Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=3)[CH2:11][C:10](=[O:24])[N:9]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3([OH:35])[CH2:34][NH:33][CH2:32]3)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:46]([O:48][CH3:49])=[O:47]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:49][O:48][C:46]([N:33]1[CH2:34][C:31]([C:28]2[CH:29]=[CH:30][C:25]([N:9]3[C:10](=[O:24])[CH2:11][C:12]4[C:17](=[CH:16][C:15]([O:18][CH:19]([CH3:20])[CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=4)[C@@H:8]3[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:26][CH:27]=2)([OH:35])[CH2:32]1)=[O:47]
Reactant: COC(=O)Cl
Reactant: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(C3(O)CNC3)cc1)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CC(O)(c2ccc(N3C(=O)Cc4cc(OC)c(OC(C)C)cc4[C@@H]3c3ccc(Cl)cc3)cc2)C1
Reaction time: 0.5 h

Procedure:
A solution of (S)-1-(4-chloro-phenyl)-2-[4-(3-hydroxy-azetidin-3-yl)-phenyl]-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one (example 56) (40 mg, 0.081 mmol) in DCM (2 ml) was immersed in an ice-bath. DIPEA (Fluka) (0.043 ml, 0.243 mmol) was added, followed by methyl chloroformate (Fluka) (8.17 μl, 0.105 mmol). Afterwards the reaction was stirred in an ice-bath for 30 min. The reaction mixture was taken up in aqueous NaHCO3 solution. The organic phase was extracted two times with DCM. The organic layers were pooled, dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product which was purified by preparative. TLC (DCM/MeOH 9:1; Rf range from 0.31 to 0.46 was scratched from the plate). The silicagel was taken up in 20 ml DCM/MeOH 1:1. The silicagel was filtered off. The filtrate was evaporated in vacuo to obtain the title compound as white solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[F:11][C:12]1[C:16]([F:17])=[CH:15][NH:14][CH:13]=1.B(F)(F)F>C(Cl)Cl>[F:11][C:12]1[C:16]([F:17])=[C:15]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=3)=[C:15]3[N:14]=[C:13]([C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=4)=[C:15]4[NH:14][C:13](=[C:1]([C:2]5[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=5)[C:13]5[C:12]([F:11])=[C:16]([F:17])[C:15](=[C:1]([C:2]6[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=6)[C:13]=1[NH:14]2)[N:14]=5)[C:12]([F:11])=[C:16]4[F:17])[C:12]([F:11])=[C:16]3[F:17]
Reactant: COc1cccc(C=O)c1
Reactant: Fc1c[nH]cc1F
Agent: FB(F)F
Solvent: ClCCl
Product: COc1cccc(-c2c3nc(c(-c4cccc(OC)c4)c4[nH]c(c(F)c4F)c(-c4cccc(OC)c4)c4nc(c(-c5cccc(OC)c5)c5[nH]c2c(F)c5F)C(F)=C4F)C(F)=C3F)c1
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
m-Anisaldehyde (0.3 mL, 2.5 mmol), 3,4-difluoropyrrole (215 mg, 2.1 mmol), and 100 mL of dry CH2Cl2 were placed under N2 in a 250 mL round-bottom flask equipped with a magnetic stir bar. The reaction was stirred while BF3 etherate (0.9 mL, 7.1 mmol) was added via syringe. To monitor the reaction, aliquots were periodically removed from the reaction vessel, oxidized with DDQ, neutralized with pyridine, and chromatographed by silica gel TLC using CHCl3 as eluent. After 30 minutes, DDQ (1 g) and pyridine (3 mL) were added. The reaction was stirred for 12 hours and filtered through a short silica gel column using CH3Cl3 as eluent, and the solvent was evaporated. A rough purification was done using a silica gel column with CHCl3 as eluent. The solvent was removed, and the product was further purified on silica gel using chloroform/hexane (1:4). The pure fractions were combined and concentrated to afford 88.8 mg of pure 2,3,7,8,12,13,17,18-octafluoro-5,10,15,20-tetrakis(3-methoxyphenyl)porphyrin in 20% yield. The product is characterized by the following data: 1H NMR (360 MHz, CDCl3) δ 7.65 (t, 12H), 7.30 (m, 4H), 4.02 (s, 12H), -4.14 (s, 2H); 19F δ (500 MHz, CDCl3, -50° C.) δ -140.9 (s, 4F), -146.0 (s, 4F); UV-vis (CH2Cl2) 406 (5.31), 500 (4.22), 533 (3.67), 581 (3.57), 636 (3.56); low-resolution FAB MS 878 (calcd 878). Anal. Calcd for C48H30F8N4O4 : C, 65.61; H, 3.44; N, 6.38. Found: C, 64.49-H, 3.46; N, 5.61.
