Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1.[OH-].[K+].C(O)(=O)C.IC[C:20]#[N:21]>O.C(O)C>[NH2:6][C:5]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:4]=1[S:3][CH2:2][C:20]#[N:21]
Reactant: N#CCI
Reactant: Nc1nc2cc(F)ccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: N#CCSc1ccc(F)cc1N
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
A suspension of 2-amino-5-fluoro-benzothiazole (3.45 g) was stirred for 7 h at 165-170 ° C. under nitrogen in a solution of potassium hydroxide (6.9 g) in water (13.5 ml). The resulting mixture was cooled on an ice bath to 10° C., supplemented with water (5 ml) and then a solution of acetic acid (3.5 ml) in water (4 ml). The mixture was diluted with 96% ethanol (20 ml) and subsequently a solution of iodoacetonitrile (3.42 g) in 96% ethanol (5 ml) was added. After stirring for 15 min the mixture was adjusted to pH ˜7 by adding acetic acid and approx. half of the solvent was removed in vacuo. The residue was diluted with water (100 ml) and extracted with ethyl acetate (50+3×25 ml). The combined extracts were dried over sodium sulfate, filtered and evaporated to give the title compound as a practically pure yellow oil. Yield 3.60 g (96%); 1H-NMR (DMSO-d6), δ (ppm): 7.32-7.43 (dd, 1H, Ar—H), 6.49-6.60 (dd, 1H, Ar—H), 6.29-6.43 (ddd, 1H, Ar—H), 5.88 (br, 2H, NH2), 3.82 (s, 2H, CH2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.P([O-])(OCC)OCC>ClCCCl>[Br:17][CH2:16][C:3]1[C:2]([Cl:1])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:15])[CH:4]=1
Reactant: Cc1cc(F)c(C(=O)NS(C)(=O)=O)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CCOP([O-])OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(CBr)cc1F
Reaction time: 5 h
Yield: 43.9 %

Procedure:
To a suspension of 5-chloro-2-fluoro-4-methyl-N-(methylsulfonyl)benzamide (Preparation 22, 118 g, 0.45 mol) in 1,2-dichloroethane (1.25 L) were added N-bromosuccinimide (91 g, 0.51 mol) and benzoyl peroxide (5 g, 20 mmol) and the mixture was heated at reflux for 18 hours. N-bromosuccinimide (30 g, 0.17 mol) was added and the mixture was heated for further 24 hours. N-bromosuccinimide (20 g, 0.11 mol) was then added and the mixture heated for another 3 hours, then cooled and washed with water (1 L) and aqueous sodium thiosulphate (0.5 M, 200 mL). The organic layer was washed with water (500 mL), dried over sodium sulfate and evaporated. The resulting crude tan solid was dissolved in EtOAc (1 L), diisopropylethylamine (130 mL, 0.75 mol) and diethyl phosphite (27.6 g, 0.2 mol) were added and the mixture was stirred for 5 hours under a nitrogen atmosphere. The reaction mixture was then washed with aqueous hydrochloric acid (2 M, 1 L), dried over magnesium sulfate and evaporated to yield a dark solid, which was triturated with diethyl ether (200 mL) to afford the title compound as a tan solid (68 g). The filtrate was purified by silica gel chromatography eluting with 10% EtOAc and 1% acetic acid in DCM, followed by recrystallization with MeCN (130 mL) to afford a second crop of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CS(C)=O>[C:11]([C:7]1[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
8.40 g (40.7 mmol) 2,6-di-tert-butylphenol was dissolved in 100 ml dried DMSO. 18.9 g (58 mmol) cesium carbonate and 8.5 g (54 mmol) p-chloronitrobenzene were added into the DMSO solution. The DMSO solution was heated to 100˜120° C. for 12 hrs with stirring. Then the reaction mixture was allowed to cool to room temperature and poured into distilled water. The aqueous solution was acidified to pH 2˜4 and yellow precipitate was collected by filtration. The yellow precipitate was washed with water and dried. The crude yield was 88%. The yellow precipitate was purified by recrystallizing in cyanomethane, mp 157˜160° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24][CH2:25][C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(CCc2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CCc3ccc(C(=O)O)cc3)s2)c1
Temperature: 100 °C
Yield: 95.4 %

