Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:28]3[CH2:30][CH2:29]3)[C:15](=[O:27])[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][CH:25]=[N:24][CH:23]=4)=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:32]B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:28]1([N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[C:4]([F:31])=[CH:3][C:2]([CH3:32])=[CH:7][N:6]=3)[CH2:9][CH2:10]2)[C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:26][CH:25]=[N:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:30][CH2:29]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncc(Br)cc2F)CC1
Reactant: CB(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)c(F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of N-(5′-Bromo-3′-fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide (170 mg), methylboronic acid (126 mg), Na2CO3 solution (2 M; 385 μL), and Pd(PPh)4 (20 mg) in dioxane (3 mL) is stirred at 80° C. overnight under an argon atmosphere. Three more portions of methylboronic acid (42 mg each) as well as PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (14 mg) are added successively over the next day until the conversion is complete. The reaction mixture is filtered through a pad of aluminium oxide and washed with dioxane. The filtrate is concentrated in vacuo and the residue is purified by preparative HPLC. LC (method 1): tR=1.15 min; Mass spectrum (ESI+): m/z=421 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.Cl.[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][C:18]=1[F:25])[CH3:15]>>[ClH:1].[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:24])[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:19][C:18]=1[F:25])[CH3:15]
Reactant: CCOc1ccc(NC)cc1F
Reactant: Cc1nc(Cl)c2ccccc2n1
Agent: Cl
Product: CCOc1ccc(N(C)c2nc(C)nc3ccccc23)cc1F

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (78 mg, 0.44 mmol) and (4-ethoxy-3-fluoro-phenyl)-methyl-amine hydrochloride (81 mg, 0.39 mmol) by a procedure similar to Example 251. 1H NMR (CDCl3) δ 8.57 (m, 1H), 7.74 (m, 1H), 7.19 (m, 1H), 7.10 (dd, J=2.6, 10.6 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.98 (ddd, J=1.5, 2.8, 8.5 Hz, 1H), 6.81 (m, 1H), 4.19 (q, J=6.9 Hz, 2H), 3.77 (s, 3H), 2.98 (s, 3H), 1.53 (t, J=7.0 Hz, 3H); LC-MS (ESI+; 312 ([M+H]+)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[C:4]([Cl:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>O1CCOCC1>[Cl:18][C:4]1[CH:3]=[C:2]([NH:1][C:26](=[O:27])[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[N:9]=1
Reactant: Nc1ccc(-c2nc(-c3ccco3)no2)c(Cl)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2nc(-c3ccco3)no2)c(Cl)c1)Oc1ccccc1
Yield: 68.5 %

