Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Cl:9][C:10](Cl)=[CH:11][C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14]>CN(C)C=O.C(Cl)Cl>[Cl:9][CH:10]=[C:11]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14]
Reactant: [O-]c1ccccc1
Reactant: C=CC(C)(C)C=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC(C)(C)C(=CCl)Oc1ccccc1
Yield: 84.1 %

Procedure:
116 g (1 mol) of sodium phenolate and 82.5 g (0.5 mole) of 1,1-dichloro-3,3-dimethyl-1,4-pentadiene in 500 ml of dimethylformamide were heated under reflux for 8 hours. The solution was diluted with methylene chloride and extracted by shaking with dilute sodium hydroxide solution. After the methylene chloride phase had been dried over sodium sulphate, the solvent was stripped off in vacuo. The residual crude product was distilled in vacuo. 93.6 g (84% of theory) of 1-chloro-3,3-dimethyl-2-phenoxy-1,4-pentadiene of boiling point 80° to 90° C./0.5 mm Hg were obtained. ##STR26##
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][N:8]3[C:7](=[O:24])[C:6]=2[CH:25]=1.O[CH2:27][CH:28]1[CH2:30][CH2:29]1>CCO.CCO.CCO.CCO.[Ti]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:27][CH:28]4[CH2:30][CH2:29]4)=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][N:8]3[C:7](=[O:24])[C:6]=2[CH:25]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Reactant: OCC1CC1
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Reaction time: 24 h

Procedure:
A mixture of 2.95 g (8.6 mmol) of tert.butyl (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 10 g of hydroxymethyl-cyclopropane and 1.6 g (6.8 mmol) of tetraethyl orthotitanate is stirred at 120° for 24 hours, about 3 ml of solvent being distilled off in vacuo after 1 hour. The mixture is subsequently evaporated in vacuo, the residue is dissolved in 40 ml of chloroform, the chloroform solution is treated with 30 ml of water and stirred for 1.25 hours. The mixture is filtered through siliceous earth, washed with chloroform, the chloroform phase is dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate/n-hexane, there is obtained cyclopropylmethyl (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 171°-172°.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]([NH2:13])=[O:12])[CH:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1)(=O)=O.CCN(C(C)C)C(C)C.[CH3:29][NH:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCOCC1>[CH3:29][N:30]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:5]1[N:10]=[C:9]([C:11]([NH2:13])=[O:12])[CH:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1
Reactant: CNCCc1ccccc1
Reactant: CS(=O)(=O)c1nc(C(N)=O)cc(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(CCc1ccccc1)c1nc(C(N)=O)cc(-c2ccccc2)n1
Temperature: 85 °C
Yield: 51.7 %

