Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]2[NH:21][C:22](=[O:44])[C:23]3([CH:27]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:26][N:25]([C:33](Cl)=[O:34])[CH:24]3[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=3[F:43])[C:18]2=[CH:17][CH:16]=1.O>CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:33]([N:25]2[CH2:26][CH:27]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]3([C:18]4[C:19](=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=4)[NH:21][C:22]3=[O:44])[CH:24]2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=2[F:43])=[O:34])=[CH:11][CH:10]=1)=[O:7]
Reactant: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(=O)N2CC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18 %

Procedure:
To a solution of methyl 4-hydroxybenzoate (Aldrich) (20 mg, 0.13 mmol) in N,N-dimethylforamide (3 mL) was added NaH (60%, 7.8 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 10 min, then rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride prepared in Example 8 (56 mg, 0.13 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Water was added. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichloromethane and hexanes to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid 4-methoxycarbonyl-phenyl ester as a white solid (Yield 14 mg, 18%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:16])([C:13]([OH:15])=O)[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:32][C:33](=[NH:35])[CH3:34]>CN(C=O)C>[CH3:17][C:9]1([CH3:18])[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:12]([CH3:16])([C:13]2[O:15][N:35]=[C:33]([CH3:34])[N:32]=2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OCC1(C)C(=O)O
Reactant: CC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1noc(C2(C)COC(C)(C)N2C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a solution of 430 mg of 3-(tert-butoxycarbonyl)-2,2,4-trimethyl-1,3-oxazolidine-4-carboxylic acid in 4 ml of DMF was added 296 mg of 1,1′-carbonyldiimidazole, followed by stirring at room temperature for 2 hours. To the reaction mixture was added 146 mg of N-hydroxyacetamidine, followed by stirring at room temperature for 1 hour, at 110° C. for 2 hours, and then at 130° C. overnight. The reaction mixture was left to be cooled to room temperature and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 390 mg of tert-butyl 2,2,4-trimethyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([Si:10]([CH3:27])([CH3:26])[O:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:13]1[CH2:24][OH:25])([CH3:9])[CH3:8].C(N(CC)CC)C>>[CH3:9][C:7]([Si:10]([CH3:27])([CH3:26])[O:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C@@H:13]1[CH2:24][O:25][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:6])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (3.85 mL, 39.29 mmol) was added to an ice cold methylene chloride solution of 1,1-dimethylethyl(2R,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy-}2-(hydroxymethyl)-1-pyrrolidinecarboxylate (6.05 g, 26.19 mmol) and triethylamine (7.28 mL, 52.38 mmol). The reaction was warmed to room temperature, stirred for 16 hours then concentrated under reduced pressure. The crude material was dissolved in ethyl acetate and washed with saturated NaHCO3, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to give the title compound as a yellow oil. (4.69 g, 11.4 mmol). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.1 (s, 6H), 0.8 (s, 9H), 1.4 (m, 9H), 1.7 (m, 1H), 2.0 (m, 1H), 3.2 (s, 3H), 3.3 (m, 2H), 3.7 (m, 1H), 4.0 (m, 1H), 4.2 (m, 1H), 4.3 (m, 1H). ES+=410.16.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]([CH3:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)=[C:5]([C:24](O)=[O:25])[N:4]=[C:3]1[C:27]([F:30])([F:29])[F:28].[NH:31]1[CH2:34][CH2:33][CH2:32]1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>>[CH3:22][N:12]1[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=[C:11]1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[C:3]([C:27]([F:28])([F:30])[F:29])=[N:4][C:5]=1[C:24]([N:31]1[CH2:34][CH2:33][CH2:32]1)=[O:25])=[O:23]
Reactant: C1CNC1
Reactant: Cn1cc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)O)nc(C(F)(F)F)n1C
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1cc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)N2CCC2)nc(C(F)(F)F)n1C

