Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17].[CH2:21]([O:23][C:24]1[CH:32]=[C:31]([CH2:33][C:34]([NH:36][CH:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH2:38][CH2:39][CH3:40])=[O:35])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])[CH3:22]>C(Cl)Cl.[Cu]Cl>[CH2:21]([O:23][C:24]1[CH:32]=[C:31]([CH2:33][C:34]([NH:36][CH:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N:47]2[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]2)[CH2:38][CH2:39][CH3:40])=[O:35])[CH:30]=[CH:29][C:25]=1[C:26]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:27])[CH3:22]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1
Reactant: CC(C)(C)O
Agent: Cl[Cu]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1ccc(C(=O)OC(C)(C)C)c(OCC)c1)c1ccccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 1.9 g (9.6 mmols) of N,N'-dicyclohexyl-carbodiimide, 1.06 ml (11.2 mmols) of absolute tert.butanol and 0.020 g (0.20 mmol) of copper(I) chloride was stirred for 60 hours at room temperature. Then, 6.6 ml of methylene chloride were added, and the resulting solution was added dropwise to a solution of 0.44 g (1 mmol) of 2-ethyoxy-4-[N-{1-(2-piperidinophenyl)-1-butyl}-aminocarbonylmethyl]-benzoic acid in 15 ml of methylene chloride. After 60 hours' stirring at 20° C., the precipitate which had formed was filtered off, washed with methylene chloride, and the methylene chloride solution was evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=9/1).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][Mg]Br.Cl[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=1.CN1CCCC1=O.O>O1CCCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: FC(F)(F)CC[Mg]Br
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(CCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
(3,3,3-trifluoropropyl)magnesium bromide (8.16 mL, 8.16 mmol, Step-1) is added to a solution of methyl 6-chloronicotinate (0.70 g, 4.08 mmol), iron(III) acetylacetonate (0.14 g, 0.41 mmol) and 1-methyl-2-pyrrolidinone (0.23 mL, 2.39 mmol) in tetrahydrofuran (23 mL) and stirred at room temperature for 30 minutes. The reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (3:1) to give 0.95 g (99% yield) of the title compound as a white solid.
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:19](OCC1C=CC=CC=1)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:7][C:8](=[O:10])[NH2:9])=[O:4].O.[NH2:37][NH2:38].C(OCC)C>CO>[NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:19]([NH:37][NH2:38])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:7][C:8](=[O:10])[NH2:9])=[O:4]
Reactant: NN
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NN
Reaction time: 8 h
Yield: 93.7 %

Procedure:
BOC-Gly-Asn-Leu-OBzl (5.0 g) was dissolved in 20 ml of methanol and 20 ml of 80% hydrazine hydrate was added thereto. The mixture was allowed to stand at room temperature overnight. Diethyl ether was added to the reaction mixture to ensure complete precipitation. The precipitate was collected by filtration, washed well with diethyl ether and re-precipitated from methanol-diethyl ether to obtain 3.9 g (yield 93.7%) of the desired material having a melting point of 204°-207° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:19][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Yield: 99.1 %

Procedure:
The product from Example 7a (0.30 gm, 1 mmol) was reacted with SnCl2 as described in Example 5I to give the title compound (0.27 gm, 100%) as an amber oil which was used without further purification.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N+:8]([O-:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]=[CH2:27])=[CH:20][CH:19]=1>>[N:1]1([CH2:6][C:7]2([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[CH2:27][CH:26]([CH2:25][O:24][C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[O:10][N:8]2[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C=CCOc1ccc(OC)cc1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1cccs1
Product: COc1ccc(OCC2CC(Cn3ccnc3)(c3cccs3)N(C)O2)cc1

