Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]([O:15]CC)=[O:14])=[C:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:7]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][CH:24]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CC(=O)OCC)c(Cc2ccc(C(=O)OC)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(Cl)c(CC(=O)O)c(Cc2ccc(C(=O)O)cc2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.2 %

Procedure:
220 mg of the product of Example 1 were introduced into 6.6 ml of ethanol and 0.6 ml of sodium hydroxide and after stirring at ambient temperature for 3 days and followed by evaporation to dryness under reduced pressure at a temperature below 40° C., the residue was dissolved in 2 ml of water and neutralized by the addition of approximately 0.6 ml of 2N hydrochloric acid. After separating and washing with water, 160 mg of product were obtained which was crystallized from 5 ml of hot isopropanol with 5 ml of water added to it. After 24 hours at 0°+5° C., 90 mg were separated and crystallized from 9 ml of ethyl acetate at reflux. After standing at rest for 24 hours, separation took place to obtain 46 mg of the expected product melting at approx. 205° C.
Reaction SMILES: O.[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:5])[CH:3]=[O:4].[CH3:17][S:18][CH:19]1[NH:22][C:21](=[O:23])[CH2:20]1.O>C1C=CC=CC=1>[OH:4][CH:3]([N:22]1[CH:19]([S:18][CH3:17])[CH2:20][C:21]1=[O:23])[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5]
Reactant: CSC1CC(=O)N1
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Solvent: O
Product: CSC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 106.3 %

Procedure:
p-Nitrobenzyl glyoxylate monohydrate (1.11 g, 4.87 mmoles) was added to a solution of 4-methylthio-2-azetidinone (570 mg, 4.87 mmoles) in benzene (30 ml) and the resulting solution was heated, whilst the water produced was removed by azeotropic distillation. After the water had been distilled off completely, the mixture was concentrated and heated at a bath temperature of 100°-110° C. for 12 hours. The solvent was then distilled off under reduced pressure to give 1.69 g of the desired compound as a viscous oil. This product may be employed in subsequent reactions without purification, although it contains a small amount of the starting compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:24])[C:10]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14]2)([CH3:12])[CH3:11])=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+].Cl.[NH2:28][OH:29].C(=O)(O)[O-].[Na+]>CO.CC(O)C.C(OCC)(=O)C>[OH:24][CH:9]([C:6]1[CH:7]=[CH:8][C:3](/[C:1](=[N:28]/[OH:29])/[NH2:2])=[CH:4][CH:5]=1)[C:10]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14]1)([CH3:12])[CH3:11]
Reactant: NO
Reactant: CCOC(=O)[C@H]1CCCN(C(C)(C)C(=O)c2ccc(C#N)cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCCN(C(C)(C)C(O)c2ccc(/C(N)=N/O)cc2)C1
Temperature: 75 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a mixture of (S)-ethyl 1-(1-(4-cyanophenyl)-2-methyl-1-oxopropan-2-yl)piperidine-3-carboxylate (90 mg, 0.274 mmol) in MeOH (5 mL) was added sodium borohydride (15 mg, 0.396 mmol). After 1 hr, the reaction was quenched with water. The reaction mixture was diluted with ethyl acetate and washed with sat NaCl. The organic layer was dried MgSO4, filtered, and concentrated. To a mixture of hydroxylamine hydrochloride (38.1 mg, 0.548 mmol) and sodium bicarbonate (92 mg, 1.096 mmol) in 2-propanol (10 mL) was added the crude product from step one. The reaction mixture was heated at 75° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried MgSO4, filtered, and concentrated to yield 100 mg of (3S)-ethyl 1-(1-hydroxy-1-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)-2-methylpropan-2-yl)piperidine-3-carboxylate. MS (m+1)=364. HPLC Peak RT=0.27 minutes (Analytical Method B).
Reaction SMILES: C([O+](CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH2:19])=O.Cl.[C:21]1([C:27]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:35]3[C@H:31]([CH2:32][NH:33][CH2:34]3)[C:30](=[O:36])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(N(CC)CC)C>[NH:19]=[C:17]([N:33]1[CH2:32][C@H:31]2[C@H:35]([C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:28][CH2:29][C:30]2=[O:36])[CH2:34]1)[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH3:8]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: COc1ccccc1CC(N)=O
Agent: CC[O+](CC)CC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=N)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 20 h
Yield: 29 %

