Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[C:7]=1[CH3:23].ClC1C=CC=C(C(OO)=[O:32])C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13]([C:14]2[NH:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[O:32])[C:7]=1[CH3:23]
Reactant: Cc1c(OCCCO)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OCCCO)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -20 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
1.0 g (3.04 mmol) of 2-[{4-(3-hydroxypropoxy)-3-methylpyridine-2-yl}methylthio]-1H-benzimidazole was dissolved in 100 ml of dichloromethane to obtain a solution. 580 mg of 90% m-chloroperbenzoic acid was added to this solution at -45° C. The obtained mixture was stirred for 2 hours. After the completion of the reaction, 470 mg of triethylamine was added to the reaction mixture. The obtained mixture was heated to -20° C., followed by the addition of 30 ml of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was stirred at a room temperature for 30 minutes and extracted with chloroform. The obtained chloroform layer was concentrated to obtain a crude product. This crude product was crystallized from dichloromethane/ether to obtain 830 mg of 2-[{4-(3-hydroxypropoxy)-3-methylpyridine-2-yl}methylsulfinyl]-1H-benzimidazole. This product was dissolved in 24 ml of 0.1N aqueous sodium hydroxide. The obtained solution was distilled together with ethanol to remove the water as an azeotropic mixture with ethanol and dried under vacuumizing with a vacuum pump. Ether was added to the obtained residue to precipitate a colorless crystal. This crystal was separated by filtration. Thus, 860 mg of the title compound was obtained (77%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:25][C:4]1[CH:3]=[C:2]([N:28]2[CH2:29][CH2:30][O:26][C:27]2=[O:31])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: O=C1NCCO1
Reactant: Cc1cc(Br)ccc1C(=O)N1CCN(c2nc(C)c(C)cc2C)CC1
Product: Cc1cc(N2CCOC2=O)ccc1C(=O)N1CCN(c2nc(C)c(C)cc2C)CC1
Yield: 74.4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (172 mg) described in Preparation Example 132 and oxazolidin-2-one (56 mg), the title compound (130 mg) was obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[C:26]1([C:32]2[N:33]=[CH:34][C:35]([NH:38][C:39](=O)[O:40]C3C=CC=CC=3)=[N:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[C:26]1([C:32]2[N:33]=[CH:34][C:35]([NH:38][C:39]([N:2]3[CH2:7][CH2:6][C:5](=[CH:8][C:9]4[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]5[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=5)[CH:10]=4)[CH2:4][CH2:3]3)=[O:40])=[N:36][CH:37]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cnc(-c2ccccc2)cn1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenyl 5-phenylpyrazin-2-ylcarbamate (0.291 g, 1.00 mmol) in DMSO (2.5 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and heated to 60° C. After 3 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10% of the 1N NH3 in MeOH, in dichloromethane) to afford the title compound (200 mg, 37%) as white crystals after trituration in diethyl ether. MS (APCI 10V) AP+ 532.25; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (t, J=5.46 Hz, 2H) 2.46 (t, J=5.46 Hz, 2H) 3.46 (t, J=5.46 Hz, 2H) 3.50 (t, J=5.46 Hz, 2H) 6.37 (s, 1H) 6.69 (d, J=8.77 Hz, 1H) 7.01-7.03 (m, 2H) 7.10 (d, J=7.81 Hz, 1H) 7.19 (d, J=8.59, Hz, 1H) 7.35-7.39 (m, 2H) 7.43-7.47 (m, 2H) 8.02 (dd, J=7.03 Hz, 1.95 Hz, 2H) 8.17 (dd, J=8.78 Hz, 2.15 Hz, 1H) 8.53 (d, J=2.5 Hz, 1H) 8.85 (s, 1H) 9.04 (s, 1H) 9.63 (s, 1H).
Reaction SMILES: C(N1C2[C:7](=[CH:8]C=CC=2)[C:6](=O)[C:5]1=O)CC.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].BrCCCC>>[CH2:5]([N:21]1[C:22]2[C:18](=[CH:17][C:16]([Cl:15])=[CH:24][CH:23]=2)[C:19](=[O:26])[C:20]1=[O:25])[CH2:6][CH2:7][CH3:8]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Solvent: CCCCBr
Product: CCCCN1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
Was made in an analogous fashion to 1-propylindoline-2,3-dione from commercially available 5-chloro isatin (purchased from Fisher Scientific) and commercially available 1-bromo butane (purchased from Fisher Scientific). 1H NMR δ 7.57 (m, 2H), 6.87 (d, 1H), 3.72 (t, 2H), 1.69 (m, 2H), 1.43 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](B(O)O)[CH:10]=2)[O:5][C:4]([CH3:16])([CH3:15])[CH2:3]1.Br[C:18]1[C:23](=[O:24])[N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:28][CH:27]=2)[C:21]([CH2:40][CH2:41][CH3:42])=[N:20][C:19]=1[CH3:43]>O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:18]3[C:23](=[O:24])[N:22]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]5[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:30][CH:31]=4)[C:21]([CH2:40][CH2:41][CH3:42])=[N:20][C:19]=3[CH3:43])[CH:10]=2)[O:5][C:4]([CH3:16])([CH3:15])[CH2:3]1
Reactant: CC1(C)CC(O)c2cc(B(O)O)ccc2O1
Reactant: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A mixture of (4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)boronic acid (0.79 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g) and 4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (4 mL) was stirred overnight at 100° C. under an argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.94 g, 76%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.O.NN.N.C(Cl)Cl>CO.[Ni]>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: CN1CCCCC1CCn1ccc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: N
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CN1CCCCC1CCn1ccc2cc(N)ccc21
Yield: 72.2 %

