Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]2[N:18]=[C:19]([NH2:21])[CH:20]=[C:14]2[CH2:13]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1COCC1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:21][C:19]2[CH:20]=[C:14]3[CH2:13][N:12]([CH3:11])[CH2:17][CH2:16][N:15]3[N:18]=2)[C:3](=[O:10])[N:4]([CH3:9])[N:5]=1
Reactant: CN1CCn2nc(N)cc2C1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: CN1CCn2nc(Nc3cc(Cl)nn(C)c3=O)cc2C1
Temperature: 0 °C
Yield: 76.2 %

Procedure:
A 250-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one 103e (1.90 g, 8.53 mmol), 101e (1.18 g, 7.75 mmol) and 1,4-dioxane (40 mL). The flask was purged with nitrogen and cooled to 0° C. A 1 M solution of lithium hexamethyldisilazide in THF (39 mL, 39.0 mmol) was added. After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (381 mg, 0.659 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (355 mg, 0.388 mmol) were added, and the reaction mixture was heated at reflux for 2 h. After this time, the mixture was cooled to room temperature and diluted with water (10 mL). The pH of the solution was adjusted to 7.6 with 2 N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromato-graphy on silica to afford a 76% yield (1.74 g) of 103f as an off-white solid: mp 184-186° C.; 1H NMR (300 MHz, DMSO-d6) d 9.62 (s, 1H), 7.72 (s, 1H), 6.00 (s, 1H), 4.04 (t, 2H, J=5.1 Hz), 3.65 (s, 3H), 3.53 (s, 2H), 2.82 (t, 2H, J=5.1 Hz), 2.37 (s, 3H); MS (ESI+) m/z 295.1 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][CH2:20][O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:25]([CH2:24][C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:30][CH2:29][CH2:28][C:27]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: Cc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(C)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-methylphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound is prepared.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24]5[N:29]=[C:28]([NH2:30])[C:27]([N+:31]([O-])=O)=[CH:26][N:25]=5)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.CO.[Pd]>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24]5[N:29]=[C:28]([NH2:30])[C:27]([NH2:31])=[CH:26][N:25]=5)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1nc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cnc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)nc1N
Temperature: 25 °C
Reaction time: 28 h
Yield: 69.6 %

Procedure:
2-[1-(9,10-Dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidylamino]-4-amino-5-nitropyrimidine (1.000 g, 2.3 mmol, prepared as described in Example 97), 0.2 weight equivalents of 10% Pd/C, and ammonium formate (1.000 g, 15.9 mmol) were combined in 20 mL 50% ethyl acetate/methanol and stirred under a nitrogen atmosphere at room temperature for 28 hours. The reaction mixture was filtered through celite and concentrated on a rotary evaporator to give the title compound as a tan glassy solid (0.643 g, 1.6 mmol, 69%), mp 138°-140° C.; MS(CI): 413 (M+H); NMR (250 MHz, DMSO-d6): 7.29-7.18(m, 5H), 6.98-6.87(m, 4H), 6.33(s, 2H), 5.75-5.72(br m, 1H), 4.32(s, 1H), 3.56(br m, 1H), 3.36(br m, 2H), 2.99-2.94(d, J=11.3 Hz, 2H), 2.47(s, 2H), 2.32-2.23(m, 2H), 1.80-1.75(m, 2H), 1.41-1.37(m, 2H).
Reaction SMILES: ClC1C=CC(N2N=CC=N2)=C(C=1)C(N[C@H]1CCC[C@@H]1NC1C=CC(C(F)(F)F)=CN=1)=O.Cl.[F:33][C:34]([F:49])([F:48])[C:35]1[CH:36]=[CH:37][C:38]([NH:41][C@H:42]2[CH2:46][CH2:45][CH2:44][C@@H:43]2[NH2:47])=[N:39][CH:40]=1.[F:50][C:51]1[C:52]([N:61]2[N:65]=[CH:64][CH:63]=[N:62]2)=[C:53]([CH:57]=[C:58]([F:60])[CH:59]=1)[C:54](O)=[O:55]>>[F:50][C:51]1[C:52]([N:61]2[N:65]=[CH:64][CH:63]=[N:62]2)=[C:53]([CH:57]=[C:58]([F:60])[CH:59]=1)[C:54]([NH:47][C@H:43]1[CH2:44][CH2:45][CH2:46][C@@H:42]1[NH:41][C:38]1[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:48])[F:49])=[CH:40][N:39]=1)=[O:55]
Reactant: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(O)c1cc(F)cc(F)c1-n1nccn1
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1nccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cc(F)cc(F)c1-n1nccn1

