Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Br[CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.ClCCl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: BrCCCc1ccccc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCc2ccccc2)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.17 g), 1-bromo-3-phenylpropane (0.08 g) and potassium carbonate (0.15 g) in dry dimethylformamide (10 ml) was stirred at room temperature under nitrogen atmosphere. After 2 hours, additional 1-bromo-3-phenylpropane (0.14 ml) and potassium carbonate (0.15 g) were added, and the mixture was stirred overnight. Water (50 ml) and dichloromethane (50 ml) were added to the mixture. The dichloromethane layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified on a silica gel column (10 g) eluting with a mixture of toluene and ethyl acetate (4:1) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)-4-(3-phenylpropyl)piperazine (0.17 g) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[OH:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]=1[NH:45][C:46](N)=[O:47].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[C:3]([C:33]2[CH:34]=[CH:35][C:30]3[O:29][C:46](=[O:47])[NH:45][C:31]=3[CH:32]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2ccc(O)c(NC(N)=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc4oc(=O)[nH]c4c3)n(-c3ccccc3)c(=O)c12
Yield: 49.1 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (35 mg, 0.07 mmol) was treated with 1-(2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (38 mg, 0.11 mmol), sodium carbonate (2M, 34 μl, 0.07 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (9 mg, 0.01 mmol) according to the method described in Example 3 to give 17 mg (48% yield) of the title compound. Purity 97%.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([CH3:15])[CH2:12]2)=[CH:7][CH:6]=1)([O-])=O.CCOCC>[Pd].C(O)C>[ClH:1].[NH2:2][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([CH3:15])[CH2:12]2)=[CH:7][CH:6]=1
Reactant: CN1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CN1CCc2ccc(N)cc2C1
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A suspension of 3.98 g (17.5 mmol) of 7-nitro-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride and 0.4 g of 10% palladium on carbon in 200 ml of ethanol was hydrogenated at 50 psi for 2 h. The catalyst was filtered and washed with a small amount of water. The filtrate was concentrated yielding an aqueous solution. Absolute ethanol was added and evaporated driving off the excess water until a solid was produced. This solid was dissolved in hot ethanol (60 ml) and ether was added slowly to induce crystallization. The product was collect to give 3.38 g (97%) of the title compound as an off-white solid, m.p. 114°-9° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[CH:20]=[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]3=[CH:17][C:16]=2[C:15]2=[N:26][N:27](C(OC(C)(C)C)=O)[C:28]([CH3:29])=[C:14]2[C:13]1=[O:37])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[CH:20]=[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]3=[CH:17][C:16]=2[C:15]2=[N:26][NH:27][C:28]([CH3:29])=[C:14]2[C:13]1=[O:37]
Reactant: Cc1c2c(=O)n(CCCNC(=O)OC(C)(C)C)c3cc4ccccc4cc3c2nn1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1[nH]nc2c1c(=O)n(CCCN)c1cc3ccccc3cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 5-{3-[(tert-butoxycarbonyl)amino]propyl}-3-methyl-4-oxo-4,5-dihydro-2H-benzo[g]pyrazolo[4,3-c]quinoline-2-carboxylate (1-7) (0.14 g, 0.28 mmol, 1.0 equiv) in CH2Cl2 (6 ml) was added trifluoroacetic acid (3 ml) and the reaction was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure and the residue was dissolved DMSO/NH4HO and purified by reverse phase liquid chromatography (H2O/CH3CN gradient w/0.05% NH4OH present) to yield 5-(3-aminopropyl)-3-methyl-2,5-dihydro-4H-benzo[g]pyrazolo[4,3-c]quinolin-4-one (1-8) as a white solid. 1H NMR (500 MHz, MeOH-d4, TFA Salt) δ 8.65 (s, 1H), 8.00 (m, 2H), 7.97 (s, 1H) 7.57 (t, 1H), 7.52 (t, 1H), 4.57 (t, 2H), 3.06 (t, 2H), 2.69 (s, 3H), 2.26 (t, 2H). LRMS m/z (M+H) 307.5 found, 307.2 required.
Reaction SMILES: Cl.N=[C:3]1[NH:7][C@@H:6]([CH2:8][CH2:9][CH2:10][C:11]2[O:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)[C@@H:5]([C:21]([F:24])([F:23])[F:22])[CH2:4]1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=[O:33].C(Cl)Cl>>[O:33]=[C:3]1[NH:7][CH:6]([CH2:8][CH2:9][CH2:10][C:11]2[O:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)[CH:5]([C:21]([F:24])([F:23])[F:22])[CH2:4]1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)c1coc(CCC[C@@H]2NC(=N)C[C@@H]2C(F)(F)F)n1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1coc(CCCC2NC(=O)CC2C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
Isomer B: (±)ethyl (cis) 2-[3-[5-imino-3-(trifluoromethyl)pyrrolidin-2-yl]propyl]oxazole-4-carboxylate, monohydrochloride ##STR230## 225A) To a stirring solution of the product of Example 224 B (5 mmol) in 10 mL of 10% TFA/DCM is added Et3SiH (7.5 mmol). After stirring for 30 min, the solvent is removed under vacuum and the residue is purified by column chromatography to provide ethyl 2-[3-[5-oxo-3-(trifluoromethyl)pyrrolidin-2-yl]propyl]oxazole-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]2=[O:25])=[C:4]([F:26])[CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[N:16]([CH3:27])[C:15]2=[O:25])=[C:4]([F:26])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1.5 h
Yield: 118.3 %