Procedure:
A solution of compound 60 (400 mg, 1.4 mmol) in methanol (10 mL) was added to Raney Nickel (slurry in H2O, 50 mg) in a round bottom flask. The suspension was treated with hydrazine hydrate (435 μL, 14.0 mmol) and heated at reflux for 10 minutes then filtered through a pad of celite. The celite pad washed with methanol (10 mL). The filtrate was concentrated to give a dark brown residue which was subjected to flash silica gel chromatography (2M NH3 in MeOH:CH2Cl2, 5:95) to give compound 61 (260 mg, 72.2%) as a viscous oil. 1H NMR (DMSO-d6) δ 7.14 (d, J=3.0 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.67 (d, J=1.8 Hz, 1H), 6.52 (dd, J=1.8, 8.7 Hz, 1H), 6.09 (d, J=1.8 Hz, 1H), 4.45 (brs, 2H), 4.04 (t, J=7.2 Hz, 2H), 2.76-2.72 (m, 1H), 2.15 (s, 3H), 2.02-1.17 (m, 10H); ESI-MS (m/z, %): 258 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH:12]=O.N1CCCCC1.[CH3:20][CH:21](C(OCC)=O)[C:22](OCC)=[O:23]>>[CH2:10]([C:4]1[N:5]=[C:6]([CH2:8][CH3:9])[CH:7]=[C:2]2[C:3]=1[CH:12]=[C:21]([CH3:20])[C:22](=[O:23])[NH:1]2)[CH3:11]
Reactant: CCc1cc(N)c(C=O)c(CC)n1
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: C1CCNCC1
Product: CCc1cc2[nH]c(=O)c(C)cc2c(CC)n1
Temperature: 120 °C

Procedure:
A mixture of 4-amino-2,6-diethylpyridine-3-carbaldehyde (2.0 g), piperidine (0.5 ml) and diethyl methylmalonate (3.0 ml) was heated together at 120° C. for 24 hours. The mixture was then purified by flash chromatography, eluting with ether, to give 5,7-diethyl-3-methyl-1,6-naphthyridin-2(1H)-one as a solid (0.265 g); m.p. 163°-166° C. dec. (after recrystallisation from acetone); NMR (d6 -DMSO): 1.22(t, 3H), 1.24(t, 3H), 2.11(s, 3H), 2.71(q, 2H), 2.99(q, 2H), 6.88(s, 1H), 7.96(s, 1H), 11.84(broad, 1H); mass spectrum (CI, ammonia): 217 (M+H)+ ; microanalysis, found: C, 72.3; H, 7.4; N, 13.1%; C13H16N2O requires: C, 72.2; H, 7.5; N, 13.0%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Cr]([O-])([O-])=O.[Cu+2]>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: CCO
Product: CC(O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 3 h