Procedure:
2-Methanesulfonyl-6-phenylpyrimidine-4-carboxamide (70 mg, 0.25 mmol), 1,4-dioxane (4 mL), DIPEA (0.3 mL, 2.0 mmol) and N-methylphenethylamine (82 mg, 0.6 mmol) were added to a 8 mL vial. The vial was sealed and heated at 85° C. for two days. The reaction mixture was allowed to cool to room temperature, and the solvent then removed by centrifugal evaporation. The residue was purified by preparative HPLC to afford 43 mg of 2-(N-methylphenethylamino)-6-phenylpyrimidine-4-carboxamide. 1H NMR (CDCl3, 300 MHz) δ 8.14 (m, 2H), 7.74 (s, 1H), 7.67 (br s, 1H), 7.47 (m, 3H), 7.25 (m, 5H), 5.79 (br s, 1H), 3.95 (t, J=6.9 Hz, 2H), 3.21 (s, 3H), 2.97 (t, J=6.9 Hz, 2H). HPLC ret. time 3.25 min, 10-100% CH3CN, 5 min run. ESI-MS m/z 333.3 (M+H)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].O.[NH2:34][NH2:35].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][C:23]1[C:3]2[C:4](=[O:22])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:35][N:34]=1
Reactant: Cc1ccccc1CC(=O)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1cccc(C(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-methylphenylacetyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (568 mg, 1.3 mmol) produced in Synthesis Example 36 in DMF (5.5 mL) was added hydrazine monohydrate (purity of 80%, 207 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-methylbenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (519 mg, yield 92%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([O:10][CH2:11][C:12]([N:21]=[N+]=[N-])([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)[CH3:13])([CH3:9])[C:5]([F:8])([F:7])[F:6].[In].Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH3:1][O:2][C:3](=[O:24])[C:4]([O:10][CH2:11][C:12]([NH2:21])([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)[CH3:13])([CH3:9])[C:5]([F:8])([F:7])[F:6]
Reactant: COC(=O)C(C)(OCC(C)(N=[N+]=[N-])c1cccc(Br)c1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [In]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(OCC(C)(N)c1cccc(Br)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the 2-[2-azido-2-(3-bromo-phenyl)-propoxy]-3,3,3-trifluoro-2-methyl-propionic acid methyl ester (4.2 g, 9.22 mmol) in THF-H2O 3:1 (48 ml) was added indium (2.116 g, 18.43 mmol) followed by 4N aqueous HCl over a period of 20 min and stirring for 1 h at 25° C. The reaction mixture was added to a 10% aqueous K2CO3 solution and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash-chromatography on NEt3 deactivated silica gel (hexane/EtOAc 2:1 to EtOAc) to provide a diastereomeric mixture of the title compound as a yellow oil: TLC (EtOAc): Rf=0.46; HPLC RtH5=0.999 min; 1H NMR (360 MHz, CDCl3): δ 7.73 (s, 1H), 7.47 (d, 1H), 7.41 (d, 1H), 7.24 (t, 1H), 3.84 and 3.83 (s, 3H), 3.59 (s, 2H), 1.61 and 1.59 (s, 3H), 1.52 and 1.51 (s, 3H); ESIMS: 384, 386 [(M+H)+].
Reaction SMILES: [C:1]([NH:4][N:5]=[C:6]([C:16]1[C:21]([CH2:22][CH:23]([OH:25])[CH3:24])=[CH:20][CH:19]=[C:18]([O:26][CH3:27])[C:17]=1[NH:28][C:29](=[O:31])[CH3:30])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>C(Cl)Cl>[C:1]([NH:4][N:5]=[C:6]([C:16]1[C:21]([CH2:22][CH:23]([O:25][S:40]([CH3:39])(=[O:42])=[O:41])[CH3:24])=[CH:20][CH:19]=[C:18]([O:26][CH3:27])[C:17]=1[NH:28][C:29](=[O:31])[CH3:30])[C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CC(C)O)c(C(=NNC(C)=O)c2ccc([N+](=O)[O-])cc2)c1NC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC(C)OS(C)(=O)=O)c(C(=NNC(C)=O)c2ccc([N+](=O)[O-])cc2)c1NC(C)=O
Reaction time: 0.5 h

Procedure:
To a solution of 23 (1.1 g) in 20 ml of CH2Cl2 was added 1.5 ml of triethyl amine, 0.60 ml of methanesulfonyl chloride at 0-10° C. After 30 min, no more starting material was detected on TLC. Water was added, extracted with CH2Cl2. The organic phase was washed with HCl (1N), brine, dried over Na2SO4. Removal of the solvent afforded product 24 (1.21 g).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[F:14][C:15]1([F:22])[CH2:21][CH2:20][CH2:19][CH:18]2[CH:16]1[O:17]2.[F-].[Na+]>ClCCl>[F:14][C:15]1([F:22])[CH2:21][CH2:20][CH2:19][C@H:18]([NH:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[C@H:16]1[OH:17]
Reactant: C[C@@H](N)c1ccccc1
Reactant: FC1(F)CCCC2OC21
Agent: C[Al](C)C
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](N[C@H]1CCCC(F)(F)[C@@H]1O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A solution of (1R)-1-phenylethanamine (22, 72 mL, 0.57 mol) in dichloromethane (200 mL) was cooled to 0° C. and treated with trimethylaluminum (260 mL, 0.52 mol) and the resulting solution was stirred for 1 hour at 0° C. To this solution was added a solution of 2,2-difluoro-7-oxabicyclo[4.1.0]heptane (66 g, 0.49 mol) in dichloromethane (200 mL) and the resulting mixture stirred at 0° C. for 3 hours. The reaction was then warmed to ambient temperature for 16 hours. The reaction was cooled to 0° C., treated with 103 g of sodium flouride and then quenched with water (90 mL, slow addition). The reaction was warmed to ambient temperature, the solids filtered and the solution evaporated in vacuo, Purification by flash chromatography (50-100% ethyl acetate in hexanes) gave 36.3 g (29%) of (1S,6R)-2,2-difluoro-6-{[(1R)-1-phenylethyl]amino}cyclohexanol 23 (plus 32 g of 1R,6S diastereomer) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.32 (5H, s), 3.90 (1H, q, =6.6 Hz), 3.39 (1H, ddd, J=19.8, 9.8, 4.2 Hz), 2.70 (1H, m), 2.11 (1H, m), 1.80 (1H, m), 1.62 (2H, m), 1.43 (1H, m), 1.36 (3H, d, J=6.6 Hz), 0.96 (1H, m).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH:10]=2)=[O:5])C.[CH2:27]([C:30]([OH:32])=[O:31])[CH2:28][NH2:29].C[O-].[Na+].CO>>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][C:11]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:12][CH:13]=2)[CH:8]=[N:7][C:6]=1[C:4]([NH:29][CH2:28][CH2:27][C:30]([OH:32])=[O:31])=[O:5]
Reactant: CCOC(=O)c1ncc2cc(NC(=O)Nc3ccccc3)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCNC(=O)c1ncc2cc(NC(=O)Nc3ccccc3)ccc2c1O
Reaction time: 24 h
Yield: 57 %

