Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=3[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:7][C:6]=12.C(N([CH2:37][CH3:38])CC)C>CN(C=O)C>[Br:1][C:2]1[N:3]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([C:38]#[C:37][Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:10][C:9]=3[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:7][C:6]=12
Reactant: CCN(CC)CC
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(I)ccc32)c1Br
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(Br)n(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 10 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 263 mg of 3-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanylethoxymethyl)-7-iodo-2H-pyrazolo[4,3-c]isoquinoline in 1.5 ml of DMF and then 1.5 ml of triethylamine. After argon has been bubbled through the mixture for 10 min, 30 mg of bis(triphenylphosphene)palladium(II) dichloride, 8.7 mg of copper(I) iodide and 118 μl of ethynyltrimethylsilane are added. The mixture is stirred at RT for 2 h, poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (40-63 μm), eluting with a mixture of DCM and methanol (99.5/0.5 by vol.), to give 140 mg of 3-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanylethoxymethyl)-7-trimethylsilanylethynyl-2H-pyrazolo[4,3-c]isoquinoline (cream solid). MS (E/I): m/z=586 (M+) 1H NMR: −0.05 (s, 9 H) 0.23 (s, 9 H) 0.89 (m, 2 H) 3.72 (m, 2 H) 5.88 (s, 2 H) 7.4 (t, J=8.1 Hz, 2H) 7.6 (broad s, 1H) 7.75 (m, 1H) 8.01 (dd, J=8.3, 1.5 Hz, 1H) 8.52 (d, J=8.3 Hz, 1H).
Reaction SMILES: [OH:1][C@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4](OC)=[O:5].O.[NH2:15][NH2:16]>CO>[OH:1][C@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4]([NH:15][NH2:16])=[O:5]
Reactant: NN
Reactant: COC(=O)C[C@H](O)c1ccccc1
Solvent: CO
Solvent: O
Product: NNC(=O)C[C@H](O)c1ccccc1
Temperature: 70 °C
Yield: 74 %

Procedure:
In a 1 liter four-necked flask were charged 200 g (1.11 mol) of methyl (S)-3-hydroxy-3-phenylpropionate (optical purity: 87%e.e.), 77.8 g (1.56 mol) of hydrazine monohydrate, and 400 ml of methanol, and the mixture was heated at 70° C. for 3 hours. The reaction mixture was cooled to 5° C. with ice-water, followed by filtration. The collected crystals were dissolved in 4.7 liter of methanol while hot and cooled to 5° C. The crystals thus precipitated were collected by filtration and dried to give 148 g (74%) of the title compound. Melting point: 179.5° C. Optical purity: >99.9%e.e.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N+:11]([O-])=O>C(O)C.[Pd]>[NH2:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[NH:2][CH3:1]
Reactant: CNc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNc1ccc(OC)cc1N

Procedure:
A solution of 0.75 g (4.1 mmol) N-methyl-4-methoxy-2-nitroaniline in 150 ml ethanol was hydrogenated at atm. pressure by using 5% Pd-C (0.1 g) as a catalyst. The reaction mixture was filtered, added 2 ml 1N hydrochloric acid and then evaporated in vacuo to give 2-amino-4-methoxy-N-methylaniline as crystals.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[O:4].C(Cl)(Cl)(Cl)Cl.BrN1C(=O)CCC1=O.[SH:28][C:29]1[NH:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1>C(O)(C)C>[OH2:4].[NH:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[S:28][CH2:12][C:8]1[N:7]=[C:6]([NH2:5])[CH:11]=[CH:10][CH:9]=1.[NH:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[S:28][CH2:12][C:8]1[N:7]=[C:6]([NH2:5])[CH:11]=[CH:10][CH:9]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1cccc(NC(=O)C(C)(C)C)n1
Agent: O=C1CCC(=O)N1Br
Solvent: CC(C)O
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1cccc(CSc2nc3ccccc3[nH]2)n1
Product: O

