Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18](=[O:20])[CH3:19])=[CH:12][CH:11]=1.[C:22](=[S:24])=[S:23].O>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:23][C:22]([SH:24])=[CH:19][C:18](=[O:20])[CH:17]=2)=[CH:12][CH:11]=1
Reactant: S=C=S
Reactant: CC(=O)CC(=O)c1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1cc(S)sc(-c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of LDA (20 mL, 40 mmol) in 40 mL anhydrous THF under an atmosphere of nitrogen was added slowly a solution of 1-(4-Bromophenyl)-butane-1,3-dione (4.84 g, 20 mmol) dissolved in THF (30 mL). After addition was complete the mixture was allowed to warm slowly to ambient temperature and stir for 10 minutes. The solution was re-cooled to −78° C. for the addition of a solution of carbon disulfide (1.2 mL, 20 mmol) in THF (20 mL). This temperature was maintained for 2 hours, before warming slowly to ambient temperature and stirred for 18 hours. Cold water (150 mL) was added and mixture was heated to 60° C. with good stirring for 3 hours. The volatiles were removed in vacuo and the aqueous solution was washed with diethyl ether (2×100 mL). The aqueous solution was acidified to pH 1 with 2N HCl, and the orange precipitate was filtered from the acid, washed with water, and dried by vacuum desiccation. Orange solid (5.07 g, 85%); LCMS m/z 299, 301 ([M+1]+) 298, 300 ([M−1]−), 1H-NMR (D6-DMSO): 7.10 (s, 1H, H-3), 7.36 (s, 1H, H-5), 7.69 (d, 2H, J=8.6 Hz, Arom), 7.76 (d, 2H, J=8.6 Hz, Arom); infrared spectrum (cm−1): 815, 950, 1008, 1072, 1202, 1451, 1364, 1451, 1487, 1508, 1584.
Reaction SMILES: [CH:1]([C:4]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8]([OH:10])=O)([CH3:3])[CH3:2].C(N(CC)CC)C.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([O:38][CH3:39])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=1.Cl>S(Cl)(Cl)=O.O>[CH:1]([C:4]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]([O:38][CH3:39])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:30]=1)=[O:10])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(OC)c1ccc(N)cc1
Reactant: Cc1ccc(C(C)C)c(OC(C)C(=O)O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)CC(OC)c1ccc(NC(=O)C(C)Oc2cc(C)ccc2C(C)C)cc1

