Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1)[CH3:2].[C:33](Cl)(=[O:35])[CH3:34]>>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[C:10]([NH:11][C:33](=[O:35])[CH3:34])=[CH:9][CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc(C2=C(c3cc(C)ccc3OCc3ccccc3)CCC2)ccc1N
Product: CCOC(=O)c1cc(C2=C(c3cc(C)ccc3OCc3ccccc3)CCC2)ccc1NC(C)=O

Procedure:
Prepared by general procedure E but using 3-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic acid ethyl ester and acetyl chloride.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:14][CH2:13]2)/[C:7](=[N:15]/C(=O)C(F)(F)F)/[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:13][CH2:14]2)[C:7](=[NH:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)C(F)(F)F)n1CC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(C(C)(C)C)cc(=N)n1CC1CC1
Yield: 87.3 %

Procedure:
A mixture of Example 27E (6.37 g, 21 mmol) and 6N NaOH aqueous (20 mL) in MeOH (100 mL) was stirred at 50° C. overnight, and then concentrated under reduced pressure. The residue was extracted by CH2Cl2 (30 mL×3) and the combined organic layers were washed with brine and concentrated to yield 3.8 g (87%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.37-0.44 (m, 2H), 0.47-0.54 (m, 2H), 1.07-1.20 (m, 1H), 1.29-1.36 (m, 9H), 3.78 (s, 3H), 4.10 (d, J=6.74 Hz, 2H), 5.60 (s, 1H), 7.19 (s, 1H); MS (+DCI) m/z 208 [M+H]−.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][O:16]S(C)(=O)=O)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:13][N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)OCc1ccc(Oc2ccc([N+](=O)[O-])cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(COc3ccc(C(F)(F)F)cc3)cn2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Methanesulfonic acid 6-(4-nitrophenoxy)-pyridin-3-ylmethyl ester (4.86 g, 15 mmol) was dissolved in DMF (250 mL), and to the resulting solution were added 4-hydroxybenzotrifluoride (2.92 g, 18 mmol) and potassium carbonate (3.11 g, 22.5 mmol). The resulting solution was stirred under a nitrogen atmosphere for 1 hour at 50° C. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane methanol=80:1), to thereby yield 5.8 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=3)=[N:13][CH:12]=[CH:11][N+:10]=2[O-])[CH:5]=[C:6]([CH3:8])[CH:7]=1.P(Cl)(Cl)([Cl:26])=O>O>[Cl:26][C:12]1[N:13]=[C:14]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)[C:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[N:10][CH:11]=1
Reactant: Cc1cc(C)cc(-c2ncc[n+]([O-])c2-c2cc(C)cc(C)c2)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(C)cc(-c2ncc(Cl)nc2-c2cc(C)cc(C)c2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Then, 7.0 g of 2,3-bis(3,5-dimethylphenyl)pyrazin-1-oxide obtained in Step 2 was put into a 100 mL three-neck flask and the air in the flask was replaced with nitrogen. Here, 20 mL of phosphoryl chloride was added and the mixture was stirred at 100° C. for 1 hour. The reacted solution was poured into water and the solution was subjected to extraction with chloroform. The obtained organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated brine, and dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, whereby the pyrazine derivative to be produced was obtained as a gray powder in a yield of 90%. A synthesis scheme of Step 3 is shown in (h-3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([CH:21]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.Cl.O1CCOCC1>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:21]=[C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5]([CH3:22])=[C:4]([CH:3]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cc(Cl)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)cc(OC2CCNCC2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 147.8 %

