Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH2:16].[CH3:17][O:18][C:19]([N:21]=[C:22]=[S:23])=[O:20]>CC(C)=O>[CH3:17][O:18][C:19]([NH:21][C:22](=[S:23])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH:16][C:22]([NH:21][C:19]([O:18][CH3:17])=[O:20])=[S:23])=[O:20]
Reactant: COC(=O)N=C=S
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1N
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(Oc2ccc(Cl)cc2)cc1NC(=S)NC(=O)OC

Procedure:
1.2 G. of 2-amino-4-(4-chlorophenoxy)-1-nitrobenzene in 3ml. concentrated hydrochloric acid is treated with a solution of 6 g. stannous chloride in 3 ml. concentrated hydrochloric acid. The mixture is heated briefly (about ten minutes) on a steam bath, then cooled and treated with potassium bicarbonate and chloroform. The chloroform layer is removed from the filtered mixture, dried and evaporated. 1,2-diamino-4-(4-chlorophenoxy)benzene is isolated as a gum. 1G. of 1,2-diamino-4-(4-chlorophenoxy)benzene in 20 ml. acetone is treated overnight at room temperature with 2.5 g. methoxy carbonyl isothiocyanate. The mixture is concentrated under vacuum and the residue triturated with methanol. Recrystallization from methanol gives pure 1,2-bis-(3-methoxycarbonyl-2-thioureido)-4-(4-chlorophenoxy)benzene.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br)(=O)C.[O:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1>>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:29]1[CH:30]=[CH:31][O:27][CH:28]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1Br
Reactant: OB(O)c1ccoc1
Product: O[C@@H]1[C@@H](O)[C@H](Oc2ccccc2-c2ccoc2)SC[C@H]1O
Yield: 57 %

Procedure:
By carrying out the operation analogously to example 29, starting from 2-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 3-furanboronic acid, the expected compound is obtained in the form of white flakes with a yield of 57%.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH2:7]([S:9][C:10]1[C:11]2[N:12]([CH:19]=[C:20]([C:22]3[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH:21]=2)[N:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[CH3:8]>O.CC(C)=O>[CH2:7]([S:9]([C:10]1[C:11]2[N:12]([CH:19]=[C:20]([C:22]3[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH:21]=2)[N:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])=[O:1])[CH3:8]
Reactant: CCSc1c(C(N)=O)cnn2cc(-c3ccc(OC)nc3)cc12
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCS(=O)c1c(C(N)=O)cnn2cc(-c3ccc(OC)nc3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of oxone (3.30 g, 5.37 mmol) in water (Volume: 40 mL) was added dropwise to a yellow suspension of impure 4-(ethylthio)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (0.787 g, 2.441 mmol) in acetone (Ratio: 1.000, Volume: 40 mL) at rt. The resulting suspension was stirred at rt for 3 h. LCMS and HPLC showed that the starting material was consumed and the desired product was formed. The suspension was filtered, washed with water (2×10 mL), and dried under high vacuum to give a green-yellow solid. 1H NMR and HPLC indicated that the desired product was the major component, but the material was impure. The amount of the material is more than theoretical weight and the material is not totally soluble when making NMR solution, indicating the possible presence of inorganic salt. The material was treated with water (10 mL), stirred for 15 min, filtered, washed with H2O (2×5 mL), and dried under high vacuum to give a green-yellow solid (591.3 mg; 44% yield over 2 steps). 1H NMR, LCMS and HPLC indicated that the material was not pure, but the major component is consistent with the desired product. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (1 H, d, J=1.54 Hz), 8.54 (1H, s), 8.28 (1 H, br. s.), 8.07 (1 H, d, J=1.54 Hz), 8.03 (2H, d, J=8.36 Hz), 7.89 (2 H, d, J=8.36 Hz), 7.80 (1 H, br. s.), 3.31-3.46 (2 7H, m), 1.35 (3 H, t, J=7.48 Hz).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[NH:12]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][O:35][CH2:34]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[N:12]2[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][O:35][CH2:34]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCCCCC1CCCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCCOC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 123.5 %