Reaction SMILES: [OH:1][CH:2]([CH2:15][NH:16][CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[CH2:27]([CH:32]=O)[CH2:28][C:29]([OH:31])=[O:30].CC(O)=O.[BH3-]C#N.[Na+]>CO.O>[OH:1][CH:2]([CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])[CH2:15][N:16]([CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:32][CH2:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: O=CCCC(=O)O
Reactant: O=C1c2ccccc2C(=O)N1CC(O)CNC1CCCc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCCN(CC(O)CN1C(=O)c2ccccc2C1=O)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.7 %

Procedure:
To a solution of N-[2-hydroxy-3-(1,2,3,4-tetrahydro-1-naphthylamino)propyl]phthalimide (93 mg, 0.27 mmol) in MeOH (1 ml) were added succinic semialdehyde (15 wt. % solution in water, 220 μl, 0.35 mmol), HOAc (17 μl, 0.30 mmol) and NaBH3CN (18 mg, 0.29 mmol), and the mixture was stirred at RT for 2.5 h. After adding water, the mixture was extracted with chloroform, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness, and the residue was adsorbed on a plate of silica gel and then developed with 10% methanol/chloroform to afford 4-[[2-hydroxy-(3-phthalimido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (101 mg, 87%): MS(ES+) m/e 437 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 8.01 (br, 1H), 7.80 (m, 2H), 7.73-7.52 (m, 3H), 7.11 (t, J=7.3 Hz, 1H), 7.02 (m, 1H), 6.92-6.78 (m, 1H), 4.63 (br, 1H), 4.44-3.96 (m, 2H), 3.77-3.54 (m, 2H), 2.99-2.81 (m, 1H), 2.77-2.51 (m, 5H), 2.43 (m, 1H), 2.32 (m, 1H), 2.19-2.04 (m, 1H), 1.97 (m, 1H), 1.83 (m, 2H), 1.66 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:23])[CH3:22])[CH:16]=3)[CH:14]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[O-:30][C:31]#[N:32].[Na+]>O>[C:21]([C:17]1[CH:16]=[C:15]([C:13]2[C:12]([O:24][CH3:25])=[CH:11][CH:10]=[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31]([NH2:32])=[O:30])=[CH:7][CH:6]=3)[CH:14]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:23])[CH3:22]
Reactant: N#C[O-]
Reactant: COc1ccc(Nc2ccc(N)cc2)cc1-c1cccc(C(C)=O)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Nc2ccc(NC(N)=O)cc2)cc1-c1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
In an 8 mL vial equipped with a stir bar was placed 1-[5′-(4-amino-phenylamino)-2′-methoxy-biphenyl-3-yl]-ethanone synthesized above (free base) (60.0 mg, 0.180 mmol), water (600 μL), acetic acid (300 μL) and sodium cyanate (46.8 mg, 0.720 mmol). The mixture was stirred at room temperature for 4 hours and then water (20 mL) was added followed by an P-traction with (2×30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The crude material was purified by column utilizing 75% acetone/DCM as the eluent to produce 32 mg of [4-(3′-acetyl-6-methoxy-biphenyl-3-ylamino)-phenyl]-urea (P-268) as a light brown solid in 47% yield. MS (APCI+): 376.1 (M+1); LC-MS: 94%.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:18](=[O:19])[N:17]([CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:16][C@H:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]=2[N:27]=1)[CH3:4].Cl[C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=1.C(N(CC)CC)C>C(O)C>[CH2:3]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:18](=[O:19])[N:17]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:29]4[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=4)[CH2:25][CH2:26]3)[CH2:16][C@H:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]=2[N:27]=1)[CH3:4]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCNCC1)C2=O
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(c3ccc(C(N)=O)cn3)CC1)C2=O
Temperature: 140 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
Compound 24 (50.9 mg, 0.122 mmol) obtained in Example 24, and 6-chloronicotinamide (38.2 mg, 0.244 mmol) were dissolved in ethanol (1.0 mL), and the mixture was stirred at 140° C. for 2 hours under microwave (CEM; Discover, 300 watts) irradiation after adding triethylamine (169 μL, 1.22 mmol). Thereafter, ethanol (1.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was filtered off and dried to give the title compound (Compound 28) (34.7 mg, 62%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[C:30]([CH:34]=1)[C:31]([OH:33])=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:31]([C:30]1[CH:34]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)=[O:33]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: O=C(O)c1cc(Cl)ccc1-n1nccn1
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-n2nccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 334 (M+H).
