Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][Cl:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:35].[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:30])[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])=[CH:27][CH:28]=2)=[CH:18][CH:17]=1
Reactant: CN(C)CCCl
Reactant: Cc1cccc2nc(CCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(CCc3ccc(C(=O)c4ccc(OCCN(C)C)cc4)cc3)n(C)c(=O)c12
Product: Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 35.4 %

Procedure:
To a solution of 3,5-dimethyl-2-[2-[4-(4-hydroxy-benzoyl)phenyl]ethyl]-4(3H)-quinazolinone (534 mg) in DMF (10 ml) were added 2-dimethylaminoethyl chloride (695 mg) and potassium carbonate (677 mg) and the mixture was stirred at 80° C. for 4 hours. This reaction mixture was concentrated and extracted with ethyl acetate. The organic layer was serially washed with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to 20 ml. To this organic solution was added 1N-hydrochloric acid (2 ml) and the mixture was extracted with water. The aqueous layer was diluted with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After concentration to 10 ml, 4N-hydrogen chloride/ethyl acetate (0.5 ml) was added, and the precipitate was collected by filtration, washed with water, and dried to provide 240 mg of white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]([O:12]CC)=O.Cl.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25]>C(O)(=O)C>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[C:10](=[O:12])[CH2:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:25]1
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Reactant: NNc1ccccc1F
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2F)=NN1c1ccccc1F
Temperature: 135 °C
Reaction time: 3 h

Procedure:
Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (2.5 g, 12 mmol) and 2-fluorophenyl hydrazine hydrochloride (1.5 g, 12 mmol, 1.0 equiv) were dissolved in acetic acid (24 mL) and placed into a preheated oil bath at 120° C. for 3 hours and then heated for an additional 2 hours at 135° C. The mixture was cooled to ambient temperature, concentrated in vacuo and then concentrated once from toluene (1×25 mL). The residue was suspended in dichloromethane, filtered and the solid was washed once with dichloromethane and dried in vacuo, providing the titled compound. The resulting filtrate was concentrated in vacuo and purified by silica gel gradient chromatography (100:0 to 65:35; hexanes:ethyl acetate), providing additional titled compound as a light brown solid.
Reaction SMILES: CS[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[O:10][N:9]=2)=[CH:5][CH:4]=1.Cl[C:29]1C=CC=C(C(OO)=O)C=1.[S:39](S([O-])=O)([O-:42])(=O)=[O:40].[Na+].[Na+]>ClCCl>[CH3:29][S:39]([C:3]1[CH:27]=[CH:26][C:6]([CH2:7][C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH2:14]3)[O:10][N:9]=2)=[CH:5][CH:4]=1)(=[O:42])=[O:40]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(Cc2noc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Cc3ccc(S(C)(=O)=O)cc3)no2)CC1
Reaction time: 1 h

Procedure:
tert-Butyl 4-{3-[4(methylthio)benzyl]-1,2,4-oxadiazol-5-yl}piperidine-1-carboxylate (3.10 g, 7.96 mmol) (Method E, step 1) was dissolved in dichloromethane(100 mL), at room temperature, under argon. 3-Chloroperbenzoic acid (60% wt, 6.87 g, 23.88 mmol) was added portionwise and stirred for 1 hour. Sodium metabisulfite (1M, 250 mL) was added and stirred and the organics separated and washed with 1N sodium hydroxide and brine, dried (MgSO4) and solvents evaporated to a clear oil which crystallised upon addition of diethyl ether (50 mL). The solid was filtered, washed with a minimum of diethyl ether and dried to give tert-butyl 4-{3-[4-(methylsulfonyl)benzyl]-1,2,4-oxadiazol-5-yl}piperidine-1-carboxylate as a white fluffy solid (2.61 g, 78% yield); NMR (CDCl3): 1.46 (9H, s), 1.61 (3H, s), 1.79 (2H, m), 2.04 (2H, m), 2.93 (2H, m), 3.04 (3H, s), 4.15 (2H, s), 7.53 (2H, d), 7.90 (2H, d).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[O:6][CH2:7][CH:8]([OH:11])[CH2:9][CH3:10].[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C.C(N(CC)CC)C.CCCCCC>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[O:6][CH2:7][CH:8]([O:11][C:25](=[O:26])[NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH3:10]
Reactant: CCC(O)COc1cccc(C(F)(F)F)c1
Reactant: O=C=NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCC(COc1cccc(C(F)(F)F)c1)OC(=O)NCc1ccccc1
Reaction time: 20 h

