Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11](=O)[NH2:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[C:11]([CH2:10][CH:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:14]([OH:16])=[O:15])#[N:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(CC#N)C(=O)O
Temperature: 23 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
20.0 g (86 mmol, 1 equiv.) of Boc-L-Asparagine (from Bachem or Sigma) was dissolved in 120 mL of dry pyridine and 20.0 g (97 mmol, 1.3 equiv. ) of dicyclohexylcarbodiimide dissolved in 60 mL of dry pyridine was added dropwise over a period of 30 minutes. The reaction was stirred for 3 hours at 23° C. and filtered through a 2μm nylon filter. The filtrate was concentrated in vacuo on a rotary evaporator and 100 ml of water was added. The pH was adjusted to 10 with 40% sodium hydroxide (aq.) and the solution filtered through a 2 μm nylon filter once again. The filtrate was passed through a 120 mL bed of Dowex 50X8-400 ion exchange resin and the resin washed with four column volumes of 1:1 methanol:water. The filtrate was concentrated in vacuo to yield 17.5 g (95% yield) of product as a white solid. 1H-NMR (CD3OD): 4.40 p.p.m (m, 1H); 2.95 p.p.m. (m, 2H); 1.40 p.p.m. (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]#[N:14])[C:7]=2[CH2:6][CH2:5][O:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([CH:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]#[N:14])[C:7]=2[CH2:6][CH2:5][O:4]1)=[O:1]
Reactant: N#Cc1cccc2c1CCOC2CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: N#Cc1cccc2c1CCOC2C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-(hydroxymethyl)-3,4-dihydro-1H-isochromene-5-carbonitrile (0.16 g, 0.85 mmol) in 4 mL of DCM was added Dess-Martin reagent (0.72 g, 1.7 mmol) in one portion at 0° C. The mixture was stirred at 0° C. for 1 hour, and then stirred at rt. overnight. The reaction mixture was filtered and the filtrate was concentrated to give 1-formyl-3,4-dihydro-1H-isochromene-5-carbonitrile. 1H-NMR (400 MHz, CDCl3) δ 9.71 (s, 1H), 7.93˜7.95 (m, 1H), 7.64˜7.68 (m, 1H), 4.99 (s, 1H), 4.03˜4.09 (m, 2H), 2.99˜3.04 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([CH2:19][OH:20])[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:18]=[C:17]([CH2:19][O:20][S:22]([CH3:21])(=[O:24])=[O:23])[O:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc(CO)n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2noc(COS(C)(=O)=O)n2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-hydroxymethyl-[1,2,4]oxadiazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.7 mmol) in methylene chloride (5 mL) was added methanesulfonyl chloride (0.1 g, 0.9 mmol) and triethyl amine (0.14 g, 1.4 mmol) at 0° C. After stirred at 0° C. for 1 hour, the mixture was diluted with EtOAc and washed with H2O, brine. After drying (Na2SO4), the solvent was removed in vacuo, and the residue was purified by silica column chromatography with EtOAc/hexanes to afford the desired product
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]3=2)[C:5](=[O:25])[N:4]([C@@H:26]2[C@@H:31]([OH:32])[CH2:30][O:29][CH2:28][CH2:27]2)[CH2:3]1.Cl.Cl[CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[C:38]([CH2:42][F:43])[CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:43][CH2:42][C:38]1[CH:37]=[C:36]([CH2:35][C:8]2[CH:7]=[C:6]3[C:11](=[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=24)[N:2]([CH3:1])[CH2:3][N:4]([C@@H:26]2[C@@H:31]([OH:32])[CH2:30][O:29][CH2:28][CH2:27]2)[C:5]3=[O:25])[CH:41]=[CH:40][N:39]=1
Reactant: FCc1cc(CCl)ccn1
Reactant: CN1CN([C@H]2CCOC[C@@H]2O)C(=O)c2cc(B3OC(C)(C)C(C)(C)O3)c3ccccc3c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CN1CN([C@H]2CCOC[C@@H]2O)C(=O)c2cc(Cc3ccnc(CF)c3)c3ccccc3c21
Temperature: 100 °C

