Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.S(O)(O)(=O)=O.CS[C:24](=[NH:26])[NH2:25].[OH-].[Na+]>O>[C:24]([N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:2]1)(=[NH:25])[NH2:26]
Reactant: CSC(=N)N
Reactant: CS(=O)(=O)Nc1cccc2c1CCNC2
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)Nc1cccc2c1CCN(C(=N)N)C2
Temperature: 80 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
To a stirred suspension of N-(1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide hydrochloride prepared as described in Example 19(b) of WO 98/30560 (100 g, 0.38 mol) and 2-methyl-2-thiopseudourea sulfate (159 g, 0.57 mol) in water (1.5 liter) was added 2N aqueous sodium hydroxide (764 ml, 1.53 mol). The resulting solution was warmed to 80° C. and stirred at this temperature for 6 hours and then left to cool to room temperature overnight. Further 2-methyl-2-thiopseudourea sulfate (27 g, 0.10 mol) and 2N aq. sodium hydroxide (48 ml, 0.10 mol) were charged and the mixture heated at 80° C. for 1 hour. After this time the resulting suspension was cooled to room temperature, filtered, washed with water (1 liter) to give a white solid that was dried in vacuo overnight at 50° C. to give 91.0 g of the title product (89%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:27]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](B(O)O)=[C:33]2[C:28]=1[CH:29]=[CH:30][CH:31]=[CH:32]2.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:10]=3)[CH:7]=2)=[C:35]2[C:40]=1[CH:39]=[CH:38][CH:37]=[CH:36]2
Reactant: OB(O)c1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Reactant: Brc1ccc2nc(-c3ccccc3)cn2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2cn3cc(-c4c5ccccc5c(-c5ccc6ccccc6c5)c5ccccc45)ccc3n2)cc1
Yield: 74.5 %

Procedure:
Dissolving 2.0 g (7.3 mmol) of 6-bromo-2-phenyl-imidazo [1,2-a] pyridine, 2.5 g (11 mmol) of 10-naphthalen-2-yl-anthracene-9-boronic acid and 0.17 g of tetrakis (triphenylphosphine) palladium into 20 milliliter of 1,2-dimethoxyethane, adding 11 milliliter of 2.0M sodium carbonate aqueous solution, the resultant suspension was refluxed under heating for 7 hours. After completion of the reaction, separation with filtration was carried out and resultant crystal were washed with water and methanol, thereby obtaining 2.7 g of yellowish white solids (yield: 75%). As a result of mass spectrum (MS) analysis, the yellowish white solids were identified as the aimed substance, and it was recognized that m/e=496 for molecular weight of 496.19.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[O:6]([CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[C:16](Cl)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[O:6]([CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[C:16]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: CCCN(CCOc1ccccc1)C(=O)Cl
Solvent: C1CCOC1
Product: CCCN(CCOc1ccccc1)C(=O)n1ccnc1
Temperature: 25 °C

Procedure:
To 75 ml. dry tetrahydrofuran were added 6.8 g. imidazole and 12.075 g. N-2-phenoxyethyl-N-propylcarbamoyl chloride. The reactants were boiled together under reflux for 24 hours, cooled to room temperature and filtered to remove imidazole hydrochloride. The solvent was then removed by evaporation from the steam bath, the last traces being removed under vacuum. An oily residue remained which was extracted into ether, washed with water, dried over anhydrous sodium sulphate, the solvent removed and the residual oil distilled under vacuum, to give 1-(N-2-phenoxyethyl-N-propylcarbamoyl) imidazole, boiling point 209° C./1.0 mm.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([OH:14])=[O:13])[CH:9]=2)[CH2:4][CH2:3]1.[OH-].[K+].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH:17](=[C:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([OH:14])=[O:13])[CH:9]=2)[CH2:4]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)C(=O)C(=Cc1ccccc1)C2
Reaction time: 0.67 h

