Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.CCN(C(C)C)C(C)C.C=O.C1(C)C=CC=CC=1>O1CCCC1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (10.0 g, 21.9 mmol) is dissolved in 50 mL of anhydrous tetrahydrofuran, add iPr2NEt (3.7 g, 28.5 mmol) anhydrous Lithium chloride (490 mg, 11.0 mmol) and molecular sieves (2.0 g), refluxed for 30 min under nitrogen atmosphere, then add paraformaldehyde (790 mg, 26.3 mmol), reflux for 2 h under nitrogen atmosphere. The reaction mixture is cooled to room temperature, add 100 mL of toluene, filter to remove the molecular sieves, the filtration is washed with 5% HCl(aq)(50 mL*2), saturated Na2CO3 and brine, dry over anhydrous Na2SO4 and concentrate under vacuum to obtain (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl), which is direct used in next step. Spectroscopic data as Example 23, Method 1.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]1)(=[O:15])[CH3:14].C(N(CC)CC)C.Cl.[CH3:33][NH:34][O:35][CH3:36]>C1COCC1.C(#N)C>[C:13]([N:16]1[CH2:17][CH2:18][CH:19]([C:22]([N:34]([O:35][CH3:36])[CH3:33])=[O:24])[CH2:20][CH2:21]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: CON(C)C(=O)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1′-Carbonyldiimidazole (6.43 g, 39.64 mmol) was added slowly to a mixture of 1-acetylpiperidine-4-carboxylic acid (5 g, 29.21 mmol) in dry THF (40 mL). The mixture was stirred at room temperature for one hour. In a separate flask, triethylamine was added to a mixture of N,O-dimethylhydroxylamine hydrochloride (3.92 g, 40.18 mmol) in acetonitrile (32 mL). The two mixtures were combined and stirred at room temperature for 12 hours. The solvents were removed under reduced pressure and the residue dissolved in DCM. The organic mixture was washed with water, HCl (0.1 N aqueous solution) and finally a concentrated aqueous Na2CO3 solution. The organic layer was dried over MgSO4, filtered and evaporated to give a crude oil. The oil was purified by chromatography to provide the title compound visible by HPLC at 214 wavelength.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][O:9][C:8]1=[O:12])(=O)C.CO>O>[O:4]1[CH2:1][CH2:11][CH:7]([C:8]([O:9][CH3:10])=[O:12])[CH2:6][CH2:5]1
Reactant: CC(=O)OCCC1CCOC1=O
Solvent: O
Solvent: CO
Product: COC(=O)C1CCOCC1
Reaction time: 12 h

Procedure:
A solution consisting of 53 wt % of 3-(2'-acetoxyethyl)-dihydro-2(3H)furanone, 39 wt % of methanol, and 8 wt % of water was evaporated at a rate 25 g per hour and the vapors were passed at a temperature of 250° C. over 90 g of aluminum oxide catalyst (diameter 1.5 mm) in a tubular reactor. The gaseous effluent was condensed in cold traps and analyzed by gas chromatography. The experiment was carried out for a period of 12 h and the total amount of starting material used was 600 g. 62 mol % of methyl tetrahydropyran-4-carboxylate was formed, plus 20 mol % of 3-(2'-methoxyethyl)-dihydro-2(3H)furanone and 3 mol % of 5-oxaspiro-[2.4]heptan-4-one. The conversion of 3-(2'-acetoxyethyl)-dihydro-2(3H)furanone was better than 99%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19].C(OCC)(=O)C>CC(C)=O>[CH2:19]([O:10][C:8]1[CH:9]=[C:4]([C:2](=[O:3])[CH3:1])[CH:5]=[CH:6][CH:7]=1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=CCOc1cccc(C(C)=O)c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
3-Hydroxyacetophenone (1.36 g, 10.0 mmol) was dissolved in acetone (50 mL), then added with potassium carbonate (2.76 g, 20.0 mmol) and allylbromide (1.27 mL, 15.0 mmol) at room temperature, and heated to reflux for 2 hours. The reaction solution was cooled to room temperature, added with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (n-hexane/ethyl acetate=10/1), and 1-(3-(allyloxy)phenyl)ethanone (1.76 g, 100%) was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:12]([O-])=O.[Na+].O.N>C(O)(=O)C>[N+:9]([C:8]1[CH:7]=[CH:6][CH:5]=[C:3]2[C:2]=1[CH:1]=[N:12][NH:4]2)([O-:11])=[O:10]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: O=N[O-]
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2-methyl-3-nitro aniline (1 mmol) in acetic acid was stirred at room temperature and sodium nitrite (1.1 mmol) was added to the reaction mixture. Reaction mixture was stirred at room temperature for 5 hours. Reaction mixture was poured into water and neutralized with ammonia. Product precipitated out, was filtered and washed with water. It was then purified by column chromatography to afford the desired compound as a pale yellow solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=[O:9]>[C].[Pd]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=[O:9]
Reactant: O=C(O)C1CC2C=CC1C2
Agent: [Pd]
Product: O=C(O)C1CC2CCC1C2
Reaction time: 17.5 h
Yield: 100.8 %