Procedure:
A solution of 1,5-anhydro-2,3-dideoxy-3-[1-methyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydrobenzo[h]quinazolin-3(2H)-yl]-L-threo-pentitol (47 mg, 0.11 mmol), 4-(chloromethyl)-2-(fluoromethyl)pyridine hydrochloride (21 mg, 0.11 mmol), cesium carbonate (98 mg, 0.30 mmol), and PdCl2(dppf)-CH2Cl2 adduct (12 mg, 0.017 mmol) in THF (0.85 mL) and water (0.10 mL) was purged subsurface with nitrogen, then capped and heated at 100° C. overnight. The reaction was diluted with water and saturated, aqueous NaHCO3, then extracted 2× with EtOAc. The organics were washed with brine, dried over MgSO4, filtered, concentrated, and dried. The residue was purified via silica gel chromatography, eluting with 20-100% ethyl acetate in hexanes to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 436.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=5.2 Hz, 1H), 8.27-8.30 (m, 1H), 7.91 (s, 1H), 7.80 (dd, J=7.6, 1.2 Hz, 1H), 7.52-7.60 (m, 2H), 7.28 (s, 1H), 6.98 (d, J=4.8 Hz, 1H), 5.42 (d, J=46.8 Hz, 2H), 4.62-4.76 (m, 3H), 4.36 (s, 2H), 4.17 (dd, J=11.2, 5.2 Hz, 1H), 4.06 (dd, J=7.6, 4.4 Hz, 1H), 3.73-3.81 (m, 1H), 3.51-3.58 (m, 1H), 3.23-3.30 (m, 1H), 3.01 (s, 3H), 2.70 (d, J=7.2 Hz, 1H), 1.86-2.06 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([Si](C)(C)C)=[C:5]2[CH2:16][CH2:17][NH:18][C:19](=[O:34])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:21]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:16][CH2:17][NH:18][C:19](=[O:34])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:21]=1
Reactant: C[Si](C)(C)c1[nH]c2c(Cl)cc(Cl)cc2c1CCNC(=O)c1cccc(Cc2cccc(F)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(NCCc1c[nH]c2c(Cl)cc(Cl)cc12)c1cccc(Cc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
A mixture of N-(2-(5,7-dichloro-2-(trimethylsilyl)-1H-indol-3-yl)ethyl)-3-(3-fluorobenzyl)benzamide (0.045 g; 0.088 mmol) and tetrabutyl ammonium fluoride (0.263 mL, 1N in THF) was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. The organic layer was dried and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) to afford 0.018 g (47%) of the title compound as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][OH:8].[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>O1CCCC1>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][O:8][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]
Reactant: OCC1COCCO1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2COCCO2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1,4-Dioxan-2-yl)methanol (380 mg) in tetrahydrofuran (30 ml) was treated with sodium hydride (60%) (245 mg) at room temperature for 30 minutes. The reaction mixture was cooled in an ice bath and 4-fluoro-3-nitrobenzenesulfonamide (675 mg) was added. The resulting mixture was stirred at room temperature for 2 hours and another portion of sodium hydride (60%, 245 mg) was added. The reaction mixture was stirred overnight and quenched with ice water (3 ml). The cloudy mixture was filtered and the filtrate was concentrated. The residue was triturated with methanol to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.[CH2:12]([NH2:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(OCC)(=O)C.[OH-].[Na+]>O1CCOCC1>[CH2:12]([NH:24][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Cc1cc(Cl)nc(C(C)C)n1
Reactant: CCCCCCCCCCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCCCCCCCCCNc1cc(C)nc(C(C)C)n1
Temperature: 109 °C
Reaction time: 0.17 h