Procedure:
A solution of tert-butyl 4-(5-chloro-3-(methoxycarbonyl)-2-methylphenoxy)piperidine-1-carboxylate (300 mg, 0.782 mmol) in DCM (3 mL) was treated with 4 M HCl/dioxane (3908 μl, 15.63 mmol) and stirred for 1 h at RT. The slurry was filtered and dried to give methyl 5-chloro-2-methyl-3-(piperidin-4-yloxy)benzoate, hydrochloride (0.185 g, 0.578 mmol, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.76-1.94 (m, 2 H) 2.02-2.16 (m, 2 H) 2.30 (s, 3 H) 2.99-3.13 (m, 2 H) 3.16-3.26 (m, 2 H) 3.83 (s, 3 H) 4.78 (dt, J=6.95, 3.60 Hz, 1 H) 7.34 (d, J=2.02 Hz, 1 H) 7.40 (d, J=2.02 Hz, 1 H) 8.83 (br. s., 2 H). MS(ES) [M+H]+ 284.1.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7](Br)[C:6]([C:10]#[N:11])=[N:5]1)[CH:2]=[CH2:3].[Li]CCCC.[F:17][C:18]([F:38])([F:37])[C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[N:25]=[CH:24]2)=[O:20]>CCOCC.C1COCC1>[CH2:1]([N:4]1[CH:8]=[C:7]([C:19]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:25]=[CH:24]3)([OH:20])[C:18]([F:37])([F:17])[F:38])[C:6]([C:10]#[N:11])=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(Br)c(C#N)n1
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c(C#N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
To a chilled (−78° C.) solution of 1-allyl-4-bromo-1H-pyrazole-3-carbonitrile (116.6 mg, 0.550 mmol) in dry ether (2 mL) was added n-BuLi (190 pt, 2.5 M in hexanes, 0.475 mmol). After 2 minutes a chilled (−78° C.) solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (154 mg, 0.500 mmol) in THF (2 mL) was added. After 15 minutes, the mixture was warmed to room temperature, quenched with 10 mL of saturated aqueous sodium bicarbonate and extracted with three 10 mL portions of ethyl ether. The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography on SiO2 (0-50% ethyl acetate in hexanes, gradient) to give 152 mg (69%) of the title compound. MS m/z 422.96 (MH+).
Reaction SMILES: C(C(CCCC)CO[C:6](=O)[CH2:7][CH2:8][S:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]1[CH:20]=[CH:21][N:22]=[C:15]1[CH:14]=[CH:13]2)C.FC1[N:34]=[C:33]([C:35]2([C:41]#[N:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=CC=1>CN(C=O)C>[CH:20]1[N:16]2[C:17]3[C:12]([CH:13]=[CH:14][C:15]2=[N:22][CH:21]=1)=[CH:11][C:10]([S:9][C:8]1[N:34]=[C:33]([C:35]2([C:41]#[N:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=[CH:6][CH:7]=1)=[CH:19][CH:18]=3
Reactant: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3nccn32)c1
Reactant: N#CC1(c2cccc(F)n2)CCOCC1
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(Sc3ccc4c(ccc5nccn54)c3)n2)CCOCC1
Temperature: 90 °C

Procedure:
1i (261 mg, 0.6 mmol) and 4-(6-Fluoro-pyridin-2-yl)-tetrahydro-pyran-4-carbonitrile (1j, 123 mg, 0.6 mmol) were dissolved in DMF and degassed with N2 for 10 minutes. Potassium tert-butoxide (81 mg, 0.72 μmmol) was added, and the mixture was degassed with N2 for an additional 10 minutes. The reaction was heated to 90° C. for 24 hours, then cooled to room temperature. The solution was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to obtain the desired product, 1k.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].O>CN(C=O)C>[O:1]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: Oc1cccc2ncccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ncccc12
Temperature: 25 °C
Yield: 109.1 %

Procedure:
5-hydroxyquinoline (101 mg) was dissolved in DMF (5 ml) under an argon atmosphere, and the resultant solution was stirred at room temperature. Imidazole (113 mg) and t-butyldimethylsilyl chloride (162 mg) were added to the solution, and the mixture was stirred at room temperature. After disappearance of the raw materials was confirmed, water (5 ml) was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The resultant residue was purified by column chromatography (silica gel:hexane/ethyl acetate=9/1) to obtain the object compound (197 mg, yield 100%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[H-].[Na+].[CH3:25][S-:26].[Na+]>CN(C)C=O>[CH3:25][S:26][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]
Reactant: C[S-]
Reactant: O=C(O)C(CC1CCCCO1)c1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C(CC2CCCCO2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
A solution of 2-(4-fluoro-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (5.20 g, 16.24 mmol) in dry N,N-dimethylformamide (90 mL) at 25° C. under argon was carefully treated with 95% sodium hydride (410 mg, 17.05 mmol). The reaction mixture was stirred at 25° C. for 30 min and then was treated with sodium thiomethoxide (2.40 g, 32.48 mmol). This mixture was heated at 100° C. for 4.5 h and then concentrated in vacuo to remove N,N-dimethylformamide. The residue was diluted with water (100 mL) and then was acidified to pH=2 using a 1N aqueous hydrochloric acid solution. The resulting aqueous layer was extracted with ethyl acetate (2×600 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 98/2 chloroform/methanol to 9/1 chloroform/methanol) afforded 2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (5.70 g, 100%) as a yellow gum: EI-HRMS m/e calcd for C16H19F3O3S (M+Na)+ 371.0899, found 371.0902.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[CH3:13][O:14][CH2:15]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: COCOC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COCOc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Yield: 95 %

