Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](=[O:12])[CH2:7]2.[N+:13]([O-])([OH:15])=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](=[O:12])[CH2:7]2
Reactant: O=[N+]([O-])O
Reactant: CN1C(=O)Cc2cccc(F)c21
Product: CN1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
7-Fluoro-1-methyl-1,3-dihydro-indol-2-one (7, 2.00 g, 0.0119 mol) is added portion wise to 70% nitric acid (10 ml) at −10° C. After the addition is complete, the reaction is allowed to warm to room temperature and then stirred for 20 hours. The mixture is diluted with ice water and the resulting precipitate filtered, washed with water, and dried under vacuum to give the title compound as a solid. HPLC r.t. 4.40 min.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.[CH:25]1[CH:30]=[C:29]([CH:31]=[O:32])[C:28]([CH:33]=O)=[CH:27][CH:26]=1.C(O)(=O)C>C(#N)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:33][C:28]5[C:29](=[CH:30][CH:25]=[CH:26][CH:27]=5)[C:31]4=[O:32])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Reactant: O=Cc1ccccc1C=O
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C1c2ccccc2CN1c1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1

Procedure:
4-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine (338.4 mg, 1.0 mmol) was reacted at reflux for 30 min with o-phthaldialdehyde (147.5 mg, 1.1 mmol) and a catalytic amount of acetic acid (57 μL, 0.1 mmol) in acetonitrile (100 mL) to give the title compound. The product obtained was purified by elution through a flash column (silica gel 40, 230–400 mesh, 100:8:1, CH2Cl:EtOH:NH4OH) to give a yellow crystalline material, yield=245 mg (53.9%). mp 175.9° C. MS (APCI): 455 [M+H]+. 1H-NMR (dmso-d6, δ): 2.59 (m, 2H) 2.66 (m, 4H) 2.77 (m, 2H) 3.43 (m, 4H) 4.98 (s, 2H) 7.30 (d, J=8.79 Hz, 2H) 7.40 (dd, J=8.67, 7.45 Hz, 1H) 7.52 (m, 2H) 7.64 (m, 2H) 7.77 (m, 3H) 8.03 (d, J=9.28 Hz, 2H).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26]COC)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH2:7][C@@H:6]1[CH3:33])=[O:4].[O:34]1[CH2:39][CH2:38][O:37][C:36]2[CH:40]=[C:41]([C:44]3([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]3=[O:50])[CH:42]=[CH:43][C:35]1=2>>[O:34]1[CH2:39][CH2:38][O:37][C:36]2[CH:40]=[C:41]([C:44]3([CH3:51])[NH:48][C:47](=[O:49])[N:46]([CH2:2][C:3]([N:5]4[CH2:10][CH2:9][N:8]([C:11]5[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:22]([F:25])([F:23])[F:24])[C:18]([F:21])([F:19])[F:20])=[CH:13][C:12]=5[CH2:30][CH2:31][CH3:32])[CH2:7][C@@H:6]4[CH3:33])=[O:4])[C:45]3=[O:50])[CH:42]=[CH:43][C:35]1=2
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)[C@@H](C)C1
Reactant: CC1(c2ccc3c(c2)OCCO3)NC(=O)NC1=O
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)OCCO4)C2=O)[C@@H](C)C1