Procedure:
To a cold (ca. 0° C.) solution of 86.4 g (0.88 mole) of 2-amino-6-methylpyridine and 101 g (0.96 mole) of triethylamine in 1.0 liter of dichloromethane was added dropwise a solution of 106.1 g (0.88 mole) of trimethylacetyl chloride in 100 ml of dichloromethane. After stirring an hour after addition was completed, the mixture was poured into water and the layers separated. The aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil that crystallized upon standing. The solid was triturated with hexane and collected by filtration, giving 115 g of 2-(trimethylacetamido)-6-methylpyridine. A 22.6 g (0.12 mMol) portion of the amide derivative was suspended in 250 ml of carbon tetrachloride containing 22.9 g (0.12 mMol) of N-bromosuccinimide and 100 mg of 2,2'-azabisisobutyronitrile. The mixture was heated at reflux under a sun lamp for one hour, after which insolubles were removed by filtration. The filtrate was concentrated in vacuo to an oil consisting of a mixture of the 6-bromomethyl-2-(trimethylacetamido)pyridine and 6-dibromomethyl-2-(trimethylacetamido)pyridine derivatives. The crude mixture was heated at reflux for fifteen minutes with 11.7 g (78 mMol) of 2-mercaptobenzimidazole in 300 ml of isopropyl alcohol. Upon cooling, a precipitate formed and was collected and washed with portions of isopropyl alcohol and diethylether. The trimethylacetyl group was removed by heating at reflux for four hours in 300 ml of 10% aqueous hydrochloric acid. After cooling, the mixture was concentrated in vacuo to an oil. The oil was dissolved in water and made alkaline with aqueous potassium carbonate. The oil that separated solidified upon addition of dichloromethane to the aqueous mixture. The solid was collected by filtration, washed with portions of water and dichloromethane, and air dried to yield 9.6 g of the title compound as an analytically pure hemihydrate. (An additional 2.5 g of the title compound was isolated from the dichloromethane washes.) Structure assignment was supported by the nmr and infrared spectra and by elemental analysis. Anal. Calc'd. for C13H12N4S*1/2 H2 0: C, 58.84; H,4.93; N, 21.11; S, 12.08. Found: C, 59.03; H, 4.40; N, 20.90; S, 12.30.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCc1cc2c(OC)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(OC)cccc2n1Cc1ccccc1
Reaction time: 1.5 h
Yield: 48.7 %

Procedure:
2-Ethyl-4-methoxy-1H-indole (4.2 g, 24 mmol) is dissolved in 30 mL of DMF and 960 mg (24 mmol) of 60% NaH/mineral oil is added. After 1.5 hours, 2.9 mL (24 mmol) of benzyl bromide is added. After 4 hours, the mixture is diluted with water extracting twice with ethyl acetate. The combined ethyl acetate is washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue is chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 3.1 g (49% yield) of 2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH2:7][N:8]1[C:12]([NH:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[N:9]1)=[O:6].C(OCC)(=O)C.Cl>O1CCOCC1.O1CCCC1>[C:5]([CH2:7][N:8]1[C:12]([NH:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[N:9]1)([OH:6])=[O:4]
Reactant: COC(=O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4N Sodium hydroxide aqueous solution (125.79 ml) was added to a solution of 1-methoxycarbonylmethyl-5-triphenylmethylaminopyrazole (100 g) in dioxane (100 ml) and the mixture was stirred for three hours at ambient temperature. The reaction mixture was added to a mixture of ethyl acetate (300 ml) and tetrahydrofuran (300 ml), and 1N hydrochloric acid was added thereto to adjust to pH 3. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-carboxymethyl-5-triphenylmethylaminopyrazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20](OC)=[O:21])[CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.CO>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][OH:21])[CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)CCC(CNC(=O)OC(C)(C)C)C2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCc2cc(CO)ccc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
In dichloromethane (10 ml), (2RS)-2-(N-tert-butoxycarbonylaminomethyl)-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene (0.47 g) was dissolved, followed by the dropwise addition of diisobutylaluminum hydride (a 0.95M hexane solution, 3.6 ml) at an external temperature of −78° C. The resulting mixture was stirred for 90 minutes without changing the temperature. Methanol was added to the reaction mixture, followed by heating to room temperature. The insoluble matter was filtered off through Celite. The filtrate was concentrated under reduced pressure. The concentrate was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby colorless crystals (0.31 g, 72%) were obtained. A portion of the crystals was recrystallized from a mixed solvent of hexane and ethyl acetate, whereby colorless crystals were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([N+:10]([O-])=O)[N:3]=1>C(OCC)(=O)C.[Ni]>[NH2:10][C:4]1[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: CNc1ccc(C)nc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CNc1ccc(C)nc1N

