Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:28]4[CH:27]=[C:26]5[C:21]([N:22]=[CH:23][CH:24]=[N:25]5)=[CH:20][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:29])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([C:28]3[CH:27]=[C:26]4[C:21]([N:22]=[CH:23][CH:24]=[N:25]4)=[CH:20][C:19]=3[O:18][CH2:17]2)[C:9]1=[O:29]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3nccnc3cc12
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2ccccc2C12COc1cc3nccnc3cc12

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one was obtained (22%): mp 206-207° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ10.78 (s, 1H), 8.68-8.61 (m, 2H), 8.06 (d, J=9.0 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.21-7.18 (m, 1H), 7.03-6.86 (m, 3H), 6.96 (ABq, 2H); MS (ES+) m/z 289.8 (M+1).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:26]([OH:32])[CH2:27][O:28][CH2:29][CH2:30]O>>[C:1]1([CH2:11][C:12]([O:14][CH2:30][CH2:29][O:28][CH2:27][CH2:26][OH:32])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: OCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(Cc1cccc2ccccc12)OCCOCCO
Temperature: 120 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A mixture of 1-naphthylacetic acid (5) (2.0 g, 0.011 mol), PTSA (200 mg, 1.1 mmol), and diethylene glycol (6) (8 ml, 72.8 mmol) was stirred at 120° C. under N2. The reaction mixture became homogeneous after 1 h, and the stirring was continued for 15 h. After the reaction was completed (confirmed by TLC), the reaction mixture was poured into 50 ml of icewater mixture. The aqueous reaction mixture was extracted by EtOAc (3×50 ml) and dried over anhydrous MgSO4. The crude product was purified by column chromatography (SiO2, EtOAc/hexanes: 8/2) to yield 2.25 g (76%) of 7 as a colorless oil. 1H NMR (CDCl3, 500 MHz, 20° C.): d 7.83 (d, 1H, J=7.1 Hz ), 7.72-7.64 (m, 2H), 7.40-7.26 (m, 4H), 4.11 (t, 2H, J=4.7Hz), 3.96 (s, 2H), 3.46 (overlapped m, 4H), 3.26 (t, 2H, J=4.4 Hz), 1.90 (s, 1H). 13C NMR (CDCl3, 90 MHz, 20° C.): d 171.7, 134.0, 132.2, 130.6, 128.9, 128.2, 126.5, 126.0, 125.7, 123.9, 72.4, 65.8, 64.2, 61.2, 39.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[N:9][N:10]=2)[CH:7]=1.O[Li].O.Cl.Cl.[F:21][C:22]1[C:23]([C:34]([F:37])([F:36])[F:35])=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:31]3[CH2:32][CH2:33][CH:28]([C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[C:23]=4[C:34]([F:37])([F:35])[F:36])[CH2:29][CH2:30]3)=[O:13])=[N:9][N:10]=2)[CH:7]=1
Reactant: Fc1cccc(C2CCNCC2)c1C(F)(F)F
Reactant: CCOC(=O)c1nnc2ccc(Br)cn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cccc(F)c2C(F)(F)F)CC1
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (75 mg, 0.28 mmol) in THF (2.3 mL) was added a solution of LiOH.H2O (23 mg, 0.56 mmol) in H2O (1.5 mL). The mixture was stirred for 20 min and was neutralized with 2N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (3.0 mL) under an atmosphere of N2. To this mixture was added 4-(3-fluoro-2-trifluoromethyl)phenylpiperidine hydrochloride (5, 78 mg, 0.28 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (245 mg, 0.556 mmol), and diisopropylethylamine (107 mg, 0.834 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL). The mixture was extracted with EtOAc (4×30 mL). The combined organic layers were washed with 5% lithium chloride solution (4×20 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes) to provide (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as an orange film (87 mg, 66%): 1H NMR (300 MHz, DMSO-d6) δ 9.13-9.10 (m, 1H), 7.75-7.62 (m, 2H), 7.52-7.46 (m, 1H), 7.38-7.25 (m, 1H), 5.30-5.17 (m, 1H), 4.78-4.64 (m, 1H), 3.42-3.28 (m, 3H, overlaps with H2O), 3.11-2.92 (m, 1H), 1.98-1.70 (m, 4H); ESI MS m/z 471 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([OH:26])=O)[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:31][O:32][C:33]1[CH:44]=[C:43]2[C:36]([NH:37][CH:38]=[C:39]2[CH2:40][CH2:41][NH2:42])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@@H:7]([C:24]([NH:42][CH2:41][CH2:40][C:39]1[C:43]2[C:36](=[CH:35][CH:34]=[C:33]([O:32][CH3:31])[CH:44]=2)[NH:37][CH:38]=1)=[O:26])[NH:8][C:9](=[O:23])[CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: COc1ccc2[nH]cc(CCNC(=O)[C@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c3ccccc3)c3ccccc3)c2c1
