Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:12]=1)=O)(C)(C)C.[ClH:30]>>[ClH:30].[ClH:30].[CH3:16][N:15]1[C:11]([CH2:10][CH2:9][NH2:8])=[N:12][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:14]1
Reactant: Cn1nc(-c2cccnc2)nc1CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Product: Cn1nc(-c2cccnc2)nc1CCN
Reaction time: 1 h
Yield: 103.6 %

Procedure:
5-[2-Bis(tert-butoxycarbonyl)aminoethyl]-1-methyl-3-pyridin-3-yl-[1,2,4]triazole (133 mg, 330 μmol) was suspended in hydrochloric acid (4M solution in dioxane, 2 mL, 8.00 mmol) and the mixture was stirred at r. t. for 1 h. The reaction mixture was evaporated and dried to give the product as colorless solid (118 mg, 342 μmol, 104%) which was used without any further purification for the next step. MS: M=204.2 (M+H)+
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][OH:13])=[CH:10][O:9][C:8]=2[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O1CCCC1>[C:28]([O:13][CH2:12][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([Si:14]([CH2:17][CH3:18])([CH2:19][CH3:20])[CH2:15][CH3:16])[O:9][CH:10]=1)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CC[Si](CC)(CC)c1occ(CO)c1-c1ccccc1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OCc1coc([Si](CC)(CC)CC)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-phenyl-2-triethylsilyl-4-furanmethanol (345 mg, 1.20 mmol) and triethylamine (182 mg, 1.80 mmol) in tetrahydrofuran (15 ml) at 0 degrees under argon was added lauroyl chloride (786 mg, 3.60 mmol). This solution was allowed to warm gradually to room temperature. After stirring an additional 2 hours the white precipitate was filtered off. The filtrate was taken up into ethyl ether, washed with saturated ammonium chloride, saturated sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 2% ethyl ether/hexanes to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=O.Cl.[CH2:10]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])[CH:11]([CH3:13])[CH3:12]>>[CH2:10]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH:17][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][CH3:8])[CH:11]([CH3:13])[CH3:12]
Reactant: CCC(C)CC(=O)O
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CCC(C)CC(=O)N[C@@H](C)C(=O)OCC(C)C

Procedure:
Following General Procedure B and using 3-methylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][OH:12])[N:5]=1)(=[O:3])[CH3:2].[CH3:13]I.[H-].[Na+]>COCCOC.[Ag]=O>[C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][O:12][CH3:13])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)c1cc(C)n(CCO)n1
Agent: O=[Ag]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COCCn1nc(C(C)=O)cc1C
Reaction time: 2 h
Yield: 22 %

