Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:24]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:24])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccccc3)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccccc3)c12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 5-allyl-7-methoxy-4-phenylamino-quinazolin-6-ol (0.16 g, 0.524 mmol) (from Example 15, Step D, supra) in acetone (30 mL) was added K2CO3 (0.36 g, 2.62 mmol) and methyl iodide (0.15 g, 1.05 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:5:0.05) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-phenyl-amine as a pale yellow solid. (Yield 0.13 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:27]1([CH2:37]Cl)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH2:37][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: ClCc1cccc2ccccc12
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(F)cc2)O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OC(c2ccc(F)cc2)C(Cc2ccc(C(F)(F)F)cc2)N1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (1 g, 2.95 mmol) in N,N-dimethylformamide (10 ml) was added 60% sodium hydride (142 mg, 3.54 mmol) and the mixture was stirred at room temperature for 15 min. To the reaction solution was added 1-naphthylmethyl chloride (480 ml, 3.25 mmol) and the mixture was stirred for 1 hr. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from diisopropyl ether-hexane gave (4RS,5SR)-5-(4-fluorophenyl)-3-(1-naphthalenylmethyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (1.23 g, 87%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1.[Br:18]Br>C(Cl)Cl>[CH3:5][C:6]1([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([Br:18])=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1
Reactant: BrBr
Reactant: CC1(C)CCC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(=O)c2cc(Br)ccc21
Temperature: 25 °C
Yield: 80 %

Procedure:
A 100 ml three-necked flask, fitted with an efficient reflux condenser and drying tube, and addition funnel, was charged with a mixture of AlCl3 9.5g (71.4 mmol) and 3 ml of CH2Cl2. The 3,4-dihydro-4,4-dimethyl-1(2H)naphthalenone (5.0 g, 28.7 mmol), was added dropwise with stirring (Caution:Exothermic Reaction|) to the mixture at room temperature. Bromine, 5.5 g (34.5 mmol), was then added very slowly, and the resulting mixture stirred for 2 hours at room temperature. (Note: if stirring stops, the mixture can be warmed to 70° C. until stirring resumes.) The reaction was then quenched by the slow addition of ice-cold 6M HCl. The mixture was extracted with Et2O and the combined organic layers washed with water, saturated aqueous NaHCO3, and saturated NaCl, before being dried over MgSO4. Removal of the solvent under reduced pressure, and distillation of the residue afforded 5.8 g (80%) of the product as a pale-yellow oil which solidified on standing, bp: 140° C./0.4 mm Hg. 1H NMR (CDCl3): δ 8.11 (1H, d, J=3.0 Hz), 7.61 (1H, dd, J=3.0, 9.0 Hz), 7.31 (1H, d, J=9.0 Hz), 2.72 (2H, t, J=6.0 Hz), 2.01 (2H, t, J=6.0 Hz), 1.28 (6H, s).
Reaction SMILES: [OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8](O)=[O:9].[C:37]([O:40][C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42])(=O)[CH3:38]>>[OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8]([N:46]1[CH2:45][CH2:44][N:43]([C:41]([O:40][CH2:37][CH3:38])=[O:42])[CH2:48][CH2:47]1)=[O:9]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)O)cc2OCC(O)CO)c1
Reactant: CC(=O)OC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(C(=O)c2cc(NS(=O)(=O)c3ccc(SC)cc3)c(Oc3cccc(OC)c3)c(OCC(O)CO)c2)CC1

Procedure:
In analogy to Example 121, by coupling 3-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-benzoic acid with 1-acetoxycarbonylpiperazine there was obtained ethyl 4-[3-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanylbenzenesulphonylamino)-benzoyl]-piperazine-1-carboxylate as a white foam.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:24]([O:29][CH3:30])(=[O:28])[C:25]([CH3:27])=[CH2:26].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:30][O:29][C:24](=[O:28])/[C:25](/[CH3:27])=[CH:26]/[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)[CH:11]=[C:12]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=1)[N:13]=3
Reactant: C=C(C)C(=O)OC
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C(C)=C/c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Temperature: 130 °C
Yield: 57.5 %

Procedure:
8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 (300 mg, 0.80 mmol), methyl methacrylate (129 μL, 1.20 mmol), triethylamine (168 μL, 1.20 mmol), tri-o-tolyl-phosphane (49 mg, 0.16 mmol) and palladium (II) acetate (9 mg, 0.04 mmol) were suspended in DMF (5 mL) and the reaction mixture degassed by bubbling argon through the suspension. The reaction mixture was heated at 130° C. for 16 h, before cooling to RT and diluting the mixture with ethyl acetate (10 mL). The reaction mixture was washed with water, extracted with ethyl acetate (2×10 mL) and the combined organic extracts washed with brine, dried (MgSO4) then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-5% methanol in DCM) to yield (E)-3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-2-methyl-acrylic acid methyl ester as a white solid (181 mg, 57%) LCMS: RT=3.63 min, [M+H]+=394.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.N[CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=O>P(Cl)(Cl)(Cl)=O>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[O:8][C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:19][CH2:20][C:11]=3[N:9]=2)=[CH:3][CH:4]=1
Reactant: NC1CCc2ccccc2C1=O
Reactant: NC(=O)c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)CCc1nc(-c3ccncc3)oc1-2
Yield: 72 %

