Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[C:33]1([CH:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:41][CH2:40][CH:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:3]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
N-[(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (160 mg, 0.44 mmol) is dissolved in THF (5 mL) under an atmosphere of argon. DIPEA (69 mg, 0.53 mmol) is added followed by 2,2-diphenylethylamine (96 mg, 0.49 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 2 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: CN1CCNCC1
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CN1CCN(c2ncc(-c3cnc4[nH]ccc4n3)c(N[C@H]3CCCN(S(C)(=O)=O)C3)n2)CC1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, N-methylpiperazine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give ((S)-1-methanesulfonyl-piperidin-3-yl)-[2-(4-methyl-piperazin-1-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-amine. MS (ES+): 472.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17](I)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:23]([OH:27])[CH2:24][C:25]#[CH:26].Cl>C(NCC)C.CN(C=O)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([C:26]#[C:25][CH2:24][CH2:23][OH:27])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(C#CCCO)cc2c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxamide (Example No. 2) (1.00 g) in diethylamine (28 mL) is added copper iodide (0.128 g) and Pd(PPh3)2Cl2 (0.032 g) followed by addition of 3-butyn-1-ol (0.20 mL). The reaction is stirred at rt for 18 h. The reaction mixture is partitioned between H2O (100 mL) and ethyl acetate (100 mL). The organic layer is removed, and the aqueous layer is extracted with ethyl acetate (2×100 mL). Combined organic layers are dried with MgSO4, filtered, and concentrated in vacuo. The resulting brown oil is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a brown solid. This material is dissolved in DMF (15 mL) and 2N HCl is added until a precipitate forms. The resulting tan solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2, 95:5). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.183 g (21%) of the title compound as a yellow, crystalline solid.
Reaction SMILES: [C:1]([C:3]1([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)[CH2:6][CH2:5][CH2:4]1)#N.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N:28]=[C:29]=[S:30])[C:23]#[N:24].C([OH:33])C.Cl>CN(C=O)C.O>[Cl:19][C:20]1[CH:21]=[C:22]([C:23]#[N:24])[CH:25]=[CH:26][C:27]=1[N:28]1[C:1](=[O:33])[C:3]2([CH2:6][CH2:5][CH2:4]2)[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)[C:29]1=[S:30]
Reactant: CNC(=O)c1ccc(NC2(C#N)CCC2)cc1F
Reactant: CCO
Reactant: N#Cc1ccc(N=C=S)c(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)cc3Cl)C(=O)C23CCC3)cc1F
Temperature: 110 °C
Yield: 23 %

Procedure:
A mixture of 6a (388 mg, 2 mmol) and 3d (494 mg, 2 mmol) in DMF (10 mL) was heated under microwave irradiation at 110° C. for 12 h. To this mixture is added ethanol (10 mL) and HCl (2N, 5 mL). The resulting mixture was refluxed for 1 h. After being cooled to room temperature, the reaction mixture was poured into cold water and extracted with ethyl acetate (3×100 mL). Combined organic layers were dried over MgSO4, concentrated. The residue was purified by silica gel column chromatography using petroleum ether:ethyl acetate (1:1), to give the title compound (Example 1, 200 mg, 23% yield). 1H NMR (CDCl3, 500 MHz): δ 8.39 (1H, t, J=9.0 Hz), 7.89 (1H, s), 7.72 (1H, dd, m), 7.54 (1H, d, J=8.0 Hz), 7.26 (1H, m.br), 7.20 (1H, d, J=11 Hz), 6.71 (1H, br s), 3.00 (3H, d, J=5 Hz), 2.70 (2H, m), 2.52 (2H, m), 2.26 (1H, m), 1.69 (1H, m, br). MS (ES-API positive): 443 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][O:22][CH2:23][CH:24]3[CH2:28][O:27]C(C)(C)[O:25]3)=[O:20])=[CH:11][C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:31])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][O:22][CH2:23][CH:24]([OH:25])[CH2:28][OH:27])=[O:20])=[CH:11][C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:31])[CH:3]=1
Reactant: CC1(C)OCC(CONC(=O)c2cc3ocnc3c(F)c2Nc2ccc(Br)cc2Cl)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NOCC(O)CO)c1cc2ocnc2c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a solution of 5-((4-bromo-2-chlorophenyl)amino)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluorobenzo[d]oxazole-6-carboxamide (473 mg, 0.92 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and washed with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH2Cl2 (10 mL×2). The combined organic layers were washed by water (10 mL) and brine (10 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 50:1, v/v) to afford the desired product (white solid, 255 mg, 44.7% yield for two steps). 1H NMR (400 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.95 (s, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 7.54 (d, 1H), 7.30 (d, 1H), 6.42 (m, 1H), 4.83 (d, 1H), 4.62 (m, 1H), 3.86 (m, 1H), 3.70 (m, 2H), 3.35 (m, 2H). MS APCI (+) m/z: 475.7, [M+H].
Reaction SMILES: C([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C)=O.[CH3:17][Mg]I>>[C:16]1([CH:11]=[CH:3][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:17]=1
Reactant: CC(C=O)(c1ccccc1)c1ccccc1
Reactant: C[Mg]I
Product: C(=Cc1ccccc1)c1ccccc1

