Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C@@H:13]1[CH2:16][C@H:15](O)[CH2:14]1.F[C:19]1[C:24]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:23][C:22]([F:31])=[CH:21][N:20]=1.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C@H:13]1[CH2:16][C@@H:15]([C:19]2[C:24]([CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:23][C:22]([F:31])=[CH:21][N:20]=2)[CH2:14]1
Reactant: O[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Reactant: Fc1cnc(F)c(C2CCOCC2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cnc([C@H]2C[C@@H](Nc3nc4ccccc4s3)C2)c(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (81.8 mg, 2.0 mmol) was added to a solution of cis-3-(benzothiazol-2-ylamino)-cyclobutanol (150 mg, 0.68 mmol) in DMF (3 mL) under argon and the mixture was stirred for 1 h at RT. Then 2,5-difluoro-3-(tetrahydro-pyran-4-yl)-pyridine, as prepared in Example 4, steps 1-4, (162 mg, 0.82 mmol) was added and the resulting mixture was heated to 100° C. for 2 h. It was cooled to RT and EtOAc and saturated NH4Cl were added. The organic layer was separated, washed with water (2×25 mL), brine (25 mL), dried over MgSO4, filtered and concentrated in vacuo to give oil, which was purified by prep-HPLC to give product (20 mg). [M+1] 400. IC50 (uM) 0.0002.
Reaction SMILES: N[C:2]1[N:6]=[CH:5][N:4]([C:7]([NH:9][CH2:10][CH2:11][CH3:12])=[S:8])[N:3]=1.[NH2:13][C:14]1N(C(NCCC)=S)N=CN=1>C(OC(OCC)OCC)(=O)C>[CH2:10]([N:9]1[C:7](=[S:8])[N:4]2[N:3]=[CH:2][N:6]=[C:5]2[N:13]=[CH:14]1)[CH2:11][CH3:12]
Reactant: CCCNC(=S)n1ncnc1N
Reactant: CCCNC(=S)n1cnc(N)n1
Agent: CCOC(OCC)OC(C)=O
Product: CCCn1cnc2ncnn2c1=S
Yield: 95 %

Procedure:
The synthesis method of Example 55 was applied. A 2:1 mixture (3.52 g) obtained in Example 47 of 5-amino-1-[n-propylamino(thiocarbonyl)]-1H-1,2,4-triazole and 3-amino-1-[n-propylamino(thiocarbonyl)]-1H-1,2,4-triazole and diethoxymethyl acetate (20 ml) were used as reagents. The mixture was reacted at 75° C. for 2 hours to give 2.22 g of white crystals (yield 95% from 5-amino-1-[n-propylamino(thiocarbonyl)]-1H-1-1,2,4-triazole), which were then subjected to recrystallization from water to give white crystals.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C@H:17]([CH3:21])[CH2:18][C:19]#[N:20])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:19]([CH2:18][C@H:17]([N:14]1[CH2:15][CH2:16][CH:11]([N:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:1])[F:22])=[CH:9][CH:8]=2)[C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=2)[CH2:12][CH2:13]1)[CH3:21])#[N:20]
Reactant: O=C(Cl)c1cccnc1
Reactant: C[C@H](CC#N)N1CCC(Nc2ccc(OC(F)F)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CC#N)N1CCC(N(C(=O)c2cccnc2)c2ccc(OC(F)F)cc2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
A solution of the above nitrile (0.20 g, 0.65 mmol) and nicotinoyl chloride hydrochloride (0.46 g, 2.6 mmol) in THF (6 mL) was then treated with DIPEA (0.56 mL, 3.2 mmol) and stirred at 80° C. for 16 h. The reaction was cooled to room temperature, concentrated under reduced pressure, diluted with CH2Cl2 (10 mL) and washed with brine solution (2×10 mL). The combined organic extracts were then dried (Na2SO4), filtered and concentrated and the crude material purified by flash column chromatography on silica gel (50:1:0.1 CH2Cl2/MeOH/NH4OH) to afford N-[(R)-1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-N-(4-difluoromethoxy-phenyl)-nicotinamide as a pale yellow oil (104 mg, 39%).
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:16](Cl)(=[O:20])[O:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([N:3]2[CH2:4][CH2:5][N:6]([C:16]([O:17][CH2:18][CH3:19])=[O:20])[CH2:7][CH2:8]2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)N1CCN(c2ccc(O)cc2)CC1

