Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(C(Cl)=O)=O.[N:20]1[CH:25]=[CH:24]C=[CH:22][CH:21]=1.C(NCC)C>C(Cl)Cl.CC(OCC)=O>[CH2:21]([N:20]([CH2:25][CH3:24])[C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[CH3:22]
Reactant: COc1ccc(OC)c(C(=O)O)c1
Reactant: c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc(OC)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a stirred solution of 2,5-dimethoxybenzoic acid (6.61 g, 36.3 mmol) in 50 ml of CH2Cl2 was added a solution of (COCl)2 in CH2Cl2 (2.0M, 20 ml, 40.0 mmol) at 0° C. under argon. After addition of catalytic amount of pyridine (0.2 ml) an evolution of gas was observed. The reaction was warmed up to room temperature and stirred for 3 hours. The volatile were removed and the residue was dissolved in 300 ml of diethyl ether. Diethylamine (5.26 ml, 50.8 mmol) was introduced dropwise at 0° C. under argon. The resulting mixture was stirred at room temperature for another 3 hours, and then quenched with saturated K2CO3 solution. The organic layer was washed with 2N NaOH and water, dried over MgSO4, filtered and then evaporated. Flash chromatography of the residue with CH2Cl2 and CH3CO2Et (1:1) provided pure title compound (8.34 g, 35.1 mmol) in 97% yield as white solid. 1H NMR (CDCl3) δ:1.05 (3H, t, J=7.1 Hz), 1.24 (3H, t, J=7.1 Hz), 3.16 (2H, q, J=7.1 Hz), 3.56 (2H, m), 3.77 (3H, s), 3.78 (3H, s), 6.77 (1H, m), 6.84 (2H, m).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH-:13].[K+].Cl>CS(C)=O.O.C(Cl)(Cl)Cl>[F:8][C:7]1[C:6]([F:9])=[CH:5][CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:13]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(F)c(F)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20 g of 2,3,4-trifluoronitrobenzene was dissolved in 150 ml of dimethyl sulfoxide, and to this mixture a solution of 10% potassium hydroxide was added dropwise while keeping the temperature at 18° to 20° C. Then, the mixture was stirred for 2 hours at room temperature and one liter of water was added to this reaction mixture and the mixture was shaken with chloroform. The water layer was acidified with hydrochloric acid and was extracted with chloroform. The extract was washed with water and was dried, then chloroform layer was concentrated. The residue was purified by silica gel column chromatography to provide 5.8 g of 2,3-difluoro-6-nitrophenol as yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([NH2:13])[CH:8]=[CH:7]2)([O-:3])=[O:2].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[ClH:15].[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([NH:13][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: Nn1ccc2cc([N+](=O)[O-])ccc21
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(ccn2Nc2ccncc2)c1
Yield: 51.5 %

Procedure:
A solution of 5-nitro-1H-indol-1-amine (4.5 g) and 4-chloropyridine hydrochloride (4.5 g) in 175 ml of isopropanol was stirred at reflux for two hours, another equivalent of 4-chloropyridine hydrochloride was added and the mixture was refluxed for two additional hours. The reaction mixture was then cooled, stirred with water, basified with sodium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to 9 g of dark oil. This oil was purified by flash chromatography (silica, ethyl acetate) to give 3.8 g of light brown solid, m.p. 183°-184° C. This material was converted to the hydrochloride salt and recrystallized twice from methanol/ether to give 3.5 g of orange needles, m.p. 300°-302° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:15]=2)=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH3:40])[CH2:35][CH2:34]2)=[N:31][CH:32]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:39]([N:36]1[CH2:35][CH2:34][N:33]([C:30]2[N:31]=[CH:32][C:27]([NH:26][C:4](=[O:5])[C:3]3[CH:7]=[C:8]([NH:11][C:12]([C:14]4[CH:19]=[CH:18][N:17]=[C:16]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)[CH:15]=4)=[O:13])[CH:9]=[CH:10][C:2]=3[Cl:1])=[CH:28][CH:29]=2)[CH2:38][CH2:37]1)[CH3:40]
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccnc(N2CCOCC2)c1
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(c2ccc(NC(=O)c3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.8 %

