Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[Na].[CH2:17]([CH:20]([CH2:23]Br)[CH2:21]Br)[CH2:18][CH3:19]>C(O)C>[CH2:10]([O:9][C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH:20]([CH2:17][CH2:18][CH3:19])[CH2:21]1)=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCC(CBr)CBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCC1CC(C(=O)OCC)(C(=O)OCC)C1
Reaction time: 1 h
Yield: 84 %

Procedure:
Diethyl malonate (96.0 g., 0.608 mol) was added to sodium ethoxide solution [prepared by the addition of 13.8 g. (0.6 gram atom) of sodium to 300 ml. of absolute ethanol] and the mixture was refluxed with stirring. Over a period of one hour, sodium ethoxide solution [prepared by the addition of 12.2 g. (0.5 gram atom) of sodiumto 200 ml. of absolute ethanol] and 2-n-propyl-1,3-dibromopropane (12.2 g., 0.5 mol, prepared as described in Reference Example 1) were added concurrently to the boiling reaction mixture. After the addition was completed, the mixture was refluxed with stirring for 2 hours, and then 400 ml. of ethanol was distilled from the reaction mixture. The residue was mixed with water and extracted with benzene (5×300 ml.). After concentration of the extracts under reduced pressure, a crude product was obtained, which was distilled in vacuo to give the title compound in 84% yield. This compound had the following physical characteristics:
Reaction SMILES: [C:1]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]C1.[OH-].[Na+].C1CCCCCCCCCCC=1.[CH:29]([Br:32])(Br)[Br:30]>[Br-].C[N+](C)(C)C.O>[Br:30][C:29]1([Br:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH:13]1[CH2:1]2
Reactant: BrC(Br)Br
Reactant: O=C1CCCCCCCCCCCC1
Agent: C1=CCCCCCCCCCC1
Agent: C[N+](C)(C)C
Agent: [Br-]
Solvent: O
Product: BrC1(Br)CCCCCCCCCC2CC21
Reaction time: 2 h
Yield: 92 %

Procedure:
cyclotridecanone: 200 ml of a 50 % aqueous solution of NaOH were added dropwise under vigorous stirring to a mixture of 132 g of cyclododecene (CHEMICAL SAMPLE Co - Columbus, Ohio - USA), 600 g of bromoform and 4 g of tetramethylammonium bromide. The mixture was then left at a temperature between 40° and 50° under stirring during 2 h, whereupon it was left at room temperature overnight and diluted with water. Finally the reaction mixture was extracted with 3 fractions of 300 ml each of ether. The combined extracts, after the usual treatments of washing, drying and evaporation, gave a residue which upon fractional distillation under reduced pressure yielded 173 g (92 %) of 2,2-dibromo-bicyclo[10.1.0]tridecane.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)C([O-])=O.[OH:30][CH2:31][CH2:32][CH2:33][NH2+:34][NH2:35].CO>C(Cl)Cl>[NH2:2][C:1]1[N:34]([CH2:33][CH2:32][CH2:31][OH:30])[N:35]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N[NH2+]CCCO
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(-c2nn(CCCO)c(N)c2C(N)=O)cc1
Yield: 43.7 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)acrylamide (464 mg, 2.0 mmol), sodium carbonate (424 mg, 4.0 mmol) and 1-(3-hydroxypropyl)hydrazinium trifluoroacetate (449 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was subjected to column chromatography (SiO2, 8% methanol in CH2Cl2) and was recrystallised from ethyl acetate to give the title compound as white crystals (240 mg) m.p. 164-165°. δH (CDCl3) 7.43 (2H, d, J 8.1 Hz), 7.26 (2H, d, J 7.8 Hz), 5.73 (2H, br s), 5.18 (2H, br s), 4.12 (2H, t, J 6.1 Hz), 3.66 (2H, t, J 5.5 Hz), 2.40 (3H, s), 2.04 (2H, quintet, J 6.1 Hz) and 1.59 (1H, br s).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12]C(=O)C)[CH:10]=2)[N:5]=[C:4](C)[CH:3]=1.[ClH:17]>CO>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[Cl:17]
Reactant: CC(=O)Nc1ccc2nc(C)cc(O)c2c1
Reactant: Cl
Solvent: CO
Product: Nc1ccc2nccc(Cl)c2c1