Procedure:
38.8 g (269 mmol) of crude 5-norbornene-2-carboxylic acid was dissolved in 740 ml of solmix, 1.92 g of 5% palladium-carbon powder was added and the mixture was stirred for 17.5 hours under an atmosphere of hydrogen. The catalyst was filtered off, the solvent was distilled away, and 38.0 g of crude 2-norbornanecarboxylic acid was obtained. Crude yield: 100%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[C:28]1[O:32][CH:31]=[N:30][CH:29]=1)[C:22](O)=[O:23].O1C2(CCN(C#N)CC2)OCC1.FC(F)(F)C(O)=O>ClCCl>[CH:15]1([N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([C:28]3[O:32][CH:31]=[N:30][CH:29]=3)=[C:19]([F:18])[CH:20]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Agent: N#CN1CCC2(CC1)OCCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(-c2cnco2)c(F)c1)N(C1CCNCC1)C1CC1

Procedure:
The title compound is prepared from 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester and 3-fluoro-4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Intermediate 1. The cleavage of the BOC group is accomplished by using trifluoroacetic acid in dichloromethane. LC (method 14): tR=0.98 min; Mass spectrum (ESI+): m/z=330 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:14]=[CH:15][C:16]4[C:17]([CH:29]=3)=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[O:19][N:20]=4)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1>[Pd]>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([C:18]([C:17]2[CH:29]=[C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[O:12][CH2:11][CH2:10][O:9]3)[CH:14]=[CH:15][C:16]=2[NH2:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(-c2onc3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc23)c1
Agent: [Pd]
Product: COc1cccc(C(=O)c2cc(C3(c4ccc(Cl)cc4)OCCO3)ccc2N)c1
Yield: 103.5 %

Procedure:
Interm (7-b) (30 g) of THF (250 ml) was hydrogenated with palladium on carbon (3 g) as a catalyst at room temperature for 12 hours under a 2.6 105Pa pressure in a Parr apparatus. After uptake of H2 (1 equivalent), the catalyst was filtered through celite and the filtrate was evaporated till dryness. The product was used without further purification, yielding 31.2 g (100%) of (3-methoxyphenyl)[2-amino-5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]phenyl]methanone (interm. 7-c).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.CCN(C(C)C)C(C)C.[N-:35]=[N+:36]=[N-:37].[Na+]>C(Cl)Cl.CCOC(C)=O.O>[N:35]([CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:36]=[N-:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)COCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CN=[N+]=[N-])COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a solution of (S)-tert-butyl 1-(benzyloxy)-3-hydroxypropan-2-ylcarbamate (1.89 g, 6.4 mmol) in DCM (50 mL) was added MsCl (0.55 mL, 7.04 mmol) followed by DIEA (1.27 mL, 7.68 mmol). The mixture was stirred at RT for 30 min and diluted with DCM (300 mL). The organic mixture washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was then dissolved in DMF (20.0 mL). To the resulting solution was added NaN3 (1.25 g, 19.2 mmol) and the mixture was heated at 80° C. for 6 h. LCMS indicated the completion of the reaction. The mixture was cooled to RT and added water (20 mL) and EtOAc (200 mL). The organic layer was separated, washed with NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-tert-butyl 1-azido-3-(benzyloxy)propan-2-ylcarbamate (1.5 g, 73% for 2 steps).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:9]([NH:14]S(C(C)(C)C)=O)[C:10]([F:13])([F:12])[F:11])[CH:6]=[N:7][CH:8]=1>CO>[Br:2][C:3]1[CH:4]=[C:5]([CH:9]([NH2:14])[C:10]([F:11])([F:12])[F:13])[CH:6]=[N:7][CH:8]=1
Reactant: CC(C)(C)S(=O)NC(c1cncc(Br)c1)C(F)(F)F
Agent: Cl
Solvent: CO
Product: NC(c1cncc(Br)c1)C(F)(F)F
Reaction time: 8 h