Procedure:
A mixture of 17 parts of 4-(1-piperazinyl)phenol dihydrobromide, 7 parts of ethyl carbonochloridate, 21 parts of potassium carbonate and 250 parts of 1,4-dioxane is stirred and refluxed for 48 hours. The reaction mixture is filtered, while hot and the filtrate is evaporated. The solid residue is dissolved in a diluted hydrochloric acid solution. The solution is alkalized with ammonium hydroxide. The product is filtered off and dried, yielding 3.5 parts of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate; mp. 168.8° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[OH-].[Na+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1>C(O)(C)C>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:4][CH2:3][CH2:1][OH:2])=[CH:10][CH:9]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: OCCNCc1ccc(Cl)cc1

Procedure:
Ethanolamine (56.9 g, 931 mmol) and sodium hydroxide (7.44 g, 186 mmol) were mixed in isopropanol (50 ml) and 4-chlorobenzyl chloride (30 g, 186 mmol) was added at such a rate that a mild reflux was achieved. The mixture was then refluxed for another 30 min. Evaporation of the solvent was followed by the addition of methylene chloride (50 ml). The solids were filtered off and the solvent was evaporated from the filtrate. The residual oil was distilled under oil pump vacuum and the fraction at 125-126° C. (0.1 mm Hg) was collected. Yield 27 g, 78%.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[C:20](=[O:21])[N:12]2[CH:13]([C:18]#[N:19])[C:14]([CH3:17])([CH3:16])[S:15][C@H:11]12.[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([C:28]([NH:9][CH:10]2[C:20](=[O:21])[N:12]3[CH:13]([C:18]#[N:19])[C:14]([CH3:16])([CH3:17])[S:15][C@H:11]23)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C#N
Reaction time: 0.33 h

Procedure:
Triethylamine (44.5g., 0.44 mole) is added to a slurry of 6-amino-2,2-dimethyl-3-cyanopenam hydrochloride (46.6g., 0.2 mole) in methylene chloride (1500 ml.) at room temperature and the resulting mixture stirred for 20 minutes. Triphenylmethyl chloride (66.9 g., 0.24 mole) is added in one portion to the mixture which is stirred at room temperature for 3.5 hours. The methylene chloride layer is separated and washed with water (5 × 100 ml.). It is then dried (Na2SO4) and concentrated in vacuo to orange-red viscous oil. Methanol (50 ml.) is added and the mixture stirred for a half hour to give a yellow-white solid. The solid is filtered, resuspended in fresh methanol, and the suspension stirred for a half hour. The solid is recovered by filtration and dried in a vacuum over at room temperature. Yield of crude = 47 gms. M.p. 116°-119° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([CH:16]1[CH2:20][CH2:19][CH:18]([C:21]2[NH:29][C:28]3[C:27](=[O:30])[N:26]([CH2:31][CH2:32][CH3:33])[C:25](=[O:34])[N:24]([CH2:35][CH2:36][CH3:37])[C:23]=3[N:22]=2)[CH2:17]1)(O)=[O:14].[NH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]#[N:45]>ClCCl.O1CCCC1>[C:39]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:13]([CH:16]1[CH2:20][CH2:19][CH:18]([C:21]2[NH:29][C:28]3[C:27](=[O:30])[N:26]([CH2:31][CH2:32][CH3:33])[C:25](=[O:34])[N:24]([CH2:35][CH2:36][CH3:37])[C:23]=3[N:22]=2)[CH2:17]1)=[O:14])#[N:38]
Reactant: N#CCCCCCN
Reactant: CCCn1c(=O)c2[nH]c(C3CCC(C(=O)O)C3)nc2n(CCC)c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C3CCC(C(=O)NCCCCCC#N)C3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
0.3 g (1.9 mmol) of carbonyldiimidazole are added to a suspension of 0.67 g (1.9 mmol) of 8-(3-carboxycyclopentyl)-1,3-dipropyl-7H-purine-2,6-dione in 20 ml of dichloromethane and 1 ml of tetrahydrofuran and the mixture is stirred for 35 minutes at ambient temperature. After the addition of 0.21 g (1.9 mmol) of 6-aminocapronitrile the mixture is stirred for a further 24 hours, acidified and washed with water. The organic phase is concentrated by evaporation, the residue is taken up in 5% sodium bicarbonate solution and this solution is extracted with dichloromethane. After drying and evaporation of the organic extracts the title compound is obtained in the form of crystals which, are purified with a mixture of dichloromethane/methanol in the ratio 95:5. 0.67 g (79.8% of theory) of the title compound are obtained in the form of colourless crystals.
Reaction SMILES: Br[C:2]1[C:3]([F:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([CH3:17])=[N:7]2.CC1(C)C(C)(C)OB([C:27]2[NH:35][C:34]3[CH2:33][CH2:32][NH:31][C:30](=[O:36])[C:29]=3[CH:28]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(Cl)Cl.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].O>[C:13]([NH:12][C:9]1[C:8]([CH3:17])=[N:7][C:6]2[C:11]([N:10]=1)=[C:2]([C:27]1[NH:35][C:34]3[CH2:33][CH2:32][NH:31][C:30](=[O:36])[C:29]=3[CH:28]=1)[C:3]([F:18])=[CH:4][CH:5]=2)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Reactant: Cc1nc2ccc(F)c(Br)c2nc1NC(C)(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc2ccc(F)c(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Temperature: 110 °C
Yield: 39.1 %