Procedure:
For example, vinylnaphthalene may be obtained by reacting formylnaphthalene with a Grignard reagent such as methyl magnesium iodide and then dehydrating the reaction product. Vinylphenylphenylethane may be obtained by reacting diphenylethane with acetyl chloride in the presence of a Friedel-Craft catalyst to produce acetylphenylphenylethane, reducing the thus produced product with sodium boron hydride and then dehydrating the thus reduced product. Isopropenylphenylphenylethane may be obtained by reacting formylphenylphenylethane with a Grignard reagent such as methyl magnesium iodide and then dehydrating the reaction product. 1,2-diphenylethylene may be obtained by reacting benzaldehyde with benzyl magnesium bromide and then dehydrating the reaction product; 1,2-diphenylpropene may likewise be obtained.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30].O>CN(C)C=O.C(OCC)(=O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1c2cc(O)ccc2CCN1Cc1cccnc1
Reactant: ClCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2cc(OCc3ccccc3Cl)ccc2CCN1Cc1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.7 %

Procedure:
To a suspension of 32 mg of sodium hydride (about 60%) in 10 ml of dimethylformamide was added 100 mg of 3,4-dihydro-7-hydroxy-2-(3-pyridylmethyl)-1 (2H)-isoquinolinone, and the resultant mixture was stirred for 15 minutes. Then, 95 mg of 2-chloromethylchlorobenzene was added to the mixture, which was stirred at room temperature for 20 hours. After finishing the reaction, the mixture was mixed with water and shaken with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate to give 144 mg of the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=O)[CH:3]=1.[OH-:13].[K+].[O-]Cl.[Na+]>C(O)C.O>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]2=[N+:6]([O-:13])[O:12][N:10]=[C:4]2[CH:3]=1
Reactant: [OH-]
Reactant: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCO
Solvent: O
Product: [O-][n+]1onc2cc(Br)c(F)cc21
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 41.7 %

Procedure:
4-Bromo-5-fluoro-2-nitroaniline (8.5 g, 36 mmol) was stirred in 200 mL ethanol and treated with 45% KOH solution (4.5 g, 36 mmol) to produce a dark solution. This solution was cooled to 0-5° C. and treated dropwise with 6% NaOCl solution (84 g, 68 mmol) over 20 min while maintaining the temperature below 10° C. After 90 min, the mixture was diluted with 300 mL water and extracted twice with 200 mL portions of ethyl acetate. The combined extracts were washed with 30 mL saturated NaCl, dried (Na2SO4) and evaporated. The crude material was chromatographed on silica gel with a 0-30% ethyl acetate-hexane gradient to give the title compound as pale yellow solid (3.5 g, 42%): mp 87-89° C.; 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.23 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −96.03; EIMS m/z 232.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[C:3]=1[O:10][CH3:11].N([O-])=[O:13].[Na+]>S(=O)(=O)(O)O>[OH:13][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[C:3]=1[O:10][CH3:11]
Reactant: O=N[O-]
Reactant: COc1c(N)ccnc1CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1c(O)ccnc1CO

Procedure:
4-Amino-2-hydroxymethyl-3-methoxypyridine is diazotised in dilute sulphuric acid with sodium nitrite and the diazonium compound is warmed to give 4-hydroxy-2-hydroxymethyl-3-methoxypyridine which may be demethylated with hydrobromic acid
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1.CCN(CC)CC>C(O)C>[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(-n2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 27.2 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 4-methylphenylhydrazine hydrochloride (237 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (108 mg, 27%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=3[O:11][C:10]=2[CH:19]=1.[CH2:20]([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCOCC1.C(#N)C>[Br-:1].[CH2:20]([N+:27]1[CH:31]=[CH:30][N:29]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]4[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=4[O:11][C:10]=3[CH:19]=2)[CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Clc1ccc2c(c1)oc1cc(OCCCBr)ccc12
Reactant: c1ccc(Cn2ccnc2)cc1
Solvent: CC#N
Solvent: C1COCCO1
Product: Clc1ccc2c(c1)oc1cc(OCCCn3cc[n+](Cc4ccccc4)c3)ccc12
Product: [Br-]
Temperature: 15 °C
Yield: 73.5 %

