Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.C([NH:24][C@H:25]([C:30]([O-:32])=O)[C:26]([CH3:29])([CH3:28])[CH3:27])(OCC1C=CC=CC=1)=O.CCN(C(C)C)C(C)C.ClC(OCC(C)C)=O.[CH2:50]([CH2:52][NH2:53])[OH:51]>C(Cl)Cl>[NH2:24][C@@H:25]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:30]([NH:53][CH2:52][CH2:50][OH:51])=[O:32]
Reactant: NCCO
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)[O-]
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[C@H](N)C(=O)NCCO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Cbz-tert-leucine dicyclohexylammonium salt (1.34 g, 3.0 mmol) and DIEA (0.7 ml) in DCM (25 mL) cooled in an ice-water bath was added isobutyl chloroformate (0.47 mL, 3.6 mmol). After stirring at 0° C. for 1 hour, ethanolamine was added (0.52 mL, 9.0 mmol) and stirred overnight. The reaction was quenched with saturated aqueous sodium bicarbonate. The organic phase was separated and dried over sodium sulfate. After evaporation under reduced pressure, the residue was dissolved in MeOH and passed through a SCX (Phenomenex®, Torrance, Calif.) cationic ion-exchange column to remove dicyclohexylamine and DIEA. The filtrate was evaporated and hydrogenated with Pd/C (0.5 g) under hydrogen at 45 psi in MeOH for 4 hours. Palladium catalyst was removed by filtration through celite. The filtrate was concentrated and dried under vacuum overnight to give intermediate 23 (0.35 g), which was used without further purification. LCMS (+ESI) m/z=175 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH2:14][CH2:15][NH2:16])[N:12]=[CH:11][C:10]=1[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH:26]([CH3:28])[CH3:27])=[N:24][N:25]=2)[N:22]=1.[C:29]1([C@@H:35]2[CH2:37][C@H:36]2[N:38]=[C:39]=[O:40])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH2:14][CH2:15][NH:16][C:39]([NH:38][CH:36]2[CH2:37][CH:35]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:40])[N:12]=[CH:11][C:10]=1[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH:26]([CH3:28])[CH3:27])=[N:24][N:25]=2)[N:22]=1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(C)c1nnc2ccc(-c3cnn(CCN)c3-c3ccc(F)cc3F)nn12
Solvent: ClCCl
Product: CC(C)c1nnc2ccc(-c3cnn(CCNC(=O)NC4CC4c4ccccc4)c3-c3ccc(F)cc3F)nn12
Reaction time: 0.17 h
Yield: 59.9 %

