Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][C@@H:33]([CH3:36])[CH2:34][OH:35]>>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][C@@H:33]([CH3:36])[CH2:34][OH:35])=[O:25])[C:6]1=[O:29]
Reactant: C[C@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: C[C@@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2S)-2-amino-1-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white solid: 1H NMR (d6-DMSO) δ 10.23 (1H, d, J=8 Hz), 8.50 (1H, s), 7.77 (1H, s), 7.32 (2H, dd, J=8.6, 6 Hz), 7.12 (2H, t, J=8.6 Hz), 5.12 (2H, m), 4.98 (1H, t, J=5 Hz), 4.11 (2H, s), 4.03 (1H, m), 3.44 (2H, m), 3.12 (3H, s), 2.82 (3H, s), 1.15 (3H, d, J=7 Hz); HRMS calcd for C23H25FN4O5+H+: 457.1887. Found: 457.1879.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2=[N:14][C:15]([OH:23])=[C:16](C(OCC)=O)[N:17]=[C:12]2[CH:11]=[N:10]1.[OH-].[Li+].C1C(=O)N([Br:33])C(=O)C1>O.CC#N>[Br:33][C:16]1[C:15](=[O:23])[NH:14][C:13]2[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:10]=[CH:11][C:12]=2[N:17]=1
Reactant: CCOC(=O)c1nc2cnn(-c3c(F)cccc3F)c2nc1O
Reactant: O=C1CCC(=O)N1Br
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=c1[nH]c2c(cnn2-c2c(F)cccc2F)nc1Br
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a mixture of ethyl 1-(2,6-difluorophenyl)-6-hydroxy-1H-pyrazolo[3,4-b]pyrazine-5-carboxylate (1.27 g, 3.70 mmol) in 2.5 mL of water and 2.5 mL of CH3CN at RT was added lithium hydroxide (209 mg, 8.72 mmol), and the resulting mixture was warmed to 60° C. for 0.5 h. The reaction mixture was cooled with an ice bath, and NBS (1059 mg, 5.95 mmol) was added in small portions. The reaction mixture was stirred at RT for 0.5 h, then partitioned between a saturated solution of NaHCO3 and EtOAc. The EtOAc layer was washed with brine, dried over MgSO4, filtered and concentrated to afford 5-bromo-1-(2,6-difluorophenyl)-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (1210 mg, 93.3% yield) a a brown amorphous solid. This crude material was used without further purification. MS (ES+): 327.0/329.0 (M+H)+.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl-:11].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:11][C:1]1[CH:6]=[CH:5][C:4]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 101.4 %

Procedure:
An 80° C. stirred solution of p-toluoyl chloride (10.0 g, 64.7 mmol) in chlorobenzene (15 ml) was treated in portions with aluminum chloride (8.63 g, 64.7 mmol) over 20 minutes. The mixture was stirred 15 hours at 80° C., cooled, and quenched by addition of ice-water and concentrated hydrochloric acid (10 ml). The mixture was extracted twice with diethyl ether and once with a small volume of dichloromethane. The combined extracts were washed with water, 10% (w/v) aqueous sodium hydroxide, and water, dried over anhydrous magnesium sulfate, and evaporated to dryness under vacuum. The residue was dissolved in boiling n-hexane, treated with activated charcoal, and filtered hot. The filtrate was cooled and the product was collected by filtration and dried to provide 7.57 g (51%) of 4-(4-chlorobenzoyl) toluene, m.p. 122°-123° C.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:21])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[NH:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[K+].C(O)(=O)C>CO>[O:21]1[CH2:2][CH:3]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[NH:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: OC(CCl)COc1cccc(-c2nc(C(F)(F)F)c[nH]2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: FC(F)(F)c1c[nH]c(-c2cccc(OCC3CO3)c2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[3-(3-chloro-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole (3.8 g.) in methanol (150 ml.) is added powdered potassium hydroxide (3. g.) and the mixture is allowed to stir 4 hours at room temperature. Glacial acetic acid (2.75 ml.) is added and the mixture concentrated under reduced pressure (20 mm. Hg.) over steam. The resulting residue is stirred with water, filtered and recrystallized from xylene to yield 2.5 g. of 2-[3-(2,3-epoxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained, m.p. 145°-146.5° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH2:14])[C:6]([NH2:13])=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:39][C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:21])[NH:13][C:6]4[CH:7]=[C:8]([C:9]([F:12])([F:11])[F:10])[C:3]([C:2]([F:15])([F:16])[F:1])=[CH:4][C:5]=4[N:14]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[C:36]([CH3:38])[N:35]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: Nc1cc(C(F)(F)F)c(C(F)(F)F)cc1N
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from 4,5-bis-trifluoromethyl-benzene-1,2-diamine [CAS-No. 30454-92-3] (244 mg, 1.0 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (325 mg, 1.0 mmol) in toluene (10 ml) under reflux conditions for 2 h according to the general procedure M and subsequent treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (132 mg, 28%).
Reaction SMILES: Br[C:2]1[C:3]([Cl:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[Cl:10][C:3]1[C:2]([C:13]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=2[F:11])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=1
Reactant: COc1ccc(Br)c(Cl)n1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(OC)nc2Cl)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
Under an argon atmosphere, to a solution of 3-bromo-2-chloro-6-methoxypyridine (4.61 g) in toluene (60 mL) were added (2-fluoro-5-methoxyphenyl)boronic acid (3.52 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichlorome thane adduct (1.69 g) and 2.0 M aqueous sodium carbonate solution (31.1 mL), and the mixture was stirred at 80° C. for 1 hr. Water was added at room temperature, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.06 g) as a white amorphous solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C:12](=[O:27])[CH2:11][CH2:10]1.O>C(#N)C.[Cu](Br)Br>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C:12](=[O:27])[CH2:11][CH2:10]1
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCBr)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: Br[Cu]Br
Solvent: CC#N
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CCC2=O
Reaction time: 8 h
Yield: 73.7 %