Yield: 36 %

Procedure:
Prepared analogously to Example 5d) from (R)-N5 -[amino (nitroimino) methyl]-N2 -(diphenylacetyl)-ornithine, 5-methoxytryptamine and TBTU in a yield of 36% of theory.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Br[CH:10]([CH3:14])[C:11](O)=[O:12].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CS(O)(=O)=O>[OH:2][C:1]1[CH:8]=[CH:7][C:6]2[C:11](=[O:12])[CH:10]([CH3:14])[O:5][C:4]=2[CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: CC(Br)C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1Oc2cc(O)ccc2C1=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of resorcinol (5.5 g, 50 mmol) in methanesulfonic acid (75 mL) was added 2-bromopropionic acid (4.7 mL, 50 mmol) and P2O5 (4.0 g, 28 mmol). The resulting mixture was stirred for 30 min at 80° C. After cooling to room temperature, the reaction mixture was poured onto ice and extracted with chloroform (2×). The combined organic extracts were washed with brine, dried with sodium sulfate, and concentrated. The orange colored crude product (˜12 g) was carefully taken up into aqueous sodium hydroxide (2N, 245 mL) at 0-5° C., and the resulting mixture was stirred at room temperature overnight. The dark brown solution was cooled to 0° C., and carefully acidified to with concentrated HCI to pH ˜3. It was then extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried with sodium sulfate, and concentrated. The crude material was purified on a silica gel column, eluting with ethyl acetate (20-75%) in hexanes. The final product was obtained as a crystalline solid upon standing at room temperature. The NMR showed a mixture of tautomers (mostly the enol form).
Reaction SMILES: [C:1]1([C:7]2([CH2:13]/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:7]2([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)/C=C/CC1(c2ccccc2)CCCCC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCCC1(c2ccccc2)CCCCC1
Reaction time: 1 h

Procedure:
To a solution of (E)-ethyl 4-(1-phenylcyclohexyl)but-2-enoate (140 mg, 0.514 mmol) in MeOH (15 mL) was added about 50 mg of 10% Pd/C and the mixture was stirred under H2 (30 psi) for 1 hr. The catalyst was filtered off and the filtrate was evaporated to give ethyl 4-(1-phenylcyclohexyl)butanoate as an oil. 1H NMR (400 MHz, CCl3D) δ ppm 7.31 (2H, s), 7.30 (2H, s), 7.13-7.20 (1H, m), 4.06 (2H, q, J=7.03 Hz), 2.04-2.13 (4H, m), 1.33-1.63 (10H, m), 1.24-1.32 (2H, m), 1.20 (3H, t, J=7.14 Hz).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([Cl:23])=[CH:9][C:8]=1[Cl:24])[C:3]([OH:5])=O.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH:25]1([NH:28][C:3](=[O:5])[CH:2]([Cl:1])[CH2:6][C:7]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH:19]([F:20])[F:21])[C:15]([CH3:22])=[N:14]3)[C:10]([Cl:23])=[CH:9][C:8]=2[Cl:24])[CH2:27][CH2:26]1
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: NC1CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(-c2cc(CC(Cl)C(=O)NC3CC3)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A stirred solution of 0.50 g (0.0013 mole) of 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionic acid (Compound 2), 0.071 g (0.0013 mole) of cyclopropylamine, 0.17 g (0.0013 mole) of 1-hydroxybenzotriazole hydrate, and 0.18 g (0.0014 mole) of N,N-diisopropylethylamine in approximately 15 mL of tetrahydrofuran was cooled to 0° C. To this cold mixture was added 0.26 g (0.0013 mole) of 1,3-dicyclohexylcarbodiimide. After complete addition, the reaction mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The reaction mixture was filtered. The filtrate was diluted with carbon tetrachloride and was washed in succession with a 1N hydrochloric acid solution, an aqueous 10% sodium hydroxide solution, water, and an aqueous saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give 0.43 g of N-cyclopropyl-2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionamide as a solid, m.p. 139°-143° C., Compound 17 of Table 1.