Procedure:
The product was obtained starting from 1-methyl-5-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethylcarbamoyl)-2-(trifluoromethyl)-1H-imidazole-4-carboxylic acid (30 mg, 71.2 μmol) and azetidine (4.98 mg, 5.88 μL, 85.4 μmol) via COMU coupling according to the method described in example 61, step 3 as white solid (20.5 mg, 44.5 μmol, 62.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=1)=[O:8].[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:25][CH2:24][CH2:23][O:22][CH3:21])[N:14]=1)=[O:8]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Reactant: COCCN
Solvent: CN1CCCC1=O
Product: COCCNCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Temperature: 80 °C

Procedure:
1-(4-Chloromethyl-thiazol-2-yl)-3-(3,4-dichloro-benzyl)-urea (Intermediate 2, 1 eq.) was taken up in NMP (0.3 M) and methoxyethylamine (2.2 eq.) was added. The reaction was heated overnight at 80° C. An aqueous workup was performed. The crude title compound was purified by column chromatography using 0-8% gradient of 7 N ammonia/MeOH and DCM.
Reaction SMILES: O=[O+][O-].[Na].[CH3:5][O:6][C:7](=[O:27])[CH:8]([C:24](=O)[CH3:25])[CH:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[N+:15](O)[O-])[C:11]([O:13][CH3:14])=[O:12].O.[NH2:29]N>CO>[CH3:14][O:13][C:11]([C:10]1[CH:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([C:7]([O:6][CH3:5])=[O:27])=[C:24]([CH3:25])[NH:29][N:15]=1)=[O:12]
Reactant: NN
Reactant: COC(=O)C(C(c1ccccc1)C(C(C)=O)C(=O)OC)=[N+]([O-])O
Agent: O=[O+][O-]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)C1=NNC(C)=C(C(=O)OC)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dry ozone is passed, in excess, into a solution of 69.0 g (0.2 mol) of the sodium salt of 2-acetyl-4-aci-nitro-3-phenyl-glutaric acid dimethyl ester in 300 ml of absolute methanol at -78° C. until the solution becomes blue-coloured. After 30 minutes, the ozone is removed by passing dry nitrogen in and the mixture is warmed to -20°, under nitrogen. 10 g (0.2 mol) of hydrazine hydrate in 50 ml of absolute methanol are added dropwise and the mixture is stirred at room temperature for 12 hours. For working up, the methanol is distilled off in vacuo, the residue is taken up in chloroform and insoluble material is filtered off. The chloroform is distilled off from the filtrate and, after adding a little isopropanol to the residue, the product slowly crystallises out. Melting point: 187°.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[N:8]([CH:9]([CH3:11])[CH3:10])[N:7]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:5]=1[CH3:16].[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:16][C:5]1[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7][N:8]([CH:9]([CH3:10])[CH3:11])[C:4]=1[O:3][CH:2]([F:1])[F:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C(F)(F)F)nn(C(C)C)c1OC(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)n1nc(C(F)(F)F)c(CBr)c1OC(F)F
Yield: 40.8 %

