Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: COc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-methoxybenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-methoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=[C:6]([C:14]([O:16]C)=[O:15])[CH:5]=1.[OH-].[Na+]>O.C1COCC1>[CH3:3][C:4]1[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(C)c2c(c1)OCCO2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.65 g (0.28 mol) LiOH in 100 mL water was metered into a solution of 33.60 g (0.16 mol) methyl 8-methyl-2,3-dihydro-1,4-benzodioxin-6-carboxylate in 200 mL THF and the reaction solution was stirred overnight at RT. To complete the reaction 150 mL 6 M NaOH were added and the mixture was stirred for a further 2 h at 50° C. The reaction mixture was evaporated down i.vac, the residue was combined with THF, acidified with conc. HCl while cooling with ice, the precipitate was filtered off, washed with 150 mL water and dried at 60° C. in the circulating air dryer.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([NH:15][CH3:16])[CH3:14])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2].C(Cl)Cl.CO>[CH3:16][NH:15][C@H:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:14]
Reactant: CN[C@@H](C)[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: CN[C@@H](C)[C@@H]1CCNC1

Procedure:
(R,S)-1-benzyl-3-[1'-(methylamino)ethyl]pyrrolidine (0.51 g of crude product) is dissolved in MeOH (10 ml) under a N2 atmosphere, Pearlman's catalyst and ammonium formate (0.89 g, 14.11 mmol) are then added. The reaction mixture is refluxed for 12 hours. The reaction mixture is then diluted with CH2Cl2 :MeOH (1:1) and filtered through a celite pad. The filtrate is washed with 15% aqueous NaOH:brine (1:1) and the aqueous layer is back extracted with CH2Cl2 (2×). The combined organic layers are dried over MgSO4, filtered and concentrated under a stream of N2 to give crude (R,S)-3-[1'-(methylamino)ethyl]pyrrolidine: 1H NMR (300 MHz, CDCl3) δ 1.05 (d, J is 6.3 Hz, 3H), 1.43 (ddd, J is 17, 12, 9 Hz, 1H), 1.87 (m, 1H), 2.02 (dd, J is 16, 8 Hz, 1H), 2.38 (s, 3H), 2.41 (m, 1H), 2.61 (broad s, 2H), 2.65 (dd, J is 11, 8 Hz, 1H), 2.91-3.00 (m, 2H), 3.13 (dd, J is 11, 8 Hz, 1H). This material is suitable for use in various reactions including but not limited to the synthesis of quinolones.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][OH:16])=[C:12]([CH2:17][CH3:18])[CH:11]=1)(C(C)(C)C)(C)C.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOCC.O>[CH2:17]([C:12]1[CH:11]=[C:10]([CH:9]=[O:8])[S:14][C:13]=1[CH2:15][O:16][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1)[CH3:18]
Reactant: C1=COCCC1
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C=O)sc1COC1CCCCO1
Temperature: 0 °C
Yield: 78 %

Procedure:
To a solution of [5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-2-thienyl]methanol (1.4 g, 5.3 mmol) that was obtained in Example 22 (22a) in dichloromethane (10 ml) were added successively 3,4-dihydro-2H-pyran (0.58 ml, 6.4 mmol) and p-toluenesulfonic acid (10 mg, 0.04 mmol) at 0° C. with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. After stirring, a saturated aqueous solution of sodium hydrogencarbonate (5 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained in tetrahydrofuran (5 ml) was added a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (6.4 ml, 6.4 mmol) with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. After stirring, the reaction mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained in dichloromethane (30 ml) was added molecular sieves 4A (10g), and after cooling to 0° C., pyridinium dichromate (3.3 g, 8.7 mmol) was furthermore added to the resulting mixture with stirring, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, ether (150 ml) was added to the reaction mixture with stirring, and insoluble materials were removed by filtration with silica gel. The filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 2:8) as the eluent to afford the title compound (0.97 g) in a yield of 78% as a colourless oily product.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:40][CH2:39][CH2:38][C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(Cl)cc3)n2)c1

Procedure:
Intermediate 4 was coupled to 2-(4-chloro-phenyl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 474. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.7 (m, 1H) 8.16 (m, 4H) 7.65 (m, 6H) 4.45 (s, 2H) 3.95 (m, 2H) 3.4 (m, 2H) 3.18 (m, 4H) 3.0 (m, 2H) 2.9 (s, 3H) 1.75 (m, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:27][CH3:28])[C:23]=1[O:24][CH2:25][CH3:26])[CH:19]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C([O-])(O)=O.[Na+]>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:19][C:18]2[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:24][CH2:25][CH3:26])=[C:16]([O:15][CH3:14])[CH:17]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOc1c(OC)cc(C=O)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1c(OC)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Temperature: 20 °C
Reaction time: 12 h

