Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:11]2[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[CH3:9])[N:3]=1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: Cc1cc(C)c(-c2cccc(Br)n2)c(C)c1
Temperature: 50 °C
Yield: 67.7 %

Procedure:
2,6-Dibromopyridine (9.47 g, 40 mmol) was dissolved in 80 mL of 1,2-dimethoxyethane (1,2-dimethoxyethane). Tetrakis(triphenylphosphine)palladium(0) (2.31 g, 2.00 mmol) was added and the mixture was heated at 50° C. for 15 min. The solution was cooled and 2,4,6-trimethylbenzeneboronic acid (6.56 g, 40 mmol) dissolved in 40 mL of 1,2 dimethoxyethane was added. Finally, potassium t-butoxide (8.97 g, 80 mmol) was added as a solution in 40 mL of t-butanol. The reaction was heated for 0.5 h at 90° C. The solution was cooled and filtered through celite. Flash chromatography (2% ethyl acetate/hexanes) gave 7.48 g (68% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.O[CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>>[N:18]1([CH2:17][CH2:16][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:14])[CH2:7][C:8]([CH3:12])([CH3:13])[O:9]3)=[CH:4][CH:3]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: OCCn1ccnc1
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Product: CC1(C)CC(=O)c2ccc(OCCn3ccnc3)cc2O1

Procedure:
Following the procedure of Example 30 but using 7-hydroxy-2,2-dimethyl-4-chromanone and 1-(2-hydroxyethyl)imidazole, there was obtained the title compound as a solid, mp 84-86° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 287 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33]C)[C:6]([NH:8][C:9]1[S:10][C:11]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[N:13]=1)=[O:7].B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[OH:33])[C:6]([NH:8][C:9]1[S:10][C:11]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[N:13]=1)=[O:7]
Reactant: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2CCc2ccccc2)cc1
Agent: BrB(Br)Br
Product: O=C(Nc1nc(-c2ccc(O)cc2)c(CCc2ccccc2)s1)c1ccc(O)c(O)c1
Yield: 53.8 %

Procedure:
A procedure similar to that in Example 7 was used. 3,4-dimethoxy-N-[4-(4-methoxy-phenyl)-5-phenylethyl-thiazol-2-yl]-benzamide prepared in Example 58 and boron tribromide were used as starting materials, the crude product was purified by recrystallization with ethyl acetate to obtain a product as a white solid in a yield of 53.8%, mp: 208-209 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 2.94 (2H, t, J=7.60 Hz, CH2), 3.11 (2H, t, J=7.60 Hz, CH2), 6.81 (3H, d, J=8.40 Hz, ArH), 7.17˜7.31 (5H, m, ArH), 7.35 (2H, t, J=7.60 Hz, CH2), 7.47˜7.55 (2H, m, ArH), 12.23 (1H, br, CONH); EI-MS m/e (%): 432.1 (M+, 4), 205.0 (100), 163.0 (28); HREI-MS Calcd. for C24H20N2O4S: 432.1144. found: 432.1140.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH:7]([NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)=[O:34])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=[O:19])[CH2:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>ClC(Cl)C>[O:36]1[CH:37]=[CH:38][CH:39]=[C:35]1[C:33]([NH:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([C:18]([NH:17][CH:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:40])=[O:5])=[O:19])=[CH:21][CH:22]=2)=[CH:31][CH:30]=1)=[O:34]
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(NC(=O)c3ccco3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C(O)CCC(NC(=O)c1ccc(-c2ccc(NC(=O)c3ccco3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
2-({4′-[(Furan-2-carbonyl)-amino]-biphenyl-4-carbonyl}-amino)-pentanedioic acid di-tert-butyl ester (369 mg, 0.67 mmol) was dissolved in dichloroethane (10 mL) and added to TFA (5 mL) at 0° C. The cooling bath was removed after the addition was complete. The mixture was stirred at room temperature for 3 hrs. and the reaction was complete as determined by TLC. After removing solvent, the residue was washed 3 times with EtOAc. The solid was then dried under vacuum to give 2-({4′-[(Furan-2-carbonyl)-amino]-biphenyl-4-carbonyl}-amino)-pentanedioic acid in 85.6% yield (251 mg). MS (ESI) m/z 437.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[N:12]([O-])=O.[Na+]>O.Cl>[F:11][C:8]([F:9])([F:10])[C:4]1[CH:3]=[C:2]([NH:1][NH2:12])[CH:7]=[CH:6][CH:5]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(C(F)(F)F)c1