Procedure:
A solution of HCl (4 M in dioxane, 0.557 m, 2.23 mmol) was added to a solution of N-(1-(5-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (400 mg, 1.114 mmol) in MeOH (2.5 mL) at room temperature. The resulting mixture was stirred at this temperature for overnight. The solvent was removed in vacuum, and the residue was treated with saturated NaHCO3 solution and extracted with ethyl acetate. The combined extracts were dried over anhydrous Na2SO4. After filtration and concentration, the title compound was obtained (230 mg). ESI-MS m/z: 256.9 [M+1]+; Retention time 1.02 min;
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].Cl.[CH3:15]O>>[NH2:1][CH:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[C:3]([O:5][CH3:15])=[O:4]
Reactant: CO
Reactant: NC(Cc1ccc(Br)cc1)C(=O)O
Agent: Cl
Product: COC(=O)C(N)Cc1ccc(Br)cc1
Yield: 92 %

Procedure:
A mixture of 2-amino-3-(4-bromophenyl)propanoic acid 3c (24.4 g, 100 mmol) in HCl/MeOH (300 mL) was stirred at reflux overnight. TLC analysis indicated the total consumption of compound 3c. The mixture was concentrated to give 3d as a pale yellow solid (24 g, 92% yield).
Reaction SMILES: [OH:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[CH2:3]([NH:4][C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:2]([CH3:12])=[O:1]
Reactant: CCOC(=O)C(=O)NCC(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred solution of ethyl 2-(2-hydroxypropylamino)-2-oxo-acetate (10.7 g, 61.07 mmol) in DCM (100.0 mL), is added Dess Martin periodinane (25.9 g, 61.07 mmol) at 0° C. The reaction mixture is stirred at room temperature for 2 hours, diluted with water (100 mL) at 0° C., and extracted with DCM (2×100 mL). The combined organic layer is washed with water (2×50 mL) and saturated brine (50 mL), dried over Na2SO4, and evaporated under reduced pressure. The crude material is purified by silica gel chromatography, eluting with hexane:ethyl acetate (1:1) to give the title compound as a light yellow oil (9.2 g, 87.03%). ESI/MS m/z 174.1 (M+H)+.
Reaction SMILES: [CH2:1]([OH:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1C1C=CC=C[NH+]=1.[Cr](Cl)([O-])(=O)=O.CCOCC>ClCCl>[CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC=Cc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1ccc(-c2cccc[nH+]2)[nH+]c1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CC=Cc1ccccc1

Procedure:
To 10 ml of dichloromethane is added 0.5 g. (3.73 mmoles) of cinnamyl alcohol. The resulting mixture is added to a stirred suspension of 3.37 g. (11.5 mmoles) of 2,2'-bipyridinium chlorochromate in 15 ml of dichloromethane. The resulting mixture is stirred for four hours after which 15 ml of anhydrous ether is added. The resulting product is filtered through a Hirsch funnel packed 1-2 cm deep with Celite® using ether as a wash solvent. The resulting clear filtrate is washed with 5% hydrochloric acid and 10% sodium carbonate, and dried over sodium sulfate. The drying agent is removed and the solvent evaporated giving a product which is a slightly yellow oil. This oil is then distilled via Kugelrohr to yield pure cinnamaldehyde in a typical yield of 0.323 g. which is 86% of theoretical yield.
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH2:8]([C:10]([CH3:17])([CH2:15][CH3:16])[C:11]([O:13]C)=O)[CH3:9].[H-].[C:19](#[N:21])[CH3:20]>C(O)C>[CH2:15]([C:10]([CH3:17])([CH2:8][CH3:9])[C:11]([CH2:20][C:19]#[N:21])=[O:13])[CH3:16]
Reactant: CC#N
Reactant: CCC(C)(CC)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(C)(CC)C(=O)CC#N

