Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:16])=[C:5](C(OCC)=O)[C:6](=[O:10])[NH:7][C:8]=1[CH3:9])[CH3:2].C([O-])(O)=O.[Na+]>Cl>[CH2:1]([C:3]1[C:4]([OH:16])=[CH:5][C:6](=[O:10])[NH:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CCOC(=O)c1c(O)c(CC)c(C)[nH]c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCc1c(O)cc(=O)[nH]c1C
Temperature: 25 °C
Yield: 54 %

Procedure:
A 50-mL round bottom flask was charged with ethyl 5-ethyl-4-hydroxy-6-methyl-2-oxo-1H-pyridine-3-carboxylate (117 mg, 0.52 mmol) and 1N HCl (10 ml). The mixture was stirred under reflux overnight. After cooling to room temperature, the mixture was neutralized by addition of aqueous NaHCO3 to pH=7. The precipitate was collected by filtration and washed with water. After dried, 5-ethyl-4-hydroxy-6-methyl-1H-pyridin-2-one was obtained (43 mg, 54% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH:15]=O)([CH3:10])[CH3:9].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C.CO>[CH:8]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH2:15][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)([CH3:10])[CH3:9]
Reactant: CN1CCNCC1
Reactant: CC(C)Oc1cc(C=O)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Oc1cc(CN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3.25 ml of 1-methylpiperazine are added to a solution of 3.06 g of 3-isopropoxy-4-nitrobenzaldehyde in 15 ml of toluene and 0.34 ml of acetic acid in a three-necked round-bottomed flask under argon. The reaction mixture is stirred at ambient temperature for 1.5 h and then 5 ml of toluene are added, followed by 4.9 g of sodium triacetoxyborohydride by spatula. The reaction mixture is stirred at ambient temperature for 16 h, and then treated with 4.5 ml of methanol and 75 ml of a saturated sodium hydrogen carbonate solution. After stirring at ambient temperature for 30 min, the mixture is extracted with 30 ml and then 2×50 ml of ethyl acetate. The organic extracts are combined, washed with water, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure, so as to give 4.24 g of 1-(3-isopropoxy-4-nitrobenzyl)-4-methylpiperazine in the form of a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[Cu][C:14]#[N:15]>CN(C=O)C.C(OCC)(=O)C>[C:14]([C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8])#[N:15]
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(CC(=O)O)ccc1F
Temperature: 130 °C
Yield: 65 %

Procedure:
To a solution of (3-bromo-4-fluoro-phenyl)-acetic acid (10 g, 42.9 mmol) in DMF (65 mL) was added copper (I) cyanide (7.7 g, 85.8 mmol) and heated at 130° C. for 24 hrs. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (250 mL). The organic layer was washed with water (5×50 mL), brine (50 mL), dried over sodium filtered and concentrated under reduced pressure. The crude material was re-crystallized from diethyl ether and hexane to afford the title compound as a yellow solid in 65% yield, 5 g.
Reaction SMILES: [C:1]([C:3]1[C:4](O)=[N:5][CH:6]=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2].CN(C=O)C.O=S(Cl)[Cl:22]>>[Cl:22][C:4]1[C:3]([C:1]#[N:2])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(O)c(C#N)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c(C#N)c1
Temperature: 25 °C

Procedure:
To a solution of 222 mg (1.16 mmol) of ethyl 5-cyano-6-hydroxynicotinate (from Step A) in 5 mL of SOCl2 was added 500 μL of DMF. After refluxing overnight, the mixture was cooled to rt and concentrated. The residue was dissolved in EtOAc (20 mL) and washed with brine (10 mL), saturated NaHCO3 (10 mL), and brine (10 mL), dried over Na2SO4, and concentrated. Chromatography on a Biotage 40M cartridge using 1:9 v/v EtOAc/hexanes gave 145 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.44 (d, J=7.1, 3H), 4.46 (q, J=7.1, 2H), 8.58 (d, J=2.1, 1H), 9.15 (d, J=2.1, 1H).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42]O)[CH:37]=2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:42][C:38]3[CH:37]=[C:36]([CH:29]([CH:26]4[CH2:27][CH2:28]4)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:41]=[CH:40][CH:39]=3)[CH:13]=[CH:12][C:11]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(F)c(-c2ccc(O)cc2-c2nnc(C(C)(C)C)s2)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(C)(C)C)s3)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.8 %

