Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C(=O)([O-])O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cnn(Cc2ccccc2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cnn(Cc2ccccc2)c1
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of (1-benzyl-1H-pyrazol-4-yl)methanol (3.84 g) in methylene chloride (100 mL) were added triethylamine (2.80 mL), 4-dimethylaminopyridine (100 mg) and tert-butyldimethylsilyl chloride (3.80 g) at room temperature, and the mixture was stirred for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and insoluble material was removed by filtration. Ethyl acetate (100 mL) was added to extract the filtrate, and the organic layer was washed with brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (6.00 g).
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([CH3:6])([OH:5])[CH3:4].[C:13](C1NC=CN=1)(C1NC=CN=1)=[O:14]>ClCCl>[C:7]1([C@@H:2]2[C:3]([CH3:6])([CH3:4])[O:5][C:13](=[O:14])[NH:1]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(O)[C@H](N)c1ccccc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: CC1(C)OC(=O)N[C@@H]1c1ccccc1
Yield: 82.2 %

Procedure:
To a solution of (13) (1.30 g, 7.89 mmol) in dichloromethane (100 ml) was added carbonyl diimidazole (1.534 g, 9.47 mmol) and the reaction mixture was refluxed for 2 hours. The reaction was quenched with hydrochloric acid (1M) and the product extracted repeatedly with dichloromethane. The combined organic extracts were dried over magnesium sulphate. After concentration in vacuo the residue was purified by flash column chromatography using 40% ethyl acetate/40-60 petroleum ether as eluant to give the title compound (15) (1.24 g, 82%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[O:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.O>O>[CH2:5]([OH:1])[CH2:4][CH2:3][CH2:2][OH:6].[CH2:9]1[CH2:10][O:6][CH2:7][CH2:8]1
Reactant: c1ccoc1
Solvent: O
Product: C1CCOC1
Product: OCCCCO

Procedure:
In carrying out the novel process, furan is reacted with water in general in a molar furan/water ratio of from 1:0.1 to 1:100, preferably from 1:0.2 to 1:50, particularly preferably from 1:1 to 1:10, to give 1,4-butanediol/THF. This is effected in the presence of hydrogen and a hydrogenation catalyst at in general 100 kPa-30 MPA (1-300 bar), preferably 500 kPa-20 MPa (5-200 bar), particularly preferably 1-15 MPa (10-150 bar), and at from 20 to 300° C., preferably from 40 to 230° C., particularly preferably from 80 to 200° C.
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:16]([NH:19][C@H:20]([CH2:24][OH:25])[C:21]([OH:23])=O)(=[O:18])[CH3:17].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:16]([NH:19][C@H:20]([CH2:24][OH:25])[C:21]([NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])(=[O:18])[CH3:17]
Reactant: CC(=O)N[C@H](CO)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Temperature: 32.5 °C
Reaction time: 0.5 h

Procedure:
4-methylmorpholine (7.3 ml) followed by isobutylchloroformate (12.35 ml) was added to a suspension of (R)-2-acetamido-3-hydroxypropanoic acid (7 grams) in tetrahydrofuran (147 ml) at −78 to −75° C., benzylamine (10.4 ml) was added to it and the reaction mixture temperature was raised to 30-35° C. then stirred for 30 minutes. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (35 ml) and washed with aqueous hydrochloric acid followed by sodium carbonate and then with water. The solvent from the methylene chloride layer was distilled off completely under reduced pressure to get the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.[CH3:18][O:19][C:20]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21].CCN(CC)CC>CC(O)C.O>[CH3:17][O:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:25]1[CH2:26][CH2:27][CH:22]([C:20]([O:19][CH3:18])=[O:21])[CH2:23][CH2:24]1)[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10]2
Reactant: COC(=O)C1CCNCC1
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)cc2c1
Solvent: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C1CCN(c2nc3ccc(OC)cc3cc2C(F)(F)F)CC1
Yield: 42.3 %