Procedure:
To a suspension of 96 g. of sodium hydride, as a 50% dispersion in mineral oil, in 300 ml. of dry tetrahydrofuran was added, with stirring, 63 g. of acetonitrile and 114 g. of methyl 2-ethyl-2-methylbutyrate. The mixture was then heated gently to 60°-65° and allowed to reflux gently at that temperature overnight. It was then cooled to ice bath temperature, and 2-ml. portions of ethanol were added to decompose the remaining hydride. When the mixture did not foam on further ethanol addition, the mixture was evaporated under vacuum to dryness, and the residue was dumped into 4 liters of water. The aqueous mixture was extracted with hexane to remove the mineral oil, and it was then made acid to pH 2 and was extracted with two 1-liter portions of diethyl ether. The ether was dried over magnesium sulfate and evaporated under vacuum to obtain 122 g. of the desired acetonitrile.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[CH:9][C:10]2[CH:11]=[C:12]3[C:25]([C:26](=O)[C:27]=2[CH:28]=1)=[CH:24][C:23]1[C:14]([C:15](=O)[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:17]=2)=[CH:13]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(CC)[O-].CC(CC)[O-].CC(CC)[O-].[Al+3]>C1(C)C=C(C)C=C(C)C=1>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]2[C:27](=[CH:26][C:25]3[C:12]([CH:11]=2)=[CH:13][C:14]2[C:23](=[CH:22][C:21]4[C:16]([CH:15]=2)=[CH:17][C:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:19][CH:20]=4)[CH:24]=3)[CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc2c(c1)C(=O)c1cc3c(cc1=C2)C(=O)c1cc(CCCCCC)ccc1C=3
Agent: CCC(C)[O-]
Agent: [Al+3]
Solvent: Cc1cc(C)cc(C)c1
Product: CCCCCCc1ccc2cc3cc4cc5cc(CCCCCC)ccc5cc4cc3cc2c1
Temperature: 155 °C

Procedure:
A mixture of 1.0 grams of 3,10-dihexylpentacene-5,12-dione and 2.5 grams of aluminum tri(sec-butoxide) in 50 mL of mesitylene was heated to 155° C. for 2 days and cooled. The reaction mixture was filtered and the residue washed with concentrated HCl to give 2,9-dihexylpentacene.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.Cl.Cl[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CN(C=O)C>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccccn2)CC1
Temperature: 70 °C
Yield: 40 %

Procedure:
A mixture of 57.5 parts of ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate, 33 parts of 2-(chloromethyl)pyridine hydrochloride, 43 parts of sodium carbonate, 0.1 parts of potassium iodide and 630 parts of DMF was stirred and heated overnight at 70° C. The reaction mixture was cooled and poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 30 parts (40%) of ethyl 4-[[1-[(2-pyridinyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp. 161.5° C. (55).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.O>C1COCC1.[Ni]>[O:13]1[CH2:14][CH2:15][N:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)nc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Example 154A (12.5, 59.5 mmol) in THF (150 mL) was added to Ra—Ni 2800, water slurry (12.5 g, 212 mmol) in a 500 mL SS pressure bottle. The mixture was pressurized (H2, 30 psi) and stirred for 2 hours at room temperature. The mixture was filtered and then concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O>C1COCC1.[Pd]>[O:13]1[CH2:14][CH2:15][N:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)nc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 4-(5-nitropyridin-2-yl)morpholine (3.89 g, 18.60 mmol) in THF (100 mL) was added catalyst Pd/C (0.5 g). The reaction was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo to give the title compound as a brown-red solid (3.30 g, 99%).
Reaction SMILES: O.[PH2]([O-])=O.[Na+].S(=O)(=O)(O)O.C=C.C([O-])([O-])=O.C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[Al:31].[Al+3].[CH2:33]([P:35](CC)(=[O:37])[O-:36])[CH3:34].[CH2:40]([P:42](CC)(=[O:44])[O-:43])[CH3:41].[CH2:47]([P:49](CC)(=[O:51])[O-:50])[CH3:48]>O>[Al+3:31].[CH2:33]([P:35]([O-:37])[O-:36])[CH3:34].[CH2:40]([P:42]([O-:44])[O-:43])[CH3:41].[CH2:47]([P:49]([O-:51])[O-:50])[CH3:48].[Al+3:31]
Reactant: [Al]
Reactant: CCP(=O)([O-])CC
Agent: C=C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCP([O-])[O-]
Temperature: 100 °C
Yield: 95 %