Procedure:
4(3,5-di-t-butyl-4-hydroxyphenyl) butane-2-ol was prepared by catalytic hydrogenation of 84.8 grams of 4-(3,5-di-t-butyl-4-hydroxyphenyl) butane-2-one in 400 milliliters of ethanol solvent in the presence of 10 grams of copper chromite catalyst at 150° C., and 1000 pounds per square inch pressure in a 1-liter autoclave. Reduction was complete in three hours. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized by the addition of hexane to yield 82.9 grams of a white solid product (97 percent yield) having a melting point between 64° C. and 66° C.
Reaction SMILES: Cl[Si:2]([NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3].[CH3:10][C-:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]([CH3:20])=[CH:12]1.[Li+]>C1COCC1>[C:6]([NH:5][Si:2]([CH3:4])([CH3:3])[C:12]1[CH:11]([CH3:10])[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[CH3:20])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)N[Si](C)(C)Cl
Reactant: Cc1c[c-](C)c2c1CCCC2
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=C([Si](C)(C)NC(C)(C)C)C(C)C2=C1CCCC2
Temperature: 25 °C
Yield: 93.4 %

Procedure:
In an argon atmosphere drybox 0.77 g of ClSiMe2NHCMe3 (4.67 mmol) was added to 50 mL of THF. To this solution 0.75 g (4.67 mmol) of lithium 1,3-dimethyl-4,5,6,7-tetrahydroindenide was added. The solution was then brought to reflux for about 3 hours and then cooled to room temperature. Chromatographic analysis showed the reaction to be complete. The solvent was then removed under reduced pressure. The residue was extracted with pentane, filtered, and the solvent again removed under reduced pressure to give 1.21 g of product (94 percent yield).
Reaction SMILES: [CH3:1][C:2]1[C:13](=[O:14])[C:6]2[N:7]3[CH2:12][CH2:11][CH2:10][C:8]3=[N:9][C:5]=2[C:4](=[O:15])[CH:3]=1.[CH2:16]1[NH:18][CH2:17]1.CC(C)=O.[K+].[Br-]>CO>[N:18]1([C:3]2[C:4](=[O:15])[C:5]3[N:9]=[C:8]4[CH2:10][CH2:11][CH2:12][N:7]4[C:6]=3[C:13](=[O:14])[C:2]=2[CH3:1])[CH2:16][CH2:17]1
Reactant: CC1=CC(=O)c2nc3n(c2C1=O)CCC3
Reactant: C1CN1
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: CC1=C(N2CC2)C(=O)c2nc3n(c2C1=O)CCC3
Reaction time: 0.5 h

Procedure:
To a solution of 35 mg (0.17 mmol) of 26 in 4 mL of dry methanol, chilled at 0° C., was added 0.5 mL of ethyleneimine. The reaction was stirred at 0° for 30 min and then at room temperature for 1 hour. The solvent was removed in vacuo and the red residue flash chromatographed on silica gel using chloroform as the eluant. The purified product was recrystallized from chloroform/hexane: 20.5 mg (48%) yield; mp 192°-194° C. dec.; TLC (acetone), Rf =0.73; IR(KBr pellet) 1674, 1632, 1575, 1518, 1377, 1338, 1315, 1137, 988 cm-1 ; 1H NMR (CDCl3) δ4.17 (2 H, t, J~7 Hz, C(1) methylene), 2.89 (2H, t, J~7 Hz, C(3) methylene), 2.65 (2 H, quintet, J~7 Hz, C(2) methylene): 2.31 (4 H, s, aziridine protons), 2.02 (3 H, s, 7-methyl): mass spectrum (EI mode) m/z 243 (P+), 228 (P+ -methyl). (Anal. Calcd for C13H13N3O2 : C, 64.18; H, 5.34; N, 17.27. Found: C, 64.02; H, 5.21; N, 16.76.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15](OCC)=[O:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][OH:16])[CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@H]1CCCN(CC(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OC[C@H]1CCCN(CC(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h