Procedure:
(S)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-2-methylpiperazin-1-yl)ethanone and 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:35][C@H:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:37].C(N(CC)CC)C>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([NH:35][C@H:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:37])=[O:16])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@H](C)N
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)NC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.00 g (0.006 mol) of 2-(4-acetamidobutyryl)-5-chloro -hydrocinnamic acid and 1.09 g (0.007 mol) of 1,1'carbonyldiimidazole are stirred at room temperature for 1.5 hours in 20 ml of tetrahydrofuran and 1.04 g (0.007 mol) of ethyl L-alaninate hydrochloride and 0.94 ml (0.007 mol) of triethylamine are then added thereto. After stirring at room temperature for 2 hours, the mixture is extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with ethyl acetatemethanol (9:1) and then on aluminum oxide with ethyl acetate and subsequent crystallization from ethyl acetate/ hexane gives ethyl N-[2-(4-acetamidobutyryl)-5-chlorohydrocinnamoyl]-L-alaninate as white crystals with melting point 106°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][C:38]1[C:39]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH3:37])[C:39]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(C)c(N4CCN(CCS(C)(=O)=O)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 120 °C
Yield: 50.5 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (115 mg, 0.227 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (Example 148, step D) (67 mg, 0.204 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (82 mg, 0.103 mmol, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.36 (s, 1H), 8.46 (s, 1H), 8.22 (d, J=5.31 Hz, 1H), 8.03 (d, J=2.01 Hz, 1H), 7.73 (dd, J=8.61, 2.01 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.49 (s, 1H), 7.40-7.45 (m, 1H), 7.32-7.39 (m, 1H), 7.25 (d, J=8.61 Hz, 1H), 7.18 (t, J=8.15 Hz, 2H), 6.94 (t, J=6.87 Hz, 1H), 6.75 (s, 1H), 6.54 (d, J=5.31 Hz, 1H), 4.25 (q, J=6.78 Hz, 2H), 3.79 (s, 3H), 3.31-3.34 (m, 2H), 3.05 (s, 3H), 2.82-2.89 (m, 4H), 2.76 (t, J=6.68 Hz, 2H), 2.52-2.63 (m, 4H), 2.13 (s, 3H), 1.41 (t, J=6.87 Hz, 3H). MS (ESI): 797 [M+H]+.
Reaction SMILES: C[O-].[Na+].[CH2:4]=[CH:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9].[N+:11]([CH3:14])([O-:13])=[O:12]>CO>[N+:11]([CH2:14][CH2:4][CH2:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])([O-:13])=[O:12]
Reactant: C=CC(=O)CCC
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(=O)CCC[N+](=O)[O-]
Temperature: -10 °C

Procedure:
A solution of sodium methoxide in MeOH is added to a solution of 1-hexen-3-one and nitromethane in MeOH at −30° C. The reaction mixture is then warmed to −10° C. for 1.5 h, quenched with half saturated ammonium chloride solution, and then extracted with dichloromethane. The combined organics are dried over sodium sulfate concentrated and then stripped from toluene and MeOH to provide 7-nitro-heptan-4-one.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][OH:14]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]2[O:14][CH2:13][CH2:12][O:8]2)[CH:9]=1
Reactant: OCCO
Reactant: COc1ccc(Br)cc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Br)cc1C1OCCO1
Yield: 126.5 %

Procedure:
A solution of 5-bromo-o-anisaldehyde (49.7 g, 231 mmol), ethylene glycol (17.2 g, 277 mmol) and p-toluene sulfonic acid (4.3 g, 23 mmol) in dry toluene (400 ml) was heated at reflux for 21 hr. And then ethylene glycol (4.3 g, 70 mmol) was added to the reaction mixture and heated at reflux for 6 hr. The resulting solution was washed with sat. NaHCO3, water and brine, dried over MgSO4 and concentrated in vacuo to give crude 2-(5-bromo-2-methoxyphenyl)-1,3-dioxolane (75.7 g) as a dark red oil. The residue was added NaHCO3 and then distilled to give 2-(5-bromo-2-methoxyphenyl)-1,3-dioxolane (52.8 g, 88.3%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([OH:27])[CH2:10]1.[F:28][CH2:29][CH2:30]I.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:30][CH2:29][F:28])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=2)[C:12](=[O:26])[CH:11]([OH:27])[CH2:10]1
Reactant: O=C1C(O)CC(c2c(O)cccc2F)N1Cc1ccc(OC(F)(F)F)cc1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(O)CC(c2c(F)cccc2OCCF)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of rac-(3R*,5S*)-5-(2-fluoro-6-hydroxyphenyl)-3-hydroxy-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (50 mg; 0.13 mmol), 1-fluoro-2-iodoethane (23 mg; 0.13 mmol), potassium carbonate (36 mg; 0.26 mmol), and cesium carbonate (8.5 mg; 0.026 mmol) in anh. DMF (1.3 ml) was stirred at rt, under nitrogen, for 72 h. Filtration of the reaction mixture, and subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 431.96 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: OCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.8 %

