Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[N:63]=[C:64]([O:66][CH:67]([CH3:69])[CH3:68])[NH2:65]>CN(C=O)C>[CH:67]([O:66][C:64]1[N:65]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:28][N:63]=1)([CH3:69])[CH3:68]
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: CC(C)OC(N)=NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 500 mg (1.20 mmol) of the carboxylic acid from Example 9A in 15.0 ml of DMF were added, at RT, 545 mg (1.43 mmol) of HATU and 0.46 ml (2.63 mmol) of N,N′-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, the mixture was admixed with 565 mg (3.56 mmol; 75% purity) of isopropyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at RT for 2 h and at 120° C. for 2 h. The reaction solution was concentrated under reduced pressure and purified directly by means of preparative HPLC. Yield: 344 mg (58% of theory)
Reaction SMILES: [CH:1]([N:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([C:13]#[N:14])[C:6]1=[O:15])([CH2:3][CH3:4])[CH3:2].[Br:16]N1C(=O)CCC1=O.CN(C)C=O>C(=O)([O-])O.[Na+]>[Br:16][C:9]1[C:8]([O:11][CH3:12])=[C:7]([C:13]#[N:14])[C:6](=[O:15])[N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(C)n1ccc(OC)c(C#N)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)n1cc(Br)c(OC)c(C#N)c1=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A mixture of 1-(sec-butyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step A (260 mg), N-bromosuccinimide (269 mg) and N,N-dimethylformamide (3 mL) was stirred at 60° C. for 2 hr 30 min. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted threetimes with ethyl acetate. The extracts were combined, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (260 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])=[CH:7][CH:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1>[CH3:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2c(C)cccc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1

Procedure:
A solution of 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid methyl ester (5 g, 20.8 mmol) in tetrahydrofuran (70 mL) was treated dropwise under nitrogen with 1 N lithium hydroxide (45 mL). The mixture was heated at reflux for 8 hours, filtered warm (Celite) and concentrated in vacuo to remove organic solvents. The aqueous residue was acidified in the cold to pH 3 with 2N hydrochloric acid. The precipitate was collected, washed with water ad dried. The residue was dissolved in ethyl acetate, treated with charcoal (with warming), filtered (Celite) and evaporated to yield the title compound as an off-white crystalline solid.
Reaction SMILES: O.[Na].[Na].[Na].[C:5]([C:8]1[N:9]=[N:10][NH:11][C:12]=1[SH:13])([OH:7])=[O:6].CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O.O.Cl>CC(C)=O>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:13][C:12]3[NH:11][N:10]=[N:9][C:8]=3[C:5]([OH:7])=[O:6])[CH2:28][S:27][C@H:22]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)c1nn[nH]c1S
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3[nH]nnc3C(=O)O)CS[C@H]12

Procedure:
4-Carboxy-1,2,3-triazole-5-thiol trisodium salt hydrate (4.4 g., 20 mmol.) was added to a stirred suspension of 4.08 g. (15 mmol.) of 7-aminocephalosporanic acid in 30 ml. of water and 15 ml. of acetone. The reaction mixture was quickly acidified to pH 7.3 with dilute hydrochloric acid, then heated at 65° for 4.5 hours. The mixture was cooled (ice bath), brought to pH 2.4 with dilute hydrochloric acid and the precipitate was collected, washed with water and acetone and dried in vacuo over phosphorus pentoxide to give the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:7][CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[C:14]([O:13][C:11](=[O:12])[NH:10][C:8]1[S:9][C:5]([CH2:3][OH:2])=[CH:6][N:7]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(CO)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-tert-butoxycarbonylamino-thiazole-5-carboxylic acid methyl ester (compound 62.1; 21.7 mmol) in THF was slowly added LAH (25 mL of a 1.0 M solution in THF). After stirring for 1 hour at room temperature the reaction is cautiously hydrolyzed with the sequential addition of water (0.95 mL), 15% aqueous NaOH (0.95 mL) and additional water (2.85 mL). After stirring for 30 minutes the reaction is filtered through a pad of Celite and the filtrate is dried and concentrated to give (5-hydroxymethyl-thiazol-2-yl)-carbamic acid tert-butyl ester (compound 62.2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:33])[CH2:14][C:15]2[C:16]([O:25]CC3C=CC=CC=3)=[C:17]3[C:21](=[CH:22][C:23]=2[Cl:24])[CH2:20][CH2:19][CH2:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:33])[CH2:14][C:15]2[C:16]([OH:25])=[C:17]3[C:21](=[CH:22][C:23]=2[Cl:24])[CH2:20][CH2:19][CH2:18]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)Cc2c(Cl)cc3c(c2OCc2ccccc2)CCC3)cc1
Agent: [Pd]
Agent: Cl
Product: Cc1ccc(S(=O)(=O)OCC(O)Cc2c(Cl)cc3c(c2O)CCC3)cc1
Yield: 91.1 %

Procedure:
Treatment of (±)-3-[4-(benzyloxy)-6-chloro-2,3-dihydro-1H-inden-5-yl]-2-hydroxypropyl 4-methylbenzenesulfonate (6.30 g, 0.013 mol) with palladium on carbon (5 wt. %, 0.51 g) and hydrogen chloride (3.4 mL, 4 M in isopropanol) generally according to the procedure described for Intermediate 4 afforded 4.7 g (91%) of (±)-3-(6-chloro-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-hydroxypropyl 4-methylbenzenesulfonate as a light yellow solid. mp 125-127° C.; Anal. calcd. for C19H21ClO5S.0.1H2O: C, 57.24; H, 5.36. Found: C, 56.92; H, 5.23.