Procedure:
Prepared according to the procedure for 5-chloro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 97) from (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 50 mg, 0.20 mmol) and 3,5-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 40a; 46 mg, 0.20 mmol) except this was purified by column chromatography (silica, 0-30% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: [Br:1][CH:2]1[C:7]2([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH2:8][CH2:9][C:4]([CH2:17][OH:18])([CH2:5][O:6]2)[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Br:1][CH:2]1[C:7]2([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH2:8][CH2:9][C:4]([CH:17]=[O:18])([CH2:5][O:6]2)[CH2:3]1
Reactant: OCC12CCC(c3ccc(Cl)cc3)(OC1)C(Br)C2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CC12CCC(c3ccc(Cl)cc3)(OC1)C(Br)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a stirred solution of [6-bromo-1-(4-chloro-phenyl)-2-oxa-bicyclo[2.2.2]oct-4-yl]-methanol (2.47 g, 7.45 mmol) in dichloromethane (100 ml) at −78° C., was added Dess-Martin periodinane (3.32 g, 7.82 mmol). The reaction mixture was allowed to warm to 0° C. for 30 minutes and then room temperature for 60 minutes. Most of the solvent was removed by evaporation under vacuum at the room temperature and the residue was purified by flash chromatography (heptanes/acetone 1/2) to afford 6-bromo-1-(4-chloro-phenyl)-2-oxa-bicyclo[2.2.2]octane-4-carbaldehyde (2.0 g, 81%) as colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.98-2.21 (m, 3H) 2.34-2.44 (m, 1H) 2.69-2.80 (m, 1H) 2.82-2.92 (m, 1H) 3.92-4.08 (m, 2H) 4.21-4.32 (m, 1H) 7.25 (d, J=8.60 Hz, 2H) 7.34 (d, J=8.60 Hz, 2H) 9.44 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CO>[Cu](I)I.CC(O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Clc1ccc(I)cn1
Reactant: Sc1ccc(Br)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Clc1ccc(Sc2ccc(Br)cc2)cn1
Temperature: 80 °C
Yield: 83.9 %

Procedure:
2-Chloro-5-iodopyridine (1.11 g, 4.64 mmol, Sigma-Aldrich, St. Louis, Mo.), 4-bromothiophenol (0.88 g, 4.64 mmol, Sigma-Aldrich, St. Louis, Mo.), copper iodide (44 mg, 0.23 mmol, Strem Chemical Inc, Newburyport, Mass.), potassium carbonate (1.28 g, 9.29 mmol), ethylene glycol (0.52 mL, 9.29 mmol), and iPrOH (10 mL) were added to a reaction vial. The vial was closed, purged with nitrogen for several minutes, and heated at 80° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (20 mL) and then EtOAc (20 mL). The combined organic extracts were combined and the solvents were removed under reduced pressure. The residue was absorbed onto a plug of silica gel and purified by column chromatography (24 g of silica gel, 0 to 10% EtOAc in hexanes), to provide 5-((4-bromophenyl)sulfanyl)-2-chloropyridine (1.17 g) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J=2.54 Hz, 1H), 7.81 (dd, J=2.54, 8.41 Hz, 1H), 7.57-7.61 (m, 2H), 7.54 (d, J=8.41 Hz, 1H), 7.30-7.35 (m, 2H); m/z (ESI, +ve ion) 300.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([N:12]3[CH:16]=[CH:15][C:14]([CH3:17])=[N:13]3)[C:8]=2[CH:18]=1)([O-])=O.C(=O)(O)[O-].[Na+].C(#N)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([N:12]3[CH:16]=[CH:15][C:14]([CH3:17])=[N:13]3)[C:8]=2[CH:18]=1
Reactant: Cc1ccn(-c2nsc3ccc([N+](=O)[O-])cc23)n1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccn(-c2nsc3ccc(N)cc23)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 5-nitro-3-(3-methylpyrazol-1-yl)-1,2-benzisothiazole (3.12 g, 12.0 mmol), sodium bicarbonate (2.00 g, 23.8 mmol), acetonitrile and water is stirred one hour at 70° C. and treated with sodium hydrosulfite (8.70 g, 50.0 mmol) in portions. The resultant mixture is stirred overnight at reflux, cooled to room temperature and diluted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is washed with a mixture of methylene chloride and ethyl acetate. The organic layer is decanted to afford the title compound as a viscous brown oil which is identified by NMR spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][CH:16]=O)=[CH:10][C:9]=2[F:18])[C:6](=[O:19])[CH:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].Cl.[CH3:31][C:32]([C:35]([O:37][CH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:36])([CH3:34])[NH2:33]>>[NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][CH2:16][NH:33][C:32]([CH3:31])([C:35]([O:37][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42]3)=[O:36])[CH3:34])=[CH:10][C:9]=2[F:18])[C:6](=[O:19])[CH:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: Nc1c(C(=O)c2ccc(F)cc2F)ccc(=O)n1-c1c(F)cc(CC=O)cc1F
Reactant: CC(C)(N)C(=O)OC1CCCC1
Agent: Cl
Product: CC(C)(NCCc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1)C(=O)OC1CCCC1