Procedure:
To a mixture of 5-(4-amino-2-chlorophenyl)--3-(2-furanyl)-1,2,4-oxadiazole (0.75 g) and 0.56 g of potassium carbonate in 30 ml of dioxane is added 0.94 g of phenyl chloroformate. The resulting mixture is heated at reflux for 2 hours and concentrated to dryness. 50 ml of water is added to the residue and the resulting mixture is extracted three times with 300 ml of chloroform. The residue is recrystallized from benzene to yield 0.75 g of the title compound, melting point 184°-185.5°C.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH2:22].O>C(O)CCC>[S:17]1[CH:21]=[CH:20][N:19]2[C:2]([CH2:5][C:6]3[CH:16]=[CH:15][C:9]4[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=4[CH:7]=3)=[CH:3][N:22]=[C:18]12
Reactant: Nc1nccs1
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Solvent: CCCCO
Solvent: O
Product: CSc1nc2ccc(Cc3cnc4sccn34)cc2s1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A stirred mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 of Example 117 (500 mg, 1.84 mmol) and thiazol-2-amine (370 mg, 3.68 mmol) in 1-butanol (22 mL) was heated at reflux overnight. The mixture was cooled to rt and water (120 mL) was added. The mixture was extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-(imidazo[2,1-b]thiazol-5-ylmethyl)-2-(methylthio)benzo[d]thiazole as a yellow solid (350 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.4 Hz, 1H), 7.55 (d, J=1.2 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.16 (d, J=0.9 Hz, 1H), 6.99 (d, J=4.5 Hz, 1H), 6.71 (dd, J=0.9 Hz, J=4.5 Hz, 1H), 4.24 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 318 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:33]([F:44])[CH:32]=2)=[CH:27][CH:26]=1.Cl>CN(C)C=O>[F:44][C:33]1[CH:32]=[C:31]([O:30][CH2:29][C:28]2[CH:45]=[CH:46][C:25]([CH2:24][N:10]3[C:11]([CH2:13][CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:12][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9]3)=[CH:26][CH:27]=2)[CH:36]=[CH:35][C:34]=1[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1F
Reactant: Fc1ccc(-c2cc(CCc3ccccc3)[nH]n2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccc(F)cc4)cc3CCc3ccccc3)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-fluorophenyl)-5-(2-phenylethyl)-1H-pyrazole (300 mg, 1.1 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 40 mg, 1.0 mmol) at 0° C., and the mixture was allowed to warm to room temperature and stirred for 30 min. Ethyl 3-(4-{[4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoate (350 mg, 1.0 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:1) to give the title compound as a yellow oil. 1H NMR (CDCl3) δ: 1.26 (3H, t, J=7.2 Hz), 2.56 (2H, t, J=7.6 Hz), 2.78-2.93 (6H, m), 4.12 (2H, q, J=7.2 Hz), 4.98 (2H, s), 5.24 (2H, s), 6.37 (1H, s), 6.59-6.68 (2H, m), 7.03-7.13 (7H, m), 7.19-7.37 (5H, m), 7.77 (2H, dd, J=9.0, 5.5 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[OH-:15].[Na+].Cl>C1COCC1>[OH:15][C:7]1[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[N:8]=1
Reactant: COC(=O)c1cc(C(=O)O)nc(Cl)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(=O)O)nc(O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Next, to a stirred solution of 2-chloro-pyrimidine-4,6-dicarboxylic acid monomethyl ester (120 mg, 0.55 mmol) in THF (3 mL) is added 1N NaOH (1.10 mL) and the mixture is stirred at room temperature for 18 hours. The solution is carefully acidified with 1N HCl and the solvent is removed under reduced pressure to give 2-hydroxypyrimidine-4,6-dicarboxylic acid. This is used as is in subsequent reactions.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][S:5]([CH3:8])(=[O:7])=[O:6].[Cl:9][C:10]1[N:15]=[C:14]([Cl:16])[C:13]([F:17])=[C:12](Cl)[N:11]=1>CN(C=O)C.C1COCC1>[Cl:9][C:10]1[N:11]=[C:12]([N:4]([CH3:3])[S:5]([CH3:8])(=[O:7])=[O:6])[C:13]([F:17])=[C:14]([Cl:16])[N:15]=1
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Reactant: CNS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(c1nc(Cl)nc(Cl)c1F)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of NaH (60% in mineral oil, 176 mg, 8.58 mmol) in anhydrous DMF (2 mL), N-methylmethanesulfonamide (436 mg, 4.0 mmol) in DMF (2 ml) was added. This reaction mixture was stirred for 30 min at room temperature and then added dropwise to the solution of 2,4,6-trichloro-5-fluoropyrimidine (804 mg, 4.0 mmol) in THF (30 ml) at 0° C. The reaction mixture was stirred from 0° C. to room temperature overnight. The solvent was evaporated and the residue was purified by silica gel chromatography (by ISCO Combiflash with gradient 0-30% ethyl acetate in Hexane with 1% TEA. A white solid (700 mg) was obtained, yield 64%. NMR (400 MHz, DMSO) 83.38 (s, 3H), 3.31 (s, 3H).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:34])[CH2:6][O:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([C:15]2[C:24]3[C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[O:27][C:23]=3[C:22]([Br:32])=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[CH:20]3)=[CH:10][C:9]=1[Br:33]>C1COCC1.CO>[Br:14][C:13]1[CH:12]=[C:11]([C:15]2[C:24]3[C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[O:27][C:23]=3[C:22]([Br:32])=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[CH:20]3)[CH:10]=[C:9]([Br:33])[C:8]=1[O:7][CH2:6][C:5]([OH:34])=[O:4]
Reactant: COC(=O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3oc4ccccc4c23)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3oc4ccccc4c23)cc1Br
Reaction time: 3 h
Yield: 93.6 %