Procedure:
To a solution of 2-chloro-6-methoxy-3-(trifluoromethyl)quinoline (1.00 g, 3.85 mmol) (see Intermediate 6, Step 8 for synthesis) in IPA (5 mL) was added methyl-4-piperidinecarboxylate (5.50 g, 38.5 mmol) and Et3N (1.17 g, 11.6 mmol). The mixture was heated to reflux for 48 hours. The mixture was diluted with water (100 mL) and extracted with DCM (100 mL×3), the combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (PE/EtOAc=15/1) to give the product (600 mg, yield 43%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[Li]CCCC.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:30][CH3:31])=[C:24]([CH:29]=1)[C:25](OC)=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1.O>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:30][CH3:31])=[C:24]([C:25]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[O:26])[CH:29]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1OC
Reactant: Cc1cncs1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OCc2ccccc2)cc1C(=O)c1ncc(C)s1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 19.3 %

Procedure:
To a stirring mixture of 5-methylthiazole (3.80 g, 38.2 mmol) in dry THF (200 mL) was added n-BuLi (2.5 M in hexane, 15.3 mL, 38.2 mmol) drop wise over 20 minutes at −78° C. under nitrogen atmosphere. The mixture was stirred between −78° C. and −60° C. for 1.5 h and then cooled to −78° C. A solution of methyl 5-(benzyloxy)-2-methoxybenzoate (10.4 g, 38.2 mmol) in THF (50 mL) was added drop wise over 30 minutes. The resulting mixture was stirred at −78° C. for 30 minutes and warmed to room temperature with stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL). The resulting mixture was adjusted to pH around 6 with HCl (1N). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (3:1) to afford (5-(benzyloxy)-2-methoxyphenyl)(5-methylthiazol-2-yl)methanone (2.5 g, 19%) as a yellow gel. 3.0 g of starting material methyl 5-(benzyloxy)-2-methoxybenzoate was recovered.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].C(OC1C=C(C=C(OCC2C=CC=CC=2)C=1)CN)C1C=CC=CC=1>>[OH:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH2:1][NH2:2]
Reactant: N#Cc1cccc(C=O)c1
Agent: NCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Product: NCc1cccc(CO)c1
Yield: 66 %

Procedure:
This compound was prepared by reduction of 3-cyanobenzaldehyde according to the procedure described in preparation of 3,5-dibenzyloxybenzylamine. Yield was 66%: 1H NMR (Acetone-d6, 500 MHz) δ7.32 (s, 1H), 7.23 (dd, 1H, J=7.6 and 7.0), 7.19, complex, 2H), 4.59 (s, 2H), 4.40 (s, 2H), 4.10 (br, 1H), 1.96 (br, 1H), 1.88 (br, 1H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[BrH:19].N([O-])=O.[Na+]>>[Br:19][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Br
Reactant: COC(=O)c1cc(N)cc(N2CCCC2=O)c1F
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)cc(N2CCCC2=O)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
To a solution of methyl 5-amino-2-fluoro-3-(2-oxo-1-pyrrolidinyl)benzoate (D150) (650 mg, 2.6 mmol, 1 equiv) in a 48% aqueous HBr solution at 0° C. was added NaNO2 portionwise and the resulting mixture was stirred at 0° C. for 30 min. CuBr (260 mg, 1.82 mmol, 0.7 equiv) in a 48% aqueous HBr solution (1 ml) was added and the resulting mixture stirred at 90° C. for 1 h then cooled to room temperature and partitioned between H2O and AcOEt. The two layers were separated and the organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 2/1) gave methyl 5-bromo-2-fluoro-3-(2-oxo-1-pyrrolidinyl)benzoate (D156) (145 mg, 18%) as a white solid. [M+H]+=318.1, RT=2.51 min.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7](OS(C(F)(F)F)(=O)=O)=[CH:8][C:9]=2[S:11]([CH3:13])=[O:12])[S:4][C:3]=1[C:22](=[O:24])[NH2:23].[O:25]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1>CN(C=O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:32]3[CH2:33][CH2:34][C:29]4([O:28][CH2:27][CH2:26][O:25]4)[CH2:30][CH2:31]3)=[CH:8][C:9]=2[S:11]([CH3:13])=[O:12])[S:4][C:3]=1[C:22]([NH2:23])=[O:24]
Reactant: CS(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2sc(C(N)=O)c(N)c12
Reactant: C1CC2(CCN1)OCCO2
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)c1cc(N2CCC3(CC2)OCCO3)nc2sc(C(N)=O)c(N)c12
Temperature: 70 °C
Yield: 42.4 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-amino-2-carbamoyl-4-methanesulfinyl-thieno[2,3-b]pyridin-6-yl ester (3.00 g, 7.44 mmol) in DMF (100 mL) was added 1,4-dioxa-8-azaspiro[4,5]-decane (2.20 g, 15.4 mmol). The mixture was heated to 70° C. for 1 h. The mixture was cooled to room temperature, diluted with H2O, and washed with CH2Cl2. The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 1.25 g (42.2%) of 3-amino-6-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methanesulfinyl-thieno[2,3-b]pyridine-2-carboxylic acid amide as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)(=[O:4])=[O:3].[H-].[Na+].I[CH2:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH2:20]([N:5]([CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCI
Reactant: CS(=O)(=O)NC1CCCOc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(C1CCCOc2ccccc21)S(C)(=O)=O