Procedure:
A solution of 14 g (0.041 mole) of 1-bromo-3-(7-chlorodibenzofuran-3-yloxy)-propane and 7.9 g (0.05 mole) of N-benzylimidazole in 25 ml of dry dioxane and 25 ml of dry acetonitrile was stirred for 40 hours at 70° C. The mixture was cooled to 15° C. in an ice bath, and the crystalline precipitate formed was then filtered off under suction, washed with 30 ml of ether and finally with 50 ml of n-pentane, and dried. 15 g (73.2% of theory) of N1 -benzyl-N3 -[3-(7-chlorodibenzofuran-3-yloxy)-propyl]-imidazolium bromide of melting point 162°-166° C. were obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH3:14])[CH2:10][CH2:9][C:8]2=[O:15].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C)C=O>[O:15]=[C:8]1[C:7]2[C:12](=[C:3]([CH2:2][O:1][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:4]=[CH:5][CH:6]=2)[N:11]([CH2:13][CH3:14])[CH2:10][CH2:9]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCN1CCC(=O)c2cccc(CO)c21
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC(=O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
8-Hydroxymethyl-1-ethyl-4-oxo-1,2,3,4-tetrahydroquinoline (1.44 g) was dissolved in dimethyl formamide (2 ml). Imidazole (1.57 g) and t-butyl dimethylsilyl chloride (1.16 g) were added to the solution and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate-toluene. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (3: 1) ] to give 4-oxo-8-t-butyldimethylsilyloxymethyl- 1-ethyl-1,2,3,4-tetrahydroquinoline (2.18 g).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>O>[F:23][C:24]([F:35])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of toluene (70 mL) and water (10 mL) was degassed with nitrogen for 30 min. A mixture of sodium carbonate (3.2 g, 30.43 mmol), 4-bromobenzaldehyde (2.0 g, 10.6 mmol), 4-trifluoromethoxyphenylboronic acid (2.86 g, 13.95 mmol) and tetrakis triphenyl phosphene palladium(0) (1.0 g, 1.562 mmol) were added to the above degassed water/toluene mixture. The reaction mixture refluxed overnight. After the reaction is completed, the reaction mixture was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ (ppm)=7.2-8.0 (m, 8H), 10.0 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][OH:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[C:17]([C:21]1[O:25][N:24]=[C:23]([OH:26])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C(=O)(O)[O-].[Na+].CS(C)=O>O>[C:17]([C:21]1[O:25][N:24]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][OH:13])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:14]([O-:16])=[O:15])[C:23](=[O:26])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(O)no1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)CCO)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1cc(=O)n(-c2ccc(S(=O)(=O)CCO)cc2[N+](=O)[O-])o1