Procedure:
Ethyl 1-(2,2-Diphenylethyl)-3(S)-piperidine carboxylate (4.90 g, 0.014 mol) dissolved in dry ether (40 mL) was added to a suspension of lithium aluminum hydride (1.93 g, 0.051 mol) in dry ether (40 mL). The solution was refluxed until the starting material was consumed and then was quenched with saturated potassium sodium tartrate solution (100 mL) and stirred for 2 hr. The layers were separated and the aqueous layer extracted with ether (2×). The combined organic extracts were dried (MgSO4) and concentrated to yield the title compound without further purification.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>[OH-].[Na+]>[CH2:21]([O:20][C:18]([NH:6][CH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7]([OH:9])=[O:8])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCN)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Boc-D-Orn-OH (0.50 g, 2.2 mmol) in aqueous NaOH (1M, 5 mL) at 0° C. was added benzyl chloroformate (0.37 mL, 2.6 mmol, 1.2 equiv) followed by aqueous NaOH (1M, 5 mL). After stirring for 2 hours at room temperature, the reaction mixture was poured to separatory funnel and extracted with ether. The aqueous layer was acidified to pH 3 with aqueous 10% citric acid and extracted with ethyl acetate. The combined organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to afford compound 3.2.1a (0.57 g, 72%) which was used for the next step without further purification. MS m/z (M+Na) 389.2. 1H NMR (400 MHz, DMSO-d6) 12.37 (br-s, 1H), 7.35-7.25 (m, 5H), 7.20 (t, J=5.31 Hz, 1H), 7.01 (d, J=8.02 Hz, 1H), 4.97 (s, 2H), 3.83-3.77 (m, 1H), 2.94 (dd, 2H), 1.67-1.56 (m, 1H), 1.53-1.37 (m, 3H), 1.34 (s, 9H).
Reaction SMILES: [Cl-].C[SiH](C)C.[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:15][C:16]1[CH:21]=[C:20]([CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[F:6])[N:19]=[CH:18][N:17]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Fc1ccccc1CBr
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccccc1Cc1cc(Cl)ncn1
Reaction time: 0.33 h
Yield: 28.2 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 1.9 g of 2-fluorobenzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution B). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution B was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.63 g of 4-chloro-6-(2-fluorobenzyl)pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[N:22])[CH:8]=2)[CH2:3]1.[C:24]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:1][C:2]1([CH3:23])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]([CH3:24])[C:16](=[O:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[N:22])[CH:8]=2)[CH2:3]1
Reactant: CC1(C)Cc2ccc(C#N)cc2C(Oc2cc[nH]c(=O)c2)C1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cn1ccc(OC2c3cc(C#N)ccc3CC(C)(C)C2O)cc1=O
Reaction time: 2 h

Procedure:
A mixture of 310 mg of 2,2-dimethyl-4-(2-oxo-1,2-dihydro-4-pyridyloxy)-6-cyano-1,2,3,4-tetrahydro-3-naphthol, 20 ml of acetone, 400 mg of K2CO3 and 0.2 ml of dimethylsulfate is boiled for 2 hours. The mixture is filtered and the filtrate is worked up in the customary manner to give 2,2-dimethyl-4-(1-methyl-2-oxo-1,2-dihydro-4-pyridyloxy)-6-cyano-1,2,3,4-tetrahydro-3-naphthol.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:40])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:39])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:28]4C(=O)C5C(=CC=CC=5)C4=O)[N:22]=3)=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.NN.[ClH:44]>C(O)C.CCOCC>[ClH:44].[NH2:28][CH2:27][C:23]1[N:22]=[C:21]([C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:11]([NH:10][C:7]3[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][N:8]=3)=[O:40])=[CH:18][CH:17]=2)=[O:39])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3cccc(CN4C(=O)c5ccccc5C4=O)n3)cc2)no1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3cccc(CN)n3)cc2)no1
Temperature: 70 °C