Procedure:
A glass microwave reaction vessel (80 mL) was charged with 8-bromo-N-(tert-butyl)-7-fluoro-3-methylquinoxalin-2-amine (286a) (1.20 g, 3.84 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609; 1.81 g, 6.92 mmol) in 1,4-dioxane (15 mL)/water (4.8 mL). Then Pd2(dba)3 (Strem Chemicals,) (0.176 g, 0.19 mmol), Xphos (Strem Chemicals,) (181 mg, 0.38 mmol) and potassium phosphate tribasic (Fisher Scientific, Fair Lawn, N.J.) (2.45 g, 11.53 mmol) were added into the reaction mixture. The glass vessel was sealed and heated in a CEM Voyager Microwave (Matthews, N.C.; large-scale unit) at 110° C. for 20 min (50 watts, Powermax feature off). The mixture was diluted with DCM (50 mL) and filtered through AW Standard Super-Celt NF (Sigma-Aldrich). The filtrate was concentrated in-vacuo and the crude residue was diluted with DCM, then filtered through a fine-fritted funnel. The crude material was purified by chromatography through an Interchim PuriFlash UP pre-packed silica-gel column (Interchim INC, San Pedro, Calif.; 200 gram), eluted with a gradient of 0-8% EtOAc in CH2Cl2 (for recovery of the starting material, 8-bromo-N-(tert-butyl)-7-fluoro-3-methylquinoxalin-2-amine), then with a gradient of 0-5% MeOH in DCM, to provide 2-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (286) (0.55 g, 1.50 mmol, 39% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (br., 1H), 7.65 (dd, J=9.00, 5.87 Hz, 1H), 7.26-7.34 (m, 1H), 6.95-7.01 (m, 1H), 6.73-6.77 (m, 1H), 6.15 (s, 1H), 3.41-3.48 (m, 2H), 2.86 (t, J,=,6.85 Hz, 2H), 2.55 (s, 3H), 1.51 (s, 9H). m/z (ESI, +ve) 368 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:14](=[O:33])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25](C(=O)N)[CH:24]=3)=[CH:18][C:17]=2[F:32])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(=O)([O-])O.[Na+].C[N:56](C)C=O>C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([C:11]1([C:14](=[O:33])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:56])[CH:24]=3)=[CH:18][C:17]=2[F:32])[CH2:12][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Ic1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1
Temperature: 25 °C

