Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([C:16](=[NH:19])[NH:17][OH:18])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.[OH-].[Na+].[CH3:29]OS(OC)(=O)=O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:11]=[CH:12][C:13]([C:16](=[NH:19])[NH:17][O:18][CH3:29])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: N=C(NO)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CONC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-hydroxycarbamimidoyl)benzamide was cooled to 0° C. in 1.5 mL of Dioxane. 5 mL of 2N NaOH was slowly added followed by dropwise addition of 33 μL of dimethylsulfate. The ice bath was removed and reaction was stirred at room temperature for 1 hour. The reaction was subsequently evaporated and extracted with water twice in Ethyl Acetate, dried with Magnesium Sulfate, filtered and concentrated to yield pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methoxycarbamimidoyl)benzamide. MS (Q1) 381 (M)+.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([OH:13])=O.Cl.[C:15]([O:19][C:20](=[O:25])[C:21]([NH2:24])([CH3:23])[CH3:22])([CH3:18])([CH3:17])[CH3:16].C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[C:15]([O:19][C:20](=[O:25])[C:21]([NH:24][C:11]([C:3]1[CH:4]=[CH:5][C:6]2[S:7][CH:8]=[CH:9][C:10]=2[C:2]=1[OH:1])=[O:13])([CH3:23])[CH3:22])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C(O)c1ccc2sccc2c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1ccc2sccc2c1O
Yield: 64.5 %

Procedure:
To a solution of 300 mg 4-Hydroxy-benzo[b]thiophene-5-carboxylic acid in 5 ml N,N-dimethylformamide were added 42 mg 1-hydroxy-benzotriaziole and 285 mg 2-amino-2-methyl-propionic acid tert-butyl ester hydrochloride. At 0° C. 0.77 ml (600 mg) ethyl-diisopropyl-amine and 444 mg (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride were added. After 16 h at room temperature 0.51 ml (400 mg) ethyl-diisopropyl-amine and 444 mg (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride were added, and after additional 16 h the reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulphate and concentrated. The resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate) to afford 315 mg 2-[(4-hydroxy-benzo[b]thiophene-5-carbonyl)-amino]-2-methyl-propionic acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][CH:3]=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(OCC)(=O)C.FC(F)(F)C(O)=O>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)=[CH:12][CH:11]=2)([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH:29]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:21][CH:22]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: CC(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccc(OC2CCCCO2)cc1)(c1ccc(OC2CCCCO2)cc1)c1ccc(OC2CCCCO2)cc1
Reaction time: 8 h
Yield: 77 %

Procedure:
2.53 g (8.26 mmol) of 1,1,1-tris(4-hydroxyphenyl)ethane was dissolved in 20 mL of ethyl acetate in a round bottom flask. 8 mL of 2,3-dihydropyran and 8 drops of trifluoroacetic acid were added to the mixture. After stirring overnight, a white precipitate had formed in the flask. This precipitate was collected by filtration and dissolved in 20 mL of dichloromethane to which was added 8 mL of 2,3-dihydropyran and 6 drops of trifluoroacetic acid. After stiffing for two days, 20 mL of 0.261 N TMAH was added; the organic phase was extracted, washed with water (20 mL) twice, and dried with MgSO4. The solvent was removed in vacuo to yield 2.82 g of THPE-THP as a white powder. Yield: 77%. 1H-NMR (300 MHz, CDCl3) δ (ppm) 1.5-2.0 (18H), 2.09 (3H), 3.60 (3H), 3.92 (3H), 5.37 (3H), 6.91 (6H), 6.98 (6H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>ClCCl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[N:19]1[CH2:20][CH2:21][N:22]([C:1]([Cl:4])=[S:2])[CH2:23][CH2:24]1
Reactant: COc1cc2ncnc(N3CCNCC3)c2cc1OC
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(N3CCN(C(=S)Cl)CC3)c2cc1OC
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To a solution of 3.06 ml (40.1 mmol) of thiophosgene in 100 ml of dichloromethane were slowly added a solution of 10 g (36.5 mmol) of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline obtained by the method described in South African Patent No. 67 06512 (1968) in 100 ml of dichloromethane and 12.4 ml (89.1 mmol) of triethylamine under ice-cooling. The resulting mixture was stirred at the same temperature in an atmosphere of argon for 2 hours. After the solvent was evaporated, the residue was purified by silica gel chromatography to give 6.65 g (52%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=C(C2CCCC(=NO)C=2)C=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].Cl>C(O)(=O)C>[C:28]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:30])[CH3:29]
Reactant: Nc1cccc(-c2cccnc2)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: ON=C1C=C(c2cccnc2)CCC1
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2cccnc2)c1
Reaction time: 3 h