Reaction SMILES: Cl.OC(C)(C)[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:32])[C@@H:12]([N:17]2[CH2:21][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])=[CH:19][C:18]2=[O:31])[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:6]1.CN1C=CC(N)=N1.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(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:32])[C@@H:12]([N:17]2[CH2:21][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])=[CH:19][C:18]2=[O:31])[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:6]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: Cn1ccc(N)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methy-1-pentanoic acid (prepared as in Example 77, 120 mg, 0.34 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-methyl-1H-pyrazol-3-ylamine (50 mg, 0.51 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (303 mg, 0.68 mmol) and N,N-diisopropylethylamine (110 mg, 0.85 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 70% ethyl acetate/hexanes) to afford (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide as a waxy material. This material was dissolved in diethyl ether (4 mL) and treated with hydrogen chloride in diethyl ether (1 M, 2 mL). Solvents were evaporated and the residue was triturated with diethyl ether. The resulting mixture was filtered to give (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide hydrochloride (58 mg, 36%) as an orange solid: HR-ES-MS m/z calculated for C20H22Cl2N4O3 [M+Na]+ 459.0961, observed 459.0961; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H) 0.92 (d, J=6.6 Hz, 3H) 1.31-1.64 (m, 2H) 1.64-1.82 (m, 1H) 3.71 (s, 3H) 4.21 (d, J=18.4 Hz, 1H) 4.59 (d, J=18.4 Hz, 1H) 4.82-4.89 (m, 1H) 4.90 (s, 1H) 6.38 (d, J=2.1 Hz, 1H) 7.40-7.57 (m, 3H) 7.62 (dd, J=7.8, 1.5 Hz, 1H) 10.73 (s, 1H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]([F:24])([F:23])[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21]C=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10].[Cl-].[Cl-].[Ca+2]>C(Cl)Cl>[F:24][C:8]([F:7])([F:23])[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:1]([C:2]([Cl:4])=[O:3])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(N1CCC(c2ccccc2)CC1)C(F)(F)F
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1

Procedure:
To a flask containing A1Cl3 (534 mg, 4.0 mmol) under an N2 atmosphere was added anhydrous CH2Cl2 (0.1 M), and the drop wise addition of oxalyl chloride (523 μL, 6.0 mmol) over a 20 min period at 15° C. Next, a solution of 2,2,2-trifluoro-1-(4-phenylpiperidin-1-yl)ethanone (17) (2.0 mmol) in anhydrous CH2Cl2 (0.1 M) was added drop-wise to the initial solution over a 45 min period at 15° C. When the reaction was complete as judged by TLC, ice was added to the solution in addition to CaCl2 (1.70 g). The product was extract into CH2Cl2, washed with brine and dried over anhydrous Na2SO4 before concentrating under reduced pressure to yield crude 4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzoyl chloride (18). (b) To a stirred solution of 18 (2.0 mmol) and DIPEA (697 μL, 4.0 mmol) in EtOAc (0.1 M) was added 10% Pd/C. The flask was then evacuated and filled with H2 gas and allowed to stir for 30 min. After which time the reaction contents were filtered and concentrated under reduced pressure to give crude product which was purified by silica gel column chromatography (hexanes:EtOAc, 2:1) to furnish 19 (320 mg, 59% (yield over 2 steps)) δH (400 MHz, CDCl3) 1.69-1.81 (m, 2H, CH2), 1.98-2.06 (m, 2H, CH2), 2.83-2.97 (m, 2H, CH2), 3.27 (td, J=12.8 and 2.4 Hz, 1H, CH), 4.13-4.21 (m, 1H, CH), 4.70-4.76 (m, 1H, CH2), 7.37 (d, J=8.4 Hz, 2H, CH), 7.85 (d, J=8.4 Hz, 2H, CH), 9.99 (s, 1H, CHO); LRMS (ES+) calcd for [C14H14F3NO2+Na] 308.09 found 308.19 [M+Na].