Procedure:
N-(4-Hydroxy-2-methylquinolin-6-yl)acetamide (0.05 g; see step (i) above), methanol (2 mL) and 5 N hydrochloric acid (6 mL) was refluxed for 90 minutes. The reaction mixture was evaporated and the residue dissolved in ethyl acetate and sodium carbonate solution. The organic phase was washed with water, dried (Na2SO4), filtered and concentrated to give the sub-title compound as a pale yellow solid.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:7]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([S:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH2:24][CH3:25])(=[O:22])=[O:23])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2O)cc1
Reaction time: 1 h

Procedure:
A solution of boron tribromide (1M in DCM, 2.3 ml) was slowly added to a stirred solution of the product from step (ii) (0.4 g) in DCM (20 ml) at 0° C. After 0.5 h a further 4 ml of boron tribromide solution was added and the mixture stirred for 1 h. The reaction was quenched with crushed ice and partitioned between water and DCM. The organics separated, dried, and evaporated under reduced pressure, yield 0.3 g.
Reaction SMILES: [I:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:9]([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.CC([O-])(C)C.[K+].[O-]C1C=CC=CC=1.[C:27]([CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)#[N:28]>C1COCC1>[I:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:9]([CH3:11])[CH3:10])=[C:6]([CH:7]=1)[O:8][CH2:29][C:27]#[N:28]
Reactant: COc1cc(C(C)C)c(O)cc1I
Reactant: Cc1ccc(S(=O)(=O)OCC#N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [O-]c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(OCC#N)cc1I
Temperature: 25 °C
Yield: 82 %

Procedure:
To a cold (1 degree C.) solution of 10.0 g of 5-iodo-2-isopropyl-4-methoxy-phenol in 25 mL THF was added 41.3 mL of 1N KOtBu in THF at a rate such that the internal temperature did not exceed 6 degrees C. To the resultant phenoxide solution was added a solution of 7.2 g of toluene-4-sulfonic acid cyanomethyl ester in 25 mL THF, and the reaction mixture was allowed to warm slowly to ambient temperature overnight. The reaction mixture was partitioned between n-heptane (50 mL) and water (50 mL), and the organic layer was displaced into n-heptane by distillation (to a pot temperature of 97 degrees C.). The concentrate in n-heptane was cooled slowly to ambient temperature and the resulting crystalline solid was washed with n-heptane and dried. In this manner, 9.26 g of (5-iodo-2-isopropyl-4-methoxy-phenoxy)-acetonitrile was isolated (81%): m.p. 67.5-68.8 degrees C.; 1H nmr (DMSO) delta: 1.18 (d, 6H, J=6.9 Hz), 3.19 (septet, 1H, J=6.9 Hz), 3.81 (s, 3H), 5.16 (s 2H), 6.88 (s, 1H), 7.50 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH:16]=3)=[C:11]([F:28])[CH:10]=2)[CH2:4]1.O[C:30]1[CH:34]=[CH:33][O:32][N:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[O:32]1[CH:33]=[CH:34][C:30]([O:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[N:5]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH2:20][CH2:19][N:18]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:17][CH:16]=4)=[C:11]([F:28])[CH:10]=3)[CH2:4]2)=[N:31]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Reactant: Oc1ccon1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Yield: 63.6 %

Procedure:
Prepared by the general method of Example 1 using as starting material 5(R)-hydroxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one (WO97/30995; 4.0 g, 10.5 mmol), 3-hydroxyisoxazole (1.0 g, 11.8 mmol), triphenylphosphine (3.24 g, 12.4 mmol) and diisopropylazodicarboxylate (2.36 g, 11.7 mmol) in tetrahydrofuran (60 ml). Purified by flash chromatography (Merck 9385 silica; tert-butyl methyl ether/EtOAc/MeOH (70:30:0.5) eluant) to give the product (3.0 g, 64%) as a colourless crystalline solid. MS: ESP30 (M+H)+=450.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[NH:9][C:10]([C:15]3[CH:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=3)=[CH:11][C:12](=[O:14])[CH:13]=2)[CH:3]=1.[CH2:22]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH2:23][CH2:24][CH3:25]>CC(O)(CC)C>[CH2:22]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[NH:9][C:10]([C:15]4[CH:20]=[C:19]([N:29]5[CH2:30][CH2:31][N:26]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28]5)[CH:18]=[CH:17][N:16]=4)=[CH:11][C:12](=[O:14])[CH:13]=3)[CH:3]=2)[CH2:28][CH2:27]1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN1CCNCC1
Reactant: O=c1cc(-c2cc(Cl)ccn2)[nH]c(-c2cc(Cl)ccn2)c1
Solvent: CCC(C)(C)O
Product: CCCCN1CCN(c2ccnc(-c3cc(=O)cc(-c4cc(N5CCN(CCCC)CC5)ccn4)[nH]3)c2)CC1