Procedure:
To a solution of 10.3 g (40.0 mmol) of 5-difluoromethoxy-4-methyl-1-iso-propyl-3-trifluoromethyl-1H-pyrazole in 40 ml of carbon tetrachloride were added 7.8 g (44.0 mmol) of N-bromosuccinimide and 0.3 (2.0 mmol) of α,α′-azobisisobutyronitrile, followed by heating and refluxing under stirring. The reaction solution was externally irradiated with a light for 1 hour. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with chloroform. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 5.5 g (yield: 40.7%) of 4-bromomethyl-5-difluoromethoxy-1-iso-propyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[O:16]([CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][C:24]([CH2:23][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][C:1](=[O:6])[CH:2]=1
Reactant: O=C(COc1ccccc1)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(COc2ccccc2)(c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 0.85 mL of methyl acetoacetate, 350 mg of NaH 60% dispersion in oil, 5 mL of 1.6M n-butyl lithium in hexane, 2.0 g of 2-phenoxy-1-phenyl ethanone and 60 mL of tetrahydrofuran. After addition of the ketone, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature and stirred for 1 hour. The crude product was triturated from diethyl ether to afford a solid (m.p. 133°-135° C.). 1 H NMR (DMSO-d6) δ3.03 (d, 1H), 3.35 (d, 1H), 4.18 (dd, 2H), 4.90 (s, 1H), 6.92-6.95 (m, 3H), 7.24-7.49 (m, 7H), 11.56 (s, 1H).
Reaction SMILES: Cl.[CH3:2]O.[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8]2>>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([O:17][CH3:2])=[O:16])[CH:9]=[CH:8]2
Reactant: CO
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: Cl
Product: COC(=O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
15 ml of 10% hydrogen chloride-methanol was added to 1.0 g (5.31 mmol) of 6-hydroxy-2-naphthoic acid and the mixture was stirred at room temperature for one day. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with water, and dried (MgSO4). The solvent was distilled off to obtain 1.07 g (5.29 mmol) of methyl 6-hydroxy-2-naphthoate as a pale yellowish brown powder. Its spectroscopic data are as follows:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[N:7][C:8]([C:12]([F:15])([F:14])[F:13])=[N:9]2)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([OH:16])=[N:7][C:8]([C:12]([F:15])([F:14])[F:13])=[N:9]3)=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Oc1nc(C(F)(F)F)nc2cc(Cl)ccc12
Reactant: C1CCNCC1
Product: Oc1nc(C(F)(F)F)nc2cc(N3CCCCC3)ccc12

Procedure:
The title compound was prepared from 7-chloro-4-hydroxy-2-trifluoromethylquinazoline (2.0 g, 8.0 mmol), as described in Example 43 (but using piperidine in place of N,N-dimethylamine) to provide the desired compound in a 96% (2.5 g) yield; m.p. 268-271° C.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18]>C1COCC1.CC(OC)(C)C.[NH4+].[Cl-]>[C:17]([C:19]1[CH:26]=[CH:25][C:22](/[CH:23]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:21][CH:20]=1)#[N:18]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A flame dried three-neck flask equipped with a thermometer, an addition funnel and a N2 inlet was charged with NaH (3.96 g, 1.1 eqs) and anhydrous THF (120 mL). With moderate stirring at RT, a suspension was formed. To this suspension was added a solution of t-butyl diethylphosphonoacetate (23.2 mL 1.1 eq.) dissolved in anhydrous THF (20 mL), dropwise via the addition funnel over a period of 30 min. The suspension turned into a clear, light yellow colored solution. An exotherm from 25° C. to 35° C. was observed during the addition. After completion of the addition, the resulting mixture was stirred at RT for another 30 min. A solution of 4-cyanobenzaldehyde (11.3 g, 86.1 mmol, 1.0 eq) dissolved in anhydrous THF (20 mL) was added to the reaction mixture dropwise via the addition funnel over a period of 30 min. An exotherm from 25° C. to 35° C. was observed. The resulting mixture was stirred at RT for 1 h. Progress of the reaction was monitored by 1H NMR. Upon completion, the reaction mixture was diluted with MTBE (200 mL) and sat. NH4Cl solution (150 mL). The organic layer was separated and washed, sequentially, with 25 mL of H2O and 25 mL of sat. NH4Cl solution. After drying over MgSO4, the organic phase was evaporated to dryness to give 20.0 g 21A as a white solid (100% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.56 (s, 9H) 6.47 (d, 1H) 7.53-7.64 (m, 3H) 7.68 (d, 2H)
Reaction SMILES: [CH2:1]([C:5]1([CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:34])[C:9]([Cl:33])=[C:10]([C:14](C(OCC)=O)([CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:15]([O:17]CC)=[O:16])[CH:11]=2)[C:6]1=[O:35])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:5]1([CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:34])[C:9]([Cl:33])=[C:10]([CH:14]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:15]([OH:17])=[O:16])[CH:11]=2)[C:6]1=[O:35])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(C2CCCC2)Cc2cc(C(CCCC(=O)OCC)(C(=O)OCC)C(=O)OCC)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC1(C2CCCC2)Cc2cc(C(CCCC(=O)O)C(=O)O)c(Cl)c(Cl)c2C1=O
Yield: 84.2 %