Procedure:
1.0 g of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine (Example 8a) were reacted with sodium hydride and iodobutane in DMF analogously to Example 11. After recrystallization of the crude product (1.0 g) from isopropanol, 0.4 g of 5-(N-butyl-N-methylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 78-79° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:10]1([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:17]=3[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:10]1([N:14]2[CH2:15][CH2:16][C:17]3[CH:24]=[CH:23][C:22]([O:25][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:21][C:18]=3[CH2:19][CH2:20]2)[CH2:13][CH2:12][CH2:11]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCOc1ccc2c(c1)CCN(C1CCC1)CC2
Temperature: 25 °C

Procedure:
Ethyl 4-bromobutyrate (2 ml, 13.8 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (2.00 g, 9.2 mmol) and potassium carbonate (3.8 g, 27.6 mmol) in 2-butanone (50 ml). After stirring at reflux for 24 hours, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography eluting with a mixture of methanol:dichloromethane (5:95) to afford the title compound (E167a). MS (ES+) m/e 332 [M+H]+
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH3:17])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.CCCCN1C=[N+](C)C=C1>[Zn]>[CH3:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][C:15]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: Cc1cccc(C)c1
Reactant: O=C(O)c1ccccc1
Agent: CCCCn1cc[n+](C)c1
Agent: [Zn]
Product: Cc1ccc(C(=O)c2ccccc2)c(C)c1
Temperature: 25 °C

Procedure:
Benzoic acid (0.31 g, 2.5 mmol), m-xylene (0.53 g, 5.0 mmol), [bmim] [NTf2] (0.50 g) and M(NTf2)2 (M=Co (0.14 g, 0.25 mmol), or Zn (0.15 g, 0.25 mmol) were placed in flasks equipped with stirrers and condensers. The contents of the flask were heated under reflux (ca 140-150° C.) for 2 days, then cooled to room temperature. The products were analysed by gas chromatographic analysis and found to give 93 and 87% conversions (for Co and Zn bis-triflimide reactions respectively) to 2,4-dimethylbenzophenone and, it is believed to be, 2,6-dimethylbenzophenone (11:1 isomer ratio in both cases). The results show that Zinc and cobalt bis-triflimide have been found to catalyse the benzoylation of m-xylene with benzoic acid. The reaction is slower that the corresponding reaction with benzoyl chloride. The catalyst was recycled and the reaction was repeated. The results of the repeat experiment are shown in Table 4.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[CH2:23]/[CH:24]=[C:25](\[CH3:34])/[CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>O.CCCCC>[N:1]([CH2:23]/[CH:24]=[C:25](\[CH3:34])/[CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C/C(=C\CCl)COC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCC
Product: C/C(=C\CN=[N+]=[N-])COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A solution of 11.43 g (175.86 mmol) of sodium azide (NaN3) and 2.20 g (6.45 mmol) of tetrabutylammonium hydrogenosulfate in 60 ml of water was added to a solution of 12.0 g (58.62 mmol) of (E)-2-(4-Chloro-2-methylbut-2-en yloxy)tetrahydro-2H-pyran in 300 ml of pentane. The reaction mixture was stirred at room temperature overnight. The organic phase was separated and the aqueous phase was extracted with 3×150 ml of Et2O. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give 11.21 g (53.06 mmol, 90% yield) of a mixture of azides isomers. No purification was done as infeasible separation was observed on silica gel. The product was used without further purification for the next step.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3]>C(OCC)(=O)C.[Pt]=O>[CH3:8][C@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:9][CH:10]=[O:11]
Reactant: CC(C)=CCC[C@@H](C)CC=O
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)CCC[C@@H](C)CC=O
Temperature: 25 °C
Reaction time: 124 h