Procedure:
79.2 g of 4-chloro-2-isopropyl-6-methylpyrimidine (464.1 mmol) are heated in 100 ml of dioxane at 100° C. A heated solution of 189.3 g of dodecylamine (1021 mmol, 2.2 eq) in 30 ml of dioxane is added dropwise thereto over the course of 2 hours, and the reaction mixture is further heated for 2 hours at 100° C. and for 9 hours at 109° C. After cooling, 400 ml of ethyl acetate and 150 ml of 4M sodium hydroxide solution (600 mmol) are added thereto and the mixture is stirred at 50° C. for 10 minutes. The lower, aqueous phase is discarded, the organic phase is washed with 300 ml of water, and 10 ml of saturated NaCl solution are added thereto. The organic phase is separated off and concentrated, and the excess dodecylamine is distilled in vacuo up to a bath temperature of 160° C. 136.1 g (91.8%); GC purity: 98%
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH2:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:22][N:23]=[C:24]=[O:25].C(OC(C)C)(C)C>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH:18][C:24]([NH:23][CH3:22])=[O:25])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:20][CH3:21]
Reactant: CN=C=O
Reactant: CCCN(CCC)C1CCc2cccc(OCCN)c2C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: CCCN(CCC)C1CCc2cccc(OCCNC(=O)NC)c2C1
Reaction time: 1 h

Procedure:
1.45 g (5 mmol) of 2-dipropylamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthalene were initially introduced into 20 ml of toluene. The reaction was catalyzed using 3 drops of triethylamine, and 0.325 ml (5.5 mmol) of methyl isocyanate was then added dropwise. The mixture was stirred for 1 h at +25° C. The mixture was evaporated, and the residue obtained was stirred with hot diisopropyl ether. The mixture was cooled, and the product was filtered off under suction.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:7]([O-:33])=[CH:6][C:5]=2[N:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Product: Cc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A solution of tert-butyl 2-[2-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (10.75 g, 29.0 mmol) in 150 mL of CHCl3 was chilled in an ice water bath. The solution was treated with 3-chloroperoxybenzoic acid (MCPBA, 70%, 10.73 g, 43.5 mmol). After stirring for 1.5 h, the reaction mixture was washed with 1% Na2CO3 (3×) solution and the layers were separated. The organic portion was washed with H2O and brine then dried over Na2SO4 and concentrated to give a sticky brown solid. The solid was triturated with ether to yield 11.21 g of tert-butyl 2-[2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light tan solid.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[C:8]([CH2:13][C@@H:14]([OH:18])[C:15]([OH:17])=[O:16])[CH:9]=[CH:10][C:11]=1[Br:12].[CH3:19][CH2:20]O>>[Br:5][C:6]1[CH:7]=[C:8]([CH2:13][C@@H:14]([OH:18])[C:15]([O:17][CH2:19][CH3:20])=[O:16])[CH:9]=[CH:10][C:11]=1[Br:12]
Reactant: CCO
Reactant: O=C(O)[C@H](O)Cc1ccc(Br)c(Br)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](O)Cc1ccc(Br)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.8 mL (10.9 mmol) thionyl chloride were added dropwise to a solution of 3.2 g (9.9 mmol) of (R)-3-(3,4-dibromo-phenyl)-2-hydroxy-propionic acid in 40 mL dry EtOH cooled to 0° C. and the reaction mixture was stirred for 1 h at RT. The reaction solution was evaporated down i.vac. the residue combined with 30 mL DCM and filtered to remove the insoluble precipitate. After the solvent had been eliminated the product was obtained as a viscous oil, which was further reacted without purification.
Reaction SMILES: [CH3:1][Mg+].[Br-].[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=[O:13])[CH2:7][CH2:6]1>C1COCC1>[OH:4][C:5]1([CH3:1])[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=[O:13])[CH2:7][CH2:6]1
Reactant: C[Mg+]
Reactant: O=C(O)CC1CCC(=O)CC1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)CCC(CC(=O)O)CC1

