Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].S([O-])([O-])(=O)=O.[Mg+2]>[N+](C)([O-])=O.CCOCC.[Sc]>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:11])[CH3:10])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Sc]
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(C)=O)cc1
Temperature: 21 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
The catalytic effect of the scandium salt of 5-trifluoromethanesulfonyl-1,3-dibutyl-2-sulfonyl-barbituric acid, obtained in Example 25, towards a Friedel-Crafts reaction of acylation was evaluated in the following manner. In 40 ml of anhydrous nitromethane, there is added 887 mg (0.7 moles) of the scandium salt of 5-trifluoromethylsulfonyl-1,3-dibutyl-2-sulfonyl-barbituric acid, and 1.08 g (10 mmoles) of anisole and 2.04 g (20 mmoles) of acetic anhydride. After stirring during 10 min at 21° C., the reaction mixture was diluted with 50 ml of ether and the reaction was inhibited with 100 ml of a saturated solution of sodium bicarbonate NaHCO3. After filtration on Celite, the solution was extracted with three fractions of 50 ml ether, then the collected ether phase was washed with a saturated solution of potassium chloride. After drying the ether phase with magnesium sulfate and evaporation, 1.46 g of p-methoxyacetophenone (95% yield) were recovered with a purity characterized by a proton RMN higher than 99%.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(CO)CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(COS(C)(=O)=O)CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.6 %

Procedure:
To a solution of ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (1.0 g, 6.3 mmol) and N,N-diethylethanamine (1.5 g, 8.2 mmol) in CH2Cl2 (30 ml) was added methanesulfonyl chloride (869 mg, 7.6 mmol). The mixture was stirred for 6 hours at ambient temperature. After dilution with CHCl3 and H2O, the organic layer was washed with H2O, dried over MgSO4, and concentrated in vacuo to give ethyl 1-{[(methylsulfonyl)oxy]methyl}cyclobutanecarboxylate (1.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:5]=O.N1C=CC=CC=1.Cl.[O:25]([NH2:27])[CH3:26]>O>[CH3:26][O:25][N:27]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:2]([OH:1])[CH:3]=1
Reactant: CON
Reactant: O=Cc1ccc(OCCN2CCCC2)c(O)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CON=Cc1ccc(OCCN2CCCC2)c(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
An amount of 3-hydroxy-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (150 mg, 0.64 mmol) is added pyridine (3.5 ml) at room temperature, followed by addition of methoxylamine hydrogen chloride (58.2 mg, 0.70 mmol). The mixture is stirred at ambient temperature for 24 h, and 4 mL of water is added. After the solvents were evaporated, the residue is dissolved 8 mL of anhydrous ether, washed successively with 2 mL of aqueous sodium bicarbonate, 2 mL of sodium bisulfite, and 2 mL of brine. Dried over magnesium sulfate, evaporated to give a yellow solid (100 mg). MS (ESI) m/z 265.8 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.N=CO[CH2:34][NH:35][C:36](=[O:39])[O:37][CH3:38].C(O)(=O)C>ClC(Cl)Cl>[C:19]1([CH:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][N:8]3[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[N:1]=[C:34]3[NH:35][C:36](=[O:39])[O:37][CH3:38])[CH2:17][CH2:16]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)NCOC=N
Reactant: Nc1ccccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1nc2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 60 parts of N-(2-aminophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine, 20 parts of methyl (iminomethoxymethyl)carbamate, 42 parts of acetic acid and 450 parts of trichloromethane is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is stirred in water. The latter is decanted and the residue is taken up again in water. The whole is alkalized with a diluted ammonium hydroxide solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding methyl [1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1H-benzimidazol-2-yl]carbamate; mp. 137.8° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH2:24])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(C2CCCN(C(=O)OCc3ccccc3)C2)cc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.2 %

Procedure:
3-(3-Amino-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester (Example 13; 230 mg, 0.71 mmol) was dissolved in 5 mL dimethylformamide. Cesium carbonate (462 mg, 1.42 mol) and ethyl bromoacetate (86 μL, 0.78 mmol) were added and the mixture stirred at ambient temperature under a nitrogen atmosphere for 72 h. An additional 86 μL of ethyl bromoacetate were added and the reaction stirred an additional 24 h. The mixture was diluted with 100 mL water and extracted with diethyl ether (2×50 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 20% ethyl acetate/hexanes to yield 152 mg (52%) of 3-[3-(ethoxycarbonylmethyl-amino)-4-methyl-phenyl]-piperidine-1-carboxylic acid benzyl ester as a clear oil.