Procedure:
The 2-(5-(2,4-difluorophenyl)-4-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazol-1-yl)ethanamine (0.075 g, 0.20 mmol) was dissolved in DCM (4 mL) then trans-2-phenylcyclopropyl isocyanate (0.033 g, 0.21 mmol) was added. The mixture was stirred for about 10 min then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with DCM/MeOH (9:1) as an eluent to give the title compound (0.065 g, 61%): LC/MS (Table 1, Method a) Rt=2.34 min; MS m/z: 543.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(NC(C)C)(C)C.[C:19]1([CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:27][CH2:26][CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
2,6-Dichloropurine (20.00 g, 106 mmol) is dissolved in THF (250 ml) under an atmosphere of argon. Diisopropylamine (16.38 g, 127 mmol) is added followed by 2,2-diphenylethylamine (25.00 g, 127 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 6 hours. 50% of the solvent is removed in vacuo and replaced with MeOH. The resulting precipitate is filtered off and dried to give the title compound. 1H nmr (d6-DMSO, 400 MHz); 8.05(br s, 1H), 7.35-7.10(m, 10H), 4.55(m, 1H), 4.10(rri, 2H), MS (ES+) m/e 350 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(Cl)cc2)cc1
Temperature: 77.5 °C
Yield: 61.5 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide from Step 1 (8 g, 26 mmol) and sodium bicarbonate (4.36 g, 52 mmol) in isopropanol (240 mL), 3-bromo-1,1,1-trifluoroacetone (5.4 mL, 52 mmol) was added. After heating the reaction mixture at 75-80° C. for 24 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (16.2 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 55/45) to give pure 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (6.7 g, 62%) as a white solid: Anal. Calc'd. for C17H14N2SO3ClF3: C, 48.75, H, 3.37, N, 6.69. Found: C, 48.56, H, 3.22, N, 6.51.
Reaction SMILES: [Mg].II.[CH2:4](Br)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br-].[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>C1COCC1>[CH2:4]([C:17]1([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1CCOCC1
Reactant: BrCCc1ccccc1
Agent: II
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(CCc2ccccc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Magnesium turnings (2.34 g, 97.6 mmol) and THF(100 mL) are placed under N2. A small crystal of I2 and a 1 mL portion of phenethyl bromide are added, and the mixture is stirred at rt for 30 min. The reaction mixture is briefly heated with a heat gun until the iodine color is discharged. An exothermic reaction commences. Thereafter, the remaining bromide (10.5 mL, total=11.5 mL, 84.6 mmol) is added at a rate to maintain a gentle reflux (ca. 10 min). When the mixture reaches rt, the reaction apparatus is placed in an ice water bath, and tetrahydropyran-4-one (6.0 mL, 43.4 mmol) is added to the reaction mixture neat via syringe over a five minute period. The cooling bath is removed, and the reaction mixture is allowed to reach rt. The reaction mixture is worked up and purified as above with compound 17 to give the product 18. Recrystallization from hexane/CH2Cl2 gives 18 as white needles (1 crop), mp 74-75° C. (5.0 g, 37%) . 1H NMR (CDCl3) 7.40-7.10(m,5), 3.90-3.70(m,4), 2.80-2.65(m,2), 1.90-1.70(m,4), 1.55(br d,2, J=11.9), 1.46(s,1); 13C NMR (CDCl3) 142.14, 128.47, 128.28, 125.87, 68.86, 63.78, 45.13, 37.58, 28.91; MS(CI/CH4, eE=70eV) m/z 207(M+H)+,205, 190, 189 (base peak), 171, 161, 143, 119, 101, 91, 83, 71; Anal. Calcd for C13H18O2 (MW=206.3): C,75.69 H,8.80. Found: C,75.46 H,8.80.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[OH-].[Na+].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>O.O1CCOCC1.O1CCOCC1>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:6]2[CH2:7][CH2:8][NH:3][CH:4]([C:9]([OH:11])=[O:10])[CH2:5]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)C1CNCCN1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CCNC(C(=O)O)C2)cc1
Temperature: 2 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a suspension of piperazine-2-carboxylic acid dihydrochlorid (13.95 g, 68.70 mmol) in water/dioxane 1:1 (280 ml) at 0° C., NaOH 5 N (48 ml) was added to achieve complete dissolution. 4-tert-butylbenzenesulfonylchloride (17.586 g, 75.57 mmol) in dioxane (140 ml) was then added dropwise at 2° C. In 1 h. The reaction mixture was stirred overnight at 2° C. and over the week-end at room temperature. Solvents were removed in vacuo and the residue obtained was crystallized in EtOH to give 17.3 g of crude 4-(4-tert-butylphenyl-sulfonyl)piperazine-2-carboxylic acid. This material was dissolved in DCM (340 ml) and triethylamine (23 ml, 158 mmol) followed by di-tert-butyl-dicarboxylate (11.5 g, 52.7 mmol) were added. The mixture was stirred at mom temperature overnight, washed with HCl 1N, and brine. Organic phase was then dried over magnesium sulfate, filtered and concentrated to give 23.5 g of a white solid. This crude was purified by flash chromatography using DCM/MeOH 95:5 then DCM/MeOH/AcOH 90:10:0.1.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:27]2
Reactant: COc1ccc2c(c1)CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(c1)CN(c1c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 70.2 %

Procedure:
298 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 230 mg of 5-methoxyisoindoline, 300 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 300 mg of the target compound.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[C:14](=O)[CH3:15])C.[CH3:18][NH2:19]>CO.[O-]S([O-])(=O)=O.[Mg+2].ClCCl>[CH3:18][N:19]1[C:14](=[CH2:15])[C:6]2[C:5](=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:8][CH:7]=2)[C:4]1=[O:3]
Reactant: CN
Reactant: CCOC(=O)c1c(C(C)=O)cccc1[N+](=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: C=C1c2cccc([N+](=O)[O-])c2C(=O)N1C
Reaction time: 0.25 h

Procedure:
Ethyl-2-acetyl-6-nitrobenzoate (11.12 g) is suspended in a mixture of MeOH (70 mL) and MgSO4. Methylamine (2 molar in THF, 28.13 mL) is added dropwise and the solution is stirred for 15 min at this temperature. Then it is preheated to 70° C. for 18 h. The solvent is eliminated in vacuo, the residue is taken up in dichloromethane (100 mL), washed with sodium chloride solution (10%) dried on magnesium sulphate, filtered off from the desiccant and the solvent is eliminated in vacuo. For purification it is recrystallised from toluene (250 mL).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].N1C=CC=CC=1.[Cl:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.Cl>C1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([CH2:19][Cl:18])=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Oc1ccc2ccccc2c1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1ccc2ccccc2c1)c1ccc(CCl)cc1