Procedure:
A 3 L indented flask equipped with a mechanical stirrer and a H2 inlet was charged with 205.7 g (1.333 mol) of (R)-citronellal in 7.4L of ethyl acetate. The flask was flushed with 0.1 cu. ft. of H2 and 0.50 g (2.0 mmol) of platinum oxide were added. The reaction was stirred under a slight over-pressure of H2 at ambient temperature for 124 hours. During this time, due to relatively rapid deactivation of the catalyst, an additional 3.50 g (143 mmol.) of platinum oxide had to be added in 5 portions (0.5 g at 3.5 hours, 0.5 g at 22.5 hours, 1.0 g at 96.5 hours and 0.5 g at 121 hours). The course of the hydrogenation was monitored by GC analysis. After 124 hours, GC indicated the hydrogenation to be almost complete with 1.4% of starting material remaining. A total of 1.133 cu. ft. of hydrogen (theoretically 1.166 cu. ft.) had been consumed. The catalyst was removed by filtration through a pad of Celite (diatomaceous earth). The clear filtrate was combined with the filtrate from a previously run, analogous reduction of 10.0 g (64.8 mmol) of (R)-citronellal and concentrated on the rotovapor. Vacuum distillation of the obtained pale yellow liquid through a 30 cm Goodloe column afforded the (R)-3,7-dimethyloctanal in following fractions:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[C:7]([NH:8][S:10]([CH3:9])(=[O:12])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccnc1Cl
Reaction time: 48 h
Yield: 93.7 %