Procedure:
Potasium hydroxide (1.0 M, 1.60 mL, 1.60 mmol) was added to a stirred solution of [2, 6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]furan-11-yl)-phenoxy]-acetic acid methyl ester (0.90 g, 1.45 mmol) in THF (9 mL) and methanol (5 mL). After 3 h, the solvent was removed, water was added and the reaction mixture was acidified with 10% HCl. After stirring overnight, the solid was filtered and washed with water, triturated with hexane and dried in vacuo at 100° C. to provide the title compound as a white solid (0.821 g, 94%): mp 250-252° C.: NMR (DMSO-d6); δ8.37 (d, J=8 Hz, 1 H), 7.90 (s, 2 H), 7.84 (d, J=8 Hz, 1 H), 7.70 (ddd, J=8, 6, 1 Hz, 1 H), 7.61 (ddd, J=8, 1, 1 Hz, 1 H)), 7.62-7.58 (m, 2 H), 7.31 (ddd, J=8, 7, 1 Hz, 1 H), 6.92 (ddd, J=8, 1,1 Hz, 1 H), 4.75 (s, 2 H); MS (EI): [M+], 3 bromine isotope pattern, 602 (40%), 604 (95%) 606 (100%) 608 (40%); Anal. Calc. for C24H13Br3O4: C, 47.64, H, 2.17, N, 0.00. Found: C, 47.33, H, 1.95, N, 0.04.
Reaction SMILES: [Cl-].[CH:2]1([C:6]2[S:7][CH:8]=[C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:10]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[N+:33]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O)([O-:35])=[O:34]>O1CCCC1.C(Cl)Cl>[CH:2]1([C:6]2[S:7][CH:8]=[C:9](/[CH:11]=[CH:39]/[C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([N+:33]([O-:35])=[O:34])[CH:37]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc([P+](Cc2csc(C3CCC3)n2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(/C=C/c2csc(C3CCC3)n2)c1
Yield: 70.4 %

Procedure:
A slurry of 1.8 g of [(2-cyclobutyl-4-thiazolyl)methyl] triphenylphosphonium chloride, in 80 ml of tetrahydrofuran was sealed under a positive argon atmosphere and the mixture cooled with an ice bath. Sodium hydride (0.2 g; 50% oil dispersion) was added and stirring and cooling continued for 30 min afterwhich 0.6 g of 3-nitrobenzaldehyde was added. The cooling bath was removed and the mixture was stirred at room temperature for 1 hr. The mixture was then filtered, condensed in vacuo and the residual materials taken up in 100 ml of methylene chloride. This solution was then washed with water, dried (MgSO4) and condensed in vacuo to yield 0.8 g of (E)-2-cyclobutyl-4-[2-(3-nitrophenyl)ethenyl]thiazole; m.p. 112°-115° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][C:19](=[O:35])[C:20]([CH3:34])([CH3:33])[CH2:21]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[CH3:17][O:18][C:19](=[O:35])[C:20]([CH3:34])([CH3:33])[CH2:21][O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COc1ccc(Br)cc1C=O
Temperature: 140 °C
Yield: 85.7 %

Procedure:
To a mixture of 5-bromo-2-hydroxy-benzaldehyde (4 g, 20 mmol), KI (1 g) and K2CO3 (4 g, 29 mmol) in DMF (10 mL) was added 2,2-dimethyl-3-(toluene-4-sulfonyloxy)-propionic acid methyl ester (6.9 g, 24 mmol). The mixture was heated at 140° C. for 2 h, and then cooled to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with water (3×), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (5.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:13]=O>CO>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:13]1[C:12]1[CH:15]=[CH:16][C:17]([OH:18])=[C:10]([Br:9])[CH:11]=1
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: Nc1ccccc1S
Solvent: CO
Product: Oc1ccc(-c2nc3ccccc3s2)cc1Br
Temperature: 25 °C
Yield: 38 %

Procedure:
In a methanol solvent, a solution including 2-aminothiophenol (1.0 eq.) and 3-bromo-4-hydroxybenzaldehyde (1.0 eq.) was stirred at room temperature. The produced precipitate was filtered and the filtered product was washed with cold methanol to obtain Compound 26.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3].[Br:14]Br.N>CO.C(Cl)Cl>[CH2:1]([N:4]1[C:8]2[C:9]([Br:14])=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3]
Reactant: CCCn1cnc2ccc(N)cc21
Reactant: BrBr
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCCn1cnc2ccc(N)c(Br)c21
Yield: 37 %

