Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@H:12](O)[C@H:11]([C:14](=[O:23])NC(C2SC=CC=2)C)[N:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[O:37]1CCOC[CH2:38]1>>[CH2:1]([N:8]1[C@H:12]2[CH2:38][O:37][C:14](=[O:23])[C@H:11]2[N:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]1=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCO1
Reactant: CC(NC(=O)[C@H]1[C@@H](O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1)c1cccs1
Agent: O=S(=O)(O)O
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of the amide-alcohol (2.0 g) prepared in Example 15, dioxane (50 ml) and 20 % sulfuric acid (30.0 g) is refluxed with stirring at 88° to 89° C for 1 hour. The reaction mixture is concentrated to one third of the original volume, diluted with water (50 ml) and cooled in an ice bath. The precipitate is collected by filtration to yield cis-1,3-dibenzyl-hexahyrofuro[3,4-d]imidazole-2,4-dione (1.36 g, 95 %). M.P. 100° to 103° C. [α]D20 + 16.4° (C = 2 in CHCl3). The infrared spectrum of the sample is identified with that of the authentic sample.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([OH:22])[C:14]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C(O)=C(C(CS(C2C=CC=CC=2OC)(=O)=O)=CC=1)[C:32](OC)=[O:33].O1C=CC(B(O)O)=C1>>[O:25]1[CH:26]=[CH:27][C:23]([C:14]2[C:15]([OH:22])=[C:16]([C:11]([CH2:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[O:33][CH3:32])(=[O:8])=[O:9])=[CH:12][CH:13]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:24]1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2OC)ccc(Br)c1O
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2OC)ccc(-c2ccoc2)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-2-hydroxy-6-(2-methoxybenzenesulphonylmethyl)benzoate (Intermediate 67) and furan-3-yl boronic acid.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.[CH3:28][N:29]([CH3:35])[S:30]([CH:33]=[CH2:34])(=[O:32])=[O:31]>>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:34][CH2:33][S:30]([N:29]([CH3:35])[CH3:28])(=[O:32])=[O:31])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Reactant: C=CS(=O)(=O)N(C)C
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(CCS(=O)(=O)N(C)C)C3)cc1OCC2

Procedure:
Following the procedure of Example 152, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with N,N-dimethylethenesulfonamide to give 197 as a white solid. 1H NMR δ (ppm) (CDCl3): 8.44 (1 H, d, J=8.28 Hz), 7.84 (1 H, d, J=0.67 Hz), 7.61 (1 H, s), 7.05 (1H, dd, J=8.32, 1.83 Hz), 6.95 (1 H, d, J=1.78 Hz), 6.00-5.90 (1 H, m), 4.48-4.39 (4 H, m), 3.80-3.72 (2 H, m), 3.72-3.64 (1 H, m), 3.27-3.19 (2 H, m), 3.02-2.89 (4 H, m), 2.87 (6 H, s), 1.56 (6 H, d, J=6.63 Hz). LCMS: RT=6.35 min, M+H+=486
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[C:17]([CH:19]=1)[NH2:18].N1C=CC=CC=1.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>C(#N)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[C:17]([NH:18][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[CH:19]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc2nc(-c3ccc(C)c(N)c3)c(Br)n2n1
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(C)c(NC(=O)C(C)(C)C)c3)c(Br)n2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
A solution of 5-(3-bromo-6-methoxyimidazo[1,2-b]pyridazin-2-yl)-2-methylaniline (0.165 g, 0.495 mmol) in acetonitrile (25 mL) containing pyridine (1.48 mmol) is added trimethylacetylchloride (0.495 mmol). The mixture is stirred at room temperature for 4 hours, then concentrated to dryness and purified via chromatography (hexanes to EtOAc) to afford 0.200 g (97%) of the title compound as a white solid: Rf 0.41 (1:1 EtOAc:hexanes); LCMS (m/z)=417.3, 419.3 [M+H]+, tR=2.76 min.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[N:17]1([CH2:21][C@@H:22]([NH2:32])[C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:21][C@@H:22]([NH:32][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CC(C)c1ccc([C@H](N)CN2CCC2)cc1
Agent: Cl
Product: CC(C)c1ccc([C@@H](CN2CCC2)Nc2ncnc3c(C(N)=O)ccnc23)cc1