Procedure:
To a solution of N2-butyl-8-(methoxy)-9H-purine-2,6-diamine (250 mg) in dry N,N-dimethylformamide (4.46 ml) at room temperature was added potassium carbonate (395 mg). The reaction mixture was stirred at 60° C. for 90 min. The reaction was cooled to room temperature and 4-(tetrahydro-2H-pyran-3-yl)butyl methanesulfonate (186 mg) was added and the reaction stirred at 90° C. for 2 hours. The reaction mixture was taken up in ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil (366 mg). The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (30-70%) to afford the title compound as an orange gum (172 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[K+].Cl[CH2:14][CH2:15][OH:16].CCOC(C)=O>CS(C)=O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][CH2:15][OH:16])[CH:6]=[CH:5]2
Reactant: OCCCl
Reactant: Ic1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: OCCn1ccc2cc(I)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an N2 atmosphere 30 g (121 mmol) 5-iodoindole are added to a suspension of 27.1 g (484 mmol) KOH in 150 mL DMSO. The reaction mixture is kept for 1 h at RT, cooled to 0° C. with ice water, 9.7 mL (145 mmol) of 2-chloroethanol in 30 mL DMSO are slowly added dropwise and stirred for 4.5 h at RT. The reaction mixture is combined with 1 L EtOAc, washed four times with in each case 800 mL water and once with 400 mL saturated NaCl solution and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 3:1).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9][CH2:8][N:7]([C:19](=[O:27])[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:6]1)=[O:4].ClOC(C)(C)C.O>C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9][CH2:8][N:7]([C:19](=[O:27])[C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH:6]=1)=[O:4]
Reactant: CNC(=O)C1CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: O
Product: CNC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-methyl 3-(4-fluorobenzoyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carbamide and TEA in DCM at 0° C. was added a cooled (0° C.) solution of tert-butyl hypochloride (57 mL, 0.5 mmol) in DCM. The reaction mixture was stirred for 1.5 hours at 0° C. Cold water was added to wash the solution. Organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed by water and dried over MgSO4. Evaporation of solvent gave a crude product, which was purified by chromatography on silica gel eluting with MeOH-DCM to give the title compound (14 mg); 1H-NMR (CDCl3): δ 10.04 (1H, br s), 7.57 (2H, m), 7.52 (1H, d), 7.37 (1H, d), 7.24 (1H, m), 7.12 (4H, m) 5.9 (1H, br s), 4.15 (2H, t), 3.27 (2H, t), 2.92 (3H, d); MS (ES): 378 (MH+).
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[C:14]([F:15])=[CH:13][N:12]=[C:11](F)[CH:10]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH2:17]([NH:24][C:11]1[CH:10]=[C:9]([NH2:8])[C:14]([F:15])=[CH:13][N:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: Nc1cc(F)ncc1F
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: Nc1cc(NCc2ccccc2)ncc1F
Yield: 58.4 %

