Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)=[NH:4].[C:26](Cl)(=O)C(Cl)=O>CO>[CH3:26][O:14][C:13](=[O:15])[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3](=[NH:4])[NH:2][OH:1])=[CH:10][CH:9]=1
Reactant: N=C(NO)c1ccc(CC(C(=O)O)c2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Product: COC(=O)C(Cc1ccc(C(=N)NO)cc1)c1cccc(C(F)(F)F)c1
Yield: 102.8 %

Procedure:
A solution of 3-[4-(N-hydroxycarbamimidoyl)-phenyl]-2-(3-trifluoromethyl-phenyl)-propionic acid (300 mg, 0.85 mmol, example 258/259 b1)) and oxalyl dichloride (119 mg, 0.95 mmol) in methanol (10 ml) was stirred for 1.5 days. The solvent was evaporated, and the residue solved in water and lyophilized to give 320 mg of the desired product (quantitative). MS m/z: 367.2 (M+H)+.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH2:20][NH:21][CH2:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:31]([O-])(=[O:33])C.[Na+]>CN(C=O)C>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH2:20][NH:21][CH2:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:27])([CH3:29])[CH3:28])[CH:17]=[CH:18][C:19]=1[CH:31]=[O:33])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)C(=O)OCCNCc1cccc(OCc2ccccc2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)OCCNCc1ccc(C=O)c(OCc2ccccc2)c1
Reaction time: 0.67 h

Procedure:
POCl3 (3.6 g, 23.4 mmol) was added to 20 ml of DMF in an ice bath. After 40 minutes, 2,2-dimethylpropionic acid 2-[(3-benzyloxyphenyl)methylamino]ethyl ester (8.0 g, 23.4 mmol) dissolved in DMF (10 ml) was added dropwise. The mixture was stirred for 16 hours. After an aqueous sodium acetate solution (20%, 100 ml) was added dropwise, the oily matter was subjected to extraction with ethyl acetate. Washing was performed with a saturated aqueous NaHCO3 solution (100 ml) and then with a saturated saline solution (100 ml). After drying over Na2SO4 and concentration, the residue was purified by silica gel chromatography to give a light yellow crystal (yield: 7.2 g (83.6%)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][N:12]3[CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:17])[NH:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11]3[N:12]([CH:14]=[CH:15][CH:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C1NC(O)(c2ccc(Br)cc2)Cn2cccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccc(Br)cc2)cn2cccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
825 mg (2.69 mmol) 3-(4-bromo-phenyl)-3-hydroxy-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one is slurried in 6.6 ml dichloromethane. Then 207 μl (2.69 mmol) trifluoroacetic acid is added. After 10 min stirring at room temperature, the reaction mixture is evaporated. The residue is triturated with saturated sodium carbonate solution. The solids are filtered off, washed with water and dried under vacuum to give 3-(4-bromo-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one as white powder; HPLC/MS 2.42 (B), [M+H] 289/291.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:29])=[CH:24][C:25]([OH:28])=[C:26]([Cl:27])[C:21]=2[S:20][CH:19]=1.[CH3:31][C:32]1[C:37]([CH2:38]O)=[CH:36][CH:35]=[C:34]([C:40]([F:43])([F:42])[F:41])[N:33]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:29])=[CH:24][C:25]([O:28][CH2:38][C:37]3[C:32]([CH3:31])=[N:33][C:34]([C:40]([F:43])([F:41])[F:42])=[CH:35][CH:36]=3)=[C:26]([Cl:27])[C:21]=2[S:20][CH:19]=1
Reactant: COC(=O)Cc1csc2c(Cl)c(O)cc(Cl)c12
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2c(Cl)c(OCc3ccc(C(F)(F)F)nc3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a mixture of tri-n-butylphosphine (0.336 mL), methyl(4,7-dichloro-6-hydroxy-1-benzothiophen-3-yl)acetate (130.7 mg), (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (94 mg) and THF (4.5 mL) was added ADDP (283 mg) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere overnight. The mixture was concentrated. To the residue was added IPE and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (153 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][Cl:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Br:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]=[C:27]=[S:28]>O1CCCC1>[Br:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][Cl:17])[C:2]=1[NH:1][C:27](=[S:28])[NH:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[Cl:18]
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(Br)c(N)c1NCCCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)c(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCCl
Yield: 62.2 %

