Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[CH3:18][CH:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH3:18])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CC(C)CCN
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Product: CCN(CC)C(=O)c1ccc(NCCC(C)C)c([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 14 h
Yield: 103.5 %

Procedure:
Following general procedure 2B, N,N-diethyl-4-fluoro-3-nitrobenzamide (1.077 g, 4.48 mmol) and 3-methyl-1-butanamine (0.68 mL, 5.83 mmol) were stirred at 85° C. for 14 h to provide the title compound (1.425 g) as an orange oil. The crude product was used in subsequent steps. 1H-NMR (CD3OD): δ 8.22 (d, J=2.0 Hz, 1H), 7.56 (dd, J=9.2 Hz, J=2.0 Hz, 1H), 7.09 (d, J=9.2 Hz, 1H), 3.52–3.40 (br m, 6H), 1.83–1.72 (m, 1H), 1.64 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 6H), 1.01 (d, J=6.8 Hz, 6H). MS (ESI) (M+H)+=308.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([OH:14])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH2:28]([NH2:34])[CH:29]1[O:33][CH2:32][CH2:31][CH2:30]1.[Cl-].[NH4+]>CN(C=O)C.C1COCC1>[CH2:28]([NH:34][C:12]([C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:14])[CH:29]1[O:33][CH2:32][CH2:31][CH2:30]1
Reactant: NCC1CCCO1
Reactant: O=C(O)c1c[nH]c2ccccc2c1=O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCC1CCCO1)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C
Yield: 47.7 %

Procedure:
To a solution of 4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (95 mg, 0.5 mmol) in a 4:1 mixture of THF:DMF (2.5 mL) and triethylamine (146 μL, 1.05 mmol) at 0° C. is added ethyl chloroformate (98 μL, 1.03 mmol). The reaction mixture is allowed to stir for 1 h before tetrahydrofurfurylamine (155 μL, 1.5 mmol) is added. The reaction mixture is stirred for ¾ h and then allowed to warm to ambient temperature for 20 h. The mixture is subsequently poured into aqueous ammonium chloride, the THF is removed in vacuo, and the mixture is extracted with ethyl acetate. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is treated with 1N NaOH (2 mL) and ethanol (0.5 mL) at reflux for 1 h. The reaction mixture is cooled, diluted with aqueous ammonium chloride and extracted 2× with dichloromethane. The combined organic layers are dried (Na2SO4), filtered, and concentrated to give 65 mg of N-tetrahydrofurfuryl 4-oxo-1,4-dihydro-quinoline-3-carboxamide (compound 1) as a cream solid; m.p. 205-209° C.
Reaction SMILES: ClC1C=CC=CC=1C(N[C@H]1CCC[C@@H]1N[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)=O.Cl.[NH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[NH:34][C:35](=[O:45])[C:36]1[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[CH:38][C:37]=1[F:44].ClC1C=CC(C(F)(F)F)=CN=1>>[F:44][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:36]=1[C:35]([NH:34][C@H:30]1[CH2:31][CH2:32][CH2:33][C@@H:29]1[NH:28][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)=[O:45]
Reactant: COc1cccc(F)c1C(=O)N[C@H]1CCC[C@@H]1N
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ccccc1Cl
Agent: Cl
Agent: FC(F)(F)c1ccc(Cl)nc1
Product: COc1cccc(F)c1C(=O)N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1

Procedure:
Prepared according to the procedure for 2-chloro-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 69) from N-[(1S,2S)-2-aminocyclopentyl]-2-fluoro-6-methoxybenzamide hydrochloride (Intermediate 20; 50 mg, 0.17 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 38 mg, 0.21 mmol) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].[CH3:14][C@H:15]1[C@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:17][C:16]1=[O:29].O1CCC1=O.Cl.CCOCC>C(O)(C)C.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@H:15]([CH3:14])[C:16]([OH:29])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C[C@@H]1C(=O)O[C@H]1CCCCc1ccccc1
Reactant: COc1ccc(S)cc1OC
Agent: Cl
Agent: O=C1CCO1
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(S[C@H](CCCCc2ccccc2)[C@H](C)C(=O)O)cc1OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.3 %