Procedure:
Compound 37 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-Azetidin-1-yl-1-(4-isopropyl-phenyl)-ethylamine dihydrochloride to give the title compound as an off-white solid. LC/MS [391 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.38-8.87 (m, 2H), 8.53 (s, 1H), 8.37 (d, J=4.4 Hz, 1H), 8.17 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 5.60-4.97 (m, 1H), 3.16-2.99 (m, 5H), 2.89-2.77 (m, 1H), 2.74 (dd, J=11.9, 4.9 Hz, 1H), 2.02-1.72 (m, 2H), 1.16 (d, J=6.8 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:16]=[CH:17]3)=[C:12]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:11]=2[CH2:33][C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:9])=[CH:4][CH:3]=1.[N:42]1[CH:47]=[CH:46][CH:45]=[C:44](B(O)O)[CH:43]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]([C:12]1[C:11]([CH2:33][C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:44]3[CH:43]=[N:42][CH:47]=[CH:46][CH:45]=3)=[CH:3][CH:4]=2)=[O:9])[N:18]2[C:13]=1[CH:14]=[C:15]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH:16]=[CH:17]2)=[O:32]
Reactant: OB(O)c1cccnc1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(OCc3ccccn3)ccn2c1C(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(OCc3ccccn3)ccn2c1C(=O)c1ccc(-c2cccnc2)cc1
Temperature: 23 °C
Yield: 65.6 %

Procedure:
A solution of ethyl 3-{3-[(4-bromophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(pyridin-2-ylmethoxy)indolizin-2-yl}-2,2-dimethylpropanoate (225 mg, 0.363 mmol), 3-pyridyl boronic acid (89.3, 0.726 mmol), tetrakis(triphenylphosphine)palladium(0) (42.0 mg, 0.036 mmol) in THF (4.0 mL) and aqueous 20% Na2CO3 (2.0 mL) is heated at 70° C. for 24 h then cooled to 23° C. The mixture is partitioned between Et2O and water then the organics are collected, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to EtOAc) gives ethyl 3-[1-(2,2-dimethylpropanoyl)-7-(pyridin-2-ylmethoxy)-3-{[4-(pyridin-3-yl)phenyl]carbonyl}indolizin-2-yl]-2,2-dimethylpropanoate (147 mg, 65%) which is dissolved in THF (1.0 mL), MeOH (1.0 mL), and 6M aqueous NaOH (0.8 mL) and heated at 50° C. for 3 h then cooled to 23° C. and acidified to pH=1 with concentrated aqueous HCl. The mixture is concentrated in vacuo, diluted with DMSO, filtered, and filtrate is purified by HPLC (25% CH3CN to 85% CH3CN in 0.1% TFA in water) to give the title compound (62 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH:22]([F:24])[F:23])[CH:12]=2)([C:9]#[N:10])[CH2:5][CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([CH2:9][NH2:10])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH:22]([F:23])[F:24])[CH:12]=2)[CH2:5][CH2:4]1
Reactant: COC1(OC)CCC(C#N)(c2ccc(OC(F)F)c(OC(F)F)c2)CC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC1(OC)CCC(CN)(c2ccc(OC(F)F)c(OC(F)F)c2)CC1
Reaction time: 6 h
Yield: 84.8 %

Procedure:
A solution of 4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexan-1-one dimethyl ketal (0.5 g, 1.33 mmol) in tetrahydrofuran (3 mL) at room temperature under an argon atmosphere was added to a suspension of lithium aluminum hydride (0.1 g, 2.66 mmol) in tetrahydrofuran (4.5 mL). After 6 h, ethyl acetate and saturated aqueous sodium potassium tartrate were added, followed by saturated aqueous sodium carbonate, and the mixture was extracted four times with ethyl acetate. The organic extract was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (0.43 g, 85%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[C:10]([N+:15]([O-:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[C:10]([N+:15]([O-:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ncccc1CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccnc1[N+](=O)[O-]

Procedure:
Methane sulfonyl chloride (0.16 mL, 2.14 mmol) was added to a solution of 3-(2-hydroxyethyl)-2-nitropyridine (0.300 g, 1.78 mmol) and triethylamine (0.37 mL, 2.67 mmol) in methylene chloride (5 mL) at 0° C. under argon. After 1 h the reaction was worked up with saturated sodium bicarbonate and methylene chloride, and the organic phase dried over sodium sulfate and concentrated to give the title compound MS 247 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:34][C:35]1[CH:40]=[C:39]([CH2:41]O)[CH:38]=[CH:37][N:36]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:34][C:35]1[CH:40]=[C:39]([CH2:41][O:14][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Nc1cc(CO)ccn1
Reactant: O=[N+]([O-])c1ccc(O)c2ccccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cc(COc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of 4-nitronaphthol (2) (5.17 g, 27.3 mmol), PPh3 (10.75 g, 41.0 mmol) and 2-aminopyridine-4-methanol (1) (5.09 g, 41.0 mmol) in THF (50 mL) was added dropwise DIAD (8.07 mL, 41.0 mmol) at −15° C. The mixture was stirred overnight at RT and the volatiles removed in vacuo. The crude product was triturated from EtOAc (150 mL), filtered off and washed with EtOAc (100 mL). A second trituration from MeOH (100 mL) gave the title compound (3) (4.54 g, 56%) as a yellow solid: m/z 296 (M+H)+ (ES+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[C@H:13]([OH:20])[CH2:12][N:11]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[Li+].[OH-].Cl>C1COCC1>[C:24]([O:23][C:21]([N:11]1[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C@H:13]([OH:20])[CH2:12]1)=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: COC(=O)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C(C(=O)O)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
(2S,5S)-1-tert-butyl 4-methyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-5,6-dihydropyridine-1,4(2H)-dicarboxylate (Intermediate 101, 4.22 g, 10.51 mmol) was dissolved in THF (64.0 mL) and water (32 mL) and then LiOH (0.277 g, 11.56 mmol) was added and stirred at rt overnight. The reaction mixture was acidified with 1N HCl, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated to obtain the desired product (4.07 g, 100%) as a transparent oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:12]2[N:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)C=Cc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reaction time: 24 h
Yield: 59.3 %

