Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25]Br)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: O=[N+]([O-])c1ccc2c(c1)N(C1CCNCC1)CC2
Product: O=[N+]([O-])c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 97.5 %

Procedure:
1-(Piperidin-4-yl)-6-nitroindoline (3.5 g) and 4-fluorophenethyl bromide (4.1 g) were treated as in Example 2 to give the title compound (5.1 g) as apaleyellowpowder (yield: 81%).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH:22]([NH2:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(N(CC)CC)C>[CH:22]([NH:35][S:18]([C:4]1[CH:5]=[C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])[CH:7]=[CH:8][C:3]=1[Cl:2])(=[O:20])=[O:19])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NC(c3ccccc3)c3ccccc3)c2)N1C

Procedure:
6.5 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 2.7 g of benzhydrylamine and 4 g of triethyl amine and worked up. Colorless solid body, decomposition beginning at 103° C, γ C=N 1620 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([CH3:34])=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([CH3:34])=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH2:23][NH:22][CH2:21][CH2:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCNC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 19; 210 mg; 0.434 mmol) in dichloromethane (3 ml) at 0° C. was added trifluoroacetic acid (3 ml) dropwise. The resulting mixture was stirred at 0° C. for 1 h, giving a pale yellow solution. Removal of the solvent and co-evaporation with toluene gave a white solid, which was triturated with diethyl ether to give the title compound as a white solid (206 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2)[CH2:2][CH2:3][CH3:4].[CH2:19]([N:23]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:20][CH2:21][CH3:22].O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([C:5]1[CH:6]=[C:7]2[N:12]([C:13]=1[C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:36][CH:35]=1)[CH:11]=[CH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(C(=O)OCC)ccn2c1
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1cc2cc(C(=O)OCC)ccn2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Yield: 37.4 %

Procedure:
A mixture of 0.35 g (38 mmoles) of 2-n-butyl 7-carbethoxy indolizine and 14.2 g (38 mmoles) of 4-(3-di-n-butylamino-propoxy) benzoyl chloride is heated at 95°-100° C. for 4.5 h. The crude product obtained is dissolved in ethyl acetate and water and is neutralized by sodium hydrogen carbonate. The organic layer is separated and dried over magnesium sulfate. It is filtered and the solvent evaporated. The residue is then purified on a column of silica with ethyl acetate as eluant in order to obtain 7.6 g of the desired compound in the form of the free base (yield: 97%). The oxalic acid salt is then formed in ethyl acetate and recovered by filtration.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH2:32][CH:33]1[CH2:38][N:37]2[N:39]=[C:40]([C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:47][CH:46]=3)[C:41]([C:42]([NH2:44])=[O:43])=[C:36]2[NH:35][CH2:34]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:11]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[N:2]1[CH2:32][CH:33]1[CH2:38][N:37]2[N:39]=[C:40]([C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:47][CH:46]=3)[C:41]([C:42]([NH2:44])=[O:43])=[C:36]2[NH:35][CH2:34]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(CO)C2
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(CN1C(=O)c3ccccc3C1=O)C2
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
To a solution of isoindoline-1,3-dione (74 mg, 0.5 mmol) in THF (20 mL) was added PPh3 (393 mg, 1.5 mmol) and 6-(hydroxymethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (180 mg, 0.5 mmol). DIAD (253 mg, 1.25 mmol) was added dropwise at 0° C. and stirred for 10 min. The mixture was allowed to warm to it and stirred for 16 hr. Concentrated and purified by chromatography column on 5 g of silica gel eluting with DCM/CH3OH to afford 200 mg (62%) of 6-((1,3-dioxoisoindolin-2-yl)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. MS (ESI) m/e [M+1]+ 493.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([NH2:16])[S:8][C:7]=1[NH2:17])=[O:5])[CH3:2].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O.FC(F)(F)C(O)=O>C(O)(C)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([N:16]=[CH:23][C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[S:8][C:7]=1[NH2:17])=[O:5])[CH3:2]
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCOC(=O)c1c(N)sc(N=Cc2cccs2)c1C(=O)OCC
Yield: 81 %