Procedure:
The synthesis is carried out in argon condition. 2.2 g (11.8 mmol) of N-Boc-piperazine and 2.5 g (11.8 mmol) of 3,5-dimethoxy-4-ethoxybenzaldehyde are mixed in 50 ml of dry of dichloromethane. After dissolution 2 drops of acetic acid is added, then 4.25 g (20 mmol) of NaBH(OAc)3 is added and the mixture is stirred for 12 h at 20° C. Then 20 ml of 5% NaHCO3 aqueous solution is added dropwise with care to the reaction mixture. The organic layer is separated, washed with 5% Na2CO3 solution, dried over sodium sulfate, filtered off, concentrated in vacuum at 50÷80° C. The residue (4.1 g of oil) is used on the next step.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1COCC1.CCOC(C)=O>[C:12]1([S:18]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Reaction time: 0.25 h

Procedure:
0.89 g (22.2 mmol) sodium hydride (60%) were added to 2.0 g (17.1 mmol) indole in 30 mL THF while cooling with an ice bath and the mixture was stirred for 15 min at this temperature. Then 2.2 mL (17.0 mmol) benzenesulphonic acid chloride were added and the mixture was stirred overnight at RT. The reaction mixture was combined with water and EtOAc and extracted several times with EtOAc. The combined organic phases were dried on sodium sulphate and evaporated down.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[N:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH2:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ON=CC(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: NCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
To a solution of oxime 52 (4.0 g, 18.9 mmol) in THF (50 mL) was added LiAlH4 (1.0 M solution in THF, 28.3 mL, 28.3 mmol) at 0° C. and the mixture was stirred at room temperature for 4 hours. Sodium sulfate decahydrate was added and the reaction was stirred for an additional hour. The solids were filtered and the filtrate was concentrated under reduced pressure to give 53 (3.14 g, 84%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](OC)=[O:15])([O-])=O.Cl>C(OCC)(=O)C.C1COCC1.[Pd]>[NH2:10][C:8]1[CH:9]=[C:4]2[C:5]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](=[O:15])[NH:1]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)NC(=O)C2(O)C(F)(F)F
Reaction time: 8 h
Yield: 6.2 %