Procedure:
1.00 g (2.41 mmol) of 3-(4-chloro-5-ethylsulfonylamino-2-fluorophenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was dissolved in 10 ml of acetone, and 0.17 g (1.20 mmol) of anhydrous potassium carbonate and 0.23 ml (2.41 mmol) of dimethyl sulfate were added thereto and the reaction was continued for 1.5 hours. After acetone was distilled off, the reaction product was dissolved in ethyl acetate, washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. Thereafter the ethyl acetate was distilled off to obtain a crude product. The crude product was recrystallized from chloroformdiethyl ether, thereby obtaining 0.61 g of the objective product (yield: 59%) in the form of light yellow crystals.
Reaction SMILES: C(OCC)(=O)C.[OH:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[NH:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14].[CH3:20][C:21]([N:28]=[C:29]=[O:30])([CH3:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>CCCCCC.C1C=CC=CC=1>[CH3:27][C:21]([NH:28][C:29]([O:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[NH:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[O:30])([CH3:20])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)CC(C)(C)N=C=O
Reactant: C=C(C)C(=O)Nc1cccc(O)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=C(C)C(=O)Nc1cccc(OC(=O)NC(C)(C)CC(C)(C)C)c1
Temperature: -15 °C

Procedure:
A reaction vessel is charged with 100 parts of ethyl acetate, 17.7 parts of 3'-hydroxy-2-methylacrylanilide, 23.3 parts of 1,1,3,3-tetramethylbutyl isocyanate and 4 parts of triethylamine. The reaction mixture is heated at reflux for about 18 hours with stirring, and then 100 parts of benzene and 50 parts of hexane are added. The reaction mixture is cooled to -15°C and filtered. The solids are washed with hexane and recrystallized from aqueous alcohol to give 12.5 parts of 3'-(1,1,3,3-tetramethylbutylcarbamoyloxy)-2-methylacrylanilide, m.p. 118°-120°C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].O[CH:28]1[CH2:32][CH2:31][O:30][CH2:29]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([Cl:25])[CH:19]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:28]2[CH2:32][CH2:31][O:30][CH2:29]2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(O)cc2)cc1Cl
Reactant: OC1CCOC1
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(OC3CCOC3)cc2)cc1Cl

Procedure:
The title compound was prepared from rac-[1-(3-chloro-4-methyl-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and rac-3-hydroxy-tetrahydrofuran in analogy to Example 9c): MS (ISN): 444.3 (M−H)−.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27])([CH3:24])[CH3:23]>C(Cl)(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[CH:22]([CH3:24])[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)c1ccccc1N
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Solvent: ClC(Cl)Cl
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C(C)C
Temperature: 150 °C
Yield: 65.4 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (400 mg, 1.23 mmol) and 2-isopropylaniline (1.0 g, 7.4 mmol) was heated to 150° C. for 30 min. The mixture was diluted with CHCl3 and extracted with 2N HCl. The organic phase was washed with a saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4 and evaporated. The residue was chromatographed (SiO2 ; CH2Cl2 :MeOH 95:5) yielding 340 mg (80.5%) of the desired product.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[CH2:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C.O>ClCCl>[CH3:1][S:2]([O:18][CH2:17][CH2:16][CH2:15][C:8]1[CH:9]=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=1[F:6])(=[O:4])=[O:3]
Reactant: OCCCc1cc(F)c(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
Methanesulfonyl chloride (0.45 g, 3.88 mmol) was added dropwise to a solution of 3-(2,4,5-trifluorophenyl)propan-1-ol (0.46 g, 2.41 mmol; from Step 2) and triethylamine (0.71 g, 7.0 mmol) in dichloromethane (5 mL) at 0° C. The mixture was stirred at room temperature for 2 h. After complete disappearance of the alcohol (HPLC monitoring), dichloromethane (10 mL) and water (10 mL) were added. The aqueous phase was saturated with NaCl and extraction performed. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give 0.66 g (100%) of the title compound as a yellow oil. Purity by HPLC: 87%. This material was used directly in the next step.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:35])[C:21]([OH:34])([CH3:33])[C:22]([NH:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[O:23])[CH2:15][N:14]([CH2:36][C:37]([F:40])([F:39])[F:38])[C:13]2[CH:41]=[CH:42][CH:43]=[CH:44][C:12]1=2)C1C=CC=CC=1>[Pd]>[OH:34][C:21]([CH3:33])([C:22]([NH:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:28])([F:29])[F:30])=[O:23])[C:20]([NH:19][C@@H:16]1[C:17](=[O:18])[N:11]([CH2:10][CH2:9][OH:8])[C:12]2[CH:44]=[CH:43][CH:42]=[CH:41][C:13]=2[N:14]([CH2:36][C:37]([F:39])([F:40])[F:38])[CH2:15]1)=[O:35]
Reactant: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CN(CC(F)(F)F)c2ccccc2N(CCOCc2ccccc2)C1=O
Agent: [Pd]
Product: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CN(CC(F)(F)F)c2ccccc2N(CCO)C1=O
Yield: 75 %

