Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][CH3:12])[N:3]=1.[F:13][C@@H:14]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][OH:21])[O:16][C@H:15]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:15]2[O:16][C@H:17]([CH2:20][OH:21])[C@@H:18]([OH:19])[C@H:14]2[F:13])=[C:4]([NH:11][CH3:12])[N:3]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Reactant: CNc1nc(N)nc2nc[nH]c12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CNc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Temperature: 37 °C

Procedure:
2-Amino-6-methylaminopurine (J. A. Montgomery and L. B. Holum, J.A.C.S. 80:404, 1958; 0.51 g; 3.1 mmoles) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.52 g, 2.1 mmoles) which may be prepared according to J. F. Codington et al. (J. Org. Chem. 29:558, 1964) were suspended in 50 ml of 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (4,000 I.U.) and purine nucleoside phosphorylase (14,000 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) were added and the suspension stirred at 37° C. On day 6, the reaction was diluted to 250 ml with 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide and 0.49 g of 2-amino-6-methylaminopurine and 4,000 I.U. thymidine phosphorylase and 14,000 I.U. purine nucleoside phosphorylase were added. On day 14, the reaction was evaporated. The residue was suspended in methanol/water and the suspension filtered. The filtrate was evaporated. The residue was dissolved in water and applied to a 2.5×13 cm column of anion exchange resin (Bio-Rad AG1X2-hydroxide form). After washing the column with water, the product was eluted with methanol/water (1/1). After the solvent was removed under vacuum, the residue was dissolved in water and filtered through a 0.22 μm-pore membrane filter. Lyophilization of the filtrate yielded title compound that anlyzed as a 0.5 hydrate.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([NH:26]C(=O)C2C=CC=CC=2)=[S:25])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1.O>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([NH2:26])=[S:25])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=S)NC(=O)c3ccccc3)cccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(N)=S)cccn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a solution of 8-[2-methyl-6-(3-benzoylthioureido)benzylamino]-3-(2propynyl)-2-methylimidazo[1,2-a]pyridine (0.59 g) in methanol (5.9 ml) and tetrahydrofuran (5.9 ml) was added a solution of potassium carbonate (0.174 g) in water (5 ml) and the mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure and the residue was dispersed into a mixture of water and chloroform. The chloroform layer was separated and washed with water and dried over magnesium sulfate. The residual oil was triturated with diethyl ether to give 8-(2-methyl-6-thioureidobenzylamino)-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (0.36 g).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:7][CH2:6]1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.O>C1(C)C=CC=CC=1>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][O:3][CH2:4][CH:5]1[CH2:7][CH2:6]1
Reactant: OCC1CC1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: BrCCCCOCC1CC1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
2.8 g of a 60% suspension of sodium hydride in mineral oil are added in portions to a solution of 5.0 g of hydroxymethylcyclopropane in 25 ml of toluene at room temperature. The mixture is then heated at 100° C. for 2 hours. After this, it is allowed to reach room temperature and a solution of 14.9 g of 1,4-dibromobutane in 15 ml of toluene is added. The mixture is left to stir at 100° C. for a further 15 hours. Then, at room temperature, 10 ml of water are added, the phases are separated, and the toluene is removed in a rotary evaporator. The product is isolated by vacuum distillation.
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]([C:18](O)=[O:19])[CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][N:13]3[CH3:21])=[CH:5][CH:4]=1.[O-:22][N+:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[C:25]([C@H:33]([NH2:35])[CH3:34])[CH:24]=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]([C:18]([NH:35][C@@H:33]([C:25]3[CH:24]=[N+:23]([O-:22])[C:28]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:26]=3)[CH3:34])=[O:19])[CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][N:13]3[CH3:21])=[CH:5][CH:4]=1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Reactant: Cn1ccc2c(-c3ccc(F)cc3)cc(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@@H](NC(=O)c1cc(-c2ccc(F)cc2)c2ccn(C)c2c1)c1ccc(C(F)(F)F)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a solution of sodium salt of 4-(4-fluorophenyl)-1-methyl-1H-indole-6-carboxylic acid (25.0 mg, 56.0 μmol), hydrochloride salt of (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (16.4 mg, 67.0 μmol) and N-methylmorpholine (30.9 μL, 0.28 mmol) in N,N-dimethylformamide (0.56 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18.9 