Procedure:
30 g of 2-(4-chloro-3-nitrobenzenesulfonyl)ethanol, 19.1 g ot 5-t-butyl-3-hydroxyiso-oxazole, 28 g of sodium bicarbonate and 200 ml of dimethylsulfoxide were mixed together and reacted at 80° C. for a period of 8 hours. After cooling, the reaction mixture was poured into of water and the mixture was extracted with ethyl acetate. The organic layer was recovered and, after removing the solvent by distillation under reduced pressure, the main product was isolated using silica gel column chromatography as an oily product.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[S:12]1[CH:16]=[CH:15][C:14]2[C:17]([NH:21][C:22]3[N:23]=[C:24](SC)[N:25]=[N:26][C:27]=3[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:18][CH:19]=[CH:20][C:13]1=2.[C:35]([O:39][C:40](=[O:49])[NH:41][C@H:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C@H:43]1[NH2:48])([CH3:38])([CH3:37])[CH3:36].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[S:12]1[CH:16]=[CH:15][C:14]2[C:17]([NH:21][C:22]3[N:23]=[C:24]([NH:48][C@@H:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C@@H:42]4[NH:41][C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:49])[N:25]=[N:26][C:27]=3[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:18][CH:19]=[CH:20][C:13]1=2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCOC(=O)c1nnc(SC)nc1Nc1cccc2sccc12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc2sccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of m-CPBA (65 mg) in chloroform (1.5 ml) was added to a solution of ethyl 5-(benzo[b]thiophen-4-ylamino)-3-(methylthio)-1,2,4-triazine-6-carboxylate obtained in the above-described Step 1 (33 mg) in chloroform (1.5 ml), the reaction solution was stirred at room temperature for 10 minutes. Thereafter, tert-butyl((1S,2R)-2-aminocyclohexyl)carbamate (60 mg) and diisopropylethylamine (0.10 ml) were added, and then the reaction solution was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate and then washed successively with an aqueous sodium bicarbonate solution and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum, and then the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain ethyl 5-(benzo[b]thiophen-4-ylamino)-3-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-1,2,4-triazine-6-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])([O-:3])=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[CH2:14][C:15]([OH:17])=[O:16])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
16.7 g of tert.butyl 2-nitro-4-trifluoromethyl-phenylacetate and 50 ml of trifluoroacetic acid are dissolved in 50 ml of methylene chloride and stirred for 3 hours at ambient temperature. After elimination of the solvent the residue is taken up in petroleum ether/ether (10:1), suction filtered and dried in vacuo at 80° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].FC(F)(F)C1C=C(O)C=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[OH:31]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[O:31][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: Oc1cccc(C(F)(F)F)c1
Product: O=C(O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl

Procedure:
2-(2,5-Dichloro-phenoxy)-5-fluoro-nicotinic acid was prepared in analogy to Example 1, Step 1, replacing 2-chloro-nicotinic acid with 2-chloro-5-fluoro-nicotinic acid ([CAS RN 38186-88-8]) and 3-trifluoromethyl-phenol with 2,5-dichloro-phenol ([CAS RN 583-78-8]). 1H NMR (400 MHz, DMSO): δ7.38 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 8.23 (dd, J=8.1 Hz, J=3.2 Hz, 1H), 8.34 (d, J=3.2 Hz, 1H), 13.65 (s, 1H). 19F NMR (376.5 MHz, DMSO): −134.6. MS (ISN): 302.0 [M−H]−.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>C(Cl)Cl>[CH2:18]([O:17][C:15]([N:4]([CH3:3])[NH:5][CH3:6])=[O:16])[CH:19]([CH3:21])[CH3:20]
Reactant: CNNC
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNN(C)C(=O)OCC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of N,N'-dimethylhydrazine dihydrochloride (940 mg) and triethylamine (2.15 g) in methylene chloride (30 ml) which was cooled to 0° C., was added isobutyl chloroformate (970 mg). The mixture was stirred at 0° C. for 1 hour. After evaporation of the solvent, the residue was dissolved in ethyl acetate (50 ml) and the solution was washed with 1M sodium bicarbonate solution and water successively, and dried over sodium sulfate. The solvent was evaporated to give N-isobutoxycarbonyl-N,N'-dimethylhydrazine (922 mg) as an oil.
Reaction SMILES: O1CCCC1.[C:6]12([C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=O)[CH:25]=[CH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:20][CH2:19]3)=O)[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[C:6]12([CH2:16][N:18]3[CH2:19][CH2:20][N:21]([CH2:24][CH:25]=[CH:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:22][CH2:23]3)[CH2:13][CH:12]3[CH2:14][CH:8]([CH2:9][CH:10]([CH2:11]3)[CH2:15]1)[CH2:7]2
Reactant: O=C(C=Cc1ccccc1)N1CCN(C(=O)C23CC4CC(CC(C4)C2)C3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C(=Cc1ccccc1)CN1CCN(CC23CC4CC(CC(C4)C2)C3)CC1
Temperature: 0 °C
Yield: 20 %

Procedure:
To 20 ml of tetrahydrofuran, 1 g of N-(1-adamantane carbonyl)-N' -cinnamoyl piperazine which was obtained in Example 1 (II) was dissolved and to this 0.24 g of lithium aluminum hydride powder were added gradually at 0° C. After refluxing for 4 hrs., it was cooled to 0° C and water was added to this at 0° C carefully to separate an organic solvent layer, subsequently the solvent was distilled away. The residues were dissolved in chloroform which was washed with water, dehydrated and then was distilled away. The residues were subjected to silica gel column chromatography (eluant: mixture of chloroform and methanol) and N-(1-adamantyl methyl)-N'-cinnamyl piperazine was obtained. Melting point of the product was 85°-87° C and the yield was 20%.