Procedure:
2-Chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzoic acid (0.162 g) was added to a stirred mixture of 5-amino-2-(4-ethylpiperazin-1-yl)pyridine (0.093 g), diisopropylethylamine (0.232 g), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.176 g) and DMF (10 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and evaporated. The residue was triturated under a mixture of isohexane and ethyl acetate. The resultant solid was isolated and dried under vacuum at 40° C. to give the title compound (0.071 g); NMR Spectrum: (DMSOd6) 1.02 (t, 3H), 2.34 (m, 2H), 2.4-2.46 (m, 4H), 3.38-3.42 (m, 4H), 3.5-3.53 (m, 4H), 3.69-3.71 (m, 4H), 6.82 (d, 1H), 7.08 (d, 2H), 7.22 (s, 1H), 7.62 (d, 1H), 7.82-7.98 (m, 3H), 8.28 (d, 1H), 8.39 (s, 1H); Mass Spectrum: M+H+ 550 and 552.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25](S(C)(=O)=O)[N:24]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([CH2:6][C:7]2[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[N:9][CH:10]=[CH:11][CH:12]=2)[N:24]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cc1cccnc1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Cc2cccnc2NC(=O)OC(C)(C)C)n1
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (19.2 ml of a 2.5M solution in hexane) was added dropwise to a stirred suspension of the product of stage (a) above (5.0 g) in dry tetrahydrofuran (100 ml) under nitrogen at -70° C. The mixture was stirred at -70° C. for 20 minutes and then at 5° C. for 3 hours. It was then cooled to -70° C. and treated with 4,6-dimethoxy-2-methylsulfonylpyrimidine (5.42 g), and the mixture was stirred at -70° C. for 1 hour, then at room temperature overnight. Saturated ammonium chloride solution (500 ml) was added, and the mixture was extracted with ethyl acetate (2×100 ml). The combined extracts were washed with saturated sodium chloride solution (50 ml), dried and evaporated to give an orange oil which was triturated with hexane to give 5.35 g of the desired product as a pale yellow solid, mp 89°-92° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([C:16]([F:19])([F:18])[F:17])[NH:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:30][C:31]1[CH:36]=[C:35](Cl)[N:34]=[C:33]([S:38][CH3:39])[N:32]=1.ClC1N=CN=C(Cl)C=1>C1COCC1>[Cl:30][C:31]1[N:32]=[C:33]([S:38][CH3:39])[N:34]=[C:35]([N:12]2[C@H:13]([C:16]([F:19])([F:17])[F:18])[CH2:14][CH2:15][C@H:10]([C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])[CH2:11]2)[CH:36]=1
Reactant: O=C(NC1CCCCC1)[C@H]1CC[C@@H](C(F)(F)F)NC1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Clc1cc(Cl)ncn1
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To cis-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (1.0 g, 3.2 mmol) in THF (15 mL) was added 1M LiHMDS in THF (11 mL, 11.00 mmol) at room temperature. After 5 minutes, 4,6-dichloro-2-(methylthio)pyrimidine (0.620 g, 3.18 mmol) was added. After 10 minutes, LCMS analysis of the reaction mixture indicated the presense of ˜85% desired product+13% of dichloropyrimidine SM. The reaction mixture was poured onto saturated NH4Cl and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. A solid cartridge was prepared by adding EtOAc (˜200 mL) to the crude and SiO2 (3 g). The mixture was concentrated. Flash chromatography (100% Hexanes to 50% EtOAc in Hexanes, then 100% EtOAc) afforded the title compound (690 mg) as an off-white solid. LC-MS (ES) m/z=437, 439 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8](S(Cl)(=O)=O)[N:9]=1)(=[O:3])[CH3:2].[CH2:14]([S:21][C:22]1[N:27]=[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[C:24]([NH:33][C@H:34]([CH3:37])[CH2:35]O)[N:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)(Cl)(=O)=O.Cl.N1C=CC=C[CH:45]=1>C1COCC1>[CH2:14]([S:21][C:22]1[N:27]=[C:26]([NH:28][S:29]([C:32]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:7])(=[O:31])=[O:30])[CH:25]=[C:24]([NH:33][C@H:34]([CH3:37])[CH2:35][CH3:45])[N:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)Nc1nc(S(=O)(=O)Cl)cs1
Reactant: c1ccncc1
Reactant: C[C@H](CO)Nc1cc(NS(C)(=O)=O)nc(SCc2ccccc2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: O=S(=O)(Cl)Cl
Product: CC[C@@H](C)Nc1cc(NS(=O)(=O)c2sc(NC(C)=O)nc2C)nc(SCc2ccccc2)n1
Reaction time: 96 h