Procedure:
1500 g (14 mol) of sodium hypophosphite monohydrate and 14 g of concentrated sulfuric acid are dissolved in 7.5 kg of water and initially charged in a 16 l steel-enamel jacketed pressure reactor. After heating the reaction mixture to 100° C., a reducing valve set to 6 bar is used to introduce ethylene into the reactor up to saturation. While stirring constantly at an ethylene pressure of 6 bar and a temperature of 100-110° C., a solution of 22 g (1 mol %) of sodium percarbonate in 300 g of water is metered in homogeneously. At a conversion of ethylene of 83.5%, the metered addition of sodium percarbonate is stopped and the reactor is decompressed. After cooling to about 90° C., 3000 g (4.67 mol of aluminum) of a 46% aqueous solution of Al2(SO4)3.14H2O were added within 60 minutes. Subsequently, the resulting solid is filtered off, washed with 2 l of hot water and dried at 130° C. under reduced pressure. The resulting mixture comprises diethylphosphinic acid aluminum(III) salt and ethylphosphonous acid aluminum(III) salt in a ratio of 76.4% by weight of diethylphosphinic acid aluminum(III) salt and 23.6% by weight of ethylphosphonous acid aluminum(III) salt (95.0% yield).
Reaction SMILES: C1OC2C=C([N+]([O-])=O)C(C=O)=CC=2O1.[CH2:15]1[O:27][C:26]2[CH:25]=[C:24]([N+:28]([O-])=O)[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:16]1.[C-]#N.[Na+]>CO.C(O)C.[O-2].[O-2].[Mn+4].[Pd]>[CH2:15]1[O:27][C:26]2[CH:25]=[C:24]([NH2:28])[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:16]1
Reactant: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Mn+4]
Agent: [Pd]
Agent: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Solvent: CO
Solvent: CCO
Product: COC(=O)c1cc2c(cc1N)OCO2

Procedure:
3,4-Methylenedioxy-6-nitrobenzaldehyde is converted to methyl 3,4-methylenedioxy-6-nitrobenzoate in methanol in the presence of sodium cyanide and manganese dioxide (Synthetic Commun., 27(7), 1281–1283 (1997)). Methyl 3,4-methylenedioxy-6-nitrobenzoate is hydrogenated in ethanol in the presence of palladium, 10% on carbon powder, at room temperature and atmospheric pressure to give methyl 3,4-methylenedioxy-6-amino-benzoate.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[OH:10].C(N(C(C)C)CC)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].CN(C1C=CC=CN=1)C>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: OC1Cc2ccccc2C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OC1Cc2ccccc2C1
Reaction time: 18 h
Yield: 77.5 %

Procedure:
2-Indanol (20.00 g, 149.5 mmol) and diisopropylethylamine (21.2 g, 164 mmol) was stirred in dichloromethane (300 mL) at 0° C. Methanesulfonyl chloride (18.78 g, 164 mmol) and dimethylaminopyridine (1.80 g) were added simultaneously and stirring continued at room temperature for 18 h. Solution was evaporated, partitioned between ethyl acetate and water, and the organic phase separated. This was washed with NaHCO3 (sat) and with citric acid solution (5%) and dried over MgSO4. The filtered solution was concentrated and the resultant solid recrystallized from isopropanol-EtOH (3:1) to give off-white crystals (24.6 g, 78%).