Procedure:
D-2. 3-(3-Aminophenyl)pyridine -- To a mixture containing 28.9 g. of 3-(3-pyridinyl)-2-cyclohexen-1-one oxime, 42 ml. of acetic acid and 42 ml. of acetic anhydride was passed gaseous hydrogen chloride whereupon the temperature rose to about 120° C. The hydrogen chloride was passed continuously into the reaction mixture until the temperature fell to about 50° C. The reaction mixture was allowed to stand for three hours and then concentrated in vacuo to yield, as a glassy material, 3-(3-acetamidophenyl)pyridine. To this material was added 100 ml. of water and 25 ml. of concentrated hydrochloric acid and the resulting mixture was refluxed for sixteen hours and concentrated in vacuo to yield a yellow solid. The solid was taken up in water and the solution was made alkaline with 35% aqueous sodium hydroxide solution. The alkaline solution was extracted three times with ethylene dichloride. The extract was washeed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield an oil. The oil was distilled under reduced pressure, collecting the fraction boiling at 141°-145° C. at 0.15 mm. to yield, a first as a yellow oil which crystallized on cooling, 17.7 g. of 3-(3-aminophenyl)pyridine, m.p. 72°-74° C.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][C:8]2[C:3]3=[C:4]([C:11]4[C:20]([C:2]=13)=[CH:19][C:18]1[CH:17]=[C:16]([C:21](OCC)=[O:22])[CH:15]=[CH:14][C:13]=1[N:12]=4)[CH:5]=[CH:6][CH:7]=2.C1COCC1.Cl>O>[CH:1]1[CH:10]=[CH:9][C:8]2[C:3]3=[C:4]([C:11]4[C:20]([C:2]=13)=[CH:19][C:18]1[CH:17]=[C:16]([CH2:21][OH:22])[CH:15]=[CH:14][C:13]=1[N:12]=4)[CH:5]=[CH:6][CH:7]=2
Reactant: CCOC(=O)c1ccc2nc3c(cc2c1)-c1cccc2cccc-3c12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2nc3c(cc2c1)-c1cccc2cccc-3c12
Yield: 81.6 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet line with bubbler was added ethyl acenaphtho[1,2-b]quinoline-10-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc., 6.75 g, 23, mmol and dry THF (400 mL). The mixture was stirred at reflux for 3 h and then poured into H2O (1 L). The reaction mixture was acidified with 1 N HCl and the resulting white solid was filtered, washed with additional H2O (500 mL) then dissolved in CH2Cl2 (500 mL), dried (Na2SO4), filtered, passed through a small plug of SiO2 using CH2Cl2 as the eluting solvent. The appropriate fractions were combined and the volume reduced to 100 mL and diluted to 400 mL with hexane. The resulting material was filtered, washed with hexane (100 mL) and placed in a vacuum oven overnight. A total of 5.52 g (81.6% yield) of acenaphtho[1,2-b]quinoline-10-methanol, mp 215°-218° was obtained which analyzed correctly (C,H,N) for the assigned structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: COc1ccc(B(O)O)c(Cl)c1
Product: COc1ccc(-c2cc3c4c(c2)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2N4CC3)c(Cl)c1