Reaction SMILES: O1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([OH:19])[CH:13]=2)=[O:9].[OH-].[Na+].C1(CBr)CC1>O.CN(C)C=O>[CH3:6][O:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([O:19][CH2:2][CH:3]1[CH2:5][CH2:4]1)[CH:13]=2)=[O:9]
Reactant: COC(=O)c1cc2ccc(O)cc2[nH]1
Reactant: C1CCOC1
Agent: BrCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(OCC3CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
To a tetrahydrofuran (8 mL) solution of 6-hydroxy-1H-indole-2-carboxylic acid methyl ester (395 mg, 2.07 mmol) described in Production Example 73-1-1 was added 5 N aqueous sodium hydroxide solution (414 μL, 2.07 mmol), which was concentrated under a reduced pressure. To an N,N-dimethylformamide (8 mL) solution of the residue was added cyclopropylmethyl bromide (241 μL, 2.48 mmol) at room temperature followed by stirring at room temperature for 12 hours. Moreover, after stirring at 50° C. for 4 hours, water was added to the reaction solution at room temperature followed by extraction with ethyl acetate. The organic layer was washed with water and sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (297 mg, 59%) as a white solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.O[CH2:13][C:14]1[CH:39]=[CH:38][C:17]([O:18][CH2:19][C:20]2[O:24][N:23]=[C:22]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:21]=2)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]2[O:24][N:23]=[C:22]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[N:21]=2)=[CH:38][CH:39]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1c1noc(COc2ccc(CO)cc2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1c1noc(COc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
Phthalimide (480 mg) was added to a solution of tert-butyl (2S)-2-(5-[4-(hydroxymethyl)phenoxymethyl]-1,2,4-oxadiazol-3-yl)-1-piperidinecarboxylate [see Preparation 13] (1.06 g) in tetrahydrofuran (10 ml). The mixture was cooled to 0° C. and triphenylphosphine (1.07 g) was added followed by diethylazodicarboxylate (0.642 ml). The resulting yellow solution was stirred at 0° C. for 10 mins. and then at room temperature for 1 hour. The mixture was evaporated to a low volume under reduced pressure and partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 70:30, by volume, hexane:ethyl acetate to afford tert-butyl (2S)-2-[5-(4-[(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl]phenoxymethyl)-1,2,4-oxadiazol-3-yl]-1-piperidinecarboxylate (1.09 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1.C1C(=O)N([I:19])C(=O)C1>>[F:11][C:2]([F:1])([F:10])[C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[I:19]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cccc(C(F)(F)F)n1
Product: Nc1ccc(I)c(C(F)(F)F)n1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 4.8 g (30 mmol) 6-trifluoromethyl-pyridin-2-ylamine and 6.7 g (30 mmol) NIS. Yield after precipitation from the reaction mixture and isolation of additional product from the mother liquid by chromatography in silica gel: 5.73 g (67%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][NH:31][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCC1CCCCC1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NCC3CCCCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 76 but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cyclohexanemethylamine (500 μl) as a white powder (27 mg; 44%). HPLC, Rt: 4.11 min. (purity 99.8%). LC/MS, M+(ESI): 419.4, M−(ESI): 417.4.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12]3[C:13](=[O:20])[C:14](=[O:19])[C:15]=3OCC)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH3:21]>C(O)C>[NH2:21][C:15]1[C:14](=[O:19])[C:13](=[O:20])[C:12]=1[NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2
Reactant: CCOc1c(Nc2cccc3cnccc23)c(=O)c1=O
Reactant: N
Solvent: CCO
Product: Nc1c(Nc2cccc3cnccc23)c(=O)c1=O
Temperature: 45 °C
Yield: 77 %

Procedure:
A suspension of the the product from Example 8, Step 1 (0.190 g, 0.700 mmol) in ethanol (3.5 mL) was saturated with ammonia, capped, and heated to 45° C. for three hours. The mixture was cooled, concentrated, and triturated with diethylether. Crude product was recrystallized from dimethylformamide/water to give 0.129 g (77%) of the title compound as a pale yellow solid, one-eighth hydrate: mp 215° C.; 1H NMR (DMSO-d6): δ9.87 (s, 1H), 9.34 (s, 1H), 8.60 (d, 1H), 7.40-8.60 (broad signal, NH2), 8.02 (d, 1H), 7.86 (d, 1H), 7.77 (d, 1H), 7.68 (t, 1H). IR (KBr): 3200, 1800, 1690, 1650 cm-1 ; MS (m/z) 240(MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[CH2:17]([O:19][C:20](=[O:27])[C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])[CH3:18]>C1CCCCC1.C(OCC)(=O)C>[CH2:17]([O:19][C:20](=[O:27])[C:21]([CH3:26])([CH3:25])[C:22]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)=[O:23])[CH3:18]