Procedure:
Prepared using an excess of MeMgBr (26 mmol) in THF (20 ml) with (4-Oxo-cyclohexyl)-acetic acid (13 mmol) as described on Journal of American Society 93 (1), 1971, 121-129.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:27]([OH:29])=O)#[N:23].[F:37][C:38]1[CH:46]=[CH:45][C:44](/[C:47](/[NH:50]O)=[N:48]/[H])=[C:43]2[C:39]=1[C:40]([CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:41][NH:42]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:22]([C:24]1[CH:25]=[C:26]([C:27]2[O:29][N:48]=[C:47]([C:44]3[CH:45]=[CH:46][C:38]([F:37])=[C:39]4[C:43]=3[NH:42][CH:41]=[C:40]4[CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])[N:50]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])#[N:23]
Reactant: [H]/N=C(\NO)c1ccc(F)c2c(CCC(=O)OCC)c[nH]c12
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc(F)c12
Reaction time: 2 h
Yield: 90.1 %

Procedure:
HOBT (149 mg) and EDCI (187 mg) were added to a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (100 mg) in THF (4 mL). The resulting solution was stirred for 2 h. Ethyl 3-{4-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D45) (186 mg) in THF (4 mL) was added. The reaction mixture was stirred at RT overnight. TBAF (612 mg) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 2.5 hours. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (25% EtOAc in hexane) to afford ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoate (D47) (203 mg) as a pale yellow solid. MS (ES): C25H23FN4O4 requires 462; found 463.2 (M+H+).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.CCCCCC.[I:19][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][CH:35]=1)[CH2:23][CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26].C(I)C>O1CCCC1>[CH2:1]([C:24]([CH2:23][C:22]1[CH:33]=[CH:34][CH:35]=[C:20]([I:19])[CH:21]=1)([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C(Cc1cccc(I)c1)C(=O)OC
Agent: [Li]CCCC
Solvent: CCI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(Cc1cccc(I)c1)(C(=O)OC)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
To a solution of diisopropylamine (0.42 g, 4.15 mmol) in tetrahydrofuran (7 ml) was added n-butyl lithium in hexane (1.56M, 2.2 ml, 3.43 mmol) under ice cooling, and the mixture was stirred for 15 minutes at 0° C. Thereto was added dimethyl (3-iodobenzyl)malonate (0.98 g, 2.82 mmol) in tetrahydrofuran (8 ml) under ice cooling, and the mixture was stirred for 10 minutes at 0° C. Thereto was added ethyl iodide (0.70 g, 4.49 mmol) and the mixture was stirred for 1 hour at 60° C. Additional ethyl iodide (0.60 g, 3.85 mmol) was added thereto and the mixture was stirred for 3 hours at 60° C. The reaction was quenched by an aqueous 5% potassium hydrogensulfate solution and extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed and the residue was purified with silica gel chromatography (hexane:ethyl acetate=4:1→3:1) to give the subject compound (0.78 g, 73%).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[NH:11]2.[Br:21]N1C(=O)CCC1=O>ClCCl.O1CCCC1>[Br:21][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:20])[NH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2c(-c3ccccc3C)cccc2[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c2cccc(-c3ccccc3C)c2c1Br
Temperature: 0 °C