Procedure:
The title compound was prepared by the method of Example 90 from tert-butyl (±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (121 mg, 0.27 mmol) and corresponding 2-chloro-4-methoxyphenylboronic acid (100 mg, 0.54 mmol), to afford after chromatographic purification the title compound (141 mg, 68%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ7.21 (d, 1H, J=8.4 Hz), 6.94-6.99 (m, 3H), 6.82 (dd, 1H, J=2.9 Hz, 8.8 Hz), 3.75-4.00 (m, 7H), 3.60-3.70 (m, 1H), 3.10-3.50 (m, 7H), 2.80-3.00 (m, 1H), 1.70-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS (CI, NH3): 441 (base, M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1O.[C:30]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:30][O:16][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][CH:20]=[C:12]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH2:3][CH2:2][O:1][C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][C:26]=3[Cl:28])[CH:5]=2)[CH:13]=1
Reactant: COc1ccc(-c2cccc(C(=O)O)c2)cc1CCO
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1ccc(Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2ccc(OC)c(CCOc3ccc(Cl)cc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
53 mg of 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]benzoic acid, 45 mg of 2,4-dichlorophenol and 73 mg of triphenyl phosphine were dissolved in 2 ml of THF, and 73 ml of diisopropyl azodicarboxylate was added thereto. The mixture was stirred overnight at room temperature, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give 84 mg of methyl-3-{3-[2-(2,4-dichlorophenoxy)ethyl]-4-methoxyphenyl}benzoate. This product was dissolved in 2 ml of of ethanol and 0.5 ml of 5N sodium hydroxide and then heated. The reaction mixture was neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The solvent was evaporated to give 42 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=3)=[O:18])[NH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:28](O)[CH3:29]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:23][CH:24]=3)=[O:18])[NH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCc2cc(NC(=O)c3ccc(C(=O)O)nc3)[nH]n2)c1
Reactant: CCO
Product: CCOC(=O)c1ccc(C(=O)Nc2cc(CCc3cccc(OC)c3)n[nH]2)cn1
Yield: 15 %

Procedure:
Preparation was analogous to that described for Example 67, except using 5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylic acid (55 mg, 0.15 mmol, 1 eq) in ethanol (0.5 mL) to give title compound as a white solid (9 mg, 15% yield); 1H NMR (400.13 MHz, DMSO) δ 1.40 (3H, t), 2.97 (4H, s), 3.79 (3H, s), 4.44 (2H, q), 6.54 (1H, s), 6.8 (1H, m), 6.87 (2H, m), 7.25 (1H, t), 8.19 (1H, d), 8.52 (1H, m), 9.25 (1H, s), 11.17 (1H, s), 12.3 (1H, s) MS m/z 395 (MH+)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[SH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[Si:5]([O:4][CH2:3][CH2:2][S:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: O=C(O)c1cccc(S)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCSc1cccc(C(=O)O)c1
Reaction time: 2 h

Procedure:
(2-Bromoethoxy)(tert-butyl)dimethylsilane (1.48 mL) was added dropwise to a suspension of 3-mercaptobenzoic acid (1.07 g) and potassium carbonate (1.91 g) in DMF (15 mL). The resulting suspension was stirred for 2 h. The reaction was carefully acidified by dropwise addition of aqueous HCl (2M, 10 mL) and poured into water (100 mL). The resulting aqueous was extracted with ethyl acetate (3×100 mL). The combined organics were washed with brine (50 mL), dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a clear oil. Yield 2.8 g.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[Na].Br[CH2:9][CH2:10][CH2:11][Cl:12].[C:13]1(C)C=CC=CC=1>>[Cl:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:5][CH2:4][CH2:3][CH2:13][C:2]1=[O:6]
Reactant: Cc1ccccc1
Reactant: ClCCCBr
Reactant: O=C1CCCN1
Agent: [Na]
Product: O=C1CCCCN1CCCCl
Temperature: 120 °C
Reaction time: 7 h

Procedure:
A mixture of 2-pyrrolidone (2 g, 23.0 mmol) and finely pulverized sodium metal (0.529 g, 23.0 mmol) in dry toluene (120 ml) was heated at 120° C. with vigrous stirring. 1-Bromo-3-chloropropane (3.97 g, 25.0 mmol) was added to the stirred reaction mixture after 6-7 hours and the heating at 120° C. was continued for 7 hours. The reaction mixture was filtered and toluene was removed under reduced pressure. The residue was distilled under reduced pressure to give the compound 3 (), B.P. 145° C./1 mm., yield 2.86 g (75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:33]1([C:39]2NN=[N:41][N:40]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:17][C:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:40][N:41]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nnc(-c2ccccc2)o1
Temperature: 100 °C
Yield: 64.1 %

