])[CH3:12])=[CH:4][N:3]=1.CC([O-])(C)C.[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN1C(=O)CCC1.C1COCC1.CN(C=O)C>[CH2:20]([N:8]1[C:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[CH:9]=[C:10]1[CH:11]([CH3:13])[CH3:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C#Cc1cnc(Cl)cc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: CC(C)c1cc2cnc(Cl)cc2n1Cc1ccccc1
Temperature: 160 °C
Reaction time: 6 h

Procedure:
To a solution of 2-chloro-5-(3-methylbut-1-ynyl)pyridin-4-amine (Compound 12, 0.82 g, 4.2 mmol) in NMP (10 ml) was added KOtBu (2.40 g, 21 mmol). The mixture was stirred at 160° C. for 6 h and was cooled to room temperature, diluted with THF (10 ml) and DMF (15 ml). Benzyl bromide (0.50 ml, 4.2 mmol) was added. The mixture was stirred at room temperature for 16 h and was quenched with H2O, extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:43]=[CH:42][C:18]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])[N:23]=[CH:22][N:21]=2)=[C:17]([F:44])[CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:44][C:17]1[CH:16]=[C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[S:13])[CH:43]=[CH:42][C:18]=1[O:19][C:20]1[CH:25]=[C:24]([NH:26][C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH2:33][CH2:34]2)=[O:28])[N:23]=[CH:22][N:21]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)ncn3)CC2)CC1
Reaction time: 3.5 h
Yield: 31 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 2.5 ml) to a solution of 4-(4-amino-2-fluorophenoxy)-6-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonylamino}pyrimidine (134 mg) and (+)-10-camphorsulfonic acid (109 mg) in ethanol (3.0 ml) at room temperature, the mixture was stirred for 3.5 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated to provide the title compound (60.7 mg, 31%) as white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16](=[O:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:31])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29]I)([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:19]([O:23][C:24](=[O:31])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[C:16](=[O:18])[CH3:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCCCI
Reactant: CC(=O)c1c(O)cccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2-benzyloxy-6-hydroxyphenyl)-ethanone (100 mg, 0.41 mmol) and (4-iodobutyl)-carbamic acid tert-butyl ester (Example 123, step A) (150 mg, 0.5 mmol) in DMF (5 mL) is added K2CO3 (113 mg, 0.82 mmol) and the mixture is stirred at RT for 18 h. Water is added and the mixture is extracted with EtOAc. The organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (10:1) as eluent to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH3:29][NH:30][CH2:31][CH3:32]>>[CH2:31]([N:30]([CH3:29])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:32]
Reactant: CCNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C20H23FN6O2, 398.2
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:11]([C:12](OC)=[O:13])[CH:10]2[O:16][CH:6]1[CH2:7][C:8]([C:18]1[N:26](C3CCCCO3)[C:25]3[C:24](=[O:33])[N:23]([CH2:34][CH2:35][CH3:36])[C:22](=[O:37])[N:21]([CH2:38][CH2:39][CH3:40])[C:20]=3[N:19]=1)([OH:17])[CH2:9]2)=O.[Li+].[BH4-]>C1COCC1>[OH:17][C:8]1([C:18]2[NH:26][C:25]3[C:24](=[O:33])[N:23]([CH2:34][CH2:35][CH3:36])[C:22](=[O:37])[N:21]([CH2:38][CH2:39][CH3:40])[C:20]=3[N:19]=2)[CH2:7][CH:6]2[O:16][CH:10]([CH:11]([CH2:12][OH:13])[CH:5]2[CH2:3][OH:2])[CH2:9]1
Reactant: CCCn1c(=O)c2c(nc(C3(O)CC4OC(C3)C(C(=O)OC)C4C(=O)OC)n2C2CCCCO2)n(CCC)c1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C3(O)CC4OC(C3)C(CO)C4CO)nc2n(CCC)c1=O
Yield: 110.5 %

Procedure:
To a solution of 3-[2,6-dioxo-1,3-dipropyl-7-(tetrahydropyran-2-yl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-3-hydroxy-8-oxa-bicyclo[3.2.1]octane-6,7-dicarboxylic acid dimethyl ester (Example 53) (0.060 mmol, 0.030 g) in THF (3 ml) was added a solution of LiBH4 (2M, 0.050 ml). The reaction was stirred at room temperature 3d. It was then carefully quenched by addition of 1N HCl and extracted with EtOAc. The combined organic extracts were washed with saturated NaHCO3 (1X) and brine, and dried (MgSO4). Filtration and evaporation provided the desired product (0.028 g, 92%) as an oil. MS (ESP+, 60V): 529.7 (M+Na, 20%), 507.32 (M+H, 43%), 423.20 (87%), 223.08 (100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)cc(OCc2ccccc2)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cc(OC)cc(OCc2ccccc2)c1
Yield: 84.7 %