Procedure:
A solution of 3,4-dimethoxybenzenethiol (0.33 g, 1.9 mmol) in isopropanol (3 mL) is cooled in an ice-bath and 1 M sodium hydroxide (1.4 mL, 1.4 mmol) is added over 2 minutes. (3S,4S)-3-Methyl-4-(4-phenylbutyl)oxetan-2-one (0.28 g, 1.3 mmol) is dissolved in isopropanol (3 mL) and cooled to 0° C. Then the thiolate is added to the oxetanone solution over 3 minutes. This mixture is stirred with ice cooling for 5 minutes and then allowed to come to room temperature and stir 3 hours. The reaction is then acidified to pH 5 with HCl/ether. Methanol is added and the reaction mixture azeotroped several times until a semi-solid residue is obtained. The crude product is purified by column chromatography (silica, 1% MeOH in CH2Cl2) to give (2R,3R)-3-(3,4-dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (0.35 g, 69%): 1H NMR (300 MHz, CDCl3) δ 7.28-7.23 (m, 2H), 7.19-7.11 (m, 3H), 7.04-6.97 (m, 2H), 6.76 (d, J=8.3 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.27-3.25 (m, 1H), 2.72-2.68 (m, 1H), 2.56 (t, J=7.1 Hz, 2H), 1.63-1.47 (m, 6H), 1.26 (d, J=7.1 Hz, 3H); MS (EI) m/e 389 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][N:17]=[C:16]4[C:19]5[C:24]([CH2:25][CH2:26][C:15]=34)=[CH:23][C:22]([CH2:27][OH:28])=[CH:21][CH:20]=5)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:28][CH2:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:16]1=[N:17][O:18][C:14]([CH:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[C:15]1[CH2:26][CH2:25]2)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc2c(c1)CCc1c-2noc1C1CCC(c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc2c(c1)CCc1c-2noc1C1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of the (3-(4-(4-chlorophenyl)cyclohexyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methanol (Preparation 27D, 0.046 g, 0.118 mmol) in dichloromethane (2.0 mL) at room temperature was added triethylamine (0.049 mL, 0.354 mmol) followed by methanesulfonyl chloride (0.014 mL, 0.177 mmol). The reaction mixture was stirred for 1 h at room temperature, concentrated under reduced pressure to yield (3-(4-(4-chlorophenyl)cyclohexyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl methanesulfonate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[N+:21]([O-])=O)[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)([O-])=O.CC(O)=O>C1COCC1.[Zn]>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([O:7][C:6]2[CH:5]=[C:4]([NH2:1])[C:20]([NH2:21])=[CH:19][CH:18]=2)=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3ccccc23)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccnc3ccccc23)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3,4-Dinitro-phenoxy)-quinoline (Step A, 400 mg, 1.2 mmol) was dissolved in THF at 0° C., and AcOH (1.5 mL) was added followed by zinc dust (2.5 g, 38 mmol). The mixture was stirred at RT for 1 h then filtered on a silica pad. The solvent was evaporated; the residue was dissolved in CH2Cl2 and washed with 1M NaOH. The organic phases were dried, filtered and evaporated to give the title compound, as a brown-orange oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH2:6]1.COCO[C@H]1CCN([C@@H](C2C=CC=CC=2)CO)C1.[CH3:37][NH:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1>>[CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]([N:38]([C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=2)[CH3:37])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: COCO[C@H]1CCN(C[C@H](O)c2ccccc2)C1
Agent: COCO[C@H]1CCN([C@H](CO)c2ccccc2)C1
Product: COCO[C@H]1CCN(CC(c2ccccc2)N(C)c2ccc(C(=O)OC)cc2)C1
Yield: 49 %