Procedure:
A solution of 150 mg (0.67 mmol) of 2-(2-isopropyl-5-methylphenoxy)propionic acid in 1 ml of thionyl chloride was boiled under reflux under argon for 30 minutes. The reaction mixture was concentrated, admixed with 2 ml of toluene and concentrated again. The residue was dissolved in 3 ml of acetonitrile under argon, admixed with 940 μl (0.67 mmol) of triethylamine and a solution of 150 mg (0.67 mmol) of ethyl 3-(4-aminophenyl)-3-methoxypropionate and stirred at room temperature for 30 minutes. The reaction mixture was diluted with water, adjusted to pH=6-7 with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under high vacuum. This gave 287 mg of ethyl 3-{4-[2-(2-isopropyl-5-methylphenoxy)propionylamino]phenyl}-3-methoxypropionate.
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.[F:26][C:27]1[CH:38]=[CH:37][CH:36]=[CH:35][C:28]=1[C:29](N(OC)C)=[O:30].Cl.O>CCOC(C)=O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([C:29](=[O:30])[C:28]3[CH:35]=[CH:36][CH:37]=[CH:38][C:27]=3[F:26])=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: CON(C)C(=O)c1ccccc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (140 mg, 300 mmol) was placed in a dry 2-neck 10 mL round-bottom flask. The flask was evacuated and purged with nitrogen, followed by the addition of THF (1 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl (0.33 mL, 2.0 M) was added dropwise. Upon completion of the addition, the reaction was stirred 90 minutes, followed by the slow addition of 2-fluoro-N-methoxy-N-methyl-benzamide (140 mg, 750 mmol). The reaction was stirred overnight, during which the ice-bath warmed to room temperature. The following day, the reaction was quenched with a small quantity of MeOH and the solvents evaporated in vacuo. The residue was subsequently treated with 4.0 M HCl (in dioxane) (1 mL, 4.0 mmol) and H2O (0.33 mL), and then stirred at 80° C. for two hours. The resultant solution was diluted with EtOAc, washed with water, saturated sodium bicarbonate, and brine; dried with MgSO4, and evaporated employing reduced pressure. The crude sulfonamide was finally purified via preparatory TLC (20% EtOAc/hexanes) and recrystallization from MeCN/H2O to afford 98 mg of the title compound: 1H NMR (400 MHz, CDCl3) δ 10.6 (s, 1 H), 8.3 (d, 1 H), 8.2 (d, 1 H), 7.74 (d, 2H), 7.6 (d, 1 H), 7.5 (d, 1 H), 7.43 (d, 2H), 7.42-7.37 (m, 2H), 1.26 (s, 9H); MS (ES) M+H expect 447.1, found 447.5.
Reaction SMILES: Br[CH2:2][C:3](Br)([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])[CH3:4].[NH:14]1[CH:18]=[N:17][CH:16]=[N:15]1.O>CN(C=O)C>[N:14]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=2[F:12])=[CH2:4])[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: c1nc[nH]n1
Reactant: CC(Br)(CBr)c1ccc(F)cc1F
Solvent: O
Solvent: CN(C)C=O
Product: C=C(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 29.9 %

Procedure:
5 g (15.9 mmol) of 1,2-dibromo-2-(2,4-difluorophenyl) propane VIII and 3.3 g (48 mmol) of 1,2,4-triazole in DMF was refluxed for 15 hours. The reaction mixture was cooled down to room temperature, water (40 mL) was added and product was extracted with EtOAc (2×50 mL). The EtOAc phase was washed with water and dried (Na2SO4). Evaporation of the solvent under reduced pressure and purification of the residue on a silica gel column with ethyl acetate as the eluent, furnished the title compound (1.05 g, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C@H:9]([CH2:10][OH:11])[C@H:8]([NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]1=[O:22].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(O)(=O)C(C)O>N1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C@H:9]([CH2:10][O:11][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[C@H:8]([NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]1=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CO)c(OC)c1
Agent: CC(O)C(=O)O
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2COS(=O)(=O)c2ccc(C)cc2)c(OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
Under stirring at 0° C., 1.73 g of cis-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-3-phenylacetamido-2-oxoazetidine is added to a solution of 1.12 g of p-toluenesulfonyl chloride in 6 ml of pyridine. The reaction mixture is stirred for 2 hours and then allowed to stand overnight in a refrigerator. To the reaction mixture is added 0.68 ml of lactic acid and the mixture is stirred for one hour. The reaction mixture is diluted with 45 ml of ethyl acetate and 15 ml of tetrahydrofuran, and then washed with dilute hydrochloric acid, and aqueous sodium chloride solution, an aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution in this order. The organic solution is dried over magnesium sulfate and the solvent is distilled off in vacuo. To the residue is added a mixed solvent of ether and ethyl acetate (5:1) and the resulting crystals are collected by filtration to give 2.21 g (91%) of cis-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-4-(p-toluenesulfonyloxymethyl)-2-oxoazetidine, m.p. 109°-110° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:15])=[CH:5][C:6]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:7][CH:8]=1.[C:16]([O-])(O)=O.[Na+]>C(O)=O>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([CH2:9][N:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:5][C:4]=2[N:15]=[CH:16]1
Reactant: O=C([O-])O
Reactant: CNc1ccc(CN2CCCC2)cc1N
Agent: [Na+]
Solvent: O=CO
Product: Cn1cnc2cc(CN3CCCC3)ccc21