Procedure:
8.35 g (50 mmol) of 2-Methyl-5-methylamino-6-nitropyridine (Heterocycles 38, 529 (1994)) were dissolved in 300 l ethyl acetate and hydrogenated with 1.5 g Raney nickel for 3.5 hours at room temperature. Then the catalyst was filtered off and the filtrate was evaporated down. After crystallization of the resulting residue from petroleum ether, 5.75 g (84% of theory) were obtained as olive-green crystals. C7H11N3 (137.20). Melting point: 112-113° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:30])[NH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.Cl[C:32]([F:38])([F:37])C(OC)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH:32]([F:38])[F:37])=[N:9][N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:4]=2[CH:3]=1
Reactant: COC(=O)C(F)(F)Cl
Reactant: O=c1[nH]n(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3 (2H)-one (Intermediate 3B; 368 mg, 0.893 mmol) and methyl 2-chloro-2,2-difluoroacetate (0.5 mL, 4.74 mmol) in DMF (2 mL) was charged with K2CO3 (2.5 g, 18.09 mmol) at room temperature. The reaction was stirred at 80° C. for 30 min. The reaction mixture was diluted with H2O and filtered to give 6-chloro-3-(difluoro-methoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine, which was carried onto the next step without further purification. MS ESI calc'd. For C26H18ClF2N3O [M+1]+ 462. found 462.
Reaction SMILES: [Cl:1][C:2](=[CH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:17]([Cl:18])=[C:16]([O:19][CH:20]([F:22])[F:21])[N:15]([CH3:23])[N:14]=2)[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])[C:3]([OH:5])=O.C(Cl)(=O)C([Cl:29])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2](=[CH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:17]([Cl:18])=[C:16]([O:19][CH:20]([F:21])[F:22])[N:15]([CH3:23])[N:14]=2)[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])[C:3]([Cl:29])=[O:5]
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cn1nc(-c2cc(C=C(Cl)C(=O)Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 90 °C

Procedure:
A solution of 27 g of 2-chloro-3-(2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl)acrylic acid (64 mmol) in 200 ml of toluene was treated with 3 drops of dimethylformamide and 33 g (0.26 mol) of oxalyl chloride. The mixture was subsequently stirred at 90° C. until the vigorous evolution of gas had ceased (after approximately 2.5 hours). The reaction mixture was then concentrated. Yield: 26 g of crude product which was further reacted without purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:3]=1[C:4]#[N:5].[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([O:25][Si](C)(C)C)=[CH2:24])[CH:13]([CH3:15])[CH3:14]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:24]/[C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:25])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: C=C(O[Si](C)(C)C)c1ccccc1OCC(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)COc1ccccc1C(=O)/C=C/c1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.5 %

Procedure:
To a solution of commercially available 2-fluoro-5-formylbenzonitrile (2.49 g, 10 mmol) in dichloromethane (40 mL) was added (1-(2-isobutoxyphenyl)vinyloxy)trimethylsilane (1.49 g, 10 mmol), followed by titanium tetrachloride (1.5 eq). The reaction was stirred at room temperature for 5 hours and then heated at 40° C. for overnight. The reaction was cooled and quenched with 1 N HCl (40 mL). The mixture was stirred for 2 hours and diluted with dichloromethane/water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by the chromatography to give (E)-2-fluoro-5-(3-(2-isobutoxyphenyl)-3-oxoprop-1-enyl)benzonitrile as a white solid (1.60 g, 50% yield). 1H NMR (400 MHz, CDCl3): δ 7.88-7.75 (m, 2H), 7.70 (d, 1H), 7.57 (d, 1H), 7.54-7.45 (m, 2H), 7.28 (d, 1H), 7.08-6.98 (m, 2H), 3.84 (d, 2H), 2.17-2.03 (m, 1H), 1.00 (d, 6H). MS (EI) for C20H18FNO2: 268 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14].[OH2:18]>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([OH:18])[CH:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: O=S(=O)(O)O
Solvent: CC(C)=O
Product: OC1CN(Cc2ccccc2)CC1O
Yield: 90 %

Procedure:
To the solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of acetone in a quartz round flask reactor, 45.6 g (0.20 mol) of (NH4)2S2O8 (ammonium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 5 days at ambient temperature with irradiation by 500W Xe lamps (UXL-500D xenon lamp produced by Ushio). After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 17.4 g of 1-benzyl-3,4-dihydroxypyrrolidine (yield 90.0%) was obtained and 1-benzyl-3-pyrroline was not recovered.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([NH2:16])=[O:15])[CH2:9]2)=[C:4]([N+:17]([O-])=O)[CH:3]=1.[H][H].[ClH:22]>C1COCC1.C(OCC)(=O)C.[Pd]>[ClH:22].[NH2:17][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([NH2:16])=[O:15])[CH2:9]1
Reactant: NC(=O)C1CCCN(c2ccc(F)cc2[N+](=O)[O-])C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)C1CCCN(c2ccc(F)cc2N)C1

Procedure:
The solution of 2.67 g of 1-(4-fluoro-2-nitrophenyl)piperidine-3-carboxamide in 100 ml of THF was admixed with 260 mg of Pd/C. This mixture was hydrogenated in a shaking vessel at atmospheric pressure until the theoretical amount of hydrogen had been taken up. The mixture is then acidified with hydrogen chloride dissolved in ethyl acetate, the solid is filtered off with suction and washed with methanol, and the filtrate is concentrated under reduced pressure. The residue is triturated with tert-butyl methyl ether and the solid is filtered off with suction and dried under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:14]([Cl:15])=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([O:16][CH3:17])[CH:3]=1.[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].O>CN(C)C=O.C(OCC)(=O)C>[Cl:15][C:14]1[C:2]([NH:1][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:3][C:4]([O:16][CH3:17])=[C:5]([CH:13]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CCOC(=O)CCCCCBr
Reactant: COc1cc(N)c(Cl)cc1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCNc1cc(OC)c(C(=O)OC(C)(C)C)cc1Cl
Reaction time: 0.33 h
Yield: 45.4 %