Procedure:
The product of Step 1 (65 mg, 0.130 mmol) was taken up in MeOH (2.0 ml) in a microwave vial, and 1.0M sodium hydroxide (0.261 ml, 0.261 mmol) was added. The reaction was heated to 100° C. for 10 min in the microwave. The colorless solution was adjusted to a pH of 3-4 with 1 N HCl, diluted with water, and extracted with 15% IPA/CHCl3 (2×). The combined organic layers were dried (MgSO4) and evaporated to afford the title compound (60 mg, 0.124 mmol, 95% yield) as a colorless solid. MS ESI: [M+H]+ m/z 485.0 1H NMR (500 MHz, DMSO-d6) δ 12.82 (s, 1H), 10.24 (s, 1H), 8.81 (d, J=4.9, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.84 (d, J=8.1, 2H), 7.43 (s, 1H), 7.39 (d, J=8.1, 2H), 7.27 (d, J=4.9, 1H), 7.12 (s, 1H), 3.41-3.20 (m, 2H), 3.13 (t, J=7.6, 2H), 2.29 (s, 3H). rhSYK activity=+++
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:10]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:5][C:6]=1[C:7](=[S:9])[NH2:8].Br[CH2:31][C:32]([C:34]1[CH:35]=[C:36]([NH:40][C:41]([C:43]2[S:44][C:45]([Cl:48])=[CH:46][CH:47]=2)=[O:42])[CH:37]=[CH:38][CH:39]=1)=O.C(O)(C(F)(F)F)=O>CN(C=O)C.CO>[NH2:10][C:4]1[S:5][C:6]([C:7]2[S:9][CH:31]=[C:32]([C:34]3[CH:35]=[C:36]([NH:40][C:41]([C:43]4[S:44][C:45]([Cl:48])=[CH:46][CH:47]=4)=[O:42])[CH:37]=[CH:38][CH:39]=3)[N:8]=2)=[C:2]([NH2:1])[N:3]=1
Reactant: NC(=S)c1sc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc1N
Reactant: O=C(CBr)c1cccc(NC(=O)c2ccc(Cl)s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1nc(N)c(-c2nc(-c3cccc(NC(=O)c4ccc(Cl)s4)c3)cs2)s1
Reaction time: 0.25 h
Yield: 36 %

Procedure:
The title compound was prepared as follows. To a solution of 1.07 g (3.0 mmol) of 4-amino-2-(trityl-amino)-thiazole-5-carbothioic acid amide (prepared analogously to the starting material described in step (ii) of Example A(1)) dissolved in DMF (12 mL), was added 5-chloro-thiophene-2-carboxylic acid (3-bromoacetyl-phenyl)-amide. After 15 minutes, the reaction was diluted with MeOH (12 mL), treated with TFA (4 mL), and stirred overnight. The resulting solution was concentrated in vacuo, diluted with ethyl acetate, extracted with 1M NaHCO3, extracted with brine, dried over MgSO4, concentrated, and purified by flash chromatography (gradient elution: 5% CH3CN/CH2Cl2 to 30% CH3CN/CH2Cl2), giving 0.47 g (36% yield) of N-[3-(2′,4′-diamino-[2,5′]bithiazolyl-4-yl)phenyl]-5-chloro-thiophene-2-carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:17]C(=O)C)[CH:5]=[CH:6][C:7]=1[C:8]([CH3:16])([CH3:15])[CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14].Cl.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:14][O:13][CH2:12][CH2:11][O:10][CH2:9][C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH2:17])=[CH:3][C:2]=1[OH:1])([CH3:16])[CH3:15]
Reactant: COCCOCC(C)(C)c1ccc(NC(C)=O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COCCOCC(C)(C)c1ccc(N)cc1O
Yield: 7.3 %