Procedure:
Triethyloxonium tetrafluoborate (8.4 g) is added to a stirred suspension of 2-(2-methoxyphenyl)acetamide (6.6 g) in anhydrous dichloromethane (20 cc). Stirring of the reaction mixture is continued for 20 hours at ambient temperature. The mixture is cooled to +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (9.8 g) and triethylamine (10.4 cc) in dichloromethane (60 cc) is then added. After the temperature has returned to ambient temperature, the reaction mixture is refluxed for 4 hours. It is then treated, after the temperature has returned to ambient temperature, with a 10% aqueous potassium carbonate solution (40 cc); the organic phase is washed with distilled water (20 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (20 cc); the crystals obtained are drained, washed with acetonitrile (5 cc) and with isopropyl ether (10 cc) and dried. The crystals are recrystallized from acetonitrile (45 cc); the crystals obtained are drained and dried. (3aR,7aR)-2-[1-imino-2-(2-methoxyphenyl)ethyl]-7,7-diphenyl-4-perhydroisoindolone (3.8 g) melting at 191° C. is obtained. [α]D20 =-255° (c=1, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:11]([O:13]CC)=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1>Cl>[NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(N)ccc21
Agent: Cl
Product: Nc1ccc2c(c1)ncn2C(CC(=O)O)c1ccccc1

Procedure:
A solution of ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (40 mg, 129 μmol) in hydrochloric acid (20 mL of a 5N solution) was stirred at room temperature for 72 hours. The solution was evaporated in vacuo and purified by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=2.61 min, MH+ 282].
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:15])[C@H:10]([OH:14])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(OC)(OC)OC.CSC.B.B([O-])([O-])[O-].CSC>O1CCCC1.CO>[CH2:1]([O:8][C@H:9]([CH3:15])[C@H:10]([OH:14])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](O)C(=O)O
Agent: B
Agent: COB(OC)OC
Agent: [O-]B([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@@H](OCc1ccccc1)[C@H](O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,3R)-3-(benzyloxy)-2-hydroxybutanoic acid (the product of step i) (0.79 g) and trimethyl borate (0.67 mL) in anhydrous tetrahydrofuran (4 mL) at 0° C. was added dropwise borane-dimethyl sulfide complex (3 mL, 2M in tetrahydrofuran). The reaction mixture was stirred at room temperature overnight, then further borate-dimethyl sulfide complex (3 mL, 2M in tetrahydrofuran) was added at 0° C. and the reaction mixture stirred at room temperature for a further 2d. The mixture was cooled to 0° C. and methanol (10 mL) slowly added. When effervescence had ceased, the volatiles were evaporated, further methanol added and the mixture concentrated again to give the subtitle compound as a yellow oil which was used without further purification. Yield: 0.68 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[CH2:14][CH3:15].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[OH:26].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH2:10][O:26][C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[Cl:18])[CH:7]=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[CH2:14][CH3:15]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CCC(=O)Nc1ccc(CBr)cc1C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)Nc1ccc(COc2ccc(Cl)cc2Cl)cc1C(=O)OC
Reaction time: 4 h
Yield: 71.8 %