Procedure:
Compound 6 (R=CH2OC6H4OCH3 -4) can be prepared by a method similar to that described in Example 1 by reacting 2-(1H-imidazol-1-yl)-N-methyl-1-(2-thienyl)ethanimine N-oxide (4) with allyl 4-methoxyphenyl ether.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].O>O1CCCC1.O.CO>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:25])=[O:2])=[CH:16][CH:15]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(CC1CCCC1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
A solution of 2-(4-benzyloxy-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.38 g, 4.08 mmol) in tetrahydrofuran/water/methanol (10.2 ml, 3:1:1) was treated with a 2N aqueous sodium hydroxide solution (3.06 mL, 6.12 mmol). The reaction was stirred at 25° C. for 16 h. At this time, an additional amount of the 2N aqueous sodium hydroxide solution (3.06 mL, 6.12 mmol) was added. The reaction was stirred at 25° C. for an additional 24 h. At this time, the reaction mixture was poured into water and extracted into methylene chloride. The layers were separated. The aqueous layer was acidified to pH=1 with a 1N aqueous hydrochloric acid solution and was then extracted with a solution of methylene chloride/methano (90/10). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(4-benzyloxy-phenyl)-3-cyclopentyl-propionic acid (0.79 g, 60.2%) as a white solid: mp 112-114° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([OH:27])=[O:26].Br>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([OH:27])=[O:26]
Reactant: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1F
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(F)cc2c1C(=O)O
Temperature: 25 °C
Yield: 98.9 %

Procedure:
To a solution of 6-fluoro-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (19.5 g, 51.4 mmol) in acetic acid (50 mL) was added hydrobromic acid (140 mL, 2.57 mol) slowly. The resulting mixture was heated to reflux for 5 days. The mixture was cooled to room temperature, diluted with water and filtered. The filter cake was washed with water and air dried to afford 6-fluoro-7-hydroxy-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (18.57 g, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ14.27 (br. s., 1H), 11.04 (s, 1H), 7.90-7.95 (m, 2H), 7.87 (d, J=7.78 Hz, 1H), 7.76 (t, J=7.65 Hz, 1H), 7.50 (d, J=2.76 Hz, 1H), 7.47 (s, 1H), 2.34 (s, 3H); MS (m/z) 366.0 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.I.O>O1CCOCC1>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:27][C:24]3[CH:25]=[N:26][C:21]([C:20]([F:29])([F:19])[F:28])=[CH:22][CH:23]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: I
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cn1
Temperature: 130 °C
Yield: 95 %

Procedure:
6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.5 g, 1.93 mmol) was dissolved in anhydrous dioxane (3 mL) and 6-trifluoromethylpyridin-3-ylamine was added (469 mg, 2.9 mmol); followed by HI/H2O (0.3 mL, 47%). The mixture was heated at 130° C. for 600 s in a Personal Chemistry microwave. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the product as an orange solid (700 mg, 95% crude). The crude product was used for the subsequent step.
Reaction SMILES: [CH2:1]=O.[CH2:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH3:4].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(#N)C>[N:12]1([CH2:1][C:8]2[CH:9]=[CH:10][C:5]([CH2:3][CH3:4])=[CH:6][C:7]=2[OH:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: CCc1cccc(O)c1
Reactant: C=O
Solvent: CC#N
Product: CCc1ccc(CN2CCOCC2)c(O)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 102.6 %

Procedure:
To a 50 gallon glass lined reactor was added 23.07 pounds (0.769 mole--1.04 equiv.) of paraformaldehyde, followed by 92 pounds (%Wt/Wt Phenol to Solvent--100%) of acetonitrile, and then 92 pounds (0.739 mole--1.0 equiv.) of 98.0% pure m-ethylphenol. The mixture was heated to 65° C., and 66.2 pounds (0.761 mole--1.03 equiv.) of morpholine was added at a rate of 0.5 lb./min. during a two hour period. Upon completion of addition, the reaction mixture was heated to 65-70° C. where it stirred for three hours. After this time, the reaction mixture was concentrated under vacuum at 70° C., yielding 171 pounds of 89.4% pure 2-(morpholin4-ylmethyl)-5-ethylphenol (93% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24]([Cl:31])=[CH:25][C:26](Cl)=[N:27]4)=[CH:22][CH:21]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[NH2:32][NH2:33]>CCO>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24]([Cl:31])=[CH:25][C:26]([NH:32][NH2:33])=[N:27]4)=[CH:22][CH:21]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: NN
Reactant: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(Cl)cc(Cl)nc4c3)c2)CCOCC1
Solvent: CCO
Product: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(Cl)cc(NN)nc4c3)c2)CCOCC1
Temperature: 60 °C