Procedure:
This ester was prepared by Method C by placing 72.1 g (0.5 mole) of β-naphthol, suspended in 150 ml of benzene, and 0.5 ml of pyridine in the vessel, adding all at once, at room temperature, a solution of 95 g (0.5 mole) of p-chloromethylbenzoyl chloride in 80 ml of benzene, and refluxing this reaction mixture for 6 hours, while passing a weak current of nitrogen through the apparatus. The HCl cleavage began at about 40° C., and at an internal temperature of 50° C., a clear, homogeneous solution had formed. After the end of the reaction time the benzene was substantially removed by distillation. The residue crystallized to a grayish pink crystal mass, the yield of which was quantitative (147.5 g). The raw ester melted at 90°-96° C. It was recrystallized from 2.5 liters of isopropanol with the addition of decolorizing carbon, yielding colorless, pearly, shiny flakes of a melting point of 102°-103.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:22]3[CH2:23][CH2:24][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=4)[CH2:26][CH2:27]3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(N3CCC(c4ccc(C(F)(F)F)cc4)CC3)c(-c3ccc(F)cc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(N3CCC(c4ccc(C(F)(F)F)cc4)CC3)c(-c3ccc(F)cc3)nc2c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-fluorophenyl)-2-(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)quinoxaline-6-carboxylate (120 mg, 0.24 mmol, 1.00 equiv) in methanol (20 mL) and a solution of sodium hydroxide (47.2 mg, 1.18 mmol, 5.00 equiv) in water (2 mL). The resulting solution was stirred for 3 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 30 mL of water. The pH value of the aqueous solution was adjusted to 3 with 1N hydrochloric acid. The resulting solids were collected by filtration and washed with 10 mL×1 of water. The solid was dried in an oven under reduced pressure. The solid was purified by re-crystallization from methanol. This resulted in 60 mg (51%) of 3-(4-fluorophenyl)-2-(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH2:10][CH2:9][C:8]([CH2:11][CH3:12])=[N:7]1)=[S:5])[CH3:2].I[CH3:14]>CO>[CH3:14][S:5][C:4]([N:6]1[CH2:10][CH2:9][C:8]([CH2:11][CH3:12])=[N:7]1)=[N:3][CH2:1][CH3:2]
Reactant: CCNC(=S)N1CCC(CC)=N1
Reactant: CI
Solvent: CO
Product: CCN=C(SC)N1CCC(CC)=N1
Temperature: 50 °C
Yield: 0.7 %

Procedure:
1.51 g (1 mol equiv.) 3-Ethyl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide was dissolved in 30 mL methanol, 5.1 mL (10 mol equiv.) iodomethane was added and the reaction mixture was heated at 50° C. for 1 hour. Volatiles were removed in vacuo. The residue was taken up in DCM and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness to give 1.44 g (89%) 3,N-diethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 1.12-1.21 (m, 6H), 2.39 (q, J=7.4 Hz, 2H), 2.48 (s, 3H), 2.70 (t, J=9.7 Hz, 2H), 3.52 (q, J=7.2 Hz, 2H), 3.75 (t, J=9.7 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11]Br>C(O)(=O)C>[Br:11][CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1cccc(Br)c1
Solvent: CC(=O)O
Product: O=C(CBr)c1cccc(Br)c1
Temperature: 60 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 1-(3-bromophenyl)ethanone (40 g, 202.02 mmol, 1.00 equiv) in acetic acid (200 mL). This was followed by the addition of a solution of Br2 (32 g, 200.00 mmol) in acetic acid (50 mL) dropwise with stirring at 60° C. The resulting solution was stirred for 3 h at 60° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was re-crystallized from petroleum ether:ethyl acetate in the ratio of 8:1. This resulted in 24 g (43%) of 2-bromo-1-(3-bromophenyl)ethanone as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][C:6]([C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>C(O)(C)C>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:10](=[O:19])[C:9]3[C:4](=[CH:5][C:6]([C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:8]=3)[N:3]=2)=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc2c(=O)n(-c3ccc(Cl)cc3)c(Cl)nc2c1
Reactant: NCc1ccc(Cl)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(=O)n(-c3ccc(Cl)cc3)c(NCc3ccc(Cl)cc3)nc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a suspension of methyl 2-chloro-3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.10 g, 0.23 mmol) in isopropyl alcohol (2.5 mL) was added N,N-diisopropylethylamine (84 μL, 0.48 mmol) and p-chlorobenzylamine (70 μL, 0.57 mmol). The reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 50% EtOAc/hexanes) to afford methyl 2-[(4-chlorobenzyl)amino]-3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (46 mg, 44%). LC-MS: (FA) ES+ 456.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:2].[CH3:18][C@H:19]([NH:28][CH3:29])[C@H:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1C=CC=CC=1>[CH3:29][N:28]1[CH:19]([CH3:18])[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:2][CH:1]1[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Reactant: CCOP(=O)(Cc1ccccc1C=O)OCC
Solvent: O
Solvent: c1ccccc1
Product: CCOP(=O)(Cc1ccccc1C1OC(c2ccccc2)C(C)N1C)OCC
Reaction time: 24 h