Procedure:
A mixture of 1.12 g (3.52 mmol) 4,4″-dichlor-1′H-[2,2′;6′,2″]terpyridin-4′-on, 10.0 g (70 mmol) 1-butyl-piperazine and 24 mg (0.18 mmol) Zn(II)-chloride in 20 ml 2-methyl-2butanol is refluxed for 18 hours. Afterwards, the solution is concentrated by a rotary evaporator. The raw product is recrystallized from a methanol/water mixture. The yellowish 4,4″-bis-(4-butyl-piperazin-1-yl)-1′H-[2,2′;6′,2″]terpyridin-4′-on is obtained. 1H-NMR (360 MHz, CDCl3): 8.31 (d, 2H, J=5.9 Hz); 7.18 (sm, 2H); 6.94 (s, 2H); 6.65 (dd, 2H, J=5.9,1.8 Hz); 3.39-3.31 (tm, 8H); 2.55-2.47 (tm, 8H); 2.36-2,28 (tm, 4H); 1.5-1.38 (m, 4H); 1.36-1.22 (m, 4H); 0.87 (t, J=7.2 Hz, 6H).
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][C:13]1=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH2:5]([CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH:13]1[NH:28][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[O:24][CH3:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1CCc2ccccc2C1Cc1ccccc1
Reactant: COc1ccccc1CN
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccccc1CNC1CCc2ccccc2C1Cc1ccccc1
Reaction time: 48 h
Yield: 76.8 %

Procedure:
Sodium cyanoborohydride (0.46 g, 7.28 mmol) was added to a solution of 1-benzyl-2-tetralone (0.86 g, 3.64 mmol), 2-methoxybenzylamine (0.50 g, 3.64 mmol), and acetic acid (0.22 g, 3.64 mmol) in methanol (10 mL) under nitrogen. After 48 h of stirring, the reaction mixture was concentrated in vacuo to provide a brown oil. Saturated aqueous sodium carbonate solution (25 mL) was added to this residue and the resulting mixture was extracted with chloroform. The chloroform extracts were combined, dried (Na2SO4), and concentrated to provide a brown oil which was purified on flash silica gel (1% methanol-chloroform to 5% methanol-chloroform) to provide 1.0 g of 1-benzyl-2-(2-methoxybenzylamino)tetralin as a brown oil.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:6]=1)(=O)=O.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[N:36]1([C:5]2[N:10]=[C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=3)[C:8]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[C:7]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])[N:6]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Fc1ccc(COc2nc(N3CCOCC3)nc(-c3ccc(Cl)cc3Cl)c2-c2ccc(Cl)cc2)cc1F

Procedure:
2-(Methylsulfonyl)-4-(3,4-difluorobenzyloxy)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 6, 48 mg, 0.085 mmol) was reacted in excess neat morpholine at 80° for 3 h by the general procedure described in Example 31, Step A. Workup (solvent removal under reduced pressure, then toluene azeotrope) and flash column chromatography on silica gel (eluted with 88/12 hexanes/ethyl acetate) afforded the title product. HPLC/MS: m/e=564 (M++1); Rt=5.00 min 1H-NMR 500 MHz (CDCl3): δ 3.80 (m, 4H), 3.86 (m, 4H), 5.38 (s, 2H), 7.02 (d, J=8 Hz, 2H), 7.08-7.20 (m, 7H), 7.31(d, J=1 Hz, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[Cl:24][CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>O1CCCC1>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][S:28]([CH2:27][CH2:26][CH2:25][Cl:24])(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCNS(=O)(=O)CCCCl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-Boc-4-(2-aminoethyl)-piperazine (1.26 g, 6.8 mmol, Aldrich) and triethylamine (1 mL) in tetrahydrofuran (10 mL), 3-chloro-propylsulfonyl chloride (0.68 mL, 6.94 mmol, Aldrich) was added slowly at room temperature. The mixture was stirred for 30 min at room temperature and the reaction was quenched with water. It was extracted with ethyl acetate and the extracts were combined and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo to give 4-[2-(3-chloro-propane-1-sulfonylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester. It was taken in tetrahydrofuran (20 mL), and cesium carbonate (500 mg) sodium iodide (80 mg) were added and the mixture was stirred at reflux overnight. The mixture was cooled to room temperature and poured into water. It was extracted with ethyl acetate (3×15 mL), and the extracts were combined and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo to give 2.01 g of 4-[2-(1,1-dioxo-isothiazolidine-2-yl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester as a solid. LR-MS: 334 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:13]=[CH:14][C:15]=1[N+]([O-])=O)[C:9]([O:11][CH3:12])=[O:10].[CH3:20][S-:21].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:13]=[CH:14][C:15]=1[S:21][CH3:20])[C:9]([O:11][CH3:12])=[O:10]
Reactant: C[S-]
Reactant: COCCOc1c([N+](=O)[O-])ccc(C(=O)OC)c1C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1c(SC)ccc(C(=O)OC)c1C
Reaction time: 0.75 h
Yield: 96.4 %