Procedure:
A mixture of N-{3-hydroxy-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide (1 g, 3.5 mmol) and HCl (5 mL) was heated at reflux for 1 h. The mixture was basified with Na2CO3 solution to pH 9 and then extracted with EtOAc (20 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography (petroleum ether-EtOAc, 100:1) to obtain 2-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)-5-aminophenol (C-25) (61 mg, 6%). 1HNMR (CDCl3) δ 9.11 (br s, 1 H), 6.96-6.98 (d,J=8 Hz, 1 H), 6.26-6.27 (d,J=4 Hz, 1 H), 6.17-6.19 (m, 1 H), 3.68-3.69 (m, 2 H), 3.56-3.59 (m, 4 H), 3.39 (s, 3 H), 1.37 (s, 6 H); ESI-MS 239.9 m/z (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:36])([F:35])[C:8]1[CH:9]=[C:10]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:11]([N:13]1[CH2:17][C@@:16]([CH2:25][CH2:26][OH:27])([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:15][CH2:14]1)=[O:12].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][S:2]([O:27][CH2:26][CH2:25][C@:16]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[O:15][CH2:14][N:13]([C:11](=[O:12])[C:10]2[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=[C:8]([C:7]([F:35])([F:6])[F:36])[CH:9]=2)[CH2:17]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CO[C@](CCO)(c2ccc(F)cc2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC[C@@]1(c2ccc(F)cc2)CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CO1
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Methanesulfonyl chloride (26 mL, 0.336 mol) was added dropwise to a solution of the compound (102.11 g, 0.226 mol) obtained in Example 1c, triethylamine (63 mL, 0.452 mol) and 4-(dimethylamino)pyridine (2.76 g, 0.0273 mol) in dichloromethane (1000 mL) under ice cooling, and the mixture was stirred under ice cooling for 1 hour. The reaction mixture was washed with water and saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-n-hexane, 30%→50%) to give the title compound (108.21 g; yield, 90%) as a white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Fc1ccc(Br)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 4.0 g, 16.4 mmol), and 4-bromofluorobenzene (3.45 g, 19.7 mmol) in THF (80 mL)) were added Palladium catalyst Pd(PPh3)4 (0.57 g, 0.49 mmol) and the freshly prepared sodium hydroxide solution (2.0 g, 49.3 mmol in 25 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.75 g (80%) of the product 4-(4-fluoro-phenyl)-1H-indole as a white solid.
Reaction SMILES: NC1C=CC=C2C=1N=C(C1C=CC=CC=1Cl)C(C[N:13]1[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]1=[O:23])=N2.CC(C)=O.Cl.N([O-])=O.[Na+].[I-].[K+]>>[C:14]1(=[O:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[NH:13]1
Reactant: Nc1cccc2nc(CN3C(=O)c4ccccc4C3=O)c(-c3ccccc3Cl)nc12
Agent: Cl
Agent: O=N[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 0 °C

Procedure:
2-((5-amino-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)isoindoline-1,3-dione (Prepared in Example 97, 0.8364 g, 2.016 mmol) was dissolved in acetone (28.80 mL, 2.016 mmol) and cooled to 0° C. While being stirred, the solution was treated first with 2 M hydrochloric acid (5.645 mL, 11.29 mmol) and then dropwise with 1 M aq. sodium nitrite (6.049 mL, 6.049 mmol) while maintaining the temperature of the mixture at 0° C. After the additions were complete, the mixture was stirred for 15 min and then treated with 5 M aq. potassium iodide (4.839 mL, 24.19 mmol) maintaining the temperature below 5° C. The mixture was then allowed to warm to 15° C. over 3 h. The acetone was removed under reduced pressure, and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic solution was washed with 10% aqueous sodium bisulfite (100 mL×3) and saturated aqueous sodium bicarbonate (100 mL×1), brine (100 mL×1), dried over MgSO4, filtered, and concentrated under reduced pressure to give a red solid. The red solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc in hexane for 25 min as eluent to give 24(3-(2-chlorophenyl)-5-iodoquinoxalin-2-yl)methyl)-isoindoline-1,3-dione as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (1 H, dd, J=7.4, 1.2 Hz), 7.97 (1 H, dd, J=8.2, 1.2 Hz), 7.83-7.91 (4 H, m), 7.51-7.75 (5 H, m), 4.96 (2 H, d, J=21.9 Hz); LC-MS (ESI) m/z 526.0 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=1.F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>CN(C=O)C>[NH2:7][C:8]1[C:13]([O:14][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Nc1ncccc1O
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cccnc2N)cc1
Yield: 72.7 %