Procedure:
2-Chloro-pyridin-3-ylamine (1.00 g, 7.75 mmol) in dichloromethane (20 mL) at 23° C. was treated with methane sulfonyl chloride (2.23 g, 19.4 mmol) and triethylamine (1.96 g, 19.4 mmol). After stirring for 48 hours, the reaction mixture was diluted with water, the layers were separated, and the aqueous phase was extracted with dichloromethane (2×). The organic layers were combined, dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (20% ethyl acetate:hexanes), concentrated under reduced pressure, and added to a 10% aqueous sodium hydroxide solution (32 mL). The solution was stirred vigorously for about 0.5 hours until homogeneous. The solution was then neutralized to pH ˜7 with 2N HCl, saturated with Na2SO4, and extracted with ethyl acetate (3×). The combined extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 1.5 g (93% yield) of the title compound. References: Tetrahedron Letters 38, 26, 4667–4670, 1997; Eur. J. Org. Chem. 2000, 1263–1270. 1H NMR (300 MHz, DMSO-d6) δ 3.12 (s, 3H), 7.46 (dd, J=4.5, 8.4 Hz, 1H), 7.89 (dd, J=1.5, 8.4 Hz, 1H), 8.27 (dd, J=1.5, 4.5 Hz, 1H), 9.72 (bs, 1H); MS (ESI) m/e 205 (M)−.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:13](Cl)(=[O:16])[CH:14]=[CH2:15]>C(Cl)Cl.O>[N:1]1([C:13](=[O:16])[CH:14]=[CH2:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(=O)Cl
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)N1CCCC1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
To a stirred solution of pyrrolidine (2 g, 28.16 mmol) in anhydrous DCM (30 ml) was added triethylamine (15.56 ml, 111.88 mmol) and acryloyl chloride (3.04 g, 33.77 mmol) at 0° C. The reaction mixture was stirred at 20-35° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers was washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get the desired compound as a brown liquid (1.1 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ 6.49-6.33 (m, 2H), 5.66 (dd, J=9.8, 2.4 Hz, 1H), 3.54 (dt, J=6.8, 3.9 Hz, 4H), 2.02-1.91 (m, 2H), 1.90-1.82 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH:38]([CH2:48][CH3:49])[C:39]([C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)=[O:40].O>O1CCCC1.CN(C)C=O>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([C:39]([CH:38]([N:23]2[C:22](=[O:26])[N:21]([C:18]3[CH:17]=[N:16][C:15]([N:12]4[CH2:11][CH2:10][N:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[CH2:14][CH2:13]4)=[N:20][CH:19]=3)[CH:25]=[N:24]2)[CH2:48][CH3:49])=[O:40])=[CH:46][CH:45]=1
Reactant: CCC(Br)C(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(N2CCN(c3ncc(-n4cn[nH]c4=O)cn3)CC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C(=O)c1ccc(Cl)cc1)n1ncn(-c2cnc(N3CCN(c4ccc(OC)cc4)CC3)nc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
2,4-Dihydro-4-[2-[4-(4-methoxyphenyl)-1-piperazinyl]-5-pyrimidinyl]-3H-1,2,4-triazol-3-one (0.019 mol) and N,N-dimethylformamide (200 ml) were stirred. A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1M) (21 ml) was added dropwise under N2 and the mixture was stirred for 30 minutes at room temperature. 2-Bromo-1-(4-chlorophenyl)-1-butanone (0.021 mol) dissolved in a little N,N-dimethylformamide was added dropwise and the mixture was stirred for 3 hours at room temperature. The mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water, dried and evaporated. The residue was crystallized from 1-propanol. The precipitate was faltered off and dried in vacuo at 75° C., yielding 6 g (60%) of (±)-2-[1 -(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[2-[4-(4-methoxyphenyl)-1-piperazinyl]-5-pyrimidinyl]-3H-1,2,4-triazol-3-one; mp. 184.6° C. (comp. 8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][CH2:7][N:8]([CH3:25])[CH2:9][CH2:10][CH2:11][CH:12]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)[C:13]#[N:14].[NH2-].[Na+].[CH:31](Br)([CH3:33])[CH3:32].O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][CH2:7][N:8]([CH3:25])[CH2:9][CH2:10][CH2:11][C:12]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)([CH:31]([CH3:33])[CH3:32])[C:13]#[N:14]
Reactant: COc1cccc(CCN(C)CCCC(C#N)c2cc(OC)cc(OC)c2)c1
Reactant: CC(C)Br
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(CCN(C)CCCC(C#N)(c2cc(OC)cc(OC)c2)C(C)C)c1
Reaction time: 2 h
Yield: 110.5 %

Procedure:
38.3 g (0.1 mole) of 5-[(3-methoxyphenethyl)-methylamino]-2-(3,5-dimethoxyphenyl)-valeronitrile were dissolved in 200 ml of toluene, and the stirred solution was refluxed with 4.7 g (0.12 mole) of powdered sodium amide for 1 hour. Thereafter, a solution of 15.7 g (0.12 mole) of isopropylbromide in 30 ml of toluene was added dropwise in the course of 60 minutes, and refluxing was continued for a further 2 hours. The cooled reaction mixture was poured into water, the toluene phase was washed several times with water and the toluene was then distilled off. The residue was dissolved in 100 ml of isopropanol, and ethanolic hydrochloric acid was added. The hydrochloride was recrystallized from isopropanol. 46.9 g (92%) of a hydrochloride of melting point 141°-143° C. were isolated.