Procedure:
3-Acetyl-1-(2-hydroxyethyl)-5-methylpyrazole (0.63 g, 3.77 mM) in ethylene glycol dimethyl ether (10 ml) was treated with silver oxide (0.87 g, 3.77 mM) and methyl iodide (0.28 ml, 4.5mM). Sodium hydride (0.17 g 60% dispersion in oil, 4.14 mM) was added and the mixture stirred for 2 h, then filtered through celite and evaporated. Purification on silica gel eluting with ethyl acetate gave the title compound (0.157 g, 22%); νmax 1681 cm-1 ; δH (CDCl3) 2.32 (3H, s), 2.50 (3H, s), 3.30 (3H, s), 3.78 (2H, t, J5.4 Hz), 4.25 (2H, t, J5.4 Hz), and 6.51 (1H, s); EI m/e 182 (65%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][N:7]1[CH:12]=[CH:11][N:10]2[CH:13]=[C:14]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:15](=[O:18])[C:16]([OH:17])=[C:9]2[C:8]1=[O:24].C(Cl)(Cl)Cl.[C:32](Cl)(=[O:34])[CH3:33].S([O-])(O)(=O)=O.[K+]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][N:7]1[CH:12]=[CH:11][N:10]2[CH:13]=[C:14]([N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:32](=[O:34])[CH3:33])[C:15](=[O:18])[C:16]([OH:17])=[C:9]2[C:8]1=[O:24]
Reactant: CC(C)CNc1cn2ccn(Cc3cccc(Cl)c3)c(=O)c2c(O)c1=O
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N(CC(C)C)c1cn2ccn(Cc3cccc(Cl)c3)c(=O)c2c(O)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(3-Chlorobenzyl)-9-hydroxy-7-isobutylamino-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (23 mg) was added to chloroform (2 ml), and pyridine (0.062 ml) and acetyl chloride (0.024 ml) were successively added at 0° C. The mixture was stirred at room temperature for 2 hr. 5% Aqueous potassium hydrogen sulfate solution was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated and the obtained residue was dissolved in tetrahydrofuran (0.5 ml)-methanol (0.1 ml), and 1N aqueous sodium hydroxide solution (0.084 ml) was added. The mixture was stirred at room temperature for 30 min. 2N Aqueous hydrochloric acid (0.056 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried and concentrated. Crystallization from ethyl acetate-diisopropyl ether gave N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-N-isobutylacetamide (18.2 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[C:18]([C:20]#[N:21])[N:19]=2)=[O:14])=[C:8]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)[CH:7]=1)[CH2:4][NH2:5].CS[C:38](SC)=[N:39][C:40]#[N:41]>C(Cl)Cl>[C:40]([N:39]=[C:38]1[NH:1][CH2:2][CH:3]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]3[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[CH:17]=[C:18]([C:20]#[N:21])[N:19]=3)=[O:14])=[C:8]([C:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=3)[CH:7]=2)[CH2:4][NH:5]1)#[N:41]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CN)CN)cc1C1=CCCCC1
Reactant: CSC(=NC#N)SC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNC(=NC#N)NC2)cc1C1=CCCCC1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-(2-amino-1-aminomethyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide (as prepared in the previous step, 15 mg, 0.030 mmol) in DCM (10 mL), dimethyl N-cyanodithioiminocarbonate (4.2 mg, 0.28 mmol) was added. The resulting solution was heated at reflux for 4 h. The reaction mixture was allowed to cool to RT and was concentrated in vacuo. The residue obtained was purified on silica (20-100% EtOAc-hexane) to obtain the title compound (11 mg, 62%): Mass spectrum (ESI, m/z): Calcd. for C28H36N8O2Si, 545.3 (M+H). found 545.1.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4][C:3]2[CH:10]=[CH:11][C:12]3[C:17]([C:2]1=2)=[CH:16][CH:15]=[CH:14][CH:13]=3.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>>[O:1]1[CH:6]([C:7]([O:9][CH2:23][CH3:24])=[O:8])[CH2:5][CH2:4][C:3]2[CH:10]=[CH:11][C:12]3[C:17]([C:2]1=2)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CCO
Reactant: O=C(O)C1CCc2ccc3ccccc3c2O1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2ccc3ccccc3c2O1
Yield: 63.5 %