Procedure:
Heated a mixture of potassium carbonate (31.38 g, 227.0 mmol), 2-aminopyridin-3-ol (10.00 g, 90.82 mmol), 4-fluorobenzonitrile (11.00 g, 90.82 mmol), and DMF (80 mL) at 90° C. for 3 hours. Cooled, partitioned between ethyl acetate and water, washed the organic layer twice with water, once with 2N NaOH, brine, dried, and concentrated. Dissolved the residue in dichloromethane (20 mL), added hexanes (150 mL), concentrated to 130 mL, filtered, and dried to afford the title compound (13.95 g, 72.72% yield) as a tan powder.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].[ClH:18].[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21]([NH:27][C:28]([C:30]1[O:31][C:32]3[CH:38]=[CH:37][C:36](Br)=[CH:35][C:33]=3[CH:34]=1)=[O:29])[CH2:20]2>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:18].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26]1)[C@@H:21]([NH:27][C:28]([C:30]1[O:31][C:32]3[CH:38]=[CH:37][C:36]([C:10]4[CH:11]=[CH:12][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:8][CH:9]=4)=[CH:35][C:33]=3[CH:34]=1)=[O:29])[CH2:20]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Br)ccc2o1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2o1
Temperature: 90 °C

Procedure:
177 mg (0.86 mmol) of 4-(4-morpholinyl)phenylboronic acid and 2.15 ml of 1N sodium hydroxide solution are added to a mixture of 250 mg (0.72 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 52 mg (0.07 mmol) of PdCl2(dppf) in 3 ml of DMF. The reaction mixture is heated at 90° C. overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered through kieselguhr. Purification takes place by preparative HPLC. The product fractions are concentrated and dissolved in acetonitrile/water, and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. Drying under high vacuum results in 23 mg (7% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][N:7]1[CH2:16][C:15](=[O:17])[NH:14][C:8]1=[N:9]2.[N+:18]([O-])([OH:20])=[O:19].[N+]([O-])(O)=O.S(=O)(=O)(O)O>C(#N)C>[N+:18]([C:13]1[C:4]([CH2:3][O:2][CH3:1])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[NH:14][C:15](=[O:17])[CH2:16][N:7]1[CH2:6]2)([O-:20])=[O:19]
Reactant: COCc1cccc2c1CN1CC(=O)NC1=N2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: COCc1c([N+](=O)[O-])ccc2c1CN1CC(=O)NC1=N2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred, 0° suspension of 11.20 g. (6.0 × 10-2 moles) of 6-methoxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one in acetonitrile (150 ml.) is added dropwise 83.0 g. (6.6 × 1012 moles of nitric acid) of a 5% nitric acid/sulfuric acid solution. The mixture is allowed to stir at 0° for 45 minutes, warmed to room temperature and stirred an additional two hours. The mixture is poured into 700 ml. of ice water, the organic layer separated, the acidic aqueous solution washed with methylene chloride (2 × 100 ml.) and filtered. The aqueous solution is made basic (pH 8) by the dropwise addition of 40% sodium hydroxide, the basic solution stirred for 30 minutes and the precipitate filtered under suction. The yellow solid is washed with water, then acetone and dried under high vacuum. The solid is suspended in water (350 ml.), the solution saturated with hydrogen chloride, heated to boiling and filtered. Saturated sodium chloride solution (100 ml.) is added, the mixture cooled and the precipitate isolated yielding the title product as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]1[O:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][N:20]=1)[CH3:15]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]2[O:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][N:20]=2)[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C1CN=C([C@H](C)N)O1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CN=C([C@H](C)NC(=O)Cc2cc(F)cc(F)c2)O1

Procedure:
Following General Procedure A and using 3,5-difluorophenylacetic acid (Aldrich) and (S)-2-(1-aminoethyl)-5(R,S)-ethoxycarbonyl-2-oxazoline (Example F), the title compound was prepared as a semisolid. The reaction was monitored by tlc (Rf=0.3 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]1)=[O:6])[CH3:3].Cl[CH2:14][CH2:15][CH2:16][N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][CH2:20][C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]1=2.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O.C(#N)C>[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[CH2:14][CH2:15][CH2:16][N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][CH2:20][C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]1=2)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1CCCCN1
Reactant: ClCCCN1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)C1CCCCN1CCCN1c2ccccc2CCc2ccccc21
Yield: 97 %