Procedure:
To a solution of methyl 3-amino-4-bromo-2-[(3-chloropropyl)amino]benzoate (520 mg, 1.59 mmol) in tetrahydrofuran (16 mL) was added 2,4-dichlorophenyl isothiocyanate (324 mg, 1.59 mmol) at room temperature. The resultant mixture was stirred at 50° C. for 1 day and at 70° C. for 5 hr and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-20% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (520 mg, 0.989 mmol, 62%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4](=[O:7])[CH:3]1[O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1.[C@@H:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>O1CCCC1.C(OCC)(=O)C>[CH:22]([NH:26][C:4](=[O:7])[CH:3]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:19])([F:18])[F:20])[CH:10]=1)[C:2]([CH3:21])([CH3:1])[CH2:6][OH:5])([CH2:24][CH3:25])[CH3:23]
Reactant: CC[C@H](C)N
Reactant: CC1(C)COC(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)CO
Reaction time: 192 h

Procedure:
To a stirring solution comprised of (+)-4-(4,4-dimethyl-2-oxo-tetrahydro-furan-3-yloxy)-2-trifluoromethyl-benzonitrile (1.345 g; 4.495 mmol) in tetrahydrofuran (5 mL) at ambient temperature under a nitrogen atmosphere is added (S)-(+)-sec-butylamine (0.4931 g; 6.742 mmol.) The reaction mixture is stirred for eight days. The reaction mixture is diluted with ethyl acetate and washed with 1N aqueous hydrochloric acid and with a brine solution. The organic phase is dried over anhydrous magnesium sulfate and is concentrated in vacuo to afford 1.633 of a white solid as a mixture of diastereomers; HPLC UV purity: 94% (two diastereomers.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-])=O)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl>C(O)C.[OH-].[Na+]>[C:1]([O:5][C:6](=[O:23])[C@@H:7]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH2:19])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](NC(=O)c1cc(Cl)ccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC[C@H](NC(=O)c1cc(Cl)ccc1N)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a stirred solution of (S)-2-(5-chloro-2-nitro-benzoylamino)-butyric acid-tert-butyl ester (5.72 g,) in ethanol (250 ml) at ambient temperature was added tin(II) chloride bis-hydrate (18.8 g). The mixture was stirred at ambient for 16 hours. The volume was reduced to approximately 50 ml under reduced pressure, and reaction mixture was then diluted with 1M NaOH until the precipitate formed re-dissolved (400 ml). The aqueous was then extracted with diethyl ether (3×100 ml). The organic extracts were combined and washed with brine, dried (MgSO4), and concentrated to give the sub-titled compound as a yellow solid (4.60 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 7.4 (1H, s), 7.2 (1H, d), 6.6 (2H, m), 5.5 (2H, m), 4.6 (1H, m), 2.0 (1H, m), 1.85 (1H, m), 1.5 (9H, s), 0.95 (3H, t) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]>CCO.C1COCC1.[Pd]>[NH2:9][C:5]1[C:6]([OH:8])=[CH:7][C:2]([F:1])=[C:3]([C:12](=[O:14])[CH3:13])[CH:4]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)cc1F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)c1cc(N)c(O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of 1-(2-fluoro-4-hydroxy-5-nitro-phenyl)-ethanone (3 g, 15.7 mmol) in EtOH (30 mL) and THF (6 mL) was added 10% Pd/C (1.5 g, 1.4 mmol) and the reaction mixture was stirred at ambient temperature under an atmosphere of H2 for 2 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give 1-(5-amino-2-fluoro-4-hydroxy-phenyl)-ethanone as black solid (2.5 g, 94%), which was used in the next step directly without further purification. 1H NMR (DMSO-d6, 400 MHz): δ 7.01 (d, J=8.0 Hz, 1H), 6.48 (d, J=12.4 Hz, 1H), 2.39 (d, J=4.8 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[CH:16][C:15]=1[CH:22]([CH3:24])[CH3:23].[OH:25][C:26]1[C:27]([CH3:40])=[C:28]([C:31]([O:36][CH2:37][CH2:38][OH:39])=[C:32]([CH3:35])[C:33]=1[CH3:34])[CH2:29][Cl:30]>CN(C)C=O>[ClH:30].[OH:25][C:26]1[C:27]([CH3:40])=[C:28]([C:31]([O:36][CH2:37][CH2:38][OH:39])=[C:32]([CH3:35])[C:33]=1[CH3:34])[CH2:29][N:10]([CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[CH:16][C:15]=1[CH:22]([CH3:24])[CH3:23])[CH3:9]
Reactant: Cc1c(C)c(OCCO)c(CCl)c(C)c1O
Reactant: CNCCOc1cc(C)c(O)cc1C(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(OCCN(C)Cc2c(C)c(O)c(C)c(C)c2OCCO)c(C(C)C)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
Triethylamine (2.8 ml) was added dropwise to a solution of N-methyl-2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethylamine hydrochloride (2.60 g) and 3-hydroxy-6-(2-hydroxyethoxy)-2,4,5-trimethylbenzyl chloride (2.45 g) in N,N-dimethylformamide (20 ml), and the mixture was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction mixture was poured on ice water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give 3.8 g of a pale brown oil. The oil was dissolved in a small amount of methanol and conc. hydrochloric acid (1.2 ml) was added. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethanol-diethyl ether to give 2.9 g of the title compound (colorless crystals).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:16]([O:18]CC)=[O:17])[C:5]([CH3:15])=[C:6]2[C:11]=1[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][CH:7]2[OH:14].[OH-].[K+]>C(O)C.[Zn]>[OH:14][CH:7]1[C:6]2[C:11](=[CH:2][CH:3]=[C:4]([C:16]([OH:18])=[O:17])[C:5]=2[CH3:15])[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8]1
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(O)CCS2(=O)=O
Agent: [K+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Product: Cc1c(C(=O)O)ccc2c1C(O)CCS2(=O)=O
Temperature: 50 °C
Yield: 143.4 %