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]2[O:14][C:15](=[O:23])[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)[CH:10]=[CH:9][C:8]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:41]=[CH:40][C:34]2[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=2[C:32]=1[CH2:42][CH2:43][CH3:44])C.O.[OH-].[Li+].S(=O)(=O)(O)[OH:50]>C1COCC1.O>[C:15]([C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[CH2:18][C:13]([C:11]1[CH:10]=[CH:9][C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:41]=[CH:40][C:34]3[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=3[C:32]=2[CH2:42][CH2:43][CH3:44])=[C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:45])[CH:12]=1)=[O:50])([OH:14])=[O:23]
Reactant: O=S(=O)(O)O
Reactant: CCCc1c(OCCCCCOc2ccc(-c3cc4ccccc4c(=O)o3)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCCCOc2ccc(C(=O)Cc3ccccc3C(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O
Reaction time: 47 h
Yield: 79.6 %

Procedure:
A mixture of 0.145 g (0.24 mmol) of 2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]-5-(1-oxo-1H-2-benzopyran-3-yl)benzenepropanoic acid ethyl ester in 5 mL of THF and 5 mL of water was treated with 29.8 mg (0.71 mmol) of lithium hydroxide monohydrate and the mixture was stirred for 47 hrs. After being acidified with 16 mL of 3N aqueous sulfuric acid, the resulting mixture was worked up in the usual manner. The crude product was crystallized from hexane-ethyl acetate to give 0.114 g (79.6%) of the title compound as a white solid, mp 178°-182° C.
Reaction SMILES: [Cl:1][C:2]1[C:12]([OH:13])=[CH:11][C:5]2[CH2:6][O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:12]([O:13][CH2:25][CH2:24][CH2:23][CH2:22][S:21][C:18]2[CH:17]=[CH:16][C:15]([CH3:14])=[CH:20][CH:19]=2)=[CH:11][C:5]2[CH2:6][O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(SCCCCCl)cc1
Reactant: O=C1Nc2cc(Cl)c(O)cc2CO1
Product: Cc1ccc(SCCCCOc2cc3c(cc2Cl)NC(=O)OC3)cc1

Procedure:
Prepared analogously to Example 4 from 7-chloro-6-hydroxy-4H-3,1-benzoxazin-2-one and 4-(4-methyl-phenylmercapto)-butylchloride.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[F:14][B-:15]([F:18])([F:17])[F:16].[CH3:19][O+](C)C>ClCCl>[F:14][B-:15]([F:18])([F:17])[F:16].[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([C:5](=[NH:7])[O:6][CH3:19])[CH:8]=[CH:9][CH:10]=1
Reactant: C[O+](C)C
Reactant: Cc1cccc(C(N)=O)c1[N+](=O)[O-]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=N)c1cccc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
To a solution of the title compound of Step A (1.07 g, 5.9 mmol) in dichloromethane (15 mL) was added trimethyloxonium tetrafluoroborate (1.06 g, 7.1 mmol) and the mixture was stirred overnight at ambient temperature. Concentration gave the title compound of Step B as a white solid (1.7 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)[CH:7]=[C:6]([C:21]([O:23]CC)=[O:22])[C:5]2=[O:26].Br>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:26]
Reactant: CCOC(=O)c1cn(-c2ccc(OC)cc2)c2cc(F)c(F)cc2c1=O
Agent: Br
Product: O=C(O)c1cn(-c2ccc(O)cc2)c2cc(F)c(F)cc2c1=O
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To ethyl 6,7-difluoro-1-(4-methoxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.70 g) is added 48% hydrobromic acid (8 ml), and the mixture is stirred at 100°-110° C. for 3 hour. After cooling, the precipitated crystals are separated by filtration, washed with water and recrystallized from dichloromethane-ethanol to give 6,7-difluoro-1-(4-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.57 g) as colorless needles, m.p. 288°-290° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:17])=[N:14][CH:15]=[CH:16][C:11]=3[S:10][CH:9]=2)=[CH:4][C:3]=1[F:18].[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1)=[C:20]=[O:21]>ClCCl>[NH2:17][C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:20]([NH:19][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)=[O:21])=[C:3]([F:18])[CH:4]=3)=[CH:9][S:10][C:11]=2[CH:16]=[CH:15][N:14]=1
Reactant: Nc1ccc(-c2csc3ccnc(N)c23)cc1F
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)Nc2ccc(-c3csc4ccnc(N)c34)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