Procedure:
This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(R)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(S)-phenylethanol and methyl 4-methylaminobenzoate in 49% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([OH:21])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(#N)C.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:19])[CH3:20])[N:11]=[C:10]([O:21][S:38]([C:35]3[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=3)(=[O:40])=[O:39])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(OS(=O)(=O)c2ccc(C)cc2)nc1C(C)C
Temperature: 2.5 °C
Yield: 84.9 %

Procedure:
In a 200 mL-volume glass flask were placed 27.6 g (95.1 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 12.5 g (123 mmol.) of triethylamine, and 95 mL of acetonitrile. The mixture of the flask was chilled to 0-5° C. in an ice bath. To the chilled mixture was slowly added 20.0 g (105 mmol.) of p-toluenesulfonyl chloride, and the resulting mixture was subjected to reaction at 20-25° C. for one hour. After the reaction was complete, to the reaction mixture was added 95 mL of water. The aqueous reaction mixture was extracted with toluene and the toluene portion was separated. The toluene portion was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The dried mixture was filtered and concentrated under reduced pressure. The residue was crystallized from methanol, to give 35.9 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)-pyrimidine as a colorless crystalline product having the below-mentioned characteristics. The yield was 85% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
Reaction SMILES: [CH3:1][C:2]1([C:7]([OH:9])=O)[NH:6][CH2:5][CH2:4][S:3]1.[CH3:10][N:11]=[C:12]=[O:13]>>[CH3:10][N:11]1[C:7](=[O:9])[C:2]2([CH3:1])[S:3][CH2:4][CH2:5][N:6]2[C:12]1=[O:13]
Reactant: CC1(C(=O)O)NCCS1
Reactant: CN=C=O
Product: CN1C(=O)N2CCSC2(C)C1=O

Procedure:
By operating in like manner as is described in Example 1 and by starting from 2-methyl-thiazolidin-2-carboxylic acid and methyl isocyanate, the desired product was obtained as a white solid having a melting point of 67°-68° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([F:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.[CH3:30][CH:31]([CH3:35])[C:32](Cl)=[O:33]>CN(C)C(=O)C>[F:28][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]3[N:6]([CH:29]=[C:3]([NH:2][C:32](=[O:33])[CH:31]([CH3:35])[CH3:30])[N:4]=3)[N:7]=2)=[CH:17][C:16]=1[NH:18][C:19]([C:21]1[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=1)=[O:20]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C(C)C)cn4n3)ccc2F)n(C)n1
Yield: 45.2 %

Procedure:
Using N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol), 2-methylpropanoyl chloride (53 mg, 0.50 mmol) and N,N-dimethylacetamide (5.0 mL), and by a reaction in the same manner as in Example 148, the title compound (98 mg, 45%) was obtained as pale-blue crystals.
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]=[N:7][C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[C:9]=2[C:23]([NH2:25])=[O:24])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[C:9]=2[C:23]([NH2:25])=[O:24])=[CH:26][CH:27]=1
Reactant: NC(=O)c1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N=Cc1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1NCc1ccc(O)cc1