Procedure:
To a solution of 2-(5-(tert-butyl)-1,3,4-thiadiazol-2-yl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-ol (109 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (91 mg) and triphenylphosphine (319 mg) in THF (6.0 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (480 μL) at 0° C., and the mixture was stirred at room temperature for 12 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (134 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[NH:9][CH:10]=1)=[O:5])[CH3:2].[H][H].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:35]1[CH2:39][CH:38]=[CH:37][CH2:36]1>CCO.CC(N(C)C)=O.[Pd].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[NH:9][CH:10]=1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]([N:35]2[CH2:39][CH:38]=[CH:37][CH2:36]2)=[O:13])[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: C1=CCNC1
Agent: [Pd]
Agent: CCOC(=O)c1c[nH]c(C(=O)OCc2ccccc2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(C(=O)N2CC=CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
1H-Imidazole-2,4-dicarboxylic acid 2-benzyl ester 4-ethyl ester was prepared in a manner substantially similar to that described by Branco, P. S.; Prabhakar, S.; Lobo, A. M.; Williams, D. Tetrahedron, 1992, 48, 6335. To a solution of 1H-imidazole-2,4-dicarboxylic acid 2-benzyl ester 4-ethyl ester (380 mg, 1.4 mmol) in EtOH (10 mL) was added Pd/C (10%) (40 mg) under N2 atmosphere. The suspension was then treated with hydrogen under 50 psi for 3 hours. The catalyst was removed by filtration through Celite® and the filtrate was evaporated. To a solution of the crude acid (140 mg, 0.76 mmol) in DMA (2 mL) was added CDI (140 mg, 0.86 mmol). The mixture was stirred at ambient temperature for 1 hour and then 2,5-dihydro-1H-pyrrole (110 mg, 1.59 mmol) was added. After stirring at ambient temperature for 2 hours, the reaction mixture was poured into water (5 mL). The aqueous solution was extracted with EtOAc (2×10 mL) and the combined organic layers dried over MgSO4, filtered, and evaporated. The crude product was purified by flash column eluting with 50% EtOAc in hexane to afford the title compound as a white solid (110 mg, 61%). MS (ES+): m/e=236.2 (M+H); Rt=2.04 minutes.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[C:17]1([CH3:25])[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>O1CCCC1>[NH2:15][C:7]1[C:6]([C:4]([C:20]2[CH:21]=[CH:22][C:17]([CH3:25])=[CH:18][CH:19]=2)=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: Cc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CCSc1ncc(C(=O)c2ccc(C)cc2)c(N)n1
Reaction time: 2 h

Procedure:
To a solution of 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (500 mg, 2.06 mmol, Example 1) in dry tetrahydrofuran (6 mL) at −30˜−40° C., was added 4-tolylmagnesium bromide (10.5 mL, Aldrich). The reaction was stirred at the same temperature for 2 hours before quenching with aqueous ammonium chloride. Work-up and purification as in Example 47 gave (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-p-tolyl-methanone as a white solid. MS (M+H)+, 274.
Reaction SMILES: [CH2:1]([N:8]([C:10]([NH:12][C:13]1[CH:14]=[N:15][N:16]([CH2:18][C:19]2[C:20]([CH3:25])=[N:21][O:22][C:23]=2[CH3:24])[CH:17]=1)=[O:11])[NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27](OCC)=[O:28].C(N(CC)CC)C.[OH-].[Na+]>C(#N)C>[CH2:1]([N:8]1[C:10](=[O:11])[N:12]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]3[C:20]([CH3:25])=[N:21][O:22][C:23]=3[CH3:24])[CH:17]=2)[C:27](=[O:28])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)N(N)Cc2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(Cc3ccccc3)c2=O)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
1-benzyl-N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)hydrazinecarboxamide (2.00 g, 5.88 mmol), ethyl chlorformate (6.38 g, 58.77 mmol), and triethylamine (1.78 g, 17.63 mmol) in acetonitrile (50 mL) were heated at 100° C. for 48 hours. The mixture was cooled to 80° C., 1 M NaOH (aq) (5 mL) was added and the reaction mixture was stirred for 1 hour. The reaction was cooled to room temperature and concentrated on the rotpvap. The residue was dissolved in dichloromethane and filtered to remove salts and the solution was concentrated to afford 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2,4-triazolidine-3,5-dione (1.28 g, 60%) as a yellow oil. MS M+H calculated 367.14; found 367.2.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)(=O)=O.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:10][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccc(CCCn3ccnc3)cc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 69.1 %