Procedure:
A mixture of 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (1.22 g), (Peschke, Bernd, Ankersen, Michael; Hansen, Birgit Sehested; Hansen, Thomas Kruse; Johansen, Nils Langeland, Lau, Jesper; Madsen, Kjeld, Petersen, Hans; Thogersen, Henning; Watson, Brett. Eur. J. Med. Chem. (1999), 34(5), 363-380), dicyclohexylcarbodiimide (1.05 g) and 5-phenyltetrazole (0.73 g) in toluene (25 ml) was heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether and solvent decanted from the precipitated gum. The gum was column chromatographed (silica gel, 0-50% ethyl acetate in pentane eluant) to give the title compound (1.1 g).
Reaction SMILES: [N:1]1([CH2:6][C:7](=[O:14])[C:8]([CH3:13])([CH3:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[K+].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CS(C)=O.O>[CH3:11][CH:9]([C:8]([CH3:12])([CH3:13])[C:7](=[O:14])[CH:6]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=1)[CH3:10]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)C(C)(C)C(=O)Cn1cncn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)C(C)(C)C(=O)C(Cc1ccc(Cl)cc1)n1cncn1
Temperature: 100 °C
Reaction time: 15 h
Yield: 67.6 %

Procedure:
15.6 g (0.08 mol) of 1-(1,2,4-triazol-1-yl)-3,3,4-trimethylpentan-2-one are dissolved in 100 ml of dimethylsulphoxide, and 4.5 g (0.08 mol) of potassium hydroxide, dissolved in 10 ml of water, are added, while cooling. 16.4 g (0.08 mol) of 4-chlorobenzyl bromide, dissolved in 50 ml of dimethylsulphoxide, are added dropwise to the mixture at a rate such that the temperature does not exceed 40° C. Thereafter, the mixture is slowly warmed to 100° C. and stirred for a further 15 hours at this temperature, and the cooled solution is poured onto 500 ml of water. The mixture is extracted with twice 250 ml of methylene chloride, the methylene chloride phase is then extracted with four times 100 ml of water, and the organic phase is evaporated down. The residue is taken up in 100 ml of acetone, and 14.4 g of naphthalene-1,5-disulphonic acid, dissolved in 50 ml of acetone, are added. The 2,3,3-trimethyl-5-(1,2,4-triazol-1-yl)-6-(4-chlorophenyl)-hexan-3-one salt of naphthalene-1,5-disulphonic acid crystallizes out. The precipitate is filtered off under suction and taken up in 250 ml of saturated sodium bicarbonate solution, the aqueous phase is extracted with four times 100 ml of methylene chloride, the methylene chloride phase is extracted with 100 ml of water, and the solvent is distilled off from the organic phase. 17.3 g (67.6% of theory) of 2,3,3-trimethyl-5-(1,2,4-triazol-1-yl)-6-(4-chlorophenyl)-hexan-4-one are obtained as colorless crystals of melting point 91°-94° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20].C(N(CC)CC)C.C(OCC)(=O)C>CS(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:10]2[C:11]([N+:19]([O-:21])=[O:20])=[CH:12][CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: Cc1ccc(N)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2c([N+](=O)[O-])cccc2[N+](=O)[O-])cc1
Reaction time: 12 h
Yield: 98.9 %