Procedure:
5-((4-hydroxybenzylidene)amino)-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide (5.0 g) was suspended in 350 mL of MeOH and sodium borohydride was added until bubbling ceased. HPLC confirmed reaction was complete (absence of imine). Once completed (1 hr), precipitate was filtered to obtain 5-((4-hydroxybenzyl)amino)-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide as an off white to light yellow powder. Product was washed with deionized water to remove excess sodium borohydride. Product was allowed to dry under vacuum for 18 hrs. 4.80 g (95% yield) of final product was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>O1CCCC1.CCOCC.[OH-].[K+]>[CH3:1][NH:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH:15]([OH:17])[CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CNc1c2c(nc3ccccc13)CCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNc1c2c(nc3ccccc13)CCCC2O
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
In 50 ml of dry tetrahydrofuran was dissolved 8.00 g of 3,4-dihydro-9-(methylamino)acridin-1(2H)-one. The mechanically stirred solution was cooled to -10° C. under N2 and 32 ml (1 eq) of 1.1M LiAlH4 solution in ether was added over 5 minutes. The stirring was continued for 45 minutes after the addition, during which the reaction went to completion. The excess LiAlH4 was neutralized with 1 ml of saturated NH4Cl and the resulting salts dissolved in 30% potassium hydroxide solution. The tetrahydrofuran solution was separated and evaporated to an oil which solidified upon trituration with 1:1 dichloromethane/hexanes. The solid was recrystallized from 10:1 hexanes/tetrahydrofuran to yield 5.89 g (73%) of a solid, melting point 160°-161° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH2:25][O:26]C2CCCCO2)[CH:5]=[CH:4][C:3]=1[C:33]1[NH:37][C:36](=[O:38])[O:35][N:34]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:33]1[NH:37][C:36](=[O:38])[O:35][N:34]=1)[O:8][CH2:9][C:10]1[S:14][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)=[N:12][C:11]=1[CH:25]=[O:26]
Reactant: Cc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)ccc1-c1noc(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C=O)ccc1-c1noc(=O)[nH]1
Temperature: 60 °C
Yield: 75.7 %

Procedure:
1.05 g 3-{2-Methyl-4-[4-(tetrahydro-pyran-2-yloxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one was suspended in 80 ml methanol. 66.0 mg p-Toluenesulfonic acid were added and the reaction mixture warmed to 60° C. until the reaction mixture became a clear solution. The cooled reaction mixture was evaporated in vacuo. The residue was dissolved in a mixture of 10 ml dimethylformamide and 40 ml dichloromethane. 3.76 g Manganese (IV) oxide on activated charcoil were added and the reaction mixture heated to reflux for two hours. The cooled reaction mixture was filtered through a celite pad. The filtrate was evaporated in vacuo to obtain 670 mg crude 5-[3-methyl-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde which was used without further purification.
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19].[CH2:20]([SH:24])[CH2:21][CH2:22][CH3:23]>C1C=CC=CC=1>[CH2:20]([S:24][CH:8]1[CH2:9][C:10](=[O:12])[CH:11]2[CH:6]([C:5]3([Cl:17])[C:14]([Cl:15])([Cl:16])[C:2]2([Cl:1])[C:3]([Cl:19])=[C:4]3[Cl:18])[C:7]1=[O:13])[CH2:21][CH2:22][CH3:23]
Reactant: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Reactant: CCCCS
Solvent: c1ccccc1
Product: CCCCSC1CC(=O)C2C(C1=O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Reaction time: 24 h

Procedure:
20 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared as in Example 1, were dissolved in 60 ml. of benzene and then 10 g. of n-butylmercaptan and a few crystals of ferric chloride were added. This reaction mixture was shaken for 24 hours (Parr shaker). When the benzene was evaporated a white solid was obtained. One recrystallization from benzene-Skelly B mixture yielded white crystals, m.p. 97°-98° C. The infrared spectrum showed strong carbonyl at 1750 cm-1.
Reaction SMILES: C(N)CCC.[CH:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=O.C1C=CC=CC=1.[N+:24]([CH2:27][CH2:28][CH2:29][CH3:30])([O-:26])=[O:25]>C(O)(=O)C.O>[N+:24](/[C:27](/[CH2:28][CH2:29][CH3:30])=[CH:6]\[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)([O-:26])=[O:25]
Reactant: CCCC[N+](=O)[O-]
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CCCCN
Solvent: O
Solvent: c1ccccc1
Product: CCC/C(=C/c1ccc(C(=O)OC)cc1)[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h
Yield: 46.7 %