Procedure:
Example 2 was synthesised using Intermediate 4 and Intermediate 7 in a similar manner to Example 1.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[S:12].C[Si](C)(C)Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH4+].[OH-]>N1C=CC=CC=1.CO>[C:23]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:3]2[O:4][C@H:5]([CH2:8][OH:9])[C@@H:6]([OH:7])[C@H:2]2[CH3:1])[C:11](=[S:12])[N:13]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=S
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Product: C[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=S
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
To a stirred solution of 2′-deoxy-2′-methylthiocytidine (0.86 g, 3.15 mmol) in dry pyridine (20 ml) was added trimethylchlorosilane (2.0 ml, 15.75 mmol), and stirring continued for 15 min. Benzoyl chloride (2.18 ml, 18.9 mmol) was added to the solution followed by stirring for 2 hr. The mixture was then cooled in an ice-bath and MeOH (10 ml) was added. After 5 mins., NH4OH (20 ml, 30% aq.) was added and the mixture stirred for 30 min. The reaction mixture was then concentrated under vacuum and the residue purified by short silica gel (70 g) column chromatography. Elution with CH2Cl2:MeOH (9:1, v/v), pooling of appropriate fractions and evaporation furnished the title compound (0.55 g, 46.6%) which crystallized from EtOH as needles, m.p. 193-194° C.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=1[O:7][C:8]1[CH:26]=[CH:25][C:11]([CH2:12][N:13]2[C:17]([CH2:18][OH:19])=[C:16]([Cl:20])[N:15]=[C:14]2[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:10][CH:9]=1)([O:3]C)=[O:2]>C(O)C.[OH-].[Na+]>[CH2:21]([C:14]1[N:13]([CH2:12][C:11]2[CH:25]=[CH:26][C:8]([O:7][C:6]3[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=3[C:1]([OH:3])=[O:2])=[CH:9][CH:10]=2)[C:17]([CH2:18][OH:19])=[C:16]([Cl:20])[N:15]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(Oc2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(Oc2ccccc2C(=O)O)cc1
Yield: 87.5 %