Procedure:
A mixture of 5-bromomethyl-2-propionylamino-benzoic acid methyl ester (200 mg, 0.67 mmol), 2,4-dichloro-phenol (119 mg, 0.73 mmol) and potassium carbonate (278 mg, 2.01 mmol) in acetone (5 ml) was heated to reflux. After 4 hours, the reaction mixture was allowed to reach room temperature, was acidified with 1 M HCl and the resulting precipitate collected by filtration, washed with water and dried under vacuum to give pure 5-(2,4-dichloro-phenoxymethyl)-2-propionylamino-benzoic acid methyl ester (184 mg, 72%). This was hydrolyzed in ethanol (3 mL) and 1.0 M NaOH (3 mL) overnight and then acidified with 1.0 M HCl. The resulting precipitate was collected by filtration, washed with water and dried under vacuum (165 mg, 93%). 1H-NMR (DMSO-d6) δ 1.12 (t, 3H), 2.42 (q, 2H), 5.21 (s, 2H), 7.27 (d, 1H), 7.39 (dd, 1H), 7.60 (d, 1H), 7.66 (dd, 1H), 8.09 (d, 1H), 8.53 (d, 1H), 11.18 (s, 1H), 13.71 (bs, 1H).
Reaction SMILES: [C:1]([O:5]/[N:6]=[C:7](\[OH:24])/[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[C:30](Cl)(=O)[C:31](Cl)=O>C1COCC1>[C:1]([O:5]/[N:6]=[C:7](\[O:24][CH2:30][CH3:31])/[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[OH:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)O/N=C(\O)c1cccnc1C(=O)c1cc(Br)ccc1O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCO/C(=N\OC(C)(C)C)c1cccnc1C(=O)c1cc(Br)ccc1O
Reaction time: 2 h

Procedure:
To a solution of (Z)-2-(5-bromo-2-hydroxybenzoyl)nicotinic acid O-t-butyloxime (540 mg) and DMF (0.02 ml) in THF (6 ml) was added, at room temperature, oxalyl chloride (0.33 ml). The mixture was stirred for 2 hours at the same temperature and then concentrated, which was dissolved in THF (2 ml). To the solution was added ethanol (8 ml) at room temperature. The mixture was stirred for 1.5 hour at the same temperature and concentrated. To the concentrate was added water, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give ethyl(Z)-2-(5-bromo-2-hydroxybenzoyl)nicotinate O-t-butyloxime (403 mg) (Compound 139).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O.[CH2:22]([C:24]1[S:28][CH:27]=[C:26]([C:29]([N:31]2[CH2:36][C:35]3([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[O:34][CH2:33][CH2:32]2)=[O:30])[CH:25]=1)[CH3:23].[Si]([O:49][CH2:50][CH2:51][C:52]1[CH:53]=[CH:54][C:55]([F:60])=[C:56]([CH:59]=1)[CH:57]=O)(C(C)(C)C)(C)C.C(O)(=O)C>CN1C(=O)CCC1>[CH2:22]([C:24]1[S:28][CH:27]=[C:26]([C:29]([N:31]2[CH2:36][C:35]3([CH2:41][CH2:40][N:39]([CH2:57][C:56]4[CH:59]=[C:52]([CH2:51][CH2:50][OH:49])[CH:53]=[CH:54][C:55]=4[F:60])[CH2:38][CH2:37]3)[O:34][CH2:33][CH2:32]2)=[O:30])[CH:25]=1)[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(F)c(C=O)c1
Reactant: CCc1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)ccc4F)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
Sodium triacetoxyborohydride (0.225 g) was added to a stirred solution at 0° C. of (5-ethylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 99, step a) (0.289 g) and 5-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzaldehyde (example 100, step b) (0.2 g) and acetic acid (0.041 ml) in NMP (20 mL). The reaction mixture was then stirred at 20° C. for 18 hours. Further sodium triacetoxyborohydride (0.150 g) was added and stirring continued for 4 hours. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The resultant gum was dissolved in THF (20 mL) and treated with TBAF (1M in THF, 1.4 ml). The solution was allowed to stand at 20° C. for 8 hours. The solvent was evaporated under reduced pressure and the crude product was purified by flash silica chromatography using 2% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.18 g.
Reaction SMILES: [CH3:1][C:2]1([C:7]23[CH2:14][CH:13]4[CH2:15][C:9]([CH2:16][N:17]5[CH2:21][CH2:20][CH2:19][S:18]5(=[O:23])=[O:22])([CH2:10][CH:11]2[CH2:12]4)[CH2:8]3)OCC[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.CCOC(C)=O>[O:22]=[S:18]1(=[O:23])[CH2:19][CH2:20][CH2:21][N:17]1[CH2:16][C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:10]1)[C:7]([C:2](=[O:3])[CH3:1])([CH2:14]3)[CH2:8]2
Reactant: CC1(C23CC4CC2CC(CN2CCCS2(=O)=O)(C4)C3)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)C12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Yield: 92.5 %