Procedure:
In a solution of 2.0 g of 3-[3-chloro-4-(hydroxymethyl)phenyl]-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 60 mL of dichloromethane, 4.0 g of silica gel and 1.3 g of pyridinium chlorochromate were added, and stirred at room temperature for 20 hours. After the completion of the reaction, the reaction mixture was filtered through glass filter in which silica gel was packed to separate a solid with a solvent. The solvent was distilled off under reduced pressure. The residual solid was washed with diisopropyl ether to obtain 1.45 g of the aimed product as pale yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]2[CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CNC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=S(=O)(c1ccc(F)cc1)N1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
Commercially available 4-fluorophenylsulfonylchloride (225 mg, 1.15 mmol) was suspended in water (8 mL), and azetidine hydrochloride (90.0 mg, 0.96 mmol) and potassium carbonate (293 mg, 2.12 mmol) were added, followed by stirring at room temperature for 16 hours. To the reaction solution, water (15 mL) was added, followed by extraction twice with diethyl ether (15 mL), and washing was carried out with saturated brine (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, followed by vacuum drying, to afford the desired compound (170 mg, yield 82%) as a white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:38])[C@@H:26]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:27]([O:32][CH3:33])[CH2:28][C:29](O)=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:40][O:41][C@@H:42]([C@@H:60]1[CH2:64][CH2:63][CH2:62][NH:61]1)[C@@H:43]([CH3:59])[C:44]([NH:46][C@H:47]([C:55]([O:57][CH3:58])=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[S:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:38])[C@@H:26]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:27]([O:32][CH3:33])[CH2:28][C:29]([N:61]3[CH2:62][CH2:63][CH2:64][C@H:60]3[C@H:42]([O:41][CH3:40])[C@@H:43]([CH3:59])[C:44]([NH:46][C@H:47]([C:55]([O:57][CH3:58])=[O:56])[CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[S:45])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=S)[C@H](C)[C@@H](OC)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure D, from #@5 (260 mg, 0.648 mmol, 1 eq.), #39 (340 mg, ≦0.629 mmol, 1 eq.), dichloromethane (10 mL, 0.065 M), HATU (296 mg, 0.778 mmol, 1.2 eq.) and diisopropylethylamine (339 μL, 1.94 mmol, 3 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 40% acetone in heptane) to give #76 (466 mg, 83% over two steps) as a solid. LC-MS: m/z 871.5 [M+H+], 893.5 [M+Na+], retention time=1.10 minutes; HPLC (Protocol C): retention time=9.249 minutes (purity >99%); 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.19 (br d, J=7.4 Hz) and 10.49 (br d, J=7.8 Hz), total 1H], 7.89 (br d, J=7.4 Hz, 2H), 7.68-7.75 (m, 2H), 7.54-7.60 (m, 1H), 7.41 (br dd, J=7.4, 7.4 Hz, 2H), 7.28-7.36 (m, 2H), 7.15-7.28 (m, 5H), [5.20 (ddd, J=10.9, 7.3, 4.4 Hz) and 5.34-5.43 (m), total 1H], 3.65 and 3.69 (2 s, total 3H), 3.24 and 3.25 (2 s, total 3H), 3.17 (br s, 3H), 2.93 and 2.98 (2 br s, total 3H), [1.15 (d, J=6.6 Hz) and 1.18 (d, J=6.6 Hz), total 3H].
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=[N:6][C:5]=2[N:4]([CH:14]([CH3:16])[CH3:15])[N:3]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:33])[NH:21][C:22]([CH3:32])=[CH:23][C:24]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([C:24]1[CH:23]=[C:22]([CH3:32])[NH:21][C:20](=[O:33])[C:19]=1[CH2:18][NH:17][C:11]([C:9]1[C:10]2[C:2]([CH3:1])=[N:3][N:4]([CH:14]([CH3:16])[CH3:15])[C:5]=2[N:6]=[CH:7][CH:8]=1)=[O:13])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1nn(C(C)C)c2nccc(C(=O)O)c12
Reactant: Cc1cc(Cc2ccccc2)c(CN)c(=O)[nH]1
Product: Cc1cc(Cc2ccccc2)c(CNC(=O)c2ccnc3c2c(C)nn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for example 11 from 3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.060 g, 0.274 mmol) and 3-(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1H)-pyridinone (0.076 g, 0.287 mmol). The product was collected as a white solid (92 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (d, J=6.82 Hz, 6 H), 2.09 (s, 3 H), 2.41 (s, 3 H), 3.98 (s, 2 H), 4.43 (d, J=5.05 Hz, 2 H), 5.16 (quin, J=6.63 Hz, 1 H), 5.79 (s, 1 H), 7.04 (d, J=4.80 Hz, 1 H), 7.16-7.34 (m, 5 H), 8.49 (d, J=4.55 Hz, 1 H), 8.75 (t, J=5.05 Hz, 1 H), 11.59 (s, 1 H). LCMS(ES) [M+H]+ 429.9
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26](S(C)(=O)=O)[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:33]([O:35][C:36](N1CCNCC1)=[O:37])[CH3:34]>>[CH2:33]([O:35][C:36]([N:26]1[CH2:25][CH2:24][N:23]([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]2)=[O:11])=[CH:20][CH:19]=3)=[O:22])[CH2:28][CH2:27]1)=[O:37])[CH3:34]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Product: CCOC(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Yield: 72 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b) and 1-ethoxycarbonylpiperazine to afford the desired product as a light-brown solid (72%). MS (ISP): 456.3 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:14])[CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:9]=1)=[O:4].[OH-].[Na+].Cl>CO>[C:10]([C:8]1[N:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:14])[CH:7]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)c1nc(C(C)(C)C)cn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C(C)(C)C)nc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-tert-butyl-1-methyl-1H-imidazole-2-carboxylic acid methyl ester (680 mg, 3.46 mmol, prepared as described in the previous step) and 1N NaOH (3.81 mL, 3.81 mmol) in MeOH (10 mL) was stirred at room temperature for 2 h. To the resulting mixture was then added 1.0 N aqueous HCl (3.85 mL). The solvent was removed under reduced pressure and the residue was treated with DCM (50 mL). The solid was filtered off through diatomaceous earth and washed with DCM. The combined organic layers were dried with Na2SO4 and concentrated in vacuo to yield 4-tert-butyl-1-methyl-1H-imidazole-2-carboxylic acid as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 7.00 (s, 1H), 4.18 (s, 3H), 1.49 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C9H14N2O2: 183.1 (M+H), Measured: 183.1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][N:8]([CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:7]2=[O:21].[CH3:22]C(N(C)C)=O.CI>O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:22])[CH2:9][N:8]([CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:7]2=[O:21]
Reactant: O=C1c2cc(Cl)ccc2NCN1CCN1CCCC1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN1CN(CCN2CCCC2)C(=O)c2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 14 %