Procedure:
A mixture of intermediate (9-a) (7 g), ethanol (160 ml) and sulfuric acid was stirred and refluxed for 1 hour. The reaction mixture was evaporated and the oily residue was taken up in water. After treating with sodium hydroxide, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 5 g (63.5%) of ethyl 3,4dihydro-2H-naphto[1,2-b]pyran-2-carboxylate (interm. 10-a).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:10]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=Cc1ccccc1Br
Reactant: C#CCCCCCCCCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC#Cc1ccccc1C=O
Temperature: 105 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
Palladium acetate (96 mg) was added to a deaerated mixture of 2-bromobenzaldehyde (7.40 g, 40 mmol), 1-tridecyne (12.2 g, 68 mmol) and triphenylphosphine (320 mg) in dry triethylamine (160 ml) and the mixture was stirred at 105° C. under a nitrogen atmosphere overnight. After cooling, the precipitated triethylamine hydrobromide was filtered off and the filtrate was evaporated to a crude red oil. Chromatography on silica gel eluting with dichloromethane:petroleum ether [bp 60°-80° C.](1:1) afforded 7.12 g (63%) of the title compound of bp0.05 212° C. (Kugelrohr), M+ 284.2141 (C20H28O requires; 284.2140).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:25][NH:26][O:27][CH3:28].CN1CCOCC1>C(Cl)Cl>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([N:26]([O:27][CH3:28])[CH3:25])=[O:17])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)Cc1ccc(OC2CCCCC2)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (4-cyclohexyloxy-phenyl)-acetic acid (181 mmol, 42.4 g) in anhydrous DCM (200 mL) at 0° C. was added oxalyl chloride (362 mmol, 36.6 mL) and continued stirring for 12 h during which time the reaction mixture slowly attained room temperature. The reaction mixture was concentrated in vacuo to remove volatile impurities and dried under high vacuum. To a stirred solution of N,O-dimethylhydroxylamine hydrochloride (226 mmol, 22.1 g) and N-methylmorpholine (407 mmol, 44.8 mL) in anhydrous DCM (200 mL) at 0° C. was added the acid chloride obtained above, dissolved in DCM (50 mL) dropwise. The reaction mixture was stirred for 12 h allowing it to slowly attain room temperature. The reaction mixture was washed with water (2×200 mL), brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified on a 330 g SiO2 cartridge with 20-30% ethyl acetate in hexanes to provide 2-(4-cyclohexyloxy-phenyl)-N-methoxy-N-methyl-acetamide.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:17]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19]C1>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:22]([CH:17]3[CH2:19][CH2:20][CH2:21]3)=[O:23])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: O=C(Cl)C1CCCC1
Product: CCC(NC(=O)C1CCC1)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 200 mg (0.90 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 120 mg (0.90 mmol) cyclopentanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:5]=1[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:5]=1[C:6]([N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)=[O:7]
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(=O)N2CCOCC2)c(N)c1
Yield: 94.5 %

Procedure:
A two liter autoclave was charged with 130.6 g of N-(2,4-dinitrobenzoyl)-morpholine, 1200 ml methanol and 6.2 g of a 5% palladium on carbon/50% water catalyst. The mixture was hydrogenated at 800 psi while maintaining the temperature between 60°-100° C. Hydrogen uptake ceased after 30 min. The mixture was cooled, filtered and methanol removed at reduced pressure. The residue was crystallized from toluene to yield 97.1 g of N-(2,4-diaminobenzoyl)morpholine, mp 114°-115° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:15][CH3:16])=[N:4][N:5]([CH2:10][CH2:11][O:12][CH2:13][CH3:14])[C:6]=1[C:7]([NH2:9])=[O:8].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>CN(C)C=O>[CH2:13]([O:12][CH2:11][CH2:10][N:5]1[C:6]2[C:7](=[O:8])[NH:9][C:17](=[O:18])[NH:1][C:2]=2[C:3]([CH2:15][CH3:16])=[N:4]1)[CH3:14]
Reactant: CCOCCn1nc(CC)c(N)c1C(N)=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCOCCn1nc(CC)c2[nH]c(=O)[nH]c(=O)c21
Temperature: 80 °C
Yield: 38.2 %

Procedure:
A mixture of 4-amino-1-(2-ethoxyethyl)-3-ethyl-1H-pyrazole-5-carboxamide from step 2 (2.44 g, 10.8 mmol) in N,N-dimethylformamide (40 mL) was treated with carbonyldiimidazole (1.92 g, 11.9 mmol) and heated at 80° C. overnight. The mixture was concentrated in vacuuo and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane as the eluent to provide 1.04 g of the title compound. MS (ESI) m/z 253.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C:16](=O)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:38](Br)([F:40])[F:39]>CN(C)C(=O)C>[C:4]([Si:1]([O:8][C@@H:9]1[CH2:10][O:11][C@@H:12]2[C:16](=[C:38]([F:40])[F:39])[CH2:15][O:14][C@H:13]12)([CH3:2])[CH3:3])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(=O)CO[C@@H]21
Reactant: FC(F)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(=C(F)F)CO[C@@H]21