Procedure:
2-(Acetylamino)-1,3-thiazole-4-sulfonyl chloride (0.19 g) was added to a solution of the subtitle product of Example 3 step (0.2 g) in pyridine (4 ml) and N,N-dimethylaminopyridine (60 mg). The reaction mixture was stirred for 4 days. To this reaction more sulfonyl chloride (0.75 g) was added and stirred for 2 days. To this reaction was added aqueous hydrochloric acid (1M, 20 ml) and THF (20 ml). This was stirred for 18 h before the solvent was evaporated and the residue diluted in EtOAc (100 ml). This was washed with H2O (3×20 ml) and brine (10 ml). The organic layer was dried (MgSO4) and concentrated to yield a solid. This material was purified by reverse phase HPLC (90% to 5% 0.02M ammonium hydroxide/acetonitrile) to yield the title compound as a solid. Yield: 20 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([CH:17]=2)[NH2:16])(=[O:10])=[O:9])[CH:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([NH:16][CH:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[CH:17]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: CN1CCC(=O)CC1
Reactant: COc1ccc(S(=O)(=O)c2cc(Br)ccc2OC)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)c2cc(Br)ccc2OC)cc1NC1CCN(C)CC1
Temperature: 27 °C
Reaction time: 4 h

Procedure:
5-(5-Bromo-2-methoxybenzenesulfonyl)-2-methoxyaniline (2 grams, 5.35 mmol) was added to 100 mL three necked round bottomed flask, followed by the addition of 1-methyl-4-piperidone (550 mg, 4.86 mmol), sodium sulfate (1.4 grams, 9.73 mmol) and acetic acid (40 mL) under nitrogen atmosphere. The reaction mass was stirred for 4 hours at room temperature (27° C.). Then sodium triacetoxy borohydride (3.08 grams, 14.60 mmol) was added to the reaction mass at 20-25° C. in 5 minutes. This reaction mixture was further stirred for another 2 hours at room temperature. The reaction mixture was then quenched into 100 mL water, basified to pH 9 with 50% aqueous sodium hydroxide solution under cooling (10° C.) and extracted the product with ethyl acetate (3×100 mL). The combined organic layer was washed with saturated brine solution (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain oily mass. The technical product was further purified by column chromatography using ethyl acetate and methanol as eluents to obtain the title product. Yield: 1.56 grams.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19]([NH:21][NH2:22])=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C(=O)(O)[O-].[Na+].[N:28]#[C:29]Br>O1CCOCC1.O.C(OCC)(=O)C>[NH2:28][C:29]1[O:20][C:19]([CH2:18][CH2:17][S:16][C:7]2[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]([OH:11])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=2)=[N:21][N:22]=1
Reactant: N#CBr
Reactant: CC(C)(C)c1cc(SCCC(=O)NN)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(SCCc2nnc(N)o2)cc(C(C)(C)C)c1O
Reaction time: 5 h
Yield: 78 %