mg, 98.0 μmol), 1-hydroxy-7-azabenzotriazole (3.8 mg, 28.1 μmol). The mixture was stirred at ambient temperature. After 18 h, the mixture was concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% NH4OH) gave the title compound (22.1 mg): HRMS [M+1] found=458.1491; 1H NMR (400 MHz, DMSO): δ 8.90 (d, J=7.3 Hz, 1H); 8.53 (s, 1H); 8.06 (s, 1H); 7.94 (d, J=8.4 Hz, 1H); 7.74 (dd, =8.4, 5.5 Hz, 2H); 7.69 (s, 1H); 7.59 (d, J=3.1 Hz, 1H); 7.55 (d, J=8.4 Hz, 1H); 7.40-7.31 (m, 2H); 6.56 (d, J=3.1 Hz, 1H); 5.27-5.18 (m, 1H); 3.90 (s, 3H); 1.56 (d, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([C:17]([OH:19])=O)=[CH:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[O:19]=[C:17]1[C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][C:8]=2[NH:7][C:1]2[C:2]1=[CH:3][CH:4]=[CH:5][CH:6]=2
Reactant: O=C(O)c1ccc(C(=O)O)c(Nc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc2c(=O)c3ccccc3[nH]c2c1
Temperature: 165 °C
Reaction time: 0.5 h
Yield: 982.5 %

Procedure:
To a round bottom flask containing polyphosphoric acid (35 g) at 165° C. was added finely ground compound 1B (3.0 g, 1.17 mmol) over 10 min. After the addition was complete, the reaction mixture was stirred for 30 min at 165° C. HPLC indicated that the reaction was complete. While at 165° C., the mixture was slowly added to a mixture of ice and sodium hydroxide. The pH was adjusted to 3.0 with additional sodium hydroxide, and the resulting mixture was filtered through a medium porosity fritted funnel to give a yellow paste which was rinsed with MeOH and DCM into a round bottom flask. The organic solvents were removed under reduced pressure and the residue was azeotripic evaporated several times with MeOH and DCM to give 2.75 g (98%) of compound 1C as a yellow solid. HPLC retention time=2.45 min. (Condition A) and LC/MS M++1=240+. 1H-NMR (500 MHz, DMSO-d6) δ 13.13 (bs, 1H), 11.96 (s, 1H), 8.31 (d, J=8.42 Hz, 1H), 8.24 (d, J=8.20 Hz, 1H), 8.18 (s, 1H), 7.77 (t, J=7.55 Hz, 1H), 7.72 (d, J=8.42 Hz, 1H), 7.55 (d, J=8.20 Hz, 1H), 7.30 (t, J=7.55 Hz, 1H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Br[CH2:14][C:15]#[N:16].N#N>C(#N)C>[O:10]1[CH2:11][CH2:12][N:7]([CH2:14][C:15]#[N:16])[CH2:8][CH2:9]1
Reactant: C1COCCN1
Reactant: N#CCBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a suspension of K2CO3 (6.50 g, 47 mmol) and morpholine (3.75 g, 43 mmol) in acetonitrile (30 mL) was added 2-bromoacetonitrile (5.16 g, 43 mmol) in one portion under the protection of N2 in an ice bath. The mixture was stirred at rt for 2 h, then filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (5.41 g, 100%).
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][O:17][C:18]=3[N:19]=2)[CH2:4][CH2:3]1.[ClH:28].C(OCC)(=O)C>>[ClH:28].[F:27][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:13][NH:14][CH2:15][CH2:16][O:17][C:18]=3[N:19]=2)[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(OC3CCC(F)(F)CC3)ccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: FC1(F)CCC(Oc2ccc3c(n2)OCCNC3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A mixture of the compound obtained in step 1 (0.23 g) and 4N hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.16 g, 82%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.Br[C:14]1[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:20][C:18]1[CH:19]=[C:14]([NH:1][C:2]2[N:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: CC(C)(C#N)c1ccc(N)nc1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(C(C)(C)C#N)cn2)c1=O
Temperature: 100 °C
Yield: 38.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (35 mL), 156c (483 mg, 3.0 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.6 g, 6.0 mmol), Pd2(dba)3 (274.5 mg, 0.30 mmol), XantPhos (346.8 mg, 0.60 mmol), and cesium carbonate (4.59 g, 15 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:1 ethyl acetate/petroleum ether to afford 156d (400 mg, 38%) as a yellow solid. MS-ESI: [M+H]+ 347.0
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[N+:13]([O-])([O-:15])=[O:14].[K+].S(=O)(=O)(O)O>ClCCl>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:10])[F:11])=[CH:4][C:5]([F:8])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)cc(C(F)(F)F)c1Br

Procedure:
2-Bromo-5-fluoro-benzotrifluoride (XVII) (50 g, purchased from ABCR, F01421) is dissolved in 750 mL of dichloromethane. Potassium-nitrate (60.54 g) is added under stirring, followed by slow addition of sulfuric acid (587.3 g, 20% SO3, Riedel de Haen 30736). The temperature of the reaction mixture is kept at 25-30° C. by gentle cooling during the addition of the sulfuric acid. The reaction mixture is stirred for additional 25 hours at room temperature, after which time an IPC indicated >97% conversion. For work-up, the layers are separated and the acid layer is extracted by stirring with dichloromethane (2×300 mL). The dichloromethane phases are combined and washed sequentially with 1,000 mL of saturated aqueous NaHCO3 solution, 1,000 mL of aqueous sulfamic acid solution (5% m/m), 1,000 mL of saturated aqueous NaHCO3 solution and 1,000 mL of water. The dichloromethane solution is dried on anhydrous MgSO4 and the solvent is evaporated under reduced pressure to obtain 2-bromo-5-fluoro-1-nitro-3-trifluoromethyl-benzene (XVIII) as a yellow liquid. GC-MS: m/z: 287, 268, 257, 241, 229. These mass peaks are accompanied by the corresponding isotope peaks characteristic for bromine containing compounds. IR (film): 3101, 1618, 1591, 1554, 1454, 1423, 1365, 1319, 1232, 1186, 1153, 1113, 883 cm−1.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>CN(C)C=O>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNC(=O)c1ccc(N2CCC(O)CC2)nc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)nc1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A mixture of 10.1 g (42.9 mmol) 4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid methylamide, 8.0 g (52 mmol) tert-butyldimethylchlorosilane and 6.5 g (94 mmol) imidazole in 90 ml N,N-dimethylformamide was stirred at room temperature over night. The reaction was quenched with water. The resulting suspension was extracted with ethyl acetate. The organic extract was washed with 3 portions of water. The combined aqueous layers were extracted with 3 portions of dichloromethane. The combined organic extracts were dried with sodium sulfate, concentrated and dried in vacuo (0.5 mbar) at 80° C. Flash column chromatography afforded 14.6 g (97.3%) of the title compound as a light yellow solid. MS m/e (%): 349 (M+, 21).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][C:13]([OH:18])([CH:15]([OH:17])[CH3:16])[CH3:14]>>[NH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[O:17][CH:15]([CH3:16])[C:13]([CH3:14])([OH:18])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(O)C(C)(C)O
Product: CC(Oc1cc(F)ccc1N)C(C)(C)O

Procedure:
Is prepared in a similar manner as intermediate III.1 from 2,4-difluoro-1-nitro-benzene and 2-methylbutane-2,3-diol.
Reaction SMILES: Cl.N[C:3]1[NH:8][C:7]2=[CH:9][CH:10]=[CH:11][C:6]2=[C:5]([OH:12])[N:4]=1.N([O-])=[O:14].[Na+]>>[OH:14][C:3]1[NH:8][C:7]2=[CH:9][CH:10]=[CH:11][C:6]2=[C:5]([OH:12])[N:4]=1
Reactant: O=N[O-]
Reactant: Nc1nc(O)c2cccc-2[nH]1
Agent: Cl
Agent: [Na+]
Product: Oc1nc(O)c2cccc-2[nH]1
Temperature: 0 °C
Yield: 75.6 %

Procedure:
To a mixture solution of 20% HCl(62 ml) and 2-amino-4-hydroxycyclopenta[d]pyrimidine (20.6 g, 0.136 mol) prepared in the above Step 1 was added aqueous solution of sodium nitrite (19.4 g) for 4 hours while keeping the temperature of the reaction system at 70° C. The reaction mixture was cooled to 0° C. and the resulting solid was filtered, dried under reduced pressure to give 15.43 g of titled compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[I-].[K+].C(=O)(O)[O-].[Na+]>CS(C)=O.O>[OH:14][CH2:13][CH2:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: OCCCCBr
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(CCCCO)c1ccccc1
Temperature: 25 °C

Procedure:
A stirred solution of 107.2 g (1 mole) of N-methylaniline, 153.0 g (1 mole) of 4-bromo-1-butanol, 166 g (1 mole) of potassium iodide, and 168 g (2 mole) of sodium bicarbonate in dimethylsulfoxide is heated at 90° C. until the reaction is complete as indicated by thin layer chromatography. After cooling to room temperature, the reaction mixture is poured into a four-fold excess of water, and the aqueous solution is extracted with methylene chloride. The solvent is removed in vacuo, and the residual product is dissolved in a small amount of methylene chloride and swirled with silica gel. After removal of the silica gel, the solution is filtered through cotton and evaporated to yield compound A.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH2:17])=[CH:13][N:12]([CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:11]1=[O:27])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:42][CH2:43][C:44](Cl)=[O:45]>ClCCl>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][C:44](=[O:45])[CH2:43][Cl:42])=[CH:13][N:12]([CH2:18][C:19]2[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=2[F:25])[C:11]1=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(NC(=O)CCl)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of {(R)-2-[5-amino-3-(2,6-difluoro-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (50 mg, 0.11 mmol) in dichloromethane (2 mL) were added triethylamine (29 μl, 0.22 mmol) and chloro-acetyl chloride (9.3 μl, 0.12 mmol) in that order, followed by stirring at room temperature for 2 hrs. Again, chloro-acetyl chloride (5.0 μl, 0.06 mmol) was added to the solution which was then stirred at room temperature for 1 hr. The solution was washed with an aqueous saturated sodium bicarbonate solution to separate an organic layer which was then concentrated. The residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate, 2/1) and dried in a vacuum to afford 44 mg of the compound as a colorless oil (yield 76%).