Reaction SMILES: O1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([OH:19])[CH:13]=2)=[O:9].[OH-].[Na+].C1(CBr)CC1>O.CN(C)C=O>[CH3:6][O:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([O:19][CH2:2][CH:3]1[CH2:5][CH2:4]1)[CH:13]=2)=[O:9]
Reactant: COC(=O)c1cc2ccc(O)cc2[nH]1
Reactant: C1CCOC1
Agent: BrCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2ccc(OCC3CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
To a tetrahydrofuran (8 mL) solution of 6-hydroxy-1H-indole-2-carboxylic acid methyl ester (395 mg, 2.07 mmol) described in Production Example 73-1-1 was added 5 N aqueous sodium hydroxide solution (414 μL, 2.07 mmol), which was concentrated under a reduced pressure. To an N,N-dimethylformamide (8 mL) solution of the residue was added cyclopropylmethyl bromide (241 μL, 2.48 mmol) at room temperature followed by stirring at room temperature for 12 hours. Moreover, after stirring at 50° C. for 4 hours, water was added to the reaction solution at room temperature followed by extraction with ethyl acetate. The organic layer was washed with water and sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (297 mg, 59%) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C@@H:6]([C:29]#[N:30])[NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:9].[BH4-].[Na+]>CO.C(Cl)Cl>[C:29]([CH:6]([NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:9])[CH2:5][CH2:4][CH2:3][OH:2])#[N:30]
Reactant: COC(=O)CC[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)NC(C#N)CCCO)cc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.5 %

Procedure:
To a solution of (S)-4-cyano-4-({(1R,2S)2-[(1-methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarbonyl}-amino)-butyric acid methyl ester (obtained from compound 3-8, 209 mg, 0.492 mmol), in 15 mL of MeOH and 15 mL of CH2Cl2, was added sodium borohydride (100 mg, 2.64 mmol). The reaction mixture was stirred at ambient temperature for 24 hours, concentrated, and purified by column chromatography (3:97, MeOH/CH2Cl2) to give 83 mg (43%) of 1-methyl-1H-indole-2-carboxylic acid [(1S,2R)-2-(1-cyano-4-hydroxy-butylcarbamoyl)-cyclohexyl]-amide as an amorphous solid. MS: 397 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH2:21]([C@H:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]1[C:34](=[O:37])[CH2:35][CH3:36])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O:38]=[C:39]1[CH2:42][N:41]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:40]1>C1COCC1>[OH:38][C:39]1([C@@H:35]([CH3:36])[C:34](=[O:37])[N:29]2[C@@H:28]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:32][O:31][C:30]2=[O:33])[CH2:42][N:41]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:40]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
To a solution of diisopropylamine (6.5 mL, 46.3 mmol) in THF (200 mL) at −78° C. was added butyllithium (17 mL of a 2.5 M solution in hexanes, 42.5 mmol) over 5 min. The solution of lithium diisopropylamide was stirred for 15 min at −78° C. A solution of (S)-4-benzyl-3-propionyl-2-oxazolidinone (9.0 g, 38.6 mmol) in THF (100 mL) was added to the lithium diisopropylamide by addition funnel over 26 min. The reaction temperature was kept below −70° C. during the course of the addition. After the addition, the mixture was stirred for a further 30 min at −78° C. Then phenylmethyl 3-oxoazetidine-1-carboxylate (9.5 g, 46.3 mmol) was added by addition funnel over 25 minutes as a solution in THF (100 mL). Again, the reaction