Procedure:
2.0 g (8 mmol) of the compound A and 1.32 g (8 mmol) of (-)-ephedrine were dissolved in 100 ml of benzene and heated under reflux in a water separator for 24 h. The solvent was then removed by rotary evaporation and the residue was chromatographed on silica gel (eluent CH2Cl2 /ethanol 9.5/0.5; Rf=0.55). The product F was obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[N:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][OH:14])[C:9](=[O:10])[C:4]=2[CH:3]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Br:1][C:2]1[CH:18]=[N:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][O:19]3)[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2cc(Br)cnc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.7 %

Procedure:
To a solution of 6-bromo-3-(3-hydroxypropyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6.2 g, 19.8 mmol) in DCM (100 mL) at 0° C. was added 3,4-dihydro-2H-pyran (6 mL, 65.7 mmol) and pyridinium p-toluenesulfonate (50 mg, 0.2 mmol). The reaction was stirred at RT for 16 h then diluted with DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (8:1 to 2:1) to give 6-bromo-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.5 g, 31.8% yield) as a white solid. 1H NMR (CDCl3) δ: 8.68 (m, 1H), 8.54-8.53 (m, 1H), 4.57 (s, 1H), 4.26-4.17 (m, 2H), 3.87-3.80 (m, 2H), 3.68 (s, 3H), 3.52-3.47 (m, 2H), 2.04-1.97 (m, 2H), 1.76-1.63 (m, 2H), 1.49-1.46 (m, 2H). LCMS: [MH+-THP] 314 and TR=1.626 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][CH3:18])[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2].C1COCC1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=S)=[C:30]([CH3:37])[CH:29]=1.NC(N)=S>CN(C1C=CN=CC=1)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=3[CH3:37])[N:17]([CH3:18])[C:12]=2[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc(N)c(NC)c1C#N
Reactant: Cc1cc(F)ccc1N=C=S
Agent: CN(C)c1ccncc1
Agent: NC(N)=S
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C(C)=O)c1ccc2nc(Nc3ccc(F)cc3C)n(C)c2c1C#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
To a 250 mL round-bottom flask was added 2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (10.8 g, 37.4 mmol), DMAP (228 mg, 1.87 mmole), and THF (80 mL). The solution was stirred with gentle heating until all the material was fully dissolved. The reaction mixture was then concentrated under vacuum to achieve a final volume of approximately 20 mL. After cooling to room temperature, 4-fluoro-1-isothiocyanato-2-methyl-benzene (9.36 g, 56.0 mmole) was added in one portion, and stirring was continued at room temperature for 12 hours, after which time all the diamine had been converted to the corresponding thiourea as determined by TLC analysis. To the reaction mixture was then added mercuric oxide (12.15 g, 56 mmole) and the resulting slurry stirred at room temperature. The slurry rapidly became black, indicating the formation of mercuric sulfide. After 1 hour, the reaction was complete as determined by TLC analysis. Silica gel was added to the mixture and the resulting thick slurry was filtered through a pad of celite, washing with several volumes of EtOAc. The clear filtrate was concentrated to produce a dark gray solid. To the solid was added diethylether, and the insoluble material was isolated by filtration to provide 2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (8.25 g, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.46-7.42 (m, 2H), 7.14 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.06 (td, 1H, J1=2.7 Hz, J2=8.6 Hz), 6.87 (d, 1H, J=8.6 Hz), 4.28-4.19 (m, 2H), 3.95 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 1.81 (s, 3H), 1.23 (t, 3H, J=7.4 Hz); ESMS (m/z): 423 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH3:12])[C:3]=1[NH2:4].[C:13]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1Cl)=[CH:25][CH:24]=[CH:23][C:22]=2[O:29][CH3:30])(=[O:17])[CH2:14][CH2:15][CH3:16]>O1CCOCC1>[C:13]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[NH:4][C:3]1[C:5]([CH3:12])=[CH:6][C:7]3[O:11][CH2:10][O:9][C:8]=3[C:2]=1[CH3:1])=[CH:25][CH:24]=[CH:23][C:22]=2[O:29][CH3:30])(=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1cc2c(c(C)c1N)OCO2
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1c(C)cc2c(c1C)OCO2
Yield: 433.2 %

Procedure:
2,6-Dimethyl-3,4-(methylenedioxy)aniline (1.67 g, 20 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (2.3 g, 10 mmol) were heated together under reflux in 1,4-dioxan (50 ml) for 2 hours. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with 2M HCl, sodium hydrogen carbonate solution (×2) and brine. The organic solution was dried, filtered and evaporated to a solid which was recrystallized from ethanol to give 3-butyryl-4-(3,4-methylenedioxy-2,6-dimethylphenylamino)-8-methoxyquinoline (17 g, 43%), m.p. 150°-2° C.