Procedure:
17.0 g of copper(II) bromide is added to 27.8 g of 7α-(5-bromopentyl)-11β-fluor-estr-4-ene-3,17-dione in 190 ml of acetonitrile at 80° C. After 8 hours, the reaction mixture is stirred into water, extracted three times with ethyl acetate, and twice with ammonium chloride, washed with sodium bicarbonate and common salt, dried and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 20.4 g of 7α-(5-bromopentyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained as colorless crystals with a melting point of 178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=4)=[CH:17][C:11]=3[N:10]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[CH3:33][NH2:34]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([NH:34][CH3:33])[N:20]=4)=[CH:17][C:11]=3[N:10]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(C(F)(F)F)c4)nc3c2)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(C(F)(F)F)c4)nc3c2)n1
Temperature: 80 °C

Procedure:
To a solution of (4-chloro-3-trifluoromethyl-phenyl)-[5-(2-methanesulfonyl-pyrimidin-4-yloxy)-1H-benzimidazol-2-yl]-amine (Step B, 120 mg, 0.2 mmol, 1.0 eq.) in anhydrous THF (4 mL) was added 1 mL of 2 M CH3NH2 in THF (2 mmol, 10 eq). The solution was heated to 80° C. for 1 h. The THF was removed under reduced pressure and the crude was purified by column chromatography (0-10% MeOH/CH2Cl2 with 1% NH4OH) to yield pure (4-chloro-3-trifluoromethyl-phenyl)-[5-(2-methylamino-pyrimidin-4-yloxy)-1H-benzimidazol-2-yl]-amine. MS m/z=435.1 (M+H)+; MW Calc'd for C19H14ClF3N6O: 434.09.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][C@@H:13]([CH2:12][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1CCNCC1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)O[C@H](CN1CCCCC1)CO2
Temperature: 120 °C

Procedure:
A mixture of [(2S)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.5 g, 1.1 mmol), piperidine (1 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and by flash chromatography, first with (DCM/MeOH) as eluent and then (EtOAc/MeOH) as eluent. Yield: 0.2 g, 72%. The amine was converted to the hydrochloric acid salt and crystallized from EtOH/Et2O. M.p. 226° C. MS m/z (rel. intensity, 70 eV) 311 (M+, 1), 310 (M+, 1), 99 (7), 98 (bp), 79 (2), 55 (4). [α]=+62° (MeOH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O[N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:16])[NH:32][CH2:33][C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][N:30]=2)[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)NCc2ccccn2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1S,3R)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid (91.6 mg, 0.4 mmol) in DMF (4 mL) was added pycoylamine (0.045 mL, 0.44 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDAC), (93 mg, 0.48 mmol), 1-hydroxybenzotriazole (HOBT), (82 mg, 0.6 mmol), and diisopropylethylamine (0.35 mL, 2 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with water (2 times) and brine. The organic layer was dried (sodium sulfate), filtered, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/dichloromethane to provide the titled compound. MS (ESI) m/z 320 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].C(N(CC)CC)C.[Br:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=1>ClCCl>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH:28][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:13])([F:12])[F:1])=[CH:24][CH:23]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1ccc(Br)cc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a mixture of 2-(trifluoromethyl)benzoyl chloride (1.0 g, 5.3 mmol) in dichloromethane (5 mL) was added dropwise a solution of triethylamine (0.41 g, 4.0 mmol) and 4-bromophenethylamine (0.80 g, 4.0 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane and extracted with 1 N aqueous hydrochloric acid. The aqueous phase was separated and extracted with additional dichloromethane. The organic extracts were then combined, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography on a silica gel column eluted with 0 to 100% ethyl acetate:hexane to provide the title compound (1.10 g) as a white solid.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[C:31](=[O:32])[N:23]3[CH:24]([C:29]#[N:30])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:33]=[N+:34]=[N-:35].[Na+].Cl.CN1CCCCC1>C(Cl)(Cl)Cl>[C:1]1([C:7]([NH:20][CH:21]2[C:31](=[O:32])[N:23]3[CH:24]([C:29]4[NH:35][N:34]=[N:33][N:30]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN1CCCCC1
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1