Procedure:
To a solution of 3-(benzyloxy)-5-methoxybenzaldehyde (5.50 g) in toluene (50 mL) was added ethyl (triphenylphosphoranylidene)acetate (7.90 g), and the mixture was heated under reflux for 4 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.00 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[C:9]([C:11]3[N:15]([CH2:16][CH:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH:14]=[N:13][C:12]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CN1CCNCC1>CC#N>[NH2:1][C:2]1[C:3]2[N:10]=[C:9]([C:11]3[N:15]([CH2:16][CH:17]4[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]4)[CH:14]=[N:13][C:12]=3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC3CCC(=O)CC3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CN1CCNCC1
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC3CCC(O)CC3)nc12
Yield: 14.9 %

Procedure:
4-{[5-(7-Amino[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-4-phenyl-1H-imidazol-1-yl]methyl}cyclohexanone (Example 179), (100 mg) was treated with sodium triacetoxyborohydride (160 mg) and 1-methylpiperazine (150 mg) in MeCN (20 mL) for 4 days at ambient temperature. The mixture was filtered and the solids washed with MeCN (2×5 mL). The combined filtrate and washes were evaporated and the residue was purified by preparative RPHPLC (eluting with a gradient of water and MeCN containing 0.1% TFA) to afford the title alcohol as a colourless solid (15 mg, 16%);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[O:20][CH:21]=[CH:22][C:23]=1[C:24](O)=[O:25]>>[CH3:18][C:19]1[O:20][CH:21]=[CH:22][C:23]=1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:25]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: Cc1occc1C(=O)O
Product: Cc1occc1C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 4 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.3 mg (0.09 mMol) 2-methyl-3-furoic acid, 0.4 mg (4%) of the title compound were recovered.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:35]=[CH:34][C:13]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]4[CH:32]=[C:31]5[C:27]([CH2:28][C:29](=[O:33])[NH:30]5)=[CH:26][CH:25]=4)[CH:18]=3)=[O:15])=[CH:12][C:11]=2[C:36]([F:39])([F:38])[F:37])[CH2:5][CH2:4]1)[CH3:2].[NH:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[CH:45]=O.N1CCCCC1>CCO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:35]=[CH:34][C:13]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]4[CH:32]=[C:31]5[C:27]([C:28](=[CH:45][C:41]6[NH:40][CH:44]=[CH:43][CH:42]=6)[C:29](=[O:33])[NH:30]5)=[CH:26][CH:25]=4)[CH:18]=3)=[O:15])=[CH:12][C:11]=2[C:36]([F:38])([F:39])[F:37])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)NC(=O)C5)c3)cc2C(F)(F)F)CC1
Reactant: O=Cc1ccc[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)NC(=O)C5=Cc4ccc[nH]4)c3)cc2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 59.5 %

Procedure:
To a suspension of 4-(4-ethyl-piperazin-1-ylmethyl)-N-[3-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-phenyl]-3-trifluoromethyl-benzamide (200 mg, 0.372 mmol) in EtOH (10 mL) are added pyrrole-2-carboxaldehyde (42 mg, 0.446 mmol) and piperidine (74 μL, 0.74 mmol). The mixture is heated at 80° C. for 2 hours. All the solvent is evaporated to dryness. The crude is recrystallized in EtOH to give 136 mg of the desired compound: 1H NMR (400 MHz, DMSO) δ 10.74 (s, 1 H), 10.34 (s, 1 H), 8.37 (s, 1 H), 8.18-8.24 (m, 2 H), 7.92 (d, 1 H); 7.67 (s, 1 H), 7.46-7.50 (t, 2 H), 7.24-7.28 (m, 3 H), 6.84 (d, 1 H), 6.76 (s, 1 H), 6.72 (m, 1 H), 6.67 (d, 1 H), 6.29-6.31 (m, 1 H), 3.69 (s, 2 H), 3.30 (s, 2 H), 2.30-2.48 (m, 8H), 1.00 (t, 3H); LC-MS: 615.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:11][CH2:12][N:13]([CH2:15][CH2:16]Cl)[CH3:14].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:14][N:13]1[CH2:15][CH2:16][N:1]([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH2:11][CH2:12]1
Reactant: Nc1cccc(O)c1
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2cccc(O)c2)CC1
Reaction time: 48 h