Procedure:
A solution of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid hydrazide (0.50 g, 1.54 mmol) in dioxane (15 mL) is added to a solution of sodium bicarbonate (0.14 g, 1.62 mmol) in water (4 mL). Cyanogen bromide (0.17 g, 1.62 mmol) is added in four equal portions at 1-minute intervals, and stirring is continued for 5 hours. The reaction mixture is diluted with ethyl acetate and sequentially washed with aqueous sodium bicarbonate, water, and brine. Drying the organic phase over magnesium sulfate and evaporation provides a solid which is crystallized from ethyl acetate/hexane to give 0.42 g (78%) of 4-[[2-(5-amino-1,3,4-oxadiazol-2-yl)ethyl]thio]-2,6-bis(1,1-dimethylethyl)phenol, mp 172.0°-174.0° C.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C)[CH:27]=[O:28]>C(N(CC)CC)C>[C:2]1([C:1]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:27]=[O:28])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=CC(CC(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
Following the procedure described in Example 1, 57.2 g (0.275 mol) of benzylideneacetophenone, 29.2 g of benzaldehyde, 25.1 g (0.1 mol) of Catalyst 2 and 400 ml of dimethylformamide are introduced successively into the 500 ml three-necked flask and after stirring for 15 minutes under nitrogen 40.4 g (0.4 mol) of triethylamine are added. The mixture is then heated to 80° C for 12 hours. For working up, the dimethylformamide is distilled off and 150 ml of isopropanol are added to the residue while it is still hot. The product which has precipitated is filtered off, washed with isopropanol and then dried. 2,2,4-Triphenyl-butane-1,4-dione is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: Clc1ccccc1CBr
Reactant: NC(=O)c1ccnc(-c2c[nH]cn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc(-c2cn(Cc3ccccc3Cl)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A mixture of 2-(1H-imidazol-4-yl)pyridine-4-carboxamide (PREPARATION 7)), 1-bromomethyl-2-chlorobenzene (260 mg, 1.28 mmol) and K2CO3 (176 mg, 1.28 mmol) in DMF (8 mL) was stirred overnight at rt, LC/MS showed the reaction was completed, purified by FCC to give the title compound (83 mg, 42%) as a yellow solid. [M+H] Calc'd for C16H13ClN4O, 313. Found, 313.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[NH:24][C:23]2=[O:33])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[C:34](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[N:24]([CH3:34])[C:23]2=[O:33])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a mixture of 0.93 g of methyl [2-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate, 0.31 g of potassium carbonate, and 10 ml of N,N-dimethylformamide was added 0.58 g of methyl iodide, and the mixture was stirred at room temperature for 2 hours. Then 50 ml of diluted hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.82 g of methyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate (compound a-5).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([OH:10])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[S:12]([CH2:18][C:19]#[N:20])([CH2:15][C:16]#[N:17])(=[O:14])=[O:13].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[C:15]([C:16]#[N:17])[S:12]([CH2:18][C:19]#[N:20])(=[O:14])=[O:13])[CH:5]=[C:4]([OH:10])[C:3]=1[OH:11]
Reactant: N#CCS(=O)(=O)CC#N
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CCS(=O)(=O)C(C#N)=Cc1cc(O)c(O)c(Br)c1
Yield: 6.3 %

Procedure:
A mixture of 500 mg of 5-bromo-3,4-dihydroxybenzaldehyde and 700 mg of sulfonly diacetonitrile in 6 ml of ethanol was refluxed with few drops of piperidine for 4 hours. Ethanol was removed in rotavap and the mixture worked up with ethyl acetate, diluted acid and brine. A portion of the crude was then purified by HPLC on a C-18 column to provide about 50 mg of 2-(3-bromo-4,5-dihydroxyphenyl)-1-cyano-1-cyanomethylsulfonly ethene.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:19][CH2:20]Br.O>CN(C)C=O>[CH2:1]([NH:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:19][CH2:20][O:16][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCCBr
Reactant: CCCCNC(=O)CCc1ccc(O)c(O)c1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNC(=O)CCc1ccc2c(c1)OCCO2
Reaction time: 4 h
Yield: 37.2 %