Procedure:
A solution of 850 mg (4.14 mmol) N1-methyl-4-pyrrolidin-1-ylmethyl-benzene-1,2-diamine in 4 mL formic acid is refluxed for 1.5 h. It is made alkaline with 250 mL semisaturated NaHCO3 solution and extracted twice with 70 mL EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:8][C:9]([S:13][CH3:14])=[N:10][C:11]=1[CH3:12])=[O:5])C.O.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:11]([CH3:12])[N:10]=[C:9]([S:13][CH3:14])[N:8]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1-c1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1nc(C)c(C(=O)O)c(-c2cccc(Cl)c2)n1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
1.44 g (4.47 mmol) of 4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-pyrimidinecarboxylic acid ethylester was dissolved in 10 ml of THF and 5 ml of water. 225 mg (5.36 mmol) of lithium hydroxide monohydrate was added and stirred at 50° C. for 12 hours. 10 ml of water was added thereto and the organic layer was batched off. The obtained aqueous layer was diluted with ethyl acetate and washed with 5 ml of 3 N hydrochloric acid and then with 5 ml of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:32])[N:17]([CH2:19][C@H:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:21][CH2:22][OH:23])[CH3:18])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16](=[O:32])[N:17]([CH2:19][C@H:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:21][CH:22]=[O:23])[CH3:18])([CH3:14])([CH3:12])[CH3:13]
Reactant: CN(C[C@@H](CCO)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of oxalyl chloride (2.84 mL) in dichloromethane (70 mL) at −78° C. was added dimethylsulfoxide (4.6 mL) in dichloromethane (35 mL). This mixture was stirred for about 7 minutes at −78° C. before (S)-[2-(3,4-dichloro-phenyl)-4-hydroxy-butyl]-methyl-carbamic acid tert-butyl ester (9.1 g) was added as a solution in dichloromethane (25 mL). This mixture was stirred at −78° C. for 30 minutes before triethylamine (18.1 mL) was added neat. The mixture was then stirred for 30 minutes at −78° C., 45 minutes at 0° C., then warmed to ambient temperature. The solution was diluted with dichloromethane, washed with dilute hydrochloric acid, aqueous sodium bicarbonate, dried and evaporated. MS: m/z=346(M+1). The product was used with no further purification.
Reaction SMILES: [Cl-].[Cl-].[CH3:3][N:4](B)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BN(C)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: CNc1ccccc1C(O)c1ccccc1
Yield: 75.7 %

Procedure:
To a solution of N-methylanilinoborane dichloride (100 mg) in methylene chloride (5 ml), a solution of benzaldehyde (56 mg) and tri-n-butylamine (99 mg) in methylene chloride (2 ml) is added with ice cooling, and the resultant mixture is stirred at room temperature for 1 hour. The reaction mixture is mixed with ice pieces and shaken with methylene chloride. The methylene chloride layer is washed with aqueous sodium carbonate and a saturated brine in that order, and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, and the product is recrystallized from chloroform-petroleum ether to give 2-methylaminobenzhydrol (85 mg) as crystals melting at 124° to 126° C. The yield is 75.0%.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:15]#[N:16].[K+].Cl.[CH3:19][NH:20][CH3:21]>C(O)C.O>[CH3:19][N:20]([CH3:21])[C:11]1([C:15]#[N:16])[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:10]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CNC
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN(C)C1(C#N)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 68 h
Yield: 96.1 %

Procedure:
A solution of 1-(phenylmethyl)-4-piperidone (9.46 g, 50 mmol) in ethanol (20 mL) was added slowly to a stirred solution of potassium cyanide (3.58 g, 55 mmol) and dimethylamine hydrochloride (4.89 g, 60 mmol) in water (60 mL). The mixture was stirred at room temperature for 68 hours, then water (100 mL) was added. The solid was collected, suspended in aqueous sodium hydrogen carbonate (saturated, 100 mL) and water (50 mL) and extracted with dichloromethane (3×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the the title compound as a cream solid (11.69 g, 96%). m/z (ES+) 244 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:15]>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(Cl)cc(Cl)cc1Cl
Product: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Yield: 93 %