Procedure:
Methyl 3-(2-methoxyethoxy)-2-methyl-4-nitrobenzoate (31 g) was dissolved in anhydrous DMF (300 mL), and sodium thiomethoxide (purity: 95%, 8.92 g) was added at room temperature, followed by stirring for 45 minutes. To the reaction mixture, ethyl acetate (400 mL) was added and washed once with 1 N hydrochloric acid (150 mL) and washed twice with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain methyl 3-(2-methoxyethoxy)-2-methyl-4-(methylthio)benzoate (30 g) as a solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:13][CH3:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:27](=[O:29])[CH3:28])[CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24]>>[OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[CH:28][C:27]([C:19]2[CH:20]=[C:21]([O:25][CH3:26])[C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=2)=[O:29])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc([N+](=O)[O-])c1O

Procedure:
The procedure described in Example 8 was repeated by using 2.0 g of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde and 2.1 g of 3',4',5'-trimethoxyacetophenone. Yield 2.2 g (57%), m.p. 123°-125° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=[O:15])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH3:2].[F:17][C:18]([Si](C)(C)C)([F:20])[F:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([OH:15])([C:18]([F:20])([F:19])[F:17])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(C)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h

Procedure:
4.4 g of 2-oxo-4-phenylvaleric acid ethyl ester is dissolved in 40 ml of tetrahydrofuran and mixed at −78° C. with 3.6 ml of trifluoromethyl-trimethylsilane and 2 ml of 1 M tetrabutylammonium fluoride in tetrahydrofuran. After 24 hours at −78° C., another 20 ml of 1 M tetrabutylammonium fluoride in tetrahydrofuran is added. It is stirred for 1.5 hours at 0° C., ethyl acetate and saturated common salt solution are added, the organic phase is separated, and it is washed with saturated common salt solution and water. Then, it is dried (Na2SO4) and concentrated by evaporation and distilled on a bulb tube. 4.4 g of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester, boiling point 95-100° C./0.04 hPa, is obtained.
Reaction SMILES: C([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:19][CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH2:19]([N:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:8])[C:17]=2[N:16]=[C:15]1[CH3:18])[CH3:20]
Reactant: CCn1c(C)nc2c(OCc3ccccc3)cccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCn1c(C)nc2c(O)cccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
To a solution of 4-benzyloxy-l-ethyl-2-methyl-1H-benzimidazole (370 mg) in ethyl acetate (3.7 ml) was added 10% palladium on carbon (18 mg), and the mixture was stirred for 5 hours at ambient temperature under hydrogen atmosphere. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. The residue was crystallized with diisopropyl ether to give 1-ethyl-4-hydroxy-2-methyl-1H-benzimidazole (220 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:7]([F:20])=[CH:8][C:9]([CH3:19])=[C:10]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([F:20])=[CH:8][C:9]([CH3:19])=[C:10]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)c1cc(N)c(F)cc1C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1cc(NC(C)=O)c(F)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Acetyl chloride (3.12 g, 40 mmol) was added to a 0° C. solution of ethyl 2-(5-amino-4-fluoro-2-methylphenyl)-2-oxoacetate (9 g, 40 mmol) and Et3N (8.1 g, 80 mmol) in CH2Cl2 (80 mL). The resulting mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure to give ethyl 2-(5-acetamido-4-fluoro-2-methylphenyl)-2-oxoacetate (10.7 g, 100% yield), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 8.71 (d, J=6.0 Hz, 1 H), 7.37 (brs, 1 H), 6.95 (d, J=8.7 Hz, 1 H), 4.39 (q, J=7.2 Hz, 2 H), 2.50 (s, 3H), 2.10 (s, 3 H), 1.40 (t, J=7.2 Hz, 3 H).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:18]([OH:21])[C:19]#[CH:20])[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15].C[Si](Cl)(C)C.Cl[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29].Cl>CCOCC.C(Cl)Cl.[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:9]=[C:8]([O:7][CH3:6])[C:13]=1[O:14][CH3:15])[C:18]([C:19]#[C:20][C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29])=[O:21]
Reactant: C#CC(O)c1cc(OC)c(OC)c(OC)c1
Reactant: CCCCOC(=O)Cl
Agent: [Mn+4]
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCOC(=O)C#CC(=O)c1cc(OC)c(OC)c(OC)c1