mixture was kept below −70° C. during the reagent addition. After stirring for an additional 1 hour at −78° C., the reaction mixture was quenched with saturated ammonium chloride solution and was then allowed to warm to rt. Water was added to dissolve any precipitated ammonium chloride, and ethyl acetate was added. The layers were partitioned, and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with 5% aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (50% ethyl acetate:50% hexanes) to provide phenylmethyl 3-hydroxy-3-{(1R)-1-methyl-2-oxo-2-[(4S)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]ethyl}azetidine-1-carboxylate as a white crystalline solid (6.03 g, 13.8 mmol, 36% yield). 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 8H), 7.20 (d, 2H), 5.12 (s, 2H), 4.66 (m, 1H), 4.27-4.20 (m, 2H), 4.10 (q, 1H), 4.03-3.93 (m, 3H), 3.28 (dd, 1H), 2.77 (dd, 1H), 1.29 (d, 3H).
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[OH:34][C:35]([C@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)([CH3:37])[CH3:36]>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:40]4[CH2:41][CH2:42][C@H:38]([C:35]([OH:34])([CH3:37])[CH3:36])[CH2:39]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: CC(C)(O)[C@H]1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](C(C)(C)O)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-(1-hydroxy-1-methyl-ethyl)-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.40 (s, 1H), 4.14 (s, 1H), 3.74 (m, 1H), 3.65 (m, 1H), 3.36 (m, 2H), 3.28 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.15 (m, 6H), 1.03 (m, 1H), 0.83 (d, 3H), 0.74 (m, 1H). m/z: 460 [M+H]
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4]([NH:16][NH2:17])[N:3]=1.CC(O)=O.[N:22]([O-])=O.[Na+]>O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[N:3]2[N:22]=[N:17][N:16]=[C:4]2[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)=[N:6][C:7]=1[CH3:8]
Reactant: O=N[O-]
Reactant: Cc1nc(N2CCN(C)CC2)c(NN)nc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(N2CCN(C)CC2)c2nnnn2c1Br
Temperature: 10 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A 25 mL round bottom flask was charged with 2-bromo-6-hydrazinyl-3-methyl-5-(4-methylpiperazin-1-yl)pyrazine (0.92 g, 3.0 mmol) and CH3COOH (2 mL). To the above was added dropwise a solution of NaNO2 (0.32 g, 4.6 mmol) in water (2 mL) at 10° C. The resulting mixture was stirred at 10° C. for 1 h. Work-up: the reaction mixture was diluted with saturated aqueous NaHCO3 (100 mL) and then extracted with CH2Cl2 (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 4% MeOH in CH2Cl2, to afford 0.72 g (75%) of the product as a white solid. MS m/z: 312 (M+H+).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][OH:20])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:21]C1C=CC(CCl)=CC=1.O>C1(C)C=CC=CC=1>[Cl:21][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][OH:20])=[N:11]2)=[CH:9][CH:8]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: OCc1nn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1nn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Yield: 23 %

Procedure:
To a suspension of 60% NaH (2.7 g; 0.07 mol) in toluene (200 ml) was added 1-benzyl-3-hydroxymethylindazole (10 g; 0.07 mol). The mixture was brought to the boiling point and left stirring at reflux for 1 hour. 4-chlorobenzyl chloride (14.4 g; 0.09 mol) was then added. The mixture was then stirred at reflux for 4 hours. The reaction was stopped by cooling the mixture to room temperature and adding water (50 ml). The organic phase was separated out and washed, respectively, with 2N HCl (50 ml) and water (5×50 ml). The solvent was evaporated off under reduced pressure. The crude residue thus obtained was purified by flash chromatography on silica gel, using as eluent a 3/1 hexane/ethyl acetate mixture. The product obtained was crystallized from a 5/1 hexane/ethyl acetate mixture to give 4.4 g of [1-(4-chlorobenzyl)-1H-indazol-3-yl]methanol.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>O1CCCC1>[CH2:26]([NH:30][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH3:10])[CH2:27][CH2:28][CH3:29]
Reactant: CC(=O)CCCCC(=O)O
Reactant: CCCCN
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCNC(=O)CCCCC(C)=O

Procedure:
The title compound was prepared by the method described for 6-oxoheptanoic acid p-toluide (IV, n=4, Y=p-methylanilino) using the following quantities: δ-acetyl-n-valeric acid (2.5 g, 1.75 mmol), N-methylmorpholine (1.9 ml, 17.5 mmol), isobutyl chloroformate (2.25 ml, 17.5 mmol), n-butylamine (1.7 ml, 17.5 mmol), tetrahydrofuran (15 ml). Recrystallization from ethyl acetate/hexanes gave 1.3 g of the desired compound as white needles, which were pure by thin layer chromatography (95:5:3 chloroform/methanol/acetic acid, Rf =0.52) m.p. 53°-54° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][NH2:14])=[O:12].C(N(CC)CC)C.[C:22](C1NC=CN=1)(C1NC=CN=1)=[O:23]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[O:12][C:22](=[O:23])[NH:14][N:13]=1
Reactant: NNC(=O)c1ccc2ccccc2c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(-c2ccc3ccccc3c2)o1
Temperature: 0 °C
Reaction time: 17 h
Yield: 96.9 %

Procedure:
To a stirred mixture of naphthalene-2-carboxylic acid hydrazide (2.0 g, 10.7 mmol, prepared as described in example 1) and triethylamine (1.1 g, 10.7 mmol) in dry tetrahydrofuran (40 ml) was added carbonyl diimidazole (2.2 g, 13.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 17 h. The resulting reaction mixture was evaporated in vacuo and to the residue was added water (50 ml) and ethyl acetate (50 ml). The phases were separated and the organic phase was washed with saturated aqueous sodium chloride (2×25 ml), dried (MgSO4) and filtered and evaporated in vacuo affording 2.2 g of crude product which was recrystallised from a mixture of ethyl acetate and heptane 1:1 (60 ml) affording after drying in vacuo at 50° C. 1.2 g (52%) of the title compound as a solid.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[C:11]([CH:20]3[NH:24][C:23](=[O:25])[CH2:22][CH2:21]3)[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I-].[Na+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>C1COCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:24]1[CH:20]([C:11]2[O:12][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:10]=2)[CH2:21][CH2:22][C:23]1=[O:25]
Reactant: COc1cccc(CCl)c1
Reactant: O=C1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(CN2C(=O)CCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.9 %

Procedure:
To a solution of NaH (60% oil, 28 mg), 5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (0.15 g) and sodium iodide (catalytic amount) in THF (1 ml) was added a solution of 3-methoxybenzyl chloride (0.11 g) in THF (2 ml). After being stirred for 4 days at room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-(3-methoxybenzyl)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (0.14 g).