Procedure:
Methyl 3-[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]acrylate (160 mg, 0.34 mmol) was dissolved in ethanol (15 ml). To the resulting solution was added palladium carbon (30 mg). The resulting mixture was vigorously stirred under a hydrogen atmosphere of 1 atmospheric pressure for 24 hours. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (94 mg, 58%) as needle crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([CH3:19])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH:32]=[CH2:33])[CH2:27][CH2:26]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(#N)C>[CH3:19][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([C:6]1[CH:7]=[C:2]([CH2:33][CH2:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[O:34])[CH:3]=[CH:4][C:5]=1[O:20][CH2:21][CH2:22][CH3:23])[NH:17][C:16]2=[O:18]
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Reactant: C=CC(=O)N1CCN(C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccc(CCC(=O)N2CCN(C)CC2)cc1-c1nc2c(C)cccc2c(=O)[nH]1

Procedure:
A stirred mixture of 2-(5-bromo-2-n-propoxyphenyl)-8-methylquinazolin-4(3H)-one (Preparation 11; 0.5 g, 0.0013 mol), 1-methyl-4-propenoylpiperazine (Makromol. Chem., 1984, 185, 1525; 0.24 g, 0.0015 mol), palladium diacetate (0.175 g, 0.00077 mol), tri-o-tolylphosphine (0.30 g, 0.001 mol), triethylamine (1 ml) and acetonitrile (25 ml) was heated under reflux under a nitrogen atmosphere for 4 days. The cool mixture was filtered and the filtrate evaporated to dryness under vacuum. The residue was suspended in saturated aqueous sodium carbonate solution (25 ml), the resulting solution extracted with dichloromethane (50 ml) and the organic extract washed with brine (2×30 ml), dried (Na2SO4) and evaporated under vacuum. Chromatography of the residue on silica gel (10 g), using a methanol in dichloromethane elution gradient (0-4%), gave the title compound which crystallized from hexane-ethyl acetate as a pale pink solid (0.072 g, 12%), m.p. 184°-185° C. Found: C,89.96; H,6.64; N,12.49. C26H30N4O3 requires C,69.93; N,6.77; N,12.55%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[Br:14][C:15]1[CH:16]=[C:17]([F:34])[C:18]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=2)=[C:19]([CH:24]=1)[C:20]([NH:22][CH3:23])=[O:21]>>[Br:14][C:15]1[CH:16]=[C:17]([F:34])[C:18]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=4[CH:13]=3)[N:27]=2)=[C:19]([CH:24]=1)[C:20]([NH:22][CH3:23])=[O:21]
Reactant: CNC(=O)c1cc(Br)cc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Product: CNC(=O)c1cc(Br)cc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
5-Bromo-2-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from 8-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 5-bromo-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as a gray solid (61 mg, 38%). m.p.=274-278° C.; LCMS (m/e) 533 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.46 (bs, 1H), 9.43 (s, 1H), 9.38 (s, 1H), 8.66-8.57 (m, 1H), 8.21 (s, 1H), 7.79 (d, 1H, J=9.6 Hz), 7.68 (s, 1H), 7.19 (d, 1H, J=8.1 Hz), 7.08 (bs, 1H), 6.97 (d, 1H, J=8.2 Hz), 2.71 (d, 3H, J=4.3 Hz), 2.58 (t, 2H, J=6.4 Hz), 2.18-2.00 (m, 4H); 19F-NMR (d6-DMSO, 400 MHz) δ −111.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].O.O.[F-].[K+].[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:8][C:7]1[NH:6][C:5](=[O:9])[NH:4][C:3](=[O:10])[C:2]=1[N:25]1[CH2:26][CH2:27][N:22]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:23][CH2:24]1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1Br
Agent: [F-]
Agent: [K+]
Solvent: O
Product: Cc1[nH]c(=O)[nH]c(=O)c1N1CCN(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
A mixture of 20.5 g (0.10 mole) of 5-bromo-6-methyl-2,4(1H,3H)pyrimidinedione and 10.3 g (0.11 mole) of potassium fluoride dihydrate in 130 ml of 1-benzylpiperazine was heated under reflux for 72 hours. The reaction mixture was then cooled and poured into 800 ml of ice water. The solid which formed was collected and washed with water to give 8.10 g of the product as an off-white solid. A 1.0 g portion of the crude product was recrystallized from methanol to give an off-white solid, mp 263° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[C:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:28]4[CH:29]=[CH:30][C:25]([C:22](=[O:24])[CH3:23])=[CH:26][CH:27]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4ccc(C(C)=O)cc4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 4-acetylphenylboronic acid (139 mg, 0.85 mmol) the subtitle compound was obtained (119 mg, 36%). 1H NMR (DMSO) δ 8.64(d, 1H), 8.46(dd, 1H), 8.16(d, 1H), 8.06(d, 2H), 7.93–7.90(m, 3H), 7.81(dd, 1H), 7.63(d, 1H), 4.05(s, 3H), 2.63(s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]3[N:35]=[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]4[CH:42]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]3[N:35]=[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]4[CH:42]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [N+](C1C=NNC=1N1CC=C(O[Si](C)(C)C)CC1)([O-])=O.[CH3:20][O:21][CH:22]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25][N:24]([C:36]2[N:40]([CH3:41])[N:39]=[CH:38][C:37]=2[N+:42]([O-])=O)[CH2:23]1>CO.[Pd]>[NH2:42][C:37]1[CH:38]=[N:39][N:40]([CH3:41])[C:36]=1[N:24]1[CH2:23][CH:22]([O:21][CH3:20])[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:26][CH2:25]1
Reactant: COC1CN(C(=O)OC(C)(C)C)CCN(c2c([N+](=O)[O-])cnn2C)C1
Agent: [Pd]
Agent: C[Si](C)(C)OC1=CCN(c2[nH]ncc2[N+](=O)[O-])CC1
Solvent: CO
Product: COC1CN(C(=O)OC(C)(C)C)CCN(c2c(N)cnn2C)C1
Yield: 96 %