Procedure:
4.7 g of 1-(3-trifluoromethylphenoxy)-butan-2-ol and 2.7 g of benzyl isocyanate are dissolved in 60 ml of ethyl acetate. After addition of one drop of triethylamine, the reaction mixture is allowed to stand for 20 hours at 22° C. The solvent is stripped off and the residue is stirred in n-hexane. The desired crystalline product, O--[1-(3-trifluoromethylphenoxy)-2-butyl]-N-benzylcarbamate, is obtained in a yield of 5.2 g; m.p. 73°-74° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].[CH2:19]1COCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]1([C:7]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:8][C:9]([O:11][CH2:12][CH3:19])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C#Cc1ccccc1
Reactant: C1CCOC1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CCOC(=O)C=C(C#C[Si](C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of TDMPP (1.4 g) and palladium acetate (700 mg) in THF (200 ml) is stirred for 15 min at room temperature and methyl phenylpropiolate (10 g, 62.5 mmol) is then added. The reaction medium is stirred for 5 min at room temperature and trimethylsilylacetylene (87.5 mmol) is then added. Stirring is continued overnight at room temperature. The reaction medium is concentrated and filtered through silica.
Reaction SMILES: CS(C)=O.[CH3:5][NH:6][C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH2:27][CH3:28])[CH3:26])=[O:24])[O:22][C:18]=2[C:17](F)=[C:16]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:15]=1[CH3:36])#[N:13].C(N(CC)CC)C>[Cl-].[Na+].O>[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH2:27][CH3:28])[CH3:26])=[O:24])[O:22][C:18]=2[C:17]([N:9]2[CH2:10][CH2:11][C@H:7]([NH:6][CH3:5])[CH2:8]2)=[C:16]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:15]=1[CH3:36])#[N:13]
Reactant: CN[C@H]1CCNC1
Reactant: CCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](NC)C3)c2o1
Reaction time: 2.67 h
Yield: 32.2 %

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (1 ml) solution of (3S)-3-(methylamino)pyrrolidine (67 μl, 633 μmol) was added at 140 to 150° C. to a dimethyl sulfoxide (10 ml) solution of 4-cyano-N-ethyl-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-285) (178 mg, 528 μmol) and triethylamine (96 μl, 686 μmol), followed by stirring at the same temperature for 160 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under the reduced pressure. The resulting residue was purified by preparative TLC (eluent, dichloromethane:methanol=10:1, v/v) to obtain the entitled compound (71 mg, 32%) as an amorphous substance.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:9]#[N:10])([C:7]#[N:8])[CH2:3][CH2:2]1.[BH4-].[Na+]>CCO>[NH2:10][CH2:9][C:4]1([C:7]#[N:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: N#CC1(C#N)CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CC1(CN)CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
A mixture of dihydro-2H-pyran-4,4(3H)-dicarbonitrile (450 mg, 3.31 mmol)<autotext key=“0BD391A6” name=“[Reactants]” index=“1” field=“Reactants” type=“field” length=“34”/> and Sodium borohydride (375 mg, 9.92 mmol)<autotext key=“0BD391A7” name=“[Reactants]” index=“2” field=“Reactants” type=“field” length=“38”/> in EtOH (15 ml)<autotext key=“0BD391A8” name=“[Solvents]” index=“l” field=“Solvents” type=“field” length=“12”/> was stirred at ambient temperature for about 4 hours. The mixture was concentrated and the resulting residue was diluted with ethyl acetate, washed with water and dried. Concentration in vacuo afforded 388 mg of the crude product which was used directly in the next step. LCMS (m/z): 141.0 [M+H]+; Retention time=0.18 min.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:14])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].[SH:15][CH2:16][CH2:17]C(N1CCC[C@H]1C(O)=O)=O.[N+](=[CH2:30])=[N-]>>[CH3:30][O:9][C:8](=[O:10])[C@@H:7]1[CH2:11][CH2:12][CH2:13][N:6]1[C:4](=[O:5])[CH:3]([CH3:14])[CH2:2][S:1][S:15][CH2:16][CH3:17]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Reactant: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reactant: C=[N+]=[N-]
Product: CCSSCC(C)C(=O)N1CCC[C@H]1C(=O)OC