Procedure:
To 5b (1.7 g, 3.7 mmol) in EtOH (60 mL) was added hydrazine, anhydrous (10 mL), and the reaction was heated to 60° C. for 2 hours. After cooling to room temperature, the mixture was concentrated, and the residue was diluted with CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product, 5c.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.[CH3:13][NH:14][NH2:15]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:11])[N:14]([CH3:13])[N:15]=2)=[CH:4][CH:3]=1
Reactant: N#CCC(=O)c1ccc(Cl)cc1
Reactant: CNN
Solvent: CCO
Product: Cn1nc(-c2ccc(Cl)cc2)cc1N
Yield: 46 %

Procedure:
A solution of 3-(4-Chloro-phenyl)-3-oxo-propionitrile (1.8 g, 10 mmol) and N-Methylhydrazine (1 mL, excess) in EtOH (30 mL) was stirred to reflux 3 hours. After cooling the precipitate was filtered off, to give the title compound (950 mg, 4.6 mmol) as white crystals in a 46% yield.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH:7]=[C:6](C)[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])[C:4]=2[O:3]1.[H][H].O1CCC[CH2:21]1>[Pd]>[O:17]=[S:2]1(=[O:1])[CH:7]([CH3:21])[CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([S:13]([NH2:16])(=[O:14])=[O:15])[C:4]=2[O:3]1
Reactant: C1CCOC1
Reactant: [H][H]
Reactant: CC1=CS(=O)(=O)Oc2c1cccc2S(N)(=O)=O
Agent: [Pd]
Product: CC1Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O

Procedure:
10.0 g of 2,2-dioxo-4-methyl-1,2-benzoxathiin-8-ylsulfonamide are dissolved in 200 ml of tetrahydrofuran and the solution is hydrogenated with hydrogen for 21/2 hours, in the presence of 2.0 g of 5% palladium on carbon catalyst, under a pressure of 4 bar and at a temperature of 40° C. After removal of the catalyst the solution is concentrated and the residue is crystallised from 120 ml of 70% aqueous ethanol, affording 9.0 g of 3,4-dihydro-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide of m.p. 185°-186° C.
Reaction SMILES: [NH:1]([C:8]1[O:9][CH2:10][C:11](=O)[C:12]=1[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1.Cl>C(Cl)Cl.O.C(N(CC)CC)C>[C:2]1([NH:1][C:8]([C:12]2[C:13](=[O:15])[O:14][CH2:10][C:11]=2[NH:37][C:36]2[CH:38]=[CH:39][C:33]([Cl:32])=[CH:34][CH:35]=2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)C1=C(Nc2ccccc2)OCC1=O
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccc1)C1=C(Nc2ccc(Cl)cc2)COC1=O
Reaction time: 0.75 h