Procedure:
m-Aminobenzotrifluoride (48.34 g: 0.3 mole) was cooled and treated with concentrated hydrochloric acid (137 ml) added dropwise. The paste was stirred at 0° and a solution of sodium nitrite (19.1 g) in water (137 ml) was added at 0°-5° with stirring. An almost clear solution was obtained. Then a solution of stannous chloride dihydrate (191.3 g) in concentrated hydrochloric acid (137 ml) was added dropwise with stirring at 0°-10°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21].C(N(CC)CC)C>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH:21][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.7 %

Procedure:
In DCM (100 mL) were dissolved ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.55 mmol), 3-chloro-4-methoxybenzylamine hydrochloride salt (4.0 g, 23.4 mmol) and triethylamine (4.35 g, 43.1 mmol). The reaction mixture was stirred at ambient temperature for 10 h and washed with water. The organic phase was dried over magnesium sulfate and concentrated to give ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate as a solid (6.0 g, 76% yield).
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH2:15][OH:16])=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C>[OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH2:15][O:16][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1c2cc(CO)ccc2-c2c(O)cccc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)C(=O)c1cccc(O)c1-2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 89.4 %

Procedure:
A mixture of 332.2 mg (1.47 mmol) of the diol from Step H, 243.5 mg (1.61 mmol) of t-butyldimethylchlorosilane, and 120 mg (1.76 mmol) of imidazole in 8 mL of sieve dried DMF was stirred at 0° C. for 45 minutes. The mixture was partitioned between EtOAc, ice-water and 2N HCl, and the organic phase was separated, washed twice with ice-water, and then with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by PLC using CH2Cl2-EtOAc (50:1) gave 447.4 mg of the title material.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][CH2:10][CH2:11][C:5]2=[N:4][N:3]=1.[Cl:16][C:17]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:20].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[N:9]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:17]=4[Cl:16])=[CH:30][CH:29]=3)=[O:27])[CH2:10][CH2:11][C:5]2=[N:4][N:3]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Reactant: Cc1nnc2n1-c1ccccc1NCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nnc2n1-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5 mmol of 5,6-dihydro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-[(2,4-dichlorobenzoyl)amino]benzoyl chloride and 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 hours and then washed with water, aqueous NaHCO and brine. The organic layer is dried (Na2SO4) and the solvent removed in vacuo to give a solid. The solid is purified by chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=[O:24].C([O-])(O)=O.[Na+].[C:31]([O:35][C:36](=[O:39])[CH2:37]Br)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([O:25][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)OCC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
To a solution of indomethacin (6.388 g, 18 mmol) in anhydrous DMF (45 mL) were successively added NaHCO3 (1.4 g, 16.7 mmol) and tert-butylbromoacetate (2.95 g, 15 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was then poured over ice-cold water, stirred, and the white solid obtained was filtered off, washed with water and dried. The product was recrystallized from EtOAc:hexane (1:4) to give the title compound (7.06 g, 88% yield) as a white soild. Mp 96–97° C. 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.0 (d, J=2.4 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 6.6 (dd, J=9.0 and 2.4 Hz, 1H), 4.52 (s, 2H), 3.83 (s, 3H), 3.77 (s, 2H), 2.37 (s, 3H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 170.1, 168.2, 166.6, 156.2, 139.2, 136.0, 133.8, 131.1 (2×C), 130.7, 130.5, 129.0 (2×C), 114.9, 112.1, 111.9, 101.1, 82.4, 61.5, 55.6, 29.7, 27.9, 13.4; LRMS (APIMS) m/z 472 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:35]2[CH2:37][O:36]2)[CH:32]=[CH:33][CH:34]=1>C(Cl)(Cl)Cl.CO>[CH2:18]([NH:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:37][C@@H:35]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=3)[OH:36])=[CH:27][CH:26]=2)[CH2:10][CH2:11]1)=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)c3cccc(Cl)c3)cc2)CC1