Reaction SMILES: O[CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>ClCCl>[Br:20][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)COc1cc(/C=C/CO)cc(OC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)COc1cc(/C=C/CBr)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of the compound (150 mg, 0.594 mmol) of Example 16-4 in dicloromethane (2 ml) were added carbon tetrabromide (207 mg, 0.623 mmol) and triphenylphosphine (163 mg, 0.623 mmol), and the mixture was stirred for 30 minutes at room temperature. By adding ether to the reaction mixture, the resulting precipitate was filtered off. The filtrate was concentrated and the residue was purified with silica gel chromatography (hexane:ethyl acetate=2:1) to give the subject compound (141 mg, 75.3%).
Reaction SMILES: [NH2:1][C:2]1O[C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1C#N)=[CH:8][C:7]1[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=1[CH:5]=2.CI.C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38]([CH3:41])[CH:39]=[O:40]>>[CH3:37][N:38]([CH3:41])[C:39]1[O:40][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:2]#[N:1])=[CH:8][C:7]1[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=1[CH:5]=2
Reactant: CN(C)C=O
Reactant: COc1cc(C2C(C#N)=C(N)Oc3cc4ccccc4cc32)cc(Br)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1cc(C2C(C#N)=C(N(C)C)Oc3cc4ccccc4cc32)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[g]chromene-3-carbonitrile (30) (24 mg) was taken in 1 ml dry DMF (dimethylformamide) and then charged with methyl iodide (30 μl) and potassium carbonate (30 mg) at room temperature. The reaction was completed after 20 h stirring at room temperature. The title compound was purified on HPLC (21 mm×250 mm, RP18, 5 mm) with a Methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 ml/min) to yield pale yellowish solids (18 mg).
Reaction SMILES: [Na].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH3:20])[CH:13]=1>CO>[CH3:20][O:19][CH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][CH:3]([C:4](=[O:5])[CH3:6])[C:2]([O:8][CH3:9])=[O:7]
Reactant: COCc1cccc(CBr)c1
Reactant: COC(=O)CC(C)=O
Agent: [Na]
Solvent: CO
Product: COCc1cccc(CC(C(C)=O)C(=O)OC)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a solution of 0.34 g (15.1 mmol) of sodium in 8 mL of anhydrous MeOH are added dropwise, at room temperature and under argon, 1.6 mL (15.1 mmol) of methyl acetoacetate. After stirring for 30 minutes, 3.25 g (15.11 mmol) of 1-(bromomethyl)-3-(methoxymethyl)benzene are rapidly added dropwise and the reaction medium is then heated for 2 hours 30 minutes at 70° C. The reaction medium is then concentrated under reduced pressure, and the residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 20% EtOAc. 3.2 g of methyl 2-[3-(methoxymethyl)benzyl]-3-oxobutanoate are obtained in the form of an oil.
Reaction SMILES: [CH:1]1([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][CH:18]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>CCCCCC>[CH:18]1([N:17]([CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([CH:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:34]([NH:33][C:27]3[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=3[F:25])=[O:35])[CH:11]=2)[C:34]([NH:33][C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[F:25])=[O:35])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: c1cc(CNC2CCCCCC2)cc(CNC2CCCCCC2)c1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CCCCCC
Product: O=C(Nc1ccc(F)cc1F)N(Cc1cccc(CN(C(=O)Nc2ccc(F)cc2F)C2CCCCCC2)c1)C1CCCCCC1
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of 1 g N,N'-dicycloheptyl-m-xylylenediamine in 50 ml n-hexane, was added dropwise with stirring 5 ml of a n-hexan solution containing 1 g 2,4-difluorophenyl isocyanate under ice cooling. Stirring was continued at room temperature for two hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and then recrystallized from isopropanol, giving 1.6 g of 1,3-bis[[1-cycloheptyl-3-(2,4-difluorophenyl)ureido]methyl]benzene.