Procedure:
0.8 g (7.4 mmol) of p-toluidine and 1.5 g of 1-chloro-2,6-dinitrobenzene were dissolved in 15 ml of dimethyl sulfoxide and 1.5 g (14.8 mmol) of triethylamine was added thereto. After stirring at 80° to 90° C. for 12 hours, ethyl acetate was added and the reaction mixture was washed with water and dried over magnesium sulfate. After concentrating, the residue was purified by silica gel column chromatography. Thus 2.0 g of N-(4-methylphenyl)-2,6-dinitroaniline was obtained. This product was dissolved in a mixture of 20 ml of methanol with 40 ml of tetrahydrofuran and hydrogenated in the presence of palladium-carbon at room temperature under atmospheric pressure. After filtering off the catalyst, the solvent was distilled off under reduced pressure. Thus 1.6 g of the title compound was obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:42]=[C:43]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:44][NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:47]>CN(C=O)C.O>[Cl:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:11]([Cl:10])[C:12]=1[C:13]([N:63]1[CH2:62][CH2:61][N:60]([C:43](=[O:42])[CH2:44][NH:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)=[O:47])[CH2:65][CH2:64]1)=[O:15]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2c(Cl)cccc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 16.8 %

Procedure:
DIPEA (159.8 mg, 0.21 mL, 1.2 mmol) was added to a stirred solution of 2,6-dichloro-benzoic acid (59 mg, 0.3 mmol) in DMF (3 mL). HOBT (45.9 mg, 0.34 mmol) and EDCI (130.4 mg, 0.68 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (120 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 25 mg (16.3% yield) of biphenyl-4-carboxylic acid {2-[4-(2,6-dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 86.98%. 1H NMR (CDCl3): δ 7.96-7.86 (d, 2H), 7.72-7.56 (dd, 4H), 7.5-7.34 (m, 6H), 7.32-7.2 (m, 2H), 4.4-4.24 (dd, 2H), 4.0-3.8 (bs, 2H), 3.8-3.6 (m, 3H), 3.6-3.5 (t, 1H), 3.4-3.24 (q, 2H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][C:5]=2[N:24]=1.[OH-:25].[K+].Cl.[CH3:28]O>>[CH3:28][O:25][C:2]1[S:3][C:4]2[C:9]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][C:5]=2[N:24]=1
Reactant: [OH-]
Reactant: CO
Reactant: CC(C)(CO)Nc1nc(SCc2ccccc2)nc2nc(Br)sc12
Agent: Cl
Agent: [K+]
Product: COc1nc2nc(SCc3ccccc3)nc(NC(C)(C)CO)c2s1
Reaction time: 0.5 h

Procedure:
To a solution of the product from example 1 step e) (0.36 g) in methanol (5 ml) was added potassium hydroxide (0.095 g) and the mixture stirred for 30 mins. The mixture was neutralised with concentrated hydrochloric acid then evaporated to dryness and purified (SiO2, ethyl acetate:dichloromethane 1:9 as eluant) to give the subtitle compound as a colourless solid (0.245 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9](=[O:22])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C[CH:24]1[CH2:29][CH2:28][CH2:27][CH:26](C)N1.C(C1CC1)#C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH:28]1([C:27]#[C:26][C:2]2[CH:3]=[C:4]([C:9](=[O:22])[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=3)=[O:11])[CH:5]=[CH:6][C:7]=2[F:8])[CH2:29][CH2:24]1
Reactant: O=C(C(=O)c1ccc(F)c(Br)c1)c1ccc(OC(F)F)cc1
Reactant: CC1CCCC(C)N1
Agent: [Pd]
Agent: C#CC1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: O=C(C(=O)c1ccc(F)c(C#CC2CC2)c1)c1ccc(OC(F)F)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(3-bromo-4-fluorophenyl)-2-[4-(difluoromethoxy)phenyl]ethane-1,2-dione (2.1 g, 5.63 mmol), 2,6-dimethylpiperidine (10 mL), and ethynylcyclopropane (0.74 g, 11.27 mmol) was degassed with argon for 5 minutes. Then, tetrakis(triphenylphosphine) palladium (0) (327 mg, 0.28 mmol) was added and the mixture was stirred at 80° C. for 5 hours. The mixture was poured into water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by ICSO (hexane/EtOAc 5/1) gave 1-[3-(cyclopropylethynyl)-4-fluorophenyl]-2-[4-(difluoromethoxy)phenyl]ethane-1,2-dione as a yellow oil solid (1.37 g); MS m/e (M)+ 358.