Procedure:
By substituting 1-(3-mercapto-2-methylpropanoyl)-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of Example 97 and then treating the product with ethereal diazomethane as in the procedure of Example 72, 1-[3-(ethyldithio)-2-methylpropanoyl]-L-proline methyl ester is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11](OC)[CH:10]=[C:9]2[C:4]=1[C:5](=[O:33])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]S(C)(=O)=O)[CH2:23][CH2:22]3)[N:16]=1)=[N:8]2.C(N1CCN([C:43]2N=[C:47]([CH:49]=O)[CH:46]=[CH:45][CH:44]=2)CC1)(C)C.[CH3:51]C1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CC(N(C)C)=O.C([O-])(O)=O.[Na+]>[CH:27]([N:24]1[CH2:23][CH2:22][N:21]([C:17]2[N:16]=[C:15]([C:7]3[NH:6][C:5](=[O:33])[C:4]4[C:9](=[CH:10][C:11]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:49]=5)=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:26][CH2:25]1)([CH3:51])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(CCS(C)(=O)=O)CC4)n3)nc2c1
Reactant: CC(C)N1CCN(c2cccc(C=O)n2)CC1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2ccccc2)cc2nc(-c3cccc(N4CCN(C(C)C)CC4)n3)[nH]c(=O)c12
Temperature: 120 °C
Yield: 18.7 %

Procedure:
A solution of 3-amino-5-methoxy-[1,1′-biphenyl]-4-carboxamide (5, 0.048 g, 0.2 mmol) and 6-(4-isopropylpiperazin-1-yl)picolinaldehyde (9, 0.046 g, 0.2 mmol) in DMA (2 mL) was treated with p-TsOH (0.084 g, 0.44 mmol) and NaHSO3 (0.042 g, 0.5 mmol) and then heated at 120° C. for 3 days. After this time, the reaction mixture was cooled to room temperature, diluted with saturated NaHCO3, extracted with CH2Cl2 (2×15 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-20% methanol in dichloromethane to afford the title compound (0.017 g, 19%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 11.16 (br s, 1H), 7.88-7.86 (m, 2H), 7.78-7.73 (m, 2H), 7.55-7.53 (m, 3H), 7.49-7.46 (m, 1H), 7.28-7.27 (m, 1H), 7.09-7.07 (m, 1H), 4.08 (s, 3H), 3.64 (br s, 4H), 2.60 (m, 1H), 2.46 (s, 4H), 0.98 (br s, 6H); ESI MS m/z 456 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]4[OH:25])[C:15]3=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1COCC1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[OH:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[N:14]1[CH2:13][C:12]2[C:16](=[CH:17][C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)=[CH:3][CH:4]=3)=[CH:10][CH:11]=2)[C:15]1=[O:18]
Reactant: O=C1c2cc(Cc3ccc(Cl)nc3)ccc2CN1[C@@H]1CCCC[C@H]1O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccc(Cc3ccc4c(c3)C(=O)N([C@@H]3CCCC[C@H]3O)C4)cn2)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a solution of rac-6-((6-chloropyridin-3-yl)methyl)-2-(trans-2-hydroxycyclohexyl)isoindolin-1-one (0.09 g) in a mixed solvent of THF (9.00 mL)-water (3.00 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.11 g), cesium carbonate (0.33 g) and bis(tri-tert-butylphosphine)palladium(0) (0.03 g), and the mixture was stirred overnight at 85° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (0.03 g).
Reaction SMILES: OC1C=CC(CC(CC2C=CC(O)=CC=2)=O)=CC=1.BrCCBr.BrCCC1C=C(C(=O)C)C=[CH:28][C:27]=1[O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][C:37]=1CCBr.[CH:48]([NH2:51])([CH3:50])[CH3:49]>>[C:42]([C:39]1[CH:38]=[CH:37][C:36]([O:35][CH2:27][CH2:28][NH:51][CH:48]([CH3:50])[CH3:49])=[CH:41][CH:40]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)c1ccc(Oc2ccc(C(C)=O)cc2CCBr)c(CCBr)c1
Reactant: CC(C)N
Agent: O=C(Cc1ccc(O)cc1)Cc1ccc(O)cc1
Solvent: BrCCBr
Product: CC(=O)c1ccc(OCCNC(C)C)cc1