Procedure:
The diethyl 2-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihyro-1-oxo-1H-inden-5-yl)-2-(ethoxycarbonyl)-1,6-hexanedioate (6.5 g) was refluxed with sodium hydroxide (5 g) dissolved in methanol (100 ml) and water (20 ml) for 3 hours. The mixture was cooled, diluted with water, acidified with hydrochloric acid and extracted with diethyl ether. The organic extracts were washed with water, dried over MgSO4 and concentrated to obtain 2-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-1,6-hexanedioic acid (4.3 g). The dioic acid was heated at 130°-135° C. for 25 minutes with copper powder (1.52 g) in quinoline (35 ml). The mixture was cooled, poured into water and extracted with diethyl ether after acidification with hydrochloric acid. The organic extracts were washed with water, dried over MgSO4 and concentrated under vacuum. The residue was chromatographed twice on silica eluting with a mixture of toluene, dioxane and acetic acid in the ratio of 900:80:10 to obtain 2.9 g of the product as viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[C:16]([F:23])[CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[NH:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[N:1]=2)=[C:16]([F:23])[CH:15]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: Fc1cc(Br)ccc1N=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Fc1cc(Br)ccc1Nc1nc2cc(C(F)(F)F)ccc2[nH]1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
1,2-Diamino-5-trifluoromethylbenzene (0.50 g, 2.84 mmol) was diluted in dichloromethane (5 mL) and treated with 4-bromo-2-fluoro-phenylisothiocyanate (0.66 g, 2.84 mmol). The dark solution was stirred at 45° C. for 15 minutes, then 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol) was added all at once. The reaction was heated in a 45° C. oil bath overnight, then cooled and concentrated at reduced pressure. The dark residue was diluted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The title compound was collected as a light pink solid (0.60 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ 11.3 (broad d, 1H), 9.87 (d, 1H), 7.50 (d, 2H), 7.61 (d, 1H), 7.55–7.41 (m, 3H), 7.35–7.30 (m, 1H); LC/MS m/z 356.2 (MH+), retention time 2.33 minutes.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:13])[C:8](=[O:9])[N:7]([CH3:10])[C:6](=[O:11])[NH:5][C:4]1=[O:12].[F:14][C:15]1[C:16]([F:28])=[C:17]([F:27])[C:18]([F:26])=[C:19]2[C:24](=O)[O:23][C:21](=[O:22])[C:20]=12.CCN(CC)CC>CC(O)=O>[CH3:10][N:7]1[C:8](=[O:9])[C:3]([CH3:13])([N:2]2[C:21](=[O:22])[C:20]3[C:19](=[C:18]([F:26])[C:17]([F:27])=[C:16]([F:28])[C:15]=3[F:14])[C:24]2=[O:23])[C:4](=[O:12])[NH:5][C:6]1=[O:11]
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: CN1C(=O)NC(=O)C(C)(N)C1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Temperature: 25 °C

Procedure:
A mixture of 5-amino-1,5-dimethylbarbituric acid hydrochloride (0.31 g, 1.50 mmol), tetrafluorophthalic anhydride (0.40 g, 1.80 mmol) and Et3N (0.21 mL, 0.15 g, 1.50 mmol) in glacial AcOH (11 mL) was stirred under reflux for 3 hours. The yellow solution was then allowed to cool down to room temperature and evaporated to dryness under reduced pressure. The oily residue was recrystallized from 70% EtOH to give 1,5-dimethyl-5-(tetrafluorophthalimido)-barbituric acid (19a) as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:13].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[N:56]1([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>O1CCOCC1>[CH3:13][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[N:59]1[CH2:58][CH2:57][N:56]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:61][CH2:60]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(Br)c(C)cc1[N+](=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 37.6 %

