Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([CH2:14][CH:15]2[CH2:20][NH:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>C(Cl)Cl>[CH:8]1([CH2:14][CH:15]2[CH2:20][N:19]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)C1CNCC(CC2CCCCC2)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(CC2CCCCC2)CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (340 mL, 2.4 mmol) was added to a solution of ethyl 5-(cyclohexylmethyl)piperidine-3-carboxylate (155 mg, 0.60 mmol) and methanesulfonyl chloride (75 mL, 0.90 mmol) in CH2Cl2 (6 mL) cooled to 0° C. The reaction was maintained at this temperature for 15 min at which point the whole was allowed to warm to RT and stir for an additional 3 h. The reaction was diluted with CH2Cl2 (20 mL) and poured into HCl (1N, 20 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were sequentially washed with H2O (10 mL) and brine before being dried over Na2SO4. Concentration under reduced pressure provided the title compound. MS m/z: 332.1 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:23])([C:17]([CH:20]2[CH2:22][CH2:21]2)([CH3:19])[CH3:18])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1.[CH3:24]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:23][CH3:24])([C:17]([CH:20]2[CH2:21][CH2:22]2)([CH3:19])[CH3:18])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C1CC1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(Cn1cncn1)(c1ccc(Cl)cc1)C(C)(C)C1CC1
Reaction time: 0.5 h

Procedure:
To a suspension of 0.8 g NaH 80% in 25 ml DMF are added dropwise, at room temperature, a solution of 7.64 g 2-(4-chlorophenyl)-3-cyclopropyl-3-methyl-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol in 50 ml DMF. The reaction is stirred at 40° for 30 minutes. Then are added dropwise, at 50°, 3.76 g CH3I. The mixture is stirred for 18 hours at 20°, then poured into one liter of water and extracted with CH2Cl2. The organic phases are washed with water, dried over MgSO4 and concentrated by continuous flask evaporation. The title compound is then obtained by chromatography of the residue on silica gel (mobile phase diethylether/triethylamine 10:2) in the form of white crystals, m.p. 87°-89°.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].Cl.Cl.[NH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]3[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]3[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])[CH2:12][CH2:11]1)(=[O:5])=[O:4]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(S(=O)(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
Dimethylsulfamoyl chloride (90 mg) was added to a solution of 6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline dihydrochloride (250 mg) (starting material Example 16) and diisopropylethylamine (184 mg) in methylene chloride (10 ml). The reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was adsorbed onto silica and the residue was purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the expected product were combined and evaporated under vacuum and the residue triturated with diethylether to give the title product as a white solid (0.23 g); 1H NMR. Spectrum: (DMSO d6) 1.72-1.86 (m, 2H), 2.00-2.12 (m, 2H), 2.76 (s, 6H); 3.12-3.23 (m, 2H), 3.40-3.51 (m, 2H), 3.94 (s, 3H), 4.68 (m, 1H), 7.19-7.30 (m, 2H), 7.43-7.54 (m, 2H), 7.85 (s, 1H), 8.37 (s, 1H), 9.52 (s, 1H); Mass Spectrum: (M+H)+ 510.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH3:14][S:15]([O:18][C:19]1[C:27]([CH2:28]/[CH:29]=[C:30](/[Cl:33])\[CH2:31]Br)=[C:26]([O:34][CH3:35])[C:25]([CH3:36])=[C:24]2[C:20]=1[C:21](=[O:37])[O:22][CH2:23]2)(=[O:17])=[O:16]>C1COCC1>[CH3:14][S:15]([O:18][C:19]1[C:27]([CH2:28]/[CH:29]=[C:30](/[Cl:33])\[CH2:31][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[C:26]([O:34][CH3:35])[C:25]([CH3:36])=[C:24]2[C:20]=1[C:21](=[O:37])[O:22][CH2:23]2)(=[O:16])=[O:17]
Reactant: COc1c(C)c2c(c(OS(C)(=O)=O)c1C/C=C(/Cl)CBr)C(=O)OC2
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C/C(Cl)=C\Cc1c(OC)c(C)c2c(c1OS(C)(=O)=O)C(=O)OC2)C(=O)OCC
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
Diethyl malonate (113 mg) was added to a suspension of 50% NaH (35 mg) in THF (3 ml) at 0° C. and the mixture stirred for 30 minutes. To this solution was added (E)-4-(1,3-dihydro-4-methanesulfonyloxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-1-bromo-2-chlorobut-2-ene (280 mg) in THF (10 ml). The ice bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was added to water (30 ml), the aqueous and organic phases separated, and the aqueous phase was extracted once with ethyl acetate (20 ml). The combined organic layers were dried over Na2SO4, evaporated and the residue passed through a short column (silica gel, hexanes-EtOAc 8:2) affording 190 mg of ethyl (E)-6-(4-methanesulfonyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -4-chloro-2-ethoxycarbonyl-4-hexenoate as a colorless oil.