Procedure:
A solution of 7.70 g of 1-[4-(2-carbomethoxyphenoxy)benzyl]-2-butyl-4-chloro-5-hydroxymethyl imidazole in 250 mL of ethanol and 125 mL of 10% aqueous sodium hydroxide was refluxed for 5 hours. After cooling, the reaction mixture was filtered, and the solvent was removed in vacuo. The residue was dissolved in water, and the solution was acidified to pH 3.5 using hydrochloric acid. The precipitated solid was recovered by filtration and recrystallized from acetone to furnish 6.52 g of 2-butyl-4-chloro-1-[4-(2-carboxyphenoxy)benzyl]-5-hydroxymethylimidazole, m.p. 178°-180°. NMR (200 MHz, DMSO) δ7.79 (d, 1H); 7.53 (t, 1H); 7.23 (t, 1H); 7.07 (d, 2H); 6.94 (d, 1H); 6.87 (d, 2H); 5.18 (s, 2H); 4.32 (s, 2H); 2.47 (t, 2H); 1.46 (quint., 2 H); 1.23 (sext., 2H); 0.78 (t, 3H).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.Cl.[OH-:22].[Na+].[OH2:24]>>[CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:17]([O-:24])(=[O:22])[CH3:18]
Reactant: [OH-]
Reactant: O
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: Cl
Agent: [Na+]
Product: CC(=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Sertraline hydrochloride (125 g) was slurried in a mixture of water (1 L) and (2.5 L). NaOH (25% aqueous, 35 mL) was added. Sertraline base partitioned into the hexane phase. The hexane layer was separated. The aqueous layer was extracted a second time with hexane (500 mL). The hexane layers were combined. The solution of sertraline base in hexane was heated to 50° C. Glacial acetic acid (23 ml) was added to the solution of sertraline base. The reaction mixture was stirred at 50° C. for 30minutes. The reaction mixture was allowed to cool to room temperature and stirred at room temperature overnight. The crystals were filtered and washed five times with a total of 250 mL of hexane. The solids were dried at 40° C. in a vacuum oven for 48 hours. The yield was 89%. mp 126° C.
Reaction SMILES: [O:1]=[C:2]([NH:7][C@H:8]([C:26]([OH:28])=O)[CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:3][CH2:4][CH2:5][CH3:6].[O:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[O:35][NH2:36].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[O:28]=[C:26]([NH:36][O:35][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][O:29]1)[CH:8]([NH:7][C:2](=[O:1])[CH2:3][CH2:4][CH2:5][CH3:6])[CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: NOC1CCCCO1
Reactant: CCCCC(=O)N[C@@H](CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCCCC(=O)NC(CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 5 h
Yield: 58.6 %

Procedure:
To a solution of the title compound of Example 11e (690 mg, 1.64 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (192 mg, 1.64 mmol) in anhydrous THF (40 mL), cooled to zero degrees C., was added EDC (330 mg, 1.72 mmol) and HOBT (264 mg, 1.72 mmol). After stirring at zero degrees C. for 5 hours and at room temperature for 18 hours, the solution was concentrated. The residue was dissolved into EtOAc (50 mL) and washed with 1M KHSO4 (2×50 mL), saturated NaHCO3 (2×50 mL), and brine (1×50 mL) and dried over Na2SO4. Purification by chromatography (1:1 EtOAc/hexane) yielded the title compound as a colorless oil (500 mg, 59%): Anal. Calcd. for C25H32N2O6S2: C, 57.67; H, 6.19; N, 5.38. Found: C, 57.48; H, 6.37; N, 5.11.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[C@@H:23]([OH:24])[C:22](=[O:25])[N:21]([CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH3:30])[C:20]3[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=3[S:18]2)=[CH:13][CH:12]=1.[Cl:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][C:38]=1[N+:46]([O-:48])=[O:47].[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51]>C(Cl)Cl.CC(C)=O>[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51].[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C@H:17]2[C@@H:23]([O:24][C:41](=[O:42])[C:40]3[CH:44]=[CH:45][C:37]([Cl:36])=[C:38]([N+:46]([O-:48])=[O:47])[CH:39]=3)[C:22](=[O:25])[N:21]([CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH3:30])[C:20]3[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=3[S:18]2)=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C)CCN1C(=O)[C@H](OC(=O)c2ccc(Cl)c([N+](=O)[O-])c2)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Yield: 62.1 %