Procedure:
8.7 ml of n-butyllithium solution (1.6M in hexane) were added at -78° to a solution of 3.0 g (13.5 mmol) of 1-(3,4,5-trimethoxyphenyl)-2-propyn-1-ol in 40 ml of ether. The reaction mixture was brought to -30°, whereupon 1.8 ml (14.2 mmol) of freshly distilled trimethylsilyl chloride were added at -30°. Thereafter, the mixture was warmed to 0°. stirred and cooled to -78° for 1 hour, whereupon 7.8 ml of n-butyllithium solution (1.6M in hexane) were added. The reaction mixture was stirred at -30° for 1 hour and then treated at -30° with 2.77 ml (20.25 mmol) of butyl chloroformate, whereupon the mixture was stirred at -30° for 30 minutes and at 0° for 1 hour and 150 ml of 1N hydrochloric acid and 150 ml of ethyl acetate were added. Subsequently. 30 ml of 25% hydrochloric acid were added, the mixture was shaken vigorously for 10 minutes in a separating funnel, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over magnesium sulphate and the solvent was distilled off. The crude product which remained behind as the residue was taken up in 10 ml of methylene chloride and added dropwise at 0° to a suspension 35.2 g (0.405 mol) of manganese dioxide in 50 ml of methylene chloride The reaction mixture was stirred at 0° for 1.5 hours, filtered over magnesium sulphate and evaporated. After chromatography of the residue on silica gel with ethyl acetate/hexane (1:4) there was obtained butyl 3-(3,4,5-trimethoxybenzoyl)propiolate as a pale yellowish oil.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:18])[C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl>CO>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:18])[C:13]([OH:15])=[O:14])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 140.4 %

Procedure:
3 ml (6 mmol) of a 2N aqueous solution of sodium hydroxide were added to a solution of 651 mg (2.92 mmol) of ethyl 4-nitrophenylglyoxylate in methanol, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 0.8 g (quantitative yield) of 4-nitrophenylglyoxylic acid as a crude product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])N(OC)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][C:23]=1[CH3:30]>[NH4+].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:19])[C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[C:23]([CH3:30])[CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc([Mg]Br)cc1C
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
A solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 11.02 mmol in 30 mL THF) was cooled to 0° C., then (4-methoxy-3-methylphenyl)magnesium bromide was added dropwise via a syringe under N2 and the reaction mixture was stirred at the same temperature for 1.5 h, then gradually warmed up to room temperature over 1 h when the reaction was judged complete by LCMS. 40 mL of saturated aqueous NH4Cl was added slowly then the aqueous solution was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried over Na2SO4 and the solvent was removed to yield the crude product. Purification by flash chromatography gave the title compound as a white solid (1.97 g, 5.62 mmol, 51% yield). MS (ESI) m/z 334.4 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.57 min. 1H NMR (400 MHz, CDCL3) δ ppm 1.48 (s, 9H) 1.62-1.91 (m, 4H) 2.27 (s, 3H) 2.78-3.02 (m, 2H) 3.27-3.46 (m, 1H) 3.91 (s, 3H) 4.12-4.27 (m, 2H) 6.87 (d, J=8.59 Hz, 1H) 7.77 (t, 2H).