Yield: 16.1 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide (0.50 g, 1.18 mmol) was reacted with (2R)-2-(3-chlorophenyl)oxirane (0.183 g, 1.18 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.063 g, 0.19 mmol).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[Na+].Cl[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1)=[O:13]>CCO.O>[O:18]1[C:17]2[CH:22]=[CH:23][C:14]([C:12](=[O:13])[CH2:11][S:3][C:2]3[S:1][CH2:7][C:5](=[O:6])[N:4]=3)=[CH:15][C:16]=2[O:21][CH2:20][CH2:19]1
Reactant: O=C(CCl)c1ccc2c(c1)OCCO2
Reactant: O=C1CSC(=S)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CSC(SCC(=O)c2ccc3c(c2)OCCO3)=N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Rhodanine (0.052 g, 0.388 mmol, 1.0 eq.) was dissolved in EtOH (2 ml) and 2 M NaOH (0.275 ml, 0.550 mmol, 1.42 eq.) with vigorous stirring. Once the Rhodanine was completely dissolved, 6-Chloroacetyl-1,4-benzodioxane (0.080 g, 0.380 mmol, 0.98 eq.) was added with constant stirring. (It should be noted that α-chloro ketones were used when the corresponding α-bromo ketones were not available.) The reaction was mixed overnight at 40° C. After 18 hrs the reaction was removed from the heat and left stirring at room temp for 48 hrs. The resulting reaction mixture was then diluted with water (5 ml) and extracted with dichloromethane (3×5 ml). The organic layer was dried over Na2SO4 and then evaporated to yield an oil. The oil was purified by chromatotron using a 50/50 mixture of ethyl acetate in hexanes as the mobile phase. The purified product, Compound 34, was then recrystallized in hexanes to complete its purification (20 mg, 0.0646 mmol, 17%). The product was characterized by 1H-NMR: (CDCl3) 7.55 (q, 2H), 6.93 (d, 1H), 4.93 (s, 2H), 4.31 (m, 4H), 4.02 (s, 2H) ppm. In addition LCMS [ES+] analysis yielded a single peak, 310 [M]+ m/e.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=3)(=[O:38])=[O:37])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: COc1cccc(S(N)(=O)=O)c1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccc(OC)c2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 3-methoxybenzenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B describe hereinabove. Yield (27%); 1H NMR (d6-DMSO) δ 12.18 (br s, 1H), 7.53-7.07 (m, 17H), 6.84 (d, J=8.0 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 3.78 (s, 3H), 2.35 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); APcI m/z: 522 (M−H−).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:9][CH:6]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH2:7]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)N2CC(N3CCNCC3)C2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (see J. Org. Chem.; 56; 1991; 6729; 25 g, 78.6 mmol), piperazine (67.7 g, 0.79 mol) and dry acetonitrile was stirred at 60° C. overnight under nitrogen. The mixture was cooled and partitioned between water and methylene chloride. The organic layer was washed with water and brine. The solution was dried over Na2SO4 and then the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel (methanol-methylene chloride 5:95). There was obtained 17.5 g (72%) of 1-[1-(diphenylmethyl)azetidin-3-yl]piperazine as a yellow oil. 1H NMR (400 MHz, CDCl3): 2.1-2.4 (m, 4H), 2.8-2.9 (m, 2H), 3.0 (m, 4H), 3.4-3.5 (m, 2H), 3.7-3.9 (m, 1H), 4.4 (s, 1H), 7.2-7.4 (m, 10H); LCMS: m/z 308 (M+1)+.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][C:7]1[CH:16]=[CH:15][C:10]2[C:11](=[O:14])[O:12][CH2:13][C:9]=2[CH:8]=1.Cl>O>[O:14]=[C:11]1[C:10]2[CH:15]=[CH:16][C:7]([CH2:6][CH:2]=[O:1])=[CH:8][C:9]=2[CH2:13][O:12]1
Reactant: O=C1OCc2cc(CC3OCCO3)ccc21
Agent: Cl
Solvent: O
Product: O=CCc1ccc2c(c1)COC2=O
Temperature: 40 °C