Reaction SMILES: [CH2:1]([N:5]([CH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1)[C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[OH:30]>>[CH2:1]([N:5]([CH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1)[C:6](=[O:20])[C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][CH:16]([NH:27][CH2:28][C@H:29]([OH:30])[C:31]3[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=3)[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCCCN(Cc1nnn[nH]1)C(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CCCCN(Cc1nnn[nH]1)C(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-butyl-4-(4-oxo-1-piperidinyl)-N-(1H-tetraazol-5-ylmethyl)benzamide (which was obtained in Example 178) (0.14 g, 0.4 mmol) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) (0.12 g, 0.48 mmol) according to the procedure shown for Example 180 to give 0.22 g of an off-white solid; m.p. 168–170° C.; MS (ES) m/z: 587.5 (MH+); HRMS (ES) Calcd. for C27H39N8O5S (MH+): 587.2759. Found: 587.2751.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.[CH2:22]([Sn](CCCC)(CCCC)C#C)[CH2:23]CC>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.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]#[CH:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(I)cc(Cl)c2OC1C(F)(F)F
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C#Cc1cc(Cl)c2c(c1)C=C(C(=O)OCC)C(C(F)(F)F)O2
Yield: 75.6 %

Procedure:
To 0.86 g (2.0 mmole) of ethyl 8-chloro-6-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 46 mg (0.040 mmole) tetrakis(triphenylphosphine)palladium(0), 6 mLs degassed toluene and 0.64 mL (0.69 g, 2.2 mmole) tributyl(ethynyl)tin. The stirred mixture was heated to reflux for 3 h. After allowing the reaction to cool, the mixture was washed with 20% aq. ammonium fluoride and the aqueous layer extracted three times with diethyl ether. The combined extracts were filtered through silica, the silica washed with diethyl ether and the organic fractions concd in vacuo. Chromatographic purification (70 g silica, 5% ethyl acetate/hexanes) afforded a solid which was triturated with hexanes to give 0.50 g (75.6%) of a crystalline solid: 1H NMR (d6-acetone/400 MHz) 1.32 (t, 3H, J=7.1 Hz), 3.73 (s,1H), 4.32 (m, 2H), 6.04 (q, 1H, J=6.9 Hz), 7.60 (m, 2H), 7.90 (s, 1H); 19F NMR (d6-acetone/400 MHz) −79.6 (d, 3F, J=6.8 Hz); MS(ESI+) 331 (M+1, 100, one Cl pattern).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:53])=[C:6]([CH2:8][N:9]([CH3:52])[C:10]([CH:12]([NH:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[N:32][CH:31]=[CH:30]3)[C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([C:20]([F:24])([F:23])[CH2:21][OH:22])=[C:15]([CH3:25])[CH:14]=2)=[O:11])[CH:7]=1.[C:54](Cl)(Cl)=[O:55]>ClCCl.C(#N)C>[Br:53][C:5]1[CH:4]=[CH:3][C:2]2=[CH:7][C:6]=1[CH2:8][N:9]([CH3:52])[C:10](=[O:11])[CH:12]([NH:26][C:27]1[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=1)[C:33]([N:37]([C:38]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:44])[C:45](=[O:46])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[N:32][CH:31]=[CH:30]3)[C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([C:20]([F:23])([F:24])[CH2:21][O:22][C:54](=[O:55])[NH:1]2)=[C:17]([CH3:19])[CH:18]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)ccc2Br)cc(C)c1C(F)(F)CO
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2cc(C)c1C(F)(F)COC(=O)Nc1ccc(Br)c(c1)CN(C)C(=O)C2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
To a solution of 4A (289 mg, 0.362 mmol) in dichloromethane (5 mL) and acetonitrile (5.00 mL) at 0° C., was added phosgene (20% in toluene) (0.242 mL, 0.488 mmol). The reaction mixture was stirred at 0° C. for 15 min. Nitrogen was bubbled though the mixture for 0.5 h, then DMPU (˜0.4 mL) was added. The resulting solution was added dropwise via a syringe pump into a solution of TEA (0.353 mL, 2.53 mmol) in dichloromethane (90 mL) at rt over 4 h, stirred for an additional 15 min and then evaporated. The crude product was purified by flash chromatography to give 4B (177 mg, 0.215 mmol, 59.3% yield) as a white solid. MS and 1H NMR are consistent with the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH:12]=2)=[CH:4][C:3]=1[C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.N>C(O)(C(F)(F)F)=O.CO>[O:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:12]=2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Agent: N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2cnn(CCN3CCNCC3)c2)cc1-c1nc2ccccc2o1