Procedure:
to a stirred solution of 1-bromo-2-methyl-5-(methyloxy)-4-nitrobenzene (9 g, 36.6 mmol) in 180 mL of Dioxane was added Pd2(dba)2 (2.14 g, 2.34 mmol), XANTPHOS (2.12 g, 3.65 mmol), cesuim carbonte (50 g, 153.6 mmol) and 1,1-dimethylethyl 1-piperazinecarboxylate (13.6 g, 73.15 mmol). The resulting slurry was warmed to 60° C. for 24 hours. The dioxane was removed under reduced pressure and the crude mixture was taken up in ether and filtered to remove cesium carbonate. The ether was, washed with water, dried (Na2SO4), filtered, and rotovaped down. The crude product was purified by flash chromatography to give 1,1-dimethylethyl 4-[2-methyl-5-(methyloxy)-4-nitrophenyl]-1-piperazinecarboxylate (4.83 g, 13.75 mmol, 38%). 1H NMR (400 MHz, CDCl3) δ ppm 7.81 (s, 1 H), 6.56 (s, 1 H), 3.92 (s, 3 H), 3.52-3.63 (m, 4 H), 2.88-2.99 (m, 4 H), 2.25 (s, 3 H), 1.47 (s, 9 H).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:33]=1[CH2:34]O>>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:34][C:33]2[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:32]=2[O:31][CH3:30])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(OC)c(CO)c1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: COc1ccc(OC)c(CN2CC[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccccc3)C2)c1
Yield: 23.8 %

Procedure:
The compound (0.20 g) obtained in Example 1 and 2,5-dimethoxybenzyl alcohol (0.12 g) were reacted and treated in the same manner as in the method described in Example 16 to obtain the title compound as colorless oil (0.060 g, 23%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]([C:18]([OH:20])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:21][O:19][C:18]([CH:10]1[N:11]([S:14]([CH3:17])(=[O:15])=[O:16])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)C(C(=O)O)C1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
To a solution of 4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester (8.4 g, crude) in DMF (50 mL) was added K2CO3 (7.5 g) and iodomethane (8.5 mL) The mixture was stirred overnight at R.T. An aqueous work-up followed by purification on silica gave 4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3.267 g). A solution of 4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3.2 g) in dry THF (20 mL) was added via cannular to a mixture of lithium aluminium hydride (0.75 g) in THF (30 mL) at 0° C. and under N2 atmosphere. The resultant mixture was then warmed to R.T. and stirred for 2.5 h. The reaction was carefully quenched with aqueous ammonium chloride (5 mL) then filtered over Celite. An aqueous work-up followed by purification on silica gave 3-hydroxymethyl-4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester (1.13 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)[CH:5]=[N:4][CH:3]=1.[CH2:18]1[C@@H:22]2[CH2:23][NH:24][CH2:25][C@@H:21]2[CH2:20][N:19]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([NH:8][C:6]1[N:7]=[C:2]([N:24]2[CH2:23][C@@H:22]3[CH2:18][N:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][C@@H:21]3[CH2:25]2)[CH:3]=[N:4][CH:5]=1)=[O:17]
Reactant: Cc1cccc(C(=O)Nc2cncc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cccc(C(=O)Nc2cncc(N3C[C@H]4CN(C(=O)OC(C)(C)C)C[C@H]4C3)n2)c1
Temperature: 110 °C

Procedure:
The product from Example 24A (130.5 mg, 0.53 mmol) was reacted with the product from Example 1C (149.6 mg, 0.70 mmol) and N,N-diisopropylethylamine (110 μL) in DMSO as described in Example 19A, except that the mixture was heated to 110° C. overnight, to afford the title compound. MS (DCI/NH3) m/z 424 (M+H)+.