Procedure:
Under nitrogen atmosphere, 8.5 ml of triethylamine was added dropwise over a period of 40 min to a solution of 2-anilino-4-oxo-3-furoic acid (13.37 grams, 0.061 mol) in 110 ml methylene chloride at 0° C. Then BOP-Cl was added in one portion and the mixture was stirred at 0°-5° C. for 45 min. A solution of p-chloroaniline (7.8 grams, 61 mmol) in 50 ml methylene chloride was added rapidly over 10 min followed by the dropwise addition (1.5 hours) of a solution of triethylamine (8.5 ml) in 10 ml methylene chloride. The reaction mixture was stirred at 0°-5° C. for 30 min and at room temperature for 20 hours. After cooling, 150 ml of water were added and the reaction mixture was acidified with 4N hydrochloric acid (pH 1), and then extracted with methylene chloride. The organic extract was washed sequentially with water, 5% aqueous solution of sodium bicarbonate, and water. The washed extract was dried over sodium sulfate and the solvent evaporated under reduced pressure. The crude product was recrystallized from toluene. Yield: 9.2 gram, mp 209°-210° C. (R=C6H4Cl--p).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1.[ClH:44]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:44][C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1
Reactant: Cl
Reactant: COC(=O)COc1nc(Cl)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1nc(Cl)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
First, isoamyl nitrite is added dropwise to a mixture of methyl [3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-chloro-2-pyridyloxy]acetate, copper (I) chloride, copper (II) chloride, and acetonitrile at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is poured into 2% hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue is subjected to silica gel column chromatography to give methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-chloro-2-pyridyloxy]acetate (compound a-108).
Reaction SMILES: [NH:1]([C:8]1[C:9](=O)[NH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:17]C1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[C:33]([C@@]1(C(O)=O)CCCN1OC)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C1(C)C=CC=CC=1>[C:33]([N:10]1[CH2:11][CH2:12][CH2:13][C@H:9]1[C:8]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:17])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CON1CCC[C@]1(C(=O)O)C(=O)OC(C)(C)C
Reactant: O=c1[nH]cccc1Nc1ccccc1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Reaction time: 18 h
Yield: 129.3 %

Procedure:
0.76 g (4.076 mmol) of anilinopyridone 2 and 1.008 g (4.076 mmol) of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate are added successively with stirring at room temperature to 1.0 g (4.076 mmol) of BOC-methoxyproline 1 as a suspension in 15 ml of toluene. The mixture is subsequently stirred at this temperature for 18 hours and then subjected to conventional work-up, giving 1.53 g (90.8%) of BOC-proline anilide derivative 3 as crude product; MS-EI (M+) 414.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][CH2:5][C:4](C2C=CC(N3C=CN=C3)=CC=2)=[N:3]1.OCC[N:23]1[C:28](=[O:29])[CH2:27][CH2:26][C:25](C2C=CC(N3C=CN=C3)=CC=2)=[N:24]1.BrBr>C(O)(=O)C>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][CH:4]=[N:3]1.[N:24]1[NH:23][C:28](=[O:29])[CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CCC(c2ccc(-n3ccnc3)cc2)=NN1CCO
Reactant: CN1N=C(c2ccc(-n3ccnc3)cc2)CCC1=O
Agent: BrBr
Solvent: CC(=O)O
Product: Cn1ncccc1=O
Product: O=c1cccn[nH]1