Procedure:
5-(1,3-Dioxolan-2-ylmethyl)-2-benzofuran-1(3H)-one (61 g, 280 mmol) was combined with water (2.2 L) in a 5 L round bottomed flask equipped with a Claisen adapter, thermocouple, stir bar and nitrogen bubbler. Aqueous HCl solution (2M, 1.14 L, 2.29 mol) was added and the resulting mixture was heated at 40° C. for 8 h. Then the mixture was stirred overnight at room temperature. The mixture was extracted three times with 2 L of ethyl acetate. The combined organic layers were concentrated to give (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde. MS: m/z 177 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9]C(=O)C)=[CH:4][C:3]=1[Cl:13].[OH-].[Na+].O>C(O)CO>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[CH:4][C:3]=1[Cl:13]
Reactant: CC(=O)Nc1cc(Cl)c(Br)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Nc1cc(Cl)c(Br)c(Cl)c1
Reaction time: 12 h

Procedure:
202 g of N-(4-bromo-3,5-dichlorophenyl)acetamide and 220 g of sodium hydroxide (as an aqueous 50% solution) in 670 ml of ethylene glycol are stirred for 5 hours at 120° C. and then for 12 hours at room temperature. 3000 ml of water are added, the mixture is filtered, the organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The residue obtained is crystallized from cyclohexane; m.p.=132° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.O.[OH-].[Na+]>C(O)C>[CH3:1][N:2]([C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1)[CH2:12][CH:14]1[O:16][CH2:15]1
Reactant: ClCC1CO1
Reactant: CNc1ccc(CC#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(CC1CO1)c1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A mixture of 4-methylaminobenzylcyanide (3.05 g, 20.9 mmol), epichlorohydrine (2.4 ml, 2.87 g, 31 mmol), ethanol (25 ml) and water (20 ml) was heated under reflux for 3 hours. After cooling the mixture was diluted with ethanol (10 ml) followed by addition of aqueous 10N NaOH (6 ml). The obtained clear solution was stirred at room temperature for one hour and the ethanol was distilled off. The residue was diluted with 100 ml of water and extracted with ether (3×50 ml). The organic extracts were washed with brine until neutral, dried over MgSO4 and concentrated. The residue was chromatographed over a silica gel column eluting with a 3:1 mixture of benzene and ethyl acetate to give 2.21 g of the oily title compound, yield: 52.2%.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1)=[C:2]=[O:3].[OH:17][CH2:18][CH2:19][NH2:20]>CN(C)C=O>[OH:17][CH2:18][CH2:19][NH:20][C:2](=[O:3])[NH:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: NCCO
Reactant: O=C=Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Solvent: CN(C)C=O
Product: O=C(NCCO)Nc1ccc(-c2c[nH]c(=O)cn2)cc1

Procedure:
In a manner similar to Example 13b, 5-[4-(isocyanato)phenyl]-2(1H)-pyrazinone was reacted with 2-hydroxyethylamine (0.5 g) in dimethylformamide (5 ml) for 17 hours at room temperature. The mixture was purified by flash chromatography (chloroform--20% methanol/80% chloroform); the desired fractions were combined and evaporated under reduced pressure to afford a residue. This residue was washed with chloroform and dried to form the title compound; δ(DMSO-d6) 3.17 (sextet, 2H, --NHCH2), 3.47 (t, 2H, --CH2OH), 7.94, 8.06 (2d, J=1 Hz, pyrazinone H's).
Reaction SMILES: CN([Si:9]([CH3:12])([CH3:11])[CH3:10])C(=O)C(F)(F)F.[CH3:13][N:14]([C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20](O)=[C:19](O)[CH:18]=1)[NH2:15]>>[CH3:13][N:14]([C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[C:19]([Si:9]([CH3:12])([CH3:11])[CH3:10])[CH:18]=1)[NH2:15]
Reactant: CN(N)C(=O)c1ccc(O)c(O)c1
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Product: CN(N)C(=O)c1ccc([Si](C)(C)C)c([Si](C)(C)C)c1
Temperature: 50 °C

Procedure:
9.53 ml of N-methyl-N-(trimethylsilyl)trifluoroacetamide (0.051 mol) was added to a suspension of 4.2 g of 3,4-dihydroxybenzoic acid, 1-methylhydrazide (0.023 mol). After warming the suspension to 50° C. for one hour, a clear solution of 3,4-bis(trimethylsilyl)benzoic acid, 1-methylhydrazide was obtained.
Reaction SMILES: [NH:1]1CCNCC1.[Cl:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=1>C(#N)C.ClCCl>[Cl:7][C:8]1[C:13]([C:12]#[N:1])=[N:14][CH:11]=[CH:10][N:9]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1nccnc1Cl
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
Piperazine (1.5 mmol) and 2-chloro-3-nitro-pyridine (1 mmol) were dissolved in acetonitrile (3 mL) and stirred for 30 min at 85° C. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was isolated, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The product was purified (SPE column chromatography, silica gel, 0-10% methanol in ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Cl[C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[C:10]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)=[O:15]
Reactant: Nc1ccc(Br)cn1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1ccc(Br)cn1

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 2-amino-5-bromopyridine and methyl chlorooxoacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:43]=[CH:42][C:36]([O:37][CH2:38][C:39](O)=[O:40])=[CH:35][CH:34]=2)[S:27]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][C:39]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:40])=[CH:42][CH:43]=2)[S:27]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 105 %

Procedure:
Using 0.79 g of t-butyl N-[2-amino-5-(4-hydroxyphenoxy)phenyl]-N-methylcarbamate, 0.84 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 0.49 g of diethyl cyanophosphonate, 0.30 g of triethylamine and 60 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to that described in Example (2-1), whereby 1.49 g of the desired compound were obtained.