Procedure:
The isonicotinamide of 2-amino-1-tetralone (1.14 g, 0.00429 mole) was placed in 12 ml of phosphorus oxychloride (phosphoryl chloride) and refluxed for 19 hours. The amide dissolved during this period of time. The excess reagent was removed under vacuum. The residue was treated with 12 ml of ethanol and 5 ml of water. The mixture was made basic with 10% KOH. On cooling, the product precipitated and was filtered to give 0.77 g (72% yield) of the oxazole, mp 129°-130° C. 1H NMR(δ, CDCl3): 3.10, 4H, A2B2 ; 7.3-7.9, 4H, m; 8.93, 4H, A2B2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:25])[CH2:12][CH2:13]OS(C2C=CC(F)=CC=2)(=O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:12][CH2:13][N:37]2[CH2:36][CH2:35][N:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH3:26])[CH2:39][CH2:38]2)[CH3:25])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CN(CCOS(=O)(=O)c1ccc(F)cc1)S(=O)(=O)c1ccc(F)cc1
Product: COc1ccccc1N1CCN(CCN(C)S(=O)(=O)c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared using the procedure described in Example 1 using 4-fluorobenzenesulfonic acid 2-((4-fluorobenzenesulfonyl)-methyl-amino)-ethyl ester (D2) and 4-(2-methoxyphenyl)-piperazine. MH+ 408.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:20])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]1=2.[C:21](Cl)(=[O:23])[CH3:22]>>[C:21]([C:18]1[CH:17]=[CH:16][C:8]2[O:9][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:6]([CH3:20])([CH3:5])[C:7]=2[CH:19]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CC1(C)c2ccccc2Oc2ncccc21
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1ccc2c(c1)C(C)(C)c1cccnc1O2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66.7 %

Procedure:
9.5 g of powdered aluminum chloride is added in small portions to a mixture of 5 g of 5,5-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine and 5.6 g of acetyl chloride, keeping the temperature at 20°-30°C. The mixture is allowed to stand at 80°C for 1.5 hours, and then poured into ice water. The mixture is extracted with benzene, and the extract is washed with water. The benzene is distilled off, and the crystalline residue is recrystallized from isopropyl ether containing a small amount of carbon tetrachloride to give 4 g of 7-acetyl-5,5-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine melting at 106°-108°C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[N:18]1([C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)=[CH:25][CH:26]=2)[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(N2CCNCC2)ccc1N1CCNCC1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution in methylene chloride (1 ml) of 1,4-bis(4-tert-butoxycarbonyl-1-piperazinyl)benzene (59 mg; 0.13 mmol) synthesized by the above process under ice cooling, and the mixture was stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure, and the resultant concentrated residue (81 mg) was dissolved in methanol-chloroform (1:2). The solution was applied to a column packed with alumina (3 g), and the column was eluted with methanol-chloroform (1:2). The eluate was concentrated under reduced pressure, thereby obtaining 31 mg (yield: 88%) of the title compound as a colorless oil.
Reaction SMILES: [NH3:1].[CH2:2]([NH:9][C@H:10]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17]C)=O)[CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH2:2]([NH:9][C@H:10]1[CH2:14][CH2:13][C@@H:12]([C:15]([NH2:1])=[O:17])[CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: COC(=O)[C@@H]1CC[C@H](NCc2ccccc2)C1
Solvent: CO
Product: NC(=O)[C@@H]1CC[C@H](NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ammonia gas was passed into a solution of (1R,3S)-methyl 3-(benzylamino)cyclopentanecarboxylate (250 mg, 1.14 mmol) in MeOH (5 ml) at −78° C. in a steel bomb. The reaction mixture was slowly warmed to room temperature, heated further to 100° C. and stirred for 24 h. The reaction mixture was concentrated and dried under vacuum to afford 250 mg of (1R,3S)-3-(benzylamino)cyclopentanecarboxamide with 50% purity as brown liquid which was proceeded as crude compound for the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:28]=[CH:27][C:15]2[CH2:16][CH:17]([CH2:22][C:23]([O:25]C)=[O:24])[C:18](=[O:21])[NH:19][CH2:20][C:14]=2[CH:13]=1.Cl.O1CCOCC1.[H][H]>[Pd].CO>[NH:3]1[CH2:4][CH2:5][CH2:6][N:1]=[C:2]1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:28]=[CH:27][C:15]2[CH2:16][CH:17]([CH2:22][C:23]([OH:25])=[O:24])[C:18](=[O:21])[NH:19][CH2:20][C:14]=2[CH:13]=1
Reactant: [H][H]
Reactant: COC(=O)CC1Cc2ccc(OCCCNc3ncccn3)cc2CNC1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)CC1Cc2ccc(OCCCNC3=NCCCN3)cc2CNC1=O
Reaction time: 18 h