Procedure:
10.0 g (31.3 mmol) of the 8-chloro-6-ethoxycarbonyl-4-hydroxy-5-methylthiochroman-1,1-dioxide obtained in the above step (7) was dissolved in 30 ml of ethanol, and 50 ml of a 16% potassium hydroxide aqueous solution and 6.1 g (93.3 mmol, 3.0 equivalents) of a zinc powder were added. The mixture was stirred under heat at 50° C. for 3 hours. After the completion of the reaction, the zinc powder was filtered off. While the reaction mixture was cooled, a 2N hydrochloric acid aqueous solution was added until the mixture had a pH of 1. Then, the mixture was extracted with ethyl acetate twice. An organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off to give 11.5 g (yield 100%) of 4-hydroxy-5-methylthiochroman-6-carboxylic acid-1,1dioxide.
Reaction SMILES: O[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1.P(Cl)(Cl)([Cl:19])=O>O>[Cl:19][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1
Reactant: Cn1c(=O)cc(O)n(-c2ccccc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(=O)cc(Cl)n(-c2ccccc2)c1=O
Temperature: 110 °C
Yield: 72 %

Procedure:
To the obtained 6-hydroxy-3-methyl-1-phenyluracil (12.2 g, 56 mM) was added phosphorus oxychloride (phosphoryl chloride, 167 ml, 2M) under cooling with ice and 3.4 ml of water was then added dropwise. The solution was heated gradually and maintained at 110° C. for 2 hours. The solvent was distilled off under reduced pressure. A product was obtained by crystallization with water and recovered by filtration to yield 6-chloro-3-methyl-1-phenyluracil (yield: 9.55 g, or 72% based on 6-hydroxy-3-methyl-1-phenyluracil).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[CH3:13][C:14]1[C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[S:16][C:15]=1[S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:13][C:14]1[C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[S:16][C:15]=1[S:24]([NH:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:5]2[NH:1][N:2]=[N:3][N:4]=2)[CH:7]=1)(=[O:25])=[O:26]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Cc1ccc2sc(S(=O)(=O)Cl)c(C)c2c1
Solvent: ClCCl
Product: Cc1ccc2sc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)c(C)c2c1
Reaction time: 4 h
Yield: 2.7 %