Procedure:
A solution of 2,4,6-trichlorobenzoic acid (1.0 g, 4.0 mmol) in SOCl2 (5 mL) was heated to reflux for 30 min under nitrogen atmosphere. The reaction was concentrated under reduced pressure to give 2,4,6-trichlorobenzoyl chloride (900 mg, 93% yield), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[N:18]=[C:6]2[CH2:5][N:4]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N+:11]([O-:31])=[CH:10][C:9]=3[N:18]=[C:6]2[CH2:5][N:4]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:3]1
Reactant: C[C@H]1CN(S(C)(=O)=O)Cc2nc3cnc4ccccc4c3n21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CN(S(C)(=O)=O)Cc2nc3c[n+]([O-])c4ccccc4c3n21
Reaction time: 8 h
Yield: 100 %

Procedure:
(11S)-11-Methyl-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline (1.01 g, 3.19 mmol) was dissolved in dichloromethane (40 mL) and treated with MCPBA (0.94 g, 77% max). After stirring overnight, the reaction was treated with 20 mL of 2% Na2CO3 solution and the layers were separated. The aqueous layer was then extracted with dichloromethane (10×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give (11S)-11-methyl-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline 5-oxide (1.06 g) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[CH:6][CH:5]=[C:4]([CH3:13])[N:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:24][CH2:23][NH:22][C:21]2=[O:25])[CH2:16][CH2:15]1>C(O)(C)C>[OH:12][CH:10]([CH2:9][O:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH3:13])=[CH:5][CH:6]=1)[CH2:11][N:14]1[CH2:15][CH2:16][CH:17]([N:20]2[CH2:24][CH2:23][NH:22][C:21]2=[O:25])[CH2:18][CH2:19]1
Reactant: Cc1ccc(OCC2CO2)c(Cl)n1
Reactant: O=C1NCCN1C1CCNCC1
Solvent: CC(C)O
Product: Cc1ccc(OCC(O)CN2CCC(N3CCNC3=O)CC2)c(Cl)n1

Procedure:
1.1 g of 2-chloro-3-(2,3-epoxy-propoxy)-6-methylpyridine and 0.76 g of 1-(4-piperidyl)-imidazolidin-2-one are refluxed in 40 ml of isopropanol for 1 hour. Evaporating off the solvent and recrystallising the residue from the isopropanol/ether yields 1-{1-[2-hydroxy-3-(2-chloro-6-methyl-3-pyridyloxy)-propyl]-4-piperidyl}-imidazolidin-2-one with a melting point of 175°-180°.
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C@H:8]([C:12]([OH:14])=O)[CH:9]([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@H:49]([NH2:51])[CH3:50])[S:48][C:44]=2[CH:43]=1>C1(C)C=CC=CC=1.O>[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@H:49]([NH:51][C:12]([C@@H:8]([NH:7][C:5](=[O:6])[O:4][CH:1]([CH3:2])[CH3:3])[CH:9]([CH3:10])[CH3:11])=[O:14])[CH3:50])[S:48][C:44]=2[CH:43]=1
Reactant: C[C@@H](N)c1nc2ccc(F)cc2s1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)OC(=O)N[C@H](C(=O)N[C@H](C)c1nc2ccc(F)cc2s1)C(C)C
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 132.2 %