Yield: 68.4 %

Procedure:
A solution of tert-butyl 4-[2-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]ethyl]piperazine-1-carboxylate (90 mg) in TFA (3 ml) was stirred at 25° C. for 1 hour. A solution 7N ammonia in methanol (20 ml) was added to the mixture and adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 2 to 8% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 3-(1,3-benzoxazol-2-yl)-5-[1-(2-piperazin-1-ylethyl)pyrazol-4-yl]pyridin-2-amine (49.0 mg). NMR Spectrum: (DMSOd6) 2.29-2.42 (m, 4H), 2.64-2.70 (m, 4H), 2.71 (t, 2H), 4.23 (t, 2H), 7.41-7.49 (m, 2H), 7.65 (bs, 2H), 7.77-7.82 (m, 1H), 7.82-7.87 (m, 1H), 7.90 (s, 1H), 8.24 (s, 1H), 8.40 (d, 1H), 8.51 (d, 1H); Mass spectrum: M+H+ 390.
Reaction SMILES: [I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[CH3:20][CH:21]([OH:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C1C=CC=CN=1)C>ClCCl>[I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([O:28][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:20])=[O:5]
Reactant: O=C(Cl)c1cc(I)cc(I)c1I
Reactant: CCCCCCC(C)O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(C)OC(=O)c1cc(I)cc(I)c1I
Temperature: 0 °C
Reaction time: 72 h

Procedure:
The 2,3,5-triiodobenzoyl chloride was dissolved in 60 ml of dry dichloromethane. The solution was cooled to 0° C. and 6.07 g (60.0 mmol) of triethylamine was added. The brown solution was placed under nitrogen and 4.30 g (33.0 mmol) of 2-octanol was added in 10 ml of dry dichloromethane. Dimethylaminopyridine (0.367 g, 3.00 mmol) was added and the resulting solution was stirred at room temperature for 72 hrs. The brown solution was partitioned between 100 ml of dichloromethane and 100 ml of 1M HCl. The dichloromethane layer was washed with saturated NaHCO3 solution (50 ml) and brine (50 ml). The solution was dried over Na2SO4 and concentrated in vacuo to yield a dark brown oil (17.43 g). The oil was purified by flash chromatography using 436 g of silica gel and 5% ethyl acetate/hexane as the eluent. The first 600 ml to elute contained nothing while the pure product eluted with the next 700 ml. Concentration in vacuo afforded 15.68 g (85%) of the product as a yellow tinted oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH:36]=[N:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:41][C:40]3[CH:39]=[CH:38][C:37]([N:32]4[CH:36]=[N:35][CH:34]=[N:33]4)=[CH:43][CH:42]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1ccc(-n2cncn2)cc1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(-n3cncn3)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 4-(1H-1,2,4-triazol-1-yl)aniline (Maybridge, 108 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].[C:13]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C1COCC1>[CH2:29]([O:28][C:26]([C:23]1([CH2:12][CH2:11][CH:10]=[CH2:9])[CH2:24][CH2:25][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:21][CH2:22]1)=[O:27])[CH3:30]
Reactant: [Li]CCCC
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CCCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
A mixture of THF (160 mL) and diisopropyl amine (9.92 mL, 70.8 mmol, 1.2 eq) was cooled to −78° C. and a 2.5 M solution of n-BuLi in heptanes (28.3 mL, 70.8 mmol, 1.2 equiv.) was added slowly. The solution was stirred for 15 min, warmed to 0° C. for 20 min and cooled back to −78° C. Ethyl N-Bocpiperidine-4-carboxylate (11 mL, 59 mmol, 1 eq.) in 10 mL of THF was added drop-wise and stirred for 40 min before it was warmed to rt. The reaction mixture was stirred for 12 h, transferred to a separatory funnel, quenched with 500 mL of water and extracted with ethyl acetate (2×300 mL). The combined organics were dried over Na2SO4 and concentrated under vacuum to give the title compound as a yellow oil (13.9 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 3-fluoro-4-nitrophenol (2.96 g, 18.81 mmol) in DMF (18.81 mL) was added 1-(chloromethyl)-4-methoxybenzene (2.55 mL, 18.81 mmol) and potassium carbonate (5.20 g, 37.6 mmol). The reaction mixture was stirred at 50° C. for 16 hours. The mixture was diluted with EtOAc (100 mL), washed with water, and the aqueous layer was back-extracted with EtOAc (25 mL). The combined organic layers were washed with 1 M aqueous NaOH (20 mL) and then with brine. The organic layer was dried over Na2SO4, filtered and evaporated. The yellow solid was triturated with ether (20 mL), and the solid was collected, rinsing with ether (5 mL). The title compound was obtained as a yellow solid (4.39 g, 84% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>>[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=3)=[O:11])[CH:5]=2)=[CH:32][CH:31]=1)=[O:29]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1