Procedure:
To a solution of 3-propyl-5-aminobenzimidazole (0.71 g, 4.3 mmol) in 10 ml of ACOH was added solution of Br2 in ACOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 0.40 g (1.6 mmol, 37%) of the product.
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=O)[CH3:2].Cl.[NH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:23]=[C:17]1[CH:16]([N:15]2[C:9](=[O:10])[C:4]3[C:5](=[CH:11][CH:12]=[CH:13][C:3]=3[CH2:1][CH3:2])[C:6]2=[O:8])[CH2:21][CH2:20][C:19](=[O:22])[NH:18]1
Reactant: CCc1cccc2c1C(=O)OC2=O
Reactant: NC1CCC(=O)NC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
2-(2,6-Dioxo(3-piperidyl))-4-ethylisoindoline-1,3-dione was prepared by the procedure of Example 1 from 3-ethylphthalic anhydride (0.860 g, 4.89 mmol), 3-aminopiperidine-2,6-dione hydrogen chloride (0.803 g, 4.88 mmol) and sodium acetate (0.420 g, 5.12 mmol) in acetic acid (10 mL). The product was a white solid (1.06 g, 76% yield); mp, 235.0-236.5° C.; 1H NMR (DMSO-d6) δ1.22 (t, J=7.4 Hz, 3H, CH3), 2.04-2.10 (m, 1H, CHH), 2.47-2.63 (m, 2H, CH2), 2.83-2.98 (m, 1H, CHH), 3.07 (q, J=7.5 Hz, 2H, CH2), 5.13 (dd, J=5.4, 12.5 Hz, 1H, NCH), 7.70-7.82 (m, 3H, Ar), 11.13 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.84, 21.95, 23.69, 30.90, 48.77, 121.09, 127.26, 131.76, 134.63, 135.39, 143.87, 166.99, 167.58, 169.85, 172.72; Anal Calcd for C15H14N2O4: C, 62.93; H, 4.93; N, 9.79. Found: C, 62.74; H, 4.84; N, 9.54.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][C:23]#[N:24]>>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1/[C:22](=[CH:6]/[C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)/[C:23]#[N:24]
Reactant: N#CCc1nc2ccccc2s1
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(/C=C(\C#N)c2nc3ccccc3s2)cc1OC
Yield: 89.2 %

Procedure:
3,4-Dimethoxybenzaldehyde (191 mg) was condensed with 2-benzothiazoleacetonitrile (200 mg) through Method B (production step 2), to thereby yield the target product (yield: 330 mg, 89%).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([OH:31])([C:29]#[CH:30])[CH3:28])[CH:22]=1>>[F:19][C:3]1[C:2]([C:30]#[C:29][C:27]([OH:31])([C:23]2[CH:22]=[C:21]([CH3:20])[CH:26]=[CH:25][N:24]=2)[CH3:28])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1cc(C)ccn1
Product: Cc1ccnc(C(C)(O)C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)c1
Yield: 10 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(4-methylpyridin-2-yl)but-3-yn-2-ol (WO2009/158011A1) to give the titled compound as a white solid (39 mg, 10%).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[N:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[C:9]([CH3:30])=[C:8]([C:31]([O:33]CC)=[CH2:32])[C:7]2=[O:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(Cl)(Cl)Cl>[C:31]([C:8]1[C:7](=[O:36])[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]2[N:12]=[C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:14]=[CH:15][C:10]=2[C:9]=1[CH3:30])(=[O:33])[CH3:32]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCC(O)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCC(O)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.5 %