Procedure:
A mixture of methyl (±)-8-[3-(pyrimidin-2-ylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.36 g, 0.94 mmol), 4 M HCl in dioxane (0.25 mL, 1 mmol), 10% palladium on charcoal (0.24 g, 0.24 mmol), and MeOH (5 mL) was stirred under a balloon of hydrogen. After 18 hr, the mixture was filtered and the filtrate was concentrated. The residue was partitioned between EtOAc and aqueous K2CO3. A solid precipitated, which was collected by filtration and dried to give the title compound as a white solid: MS m/e 375.4 (M+H)+. Anal. Calcd for C19H26N4O4.2.5 H2O: C, 54.40; H, 7.45; N, 13.35. Found: C, 54.68; H, 7.12; N, 13.39.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:20])([S:17][S:18][CH3:19])[CH3:16])(=O)=O)=CC=1.O[C:22]1[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:25]=[C:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:20][C:15]([S:17][S:18][CH3:19])([CH3:16])[CH2:14][CH2:13][CH2:12][O:11][C:22]1[CH:23]=[C:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:27]=1
Reactant: CSSC(C)(C)CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCCCC(C)(C)SSC)cc(C(=O)OCC)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 52.1 %

Procedure:
To a stirred solution of 4-methyl-4-(methyldisulfanyl)pentyl 4-methylbenzenesulfonate (5c) (0.48 g, 1.435 mmol) and diethyl 4-hydroxypyridine-2,6-dicarboxylate (5a)(0.343 g, 1.435 mmol) in anhydrous dimethylformamide (6.5 mL) was added Potassium carbonate (0.297 g, 2.152 mmol). The reaction was stirred at 90° C. for 18 hours. Then allowed to cool to ambient temperature and quenched with saturated ammonium chloride. The mixture was extracted three times with ethyl acetate. The extracts were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (30% hexanes/ethyl acetate) yielded diethyl 4-(4-methyl-4-(methyldisulfanyl)pentyloxy)pyridine-2,6-dicarboxylate (5d)(300 mg, 52%); 1H NMR (400 Hz, CDCl3): δ 7.70 (s, 2H), 4.40 (q, 4H, J=7.2, 14.4 Hz), 4.07 (t, 2H, J=6. Hz), 2.35 (s, 3H), 1.86 (m, 2H), 1.70 (m, 2H), 1.38 (t, 6H, J=7.2 Hz), 1.27 (s, 6H); MS (m/z). found 424.1 (M+Na), 440.1 (M+K). See FIG. 5.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH:17]([CH2:26][C:27]([O-:29])=O)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:6][O:7][C:8]=2[CH:9]2[CH2:12][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10]2)[CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[NH2:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[Cl:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[NH:38][C:27]([CH2:26][CH:17]([C:5]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:8]([CH:9]2[CH2:10][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:12]2)[O:7][N:6]=1)[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:29]
Reactant: Cc1ccc(N)c(Cl)c1
Reactant: CC(C)CC1CC(c2onc(C(CC(=O)[O-])CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)CC(CC(=O)OC(C)(C)C)c2noc(C3CC(CC(C)C)C3)c2C2CC2)c(Cl)c1
Yield: 52.3 %