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][O:38][C:39]1[CH:47]=[CH:46][C:42]([CH2:43][CH2:44][NH2:45])=[CH:41][CH:40]=1>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:45][CH2:44][CH2:43][C:42]4[CH:46]=[CH:47][C:39]([O:38][CH3:37])=[CH:40][CH:41]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: COc1ccc(CCN)cc1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: COc1ccc(CCNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(C)c2)C3)cc1

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 4-methoxyphenethylamine, m.p. 170-172° C. MS [(+)ESI, m/z]: 570 [M+H]+ Anal. Calcd for C37H35N3O3: C, 78.01; H, 6.19; N, 7.38. Found: C, 77.93; H, 6.15; N, 7.30.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][NH:14]2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@:19]12([CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[C:26]([CH3:28])([CH3:27])[CH:23]([CH2:24][CH2:25]1)[CH2:22][C:20]2=[O:21]>C(#N)C>[C@:19]12([CH2:29][S:30]([OH:33])(=[O:31])=[O:32])[C:26]([CH3:28])([CH3:27])[CH:23]([CH2:24][CH2:25]1)[CH2:22][C:20]2=[O:21].[CH2:1]([N:8]1[C:16](=[O:17])[C@H:15]2[C@H:10]([CH2:11][CH2:12][CH2:13][NH:14]2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1[C@H]2NCCC[C@H]2C(=O)N1Cc1ccccc1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC#N
Product: O=C1[C@H]2CCCN[C@H]2C(=O)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
0.52 g (2.12 mmol) of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane (racemate) and 0.49 g (2.12 mmol) of (1S)-camphor sulfonic acid are dissolved in 5 ml of acetonitrile under reflux to give a clear solution and cooled to room temperature. The precipitated solid is filtered off with suction and dried in vacuo to give 0.11 g (0.49 mmol) of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane-(1S)-camphorsulfonic acid salt.
Reaction SMILES: [CH2:1](O)COCCOCCO.C(Cl)(Cl)=O.C1(C)C=CC=CC=1.[CH2:22]([OH:40])[CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][OH:39]>CCOC(C)=O>[CH3:1][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][OH:40]
Reactant: OCCOCCOCCO
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCCOCCOCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The following description refers to the scheme illustrated in FIG. 10. Non-polydispersed activated hexaethylene glycol monomethyl ether was prepared analogously to that of non-polydispersed triethylene glycol in Example 39 above. A 20% phosgene in toluene solution (35 mL, 6.66 g, 67.4 mmol phosgene) was chilled under a N2 atmosphere in an ice/salt water bath. Non-polydispersed hexaethylene glycol 50 (1.85 mL, 2.0 g, 6.74 mmol) was dissolved in 5 mL anhydrous EtOAc and added to the phosgene solution via syringe. The reaction mixture was kept stirring in the ice bath for one hour, removed and stirred a further 2.5 hours at room temperature. The phosgene, EtOAc, and toluene were removed by vacuum distillation, leaving non-polydispersed compound 51 as a clear, oily residue.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([Cl:11])[N:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:15][O:14][C:12]([N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH2:1][Br:16])[C:10]=2[N:9]=[C:8]1[Cl:11])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)n1c(Cl)nc2c(C)cccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)n1c(Cl)nc2c(CBr)cccc21
Yield: 72.2 %

Procedure:
A mixture of methyl 4-methyl-2-chloro-1H-benzimidazole-1-carboxylate (17.5 g, 0.078 mol), N-bromosuccinimide (13.9 g, 0.078 mol) and benzoyl peroxide (2.0 g) in carbon tetrachloride (175 mL) was stirred at reflux for 2 hours. The solution was cooled, filtered to remove succinimide by-products, evaporated and crystallized from ethyl acetate:hexane to give 17.1 g of methyl-4-(bromomethyl)-2-chloro-1H-benzimidazole-1-carboxylate as a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH2:22]([NH:25][C:26](=[O:33])[CH2:27][C:28]1[N:29]=[CH:30][NH:31][CH:32]=1)[CH:23]=[CH2:24]>>[CH2:22]([NH:25][C:26](=[O:33])[CH2:27][C:28]1[N:29]=[CH:30][N:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:32]=1)[CH:23]=[CH2:24]
Reactant: C=CCNC(=O)Cc1c[nH]cn1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: C=CCNC(=O)Cc1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])cn1
Yield: 52 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with N-allyl-2-(1H-imidazol-4-yl)-acetamide according to the GPA affording 28 mg (52%) of a yellowish powder. Rt=2.36 min.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C([O:55][C:56](=O)[CH:57]([CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=1)[CH2:58][CH3:59])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[CH2:58]([CH:57]1[CH2:60][N:61]([CH2:62][C:63]2[CH:64]=[CH:65][C:66]([F:69])=[CH:67][CH:68]=2)[C:19](=[O:21])[C:18]([C:12]2[NH:11][C:10]3[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=3[S:14](=[O:16])(=[O:17])[N:13]=2)=[C:56]1[OH:55])[CH3:59]
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C(CC)CNCc1ccc(F)cc1
Agent: CC[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCC1CN(Cc2ccc(F)cc2)C(=O)C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)=C1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.113 g, 0.320 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.134 g, 0.352 mmol) and 4-methylmorpholine (0.070 mL, 0.637 mmol) were added sequentially to a solution of rac-2-[(4-fluoro-benzylamino)-methyl]-butyric acid ethyl ester (0.081 g, 0.320 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (10 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.622 mL, 1.92 mmol) was added and the reaction mixture was heated to 70° C. for 18 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 50-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[5-ethyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.061 g, 0.112 mmol, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.78 (3H, t, J=7.0 Hz), 1.30-1.38 (1H, m), 1.60-1.66 (1H, m), 2.95 (3H, s), 3.22 (1H, dd, J=4.5 Hz, J2=12.1 Hz), 3.56 (1H, dd, J=4.2 Hz, J2=12.8 Hz), 4.24 (2H, d, J=6.3 Hz), 4.45 (1H, d, J=14.7 Hz), 4.75 (1H, d, J=14.9 Hz), 7.14-7.18 (2H, m), 7.25 (1H, s), 7.36-7.39 (2H, m), 7.64 (1H, t, J=5.0 Hz). LC-MS (ESI) calculated for C21H23FN4O6S3 542.08. found 543.0 [M+H+].
Reaction SMILES: [SH-].[Na+].[CH3:3][C:4]1([CH3:13])[O:8][N:7]=[C:6]([S:9]([CH3:12])(=O)=O)[CH2:5]1.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+].ClC[C:28]1[C:29]([O:38][CH3:39])=[N:30][CH:31]=[N:32][C:33]=1[C:34]([F:37])([F:36])[F:35]>CN(C)C=O.O>[CH3:3][C:4]1([CH3:13])[O:8][N:7]=[C:6]([S:9][CH2:12][C:28]2[C:29]([O:38][CH3:39])=[N:30][CH:31]=[N:32][C:33]=2[C:34]([F:36])([F:37])[F:35])[CH2:5]1
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Reactant: COc1ncnc(C(F)(F)F)c1CCl
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncnc(C(F)(F)F)c1CSC1=NOC(C)(C)C1
Reaction time: 2 h
Yield: 85.6 %

Procedure:
0.32 g of sodium hydrosulfide (purity: 70%, 4.00 mmoles) was added, at room temperature, to a solution of 0.35 g (2.00 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 10 ml of dimethylformamide. The mixture was stirred for 2 hours. To the reaction mixture were added 0.28 g (2.00 mmoles) of anhydrous potassium carbonate, 0.31 g (2.00 mmoles) of Rongalit and 0.45 g (2.00 mmoles) of 5-chloromethyl-4-methoxy-6-trifluoromethylpyrimidine. The resulting mixture was stirred at room temperature for 2 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 0.55 g (yield: 85.9%) of 5,5-dimethyl-[(4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methylthio]-2-isoxazoline.