Reactant: CCOC(=O)C(C)(C)C(=O)O
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCOC(=O)C(C)(C)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
The title compound is prepared in analogy to example 2, starting from 4-(3-fluoro-benzyloxy)-phenylamine and 2,2-dimethyl-malonic acid monoethyl ester (Holmes et al., J. Amer Chem. Soc. 1984, 106, 2353). Yield after flash-chromatography with cyclohexane/ethyl acetate 7:3: 79%. Colorless oil. MS: m/e=359 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[NH:9][CH2:8][CH2:7]2.C(N(C(C)C)CC)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>ClCCCl.CO>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=1)[N:9]([C:39]([NH:38][C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1)=[O:40])[CH2:8][CH2:7]2
Reactant: Fc1cccc2c1C(c1ccc(C(F)(F)F)cc1)NCC2
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)N1CCc2cccc(F)c2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 8-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.4 g, 1.4 mmol) and diisopropylethylamine (0.5 mL, 2.9 mmol) in anhydrous 1,2-dichloroethane (10 mL) was treated with 4-fluorophenyl isocyanate (0.14 mL, 1.2 mmol) and stirred at RT for 16 h. The solvent was removed under vacuum and the residue was purified by preparative HPLC [gradient 10-90% MeCN (0.1% TFA)/H2O (0.1% TFA)] to give the pure product which was dissolved in methanol (10 mL) and neutralized by passing the solution through a Polymer Lab-HCO3 Macroporous resin cartridge, and the filtrate was concentrated to give 8-fluoro-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI pos. ion) m/z: 433 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccc3[nH]ccc3c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a stirred solution of 80 mg (9.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 55 mg (0.417 mmol) of 5-aminoindole was added. The resulting mixture was stirred at room temperature for one hour and the final product was collected by filtration and washed with diethylether to yield the title compound (97 mg, 93.3% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7]1.Cl.[C:19]1([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[CH3:13][N:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7][CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]2[CH2:27][CH:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)[C:11]1=[O:12]
Reactant: CN1C(=O)C(CCCCBr)Sc2ccccc21
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1C(=O)C(CCCCN2CC=C(c3ccccc3)CC2)Sc2ccccc21
Yield: 70.3 %

Procedure:
2.4 g (=0.0076 m) of 2-(4-bromobutyl)-4-methyl-2H-1,4-benzothiazine-3(4H)-one, 1.49 g (=0.0076 m) of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and 3.09 g of triethylamine were introduced into 20 ml of toluene. The resulting suspension was heated for 10.5 hours with stirring. The mixture was worked up by cooling and introducing the suspension into 30 ml of 20% strength aqueous hydrochloric acid solution. The resulting precipitate was filtered out, and the aqueous phase was rendered alkaline and extracted with 200 ml of dichloromethane. The precipitate was introduced into an aqueous alkaline solution and extracted with 450 ml of dichloromethane. The combined dichloromethane extracts were washed, dried over sodium sulfate, and the solvent was distilled off. 2.1 g of 4-methyl-2-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl]-2H-1,4-benzothiazine-3(4H)-one were obtained as a beige-colored powder.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:11][C:12]1[N:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]3[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH:20]3[CH2:19]2)=[CH:14][CH:13]=1>>[Br:8][C:6]1[CH:7]=[C:2]([NH:11][C:12]2[N:17]=[CH:16][C:15]([N:18]3[CH2:19][CH:20]4[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH:21]4[CH2:22]3)=[CH:14][CH:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3ccc(N)nc3)CC2C1