Procedure:
3-Oxo-5-indaneacetic acid (4.94 g, 0.026 mol) was added to a stirred solution of 85% KOH (3.43 g, 0.052 mol) in EtOH (73 ml) containing benzaldehyde (2.76 g, 0.026 mol) at 10° C. and stirred for 40 minutes. The potassium salt of the precipitated product was filtered off, dissolved in H2O (100 ml) was acidified with conc. HCl to give the title product, m.p. 202°-4° C. (EtOH).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20](=[O:24])[CH:21]([CH3:23])[CH3:22]>C1COCC1>[OH:24][CH:20]([CH:21]([CH3:23])[CH3:22])[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(C)C=O
Reactant: CC(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(O)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Acetophenone (11.433 gm, 95 mmol) was added dropwise over a five minute period to a solution of lithium bis(trimethylsilyl)amide (1.0M in THF, 100 ml, 100 mmol) in THF (50 ml) kept at -78° C. After 30 minutes, isobutyraldehyde (6.87 gm, 95 mmol) was added dropwise and stirring was continued for an additional hour. The mixture was quenched with saturated NH4Cl (100 ml), warmed to room temperature, diluted with H2O and extracted 2× with Et2O. The combined Et2O extracts were washed with brine, dried (Na2SO4), filtered and stripped to yield an oil. The oil was distilled (P=1.5 mm) and the fraction boiling between 120°-124° C. was chromatographed (flash, Merck SiO2, 15% EtOAc in hexane) to give the desired 3-hydroxy-4-methyl-1-phenyl-1-pentanone as a colorless liquid (9.13 gm, 50%)
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[CH3:19][C:17]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[S:8][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: NC(=S)c1ccncc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccncc2)nc1C
Yield: 40.3 %

Procedure:
A mixture of thioisonicotinamide (2.76 g) and ethyl 2-chloroacetoacetate (3.6 g) in ethanol (30 ml) was heated for 20 hours under reflux and the solvent was evaporated. To the residue was added saturated sodium hydrogen carbonate solution, and the solution was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was subjected to silica gel chromatography, and eluted with hexane-ethyl acetate (2:1) to give the title compound as crystals (2.0 g, 40.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Reactant: [O-]B([O-])Oc1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3ccc(Cl)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
Under argon atmosphere, methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.70 g), a mixture of 4-chlorophenyl borate (0.38 g) and potassium carbonate (0.59 g) in toluene/ethanol/water (20/2/2 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.12 g), and the mixture was refluxed for 20 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:1) and recrystallized from ethyl acetate/hexane to give to give pale yellow crystals of methyl 7-(4-chlorophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (466 mg).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH:8]([OH:11])CO)[N:3]=[CH:2]1.CCOC(C)=O>C1COCC1.O>[S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH:8]=[O:11])[N:3]=[CH:2]1
Reactant: OCC(O)CCc1cscn1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=CCCc1cscn1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
NaIO4 (2.40 g, 11.3 mmol) was added to a sol. of (rac.)-4-thiazol-4-ylbutane-1,2-diol (1.62 g, 9.37 mmol) in THF (20 mL) and water (10 mL). The mixture was stirred for 2 h, and EtOAc was added. The mixture was washed with brine, and with aq. sat. NaHCO3. The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (1.04 g, 79%), which was used further without purification. LC-MS: tR=0.32, ES+: 142.11.
Reaction SMILES: C(O)(=O)C.C([Si](C)(C)[O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2(O)[C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[CH:13][C:12]=1[O:34][CH3:35])(C)(C)C.C([O-])(O)=O.[Na+]>O>[OH:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH:17]=[C:18]2[C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[CH:13][C:12]=1[O:34][CH3:35]
Reactant: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)C(O)(c1cc(OC)c(OC)c(OC)c1)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(cc1O)C(c1cc(OC)c(OC)c(OC)c1)=CCC2
Temperature: 25 °C
Yield: 86.2 %