Procedure:
To a solution of EXAMPLE 126A (205 mg) in dichloromethane (5 ml) and tetrahydrofuran (5 ml) at 0° C. was added dropwise N-bromosuccinimide (144 mg) in tetrahydrofuran (3 ml). The mixture was stirred while the ice bath slowly reached room temperature. The reaction mixture was concentrated and the residue was dissolved in dichloromethane and purified by flash chromatography, eluting with 0-100% dichloromethane in hexane to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].[CH3:23][O:24][C:25]1[N:30]=[C:29](S(C)(=O)=O)[N:28]=[C:27]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:26]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][C:29]1[N:28]=[C:27]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:26]=[C:25]([O:24][CH3:23])[N:30]=1
Reactant: COC(=O)COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(OC)nc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a mixture of 400 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol, 359 mg of 6-methoxy-4-(methoxycarbonyl)methoxy-2-methylsulfonylpyrimidine and 3 ml of N,N-dimethylformamide, 196 mg of potassium carbonate was added, and the mixture was stirred for 1 hour at 80° C. The reaction solution was cooled to room temperature, then, this reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 620 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-4-(methoxycarbonyl)methoxypyrimidine [present compound 1-45].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:31]=[CH:30][C:15]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22](=[O:29])[CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22](=[O:29])[CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:30][CH:31]=1)=[O:6]
Reactant: Cc1ccccc1C(=O)O
Reactant: Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1

Procedure:
Using o-methylbenzoic acid and 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one as starting materials, the procedure of Reference Example 3 was repeated to obtain 2-methyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[C:13]([F:14])=[C:12]([CH3:15])[C:11]([F:16])=[C:10](F)[N:9]=2)=[CH:5][C:4]([C:18]([F:21])([F:20])[F:19])=[N:3]1.[H-].[Na+].[F:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31]>S1(CCCC1)(=O)=O.CCCCC.C(OCC)(=O)C>[F:14][C:13]1[C:8]([O:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=2)=[N:9][C:10]([O:32][C:27]2[CH:28]=[CH:29][C:30]([F:31])=[C:25]([F:24])[CH:26]=2)=[C:11]([F:16])[C:12]=1[CH3:15]
Reactant: Cc1c(F)c(F)nc(Oc2cc(C(F)(F)F)nn2C)c1F
Reactant: Oc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: Cc1c(F)c(Oc2ccc(F)c(F)c2)nc(Oc2cc(C(F)(F)F)nn2C)c1F
Temperature: 90 °C
Yield: 53.4 %

Procedure:
A mixture of 2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-4-methyl-3,5,6-trifluoropyridine (1.2 g, 4 mmol; see Example 2), 60% sodium hydride (0.2 g, 4 mmol) and 3,4-difluorophenol (0.65 g, 5 mmol) in anhydrous sulfolane (5 ml) is heated to 90° C. overnight. The reaction mixture is diluted with pentane/ethyl acetate (1/1 by volume) and filtered through a bed of silica gel. The filtrate is washed 8 times with water, the organic layer is dried with anhydrous magnesium sulfate, and the solvents are removed in vacuo. The residue is purified by a flash silica gel chromatography using pentane/ethyl acetate in a ratio of 9/1. 0.9 g (53% yield) of the title compound are obtained as a colourless solid, m.p. 93° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:40])[C:5]([CH3:39])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:35]C(=O)C)=[C:17]([CH:34]=2)[C:18]([NH:20][C:21]2[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:40])[C:5]([CH3:39])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:35])=[C:17]([CH:34]=2)[C:18]([NH:20][C:21]2[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(=O)OC(C)(C)C)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(C(=O)OC(C)(C)C)cc3)c2)=C(C)C1=O
Yield: 51.9 %

Procedure:
tert-Butyl N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-aminobenzoate (0.240 g, 0.437 mmol) was dissolved in methanol (5 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=95:5) and then recrystallized from ether to obtain the titled compound (0.115 g, 0.227 mmol, 52%).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[Br:17]Br>>[OH:1][C:2]1[C:6]([Br:17])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: BrBr
Reactant: COC(=O)c1sc(-c2ccccc2)cc1O
Product: COC(=O)c1sc(-c2ccccc2)c(Br)c1O
Yield: 60.8 %

Procedure:
Prepared by the method described in Example 4 from methyl 3-hydroxy-5-phenyl-2-thiophenecarboxylate (5.0 g, 21 mmoles) and bromine (3.4 g, 21 mmoles). Recrystallization from methanol gave the product (4.0 g); mp 85°-87° C.