Procedure:
In a round bottom flask (50 mL), 2,5-diamino-thiophene-3,4-dicarboxylic acid diethyl ester (50 mg) was added to 20 mL isopropanol to which was added 2-thiophenecarboxaldehyde (24 mg) and a catalytic amount of trifluoroacetic acid (TFA). The mixture was refluxed for 20 hours. Complete removal of the solvent provides an orange solid which was purified by flash chromatography (SiO2), yielding the title compound as an orange solid (81%). M.p.: 114°-116° C. 1H-NMR (300 MHz, [D] acetone): δ=8.24 (s, 1H), 7.63 (d, 1H, 3J=5.0 Hz), 7.52 (dd, 1H, 3J=3.7 Hz and 4J=0.7 Hz), 7.48 (s, 2H), 7.14 (dd, 1H, 3J=5.0 Hz and 3.7 Hz), 4.32 (q, 2H, 3J=7.2 Hz), 4.19 (q, 2H, 3J=7.1 Hz), 1.37 (t, 3H, 3J=7.1 Hz), 1.26 (t, 3H, 3J=7.1 Hz). 13C-NMR (300 MHz, [D] acetone): δ=165.0, 164.3, 161.1, 161.0, 146.1, 143.2, 132.8, 132.1, 130.5, 128.4, 101.8, 61.0, 60.0, 14.3, 14.1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[N:20]=[N:19][C:18]([C:21]3[N:26]=[C:25]([C:27]([O:29]C)=[O:28])[CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOCC>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[N:20]=[N:19][C:18]([C:21]3[N:26]=[C:25]([C:27]([OH:29])=[O:28])[CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2ccc(C(=O)CCCCCCc3ccccc3)nn2)n1
Solvent: CCOCC
Product: O=C(O)c1cccc(-c2ccc(C(=O)CCCCCCc3ccccc3)nn2)n1
Yield: 71 %

Procedure:
The title compound was prepared from 13f (1.9 mg, 0.0047 mmol) following general procedure A. Tritration with Et2O afforded the title compound (1.3 mg, 71%) as a white solid: 1H NMR (CDCl3, 600 MHz) δ 9.06 (d, 1H, J=7.8 Hz), 8.65 (d, 1H, J=8.7 Hz), 8.42 (d, 1H, J=7.5 Hz), 8.32 (d, 1H, J=8.7 Hz), 8.23 (t, 1H, J=7.8 Hz), 7.27 (m, 2H), 7.17 (m, 3H), 3.45 (t, 2H, J=7.4 Hz), 2.62 (t, 2H, J=7.8 Hz), 1.83 (m, 2H), 1.66 (m, 2H), 1.46 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 200.2, 163.5, 158.2, 155.7, 152.2, 146.4, 142.9, 140.2, 128.5, 128.4, 126.7, 126.0, 125.8, 125.7, 125.2, 38.5, 36.1, 31.5, 29.3, 29.2, 24.0; HRMS-ESI-TOF m/z 390.1811 ([M+H]+, C23H23N3O3 requires 390.1812).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:13])=[C:7]([O:22][CH3:23])[CH:6]=1.[OH-].[Na+]>CO>[CH3:23][O:22][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:24])=[O:2])[CH:10]=[CH:9][C:8]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[O:13]
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
A suspension of [3-methoxy-4-(3-o-tolylureido)phenyl]-acetic acid methyl ester (19.43 g, Reference Example 6) in methanol (195 ml) was treated with sodium hydroxide solution (65 ml, 1N) and the mixture was heated at reflux for 1 hour giving a clear solution. The reaction mixture was cooled to room temperature and then filtered. The filtrate was diluted to 390 ml with water, then heated to 50° C. and then acidified to pH 1 by the addition of hydrochloric acid (80 ml, 1N) over 1 hour. The resulting suspension was stirred for a further 30 minutes at 50° C., then allowed to cool to room temperature and then filtered. The solid was washed with twice with water (200 ml) then dried to give the title compound (15.72 g) as a white solid, m. p. 179-181° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH:16]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:11]3[O:10]2)=[O:8])=[CH:5][CH:4]=1.[CH2:25]([O:27][C:28](=O)C)C.CCCCCC>>[CH3:25][O:27]/[CH:28]=[C:18](\[C:9]1([C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:17][CH:16]=[C:12]2[CH:13]=[CH:14][CH:15]=[C:11]2[O:10]1)/[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(C)=O
Reactant: COC(=O)CC1(C(=O)c2ccc(OC)cc2)CC=C2C=CC=C2O1
Solvent: CCCCCC
Product: CO/C=C(/C(=O)OC)C1(C(=O)c2ccc(OC)cc2)CC=C2C=CC=C2O1