Procedure:
Mono-tert-butyl 3-[4-cyclopropyl-5-(3-isobutylcyclobutyl)isoxazol-3-yl]glutarate (245 mg) and DMF (2 mL) were mixed. After an addition of 2-chloro-4-methylphenylamine (67 mg), HOBt.H2O (87 mg) and WSC.HCl (108 mg) to the mixture, the reaction mixture was stirred at RT. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: ethyl acetate/hexane=1/4) to give the title compound (131 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:42])[NH2:41])=[CH:36][C:35]=1[C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=O)=O>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:34]2[CH:39]=[CH:38][C:37]([C:40](=[NH:41])[NH2:42])=[CH:36][C:35]=2[C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(=O)Oc2ccc(C(=N)N)cc2C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
To a solution of 1.79 g of 4-acetylaminobenzoic acid in 50 ml of dried pyridine, was added 3.1 g of DCC. The mixture was stirred for 30 minutes while being cooled in ice. After addition of 3.36 g of 4-amidino-2-benzoylphenol methanesulfonate, the mixture was further stirred overnight. The reaction mixture was removed of the insolubles and mixed with ethyl ether to obtain a colorless solid substance which on recrystallization from methanol yielded 0.9 g of colorless crystals of 4-amidino-2-benzoylphenyl 4-acetylaminobenzoate methanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=3)[C:4]=2[N:5]=[C:6](Cl)[N:7]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[CH3:24]>>[NH2:1][C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=3)[C:4]=2[N:5]=[C:6]([NH:37][C:34]2[CH:35]=[N:36][C:31]([N:28]3[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]3)=[CH:32][CH:33]=2)[N:7]=1
Reactant: CS(=O)(=O)Nc1cccc(-c2csc3c(N)nc(Cl)nc23)c1
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Product: CCN1CCN(c2ccc(Nc3nc(N)c4scc(-c5cccc(NS(C)(=O)=O)c5)c4n3)cn2)CC1
Yield: 74.9 %

Procedure:
The target compound of Example 27 (22 mg, 74% yield) was prepared in the same manner as Step 9 of Example 1 using N-(3-(4-amino-2-chlorothieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide (20 mg, 0.056 mmol) and 6-(4-ethylpiperazin-1-yl)pyridin-3-amine (31 mg, 0.17 mmol).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][OH:12])[CH:7]=[C:8]([F:10])[CH:9]=1.CI.N[C@H:16](C(O)=O)CCSC>CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][O:12][CH3:16])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: OCc1cc(F)cc(Br)c1
Reactant: CSCC[C@H](N)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 231.1 %

Procedure:
NaH (60% dispersion in mineral oil, 245 mg, 6.12 mmol) was added to a solution of (3-bromo-5-fluorophenyl)methanol (1.195 g, 5.83 mmol) in 2-Me THF (20 mL). After gas evolution had ceased, MeI (0.455 mL, 7.29 mmol) was added and the resulting mixture was stirred at r.t. for 16 h. Another portion of NaH (50 mg, 2.1 mmol) and Met (0.10 mL, 1.6 mmol) were added and the mixture was heated to 60° C. for 2 h. The cooled mixture was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (gradient of 0-15% EtOAc in heptane) to give 0.810 g (63% yield) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.30 (s, 3H), 4.38-4.46 (m, 2H), 7.18 (m, 1H), 7.37 (s, 1H), 7.44-7.50 (m, 1H); MS (EI) m/z 218 M′.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=1)=[O:5].C(N(CC)CC)C.Cl.OC(C)(C)CN1C=CC(NC(=O)[C@@H](N2[CH2:51][C:50]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([Cl:59])[C:54]=3[Cl:60])=[CH:49][C:48]2=[O:61])CC(C)C)=N1>CO>[Cl:60][C:54]1[C:55]([Cl:59])=[CH:56][CH:57]=[CH:58][C:53]=1[O:52][C:50]1[CH2:51][N:2]([C@@H:3]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]([NH:6][C:7]2[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[N:8]=2)=[O:5])[C:48](=[O:61])[CH:49]=1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@@H](N)CC2CCCCO2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCO2)N2CC(Oc3cccc(Cl)c3Cl)=CC2=O)n1
Yield: 3.7 %

Procedure:
(S)-2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydropyran-2-yl)-propionamide hydrochloride (118 mg, 0.30 mmol) was dissolved in methanol (2 mL) and triethylamine (0.2 mL) was added. The mixture was evaporated to dryness. The residue was dissolved in acetonitrile (5 mL). To this solution was added (E)-4-bromo-3-(2,3-dichloro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 77, 109 mg, 0.30 mmol). The mixture was refluxed for 40 h. The mixture was evaporated and the residue was treated with ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate and concentrated to give a crude product (180 mg). One part of the crude product (30 mg) was purified through reverse phase preparative HPLC (acetonitrile in water, 25% to 100% linear gradient) to afford (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-2-yl)-propionamide as a white powder (6 mg): LR-ES-MS m/z calculated for C25H30Cl2N4O5 [M]+ 536, observed [M+H]+ 537; 1H-NMR (CDCl3) δ ppm 1.16 (s, 6H), 1.25-1.73 (m, 5H), 1.73-2.00 (m, 2H), 2.17-2.34 (m, 1H), 3.29-3.49 (m, 2H), 3.88-4.06 (m, 3H), 4.24 (d, J=17.8 Hz, 1H), 4.42 (d, J=17.8 Hz, 1H), 4.89 (s, 1H), 5.02-5.16 (m, 1H), 6.70 (br s, 1H), 7.14-7.23 (m, 1H), 7.28-7.37 (m, 3H), 7.42 (d, J=8.2 Hz, 1H), 8.76 (br s, 1H).