Procedure:
To a solution of methyl 2-(2,4-dinitrophenyl)-3,3,3-trifluoro-2-hydroxypropanoate (1.3 g, 4.01 mmol) in ethyl acetate (18 mL) was added pH3 HCl (5.2 mL) followed by 10% Pd/C (350 mg) in ethyl acetate (3 mL). The mixture was stirred overnight under an atmosphere of H2. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The crude residue obtained was partitioned between, dichloromethane (25 mL) and aqueous saturated NaHCO3 (15 mL). The organic phase was separated and the aqueous phase was extracted dichloromethane (2×25 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (50-100% ethyl acetate/hexanes) provided 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (921 mg, 99%) To a solution of 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (58 mg, 0.25 mmol) in THF (0.5 mL) at 0° C. was added BH3.THF complex (1 M in THF, 1 mL, 0.95 mmol) dropwise. The mixture was stirred for 5 min at 0° C. then for 3 h at room temperature. The reaction was quenched by adding very carefully 6M HCl (3.5 mL) until no more gas release was observed. The mixture was then stirred at 80° C. for 2 h. The solvent was removed under reduce pressure and the solid residue obtained was dissolved in DMF (3 mL), filtered and purified by reverse phase HPLC (10-99% CH3CN/H2O) to provide 3-(trifluoromethyl)-1H-indol-6-amine (30 mg, 54%, TFA salt).
Reaction SMILES: [H-].[Na+].C1C=CC([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=CC=1.[Br-].[CH:30]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32][C:31]2=O>CS(C)=O>[CH:30]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32][C:31]2=[CH:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C1CCC2CCC1C2
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CCCC=C1CCC2CCC1C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
A mixture of 3.92 g (93 mmol) of sodium hydride (57% oil dispersion) and 30 ml of dry dimethylsulfoxide was heated at 70-80° under nitrogen until gas evolution ceased (2.5 hr). The mixture was cooled, and 19.7 g (44.3 mmol) of 4-(carboxybutyl)triphenylphosphonium bromide (Aldrich # 15,794-5) was added, followed by 20 ml of dimethylsulfoxide. The resulting deep red mixture was stirred for 45 min at room temperature under nitrogen before a solution of 5.0 g (40.2 mmol) of bicyclo[3.2.1]octan-2-one (Aldrich #11,903-2) in 20 ml of dimethylsulfoxide was added dropwise over 1.75 hr. The resulting mixture was stirred for 16 hr at room temperature before it was quenched by the additon of 125 ml of water. The resulting solution was extracted with three 250 ml portions of ether/ethyl acetate-1:1 (V/V) to remove neutral by products. The remaining aqueous phase was acidified by the addition of 15 ml of concentrated hydrochloric acid and extracted with three 250 ml portions of ether-hexane-1:1 (V/V). These combined acidic ether-hexane extracts were dried (MgSO4), and evaporated in vacuo to yield 6.0 g of crude 5-(bicyclo[3.2.1]oct-2-ylidene)pentanoic acid as an oil. This oil was purified by chromato graphy on silica gel 60 (elution with CHCl3 containing 0.5% formic acid) to yield 4.1 g (49%) of pure material as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(CCCCN)(CCCc1cccnc1)C(=O)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(CCCCNS(=O)(=O)c1ccc(Cl)cc1)(CCCc1cccnc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 15.0 g (42.8 mmol) of diethyl [4-aminobutyl][3-(3-pyridyl)propyl]-malonate in 115 ml methylene chloride is cooled to 0° and 0.1 g 4-dimethylaminopyridine is added followed by 8.4 ml (60 mmol) triethylamine and 10.12 g (46.5 mmol) p-chlorophenylsulfonyl chloride. The solution is stirred at room temperature for 48 h and then washed with saturated aqueous sodium bicarbonate solution. The organic phase is dried (MgSO4), filtered and evaporated to give diethyl [4-(p-chlorophenylsulfonamido)butyl][3-(3-pyridyl)propyl]-malonate as an oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1([OH:22])[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH3:3].C[O:24][C:25](=[O:48])[C@H:26]([C@@H:45]([CH3:47])O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[CH2:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1([O:22][C@H:45]([CH3:47])[C@@H:26]([C:25]([OH:48])=[O:24])[NH2:27])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:2][CH3:3]
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: CCCc1ccsc1C1(O)c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1ccsc1C1(O[C@H](C)[C@H](N)C(=O)O)c2ccccc2-c2ccccc21

Procedure:
from 9-(3-propylthien-2-yl)-9H-fluoren-9-ol and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]2[CH2:17][CH:16]([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=O)=[CH:3][CH:2]=1.O.[NH2:21][NH2:22]>C(O)(C)C>[CH3:18][CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2=[N:21][NH:22][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[C:8]2[CH2:17]1
Reactant: NN
Reactant: CC1CC(=Cc2ccncc2)C(=O)c2ccccc21
Solvent: CC(C)O
Solvent: O
Product: CC1Cc2c(n[nH]c2-c2ccncc2)-c2ccccc21

Procedure:
To 24.0 grams (0.1 oles) of the compound of Step A of this exampel in a flask equipped with stirrer and condenser are added 4.8 grams (0.15 Mole) of hydrazine hydrate (95%) and 150 ml. of isopropanol. The mixture is stirred and refluxed for about 24 hours and the solvent is then crystallized from methanol to given 4,5-dihydro-5-methyl-3-(4-pyridyl)-2h-naphtho[1,2-c]pyrazole.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:11][CH:12]=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(=CC)C.C1C[O:30]CC1.[O-]Cl=O.[Na+]>C(O)(C)(C)C.O>[Si:1]([O:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:11][C:12]([OH:30])=[O:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(CC=O)c1ccc(F)c(Cl)c1
Reactant: C1CCOC1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)[Si](C)(C)OCC(CC(=O)O)c1ccc(F)c(Cl)c1
Reaction time: 0.08 h
Yield: 85.2 %