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: Cn1cc(Br)cc(Nc2ccc(N3CC4CN(C(=O)OC(C)(C)C)CC4C3)cn2)c1=O
Yield: 59.9 %

Procedure:
Following Example 188c, 3,5-dibromo-1-methylpyridin-2(1H)-one (212 mg, 0.79 mmol) and 335b (200 mg, 0.66 mmol) were reacted to give 335c as a yellow solid (194 mg, 60%). MS: [M+H]+ 492
Reaction SMILES: OO.O.[OH-].[Li+].[CH2:6]([S:26][C@@H:27]([CH2:43][CH3:44])[C:28](N1[C@@H](C)[C@@H](C2C=CC=CC=2)OC1=O)=[O:29])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25].[O-:45]S([O-])=O.[Na+].[Na+].Cl>O1CCCC1.O>[CH2:6]([S:26][C@@H:27]([CH2:43][CH3:44])[C:28]([OH:29])=[O:45])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCS[C@@H](CC)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCS[C@@H](CC)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
Hydrogen peroxide (30% in water, 0.71 mL, 6.91 mmol) and lithium hydroxide monohydrate (0.15 g, 3.46 mmol) was added to a solution of (4S,5R)-3-((S)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenylthio)butanoyl)-4-methyl-5-phenyloxazolidin-2-one (0.95 g, 1.73 mmol) in tetrahydrofuran (12 mL) and water (4 mL) held at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 30 minutes. 10% Na2SO3 (aq) (30 mL) was added, the pH was adjusted to ˜2 with 5M HCl and the mixture was extracted twice with heptane (30 mL). The combined organic extract was dried (Na2SO4), filtered and concentrated. The residue was subjected to flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (98:8→1:1) as eluent. Concentration of the appropriate fractions afforded 0.15 g (17% yield) of the title product as an oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:9]2[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][C:8]=2[O:7][N:6]=1)[C:2]#[CH:3].[ClH:22]>C(OCC)(=O)C>[ClH:22].[CH2:1]([O:4][C:5]1[C:9]2[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][C:8]=2[O:7][N:6]=1)[C:2]#[CH:3]
Reactant: C#CCOc1noc2c1CN(C(=O)OC(C)(C)C)CCC2
Agent: Cl
Solvent: CCOC(C)=O
Product: C#CCOc1noc2c1CNCCC2
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 530 mg (1.82 mmol) of tert.butyl 3-(2-propynyloxy)-5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepine-5-carboxylate (from Example 8) in ethyl acetate (10 ml) was added 10 ml of 1N solution of hydrochloric acid in ethyl acetate. The mixture was stirred at room temperature for 60 hours. The precipitate was collected and recrystallized from acetonitrile-ether yielding 267 mg (64%) of analytically pure title compound, MP 173°-175° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:11][NH2:12])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:18]>CCO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:11]([NH2:12])=[O:18])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NSc1nc(N)nc2nc[nH]c12
Solvent: CCO
Product: Nc1nc(S(N)=O)c2[nH]cnc2n1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
2-Aminopurine-6-sulfenamide 2 (182 mg, 1 mmol) was suspended in EtOH (100 mL) and cooled to 0° C. m-Chloroperoxybenzoic acid (85%, 200 mg, 1 mmol) was added portionwise during 1 h with stirring, and stirring continued for additional 30 min. After filtration, the filtrate was concentrated to half the volume in vacuo. Ethyl ether (50 mL) was added and allowed to stand in a refrigerator overnight. The precipitate was collected by filtration and washed with ether to obtain 115 mg (58%) of the desired compound, mp. >250° C., : UV λmax (pH 1) 332 nm (ε 4,600) 240 nm (sh): λmax (pH 7) 326 nm (ε 4,500): λmax (pH 11) 326 nm (ε 4,200), 283 nm (ε 2,800): IR(KBr): 1140 (SO) cm-1 : 1H NMR (DMSO-d6): δ 6.59 (br s, 2,--SONH2, exchangeable in D2O), 6.57 (br s, 2, NH2, exchangeable in D2O), 8.12 (s, 1, C8H), 12.50 (br s, 1, NH, exchangeable in D2O). Anal. Calcd for C5H6N6OS (198.21): C, 30.30: H, 3.05: N, 42.40: S, 16.18. Found: C, 30.02: H, 2.82: N, 42.64: S, 15.97.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: OCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
1.00 g of 1-(diphenylmethyl)piperazine was dissolved in 10 ml of N,N-dimethylformamide; 0.42 ml of 2-(2-chloroethoxy)ethanol, 0.59 g of sodium iodide and 0.66 g of potassium carbonate were added, followed by stirring at 100° C. for 1 hour. Ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with dichloromethane:ethyl acetate:methanol (10:10:1). The desired fraction was collected and concentrated to yield 1.47 g of the title compound.