Procedure:
1-[4-(2-Carbamoylpyridin-4-yloxy)-2-fluorophenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester (10 g) was dissolved in N,N-dimethylformamide (100 ml) at room temperature, and water (2.41 ml) was added. Iodobenzene diacetate (7.91 g) was added with stirring at room temperature, the reaction mixture was stirred for 3 hours, iodobenzene diacetate (360 mg) was further added, and the reaction mixture was stirred for 2 hours. Ethyl acetate (100 ml) and a 5% aqueous solution of sodium hydrogencarbonate (100 g) were added to the reaction mixture, and layers were separated. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated. Ethyl acetate (30 ml) was added to the resultant crude crystals, and the mixture was heated and stirred at 60° C. After confirming the crystals were dissolved, the mixture was allowed to cool down to room temperature. Seed crystals obtained in Method 1 (50 mg) were added, and the mixture was stirred for 30 minutes. After confirming the precipitation of the crystals, heptane (100 ml) was added, and the mixture was further stirred for 30 minutes. The crystals were collected by filtration and dried to give the title compound (6.84 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Li+].[OH-]>C1COCC1>[CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: COC(=O)c1cccc2cc(-c3cccc4cnccc34)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccc2cc(-c3cccc4cnccc34)ccc12
Temperature: 25 °C
Yield: 125.3 %

Procedure:
To a solution of Methyl 6-(isoquinolin-5-yl)-1-naphthoate (1.4 g, 4.4 mmol) in THF (445 mL) was added 1N LiOH (89 mL) and the resulting mixture was stirred at room temperature. The mixture was concentrated down to a small aqueous volume, which was acidified to pH 5 with conc HCl. The solid was isolated by filtration, washed with a small amount of water and dried overnight under vacuum to give 1.65 g of the titled compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH3:32])[C:15]2[N:20]=[CH:19][N:18]=[C:17]3[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:22]=[CH:23][C:16]=23)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd]>[CH3:32][N:14]([C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[C:15]1[N:20]=[CH:19][N:18]=[C:17]2[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[N:22]=[CH:23][C:16]=12
Reactant: CN(c1ncnc2c1cnn2COCC[Si](C)(C)C)[C@H]1CCCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CN(c1ncnc2c1cnn2COCC[Si](C)(C)C)[C@H]1CCCNC1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a solution of (S)—N-(1-benzylpiperidin-3-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (540 mg, 1.19 mmol) in McOH under nitrogen, 10% Pd/C (540 mg) was added. To this suspension, ammonium formate (752 mg, 11.9 mmol) was added and the reaction mixture was refluxed under nitrogen for 4 h. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to rt and filtered over celite. The filtrate was concentrated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the titled intermediate (325 mg, 80%). 1H NMR (400 MHz, CD3OD): δ 8.34 (s, 1H), 8.29 (s, 1H), 5.70 (s, 2H), 3.63 (t, J=8.4 Hz, 2H), 3.39 (s, 3H), 3.22 (m, 2H), 3.03 (m, 1H), 2.11 (m, 1H), 2.00 (m, 1H), 1.32 (m, 4H), 0.87 (t, J=8.4 Hz, 2H), 0.00 (9H). LC-MS: m/z [M+1]=363.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[C:6]([C:8]1[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[N:10][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:12][C:13]=1O)#[N:7].CN(C)C1C=CC=CC=1>O1CCOCC1>[Cl:3][C:13]1[N:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:8]=1[C:6]#[N:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(O)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Solvent: C1COCCO1
Solvent: CN(C)c1ccccc1
Product: N#Cc1c(Cl)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
POCl3 (50 ml) was added to a stirred solution of 5-cyano-4-(3-nitrophenyl)-2-phenyl-6-hydroxy-pyrimidine (example 31(a), 15.0 g) and dimethylaniline (0.5 ml) in dry 1,4-dioxane p.a. (200 ml). After 3 h at 90° C., the warm mixture was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane and ice water was added. The resulting precipitate was filtered off and washed with water. Residual water was removed by coevaporation with 1,4-dioxane.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:10][CH2:11][CH3:12])[NH:6][C:7]=1[CH:8]=[O:9])[CH3:2].[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[C:30](=[O:38])[C:31](=[O:37])[C:32]=2[O:33][CH:34]([CH3:36])[CH3:35])=[CH:19][CH:18]=1.CC(O)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:10][CH2:11][CH3:12])[N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[C:30](=[O:38])[C:31](=[O:37])[C:32]=3[O:33][CH:34]([CH3:36])[CH3:35])=[CH:21][CH:22]=2)[C:7]=1[CH:8]=[O:9])[CH3:2]
Reactant: CCCc1nc(CC)c(C=O)[nH]1
Reactant: CC(C)Oc1c(-c2ccccc2-c2ccc(CBr)cc2)c(=O)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(C=O)n1Cc1ccc(-c2ccccc2-c2c(OC(C)C)c(=O)c2=O)cc1
Reaction time: 0.75 h