Procedure:
Alternatively, ketone (87) may be treated with triphenylphosphine and dibromodifluoromethane in N,N-dimethylacetamide to give tert-butyl((3R,3aS,6aR)-6-(difluoromethylene)hexahydrofuro[3,2-b]furan-3-yloxy)dimethylsilane (97) as detailed in Scheme 8.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=[C:30]([CH3:38])[C:15]=1[C:16]([C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][N:21]=[CH:20][C:19]=1[O:28][CH3:29])=[O:17]>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=[C:30]([CH3:38])[C:15]=1[C:16]([C:18]1[C:23]([C:24]([F:27])([F:25])[F:26])=[CH:22][N+:21]([O-:9])=[CH:20][C:19]=1[O:28][CH3:29])=[O:17]
Reactant: COc1cc(C)c(C(=O)c2c(OC)cncc2C(F)(F)F)c(OC)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(C)c(C(=O)c2c(OC)c[n+]([O-])cc2C(F)(F)F)c(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
6.1 g (28 mmol) of m-chloroperbenzoic acid (m-CPBA) was added to a chloroform 100 ml solution of 5.6 g (15 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-methoxy-5-trifluoromethylpyridine (compound No. 122) at 0° C., followed by stirring at room temperature for 18 hours. The reaction solution was washed with an aqueous sodium hydroxide solution, and the solvent was distilled off under reduced pressure to obtain 5.8 g (yield 99%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-methoxy-5-trifluoromethylpyridine-N-oxide (m.p. 128-134° C.).
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13])C.Cl.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][NH2:40])=[CH:35][CH:34]=1)#[N:32].O>CN(C)C=O>[CH3:25][N:9]1[C:8](=[O:26])[C:7]([C:6]2[N:39]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[N:40]=[CH:4][CH:5]=2)=[C:12]([CH3:13])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:10]1=[O:24]
Reactant: N#Cc1ccc(NN)cc1
Reactant: CCOC(C#Cc1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1=O)OCC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 5-(3,3-diethoxyprop-1-ynyl)-3,6-dimethyl-1-(3-trifluoromethylphenyl)-pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 61) and 4-cyanophenylhydrazine hydrochloride (27.9 mg) in N,N-dimethy formamide (2.0 ml) was stirred at 130° C. for seven hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with water (10 ml×2) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (17.9 mg).
Reaction SMILES: CO[C:3](OC)([N:5]([CH3:7])[CH3:6])[CH3:4].[C:10]([O:14][C:15](=[O:22])[NH:16][CH2:17][CH2:18][C:19](=[S:21])[NH2:20])([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[C:10]([O:14][C:15](=[O:22])[NH:16][CH2:17][CH2:18][C:19](=[S:21])[N:20]=[C:3]([N:5]([CH3:7])[CH3:6])[CH3:4])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCC(N)=S
Reactant: COC(C)(OC)N(C)C
Solvent: ClCCl
Product: CC(=NC(=S)CCNC(=O)OC(C)(C)C)N(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dimethylacetamide dimethylacetal (1.56 g, 11.7 mmol) is added to a stirred solution of (2-thiocarbamoyl-ethyl)-carbamic acid tert-butyl ester (1.0 g, 4.9 mmol) in DCM (50 ml). The reaction is stirred for 24 hours at room temperature followed by removal of the solvent. The residue is purified by chromatography on silica, eluting with ethyl acetate-diethyl ether (1:1) to give the titled compound as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=O)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH2:28][CH:29]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH2:1]([N:8]1[C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:29][CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1cncn1Cc1ccccc1
Reactant: O=CCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(C(=CCc2ccccc2)c2cncn2Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Titanium tetrachloride (0,03 mol) is added dropwise to a stirred suspension of zinc powder (0,06 mol) in tetrahydrofuran (30 ml) at -10° C. under dry nitrogen. The mixture is heated to reflux and refluxing is continued for 1 hour. The solution is cooled to 0° C. and 1-benzyl-5-[1-(4-fluorophenyl)-1-oxomethyl]-1H-imidazole (0,005 mol) in tetrahydrofuran (10 ml) and phenylacetaldehyde (0,006 mol) in tetrahydrofuran (10 ml) are added into the mixture, respectively. The mixture is refluxed with stirring for 1 hour. The dark mixture is poured into water (60 ml), tetrahydrofuran is evaporated and the mixture is extracted with methylene chloride (2×100 ml). The methylene chloride solution is washed with 2N sodium hydroxide and water, dried with sodium sulphate and evaporated to dryness. The residue is purified by flash chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:26][C:25]([F:27])([F:28])[C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)=[CH:19][CH:20]=1)([OH:33])[C:29]([F:30])([F:32])[F:31]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Yield: 89.5 %