Procedure:
To a solution of 3-(1H-tetrazol-5-yl)-phenylamine (161 mg, 10 mmol) in dry CH2Cl2 (10 mL) pyridine (0.5 mL) and 3,5-dimethyl-benzothiophene-2-sulfonyl chloride (Intermediate 13) (260 mg, 10 mmol) were added. The mixture was stirred for 4 h and then concentrated in vacuo. The product was purified by column chromatography on silica gel (eluent: 2 to 15% MeOH in CHCl3) affording 104 mg (27%) of the title compound. 1H NMR (DMSO-d6) δ ppm 2.40 (s, 3H) 2.52 (s, 3H) 7.29 (d, 1H) 7.35 (d, 1H) 7.42 (t, 1H) 7.70 (m, 2H) 7.85 (d, 1H) 7.92 (s, 1H). MS (ESI+) calcd for C17H15N5O2S2 385.066716, found 385.065826.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20](Cl)[N:19]=3)[CH2:14][CH2:13]2)=[N:7][CH:6]=1)[CH3:2].[CH3:33][CH:34]1[CH2:38][CH2:37][CH2:36][NH:35]1>CC(N(C)C)=O>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[N:21]=[C:20]([N:35]4[CH2:36][CH2:37][CH2:38][CH:34]4[CH3:33])[N:19]=3)[CH2:16][CH2:17]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CC1CCCN1
Reactant: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(Cl)n3)CC2)c(Cl)c1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCCC4C)n3)CC2)c(Cl)c1

Procedure:
Heat a mixture of 5-chloro-6-{4-[2-chloro-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-nicotinic acid ethyl ester (1.19 g, 0.0025 mol) and 2-methylpyrrolidine (2.5 mL, 0.025 mol) in DMA at 120° C. for 14 h. Partition the reaction mixture between EtOAc and water. Wash the organic layer with water (1×) and brine (1×), then dry (Na2SO4) and concentrate under reduced pressure. Filter the crude product through a silica gel pad (2 inches deep×3 inches in diameter) eluting with 700 mL of 30% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound as an off-white foam.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])=O)C1C=CC=CC=1.[CH:29]([C:31]1[N:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][C:35]([C:41]#[N:42])=[C:34]2[O:43][CH:44]([CH3:46])[CH3:45])=O.N1CCCCC1>CC(O)C>[CH:44]([O:43][C:34]1[C:33]2[C:38](=[CH:39][CH:40]=[C:31]([CH:29]=[C:15]3[C:14](=[O:16])[N:13]=[C:12]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:26])([F:27])[F:28])[NH:11]3)[N:32]=2)[N:37]=[CH:36][C:35]=1[C:41]#[N:42])([CH3:46])[CH3:45]
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccccc2C(F)(F)F)=N1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(C)Oc1c(C#N)cnc2ccc(C=C3NC(NCc4ccccc4C(F)(F)F)=NC3=O)nc12
Temperature: 25 °C

Procedure:
To a mixture of 4-oxo-2-(2-trifluoromethyl-benzylamino)-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (70.4 mg, 0.18 mmol) (prepared as described in C-H Kwon et al. J. Med. Chem. 1991, 34, 1845-1849), 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (56.5 mg, 0.23 mmol) (see Example 1) and iPrOH (5 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 5 h to give a brown solution. The reaction mixture was cooled to r.t. and concentrated to give a light yellow solid, 66.3 mg, which was purified by flash column purification to give 4-isopropoxy-6-[5-oxo-2-(2-trifluoromethyl-benzylamino)-3,5-dihydro-imidazol-4-ylidenemethyl]-[1,5]naphthyridine-3-carbonitrile, as a light yellow solid, 18.6 mg (21.5%). HR-ES (+) m/e calcd for C24H19F3N6O2 (M+H)+ 481.1595. found 481.1595.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[N:11]=1.[H-].[Na+]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: COc1cc(OC)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(OC)nc(Oc2ccc(I)cc2)n1
Yield: 88.7 %