Procedure:
To a stirred solution of 4-ethyl-2-propyl-1H-imidazole-5-carboxaldehyde (0.15 g; preparable as described in WO92/00977; Dupont) in dry dimethylformamide (3 ml) was added sodium hydride (60% dispersion in mineral oil; 36 mg) and stirring was continued for approximately 45 minutes. The resulting solution was then added via canula to a stirred solution of 3-(4'-bromomethylbiphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione (0.35 g; preparable as in Example 1(c)) in dry dimethylformamide (3 ml). After stirring for 1 hour, 2-propanol (0.1 ml) was added. The mixture obtained was poured into ethyl acetate (20 ml) then washed with water (15 ml). The aqueous washings were extracted with ethyl acetate (10 ml) and the combined organic phases were washed with water (5×15 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue obtained was purified by flash chromatography on silica gel (eluting with ethyl acetate/petroleum ether (b.p. 60°-80° C.) (75:25)) to give 4-ethyl-1-[2'-(3,4-dioxo-2-isopropoxycyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-2-propyl-1H-imidazole-5-carboxaldehyde, an active compound of the present invention, as a foam (0.194 g).
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37]CC)=[O:36])[CH:30]=2)=[O:27])[C:9]1=[O:40])=[O:6])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH:10]([NH:25][C:26](=[O:27])[NH:28][C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[C:35]([OH:37])=[O:36])[C:9]1=[O:40])=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)O)c2)CN(C(=O)C(C)(C)C)c2ccccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
1-(tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea (500 mg) was dissolved in methanol (20 ml), the solution of lithium hydroxide monohydrate (191 mg) in water (10 ml) was added, the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, after acidification with 1N hydrochloric acid, the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and recrystallized from ethanol and isopropyl ether, to thereby obtain 380 mg of the titled compound (Yield: 73%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C@H:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)[CH3:7])[N:3]=[CH:2]1.[C:17]([NH:24][C@H:25]([C:33](O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C>[NH:1]1[CH:5]=[C:4]([C@H:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH2:14][O:15][C:33](=[O:34])[CH:25]([NH:24][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:7])[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1c(CO)cccc1[C@H](C)c1c[nH]cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Product: Cc1c(COC(=O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)cccc1[C@H](C)c1c[nH]cn1

Procedure:
The title compound was prepared from (S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol (216 mg, 1.0 mmol), Boc-L-Phenylalanine (795 mg, 3.0 mmol), EDCI (671 mg, 3.5 mmol) and DMAP (427 mg, 3.5 mmol) according to the procedure described in Example 3. Intermediate 12 was purified by a column chromatography using 35-100% ethyl acetate in hexane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(Br)cc1O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1C(C)=O
Reaction time: 20 h
Yield: 99 %

Procedure:
To a stirred solution of 1-(4-bromo-2-hydroxyphenyl)-1-ethanone (28.8 g, 134 mmol), potassium carbonate (48.6 g, 352 mmol) in DMF (63 ml) was added methyl iodide (25 g, 176 mmol), and the mixture was stirred for 20 hours. The mixture was poured into water. The whole was extracted with diethylether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without purification. (31.5 g, 99% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH:8]=[C:7]([OH:13])[CH:6]=[CH:5]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[F:12][C:10]1[CH:11]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:3]=[C:4]2[C:9]=1[CH:8]=[C:7]([OH:13])[CH:6]=[CH:5]2
Reactant: COc1ccc(B(O)O)cc1
Reactant: Oc1ccc2cc(Br)cc(F)c2c1
Product: COc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 6-bromo-8-fluoro-2-naphthol (0.39 g, 1.62 mmol) with 4-methoxyphenyl boronic acid (0.34 g, 2.27 mmol) according to method A to yield 0.35 g (81%) of a white solid: mp 150-151° C.; 1H NMR (DMSO-d6): δ 3.81 (3H, s), 7.05 (2H, d, J=8.75 Hz), 7.16-7.20,(2H, m), 7.57 (1H, dd, J=1.21 Hz, J=12.76 Hz), 7.74 (2H, d, J=8.74 Hz), 7.89-7.92 (2H, m), 10.10 (1H, s); MS (ESI) m/z269 (M−H)+.