Procedure:
4-Hydroxy-7-(3-phenyl-ureido)-isoquinoline-3-carboxylic acid ethyl ester (75 mg, 0.2135 mmol) and B-alanine (191 mg, 2.135 mmol) were combined in a dry flask. 0.5M sodium methoxide in methanol (4.2 mL, 2.135 mmol) was added with stirring and the solution brought to reflux and held for 24 h. The mixture was cooled, concentrated in vacuo and the residue dissolved in water. The solution was acidified to pH 3 with 1M hydrochloric acid and the precipitate isolated by filtration. The crude product was purified by trituration with a minimal volume of methanol to provide the title compound in 57% yield. MS ESI(+) m/e: 395.1345 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][CH:4]=[CH2:5].O.CC(C)=[O:14]>>[OH:1][CH:2]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][CH:4]=[CH2:5].[OH:14][CH:6]1[CH:2]([CH2:3][CH:4]=[CH2:5])[C:8](=[O:7])[CH:9]=[CH:10]1
Reactant: CC(C)=O
Agent: C=CCC(O)c1ccco1
Solvent: O
Product: C=CCC1C(=O)C=CC1O
Temperature: 55 °C
Reaction time: 48 h
Yield: 65.5 %

Procedure:
Into 350 ml of a water-acetone (1:6 by volume) mixture, was dissolved 10 g of 2-(1-hydroxy-3-butenyl) furan. To the solution heated at b 55° C. under reflux, was added dropwise 6.6 g of polyphosphoric acid. After having been stirred at 55° C. for 48 hours, the reaction mixture was stripped of the acetone by distillation and the residue was extracted twice with 300 ml of ether. The extract solution was washed with an aqueous sodium hydrogencarbonate solution, then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and freed from the solvent by distillation to obtain 9.5 g of a concentrate. On distillation of the concentrate, there were obtained 4.2 g of 2-(1-hydroxy-3-butenyl)furan (b.p. 78° C./10 mmHg) and 3.8 g (65.5% yield based on consumed starting material) of the intended 4-hydroxy-5-allyl-2-cyclopentenone (b.p. 97° C./0.7 mmHg).
Reaction SMILES: [OH-].[Na+].C(N1CCN(C(N)=O)CC1)(=O)C.Cl[O-].[Na+].[C:18]([N:21]1[CH2:26][CH2:25][N:24]([NH:27][C:28](=[O:30])O)[CH2:23][CH2:22]1)(=[O:20])[CH3:19].Cl.[F:32][C:33]1[CH:41]=[CH:40][C:36](C(Cl)=O)=[CH:35][CH:34]=1>O1CCCC1.O>[C:18]([N:21]1[CH2:22][CH2:23][N:24]([NH:27][C:28](=[O:30])[C:36]2[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=2)[CH2:25][CH2:26]1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1CCN(NC(=O)O)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CC(=O)N1CCN(C(N)=O)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCN(NC(=O)c2ccc(F)cc2)CC1