Procedure:
A mixture of 3-(4-benzyloxyphenyl)propyl methanesulfonate (55.0 g), imidazole (17.6 g), potassium carbonate (35.7 g) and N,N-dimethylformamide (500 ml) was stirred for 6 hours at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure to give 1-[3-(4-benzyloxyphenyl)propyl]imidazole (34.7 g, 69%). Recrystallization from ethyl acetate-hexane gave colorless needles, mp 80-81° C.
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:19]([NH:26][CH2:2][CH:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCC=C1c2ccccc2C=Cc2ccccc21
Reactant: NCc1ccccc1
Solvent: CC#N
Product: C1=Cc2ccccc2C(=CCNCc2ccccc2)c2ccccc21

Procedure:
To a solution of 5-(2'-chloroethylidene)-5H dibenzo[a,d]cycloheptene (1.25 g, 5 mmol) in acetonitrile (30 ml) is added benzylamine (1.6 g, 15 mmol) and the mixture is refluxed for 4 hours under argon atmosphere. The solution is concentrated in vacuo, the residue is taken up in water, and the solution is basified with concentrated aqueous sodium bicarbonate. The water phase is extracted with ethyl acetate. The organic mixture is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue (1.2 g) is dissolved in ether and a solution of oxalic acid (0.5 g) in tetrahydrofuran is added. The oxalate salt precipitates, and is recrystallized twice from ethanol, m.p. 209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](/[CH:23]=[CH:24]/[O:25]C)[C:18]=3[CH3:27])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[I-].[Na+].C[Si](Cl)(C)C.O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH3:27])=[C:19]([CH2:23][CH:24]=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CO/C=C/c1cccc(-c2nsc(-c3ccc(OC(C)C)c(Cl)c3)n2)c1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1c(CC=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-3-{2-methyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazole (D105) (130 mg, 0.324 mmol) and sodium iodide (97 mg, 0.649 mmol) in Acetonitrile (8 mL) stirred under nitrogen at room temperature was added TMSCl (0.083 mL, 0.649 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hr. Water was added. The aqeuous solution was extracted with EA for 3 times. The organic phase was washed with saturated Na2S2O3 solution and saturated brine, dried over sodium sulphate and evaporated in vacuo to afford the crude product [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-methylphenyl]acetaldehyde (D106) (120 mg) as a yellow oil, which was used for the next step without further purification. MS (ES): C20H19ClN2O2S requires 386.1. found 387.2 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].CC1C=CC(S(O)(=O)=O)=CC=1.CN1CCOCC1.[NH:35]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@@H:36]([C:47](O)=[O:48])[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(OCC)(=O)C.O>[NH:35]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@@H:36]([C:47]([NH:1][C@@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:48])[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCCC[C@@H](N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC[C@@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of H-DNle-OBzl.TsOH (1.27 g) in dichloromethane (20 ml) were added NMM (0.53 ml), Boc-DTrp-OH (1.22 g), HOBT.H2O (734 mg) and EDCI.HCl (926 mg) successively under ice cooling. The mixture was stirred at the same temperature for 1 h and at room s temperature for 2 h. The mixture was diluted with ethyl acetate, washed with sat. aq. NaHCO3, 10% aq. citric acid, and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was recrystallized from ethyl acetate and hexane to give Boc-DTrp-DNle-OBzl (1.56 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[C:29]([F:28])[CH:30]=4)[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Cl)c3)C(C)(C)C2=O)cc1
Reactant: Nc1cccc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Nc4cccc(F)c4)c3)C(C)(C)C2=O)cc1
Temperature: 95 °C

Procedure:
To a solution of 0.5 g of 3-(4-tert-butylphenyl)-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage a) of Example 7 in 15 mL of dioxane are successively added, under argon, 250 μl of 3-fluoroaniline, 1.6 g of caesium carbonate, 90 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) [xantphos] and 29 mg of palladium diacetate. The reaction mixture is heated at 95° C. for 2 hours, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of cyclohexane and ethyl acetate (60/40 by volume) to give 451 mg of 3-(4-tert-butylphenyl)-1-({2-[(3-fluorophenyl)amino]pyridin-4-yl}methyl)-5,5-dimethyl-imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [C:1]1([N:7]2[C:19](=[O:20])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:22]C1C=CC=CC=1NN>>[F:22][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[N:7]1[C:19](=[O:20])[C:10]2=[CH:11][NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]2=[N:8]1
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1
Reactant: NNc1ccccc1F
Agent: Cl
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1F