Procedure:
A suspension of N-(4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)phenyl)-6-((1,3-dioxoisoindolin-2-yl)methyl)picolinamide (60 mg, 0.11 mmol) from Step 1 of this example in ethanol was heated at 70° C. until a clear solution was observed. Hydrazine hydrate (0.1 mL) was then added, the resulting mixture was heated at 70° C. for 1 h. The reaction mixture was cooled to 0° C. and filtered through celite. The filtrate was concentrated under reduced pressure, and the crude residue was purified by preparative TLC, eluting with MeOH in DCM (10:1, v:v). The compound obtained was treated with 2N HCl in Et2O to form the corresponding hydrochloric acid salt. The salt was washed with cold water and dried in a vacuum oven to afford 6-(aminomethyl)-N-(4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)phenyl)picolinamide hydrochloride (8 mg, 16%). LC-MS (ESI) m/z 409 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1ccc(C#N)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c([N+](=O)[O-])c1
Yield: 53.1 %

Procedure:
A solution of 4-methyl-3-nitrobenzonitrile (30 g), N-bromosuccinimide (37 g) and azobisisobutyronitrile (3.1 g) in carbon tetrachloride (300 ml) was refluxed under heating for 8 hr. To the reaction mixture was added water (100 ml) and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:4) and recrystallized from ethyl acetate-hexane to give the title compound (23.7 g) as pale-yellow crystals, m.p.=85-89° C.
Reaction SMILES: [CH2:1](Br)[C:2]#[C:3][CH3:4].[CH2:6]([O:8][C:9]([CH2:11][NH:12][C:13](=[N:21][C:22]#[N:23])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:6]([O:8][C:9]([CH2:11][N:12]([CH2:1][C:2]#[C:3][CH3:4])[C:13](=[N:21][C:22]#[N:23])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10])[CH3:7]
Reactant: CC#CCBr
Reactant: CCOC(=O)CNC(=NC#N)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCN(CC(=O)OCC)C(=NC#N)Oc1ccccc1

Procedure:
11 ml but-2-ynylbromide are added to a mixture of 30.2 g 1-ethoxycarbonylmethyl-3-cyano-2-phenyl-isourea and 20.0 g potassium carbonate in 200 ml acetone. After 1 d (day) stirring at ambient temperature a further 6.5 g potassium carbonate and 3.5 ml but-2-ynylbromide are added. After another 20 h at ambient temperature the solvent is removed and ethyl acetate is added. The organic phase is washed with water, dried over sodium sulphate and evaporated to dryness.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[CH:12][O:11][CH:10]=2)=[CH:5][C:3]=1[NH2:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([NH:4][C:3]2[CH:5]=[C:6]([C:9]3[CH:13]=[CH:12][O:11][CH:10]=3)[CH:7]=[CH:8][C:2]=2[F:1])=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1cc(-c2ccoc2)ccc1F
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cc(-c2ccoc2)ccc1F

Procedure:
Using the same method as in Example 15-(i), 2-fluoro-5-(furan-3-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([2-fluoro-5-(furan-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 87%).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:10]=[C:9]([C:24]([NH:26][NH2:27])=[O:25])[CH:8]=1>>[C:2](=[N:27][NH:26][C:24](=[O:25])[C:9]1[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[N:10]=1)([CH3:4])[CH3:1]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Reactant: CC(C)=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN=C(C)C)c1

Procedure:
Acetone (10 ml, 0.0015×91 mol) was added to 4-methoxy-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.5 g, 0.0015 mol). The resultant mixture was stirred at room temperature for about one hours. The obtained reaction solution was concentrated, thereby obtaining an aimed product.