Procedure:
A stirred solution of the compound obtained by Step I (0.68 g, 2.0 mmol) and p-toluenesulfonic acid (38 mg, 0.2 mmol) in acetone (8 mL) was refluxed for 4 h. The reaction mixture was diluted with EtOAc and washed with 10% aq. NaHCO3 and brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure to obtain 1-{1-[(1,1-dioxido isothiazolidin-2-yl)methyl]tricyclo[3.3.1.03,7]non-3-yl}ethanone (0.55 g) in 92% yield as a viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:25]([OH:29])[C:26]([OH:28])=[O:27].[H-].[Na+].[CH3:32]I>COCCOC.[Cl-].[NH4+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:25]([O:29][CH3:32])[C:26]([OH:28])=[O:27]
Reactant: CI
Reactant: O=C(O)C(O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: COCCOC
Product: COC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a stirred solution of Example 1 Part B compound (112 mg, 0.243 mmol) in DME (1 mL) under argon at room temperature was added sodium hydride (60% mineral oil dispersion, 9.7 mg, 0.24 mmol). After 30 min, methyl iodide (15 μL, 0.24 mmol) was added, the reaction mixture was stirred for 18 h and then diluted with saturated ammonium chloride solution. The mixture was extracted three times with Et2O. The organic extracts were combined, washed once with water, once with brine, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 67 mg (58% yield). LC/MS gave the correct molecular ion [(M+H)+=475] for the desired compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:29]1([C:32](O)=O)[CH2:31][CH2:30]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[CH:29]1([C:32]2[O:24][C:23]([C:22]3[CH:21]=[CH:20][C:19]([O:18][C@H:15]4[CH2:16][CH2:17][C@H:12]([C:10]([N:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[O:11])[CH2:13][CH2:14]4)=[CH:28][CH:27]=3)=[N:25][N:26]=2)[CH2:31][CH2:30]1
Reactant: O=C(O)C1CC1
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NN)cc3)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(-c4nnc(C5CC5)o4)cc3)CC2)CC1

Procedure:
A mixture of 80 mg (0.21 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid hydrazide, 0.02 ml (0.26 mmol) of cyclopropanecarboxylic acid and 2 ml of phosphorus oxychloride was refluxed for 2 hr. To the mixture, 1N NaOH solution was added. The mixture was extracted with AcOEt, washed with saturated NaHCO3 solution, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane and methanol=from 98:2 to 19:1. The combined product fractions were evaporated to dryness to yield 56 mg (56%) of the title compound. MS (m/e): 439.4 (MH+).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:9]([CH:14]1[C:19](=O)[CH2:18][CH2:17][NH:16][CH2:15]1)(OCC)=[O:10].OS(O)(=O)=O.[NH4+].[OH-]>C(Cl)(Cl)Cl>[CH2:18]1[CH2:17][NH:16][CH2:15][C:14]2[C:9](=[O:10])[O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[C:19]1=2
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C1CNCCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: O=c1oc2ccccc2c2c1CNCC2
Temperature: 0 °C