Procedure:
n-Butylamine (8.31 ml, 84.1 mmol) and methyl 4-formylbenzoate (10.6 g, 64.7 mmol) was heated with reflux benzene (50 ml) in a Dean-Stark trap until a theoretical amount of water was recovered. The solvent was evaporated under reduced pressure. To the residue were added glacial acetic acid (30 ml) and nitrobutane (10.0 g, 97.0 mmol), and the mixture was stirred at 110° C. for 4 hrs. and allowed to cool to room temperature. The insoluble materials were filtered off and dried to give the title compound (7.53 g) as a pale-yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:17].[OH-].[Na+].[Cl-].[NH4+]>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][NH:17][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1[nH]ccc(=O)c1OCc1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
The compound 2 (162.2 g, 750 mmol) was dissolved in ethanol (487 ml), and aqueous ammonia (28%, 974 ml) and a 6N aqueous sodium hydroxide solution (150 ml, 900 mmol) were added. After the reaction solution was stirred at 90° C. for 1 hour, this was cooled to under ice-cooling, and ammonium chloride (58 g, 1080 mmol) was added. To the reaction solution was added chloroform, this was extracted, and the organic layer was washed with an aqueous saturated sodium bicarbonate solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, isopropyl alcohol and diethyl ether were added to the residue, and precipitated crystals were filtered to obtain 3-benzyloxy-2-methyl-1H-pyridine-4-one 3 (69.1 g, 43%) as a pale yellow crystal.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7](O)=[O:8])[CH2:5][CH2:4][N:3]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1.O[N:29]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>C1COCC1>[O:1]=[C:2]1[CH:6]([C:7]([NH2:29])=[O:8])[CH2:5][CH2:4][N:3]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)C1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)C1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)C1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.9 %

Procedure:
150 mg (0.4 mmol) (RS)-2-oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid is dissolved in 4 ml THF. 59 mg (0.43 mmol) of 1-hydroxybenzotriazole and 80 mg (0.42 mmol) of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide-hydrochloride is added and the reaction mixture is stirred at RT for 30 min. After cooling to 0° C. 4 ml of concentrated ammonia is added and the resulting mixture stirred at RT for 1 hour. Dilution with water, extraction and chromatography (silica gel, ethyl acetate) yields 15 mg (10%) of a colorless solid. MS: m/e=379.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH:19]([N:22]([CH3:24])[CH3:23])[CH2:18]3)=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[CH3:23][N:22]([CH3:24])[CH:19]1[CH2:20][CH2:21][N:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:26][CH:25]=3)=[CH:16][CH:15]=2)[CH2:18]1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)C3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(C(=O)O)cc3)cc2)C1

Procedure:
N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]terephthalamic acid methyl ester (1.7 g) dissolved in methanol (20 ml) was stirred with sodium hydroxide solution (2N, 15 ml) at room temperature for 24 hours. If conversion is incomplete, it is also possible to heat to reflux. The organic solvent was distilled off, and the mixture was acidified with hydrochloric acid. The precipitate which separated out was filtered off with suction and dried. This resulted in the product with the molecular weight of 353.42 (C20H23N3O3); MS (ESI): 354 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][N:4]=[CH:3]1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]([OH:48])(=[S:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:1][N:2]1[C:6]([CH2:7][S:47][C:40](=[O:48])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:5][N:4]=[CH:3]1
Reactant: OC(=S)c1ccccc1
Reactant: Cn1cncc1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cn1cncc1CSC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, 1-methyl-5-hydroxymethylimidazole (2.52 g), diethylazodicarboxylate (4.26 ml) was added successively to a solution of triphenylphosphine (7.07 g) in THFe (50 ml) with ice cooling, while the reaction temperature was kept below 15 degree. After stirring for 1 hour at 0° C., 3.9 ml of thiobenzoic acid was added slowly. The mixture was poured into a mixture of ethyl acetate and aqueous sodium hydrogen carbonate. The aqueous layer was separated, the organic layer was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified on silica gel (eluent: dichloromethane-acetone) to afford 1-methyl-5-(benzoylthiomethyl)imidazole (993 mg).