Procedure:
To a solution of 314 (302 mg, 0.913 mmol) in tert-BuOH (20 mL) and H2O (5 mL) was added 2M solution of 2-methyl-2-butene in THF (4.56 mL, 9.13 mmol) then NaH2PO4 (1.204 g, 10.0 mmol). The reaction was stirred 5 min, then NaClO2 (495 mg, 5.48 mmol) was added and the reaction stirred at RT overnight. The reaction was partitioned between EtOAc (50 mL) and 0.5M HCl (30 mL), phases separated and the aqueous phase extracted with EtOAc (50 mL). The combined organic extracts were washed with satd. aq. NaCl (50 mL), dried (MgSO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with 10% EtOAc/hexane to afford 270 mg (85%) of 4-(tert-butyldimethylsilyloxy)-3-(3-chloro-4-fluorophenyl)butanoic acid (316) as a gray crystalline solid: 1H NMR (400 MHz, CDCl3) δ 7.27 (dd, J=2.3, 7.1 Hz, 1H), 7.08 (m, 2H), 3.74 (m, 1H), 3.61 (m, 1H), 3.26 (m, 1H), 2.91 (m, 1H), 2.61 (m, 1H), 0.86 (s, 9H), −0.03 (d, J=1.6 Hz, 6H); MS LRMS (APCI neg) m/e=345.1 (M−H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:55]=[CH:54][CH:53]=[CH:52][C:14]=1[C:15]([NH:17][C:18]1[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]2[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]2)=[O:39])=[O:23])=[CH:20][C:19]=1[O:50][CH3:51])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:62].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:55]=[CH:54][CH:53]=[CH:52][C:14]=1[C:15]([NH:17][C:18]1[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]2[CH2:45][CH2:44][CH:43]([NH2:62])[CH2:42][CH2:41]2)=[O:39])=[O:23])=[CH:20][C:19]=1[O:50][CH3:51])=[O:16])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: [BH3-]C#N
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(=O)CC2)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(N)CC2)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.4 %

Procedure:
To a mixture of 4-[2-[(3-tert-butoxycarbonylaminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(4-oxopiperidin-1-yl)carbonylpent-1-yl]oxy-4-methylphenyl]benzamide (250 mg), ammonium acetate (51 mg) and acetic acid (0.5 ml) in methanol (10 ml) was added sodium cyanoborohydride (21 mg) at 0° C. and the mixture was stirred at ambient temperature for 12 hours. The mixture was poured into ice-cooled 1N aqueous sodium hydroxide solution (15 ml) and the solution was extracted with chloroform (15 ml×3). The organic layer was washed with brine and dried over potassium carbonate. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (SiO2 40 g, 5-15% methanol in chloroform) to give 4-[2-[(3-tert-butoxycarbonylaminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(4-aminopiperidin-1-yl)carbonylpent-1-yl]oxy-4-methylphenyl]benzamide (91 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:18])[C:13](=O)[NH:12][C@H:11]2[CH2:15][CH2:16][CH2:17][C@H:10]2[NH:9]1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].[H][H]>O1CCOCC1>[CH3:7][C:8]1([CH3:18])[NH:9][C@H:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[NH:12][CH2:13]1
Reactant: CC1(C)N[C@@H]2CCC[C@@H]2NC1=O
Reactant: [H][H]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)CN[C@@H]2CCC[C@@H]2N1
Temperature: 25 °C
Yield: 91 %

Procedure:
Lithium aluminum hydride (541 mg, 14.3 mmol) was added to an anhydrous dioxane (40 mL) solution of cis-3,3-dimethyloctahydrocyclopentapyrazin-2-one (2.00 g, 11.9 mmol) with stirring at room temperature, and the mixture was gradually heated and stirred for 10 minutes under reflux. The reaction mixture was cooled to ice temperature. Then, sodium sulfate decahydrate was added thereto in small portions until no hydrogen gas was generated. Then, the mixture was stirred at room temperature for 1 hour. Insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane= 1/10) to obtain cis-2,2-dimethyloctahydro-1H-cyclopenta[b]pyrazine (1.67 g, 91%) in a pale yellow oil form.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+].[N+]([O-])(O)=O.CC1C=C(C)[N:35]([C:39](N)=[NH:40])N=1>C(O)C>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)[C:39]([NH2:40])=[NH:35]
Reactant: Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Reactant: Cc1cc(C)n(C(=N)N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Yield: 50 %

Procedure:
A mixture of 5-amino-3-(quinol-4-ylmethylene)-2-oxindole (2.873 g, 10 mmol) and sodium bicarbonate (0.168 g, 2 mmol) in refluxing ethanol (100 ml) was treated with 3,5-dimethylpyrazole-1-carboxamidine nitrate (3.018 g, 15 mmol) for 20 h. The solvent was removed from the cooled solution, and the residue was chromatographed on silica gel with gradient elution (1 to 5% EtOH in CHCl3) to afford pure title compound in about 50% yield.