Procedure:
In 500 ml of toluene, 18.9 g (0.093 mol) of N-isopropoxycarbonyl-L-valine was dissolved. The solution was cooled to −5° C. Thereto were dropwise added, at −5° C., 23.0 g (0.233 mol) of N-methylmorpholine and 12.7 g (0.093 mol) of isobutyl chlorocarbonate. Thereto was added, at −5° C., 17.4 g (0.047 mol) of (R)-1-(6-fluoro-2-benzothiazolyl)ethylamine p-toluenesulfonate in one portion. The mixture was stirred at the same temperature for 0.5 hour and then at room temperature for 2 hours. To the reaction mixture was added 300 ml of water. The mixture was heated to 70° C. to dissolve the solid. The toluene layer was separated, washed with hot water, and then cooled, whereby a solid was precipitated. The solid was collected by filtration and dried to obtain 23.7 g (yield: 70%) of isopropyl {(S)-1-[(R)-1-(6-fluorobenzothiazol-2-yl)ethylcarbamoyl]-2-methylpropyl}carbamate. The compound obtained was confirmed for the structure by IR analysis and NMR analysis in comparison with its authentic material and identified.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:20]2[CH:24]=[CH:23][N:22]=[N:21]2)=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1c[nH]nn1
Reactant: ICCCCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(CCCCn3ccnn3)cc2)cc1
Temperature: 70 °C
Reaction time: 26.5 h
Yield: 42.4 %

Procedure:
Benzyl 4-(4-iodobutyl)phenyl ether (1.1 g), 1H-1,2,3-triazole (0.31 g), and potassium carbonate (0.622 g) were suspended in DMF (7.5 ml), followed by stirring at 70° C. for 26.5 hours. After cooling, the reaction mixture was extracted with ethyl acetate and washed with water and saturated saline. Under reduced pressure, the solvent was distilled off; the residue was subjected to silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:3) to yield the titled compound (0.391 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1Br.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O.O1CCOCC1.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>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2nc(-c3ccccc3)c(N)nc2-c2ccccc2)ccc1=O
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A mixture of 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg), phenylboronic acid (79 mg), Pd(PPh3)4 (9 mg), a solution of Na2CO3 (110 mg) in water (0.8 ml) and dioxane (2.0 ml) was heated at 90° C. with stirring for 1 hour. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was recrystallized from MeOH-IPE and dried in vacuo to give 5-(5-amino-3,6-diphenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (84 mg).
Reaction SMILES: C[Si](Br)(C)C.[CH3:6][O:7][C:8]1[C:9]([O:40]COC)=[C:10]([C:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[CH:19][CH:20]=1)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])O.[Na+]>ClCCl>[OH:40][C:9]1[C:8]([O:7][CH3:6])=[CH:20][CH:19]=[C:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: COCOc1c(OC)ccc(COc2ccc(-c3ccc(CC(=O)OC)cc3)cc2)c1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(OC)c(O)c3C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.7 %

Procedure:
After trimethylsilyl bromide (55 μl, 0.414 mmol) was added to a solution of tert-butyl 3-methoxy-2-(methoxymethoxy)-6-[({4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]benzoate (180 mg, 0.344 mmol) obtained in Example (51-1) in dichloromethane (4.0 ml), the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into an aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: n-hexane/ethyl acetate=2/1) to give tert-butyl 2-hydroxy-3-methoxy-6-[({4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]benzoate (146 mg, yield: 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][C:13]([OH:16])([CH3:15])[CH3:14]>>[C:13]([O:16][C:10](=[O:11])[NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)([CH3:15])([CH3:14])[CH3:12]
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)O
Product: CC(C)(C)OC(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 84 %

Procedure:
A solution of 3,5-dichloro-phenyl isocyanate (5 g, 26.6 mmol) in t-BuOH (100 mL) was heated at 80° C. for 16 h. The mixture was concentrated by rotary evaporation to give a white solid which was triturated with toluene and evaporated to dryness. Addition of toluene and concentration under vacuum gave (3,5-dichloro-phenyl)carbamic acid-tert-butyl ester as a white solid (6 g, 22.9 mmol, 84%). 1H NMR (300 MHz, CDCl3): δ 7.42 (s, 2H), 7.18 (s, 1H), 6.6 (br s, NH), 1.62 (s, 9H).