Procedure:
To 1.12 g (5.9 mmol) of 2-chloro-4-fluoro-5-nitrophenol in 100 ml CH2Cl2 was added 2 ml of dimethoxymethane followed by 7.48 g (53 mmol) of phosphorus pentoxide. The reaction was stirred at room temperature for 3 hours after which time an additional 100 ml of CH2Cl2 was added. The reaction was poured onto 200 ml ice and the resulting layers were separated. The aqueous phase was extracted once more with water (2×100 ml), dried over MgSO4 and concentrated to afford 1.16 g (95% yield) of the desired product as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26](C(OC(C)(C)C)=O)[N:25]=1.C(O)(=O)C>CC(N(C)C)=O>[F:21][C:13]([F:22])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:4]1[N:3]=[C:2]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(F)c3n2)nc1
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(F)cccc23)n[nH]1
Temperature: 100 °C
Yield: 4 %

Procedure:
To 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoroquinazoline (295 mg, 0.90 mmol) in DMA (2.2 mL) were added tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate and acetic acid (0.12 mL), and the mixture was heated at 100° C. for 6.5 h. The mixture was allowed to cool to rt and was purified by preparative reverse-phase HPLC using an ammonium acetate modifier. A later eluting fraction was treated with saturated aq NaHCO3 and concentrated under reduced pressure. The aqueous residue was extracted with DCM (3×30 mL) and the combined extracts were washed with saturated aq NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM, whereupon a precipitate formed, which was collected by filtration to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as a colorless solid (13 mg, 4%). 1H NMR (300 MHz, DMSO-d6) δ 12.23 (br s, 1H), 10.86 (br s, 1H), 8.67 (s, 1H), 8.52 (d, J=9 Hz, 1H), 8.00-8.02 (m, 2H), 7.77 (m, 1H), 7.63 (m, 1H), 5.97 (s, 1H), 2.17 (s, 3H). LCMS (ESI) m/z 389 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6].[N:23]([O-])=[O:24].[Na+].CO.C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Yield: 27.3 %

Procedure:
5.4 g of 1-(2-chloroethyl)-3-n-butyl-3-D-mannopyranosylurea are dissolved in 20 ml of formic acid, and 3.5 g of sodium nitrite are added gradually thereto for 2 hours under ice-cooling and stirring. 40 ml of methanol and 30 g of potassium carbonate anhydrate are added to said mixture. Then, said mixture is further stirred for 10 minutes under ice-cooling. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.6 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-mannopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]([NH:23][CH:24]([C:30](=O)[CH3:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:22])[NH:13]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C.O1CCOCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:30]([CH3:31])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:23][C:21]=1[OH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(NC(=O)[C@H](CCCOCc1ccccc1)NC(=O)OC(C)(C)C)C(C)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1nc(O)c(CCCOCc2ccccc2)nc1C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-{[5-(benzyloxy)-N-(tert-butoxycarbonyl)-L-norvalyl]amino}-3-oxobutanoate (5.31 g, 11.8 mmol) in ethanol (20 mL) was added 4N hydrochloric acid in 1,4-dioxane (20 mL) at room temperature. After being stirred for 16 h at same temperature, the reaction mixture was concentrated in vacuo. A solution of the residue in pyridine (40 mL) was heated at 60° C. for 23 h. After being cooled to ambient temperature, the mixture was concentrated in vacuo. The residue was poured into water, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. To a solution of the residue in dichloromethane (20 mL) was added manganes dioxide (1.03 g) at room temperature. After being stirred for 1.5 h at same temperature, the reaction mixture was filtrated through celite with chloroform. The filtrate was combined and concentrated in vacuo. The crude was purified by silica gel column chromatography (chloroform to chloroform:methanol=19:1) to give ethyl 5-[3-(benzyloxy)propyl]-6-hydroxy-3-methylpyrazine-2-carboxylate. MS (APCI): m/z 331 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)=CCN1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To 0.75 g (3.75 mmol) Piperidin-4-yl-carbamic acid tert-butyl ester and 0.78 g (5.62 mmol) K2CO3 in 5 mL THF was added drop wise 0.65 mL (5.62 mmol) of 1-Bromo-3-methyl-but-2-ene and stirring was continued for 2 h at room temperature. The reaction mixture was filtered, the filtrate was concentrated and the residue purified by column chromatography (silica, EtOAc).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:28])[C:12]=1[NH:13][C:14]1[C:23]2[C:18](=[C:19]([OH:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[O:17][C:16](=[O:27])[CH:15]=1>>[Br:1][CH2:2][CH2:3][CH2:4][O:26][C:19]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[C:23]2[C:18]=1[O:17][C:16](=[O:27])[CH:15]=[C:14]2[NH:13][C:12]1[C:11]([Cl:28])=[CH:10][N:9]=[CH:8][C:7]=1[Cl:6]
Reactant: BrCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCBr

Procedure:
The title compound was prepared from 1,3-dibromopropane and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 8.81 (s, 2H), 7.96 (d, 1H), 7.22 (d, 1H), 4.65 (s, 1H), 4.11 (t, 2H), 3.93 (s, 3H), 3.77 (t, 2H), 2.18 (m, 2H); MS (ESI): 472.7.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH:36]3[CH2:39][CH2:38][CH2:37]3)[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH:36]3[CH2:39][CH2:38][CH2:37]3)[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)CO
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNC4CCC4)c23)ccc1OCc1ccccn1
Product: O=C(CO)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C1CCC1
Yield: 22 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(cyclobutylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 17, preparation of starting materials) to give the title compound in 22% yield; NMR spectrum (DMSO-d6) 1.49-1.65 (m, 2H), 2.08-2.27 (m, 4H), 3.97 (s, 2H), 4.12 (d, 2H), 4.20-4.29 (m, 1H), 4.32-4.43 (m, 3H), 5.31 (s, 2H), 7.21 (d, 1H), 7.26 (d, 1H), 7.33-7.40 (m, 2H), 7.57-7.63 (m, 2H), 7.71-7.76 (m, 1H), 7.86-7.92 (m, 1H), 8.02 (s, 1H), 8.47 (s, 1H), 8.60 (d, 1H), 9.92 (s, 1H); Mass spectrum MH+ 534.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1.Cl[CH2:19][CH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)=[O:23])[CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCSC3)c1ccc(F)cc1
Yield: 67 %

Procedure:
To a solution of (7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole from EXAMPLE 1 (80 mg, 0.32 mmol) in 1,4-dioxane (15 ml) at 25° C. was added 4-chloro-1-(4-fluorophenyl)butan-1-one (96 mg, 0.48 mmol), K2CO3 (100 mg, 0.72 mmol), and KI (32 mg, 0.19 mmol), respectively. The mixture was stirred at ambient temperature for 16 hours before H2O (10 mL) was added and then extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to give the title compound of EXAMPLE 4 as an oil (88 mg, 67%). 1H NMR(CDCl3, 300 MHz): δ 8.01 (m, 2H), 7.15 (m, 2H), 6.96 (d, 1H, J=6.6 Hz), 6.92 (d, 1H, J=6.6 Hz), 3.82 (m, 2H), 3.25 (m, 2H), 3.19-2.60 (m, 8H), 2.42 (m, 2H), 1.95 (m, 5H). LRMS (ES)+: 411 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CS(Cl)(=O)=O.[S:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37].[H-].[Na+]>CCN(CC)CC>[CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:33]3[C:34](=[O:36])[CH2:35][S:31][C:32]3=[O:37])=[CH:22][CH:23]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: O=C1CSC(=O)N1
Reactant: C=C(c1ccc(CO)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C=C(c1ccc(CN2C(=O)CSC2=O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Yield: 38.6 %

Procedure:
Adopting the procedure outlined for example 9 using 40.0 mg (0.12 mmol) of {4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-methanol, 0.05 mL of Methanesulfonyl chloride, 0.10 mL of NEt3, 280 mg of thiazolidine-2,4-dione, and 57 mg of NaH, 20.1 mg of the product was obtained.