Procedure:
The compound (480 mg, 1.86 mmol) obtained in Example 99a was dissolved in N,N-dimethylformamide (6 mL), 55% sodium hydride (89 mg, 2.79 mmol) was added under ice cooling, and the mixture was stirred at the same temperature under a nitrogen atmosphere for 20 minutes. Subsequently, ethyl 6-bromohexanoate (623 mg, 2.79 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 1:3, v/v) to give the title compound (338 mg; yield, 45%) as a pale orange color oily substance.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:26]([O:28][C:29](=[O:41])[NH:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1O)[CH3:27].CCOC(/N=N/C(OCC)=O)=O>>[CH2:26]([O:28][C:29](=[O:41])[NH:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][C:36]=1[O:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:27]
Reactant: OC1CCCC1
Reactant: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1OC1CCCC1
Temperature: 25 °C

Procedure:
Cyclopentanol (7.24 mL, 376 mM in dry tetrahydrofuran) was added to triphenylphosphine (1.44 g, polystyrene bound, 1.89 mMol/g) under argon, followed by the addition of a solution of (2-Hydroxy-4-nitrophenyl)-carbamic acid ethyl ester (25.6 mL, 62 mM in dry tetrahydrofuran) and a solution of diethylazodicarboxylate (7.24 mL, 376 mM in dry tetrahydrofuran). The reaction mixture was shaken at room temperature over night. The resin was filtered and washed with tetrahydrofuran (THF) (35 mL) and methanol (35 mL). The combined organic phase was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, heptane/ethyl acetate, gradient) to yield the title compound as slightly yellow solid (294 mg, 64%).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH:15]2[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([OH:27])(=[O:26])[C@@H:19]([C@H:21]([C:23]([OH:25])=[O:24])[OH:22])[OH:20]>CCO>[C:1]([O:9][C@@H:10]1[CH:15]2[CH2:14][CH2:13][N:12]([CH2:17][CH2:16]2)[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:23]([C@@H:21]([C@H:19]([C:18]([O-:27])=[O:26])[OH:20])[OH:22])([O-:25])=[O:24]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: O=C(OC1CN2CCC1CC2)c1ccccc1
Solvent: CCO
Product: O=C(O[C@H]1CN2CCC1CC2)c1ccccc1
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Yield: 22.1 %

Procedure:
(+/−)-3-Quinuclidinol benzoate (Sigma, 17.9 g, 77.5 mmol) was treated with L-tartaric acid (Aldrich, 99% ee, 11.63 g, 77.5 mmol) in EtOH (80%, 222 mL) at ambient temperature for 1 week. The white solid was filtered off and dried under reduced pressure. 6.5 g of 3-(R)-quinuclidinol benzoate·(L)-tartrate was obtained with ˜80% ee (assayed by HPLC. HPLC conditions: chiralpak AD column 25 cm×4 mm ID. solvent, EtOH:hexanes=15:85. flow rate, 1 mL/min. uv, 220 nm. Retention time: (S)-3-quinuclidinol benzoate, 7.87 min; (R)-3-quinuclidinol benzoate 13.3 min.) Recrystallization of the above solid in EtOH (80%, 35 mL) gave the title product (4.5 g, yield, 15%, >98% ee). MS (DCI/NH3) m/z 232 (M+H)+.
Reaction SMILES: C(O[C:5]1[N:10]=[C:9]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[O:12])[C:8](C)=[CH:7][CH:6]=1)(=O)C.[OH-:27].[K+].[CH3:29]O>>[OH:27][CH2:29][C:5]1[N:10]=[C:9]([C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]2)=[O:12])[CH:8]=[CH:7][CH:6]=1
Reactant: CO
Reactant: CC(=O)Oc1ccc(C)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: [OH-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(CO)n2)CC1

Procedure:
To a solution of 3.7 g of t-butyl 4-(6-acetoxy-methylpyridine-2-carbonyl)piperazine-1-carboxylate in 10 mL of methanol was added 840 mg of potassium hydroxide and the mixture was heated to reflux for 4 hours. After the solvent was removed, water was added to the solution and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (methylene chloride-ethanol=50:1) to give 1.26 g of t-butyl 4-(6-hydroxymethylpyridine-2-carbonyl)piperazine-1-carboxylate as a colorless oil.