Procedure:
In an analogous procedure to that described in Example 8d), the hydrogenolysis of the first eluting epimer (R or S)-(−)-N-[(S)-1-(2-benzyloxy-ethyl)-2-oxo-5-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-hydroxy-2-methyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide using palladium on carbon (10%) as the catalyst yielded the title compound as a white foam (yield 75% of theory); MS (m/e): 551 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:29])=[C:7]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:29])=[C:7]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Cl)cc2C2(CCOCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2ccc(Cl)cc2C2(CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.8 %

Procedure:
The mixture of 1,1-dimethylethyl N-((7-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (2.23 g, 5 mmol) in TFA (8 mL, 108 mmol) was stirred at room temperature for 20 minutes. The majority of the TFA was removed in vacuo and then water was added. The resulting precipitate was filtered and washed with water to give the desired product as a white solid (1.13 g). MS (m/e)=366.1 (M+H)+. Calculated for C17H16ClNO6 365.07.
Reaction SMILES: [CH3:1]N(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:39])[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.CI>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH3:1])[C:31](=[O:39])[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCCC4)c(Cl)c3)c2cc1OC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(N(C)C(=O)OC4CCCCC4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (12 mg), and cyclohexyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (70 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of methyl iodide (43 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (70 mg, yield 99%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:15]([O:17]C)=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.I[CH2:20][CH:21]([CH3:23])[CH3:22]>O1CCCC1>[CH2:20]([C:9]1([CH2:15][OH:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)[CH:21]([CH3:23])[CH3:22]
Reactant: COC(=O)C1CCCCC1
Reactant: CC(C)CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC1(CO)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of lithium diisopropylamide (2.0 M, 7.74 mL) at −78° C. was added methyl cyclohexanecarboxylate (2.0 g) dropwise as a solution in tetrahydrofuran (20 mL). After stirring for 30 minutes, 1-iodo-2-methylpropane (1.956 mL) was added dropwise as a solution in tetrahydrofuran (1 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 1N HCl (25 mL) and diluted with water (25 mL) and extracted into diethyl ether (50 mL). The ether layer was washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in diethyl ether (25 mL) and lithium aluminum hydride (1.0M in tetrahydrofuran, 16.88 mL) was added dropwise. After stirring overnight, the reaction was quenched with water (0.65 mL), 15% aqueous NaOH (0.65 mL), more water (1.95 mL), then magnesium sulfate was added and the reaction filtered and concentrated. The residue was loaded onto silica gel and eluted using a gradient of 3% to 20% ethyl acetate/hexanes to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=1)[CH3:6])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(C)c1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-hydroxy-phenyl)-propionic acid ethyl ester (9.02 g) in acetic acid (75 mL) was added nitric acid (60%, 5.24 g in AcOH) at room temperature. The reaction mixture was stirred for 30 minutes at room temperature and added water. The mixture was extracted with EtOAc and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=10:1) to afford the product as yellow oil. (9.71 g)
Reaction SMILES: [Na].[CH2:2]([C:9]1[CH:18]=[CH:17][C:12]2[NH:13][C:14](=[S:16])[NH:15][C:11]=2[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:20][C:21](=[O:23])[CH3:22]>C(O)C>[CH2:2]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[C:14]([S:16][CH2:20][C:21](=[O:23])[CH3:22])[NH:15][C:11]=2[CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Reactant: CC(=O)CCl
Agent: [Na]
Solvent: CCO
Product: CC(=O)CSc1nc2ccc(Cc3ccccc3)cc2[nH]1
Reaction time: 1 h