Procedure:
1 N Aqueous sodium hydroxide (70 ml) and water (30 ml) were cooled at 5 to 10° C., and 4-acetyl-1-piperazinecarboxamide (10.0 g) was added thereto and dissolved under stirring. 10% Aqueous sodium hypochlorite (43.5 ml) was added in one portion thereto at the same temperature and allowed to react for 1 hour at the same temperature, and after the temperature was raised, the mixture was further reacted for 2 hours at a temperature of 15 to 20° C. The reaction solution containing 4-acetyl-1-piperazinylcarbamic acid was adjusted to pH 6.5-7.5 with 1 N hydrochloric acid (about 23 ml), followed by adding tetrahydrofuran (100 ml). A solution of 4-fluorobenzoyl chloride (11.1 g) in tetrahydrofuran (20 ml) was added dropwise thereto at 20 to 30° C. over the period of 1 hour. Because the pH was decreased during the addition, the reaction solution was kept at pH 6.0 to 7.0 with 1 N aqueous sodium hydroxide. After this dropwise addition was finished, the solution was further reacted for 2 hours at the same temperature and at the same pH. The reaction solution was concentrated to 50 ml under reduced pressure, then cooled on ice and stirred at 5 to 10° C. for 1 hour to precipitate N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide. The resultant crystals were collected at the same temperature by filtration, washed with cold water (50 ml) and dried under reduced pressure to give N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide (8.35 g). NMR (DMSO-d6, δ): 2.03 (3H, s), 2.77-2.92 (4H, m), 3.50-3.52 (4H, m), 7.23-7.34 (2H, m), 7.82-7.89 (2H, m), 9.58 (1H, s)
Reaction SMILES: [O:1]=[O+][O-].[Cl:4][C:5]([Cl:26])([Cl:25])[CH2:6][O:7][C:8](=[O:24])[C:9]([N:13]1[C@H:16]([S:17][C:18](=[O:20])[CH3:19])[C@@H:15]([O:21][CH3:22])[C:14]1=[O:23])=C(C)C>C(OC)(=O)C>[Cl:4][C:5]([Cl:26])([Cl:25])[CH2:6][O:7][C:8](=[O:24])[C:9]([N:13]1[C@H:16]([S:17][C:18](=[O:20])[CH3:19])[C@@H:15]([O:21][CH3:22])[C:14]1=[O:23])=[O:1]
Reactant: O=[O+][O-]
Reactant: CO[C@H]1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(C)C)[C@@H]1SC(C)=O
Solvent: COC(C)=O
Product: CO[C@H]1C(=O)N(C(=O)C(=O)OCC(Cl)(Cl)Cl)[C@@H]1SC(C)=O
Reaction time: 0.25 h

Procedure:
3 equivalents of ozone are conveyed through a solution, cooled to -30°, of 8.4 g of 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonic acid 2,2,2-trichloroethyl ester in 765 ml of methyl acetate. After treating with ozone, the reaction mixture is left to stand at the same temperature for 15 minutes and then the excess ozone is removed by a nitrogen current. The reaction mixture is washed at 0° with a 10% aqueous sodium bisulphite solution and then with sodium chloride solution. After separating off, the combined aqueous phases are extracted a further 4 times with methyl acetate. The combined methyl ester solutions are dried over sodium sulphate and concentrated by evaporation in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([C:25]([O:27]CC)=[O:26])=[C:22]([CH3:24])[N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([C:25]([OH:27])=[O:26])=[C:22]([CH3:24])[N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1sc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)sc1C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A mixture of ethyl 2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylate (Example 2) (0.482 g, 1.06 mmol) and a 1N NaOH solution (5.5 mL, 5.5 mmol) in ethanol (20 mL) was stirred at 50° C. for 45 min. The reaction was not complete, a 1N NaOH solution (20 mL, 20 mmol) was added and the reaction mixture was stirred for 1 h 30 at 50° C. The solvent was evaporated and the residue was acidified with a 1N HCl solution (25 mL) to pH=1. The precipitate formed was filtered, washed with water and coevaporated with Ethanol. The solid was recrystallised from methanol and washed with DCM to give the title compound as a white solid (418 mg, 92%). HRMS calculated for C16H13Cl2N5O3S (M+H)+426.0194, found: 426.0165, Rt: 2.24 min. MP: 262.6° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:34]1[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]1)=[O:20])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(F)c(F)cc4nc3OC)CC2)c1
Yield: 70 %

Procedure:
Ethyl N-(6,7-di fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-di methoxyphenyl)piperazine were reacted by the same way with the example 169 to obtain the titled compound (yield, 70%). MS (ESI) m/z 460 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[F:19][C:20]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].C(N(CC)C(C)C)(C)C.C(Cl)CCl>CN(C=O)C>[F:19][C:20]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:21]=1[C:22]([NH:16][C:11]1[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:23]
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(C#N)cc2F)cc1
Reaction time: 48 h
Yield: 39.9 %