Procedure:
Using the procedure of this Example, reaction of 4,5-dihydro-2-methyl-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone and 4,5-dihydro-2-(2-hydroxyethyl)-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone with bromine in acetic acid gives 6-[4-1H-imidazol-1-yl)phenyl]-2-methyl-3(2H)-pyridazinone (13e) and 2-(2-hydroxyethyl)-6-[4-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone respectively (13f).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4](Cl)[N:3]=1.[NH3:18]>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:18])[N:3]=1
Reactant: N
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: CO
Product: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (55 g) was dissolved in 7N-aqueous ammonia in methanol (500 ml) and heated at 100° C. in a sealed flask for 6 h. The reaction mixture was cooled to rt and left overnight. Filtration afforded the subtitle compound. Yield 40 g.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)#[N:4].Cl[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH2:24]2)=[CH:18][N+:17]=1[O-].Cl.P(Cl)(Cl)Cl>CN(C)C=O.C(OCC)(=O)C>[OH:14][C:9]1[NH:10][C:11]2[C:7]([C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH2:24]3)=[CH:18][N:17]=1)=[CH:6][C:5]([C:3]#[N:4])=[CH:13][CH:12]=2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: CC1CCCN(Cc2ccc(Cl)[n+]([O-])c2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CCCN(Cc2ccc(-c3c(O)[nH]c4ccc(C#N)cc34)nc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.1 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 45 mg, 1.12 mmol) in N,N-dimethylformamide (1 mL) was added 5-cyanooxindole (133 mg, 0.84 mmol), and the mixture was stirred at ambient temperature for 10 min. To the obtained brownish solution was added a solution of 2-chloro-5-[(3-methylpiperidin-1-yl)methyl]pyridine 1-oxide (0.56 mmol) in N,N-dimethylformamide (1.5 mL). The reaction mixture was heated at 130° C. for 30 min, and was then allowed to cool. To the residue was added 2 M HCl(aq) and the obtained suspension was washed with ethyl acetate. The aqueous layer was neutalized with 45% NaOH(aq) and alkalized to saturation with NaHCO3 (s), and extracted two times with ethyl acetate. The extracts were combined, dried (MgSO4) and the solvent was removed in vacuo affording 84 mg of the crude product. The material was dissolved in ethyl acetate (10 mL), and to the solution was added phosphorus trichloride (0.2 mL, 2.24 mmol). The obtained orange suspension was heated at reflux for 1 h and was then allowed to cool. The precipitate was filtered, washed with ethyl acetate, and dried in vacuo affording 70 mg of an orange residue. The material was was purified by preparative HPLC (column: Xterra, C8, 7 μm, 19×300 mm; eluent: 0.1 M NH4OAc buffer/acetonitrile, 8:2 to 4:6) affording 15 mg (8% yield) of the title compund as an orange solid: 1H NMR (aceton-d6, 400 MHz) δ 9.86 (br s, 1 H), 8.11 (s, 1 H), 7.91 (dd, J=9, 2 Hz, 1 H), 7.84 (d, J=9 Hz, 1 H), 7.82 (d, J=1 Hz, 1 H), 7.26 (dd, J=8, 2 Hz, 1 H), 7.11 (d, J=8 Hz, 1 H), 3.44 (s, 2 H), 2.00-1.50 (m, 6 H), 0.95-0.81 (m, 4 H); MS (ES) m/z 347 (M++1).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[C-:26]#[N:27].[Na+].[C:29]([C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)#[N:30]>>[C:29]([C:31]1[CH:37]=[CH:36][C:34]([NH:35][C:2]2([C:26]#[N:27])[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:4][CH2:3]2)=[CH:33][CH:32]=1)#[N:30]
Reactant: N#Cc1ccc(N)cc1
Reactant: [C-]#N
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4ccc(C#N)cc4)CC3)c(F)c2)C(=O)O1
Yield: 55 %

Procedure:
By using procedure as described in Example 45 and by reacting (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with sodium cyanide and 4-cyanoaniline the title compound was obtained in 55% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[C:18]([CH3:26])[CH:17]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[C:18]([CH3:26])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc(Br)cc1
Temperature: 150 °C
Reaction time: 14 h
Yield: 68.8 %

Procedure:
37.5 g (216.7 mmol) of 4-bromophenol and 35.4 g (256.2 mmol) of potassium carbonate are suspended in 500 ml of N,N-dimethylformamide and the suspension is stirred at room temperature for 1 h, before 36.6 g (197.0 mmol) of 4-chloro-2,5-dimethylnitrobenzene are added. The mixture is subsequently stirred at 150° C. for 14 h, water is added, and repeated extraction is carried out with ethyl acetate. The extracts are dried over Na2SO4 and filtered and the solvent is removed under reduced pressure. This is followed by purification by column chromatography (48.0 g, purity 91.0%, yield 68.8%, log P (pH 2.3)=4.86).