Procedure:
543 Milligrammes (22.5 mmoles) of 60% sodium hydride are added to 3.50 grammes (12.5 mmoles) of 6-chloro-2,3-dihydro-3-[2-(pyrrolidino)ethyl]-4(1H)-quinazolinone in 25 mlof anhydrous dimethylacetamide and the solution is left at room temperature, in agitation and in an inert gas atmosphere, for 30 minutes. 0.86 Ml (13.8 mmoles) of methyl iodide are slowly dripped and the reactionmixture is kept for 6 hours at room temperature. The reaction mixture is then diluted with water and ice and the product is extracted with ethyl ether and recovered through evaporation of the organic solvent, obtaining an oily substance, with a yield of 14%, presenting the following chemical-physical characteristics:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[O:18]=[C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:21](=[O:36])[N:20]1[CH2:37][CH2:38][CH2:39][CH2:40][NH2:41].Cl>>[O:18]=[C:19]1[C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:22]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:21](=[O:36])[N:20]1[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:9](=[O:11])[CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: NCCCCN1C(=O)C(c2ccccc2)=C(c2ccccc2)C1=O
Reactant: O=C(O)CCc1cccnc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Product: O=C(CCc1cccnc1)NCCCCN1C(=O)C(c2ccccc2)=C(c2ccccc2)C1=O