Procedure:
The title compound was prepared following the procedure described in Step 3 for the synthesis of 4a, using 2-fluorophenyl hydrazine hydrochloride instead of phenyl hydrazine hydrochloride. 1H NMR (DMSO-d6) δ (ppm): 7.13-7.46 (3H, m), 7.48-7.62 (2H, m), 7.67 (1H, dd, J=6.87, 1.37 Hz), 7.73 (1H, d, J=8.24 Hz), 8.11 (1H, dd, J=8.24, 1.09 Hz), 8.70 (1H, d, J=6.31 Hz). m/z 280.3 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)([O-:14])(=[O:13])=[S:12].[K+]>C(O)C>[C:5]1([CH2:4][CH2:3][CH2:2][O:14][S:11]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[S:12])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Reactant: BrCCCc1ccccc1
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=S)OCCCc2ccccc2)cc1

Procedure:
The title compound was prepared as described in General Method 2 using 1-bromo-3-phenylpropane (0.044 mmol), potassium thiotosylate (0.044 mmol) and absolute ethanol (125 mL) to give an oil which was used without purification. 1H NMR (CDCl3) δ 1.95 (quint., 2 H), 2.459 (s, 3 H), 2.63 (t, 2 H), 2.95 (t, 2 H), 7.0-7.4 (m, 8 H), 7.7 (d, 2 H).
Reaction SMILES: [C:1]1([S:7]([NH:10][C@H:11]([CH2:15][C:16]#[CH:17])[C:12]([OH:14])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:37][O:38][CH:39]([O:42][CH3:43])[CH2:40][NH2:41].CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:37][O:38][CH:39]([O:42][CH3:43])[CH2:40][NH:41][C:12](=[O:14])[C@H:11]([NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[CH2:15][C:16]#[CH:17]
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)O
Reactant: COC(CN)OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)NCC(OC)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-2-(benzenesulfonamido)pent-4-ynoic acid (11.66 g, 46.04 mmol), HOBt (7.46 g, 55.24 mmol), iPr2NEt (7.13 g, 55.24 mmol), (2,2-dimethoxyethyl)amine (5.81 g, 55.24 mmol), and EDCI (10.53 g, 55.24 mmol) in DMF (100 mL) was stirred for 24 h at RT. The reaction mixture was concentrated and taken up in H2O (100 mL). The aqueous layer was extracted with EtOAc (3×), dried over MgSO4, and concentrated to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 2.43 (m, 2H), 2.71 (s, 3H), 2.85 (s, 1H), 2.89 (s, 3H), 2.96 (m, 2H), 3.98 (t, 7.1 Hz, 3H), 4.15 (t, 5.5 Hz, 1H), 7.55 (m, 3H), 7.80 (d, 8.0 Hz, 2H), 7.97 (s, 1H), 8.11 (t, 5.5 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:15](=[O:17])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)[CH2:30][CH2:29]2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(c3ccc(F)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-(4-fluoro-phenyl)-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H25FN2O5 [M+H]+: 417.
Reaction SMILES: [C:1]12([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>C(OCC)(=O)C.[Pt]>[C:1]12([NH:11][C:12]3[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=[N+]([O-])c1ccccc1NC12CC3CC(CC(C3)C1)C2
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC12CC3CC(CC(C3)C1)C2
Yield: 64.6 %

Procedure:
A solution of N-Adamantan-1-yl-2-nitro-phenylamine (6 g) prepared as in intermediate 10 in ethyl acetate (120 ml) was hydrogenated at 23° and 1 atm. pressure over 5% platinum on carbon (600 mg) for 2 h. The catalyst was removed by filtration through hyflo and the filtrate evaporated to give a brown solid. This was adsorbed onto silica and chromatographed with hexane-EA (20:3) as eluent to give the title compound (3.45 g) as cream crystals, m.p. -69°-71°.
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:11][C:12]([NH2:14])=[S:13].C([O-])([O-])=O.[Na+].[Na+]>CC#N.C1COCC1>[NH2:14][C:12]1[S:13][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH3:10])[N:11]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N)nc1C
Temperature: 120 °C
Yield: 37.6 %

Procedure:
To a stirred solution of ethyl 2-chloroacetoacetate (6.0 mL, 43.35 mmol) in MeCN (24 mL) and THF (6 mL) was added thiourea (3.0 g, 39.41 mmol) and Na2CO3 (0.417 g, 39.41 mmol). The reaction mixture was heated at 120° C. under microwave irradiation for 30 minutes, cooled to r.t., partitioned between EtOAc and water, and the organic fraction was dried (MgSO4), filtered and concentrated in vacuo to give the title compound (2.76 g, 38%) as a cream solid. δH (CDCl3) 5.47 (2H, br. s), 4.27 (2H, q, J 7.2 Hz), 2.53 (3H, s), 1.33 (3H, t, J 7.2 Hz). MS (ES+) 187.0 (M+H)+.