Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].[K+].C(C([O:9][C:10]([C:13]([O:19]C(C(C(F)(F)F)(F)F)(F)F)([C:15]([F:18])([F:17])[F:16])F)(F)[F:11])F)(F)(F)F>>[C:15]([C:13]([C:10]([F:11])=[O:9])=[O:19])([F:18])([F:17])[F:16]
Reactant: FC(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Product: O=C(F)C(=O)C(F)(F)F
Temperature: 120 °C

Procedure:
The formed product obtained in Example 2-2 (42.0 g) was charged into a 200 cc autoclave together with KF powder (0.5 g) and CF3CFHOCF2CF(CF3)OCF2CF2CF3 and heated in a sealed state at from 80 to 120° C. for 13 hours and 120° C. for 14 hours in an oil bath, while vigorously stirring. At the outlet of the autoclave, a pressure resistant container cooled to −78° C. was installed, and when the internal pressure of the reactor became at least 0.28 MPa, the gas in the reactor was liquefied and recovered. 0.8 g of a sample was recovered. The recovered sample was gaseous at room temperature, and as a result of the analysis by GC-MS, the above-identified compound was confirmed to be the main product. The yield of the above-identified compound was 9.4%.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1)[CH2:4][NH:5][CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9].NCCCC1C=CC(O)=CC=1.FC(F)(F)C(O)=O>ClCCl>[OH:1][CH2:2][CH:3]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][CH:21]=1)[CH2:4][NH:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CC(C)(C)OC(=O)CCNCC(CO)Cc1ccc(OCCCc2ccccc2)cc1
Agent: NCCCc1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCNCC(CO)Cc1ccc(OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl N-{3-hydroxy-2-[4-(3-phenylpropoxy)benzyl]propyl}-β-alaninate (65 mg; prepared by following the procedure of Example 4 using the compound prepared in Example 15 as a substitute for 4-(3-aminopropyl)phenol) in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was dropped at 0° C., followed by stirring at room temperature for 2 hours. Then, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia=80:20:4). The crude product thus obtained was washed with diethyl ether to give the title compound (38 mg) having the following physical properties.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.O.Cl.[NH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:19]3[CH2:20][CH2:21][NH:16][CH2:17][CH:18]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: FC(F)(F)c1ccc2c(C3=CCNCC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 6-trifluoromethylindole (4.0 g, 22 mmol) and 4-piperidone hydrochloride hydrate (6.6 g, 43 mmol). The product was isolated as a white solid. Yield 3.7 g (64%). mp °C. FDMS m/e=266 (M+ of free base).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH3:11])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:25]([O:30][CH2:31][CH3:32])(=[O:29])[C:26]#[C:27][CH3:28].[Cl-].[Li+].C(=O)(O)O>CN(C)C=O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([CH:10]([N:9]2[C:3]3[N:4]=[C:5]([Cl:8])[N:6]=[CH:7][C:2]=3[C:26]([C:25]([O:30][CH2:31][CH3:32])=[O:29])=[C:27]2[CH3:28])[CH3:11])[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC#CC(=O)OCC
Reactant: CC(Nc1nc(Cl)ncc1Br)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)(C)C)CC2)c2nc(Cl)ncc12
Yield: 17.5 %

Procedure:
Into the vial were added tert-butyl 4-(1-((5-bromo-2-chloropyrimidin-4-yl)amino)ethyl)piperidine-1-carboxylate (400 mg, 0.95 mmol) and ethyl but-2-ynoate (128 mg, 1.14 mmol), palladium(II) diacetate (42 mg, 0.19 mmol), lithium chloride (51.8 mg, 1.23 mmol), carbonic acid (393 mg, 2.85 mmol) in N,N-dimethyl formamide. The mixture was degassed for 10 min and refilled with nitrogen, and irradiated in the microwave on a Biotage smith synthesizer at 120° C. for 40 min. The reaction mixture was cooled down and added to water (30 ml), and extracted with ethyl acetate (10 ml×3). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (petroleum/ethyl acetate: 20:1 to 10:1) to give compound ethyl 7-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-2-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (75 mg, yield: 17.4%) as a yellow oil. LRMS (M+H+) m/z: calcd 450.2. found 451.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16](OCC4C=CC=CC=4)[CH:17]=[CH:18][C:19]=3[C:11]=2[C:10](C)(C)[CH2:9][N:8]([C:30](=[O:38])[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:7]=1)=[O:5])[CH3:2].C([O:41]C(C1C2NC3C=CC(OCC4C=CC=CC=4)=CC=3C=2C(C)(C)CN(C(=O)C2C=CC(F)=CC=2)C=1)=O)C.C(OC(C1C2NC3C=CC(N(CC4C=CC=CC=4)CC4C=CC=CC=4)=CC=3C=2C(C)(C)CN(C(=O)C2C=CC(F)=CC=2)C=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([OH:41])[C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:30](=[O:38])[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(OCc3ccccc3)ccc21
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccc(OCc3ccccc3)cc21
Agent: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccc(N(Cc3ccccc3)Cc3ccccc3)cc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1cccc(O)c21