Procedure:
A solution of Intermediate 47, tert-butyl 6-methoxy-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (114 mg, 0.32 mmol) in MeOH (15 mL) was passed through the H-Cube® (full H2, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-6-methoxy-1,4-diazepane-1-carboxylate as a pink solid (100 mg). To a solution of this solid in DCM (5 mL) was added DIPEA (0.84 mL, 48 mmol), PyBOP (219 mg, 0.42 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (118 mg, 0.33 mmol) and the mixture was stirred at room temperature for 65 hr. The mixture was diluted with DCM (50 mL) and washed with water (10 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave tert-butyl 4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6-methoxy-1,4-diazepane-1-carboxylate as a pink solid (160 mg). This solid (159 mg, 0.24 mmol) was dissolved in HCl in 1,4-dioxane (4 M, 3 mL, 12.0 mmol) and MeOH (3 mL) and heated in a sealed pressure vessel behind a blast shield at 60° C. for 16 hr. The solvents were removed under reduced pressure and the crude residue re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 0-10% 7 N ammonia in MeOH/DCM to give 194 as a pale brown solid (53 mg, 36% over three steps). 1H NMR (400 MHz, CDCl3) δ 11.35 (s, 1H), 8.13 (s, 1H), 7.39-7.29 (m, 1H), 7.04 (t, J=8.6 Hz, 2H), 6.33 (s, 2H), 3.74 (s, 3H), 3.41-3.28 (m, 4H), 3.36-3.00 (m, 6H), 2.88-2.77 (m, 1H), 2.69 (dd, J=12.7, 7.6 Hz, 1H). Alkyl NH not observed. LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=O)C.[C:16](#[N:20])[CH2:17][C:18]#[N:19]>>[NH2:19][C:18]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:6]=2[C:7](=[O:8])[C:17]=1[C:16]#[N:20]
Reactant: COc1ccc(OC(C)=O)c(C(=O)Cl)c1
Reactant: N#CCC#N
Product: COc1ccc2oc(N)c(C#N)c(=O)c2c1

Procedure:
In the same way as described in Example 3, 2-acetoxy-5-methoxy benzoyl-chloride and malononitrile are reacted to give crystals, mp 320°C after recrystallization from methanol.