Procedure:
A mixture of 6-triphenylmethylamino-2,2-dimethyl-3-cyanopenam (10 g. 0.0193 mole) sodium azide (7.41 g., 0.114 mole), N-methylpiperidine hydrochloride (3.39 g., 0.025 mole) and chloroform (100 ml.) is refluxed for four hours in a round-bottomed flask equipped with stirrer, condenser, and drying tube. The reaction mixture is then cooled and water (300 ml.) and chloroform (100 ml.) added. The mixture is thoroughly mixed, the chloroform layer separated and washed successively with 1N hydrochloric acid (100 ml.) and saturated brine (100 ml.). It is then filtered quickly through anhydrous sodium sulfate and concentrated under reduced pressure to about 75 ml. Hexane (20 ml.) is added to the concentrate to precipitate the product as white crystals. The crystals are recovered by filtration, washed with 20% hexane-methylene chloride (50 ml.) and dried in vacuo at room temperature. Yield = 2.7 g. (29.6%) m.p. 133°-136° C.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:15]([C:18]1[C:26]2[O:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=2[CH:21]=[CH:20][C:19]=1[O:31][CH2:32][CH2:33][CH2:34]Br)[CH2:16][CH3:17]>>[CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:5](=[O:7])[N:4]([CH2:34][CH2:33][CH2:32][O:31][C:19]2[CH:20]=[CH:21][C:22]3[C:23]([C:27]([F:29])([F:30])[F:28])=[N:24][O:25][C:26]=3[C:18]=2[CH2:15][CH2:16][CH3:17])[C:3]1=[O:8]
Reactant: CC1(c2ccccc2)CC(=O)NC1=O
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2C(=O)CC(C)(c3ccccc3)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
3-Methyl-3-phenyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione was prepared as for Example 10 from 3-methyl-3-phenylpyrrolidine-2,5-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[CH2:14]([C:16]1[N:21]=[C:20]([NH2:22])[CH:19]=[CH:18][CH:17]=1)[CH3:15]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:14][CH3:15])[N:21]=1)=[O:5])[CH3:2]
Reactant: CCc1cccc(N)n1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(CC)n1
Temperature: 140 °C
Yield: 35.5 %

Procedure:
4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester (500 mg, 2.26 mmol) and 6-ethylpyridin-2-amine 415 mg, 3.39 mmol) were dissolved in acetonitrile (7 mL), then heated at 140° C. for 3 d. The reaction mixture was cooled and concentrated in vacuo. Purification by chromatography (silica, 5 to 50% ethyl acetate in hexanes) gave 6-chloro-4-(6-ethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester (246 mg, 35%) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.68 (br. s., 1H) 9.30 (s, 1H) 7.61 (t, J=7.8 Hz, 1H) 6.91 (d, J=7.3 Hz, 1H) 6.77 (d, J=7.8 Hz, 1H) 4.57 (q, J=7.2 Hz, 2H) 2.86 (q, J=7.6 Hz, 2H) 1.52 (t, J=7.1 Hz, 3H) 1.38 (t, J=7.5 Hz, 3H); LCMS (EI/CI) m/z: 307 [M+H].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:5]=[C:6]2[C@@H:11]([NH:12][CH2:13][C@H:14]([C@@H:16]([NH:20][C:21](=[O:23])[CH3:22])[CH2:17][CH:18]=[CH2:19])[OH:15])[CH2:10][C:9]3([CH2:26][CH2:25][CH2:24]3)[O:8][C:7]=12.[CH3:32][N:33](C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CN.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>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].C1COCC1>[CH3:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:4]1[CH:5]=[C:6]2[C@@H:11]([NH:12][CH2:13][C@H:14]([C@@H:16]([NH:20][C:21](=[O:23])[CH3:22])[CH2:17][CH:18]=[CH2:19])[OH:15])[CH2:10][C:9]3([CH2:26][CH2:25][CH2:24]3)[O:8][C:7]2=[C:2]([NH:33][CH3:32])[N:3]=1
Reactant: C=CC[C@H](NC(C)=O)[C@H](O)CN[C@H]1CC2(CCC2)Oc2c1cc(CC(C)(C)C)nc2Cl
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: CN
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: C=CC[C@H](NC(C)=O)[C@H](O)CN[C@H]1CC2(CCC2)Oc2c1cc(CC(C)(C)C)nc2NC
Temperature: 110 °C