Procedure:
In a manner similar to that described above in Step A, but replacing 7-benzyloxy-3-(4-fluorobenzoyl)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester with 8-benzyloxy-3-(4-fluorobenzoyl)1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester, 9-benzyloxy-3-(4-fluorobenzoyl)1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester or 9-dibenzylamino-3-(4-fluorobenzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester, the following compounds were prepared:
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:14](=[O:22])[O:15][C:16]3([CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12]=2[C:11]2[C@@H:10]([OH:23])[CH2:9][C:8]([CH3:25])([CH3:24])[CH2:7][C:6]=2[N:5]=1)([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[C:34]([Si:38](OS(C(F)(F)F)(=O)=O)([CH3:40])[CH3:39])([CH3:37])([CH3:36])[CH3:35]>O1CCCC1>[Si:38]([O:23][C@H:10]1[CH2:9][C:8]([CH3:25])([CH3:24])[CH2:7][C:6]2[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]3[C:14](=[O:22])[O:15][C:16]4([CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[C:12]=3[C:11]1=2)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)c1nc2c(c3c1C(=O)OC31CCOCC1)[C@@H](O)CC(C)(C)C2
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CC(C)c1nc2c(c3c1C(=O)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.2 g (S)-4-Isopropyl-9-hydroxy-7,7-dimethyl-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3-one are dissolved in 15 ml tetrahydrofurane and 1.31 ml 2,6-lutidine and 2.44 ml trifluoromethanesulfonic acid-tert.-butyldimethylsilylester are added dropwise and the mixture is stirred for 4 hours at room temperature. Then the reaction is absorbed onto silica gel and chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 50:50).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1CCO.CCCCC.C([Li])(C)(C)C.C([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=O)=[CH:25][C:24]=1O)=O.[Cl-].[NH4+]>O1CCCC1.O>[C:2]1([CH:27]([C:26]2[CH:25]=[CH:24][CH:23]=[CH:32][CH:31]=2)[OH:29])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C=O)c(O)c1
Reactant: OCCc1ccccc1Br
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 54.8 %

Procedure:
To a solution of 2-(bromophenyl)ethylalcohol (1.7 g) in tetrahydrofuran (100 mL) was added 1.45 mol/L tert-butyllithium n-pentane solution (12.6 mL) under an argon atmosphere at −78° C. After the mixture was stirred at −78° C. for 10 minutes, a solution of methyl 4-formyl-3-hydroxybenzoate (0.50 g) in tetrahydrofuran (10 mL) was added to the reaction mixture. After the reaction mixture was stirred for 30 minutes under ice-cooling, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3) to give a diphenylmethanol compound (0.28 g). The obtained diphenylmethanol compound (0.28 g) was dissolved in methanol (5 mL), and 10% palladium-carbon powder (0.14 g) was added to the solution. After the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give methyl 3-hydroxy-4-[4-(2-hydroxyethyl)benzyl]benzoate (0.26 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:32])([F:31])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](/[CH:26]=[CH:27]/[N+:28]([O-:30])=[O:29])[CH:21]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][C@@H:27]([N+:28]([O-:30])=[O:29])[C@H:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:18]([F:17])([F:31])[F:32])[CH:21]=2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=[N+]([O-])/C=C/c1cccc(OC(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])[C@@H]1CN(Cc2ccccc2)C[C@H]1c1cccc(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine was added to a solution of 1-trifluoromethoxy-3-((E)-2-nitro-vinyl)-benzene (6.00 g; 35.90 mmol) in DCM (50 ml). The reaction solution was cooled to 0° C., TFA (0.30 ml; 3.95 mmol) was added dropwise, and stirred overnight at RT. The reaction solution was washed with H2O and brine, dried over MgSO4, filtered, and concentrated. The crude material was purified via Biotage (340 g column) eluting with 5% EtOAc in hexane to provide the desired product 5.5 g, yield 51%.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C@H:13]2[CH2:15][C@@H:14]2[CH2:16][NH2:17])=[N:5]1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[CH3:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C@H:13]2[CH2:15][C@@H:14]2[CH2:16][NH:17][C:25](=[O:27])[CH3:26])=[N:5]1
Reactant: Cn1cc2c([C@H]3C[C@@H]3CN)cccc2n1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1C[C@@H]1c1cccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 1-[(1S,2S)-2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine dihydrochloride (300 mg, 1.09 mmol) and triethylamine (305 μL, 2.19 mmol) in tetrahydrofuran (10 mL) was added acetic anhydride (124 μL, 1.31 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=5/95→20/80) to give the title compound (242 mg, yield 99%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)=[O:4].[CH2:15]([CH: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>C(OCC)C>[CH2:15]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]([NH:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[CH:9]3)=[O:4])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2[nH]ncc2c1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc2[nH]ncc2c1