Procedure:
To 1 ml of N-methylpyrrolidone was added 410 mg of 4-amino-2,5-difluoropyridine together with 930 mg of benzylamine, and the mixture was allowed to react in nitrogen atmosphere at 150° C. for 3 days and allowed to cool. After adding 30 ml of chloroform, the mixture was washed twice with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 15 g; eluent:chloroform:methanol, 1:0 and then, 50:1) to obtain 400 mg of the title compound as a colorless solid.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.N#N.[F:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][N:17]=1.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[Si:28]([C:20]1[C:19]([F:23])=[CH:18][N:17]=[C:16]([F:15])[C:21]=1[F:22])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Fc1cnc(F)c(F)c1
Agent: N#N
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)c1c(F)cnc(F)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
n-BuLi (41.09 mL of 1.6 M, 65.75 mmol) was added dropwise to a solution of diisopropylamine (6.919 g, 9.583 mL, 68.38 mmol) in THF (130 mL), cooled to −5° C. (under N2). After stirring for 15 min, the reaction mixture was cooled down to −78° C. 2,3,5-Trifluoropyridine (7 g, 52.60 mmol) was added dropwise to the reaction mixture which was stirred for 45 min. A solution of tert-butyl-chloro-dimethyl-silane (10.31 g, 68.38 mmol) in THF (15 mL) was added to the reaction mixture. The reaction mixture was stirred at −78° C. for 2 hours. It was quenched with a saturated ammonium chloride aqueous solution (˜50 ml). The reaction mixture was partitioned between ethyl acetate and a saturated sodium bicarbonate aqueous solution. The aqueous was extracted with ethyl acetate twice. The combined organics were washed with brine. The organic was dried over magnesium sulfate and concentrated in vacuo after filtration. The crude mixture was purified on silica gel, eluting with petrol ether/ethyl acetate 0 to 20% to afford the title compound as a pale yellow solid (11.8 g, 90%). 1H NMR (CDCl3) 0.34 (6H, s), 0.87 (9H, s), 7.71 (1H, s).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[O:17])[CH2:7][CH2:8][NH:9]C(=O)OC(C)(C)C)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:9][CH2:8][CH2:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:17]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NC(=O)CCN
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
tert-butyl 3-(methylsulfonamido)-3-oxopropylcarbamate (3.6 g, 15.1 mmol) was dissolved in DCM (60 mL). Then CF3COOH (1.1 mL, 0.3 mmol, 20 equiv) was added to the mixture at 0° C. and stirred for 2 h at 0° C. The reaction mixture was concentrated. The residue was purified by flash chromatography to give 3-amino-N-(methylsulfonyl)propanamide as a transparent solid (1.8 g, 80%). (mobile phase: CH3OH/H2O=0˜5%). ESI-MS (M+1)+: 167.0. 1H NMR (400 MHz, CD3OD) δ: 3.21˜3.11 (m, 2H), 3.07 (s, 3H), 2.60˜2.54 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].O[N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][N:7]1[C:11](=[O:12])[C:10]2[C:9](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]1=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
2-methoxyethanol (2.00 g, 26.3 mmol), N-hydroxyphthalimide (4.72 g, 28.9 mmol, 1.1 eq., and triphenylphosphine (7.58 g, 28.9 mmol, 1.1 eq.) were dissolved in 85 mL of dry THF and then the mixture was cooled in an ice bath. Diisopropyl azodicarboxylate (6.91 g, 34.2 mmol, 1.3 eq.) was dissolved in 15 mL of dry THF and was added slowly to the above mixture. The reaction was stirred in the ice bath for 10 minutes and then the ice bath was removed. The reaction then was allowed to stir at room temperature under N2 overnight. The reaction was done by LC/MS and was concentrated to an oil. It was then purified by flash column chromatography using hexane/ethyl acetate 70/30 to give 2-(2-methoxyethoxy)isoindoline-1,3-dione (2A, 5.19 g, 89.2% yield). ESI-MS: m/z 222.3 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:25])[N:15]([CH3:24])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2ccccc2n(C)c1=O
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(=O)c(C(=O)NC2CCCCC2)c(O)c2ccccc21
Yield: 69.5 %

Procedure:
Cyclohexylamine (2.0 mL, 18.20 mmol) was added to a solution of Compound 1 (2.25 g, 9.1 mmol) in toluene (20 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered to yield 1.9 g (70%) of white solids. M.P. 145° C. 1H NMR (DMSO-d6): δ 1.26 (m, 1H), 1.38 (m, 4H), 1.54 (m, 1H), 1.68 (m, 2H), 1.86 (m, 2H), 3.62 (s, 3H), 3.87 (m, 1H), 7.37 (t, J=7.5 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.80 (t, J=8.4 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 10.46 (s, 1H), 17.46 (s, 1H). EIMS m/z 301 (M+1), 323 (M+23). Anal. (C17H20N2O3) C, H, N.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[C:9]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[N:8][CH:7]=[CH:6][N:5]=1>O.CS(C)=O>[CH:16]([N:13]1[CH2:14][CH2:15][N:10]([C:9]2[C:4](=[O:1])[NH:5][CH:6]=[CH:7][N:8]=2)[CH2:11][CH2:12]1)([CH3:18])[CH3:17]
Reactant: [OH-]
Reactant: CC(C)N1CCN(c2nccnc2Cl)CC1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N1CCN(c2ncc[nH]c2=O)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of NaOH (5.4 g, 125 mmol) in a mixture of water/DMSO (1: 1; 15 mL) was added 2-chloro-3-(4-isopropylpiperazin-1-yl)pyrazine (2.66 g, 12 mmol; from Step 1). After being stirred at 80° C. for 2 h, the dark red solution was cooled to room temperature, extracted with EtOAc overnight to give, after drying and solvent removal in vacuo, 2.6 g (70%) of the title compound as a white solid. HPLC purity: 87%. MS m/z 223 (M+H)+. HRMS m/z calcd for C11H18N4O (M)+ 222.1481, found 222.1489.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)([CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[C:35]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C.CCOCC.Cl>[C:35]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43][N:19]2[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:24][C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)([CH3:23])[C:4]([OH:32])=[O:3])=[CH:8][CH:9]=3)[N:17]([CH3:22])[C:18]2=[O:21])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1C(=O)N(Cc2ccc(C(C)(C)C)cc2)CC1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 45 %