Procedure:
In the same manner as in Reference Example 8, 4-iodophenol (223 mg) and 2-chloro-4,6-dimethoxypyrimidine (192 mg) were reacted by using sodium hydride to obtain 2-(4-iodophenoxy)-4,6-dimethoxypyrimidine (322 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]2[C:17](Cl)=[CH:18][C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])=[N:20][CH:21]=2)=[O:14])=[CH:11][C:10]=1[F:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]2[O:14][C:17]3[CH:18]=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[N:20]=[CH:21][C:16]=3[N:15]=2)=[CH:11][C:10]=1[F:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2ccc(OCc3ccccc3)c(F)c2)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCc4ccccc4)c(F)c3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 3 h
Yield: 29.4 %

Procedure:
A suspension of tert-butyl ((2S)-1-((5-((4-(benzyloxy)-3-fluorobenzoyl)amino)-4-chloropyridin-2-yl)oxy)propan-2-yl)carbamate (6.28 g), potassium carbonate (3.28 g) and copper(I) iodide (226 mg) in DMF (40 mL) was stirred at 160° C. for 3 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.72 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13]([C:14]2[C:18]([Cl:19])=[C:17]([O:20][CH:21]([F:23])[F:22])[N:16]([CH3:24])[N:15]=2)=[C:12]([F:25])[CH:11]=[C:10]([Cl:26])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C(Cl)Cl>[CH2:1]([N:8]1[C:13]([C:14]2[C:18]([Cl:19])=[C:17]([O:20][CH:21]([F:23])[F:22])[N:16]([CH3:24])[N:15]=2)=[C:12]([F:25])[CH:11]=[C:10]([Cl:26])[C:9]1=[S:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2c(F)cc(Cl)c(=O)n2Cc2ccccc2)c(Cl)c1OC(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cn1nc(-c2c(F)cc(Cl)c(=S)n2Cc2ccccc2)c(Cl)c1OC(F)F
Temperature: 120 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
0.50 g of 1-benzyl-3-chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-[1H]-pyrazol-3-yl)-5-fluoro-[1H]-pyridin-2-one is introduced into 5 ml of toluene, 0.63 g of Lawesson's reagent is added and the resulting yellow suspension is stirred overnight at 120° C. The next day, the mixture is cooled to 22° C., diluted with methylene chloride and, after the addition of 3 g of silica gel, concentrated to dryness in vacuo. The silica gel is applied to a flash chromatography column and eluted first with toluene/ethyl acetate 30/1 (v/v) and then with n-hexane/ethyl acetate 2/1 (v/v). 0.32 g of the desired title compound is obtained in the form of a yellow solid having a melting point of 135-138° C.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1)#[N:3].CN(C=O)C.[CH:29](I)([CH3:31])[CH3:30]>O>[C:2]([C:4]1[CH:20]=[CH:19][C:7]([N:8]([CH:29]([CH3:31])[CH3:30])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1)#[N:3]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2[N+](=O)[O-])cc1
Reactant: CC(C)I
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(c2ccc(C#N)cc2[N+](=O)[O-])C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.8 %

Procedure:
To a mixture of 4′-cyano-2′-nitro-p-toluenesulfonanilide sodium salt (1330 g (3.92 mol)) and DMF (3000 ml), under heating in an oil bath kept at 110° C., isopropyl iodide (2019 g (11.8 mol)) was added over a period of 1.5 hours. After completion of the addition, the mixture was further heated at the same temperature with stirring for 3 hours, and then left to cool to room temperature. Water (1500 ml) was added to bring about separation of crystals. The crystals were filtered, washed with water, dried, and then suspended in diethyl ether. The suspension was stirred for 4 hours, and the insolubles were removed by filtration, the diethyl ether solution was washed with 0.1% aqueous sodium hydroxide solution to remove the remaining starting material, 4′-cyano-2′-nitro-p-toluenesulfonanilide. The diethyl ether layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give crude crystals which were, after washing with ethanol, recrystallized from ethyl acetate to give 124 g (8.8%) of the title compound as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:12][C:13]([F:23])([F:22])[S:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([S:14][C:13]([Cl:12])([F:22])[F:23])=[CH:16][CH:17]=1)=[O:9]
Reactant: Nc1ccc(SC(F)(F)Cl)cc1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 11.2 using 5-bromo-6-chloro-nicotinic acid and 4-((chloro-difluoromethyl)thio)aniline (Stage 217.3) to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.78 min, UPLC-MS (Condition 3) tR=1.32 min, m/z=425 [M−H]−.