Procedure:
The title compound is prepared from 2-chloro-N-(1H-indazol-5-yl)-acetamide and 4-benzyl-piperidine (Aldrich) according to the method described in Example 142b. Melting Point: 170-174° C. (diethylether)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNC(=O)c3ccc(F)cc3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 13 μL (0.11 mmol) 4-fluorobenzoyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O.C([C:25]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]3[N:55]=[CH:54][CH:53]=[CH:52][C:40]=3[C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:45]=3[F:51])=[O:42])=[CH:34][C:33]=2[F:56])[CH:28]=[CH:27][N:26]=1)(=O)N.O.[N:58]1C=CC=CC=1.[ClH:64]>CN(C=O)C>[ClH:64].[NH2:58][C:25]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]3[N:55]=[CH:54][CH:53]=[CH:52][C:40]=3[C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:45]=3[F:51])=[O:42])=[CH:34][C:33]=2[F:56])[CH:28]=[CH:27][N:26]=1
Reactant: NC(=O)c1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Reactant: c1ccncc1
Agent: Cl
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Temperature: 0 °C
Yield: 35 %

Procedure:
Bis(trifluoroacetoxy)iodobenzene (0.10 g, 0.23 mmol) was added to a solution of 2-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide (0.080 g, 0.17 mmol), water (0.006 g, 0.33 mmol) and pyridine (0.27 mL, 3.33 mmol) in anhydrous DMF (5 mL) at room temperature. The reaction mixture was stirred for 69 hours before 6N aq HCl (2 mL) was added and the reaction stirred for an additional fifteen minutes. The mixture was extracted twice with Et2O and the combined organic layers discarded. The aqueous layer was neutralized with 1M NaHCO3(aq) then extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The resultant residue was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 34% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and lyophilized to an off-white solid that was dissolved in anhydrous THF (2 mL), cooled to 0° C. and treated with HCl (4N in dioxane, 1.0 mL, 4.0 mmol). The reaction mixture was stirred for ten minutes, before being lyophilized to afford the title compound (0.029 g, 35%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.72 (s, 1H), 10.49 (s, 1H), 8.32-8.40 (m, 2H), 8.13 (dd, 1H, J=13.7, 2.4 Hz), 7.82-7.92 (m, 3H), 7.29-7.53 (m, 4H), 7.05-7.15 (m, 1H), 6.97-7.01 (m, 1H), 6.64-6.66 (m, 1H), 6.12 (d, 1H, J=2.4 Hz); HRMS(ESI+), 452.1334 (M+H)+ calc, 452.1341 (M+H)+ found.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([O:15][C:16]([NH:18][CH:19]1[CH2:24][NH:23][CH2:22][CH2:21][CH2:20]1)=[O:17])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CCO>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:23]1[CH2:22][CH2:21][CH2:20][CH:19]([NH:18][C:16](=[O:17])[O:15][C:12]([CH3:13])([CH3:11])[CH3:14])[CH2:24]1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccccc2[N+](=O)[O-])C1
Yield: 85 %