Procedure:
1.5 g of N-butyl-3-(3,4- dihydroxyphenyl)propionamide was dissolved in 10 ml of N,N-dimethylformamide and 2.3 g of potassium carbonate anhydride was added to the solution. Then 2.3 g of 1,2-dibromoethane and 100 mg of cupric oxide were added to the solution and the resulting solution was stirred at 130°-140° C. for 4 hours. After cooling, the solution was poured over iced water and extracted with ethyl acetate; the organic layer was isolated, washed with water, dried with sodium sulfate anhydride and the solvent was removed by evaporation under reduced pressure. The residue was purified by chromatography on a silica gel column with a mixed solvent (chloroform:methanol=100:l) and thus 0.62 g of oily N-butyl-3-(1,4-benzodioxane-6-yl)propionamide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:10]=[C:11]([C:16](=[O:18])[CH:17]=2)[C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1.C(O)(=O)C>CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH:10]=[C:11]([C:16](=[O:18])[CH:17]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cn(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2)cc1=O
Yield: 83.3 %

Procedure:
In a mixed solvent of 5 ml of methanol and 5 ml of 1N aqueous sodium hydroxide solution was dissolved 0.5 g of methyl 6-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinate, and they were reacted at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was adjusted to a pH of 5.5 with acetic acid, and the precipitated crystals were collected by filtration, washed with 10 ml of water and dried to obtain 0.4 g of 6-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 199°-204° C.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[C:23]2[C:29]3[CH:30]=CC=C[C:28]=3[CH:27]=[CH:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]2=3)[CH2:19][CH2:18]1)=[O:16])[C:10](OC)=[O:11])=O)(C)(C)C>C(O)C.[H][H].[C].[Pd]>[CH:10]1[C:28]2[CH2:27][CH2:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[C:23](=[C:20]3[CH2:19][CH2:18][N:17]([C:15](=[O:16])[CH2:14][C@@H:9]([NH:8][C:6](=[O:5])[C:20]([CH3:23])([CH3:21])[CH3:19])[CH2:10][OH:11])[CH2:22][CH2:21]3)[C:29]=2[CH:30]=[CH:14][CH:9]=1
Reactant: COC(=O)[C@@H](CC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)C(=O)N[C@@H](CO)CC(=O)N1CCC(=C2c3ccccc3CCc3ccccc32)CC1

Procedure:
745 mg (1.48 mmol) of methyl (R)-2-[(t-butoxycarbonyl)amino]-4-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-4-oxobutanoate was dissolved in 70 ml of ethanol. 1.49 g of palladium carbon (10% w/v) was added to the obtained solution, and they were stirred at room temperature in hydrogen gas atmosphere under 4.4 atm. for 3.5 hours. The catalyst was filtered out, and the filtrate was concentrated under reduced pressure. The intended product was obtained from the resultant residue in the same manner as that in steps 3 and 4 in Example 50.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[C:7]1([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:7]1([N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Ic1ccccc1
Reactant: c1c[nH]nn1
Solvent: ClCCl
Product: c1ccc(-n2ccnn2)cc1
Product: c1ccc(-n2nccn2)cc1
Yield: 48 %
Yield: 41 %

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-[1,2,3]triazole (87 μL, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crude brown oil was purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50 then pure dichloro-methane) to provide 60 mg of 2-phenyl-2H-[1,2,3]triazole (41% yield) as an uncolored oil and 70 mg of 1-phenyl-1H-[1,2,3]triazole (48% isolated yield) as a light yellow solid.