Procedure:
Using the procedure of Example 1, methyl 2-(4-methoxy-benzoyl) -7-benzofuranacetate, prepared hereafter, was reacted to obtain the desired product with a Rf 0.07 (eluant: hexane - ethyl acetate (75-25)).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]1[C:13]([CH2:14][CH2:15][CH2:16][C:17](O)=[S:18])=[N:12][N:11]=[N:10]1.[CH2:20]1[CH2:30][CH2:29][N:28]2[C:23](=NC[CH2:26][CH2:27]2)[CH2:22][CH2:21]1.ClC(OCC(C)C)=O.C(NC1CCCCC1)C>O1CCCC1>[CH2:27]([N:28]([CH:23]1[CH2:22][CH2:21][CH2:20][CH2:30][CH2:29]1)[C:17](=[S:18])[CH2:16][CH2:15][CH2:14][C:13]1[N:9]([CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]2[O:2][CH3:1])[N:10]=[N:11][N:12]=1)[CH3:26]
Reactant: COC1CCCCC1n1nnnc1CCCC(O)=S
Reactant: C1CCC2=NCCCN2CC1
Agent: CC(C)COC(=O)Cl
Agent: CCNC1CCCCC1
Solvent: C1CCOC1
Product: CCN(C(=S)CCCc1nnnn1C1CCCCC1OC)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
4-[1-(2-Methoxycyclohexyl)-1,2,3,4-tetrazol-5-yl]thio-butyric acid (45 mmole) is dissolved in tetrahydrofuran (50 ml), and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate (50 mmole) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise N-ethyl-cyclohexylamine (54 mmole), and the mixture is further stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure, and the residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After distilling off chloroform, the resulting residue is subjected to column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-ethyl-N-cyclohexyl-4-[1-(2-methoxycyclohexyl)-1,2,3,4-tetrazol-5-yl]thio-butyramide (yield: 45%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][N:13]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:13][CH2:12][C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH2:9][CH2:8][NH:7][C:6](=[O:24])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C

Procedure:
A solution of 188 mg (0.55 mmol) of tert-butyl-{(4S)-5-azido-4-[(tert-butoxycarbonyl) amino]pentyl}carbamate (Example Z8) in ethanol is hydrogenated after the addition of 20 mg of palladium on activated carbon (10%) under atmospheric pressure at RT for 12 h. The mixture is filtered through kieselguhr, and the residue is washed with ethanol. The filtrate is evaporated to dryness in vacuo. The product is reacted without further purification.
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](OCC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.[BH4-].[Li+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[OH:19][CH2:18][CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:23]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)(=[O:25])=[O:24])=[N:16][CH2:15]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a mixture of ethyl (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.21 g), lithium borohydride (20 mg) and tetrahydrofuran (10 mL) was added methanol (2 mL), and the mixture was stirred at room temperature for 3 hr. Aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (182 mg, yield: 96%) as pale-yellow crystals. A part of the crystals was recrystallized from ethyl acetate-hexane to give pale-yellow crystals. MS: 422 (MH+). melting point 174-175° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].C([Li])CCC.CCCCCC.CON(C)[C:24](=[O:26])[CH3:25]>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][C:24](=[O:26])[CH3:25])[CH3:2]
Reactant: CON(C)C(C)=O
Reactant: C#CC(OCC)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(C#CC(C)=O)OCC
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Propargylaldehyde diethylacetal (40 g, 312 mmol) was dissolved in THF (200 mL) under argon and cooled to −70° C. Then a 1.6 M solution of n-butyllithium in hexane (234 mL, 374 mmol) was added and stirring continued for 30 min at −30° C. Then N-methoxy-N-methylacetamide (38.6 g, 374 mmol) in THF (10 mL) was added. After 30 min at −30° C., the reaction was quenched by addition of saturated NH4Cl solution (20 mL). The product was extracted with AcOEt (2×200 mL), saturated solution of NH4Cl (2×200 mL), dried and concentrated. Chromatography on silica gel with a heptane/ethyl acetate gradient 100:0 to 95:5 gave 38.5 g (72%) of a colorless oil. GC/MS: m/z=232(M).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:20])[N:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:23].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:20])[N:16]=3)[N:11]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)[CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:23]
Reactant: COc1ccc(C(=O)c2c[nH]c3ccc(C)nc3c2=O)cc1C
Reactant: Cc1cccc(CBr)n1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C)n3)c3ccc(C)nc3c2=O)cc1C
Yield: 26 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 100 mg (0.324 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one, 72.4 mg (0.389 mmol) of 2-Bromomethyl-6-methyl-pyridine, 15.6 mg (0.389 mmol, 60% dispersion in oil), and 1 mL of N,N-dimethylformamide. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 34.8 mg of 3-(4-Methoxy-3-methyl-benzoyl)-6-methyl-1-(6-methyl-pyridin-2-ylmethyl)-1H-[1,5]naphthyridin-4-one. LC-MSD, m/z for C25H23N3O3 [M+H]: 414.17 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 1.8 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.OC[CH2:24][C:25]1[N:26]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2>C(Cl)Cl>[Br:20][CH2:24][C:25]1[N:26]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2
Reactant: Cc1ccc(S(=O)(=O)n2c(CCO)cc3ccccc32)cc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(CBr)cc3ccccc32)cc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of triphenylphosphine (20.2 g, 77 mmol) in dry CH2Cl2 (80 mL) was added dropwise a solution of bromine (11.9 g, 77 mmol) in dry CH2Cl2 (40 mL). The stirring was continued for one hour and then a solution of compound of step 2 (23.2 g, 77 mmol) in dry CH2Cl2 (40 mL) was added dropwise. The resulting mixture left stirring for 12 hours. After removing the solvent the residue was taken up in ethyl acetate and washed with water. The organic extract was dried over MgSO4 and the solvent evaporated in vacuo. The residue was chromatographed over silica gel using toluene as eluant to give a yellow oil (21.0 g, 75 %); IR (film) 1600 cm-1, MS ((70eV): m/z 363 (M+,12.6), 129 (100).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[CH3:27][C:28]([CH3:30])=O>>[CH:28]([NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=1[O:24][CH3:25])([CH3:30])[CH3:27]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: CC(C)=O
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1NC(C)C