Procedure:
The method of Example 1 was followed using 1-fluoro-2-nitrobenzene (1.0 eq), 3-N-Boc-aminopiperidine (1.0 eq), and DIEA (2.0 eq) in EtOH at 50° C. for 48 hours yielding tert-butyl 1-(2-nitrophenyl)piperidin-3-ylcarbamate (85%). LCMS (m/z): 322.2 (MH+); LC Rt=3.23 min.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].O.S(OC)(O[CH3:20])(=O)=O>C(OCC)C>[CH3:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
Ethyl 4-hydroxybenzoate (15.0 g, 0.09 mol) is stirred into an initial mixture of KOH (6.3 g, 0.11 mol) in dist. water (60 ml) under protective gas. Dimethyl sulfate (8.8 ml, 0.09 mol) is added dropwise to the clear solution with stirring and ice-cooling such that the temperature does not exceed 15° C. After addition is complete, the cooling is removed, and to complete the reaction the reaction mixture is stirred at RT for 45 min and under reflux for 2 h, then cooled to RT. The deposited oil is taken up in diethyl ether (50 ml). The aqueous phase separated off is extracted with diethyl ether (150 ml), and the ethereal extracts obtained are combined, washed with sodium hydroxide solution (10% strength, 50 ml) and with saturated NaCl solution, dried over Na2SO4 sicc. and concentrated in vacuo: colorless oil, yield: 15.7 g (97%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([NH:16][CH3:17])[N:8]=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:35])[C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=2)[CH:21]=[CH:22][CH:23]=1.C[CH2:37][N:38]=[C:39]=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.CNC>CN(C)C=O.CN(C)C1C=CN=CC=1.O1CCCC1.C(N(CC)CC)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([NH:16][CH3:17])[N:8]=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:35])[C:26]2[CH:34]=[CH:33][C:29]([C:30]([N:38]([CH3:39])[CH3:37])=[O:32])=[CH:28][CH:27]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CNc1nc(-c2cccc(NC(=O)c3ccc(C(=O)O)cc3)c2)c2cc(OC)c(OC)cc2n1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNc1nc(-c2cccc(NC(=O)c3ccc(C(=O)N(C)C)cc3)c2)c2cc(OC)c(OC)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a solution of 100 mg of N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid hydrochloride dissolved in 2 mL of dimethylformamide were added 60 mg of WSC, 41 mg of 1-hydroxybenzotriazole, 42 μL of triethylamine, and 10 mg of 4-dimethylaminopyridine, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 200 μL of a dimethylamine solution in tetrahydrofuran, followed by stirring at room temperature for 15 hours. To the reaction mixture was added 2 mL of tetrahydrofuran, and the reaction mixture was partitioned after addition of a saturated sodium hydrogencarbonate solution. The organic layer was extracted with 10 mL of ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The anhydrous magnesium sulfate was removed by filtration, and the organic layer was concentrated to dryness, and the residue was triturated with a mixed solution consisting of ethyl acetate:n-heptane=1:1. The obtained solid was filtrated, washed with diethyl ether, and dried under aeration to give 85 mg of a target product. Yield: 87%.
Reaction SMILES: [CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1.Cl[Si](C)(C)C.C(N(CC)CC)C.[N-]1C=CN=C1>CN(C)C=O>[CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([NH:32][C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[O:17])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Reactant: Nc1nnn[nH]1
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1
Reaction time: 2 h
Yield: 29.5 %

Procedure:
1.86 g (0.00715 mol) of 2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid (Example 1) and 1.62 g (0.01 mol) of 1,1'carbonyldiimidazole (Aldrich Chemical Company) in 210 ml of dimethylformamide are stirred at 50° C. for sixteen hours. To 0.83 g (0.008 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) in 50 ml of dimethylformamide cooled to 0°-5° C. is added 3.0 ml (0.024 mol) of chlorotrimethylsilane (Aldrich Chemical Company) and 6.0 ml (0.043 mol) of triethylamine. After thirty minutes the mixture is allowed to reach room temperature and is stirred for an additional two hours. This mixture is combined with the previous cooled imidazolide mixture and stirred for three days at room temperature. The resulting precipitate is collected, slurried in boiling glacial acetic acid, the mixture is cooled and filtered to give 0.69 g of 2-methyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2 -a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 306°-310° C. (dec).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:45])[O:16][C@@H:17]2[C@@H:29]3[C:30](=[O:33])[O:31][CH2:32][C@H:28]3[C@H:27]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([OH:42])=[C:36]([O:43][CH3:44])[CH:35]=3)[C:26]3[C:18]2=[CH:19][C:20]2[O:24][CH2:23][O:22][C:21]=2[CH:25]=3)=[CH:10][CH:9]=1.Cl[C:47]([O:49][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=1)=[O:48].C([O-])(O)=O.[Na+]>ClCCl>[C:47](=[O:48])([O:49][C:50]1[CH:51]=[CH:52][C:53]([N+:56]([O-:58])=[O:57])=[CH:54][CH:55]=1)[O:42][C:37]1[C:36]([O:43][CH3:44])=[CH:35][C:34]([C@H:27]2[C@@H:28]3[CH2:32][O:31][C:30](=[O:33])[C@H:29]3[C@@H:17]([O:16][C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=3)=[O:45])[C:18]3[C:26]2=[CH:25][C:21]2[O:22][CH2:23][O:24][C:20]=2[CH:19]=3)=[CH:39][C:38]=1[O:40][CH3:41]
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](OC(=O)Nc3ccc(F)cc3)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc([C@@H]2c3cc4c(cc3[C@H](OC(=O)Nc3ccc(F)cc3)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
1.07 mmol of pyridine and then, dropwise, a solution of 0.59 mmol of the compound of Example 4 in 5 ml of dichloromethane, are added, under argon, to a solution of 0.83 mmol of para-nitrophenyl chloroformate in 20 ml of anhydrous dichloromethane. After stirring for 1 hour, the reaction mixture is hydrolysed by the addition of a saturated aqueous NaHCO3 solution, and then the extracted organic phases are washed, neutralised, dried, filtered and concentrated under reduced pressure. Chromatography on silica gel (cyclohexane/ethyl acetate: 3/1) enables the expected product to be isolated.