Product: COC(=O)c1ccc(-c2cccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)c2)cc1

Procedure:
In analogy to example 19, from 3-(3-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 98, step 5) and 4-methoxycarbonyl-phenylboronic acid was prepared the title compound as a yellow foam, MS (ESI+): m/z=450.3 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[CH3:17][C:18]1[CH:29]=[CH:28][C:21]([CH2:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:20][CH:19]=1>>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:27][CH2:26][N:25]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:24]2)=[CH:28][CH:29]=1
Reactant: Cc1ccc(CC2CCNC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(CC2CCN(C(=O)c3cnoc3-c3ccc(C)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-methylbenzyl)pyrrolidine hydrochloride (12.7 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (5.8 mg). Calcd for C23H24N2O2: 360.1838, found 360.1848.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH2:28]([O:30][CH:31]([O:34][CH2:35][CH3:36])[CH2:32][NH2:33])[CH3:29]>>[CH2:28]([O:30][CH:31]([O:34][CH2:35][CH3:36])[CH2:32][NH:33][C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:16][CH2:15]2)=[O:18])=[CH:27][CH:26]=1)=[O:24])[CH3:29]
Reactant: CCOC(CN)OCC
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Product: CCOC(CNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1)OCC
Yield: 76 %

Procedure:
By the same procedure as described in the example 46, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using 2,2-diethoxyethylamine. Then, the product was recrystallized using ethanol and isopropyl ether to give the desired compound.
Reaction SMILES: C1(OC(=O)N[C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([CH2:13][NH:12][C:11]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)[CH2:30][CH2:31]2)=[O:19])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(CNC(=O)N2CCN(c3ccc(F)cc3)CC2)c(OC)nc1C
Yield: 63 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Br:12])[CH:6]=2.[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]1.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>[NH2:1][C:2]1[C:3]([C:13]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[N:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([NH2:29])[CH2:24]2)=[O:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Br:12])[CH:6]=2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Reactant: Nc1cc2ccc(Br)cc2nc1C(=O)O
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
Product: Nc1cc2ccc(Br)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
To a mixture of 3-amino-7-bromoquinoline-2-carboxylic acid (27.4 mg, 0.103 mmol), tert-butyl [(3S)-1-(3-aminopyridin-4-yl)piperidin-3-yl]carbamate (31.4 mg, 0.107 mmol) and HATU (78.2 mg, 0.206 mmol), DMF (1.00 mL) was added, followed by DIPEA (83.6 mg, 0.647 mmol). The mixture was stirred at room temperature. After 3 h, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in DCM (2.0 mL); then TFA (1.0 mL) was added. The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to give the title compound as a yellow solid (10.1 mg, 22%). LCMS calc. for C20H22BrN6O (M+H)+: m/z=441.1. found 441.1.
Reaction SMILES: [N+](=[C:3](P(=O)(OC)OC)C(=O)C)=[N-].[N:13]1([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]=O)=[CH:21][CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CO.C(OCC)C>[CH2:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:20][CH:21]=1)[CH2:26][C:27]#[CH:3]
Reactant: O=CCCc1ccc(CN2CCCC2)cc1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: C#CCCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
815 mg (4.2 mmol) dimethyl (1-diazo-2-oxo-propyl)-phosphonate is added to a mixture of 760 mg (3.5 mmol) 3-(4-pyrrolidin-1-ylmethyl-phenyl)-propionaldehyde and 970 mg (7.0 mmol) K2CO3 in 100 mL dry MeOH under an argon atmosphere and stirred overnight at RT. The reaction mixture is diluted with diethyl ether, the organic phase is washed with saturated, aqueous NaHCO3 solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5).