Procedure:
A mixture of 18.8 g (0.2 m) of phenol and 20.7 g (0.1 m) of 3-carbethoxy-4-piperidone HCl was cooled in an ice bath and treated with 75 cc of 73% v/v H2SO4 in one-half hr. with stirring and protection from moisture. After stirring 4 days at room temperature the reaction was chilled and treated with an additional 10 g (0.106 m) of phenol. After 5 days a second 10 g portion of phenol was added. After stirring 6 days the reaction was treated with 100 g of ice and conc. NH4OH to pH 8-9. The resultant gum was stirred with 100 cc CHCl3 for one-half hr. and was filtered. The filtrate was evaporated and the resultant gum was triturated with pet ether followed by ethyl ether. The resultant solid was crystallized from 100 cc 3N HCl affording 2.3 g (10%) of product mp. 330°-5°C.
Reaction SMILES: [F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([OH:14])=O)=[CH:7][CH:6]=2.N1(C(N2C=CN=C2)=O)C=CN=C1.[NH2:27][NH:28][C:29]([NH2:31])=[S:30]>CN(C=O)C>[F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([NH:27][NH:28][C:29]([NH2:31])=[S:30])=[O:14])=[CH:7][CH:6]=2
Reactant: O=C(O)c1ccc2cnc(F)cc2c1
Reactant: NNC(N)=S
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=S)NNC(=O)c1ccc2cnc(F)cc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
A mixture of 3-fluoroisoquinoline-6-carboxylic acid (0.71 g, 3.72 mmol) and di(1H-imidazol-1-yl)methanone (1.21 g, 7.44 mmol) in DMF (9.0 mL) was stirred at room temperature for 1 hour and 20 minutes until no gas was evolved. The reaction mixture was heated at 70° C. for 40 minutes. Thiosemicarbazide (1.02 g, 11.2 mmol) was added, and the reaction mixture was stirred at 70° C. for another 30 minutes. The solvents were removed under reduced pressure. HCl (1.0 N, 50 mL) was added, and the solids were recovered by filtration, and washed with water to provide the product as an off-white solid (0.86 g, 89%). LCMS (API-ES) m/z: 265 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33]>>[C:32]([N:35]1[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][N:4]2[C:28](=[O:29])[N:7]3[CH:8]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=4)[C:9]4[NH:10][C:11]5[C:16]([C:17]=4[CH2:18][C:6]3([CH3:30])[C:5]2=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=5)[CH2:37][CH2:36]1)(=[O:34])[CH3:33]
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Reactant: CC(=O)N1CCNCC1
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCN2CCN(C(C)=O)CC2)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 29 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and N-acetyl piperazine as starting materials. MS: m/z (MH+)=532.1
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:7]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: c1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
The residue was dissolved in benzene and then there was added tetrabutylammonium bromide, aqueous Na2CO3 and 2-(tert-butylaminosulfonyl)phenylboronic. This solution was degassed with a stream of nitrogen for 30 minutes. Following the purge, tetrakis(triphenylphosphine)palladium(0) was added and the solution was stirred overnight at reflux. The solution was diluted with EtOAc and washed twice with brine and the organics dried over MgSO4, filtered and the volatiles removed under reduced pressure. The residue was purified by column chromatography (elution with 1:1 hexane/EtOAc) to afford an intermediate biphenyl compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:18])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)N
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)NC(C)C)cc2)=C(C)C1=O
Yield: 51.6 %

Procedure:
4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid (100 mg, 0.31 mmol) obtained in Example 21 and isopropylamine (0.28 ml, 3.3 mmol) were used, and a method similar to that described in Example 22 was employed to obtain the title compound (58 mg, 0.16 mmol, yield 49%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[CH:5]=[N:4][CH:3]=[N:2]1.CN(C=O)C.[H-].[Na+].[CH2:28](Br)[CH3:29]>O>[CH2:28]([N:16]1[C:17]2[C:12](=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:19][CH:18]=2)[CH2:13][CH2:14][C:15]1=[O:20])[CH3:29]
Reactant: CCBr
Reactant: O=C1CCc2cc(OCCCn3cncn3)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)CCc2cc(OCCCn3cncn3)ccc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2 g (7.35 mM) of 6-[3-(1,2,4-triazol-1-yl)propoxy]-3,4-dihydrocarbostyril with 20 ml of DMF was added 350 mg (8.8 mM) of sodium hydride (60% in oil) and the mixture was heated at 60° C. for 30 minutes. Then under ice-cooling condition, 0.6 ml (8.1 mM) of ethyl bromide was added dropwise, further the reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water, then extracted with chloroform, the chloroform layer was washed with water, dried with anhydrous sodium sulfate, and concentrated by removing the solvent by evaporation. The resulting residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol =30:1), then recrystallized from ethyl acetate-n-hexane to yield 1.8 g of 1-ethyl-6-[3-(1,2,4-triazol-1-yl)propoxy] -3,4-dihydrocarbostyril. Colorless needle-like crystals.