Procedure:
Batch size: 2.1 g (13.8 mmol) 3-(3-pyridyl)-propionic acid, 1.6 ml (47.4 mmol) oxalyl chloride, 3.8 ml (27.4 mmol) TEA and 4.0 g (12.5 mmol) 4-(2,5-dioxo-3,4-diphenyl-2,5-dihydropyrrol-1-yl)-butylamine•hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:7])[CH3:2].[CH3:19][S:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31]CS([O-])(=O)=O)=[CH:26][CH:25]=1)(=[O:22])=[O:21]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH:6]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][S:20]([CH3:19])(=[O:21])=[O:22])=[CH:29][CH:28]=2)=[CH:12][CH:13]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(OCC)C(C)c1ccc(O)cc1
Reactant: CS(=O)(=O)Oc1ccc(CCCS(=O)(=O)[O-])cc1
Product: CCOC(=O)C(OCC)C(C)c1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1

Procedure:
3-(4-Hydroxyphenyl)-2-ethoxybutanoic acid ethyl ester was alkylated with 2-(4-methanesulfonyloxyphenyl)ethylmethanesulfonate (described in Example 1a) using the same method as in Example 1(b) to give 2-ethoxy-3-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]-phenyl}butanoic acid ethyl ester as a diastereomeric mixture.
Reaction SMILES: [OH:1][CH:2]([C:6]1[N:7]=[C:8]([CH2:50][CH2:51][CH3:52])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:10]=1[C:11]#[N:12])[CH:3]([CH3:5])[CH3:4]>C(O)(=O)C>[OH:1][CH:2]([C:6]1[N:7]=[C:8]([CH2:50][CH2:51][CH3:52])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:10]=1[C:11]#[N:12])[CH:3]([CH3:5])[CH3:4]
Reactant: CCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 99.1 %

Procedure:
Following a procedure similar to than described in Example 74(c), but using 1.36 g of 4-(1-hydroxy-2-methylpropyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (b) above] in 75% v/v aqueous acetic acid, 0.87 g of the title compound was obtained as a glass.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:12])[N:6]([CH2:8][CH2:9][CH2:10][NH2:11])[CH3:7])([CH3:3])[CH3:2].[Br:13][C:14]1[N:18]2[N:19]=[C:20](Cl)[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1.CCN(C(C)C)C(C)C>>[CH:1]([O:4][C:5](=[O:12])[N:6]([CH2:8][CH2:9][CH2:10][NH:11][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([Br:13])=[CH:15][N:16]=2)[N:19]=1)[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N(C)CCCN
Reactant: Clc1ccc2ncc(Br)n2n1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N(C)CCCNc1ccc2ncc(Br)n2n1
Temperature: 85 °C
Yield: 87.1 %

Procedure:
A stirred mixture of (3-amino-propyl)-methyl-carbamic acid isopropyl ester (3.0 g, 17.0 mmol), 3-bromo-6-chloro-imidazo[1,2-b]pyridazine [13526-66-4] (723.7 mg, 3.1 mmol), and Hunig's base [7087-68-5] (0.6 mL, 3.2 mmol) was heated to 85° C., under N2 blanket, for 3d then preabsorbed on silica gel and flash chromatographed (silica gel eluted with 10% (v/v) methanol/ethyl acetate) to obtain 1.0 g of clear yellow oil. LRMS (ESI) m/z 370.2/372.2 [(M+H)]+, calc'd for C14H20BrN5O2: 370.25.