Procedure:
4-Hydroxyphenylmethyl ketone is reacted with 1,2-dibromoethane in the presence of base. The product of that reaction, 2-bromoethyl-4-acetylphenyl ether is then reacted with isopropylamine as in Preparation 1 to give the title compound.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-].[Na+].[Na+].[CH3:7][O:8][CH2:9][C:10]1([N:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17](=[O:20])[CH2:18][CH3:19])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CC1C=CC(S(O[CH2:38][CH2:39][C:40]2[O:41][CH:42]=[CH:43][CH:44]=2)(=O)=[O:35])=CC=1>CC(C)CC(=O)C>[C:17]([OH:20])(=[O:35])[C:1]([OH:3])=[O:4].[O:41]1[CH:42]=[CH:43][CH:44]=[C:40]1[CH2:39][CH2:38][N:13]1[CH2:14][CH2:15][C:10]([N:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:17](=[O:20])[CH2:18][CH3:19])([CH2:9][O:8][CH3:7])[CH2:11][CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccco2)cc1
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2ccco2)CC1
Product: O=C(O)C(=O)O
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a stirred and refluxing mixture of 9.5 parts of sodium carbonate and 240 parts of 4-methyl-2-pentanone are added 8.3 parts of N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide and 9.6 parts of [2-(2-furanyl)ethyl] 4-methylbenzenesulfonate (water-separator). The whole is stirred and refluxed for 21 hours. The reaction mixture is cooled to room temperature and poured onto water. The organic phase is separated, washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 7% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the ethanedioate salt in 2-propanol. The salt is filtered off and crystallized from 2-propanol, yielding 5.4 parts (39.1%) of N-{1-[2-(2-furanyl)ethyl]-4-(methoxymethyl)-4-piperidinyl}-N-phenylpropanamide ethanedioate; mp. 178.6° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8](=S)[NH2:9])(C)C.O.[NH2:19]N.C[N:22]([CH:24]=O)C>C(O)=O>[CH3:1][O:4][C:5]1[CH:6]=[C:7]([C:8]2[N:22]=[CH:24][NH:19][N:9]=2)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1
Reactant: CN(C)C=O
Reactant: CC(C)Oc1cc(C(N)=S)cc(C(F)(F)F)c1
Reactant: NN
Solvent: O=CO
Solvent: O
Product: COc1cc(-c2nc[nH]n2)cc(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
3-Isopropoxy-5-(trifluoromethyl)benzothioamide (646 g; 2.74 moles) was combined with hydrazine hydrate (140 g; 4.4 moles) and DMF (3200 mL; 5V). The mixture was stirred for 30 minutes and cooled to 10° C. To this reaction mixture was added formic acid (3200 mL) dropwise. Reaction mixture was heated to 90 to 100° C. and maintained for 12 hrs. After reaction completion by HPLC, reaction mass was cooled to 25 to 30° C. and quenched with ice-cold water. The mixture was extracted in MTBE. The organic layer was washed with brine followed by aqueous sodium bicarbonate, and concentrated under vacuum. The residue was chased off using hexane, the resulting residue was slurried at 10° C. for 1 hour. The solid obtained was filtered and dried for 12 hours at 25 to 30° C. to yield 550 g (2.26 moles: 82%) of the product 3-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazole. HPLC purity—95.24% a/a.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5](OC)=[O:6].[NH3:16]>CN(C)C=O.C(OCC)(=O)C>[N+:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:3]2[C:4]=1[C:5](=[O:6])[NH:16][CH2:2]2)([O-:15])=[O:14]
Reactant: N
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1NCc2cccc([N+](=O)[O-])c21