Procedure:
0.5 ml of triethylamine is added to a solution of 430 mg of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(-N-methyl-N-ethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride in 10 ml of methylene chloride, and 270 mg of 4-chloro-3-nitrobenzoyl chloride are added thereto under ice-cooling and stirring. The mixture is stirred at room temperature overnight. The mixture is washed with water, dried and then condensed under reduced pressure to dryness. The residue is dissolved in acetone, and 90 mg of oxalic acid are added thereto. The mixture is allowed to stand. Crystalline precipitates are collected by filtration and dried. 410 mg of (+)-cis-2-(4-methoxyphenyl)-3-(4-chloro-3-nitrobenzoyloxy)-5-[2-(N-methyl-N-ethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate are obtained as colorless needles. Yield: 61%.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[BrH:12].[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:11][C:10]1[CH:9]=[C:8]2[C:3](=[C:1]([Br:12])[N:2]=1)[N:4]=[CH:5][CH:6]=[CH:7]2
Reactant: N#CCc1cccnc1C#N
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Nc1cc2cccnc2c(Br)n1

Procedure:
Through a stirred solution of 2-Cyano-3-pyridylacetonitrile (3.6 g, 0.025 mol) in toluene (80 ml) is bubbled HBr for 5 h. Then, 4N NaOH is carefully added and the suspension stirred vigorously. The mixture is filtered and the product washed with water and dried. Crystallisation from toluene affords the title compound. Mass M+H 225. Melting point 188° C., decomposition.
Reaction SMILES: C(O[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=O)C.[OH2:20]>>[CH3:19][C:14]1[C:13]2[C:18](=[CH:4][N:6]=[C:7]3[C:8]=2[C:9](=[O:20])[CH2:10][CH:11]=[CH:12]3)[CH:17]=[CH:16][CH:15]=1
Reactant: O
Reactant: CCOC(=O)Nc1ccccc1-c1ccccc1C
Product: Cc1cccc2cnc3c(c12)C(=O)CC=C3
Temperature: 170 °C
Yield: 65 %

Procedure:
The above compound, N-ethoxycarbonyl-2-amino-2′methyl biphenyl (6.7 g, 26 mmol) was added to polyphosphoric acid (15 g) and heated to 170° C. overnight. After cooling, water was added and the white precipitate collected by vacuum filtration to give the 10-methyl-phenanthridinone (3.5 g, 65% yield) whose structure was consistent with CGMS and NMR.
Reaction SMILES: F[C:2]1[C:22]([F:23])=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>CS(C)=O>[F:23][C:22]1[C:2]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=3)[CH2:36][CH2:35]2)=[CH:3][C:4]2[N:13]=[CH:12][C:11]3[N:10]([CH3:14])[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=3[C:5]=2[CH:21]=1
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(F)c(F)cc3c2c1=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2cnc3cc(N4CCN(c5ccc(F)cc5)CC4)c(F)cc3c2c1=O
Temperature: 90 °C
Reaction time: 96 h
Yield: 34.1 %

Procedure:
A suspension of 1.5 g of ethyl 8,9-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and 1.7 g of 1-(4-fluorophenyl)piperazine in 30 cm3 of dimethyl sulphoxide was heated, with stirring, at a temperature of 90° C. for 4 days. After cooling to 20° C., the mixture was poured into 150 cm3 of ice-cold water. The medium was extracted 3 times with 150 cm3 of dichloromethane. The organic extracts were washed 3 times with 100 cm3 of water and dried over sodium sulphate. After filtration and concentration under reduced pressure (5.2 kPa), the compound obtained was purified by chromatography on silica gel (0.06-0.20 mm). Elution was carried out with 7.8 liters of a dichloromethane-ethanol mixture (97-3 by volume), and 200 cm3 fractions were collected. The fractions between 5.6 and 7.8 liters were concentrated under reduced pressure (5.2 kPa). 0.77 g of ethyl 9-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of yellow crystals, which melted at 300° C.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[CH3:28]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>ClCCl.CO>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([O:20][CH3:28])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
Boc-Lys(Cbz)-OH (25 g) was dissolved in dichloromethane/methanol=9/1 v/v (500 ml). TBTU (21.1 g) was added and the solution adjusted to pH 8 by addition of triethylamine. The reaction mixture was stirred for 1 h at room temperature. The mixture was washed successively with cold 2N hydrogen chloride solution, water, 5% sodium hydrogencarbonate, and water. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica (eluent: ethyl acetate/heptane =1/4 v/v) to yield Boc-Lys(Cbz)-OMe (26.7 g). TLC: Rf=0.79, silica gel, ethyl acetate/heptane=3/1 v/v.