A solution of Example 1C (125 mg, 0.48 mmol) in dichloromethane (1 mL) was treated with 1-isocyanato-3-methylbenzene (0.065 mL, 0.5 mmol), stirred overnight at room temperature, and filtered. The filter cake was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a solvent gradient of 10% to 100% acetonitrile/10 mM aqueous ammonium acetate over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute to provide 74 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H), 5.48 (s, 2H), 6.83 (d, J=7.8 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.22–7.29 (m, 2H), 7.28 (d, J=5.8 Hz, 1H), 7.32 (s, 1H), 7.38 (dd, J=12.0, 1.9 Hz, 1H), 7.50 (s, 1H), 7.84 (d, J=5.8 Hz, 1H), 8.31 (t, J=8.5 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 9.06 (s, 1H), MS (ESI(+)) m/e 393.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)[O:4][N:3]=1.[NH2:21][CH2:22][CH2:23][SH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]3[NH:21][CH2:22][CH2:23][S:24]3)=[CH:15][CH:14]=2)[O:4][N:3]=1
Reactant: Cc1cc(CCCCCOc2ccc(C=O)cc2)on1
Reactant: NCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(CCCCCOc2ccc(C3NCCS3)cc2)on1
Yield: 39.7 %

Procedure:
A solution of 4.00 g of 4-[5-(3-methyl-5-isoxazolyl)pentyloxy]benzaldehyde (Example 35a), 1.22 g of 2-aminoethanethiol and a trace of p-toluenesulfonic acid in 30 ml of toluene was heated at reflux for 2 hours using a Dean-Stark trap. The product was isolated and recrystallized from isopropyl acetate-hexane to give 1.93 g of the above-indicated product, m.p. 82-84° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[NH:27])[CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:22]([O:24]CC)=O)[CH2:10][CH2:9]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[NH:27][C:22](=[O:24])[C:17]3[N:16]([C:20]([CH3:21])=[CH:19][CH:18]=3)[CH:15]=2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1ccc(C)n1CC(=N)N1CCN(c2ccccc2F)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(=O)[nH]c(N3CCN(c4ccccc4F)CC3)cn12
Temperature: 150 °C
Yield: 88.1 %

Procedure:
A mixture of ethyl 1-(2-(4-(2-fluorophenyl)piperazin-1-yl)-2-iminoethyl)-5-methyl-1H-pyrrole-2-carboxylate (150 mg, 0.4 mmol) and N,N-diisopropylethylamine (1.41 mL, 8 mmol) in tetrahydrofuran (4 mL) was heated at 150° C. in a microwave reactor for 3 h. At this time, the solution was cooled to room temperature. The resulting precipitate was collected by filtration, washed with minimal ethyl acetate and air dried to afford 3-[4-(2-fluoro-phenyl)-piperazin-1-yl]-6-methyl-2H-pyrrolo[1,2-a]pyrazin-1-one (115 mg, 87.5%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.55 (s, 1H), 7.21-7.06 (m, 3H), 7.05-6.96 (m, 1H), 6.73 (d, 1H), 6.53 (s, 1H), 6.26 (d, 1H), 3.15 (s, 8H), 2.26 (s, 3H). LC-MS calcd. for C18H20FN4O [(M+H)+] 327, obsd. 326.9.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[S:36]>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:35]([NH:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH3:26])=[S:36])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: COc1ccccc1N=C=S
Solvent: CC#N
Product: COc1ccccc1NC(=S)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 55 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 8 ml of acetonitrile. 83 μl (2 molar equivalents) of 2-methoxyphenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 45 hours at 55° C. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 142 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=95%) which was characterized as follows:
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][C@H:15]1[CH2:19][CH2:18][O:17][C:16]1=[O:20]>CN(C)C=O>[Si:6]([O:14][C@H:15]1[CH2:19][CH2:18][O:17][C:16]1=[O:20])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1OCC[C@@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCOC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.2 %

Procedure:
Imidazole (241 mg, 3.54 mmol, 2.2 equiv) and tert-butyl-dimethylsilyl chloride (267 mg, 1.77 mmol, 1.1 equiv) are added to a solution of (3S)-dihydro-3-hydroxy-2(3H)-furanone 11 (164 mg, 1.61 mmol) in dimethyl formamide (1.5 ml). The mixture is stirred for 24 h at r.t. Purification of the reaction mixture by flash column chromatography (pentane/diethyl ether 10:1) affords (S)-2-(tert-butyidimethylsilyloxy)-γ-butyrolactone 12 (321 mg, 93%) as a colourless oil. [α]D20=−31.7; [α]54620=−37.4 (c=0.86, CHCl3); 13C-NMR (100 MHz, CDCL3): δ(ppm)=175.8; 68.2; 64.7; 32.3; 25.6; 18.2; −4.8; −5.3