Procedure:
The title compound, off-white foam, MS: m/e=427.2 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and acetone.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[C:2]=[S:3].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].O>O1CCCC1>[CH2:14]([N:16]([CH2:17][CH3:18])[C:2](=[S:3])[NH:1][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:15]
Reactant: COC(=O)c1ccccc1N=C=S
Reactant: CCNCC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=S)Nc1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Methyl 2-isothiocyanatobenzoate (Acros) (20.0 g, 104 mmol) was dissolved in tetrahydrofuran (300 mL), followed by addition of diethylamine (35.9 mL, 349 mmol). The reaction mixture was stirred at room temperature. After 1 hour, the mixture was poured into water (800 mL). The precipitate was collected by filtration, washed with water and dried under vacuum to give the title compound (26.2 g, yield 94.2%).
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:5])C.Cl.[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1.C(N(CC)CC)C.O>ClCCl.CO>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:25]([C:22]3[CH:23]=[CH:24][C:19]([S:18][CH3:17])=[CH:20][CH:21]=3)[N:26]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: CCOC(C)=NC(=O)c1ccc(Cl)cc1
Reactant: CSc1ccc(NN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CSc1ccc(-n2nc(C)nc2-c2ccc(Cl)cc2)cc1
Reaction time: 8 h
Yield: 59085.1 %

Procedure:
N-(1-ethoxy-ethylidene)-4-chloro benzamide 472 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and (4-methylsulfanyl-phenyl)-hydrazine hydrochloride 439 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was purified through a flash column chromatography (ethyl acetate:normal hexane=l:1). As a result, 5-(4-chloro-phenyl)-3-methyl-1-(4-methylsulfanyl-phenyl)-1H-[1,2,4]triazole (390 g, yield: 59%) was obtained as a liquid phase.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH3:10])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH3:10])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:24][OH:25])[CH:26]=[CH:27][CH:28]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CO)c1
Reactant: COc1cccc([C@@H](C)Nc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc([C@@H](C)Nc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 105 °C
Yield: 100.2 %

Procedure:
Into a reaction flask were added 2,5-dichloro-N-[(1R)-1-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.21 g, 0.70 mmol), 1,4-dioxane (20 mL), 3-aminobenzyl alcohol (0.13 g, 1.0 mmol), and p-toluenesulfonic acid monohydrate (0.049 g, 0.26 mmol). The mixture was heated at 105° C. for 2 days. To the reaction mixture was added NaHCO3 (saturated aqueous solution) and the organic solvent was removed under vacuum. Water and EtOAc were added to the residue. The aqueous layer was extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give the desired product (0.27 g, 96%). LCMS for C20H22ClN4O2 (M+H)+: m/z=385.1.