Procedure:
A mixture of 2-piperidinecarboxylic acid ethyl ester hydrochloride (0.60 g, 0.003 mol), acetonitrile (10 ml), 5-(3-chloropropyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (0.60 g, 0.002 mol, prepared similarly as described in example 1), potassium iodide (0.40 g, 0.002 mol), potassium carbonate (1.03 g, 0.008 mol) and N,N-dimethylformamide (5 ml) was heated at reflux temperature for 85 h. Water (50 ml) was added, and the aqueous solution was extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (2×50 ml), dried (MgSO4) and concentrated in vacuo. The product was purified by column chromatography on silica gel (15 g) using a gradient of heptane and ethyl acetate (100:0→100:25), affording 0.83 g (97%) of 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=O.[NH2:22][C:23]1[N:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH2:20][NH:22][C:23]1[N:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: O=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Reactant: N#Cc1cccnc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cccnc1NCc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.439 g, 1.45 mmol), 2-aminonicotinonitrile (0.150 g, 1.26 mmol) and anhydrous sodium sulfate (2.1 g, 14.5 mmol) in acetic acid (10 mL) was stirred at ambient temperature for 24 hours. The mixture was now warmed to 80° C. for 24 hours. The reaction was cooled to ambient temperature and sodium triacetoxyborohydride (1.3 g, 6.13 mmol) was added portionwise. The reaction was stirred for 16 hours and then quenched by carefully pouring it into a mixture of saturated aqueous sodium bicarbonate (150 mL) and ethyl acetate (20 mL). This quenching solution was stirred 30 min. The phases were separated and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (50 g) with elution proceeding as follows: 20% ethyl acetate/hexane (350 mL), nil; 30% ethyl acetate/hexane (350 mL), unweighed 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-methanol; 40% ethyl acetate/hexane (400 mL), impure product. This partially purified product was flash chromatographed on silica gel (20 g) with elution proceeding as follows: 5% ethyl acetate/hexane (1000 mL), nil; 10% ethyl acetate/hexane (1000 mL), nil; 15% ethyl acetate/hexane (750 mL), nil; (500 mL), unweighed impurity; 20% ethyl acetate/hexane (1000 mL), nil; (1000 mL), unweighed impurity; 30% ethyl acetate/hexane (600 mL), 0.050 g (10%) of 2-{[3-(2-chloro-phenyl]-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl]-amino}-nicotinonitrile as a light tan solid which had: mp 145-150° C.; 1H NMR δ 8.16 (d, J=5 Hz, 1 H), 7.93 (dd, J=3, 8 Hz, 1 H), 7.84 (dd, J=5, 9 Hz, 1 H), 7.71-7.63 (m, 2 H), 7.56-7.51 (m, 3 H), 7.40 (d, J=7 Hz, 1 H), 6.85 (s, 1 H), 6.62 (dd, J=5, 7 Hz, 1 H), 4.23 (ABq, Δv1-3=74 Hz, J=19 Hz, 2 H); APCI MS m/z=406.2 (P+1).
Reaction SMILES: C(OC(=O)C[C@H]([NH:20][C:21](N)=[O:22])CC1C=CC(C2C=CC=CC=2)=CC=1)C.Br[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCO>[CH2:31]([O:30][C:28]([C:27]1[N:20]=[CH:21][O:22][CH:26]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(N)=O
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cocn1
Temperature: 25 °C

Procedure:
To a suspension of (R)-4-biphenyl-4-yl-3-ureido-butyric acid ethyl ester (169 mg, 0.518 mmol) in EtOH (5 ml) at ice bath is added ethyl bromopyruvate (0.098 ml, 0.777 mmol). The reaction is warmed up slowly to room temperature and stirred at reflux overnight. The reaction is concentrated and the residue is taken up in EtOAc and H2O. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(R)-1-biphenyl-4-ylmethyl-2-ethoxycarbonyl-ethylamino)-oxazole-4-carboxylic acid ethyl ester. HPLC retention time=1.42 minutes (condition B); MS (m+1)=423.