Procedure:
1.5 g (5.473 mmol) methyl 2-bromomethyl-6-nitro-benzoate are dissolved in 20 ml N,N-dimethylformamide and combined with 15 ml of methanolic ammonia (7 mmol/ml). After 20 h at 25° C. the mixture is diluted with 100 ml of ethyl acetate and extracted 3 times with saturated sodium hydrogen carbonate solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: CCc1ccc(CBr)cc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: CCc1ccc(Cn2ccc(-c3nc(C)c(C(=O)NCc4cccnc4)s3)n2)cc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-bromomethyl-4-ethyl-benzene as described in Example 49 and isolated as a white solid (0.056 g, 42 (% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.52-8.58 (m, 1H), 7.72 (d, J=8 Hz, 1H), 7.06-7.48 (m, 6H), 6.80-6.84 (m, 1H), 6.08-6.15 (m, 1H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H), 2.61-2.70 (m, 2H), 1.13-1.26 (m, 3H); MS (M+H)+=418.2; Rt=1.38 min; HRMS (M+H)+=418.17.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH3:14][N:15](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:16].F[P-](F)(F)(F)(F)F.CNC.C(N(CC)CC)C>C1COCC1>[CH3:14][N:15]([CH3:16])[C:9]([C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)=[O:10]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N(C)C)cc1
Reaction time: 4 h
Yield: 82.5 %

Procedure:
To a soln. of 4-(methoxycarbonyl)benzoic acid (100 mg, 0.555 mmol) in THF (5 ml) was added HATU (211 mg, 0.555 mmol), dimethylamine (0.278 ml, 0.555 mmol) and triethylamine (0.077 ml, 0.555 mmol) at r.t. The mixture was stirred at r.t for 4 hrs. Evaporated to remove the solvent. The residue was dissolved in EtOAc (10 ml), washed w/water (3×), brine. Dried (Na2SO4), and evaporated to afford methyl 4-(dimethylcarbamoyl)benzoate (100 mg, 0.458 mmol, 83% yield) as solid. 1H-NMR (CD3OD, 500 MHz): δ 8.10 (1H, d, J=6.4 Hz), 7.55 (1H, d, J=6.4 Hz), 3.94 (3H, s), 3.13 (3H, s), 2.99 (3H, s). m/e (M+H): 208.1
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].CS(O[CH2:28][CH2:29][C:30]1[CH:34]=[CH:33][S:32][CH:31]=1)(=O)=O.O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:28][CH2:29][C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: CS(=O)(=O)OCCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(c2cn(CCc3ccsc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
Under inert atmosphere, a solution of 6.9 g (0.025 mol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester in 25 mL of anhydrous DMF was added dropwise to a suspension containing 1.2 g (0.030 mol) of sodium hydride (60% in mineral oil) in 70 mL of anhydrous DMF. After stirring at room temperature for 1 hour, a solution of 6.2 g (0.03 mol) of 2-thiophen-3-yl-ethyl methansulfonate in 15 mL of anhydrous DMF was added. The reaction mixture was stirred at room temperature for 30 minutes and then heated at 60° for 3 hours. The crude mixture was poured into water and extracted with dichloromethane. After drying, the solvent was removed under reduced pressure and 10.3 g of a crude oil were obtained. The crude mixture was purified by flash chromatography over silica gel affording 8.3 g (86% of yield) of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CO[CH:13](OC)[CH2:14][C:15](=O)[CH3:16]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:14][C:15]([CH3:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:15]([CH3:16])=[CH:14][CH:13]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(CC(C)=O)OC
Reactant: NNc1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CCO
Product: Cc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Product: Cc1ccnn1-c1ccc(Cl)c(Cl)c1
Yield: 29 %
Yield: 66 %

Procedure:
A solution of of 3,4-dichlorophenylhydrazine (4.27 g, 20.0 mmol) in EtOH (50 ml) and H2O (50 ml) was treated with 3-oxobutyraldehyde dimethyl acetal (2.64 g, 20.0 mmol) and refluxed for 1 h. The alcohol was removed in vacuo and the aqueous residue was extracted with AcOEt (2×150 ml). The organic phase was dried (Na2SO4), filtered and evaporated. The remaining oil was chromatographed [silica, elution with gradient hexane to 10% (hexane/AcOEt=1:1)] to obtain 3.01 g (66%) of 1-(3,4-dichloro-phenyl)-3-methyl-1H-pyrazole [Mp. 57-58° C. (AcOEt/hexane), MS: m/e=226 (M+)] as off-white crystals and 1.32 g (29%) of 1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazole [Mp. 46-47° C. (hexane), MS: m/e=226 (M+)] as white crystals.