Procedure:
To a solution of acetic acid (10 mL) in H2O (60 mL), was added 7-[(tertbutyldimethylsilyl)oxy]-1-hydroxy-6-methoxy-1-(3′,4′,5′-trimethoxyphenyl)-tetralin (137 mg, 0.29 mmol). The solution was heated to reflux for 8 hour, and then cooled down to rt. NaHCO3 (20 mL, saturated solution) was added, and the mixture was partitioned between CH2Cl2 and water. The organic layer was dried over anhydrous sodium sulfate, and after filtration, the organic layer was concentrated in vacuo to provide a yellow oil. 7-Hydroxy-6-methoxy-1-(3′,4′,5′-trimethoxyphenyl)-3,4-dihydronaphthalene (84.3 mg, 0.25 mmol, 86%) was obtained following purification by column chromatography. 1H-NMR (CDCl3, 300 MHz) 2.37 (m, 2H), 2.78 (t, J=7.7 Hz, 2H), 3.84 (s, 6H), 3.88 (s, 3H), 3.91 (s, 3H), 5.41 (s, 1H), 5.98 (t, J=4.6 Hz, 1H), 6.54 (s, 2H), 6.68 (s, 1H), 6.81 (s, 1H).
Reaction SMILES: [CH2:1]([C:10]([C:21]#[N:22])([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.Cl[C:24]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[CH2:1]([C:10]1([C:21]#[N:22])[CH2:11][CH2:12][C:13](=[O:15])[CH:17]([C:18]([O:20][CH3:24])=[O:19])[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: COc1cccc(CC(C#N)(CCC(=O)O)CCC(=O)O)c1
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CC(C#N)(Cc2cccc(OC)c2)CCC1=O
Yield: 99 %

Procedure:
Following the procedure of Preparation I, Part b, but substituting 30.34 gm. (0.0951 mole) of the dimethyl ester of 4-(m-anisyl)-4-cyanopimelic acid (prepared in Part a, above) for the 34.97 gm. of the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 620 ml. of the tetrahydrofuran, 21.3 gm. (0.19 mole) of the potassium tert-butoxide, and 150 ml. of the 2.5 N glacial acetic acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respectively, there is prepared 29.1 gm. (99% yield) of 4-(m-anisyl)-2-carbomethoxy-4-cyanocyclohexanone as a gum.
Reaction SMILES: C(O[C:6]1[C:14](OC)=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][C:7]=1OC)CCC.[NH2:19]CC1(N(C)C)CCOCC1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:10]([NH2:19])(=[O:11])[C:9]1[CH:13]=[CH:14][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCOc1c(OC)cc(C(=O)O)cc1OC
Reactant: CN(C)C1(CN)CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
4-n-butoxy-3,5-dimethoxybenzoic acid represented by Formula 90 (6 g, 23.60 mmol) prepared in Preparative Example 2 above was slowly added to a solution of 4-(aminomethyl)-N,N-dimethyltetrahydro-2H-pyran-4-amine represented by Formula 95 (3.73 g, 23.60 mmol) and diisopropylethylamine (12.36 mL, 70.78 mmol) in DMF (80 mL) at room temperature. After cooling the reaction mixture to 0° C. and adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 8.97 g, 23.60 mmol) thereto, the mixture was agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and ethyl acetate was added to the remaining concentrate to prepare a solution. The prepared solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. Then, after drying the organic layer with magnesium sulfate (MgSO4), the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (chloroform/methanol, 10:1) using silica gel (SiO2). After dissolving the obtained organic product in ethyl acetate, 2 M-ethylether chloride solution (14.16 mL, 28.31 mmol) was added thereto, followed by agitation at 45° C. for 15 minutes. Thereafter, the solvent was filtered to obtain a product in a powder form and the product was recrystallized in ethanol-methanol to thus produce a benzamide compound represented by Formula 6 as a desired product (VVZ-005; 6.77 g, 66% yield).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](F)[N:10]=1>C1COCC1>[CH:1]1([CH2:4][O:5][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[N:10]=2)[CH2:3][CH2:2]1
Reactant: Fc1cccc(F)n1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cccc(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
To a solution of cyclopropylmethanol (3.87 g, 47.7 mmol) in THF (50 mL) was added sodium hydride (oil, 60%, 2.08 g, 52.1 mmol), and the mixture was stirred at room temperature for 20 min. To this solution was added 2,6-difluoropyridine (5.00 g, 43.4 mmol) and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1 to 4:1) to give the title compound (5.69 g, yield 78%) as an oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23](=[O:28])[CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23]([OH:28])([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)[CH2:24]2)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Brc1cncnc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cncnc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.3 %