Reaction SMILES: Cl.[S:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18]([C:20](Cl)=[O:21])=[CH:17][C:16]=2[CH:23]=1.[CH2:24]([NH:31][CH3:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(CC)CC>C(Cl)Cl>[CH2:24]([N:31]([CH3:32])[C:20]([C:18]1[O:19][C:15]2[CH:14]=[CH:13][C:12]([O:11][C:3]3[S:2][C:10]4[C:5]([N:4]=3)=[N:6][CH:7]=[CH:8][CH:9]=4)=[CH:23][C:16]=2[CH:17]=1)=[O:21])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CNCc1ccccc1
Reactant: O=C(Cl)c1cc2cc(Oc3nc4ncccc4s3)ccc2o1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)C(=O)c1cc2cc(Oc3nc4ncccc4s3)ccc2o1
Yield: 15.1 %

Procedure:
To a solution of 5-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-2-carbonyl chloride hydrochloride (150 mg, 0.43 mmol) in CH2Cl2 (4.3 mL) was added N-benzyl-N-methylamine (55 μL, 0.43 mmol) and Et3N (0.12 mL, 0.86 mmol). The reaction mixture was stirred (rt, 2 h) before additional N-benzyl-N-methylamine (55 μL, 0.43 mmol) was added. The mixture was concentrated and purified by reverse phase chromatography to provide the title product as an orange oil (27 mg, 15%). MS (ESI): mass calcd. for C23H17N3O3S, 415.10; m/z found, 416.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.60 (d, J=3.7, 1H), 8.09 (dd, J=7.9, 1.5, 1H), 7.75 (br s, 1H), 7.66-7.49 (m, 1H), 7.46-7.28 (m, 8H), 5.05-4.62 (m, 2H), 3.45-2.94 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][C:32]=1[F:33])[O:19][C:20]1[C:25]([F:26])=[CH:24][C:23]([CH2:27][OH:28])=[CH:22][C:21]=1[F:29]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][C:32]=1[F:33])[O:19][C:20]1[C:21]([F:29])=[CH:22][C:23]([CH2:27][O:28][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)=[CH:24][C:25]=1[F:26]
Reactant: OCc1cc(F)c(Oc2ccc(F)c(Cl)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(F)c(Cl)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50 mg, 0.269 mmol), sodium hydride (21.55 mg, 0.539 mmol) and (4-(3-chloro-4-fluorophenoxy)-3,5-difluorophenyl)methanol (78 mg, 0.269 mmol) in DMF (2 mL).
Reaction SMILES: C(C1[CH:4]=[CH:5][N:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=12)#N.S(=O)(=O)(O)O.[C:17]([OH:20])(=[O:19])[CH3:18]>O>[C:17]([C:18]1[CH:4]=[CH:5][N:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=12)([OH:20])=[O:19]
Reactant: CC(=O)O
Reactant: N#Cc1ccn2ccncc12
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccn2ccncc12
Temperature: 0 °C

Procedure:
To 1 g of 8-cyanopyrrolo[1,2-a]pyrazine prepared in Preparation Example 8 were added 10 ml of concentrated sulfuric acid, 10 ml of acetic acid and 10 ml of distilled water; and the mixture was refluxed for 1 hour. The reaction mixture was cooled and poured into 100 ml of ice-water. The resulting solid was filtered and dried under reduced pressure to obtain 0.5 g of title compound.