Procedure:
A mixture of 1-(4-nitrophenyl)piperazine (19.30 mmol, 4 g), 2-(4-(bromomethyl)-phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (19.30 mmol, 6.51 g) and potassium carbonate (19.30 mmol, 2.67 g) in acetonitrile (10 mL) was refluxed for 20 hours and was then concentrated under reduced pressure. Dichloromethane was added and the insolubles were filtered off. The filtrate was chromatographed on silica eluting with a gradient of dichloromethane to dichloromethane/ethyl acetate (10%) to give the title compound (8 g).
Reaction SMILES: Cl[C:2]1[C:3]([C:15]#[N:16])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:8])[N:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[C:3]([C:15]#[N:16])=[N:4][C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[C:6]([CH3:8])[N:7]=3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cc1nc(Cl)c(C#N)nc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(c3ccc(F)cc3)CC2)c(C#N)nc1-c1ccccc1

Procedure:
In analogy to the procedure described in example 75a-c, 1-phenyl-1,2-propanedione and 2-aminomalonamide were heated in an aqueous solution to give 5-methyl-3-oxo-6-phenyl-3,4-dihydro-pyrazine-2-carboxylic acid amide. Then, the 5-methyl-3-oxo-6-phenyl-3,4-dihydro-pyrazine-2-carboxylic acid amide was treated with triethylamine and phosphorus pentachloride in phosphorus oxychloride at reflux to give 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile. The 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile was finally treated with 1-(4-fluorophenyl)piperazine and N-ethyldiiso-propyl-amine in N,N-dimethylformamide at room temperature to yield the 4-(4-fluoro-phenyl)-6′-methyl-5′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-carbonitrile as yellow solid; m.p. 117-120° C.; MS: 374 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:31])[C@@H:12]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][O:14]CC1C=CC=CC=1)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.C(O)C.[Pd]>[CH3:9][C:2]([NH:10][C:11](=[O:31])[C@@H:12]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][OH:14])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(NC(=O)[C@H](COCc1ccccc1)NC(=O)c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(NC(=O)[C@H](CO)NC(=O)c1ccccc1)c1ccccc1
Yield: 89.3 %

Procedure:
2.0 g of (2S)-N-(α,α-dimethylbenzyl)-2-benzoylamino-3-benzyloxypropionamide (prepared as described in Example 5) was catalytically reduced with hydrogen gas in the presence of 0.4 g of 10% w/w palladium-on-carbon in a mixture of 4 ml of acetic acid and 60 ml of ethanol. After completion of the reaction, the catalyst was filtered off and the solvent was distilled off. Recrystallization of the resulting residue from acetic acid and hexane gave 1.4 g of the title compound, melting at 152°-153° C.