Procedure:
n-Butyl lithium (2.5 M, 1.8 mL, 4.5 mmol) was added dropwise to a solution of 5-bromo-pyrimidine (0.668 g, 4.2 mmol) in THF (10 mL), under nitrogen at −78° C. and stirred for 1 hour. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.675 g, 3.0 mmol) in THF (5 mL) was added dropwise at −78° C. and the reaction mixture warmed to room temperature over 1 hour. Saturated aqueous ammonium chloride and ethyl acetate were added, the organics separated, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 10% methanol/ethyl acetate. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.14 g). LCMS m/z 306 [M+H]+. R.T.=2.89 min (Analytical Method 3).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([CH2:7][C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH2:18][CH2:19][OH:20])(=[O:17])=[O:16])[CH:11]=[CH:10][C:9]=1[N+:21]([O-])=O)(=[O:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+]>[Fe].O>[OH:1][CH2:2][CH2:3][S:4]([CH2:7][C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH2:18][CH2:19][OH:20])(=[O:17])=[O:16])[CH:11]=[CH:10][C:9]=1[NH2:21])(=[O:6])=[O:5]
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)CCO)cc1CS(=O)(=O)CCO
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(CS(=O)(=O)CCO)cc1CS(=O)(=O)CCO
Reaction time: 0.5 h

Procedure:
100 parts of 2,4-bis(hydroxyethylsulfonylmethyl)nitrobenzene are added at a constant rate over a period of 30 minutes with stirring to a mixture heated to 80° to 85° C. and consisting of 40 parts of iron powder and 200 parts of water, the reaction temperature being maintained at 80° to 85° C. during the addition. After the addition is completed, stirring is continued for 30 minutes, the pH is adjusted to 8.5 with aqueous sodium carbonate solution, and the mixture is clarified while hot by removing the precipitated iron hydroxide. The filter residue is washed twice with a small amount of hot water. The combined filtrates are subsequently concentrated in vacuo to 150 parts by volume and subsequently cooled to 0° to 5° C. with stirring. The slightly brownish precipitate is isolated on a nutsche filter, covered with a small amount of ice water and dried in vacuo at 60° C. This gives 84.7 parts of 2,4-bis(hydroxyethylsulfonylmethyl)aniline of the formula ##STR23## of melting point 183° to 185° C. and a purity (by diazotization) of 99.5%.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:28])=[C:24]([CH:27]=1)[C:25]#[N:26]>>[C:25]([C:24]1[CH:27]=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:21]=[CH:22][C:23]=1[F:28])#[N:26]
Reactant: N#Cc1cc(N)ccc1F
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: N#Cc1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 22.7 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and 163 mg of 5-amino-2-fluorobenzonitrile in place of the 3-(tert-butyl)aniline. The reaction mixture is concentrated to dryness under reduced pressure and the residue is then purified by silica column chromatography, elution being carried out with a gradient of the eluent CH2Cl2/MeOH: 90/10 in dichloromethane of 0% to 100%. 81 mg of N-(3-cyano-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of an amber solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16])[CH2:2][CH2:3][CH3:4].B>C1COCC1.C(OCC)C>[CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1cccc(OC)c1OC
Agent: B
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCNCc1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.3 %

Procedure:
N-Butyl-2,3-dimethoxybenzamide (5.37 g, 22.6 mmol) was dissolved in freshly distilled THF (230 mL) and cooled in an ice bath under an argon atmosphere. Borane (28 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed overnight and was then allowed to cool to room temperature. The reaction was quenched by careful addition of 10% HCl (11 mL) and the mixture was stirred for four hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (300 mL) and washed with aqueous 2 M K2CO3 (3×100 mL), and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (160 g) with ethyl acetate (33-100% gradient) in heptane and finally 5% ethanol in ethyl acetate as the eluent yielded 2.74 g (54%) of a light yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[Cl:17][C:18]1[N:19]=[C:20]([C:26](O)=[O:27])[NH:21][C:22]=1[CH2:23][CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:17][C:18]1[N:19]=[C:20]([C:26]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:27])[NH:21][C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example 1e) (0.39 g, 1.69 mmol), 4-chloro-5-propyl-1H-imidazole-2-carboxylic acid obtained in Example (46d) (0.16 g, 0.85 mmol), WSC hydrochloride (0.50 g, 2.58 mmol) and HOBT (0.12 g, 0.87 mmol), to obtain 0.32 g of the title compound as a white foamy substance (94%).