Procedure:
3-Aminophenol (2 g, 18 mmol) is brought to the reflux point of 1-butanol (30 ml) in the presence of 2-chloro-N-(chloroethyl)-N-methylethanamine hydrochloride (3.5 g, 18 mmol) and sodium carbonate (95 mg, 9 mmol). After 48 h, the reaction mixture is concentrated and adsorbed on silica and then purified by flash chromatography with a mixture (90/10) of dichloromethane/methanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:15]1CCOCC1.ClC(OCC(C)C)=O.[OH-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH3:13])[C:10]([NH2:15])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of (2S)-2-[(tert-butoxycarbonyl)amino]propanoic acid (1 g, 0.005 mol) in THF at 0° C. was added 4-methylmorpholine (0.588 g, 0.00581 mol) followed by dropwise addition of isobutyl chloroformate (0.794 g, 0.00581 mol) over 2 min. The reaction was stirred at 0° C. for 30 min. after which a solution of 30 wt. % ammonium hydroxide (12.0 mL, 0.0925 mol) was quickly poured into the reaction. The reaction was warmed to room temperature and stirred for 5 h. The reaction mixture was concentrated. Water was added and the mixture extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford the crude product which was directly used in the next step reaction without further purification (800 mg, 80%). 1H-NMR (300 MHz, DMSO-d6): 12.40 (s, 1H), 7.10 (d, J=7.0 Hz, 1H), 3.88 (m, 1H), 1.35 (s, 9H), 1.20 (d, J=7.3 Hz, 3H).
Reaction SMILES: C[C:2]([CH3:5])([O-])[CH3:3].[Li+].[C:7]([O:11][C:12]([N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[C:7]([O:11][C:12]([N:14]1[C@H:15]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[CH2:16]/[C:17](=[CH:12]\[N:14]([CH:15]([CH3:20])[CH3:16])[CH:2]([CH3:5])[CH3:3])/[C:18]1=[O:19])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of lithium tert-butoxide (2.8 eq, 2.8 mmol, 1 M solution in THF) and N,N,N′N′-tetramethylformamidinium chloride (18, R6=Me, R7=Me) (3 eq, 3 mmol) are stirred at 60° C. for 1 h. The mixture is then cooled to room temperature. The mixture is then diluted with tetrahydrofuran to a total volume of 5 ml. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (8-a, R1=Boc) (1 eq, 1 mmol) is then added to the mixture. The mixture is then stirred at room temperature for 3 h. The volatiles are removed under reduced pressure. Ethyl acetate (20 ml) is added to the mixture. The phases are separated and the organic phase is washed with saturated sodium carbonate solution (2×20 ml) and brine (20 ml). The organic phase is dried (Na2SO4) and concentrated under reduced pressure to afford (R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) or a salt thereof. The solutions are analysed by TLC (50% ethyl acetate in hexane). RF 0.21 (salt of 7-a, R1=Boc, R6=Me, R7=Me); RF 0.27 (7-a, R1=Boc, R6=Me, R7=Me); RF 0.68 (8-a, R1=Boc).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[OH:37].[ClH:38]>CC#N>[ClH:38].[OH:37][C:23]1[CH:24]=[CH:25][C:26]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=3)[CH:7]=2)=[CH:27][C:22]=1[O:21][CH3:20]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1cccnc1
Agent: Cl
Solvent: CC#N
Product: COc1cc(-c2ccc3nc(NC(=O)c4cccnc4)nn3c2)ccc1O

Procedure:
The title compound was prepared following procedure described for example 56 but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 400 mg; 1.26 mmol; 1.0 eq.) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (629 mg; 2.51 mmol; 2.0 eq.) as a light yellow solid (249 mg, 55%). HPLC, Rt: 1.71 min. (purity 60.7%). LC/MS, M+(ESI): 362.0, M−(ESI): 360.0. CHN analysis: [C19H15N5O3.1 HCl.0.4 CH3CN.0.6H20] Corrected: C, 55.95%; H, 4.36%; N, 17.79%. Found: C, 55.95%; H, 4.76%; N, 17.53%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[OH:30][N:29]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(C(=O)O)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(C(=O)O)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 4-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3.3:1) as a colorless oil, MS (ESI+): m/z=375.1702 ([M+H]+).