Procedure:
To a mixture of 80 mg of 2-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 18 mg of NaH (0.45 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 min. Then 0.08 mL of 4-tert-butylbenzyl bromide is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.4 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 45 mg (45%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.33 (d, 2H, J=8.4 Hz), 7.18, 7.16 (ABq, 4H, J=8.6 Hz), 6.96-6.92 (m, 2H), 6.88-6.85 (m, 2H), 6.77 (d, 2H, J=8.8 Hz), 4.38, 4.29 (ABq, 2H, J=14.8 Hz), 3.98 (t, 2H, J=6.0 Hz), 3.69 (bs, 1H), 3.73-3.66 (m, 1H), 3.44 (t, 1H, J=8.6 Hz), 3.25, 3.11 (ABq, 2H, J=13.8 Hz), 3.06 (t, 1H, J=8.6 Hz), 2.86 (s, 3H), 2.28-2.19 (m, 1H), 1.97-1.89 (m, 1H), 1.38 (s, 3H), 1.30 (s, 9H). HRMS (ES+) m/z exact mass calcd for C33H40N2O5F (m+1) 563.2921, found 563.2917.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12](=O)[C:10]2=[O:11])=[CH:5][CH:4]=1.[OH-:20].[K+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:5](=[C:12]([C:10]([OH:20])=[O:11])[C:14]3[C:19]([N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc(N2C(=O)C(=O)c3ccccc32)cc1
Agent: [K+]
Product: COc1ccc2nc3ccccc3c(C(=O)O)c2c1

Procedure:
The title compound can be prepared from N (4-methoxy phenyl) isatin of example 15 and 10% KOH by heating for 12 hours on a steam bath. The product is isolated as in example 25.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:17][CH2:16]1.O>CN(C=O)C>[N:1]1([CH2:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[Cl:8])([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[OH:17])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Fc1ccc(C2(c3ccccc3Cl)CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC(Cn1cncn1)(c1ccc(F)cc1)c1ccccc1Cl
Temperature: 25 °C
Yield: 70 %

Procedure:
1,2,4-Triazole (0.04 mol) was added portionwise to sodium hydride (0.04 mol) in DMF (40 ml) and the solution stirred at room temperature until effervescence ceased. 1-o-Chlorophenyl-1-p-fluorophenyl ethylene oxide (0.02 mol) in DMF (10 ml) was added dropwise and the solution stirred at 80° for 4 hours. The solution was poured into water and triturated with petroleum ether to give a white crystalline solid which was filtered off and dried. Recrystallisation from petroleum ether (60°-80°)/methylene chloride gave the title compound (70%) as a white crystalline solid, m.p. 115°-116°.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[C:4]([NH:11][C:12]2[NH:13][CH2:14][CH2:15][N:16]=2)[CH:3]=1.[Br:17]Br.N>>[Br:17][C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[C:2]([Cl:1])=[CH:3][C:4]=1[NH:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1
Reactant: Clc1cc(NC2=NCCN2)cc2[nH]cnc12
Reactant: BrBr
Agent: N
Product: Clc1cc(NC2=NCCN2)c(Br)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 33 %