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Mg]Br.[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[C:20]#[N:21]>C1(C)C=CC=CC=1.C(OCC)C>[CH:8]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:20](=[NH:21])[C:19]2[C:18]([F:17])=[CH:25][CH:24]=[CH:23][C:22]=2[F:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: N#Cc1c(F)cccc1F
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: N=C(c1c(F)cccc1F)N(C1CCCCC1)C1CCCCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
Dicyclohexylamine (9.06 g, 50.1 mmol) was dissolved in toluene (125 mL). The solution was warmed to 50° C. and a solution of methylmagnesiumbromide was added (16.7 mL, 3.0 M in diethylether, 50.1 mmol) and the reaction mixture was stirred for 2 hours at 50° C. The mixture was cooled to 0° C. and 2,6-difluorobenzonitrile (6.80 g, 48.9 mmol). After 45 hours, the reaction mixture was quenched with a solution of ammoniumchloride in water (3.0 g in 80 mL). The water and organic phases were separated and the water layer was extracted 3 times with diethylether (40 mL). The combined organic solutions were dried over sodium sulphate. The sodium sulphate was filtered off and the filtrate was evaporated to dryness yielding 14.2 g (89%) of the product. The product was characterized by 1H NMR (300 MHz) (CDCl3) δ (ppm): 7.2 (pent, 1H), 6.8 (dd, 2H), 5.9 (bs, 1H), 3.5-2.3 (bm, 3H), 1.9-0.6 (bm, 19H), by 13C NMR (75 MHz) (CDCl3) δ (ppm): 158.9 (dd, J=248 Hz, J=8 Hz) 156.4, 130.1, 130.0, 129.8, 118.8, 118.4, 118.1, 12.1, 111.7, 61.3 (bs), 56.9 (bs), 32.0 (bs), 30.1 (bs), 26.8 (bs), 25.8 and by 19F NMR (282 MHz) (CDCl3) δ (ppm): −114.3 (s).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([O:32][CH3:33])=[CH:9][C:10]2[C:11]3[C:12]4[C:29](=[O:30])[NH:28][C:27](=[O:31])[C:13]=4[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:15][C:16]=3[NH:17][C:18]=2[CH:19]=1)(=O)=O.C([Sn](CCCC)(CCCC)/[CH:41]=[CH:42]/[CH2:43][CH2:44][OH:45])CCC.[Cl-].[Li+].C(OCC)(=O)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:14]1[C:13]2[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:12]=2[C:11]2[C:10]3[CH:9]=[C:8]([O:32][CH3:33])[C:7](/[CH:41]=[CH:42]/[CH2:43][CH2:44][OH:45])=[CH:19][C:18]=3[NH:17][C:16]=2[CH:15]=1
Reactant: CCCC[Sn](/C=C/CCO)(CCCC)CCCC
Reactant: COc1cc2c(cc1OS(=O)(=O)C(F)(F)F)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1/C=C/CCO)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Yield: 95.9 %

Procedure:
A solution of the triflate (169) (0.20 g, 0.35 mmol) prepared as described in example 308, (3E)-4-(tributylstannyl)-3-buten-1-ol (0.19 g, 0.53 mmol) and lithium chloride (29 mg, 0.70 mmol) in DMF (10 mL) was purged by bubbling nitrogen through the liquid for 10 min. Bis(triphenylphosphine)palladium dichloride (12 mg, 0.017 mmol) was added last and the solution was flushed with nitrogen for 2 min more, then warmed under an atmosphere of nitrogen for 3 h. The mixture was diluted with brine, extracted with ethyl acetate and worked up to give an oil which was chromatographed on silica. Elution with ethyl acetate/petroleum ether (1:5) gave foreruns, while ethyl acetate/petroleum ether (1:1) increasing to pure ethyl acetate gave (170) as a yellow solid (0.15 g, 95%), mp 271–275° C. 1H NMR δ [(CD3)2SO] 11.86 (br s, 1H), 11.07 (br s, 1H), 8.45 (s, 1H), 7.70 (s, 1H), 7.58 (dd, J=8.1, 2.2 Hz, 1H), 7.55 (s, 1H), 7.51–7.41 (m, 3H), 6.87 (d, J=16.0 Hz, 1H), 6.44 (dt, J=16.0, 7.1 Hz, 1H), 4.62 (t, J=5.3 Hz, 1H), 3.94 (s, 3H), 3.58 (m, 2H), 2.42 (m, 2H). Found: C, 67.09; H, 4.36; N, 5.98. C25H19ClN2O4 requires C, 67.19; H, 4.28; N, 6.27.