Procedure:
0.46 g of sodium metal are dissolved in ethanol, then 2.4 g (10 mmoles) of 5-benzyl-benzimidazoline-2-thione are added to this solution under heating. Then 2.4 ml (30 mmoles) of chloroacetone are added dropwise. The reaction mixture is boiled for 1 hour, evaporated, then 40 ml benzene and 20 ml of aqueous 1N sodium hydroxide solution are added. The phases are separated, and the distillation residue of the benzene solution is crytallized with ether. Thereafter the title product thus obtained is recrystallized from isopropanol. M.p.: 102° C.
Reaction SMILES: [Br:1][C:2]1[C:6](Br)=[CH:5][S:4][CH:3]=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:6]([S:4][CH2:3][CH2:2][CH3:6])=[CH:5][S:4][CH:3]=1
Reactant: Brc1cscc1Br
Solvent: Cc1ccccc1C
Product: CCCSc1cscc1Br
Reaction time: 31 h
Yield: 43.2 %

Procedure:
A mixture of 50 g of 3,4-dibromothiophene, 30 g of 85% potassium propyl mercaptide and 4.5 g of Carbowax® 2000 in 50 ml of xylene was heated at reflux for 18 hours. The reaction was cooled, an additional 9 g of the mercaptide was added, and refluxing was continued for an additional 31 hours. After cooling, the mixture was filtered and the filtrate distilled to provide 10.6 g (21.3%) of 3-bromo-4-(propylthio)thiophene, bp 91°-102° C. (1.4 mm).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13](C=O)=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:26])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cnn(-c2ccc(C=O)cc2)c1
Solvent: ClCCl
Product: COC(=O)c1cnn(-c2ccc(O)cc2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 1-(4-formylphenyl)-1H-pyrazol-4-carboxylic acid methyl ester (5.0 g) in dichloromethane (100 ml) was treated with 3-chloroperbenzoic acid for 5 minutes at room temperature. The solution was heated at 50° C. for 4 hours, during which period additional 3-chloroperbenzoic acid (1.87 g) was added. After concentration, methanol (150 ml) and potassium carbonate (9.00 g) were added to the residue, and the mixture was stirred for 14 hours at ambient temperature. The reaction mixture was poured into water, adjusted to pH 8 with 1N HCl and the resulting precipitate was collected by filtration to give 1-(4-hydroxyphenyl)-1H-pyrazol-4-carboxylic acid methyl ester (0.51 g).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][N:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH3:9].C(Cl)(=O)C(C)(C)C.[CH:42]([NH2:45])([CH3:44])[CH3:43]>C(Cl)Cl>[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30](=[O:32])[NH:45][CH:42]([CH3:44])[CH3:43])=[CH:28][N:27]=3)=[O:25])[CH2:22][CH2:23]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:9])[CH3:10]
Reactant: CC(C)N
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Reaction time: 1 h
Yield: 81 %

Procedure:
Triethylamine (1.6 ml) was added to 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid (4 g) in methylene chloride (50 ml) for dissolution and cooled. With the slow addition of pivaloyl chloride (1.4 ml) at 0° C.˜5° C., the mixture was stirred at 5 C for 1 hour. With the addition of triethylamine (1.7 ml) and isopropylamine (1.2 ml), the mixture was stirred at 10° C. for 2 hours. The solution was washed with aqueous sodium bicarbonate and water twice. The separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Isopropanol (40 ml) was added to the concentrated residue, stirred and filtered. The solid was recrystallized with ethyl acetate and ether to give a desired compound of 3.6 g (yield: 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16]C(=O)C4C=CC=CC=4)=[CH:13][CH:14]=3)[C:9]([C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([O:37][CH3:38])=[O:36])=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([O:37][CH3:38])=[O:36])=[CH:41][CH:42]=1
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)c2ccccc2)c2cc(OC(=O)c3ccccc3)ccc2n1Cc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C)Cc1c(C(=O)c2ccccc2)c2cc(O)ccc2n1Cc1ccc(Cl)cc1

Procedure:
The compound from Step A (300 mg) was dissolved in 4 mL of MeOH and treated with 1 mL of a 1.4M solution of NaOMe in MeOH under argon for 3 hrs. The mixture was poured onto 20 mL of NH4OAc (25% solution), extracted with 3×15 mL of ether, washed with 10 mL of H2O, dried over MgSO4 and the solvent removed under vacuum. The resulting oil was purified by chromatography on silica gel to afford the title compound.