Procedure:
To a solution of 7-chloro-5-(2-imidazolin-2-ylamino)benzimidazole (0.61 g, 2.6 mmol) in 10 ml of ACOH was added 0.3 ml of Br2. Resulting reaction mixture was stirred for 12 h at 25° C. and concentrated in vacuo, yielding an oil, which was subjected to column chromatography (NH3 sat'd 30% MeOH/EtOAc) to yield 0.23 g (0.85 mmol, 33%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from MeOH to afford 0.12 g (12%) of the product as a light yellow solid: mp 244-246° C.; Anal. Calc. for C10H9N5BrCl.1.0C4H4O4.0.5H2O requires C, 37.77; H, 3.17; N, 18.35. Found: C, 37.75; H, 3.08; N, 18.21.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([Cl:34])[C:13]([N:20]3[CH2:24][CH2:23][C@H:22]([N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:26])[CH2:21]3)=[C:14]([F:19])[CH:15]=2)[N:10]([CH:35]2[CH2:37][CH2:36]2)[C:9]1=[O:38])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:43]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:39])[N:7]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([Cl:34])[C:13]([N:20]3[CH2:24][CH2:23][C@H:22]([N:25]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH3:26])[CH2:21]3)=[C:14]([F:19])[CH:15]=2)[N:10]([CH:35]2[CH2:36][CH2:37]2)[C:9]1=[O:38])[CH3:43])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2c(F)cc3c(=O)n(NC(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2Cl)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2c(F)cc3c(=O)n(N(C)C(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of {7-[(S)-3-(tert-butoxycarbonyl-N-methylamino)-pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid tert-butyl ester from Example 8 (0.238 g, 0.421 mmol) in N,N-dimethylformamide (5 mL) at −78° C. under nitrogen atmosphere is added sodium hydride (60% dispersion in mineral oil, 0.025 g, 0.631 mmol). After 30 minutes, iodomethane (0.052 mL, 0.842 mmol) is added, and the reaction mixture is warmed to room temperature. After 1 hour, the reaction mixture is diluted with ethyl acetate and washed with saturated ammonium chloride solution, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate concentrated. The resulting residue is purified by flash column chromatography (1:1 ethyl acetate/hexanes) to afford the title compound (0.118 g). 1H NMR (CDCl3): δ 7.63 (dd, 1H), 4.78 (bs, 1H), 3.87-3.45 (m, 6H), 2.62-2.44 (m, 6H), 2.31-2.12 (m, 2H), 1.49-1.47 (m, 18H), 1.23-1.07 (m, 2H), 0.75-0.53 (m, 2H). MS CI: m/z 582 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]([OH:17])=[CH:5][C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].[OH-].[Na+].CO.Cl>CCOC(C)=O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:6](=[O:16])[CH:5]=[C:4]([OH:17])[C:3]([OH:18])=[O:2]
Reactant: COC(=O)C(O)=CC(=O)CCc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(C=C(O)C(=O)O)CCc1ccccc1Cl
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Intermediate 1B (320 mg, 1.2 mmol) was treated with 1.31 ml of 1 N NaOH, a small amount of MeOH was added to aid dissolution of the ester. The resulting suspension was stirred for 2 h then acidified with 1N HCl and EtOAc was added. The organic layer was separated, washed with brine, dried over Na2SO4 then filtered and the solvent removed to yield 240 mg oil. The crude product was purified by reverse phase preparative HPLC (C18, MeOH/H2O (0.1% TFA)-gradient). MS (M−H) calcd for C12H10NO4Cl: 253.0268; found: 253.0267.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[Br:26]C1C=CN=CC=1>>[Br:26][C:14]1[C:13]2[C:17](=[CH:18][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[CH:11][CH:12]=2)[N:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:15]=1
Reactant: Brc1ccncc1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3ccn(-c4ccncc4)c3c2)c1
Agent: Cl
Product: O=[N+]([O-])c1cccc(-c2ccc3c(Br)cn(-c4ccncc4)c3c2)c1

Procedure:
The target compound was prepared as in Example 1 using 6-(3-nitrophenyl)-1-(pyridin-4-yl)-1H-indole (70 mg, 0.222 mmol) and 4-bromopyridine hydrochloride (40 mg, 0.222 mmol).