Procedure:
To a flame-dried microwave vial under Ar gas was added N-((1S)-1-((1R)-2-(((4′S)-8′-chloro-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-hydroxyethyl)-3-buten-1-yl)acetamide (120 mg, 267 μmol), Pd2 dba3 (49 mg, 53 μmol), and DavePhos (46 mg, 117 μmol). The vial was purged with N2 5×, then THF (3 mL), methanamine (533 μl, 1067 μmol), and LiHMDS (2400 μl, 2400 μmol) were added. The vial was sealed and heated in a microwave at 110° C. for 10 min. The reaction mixture was directly purified by reverse phase HPLC to give the title compound as an amorphous white solid. MS m/z: 445.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)=[CH:4][CH:3]=1.[C:22]1([NH:32]N)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:32]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(Cl)cc2)ccc1=O
Reactant: NNc1cccc2ccccc12
Product: O=c1ccn(-c2ccc(Cl)cc2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 1-(4-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-24) and naphthalen-1-yl-hydrazine according to the method described for example 1. MS: M=399.1 (M+H)+
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.COC1C=CC(O)=CC=1.[OH:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH:30]=O.S(=O)(=O)(O)O>C(Cl)(Cl)Cl.[Cu].O>[C:1]([O:6][CH2:30][C:29]([CH3:33])([CH3:32])[CH:28]=[O:27])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CC(C)(C=O)CO
Agent: [Cu]
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)OCC(C)(C)C=O
Yield: 48 %

Procedure:
320 parts of methacrylic acid, 4 parts of p-toluene-sulfonic acid, 1 parts of copper-II chloride and 1.6 parts of hydroquinone monomethyl ether are dissolved in 1,200 parts of chloroform in a reaction vessel equipped with a reflux condenser and stirrer, and the solution is heated to the boil. A solution of 344 parts of hydroxypivalaldehyde in 1,200 parts of chloroform is run into the boiling solution over 4 hours. After this addition, 4 parts of 96% strength sulfuric acid are added and the water formed during the reaction is distilled off azeotropically. After completion of the reaction, and after cooling, the reaction mixture is washed with dilute aqueous sodium bicarbonate solution. After distilling off the chloroform under reduced pressure until the boiling point reaches 45° C., the residue is distilled in a thin film evaporator at 95° C./0.4 mm Hg. 274 parts of methacryloxypivalaldehyde (48% of theory, based on hydroxyaldehyde) of boiling point 51°-56° C./0.3 mm Hg are obtained. Analyses:
Reaction SMILES: [CH:1]12[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH:5]1[CH2:4][CH2:3][NH:2]2.[OH-].[Na+].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1.O>[CH:1]12[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH:5]1[CH2:4][CH2:3][N:2]2[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC2CCNC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CCC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
13 g (61.2 mmol) of tert.-butyl 2,7-diazabicyclo[3.3.0]octane-7-carboxylate are dissolved in 100 ml of toluene, a solution of 3 g of sodium hydroxide in 20 ml of water is added, and 7 g (64.5 mmol) of ethyl chloroformate are added dropwise at room temperature. The mixture is stirred for 3 hours at room temperature, and the aqueous phase is separated off and extracted twice using 100 ml portions of methylene chloride. The organic solutions are dried over magnesium sulphate, concentrated and distilled.
Reaction SMILES: Cl.[CH2:2]([NH2:7])[CH:3]([NH2:6])[CH2:4][CH3:5].C(N(C(C)C)CC)(C)C.O=[C:18]([C:24](OCC)=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH2:4]([C:3]1[N:6]=[C:24]([OH:25])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:7][CH:2]=1)[CH3:5]
Reactant: CCC(N)CN
Reactant: CCOC(=O)C(=O)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ncc(CC)nc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.2 %

Procedure:
To a suspension of butane-1,2-diamine hydrochloride (6.40 g, 39.7 mmol) in ethanol (60 mL) was added diisopropylethylamine (14 mL, 80.4 mmol), and the mixture was stirred at room temperature for 10 min. To this solution was added dropwise diethyl ketomalonate (6 mL, 39.3 mmol) at 0° C., and the mixture was stirred at room temperature for 1.5 hr with heating under reflux for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a small amount of ethanol. The solution was passed through silica gel (100 g, eluent, hexane:ethyl acetate=1:1→ethyl acetate). The eluate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=2:1→ethyl acetate) to give the title compound (1.94 g, 25%) as a pale-yellow powder.