Procedure:
To a solution of 8-cyclopentyl-6-(1-ethoxy-vinyl)-2-(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (255 mg, 0.52 mmol) in chloroform (2 mL) was added hydrogen chloride (2 M ethereal solution, 5.0 mL, 10.0 mmol). The reaction mixture was stirred at RT for 12 h. The solvents were evaporated and the residue was dissolved in ethanol. The ethanol was evaporated to give 6-acetyl-8-cyclopentyl-2-(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (213 mg, 0.46 mmol). MS (APCI+) 463 (M+1, 100); 1HNMR δ(400 MHz, DMSO-d6) 10.90 (br, 1H), 9.07 (s, 1H), 8.19 (s, 1H), 7.91 (br, 2H), 5.91-5.89 (m, 1H), 3.77 (br, 1H), 3.62 (br, 2H), 3.07 (br, 2H), 2.58 (s, 3H), 2.40 (s, 3H), 2.30 (br, 2H), 1.98-1.86 (m, 5H), 1.65 (br, 4H); Anal. Calc'd for C25H30N6O3, 1.76C3H8O1, 0.36CHCl3: C, 60.20; H, 7.33; N, 13.75. Found: C, 60.48; H, 6.97; N, 13.35.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[O:11][CH2:10][CH2:9][NH:8][C:7]2=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=1)([O-])=O.[C:17]1([CH3:40])[CH:22]=[CH:21][C:20]([S:23](NC2C=C3C(=C(C(O)=O)C=2)NCCC3)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[C:17]1([CH3:40])[CH:22]=[CH:21][C:20]([S:23]([NH:1][C:4]2[CH:5]=[C:6]3[O:11][CH2:10][CH2:9][NH:8][C:7]3=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cc3c(c(C(=O)O)c2)NCCC3)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c1NCCO2
Product: Cc1ccc(S(=O)(=O)Nc2cc3c(c(C(=O)O)c2)NCCO3)cc1
Yield: 5.3 %

Procedure:
The title compound was prepared (5.3% yield) from 3,4- dihydro-7-nitro-2H-1,4-benzoxazine-5-carboxylic acid by the same procedure as in Examples 31 and 32 (b). This compound was recrystallized form ethanol to give colorless crystals, mp 213°-215° C.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:38]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39]1>C1COCC1>[CH:38]1([NH:43][CH2:26][CH2:25][CH2:24][O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: NC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OCCCNC3CCCC3)cc12
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (0.080 mg, 0.15 mmol) and cyclopentylamine (0.45-0.75 mmol) in THF (10 mL) was stirred at 90° C. for 2 hours in a sealed tube. After cooling to ambient temperature, the reaction mixture was solvent evaporated. It was partitioned in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.75% ammonium hydroxide/7.5% methanol in chloroform to give cyclopentyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine as a beige foam (70.6 mg, 100%). This compound was dissolved in methanol, and ethereal hydrochloride was added. Concentrating and drying in vacuo for 12.5 hours at 83° C. gave the hydrochloride as a light brown foam (69.7 mg, 95.6%); Mass Spectrum (+EI, [M+H]+) m/z 450. 1HNMR (500 MHz, DMSO-d6): δ14.15-14.21 (br, 1H), 8.70-8.83 (m, 3H), 8.51-8.53 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.54-7.65 (m, 3H), 7.30 (d, 1H, J=2.20 Hz), 7.09 (dd, 1H, J=9.15 Hz and 2.31 Hz), 4.11 (t, 2H, J=6.10 Hz), 3.43-3.49 (m, 1H), 3.06 (br, s, 2H), 2.05-2.14 (m, 2H), 1.88-1.96 (m, 2H), 1.43-1.71 ppm (m, 6H). Elemental Analysis for C25H27N3O3S.1.00 mol HCl.0.75 mol H2O: Calcd: C, 60.11; H, 5.95; N, 8.41; Found: C, 59.71; H, 5.83; N, 8.25.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[CH:18][NH:17][C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:24]N(C)C=O>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[CH:18][N:17]([CH3:24])[C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O
Product: Cc1cn(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,5-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 177°-180° C.,
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]4[OH:32])=[CH:21][C:20]=3[OH:33])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34](Cl)(=[O:36])[CH3:35].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:13]1([C:11]2[N:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]4[O:32][C:34](=[O:36])[CH3:35])=[CH:21][C:20]=3[OH:33])[N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)Cl
Reactant: Oc1cc(OC2CCCCC2O)ccc1-c1nc(-c2ccccc2)nc(-c2ccccc2)n1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC1CCCCC1Oc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)c1
Reaction time: 6 h

Procedure:
A mixture of 13.0 g (29.6 mmol) of 2,4-diphenyl-6-(2'-hydroxy4'-(2"-hydroxycyclohexyloxy)phenyl)-1,3,5-triazine, 7.0 g (89.2 mmol) of acetyl chloride (Fluka, 99%) and 0.6 g (7.6 mmol) of pyridine in 140 ml of toluene (Merck, 99.5%) is stirred under nitrogen and held at 50° C. for 6 h.