Procedure:
To a solution of N1-(4-methoxybenzoyl)-1,2-benzenediamine (0.5 g, 1.8 mmol), 2-fluoro-4-cyanobenzoic acid (0.3 g, 1.8 mmol) and N,N-diisopropylethylamine (0.23 g, 1.8 mmol) in DMF (5 mL) was added EDC (0.42 g, 2.2 mmol). After 48 h, 2-fluoro-4-cyanobenzoic acid (0.3 g, 1.8 mmol) and EDC (0.35 g, 1.8 mmol) were added. After an additional 24 h, the reaction was concentrated; and the residue was dissolved in ethyl acetate, washed with 1 N citric acid, brine, satd aq NaHCO3 and brine. The organic layer was MgSO4 dried, crystallized, filtered with ether wash, and dried under vacuum to give the title compound as a white solid 280 mg (40%); MS(FD): 389.1
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=2)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:7]1[CH2:8][CH:9]2[CH:11]([C:10]2([CH3:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=2)[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2cccs2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(-c2cccs2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Hexyl-6-methyl-6-[3-(2-thienyl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one (Preparation 69, 64 mg, 0.19 mmol) was dissolved in tetrahydrofuran (20 ml) at 0° C. Lithium aluminium hydride (1M in tetrahydrofuran, 0.4 ml, 0.4 mmol) was added under nitrogen and then the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by adding aqueous sodium hydroxide solution (2N, 0.8 ml), followed by solid sodium hydrogen carbonate and ethyl acetate. The reaction mixture was stirred vigorously and then filtered through Celite®. The filtrate was concentrated in vacuo and the residue chromatographed on silica gel eluting the product with hexane:ethyl acetate (2:1) as a colourless oil (66 mg, 64%).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH2:9][CH2:10][CH3:11])CC(O)=O.Cl>CCCCCCCCC>[C:14]1([CH2:13][CH2:12][C:4](=[O:3])[CH2:9][CH2:10][CH3:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC(O)(CCc1ccccc1)CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCCCC
Product: CCCC(=O)CCc1ccccc1
Temperature: 155 °C
Reaction time: 2 h

Procedure:
6.8 g of sodium hydroxide prills (170 mmol) in 100 ml of a nonane fraction (b.p.: 148-153° C.) were initially introduced at room temperature into a three-necked flask having a reflux condenser, internal thermometer and stirrer. After 20 g of 3-hydroxy-3-(2′-phenylethyl)hexanoic acid (85 mmol), prepared according to K. S. Fors, J. R. Gage, R. F. Heier, R. C. Kelly, W. R. Perrault and N. Wicnienski, J. ORG. CHEM. 63, 7348 (1998), had been added, the mixture was heated to 155° C., a clear solution initially forming. The mixture was stirred for 2 h at 150° C., a colorless precipitate forming. The mixture was then allowed to cool to 20° C., hydrolyzed with 80 ml of 2 N hydrochloric acid (pH 1) and stirred for 15 min and the organic phase separated. The organic phase was washed with 30 ml of saturated sodium bicarbonate solution. After phase separation, drying was effected over sodium sulfate and the solvent was distilled off under reduced pressure (>90% of the solvent was recovered). 1-phenylhexan-3-one was obtained in a yield of 13.6 g (91% of theory) with a boiling point of 134° C. (13 mbar).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[C:26]([C:31]([OH:33])=O)[CH:25]=[CH:24]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:34][C@H:35]([C:37]([NH2:39])=[O:38])[CH3:36].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:19]([O:18][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]=[C:26]([C:31](=[O:33])[NH:34][CH:35]([C:37](=[O:38])[NH2:39])[CH3:36])[CH:25]=[CH:24]4)=[N:9][C:10]=2[CH:15]=1)=[O:17])[CH3:20]
Reactant: C[C@H](N)C(N)=O
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)O)ccc3c1)n2C1CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)NC(C)C(N)=O)ccc3c1)n2C1CCCCC1
Reaction time: 24 h
Yield: 42.3 %

Procedure:
A solution of 100 mg (0.23 mmol) of Compound 402a, 86 mg (0.69 mmol) of L-alaninamide, 322 mg (0.69 mmol) of PyBroP, 84 mg (0.69 mmol) DMAP and 89 mg (0.69 mmol) DIEA in 5 mL anhydrous CH2Cl2 was stirred at room temperature for 24 h. To this solution was added 214 mg (0.92 mmol) of CSA. The solution was stirred for another 24 h, diluted with 10 mL CH2Cl2 and washed with 10 mL H2O. The solvent was dried and evaporated. The residue was chromatographed on silica gel using first hexane/EtOAc then CH2Cl2/MeOH as eluent yielding 50 mg yellow oil. MS: 514.28 (M+H+).