Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:8]([O:9][CH2:10][CH3:11])=[N:7][S:6](=[O:13])(=[O:12])[N:5]=1)C.[C:14]([O:18][C:19](=[O:30])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH2:21])([CH3:17])([CH3:16])[CH3:15]>C(O)C>[C:14]([O:18][C:19](=[O:30])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:21][C:4]1[C:8]([O:9][CH2:10][CH3:11])=[N:7][S:6](=[O:12])(=[O:13])[N:5]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCOC1=NS(=O)(=O)N=C1OCC
Solvent: CCO
Product: CCOC1=NS(=O)(=O)N=C1N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of 3,4-diethyloxy-1,1-dioxo-1,2,5-thiadiazole (400 mg, 1.94 mmol)and L-tyrosine t-butyl ester (1.25 g, 5.2 mmol) in ethanol (25 mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure and the product used in further transformations without further purification (Yield 790 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10].[C:11]1([CH2:17][CH2:18][OH:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:19][CH2:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCc1ccccc1
Reactant: BrCCCCCCCCBr
Product: BrCCCCCCCCOCCc1ccccc1

Procedure:
(4.3 g), T.l.c. [B] Rf 0.3, from 1,8-dibromooctane (13.4 g) and benzeneethanol (20 g).
Reaction SMILES: [CH3:1][C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16]C(=O)[N:14]([CH2:18][CH2:19][C:20]4[CH:44]=[CH:43][C:23]([O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]5[CH:30]=[C:31]([NH:35][C:36]([C:38]6[O:39][CH:40]=[CH:41][CH:42]=6)=[O:37])[CH:32]=[CH:33][CH:34]=5)=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.O([Si](C)(C)C)[K]>C1COCC1>[C:2]([OH:7])(=[O:3])[CH3:1].[OH:16][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:18][CH2:19][C:20]1[CH:44]=[CH:43][C:23]([O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]2[CH:30]=[C:31]([NH:35][C:36]([C:38]3[O:39][CH:40]=[CH:41][CH:42]=3)=[O:37])[CH:32]=[CH:33][CH:34]=2)=[CH:22][CH:21]=1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(NC(=O)c6ccco6)c5)cc4)C(=O)O3)ccc2O1
Agent: C[Si](C)(C)O[K]
Solvent: C1CCOC1
Product: CC(=O)O
Product: O=C(Nc1cccc(COCCOc2ccc(CCNC[C@H](O)c3ccc(O)c(CO)c3)cc2)c1)c1ccco1
Temperature: 75 °C
Yield: 20.2 %

Procedure:
N-(3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)-2-furamide (34 mg) in THF (2 mL) was treated with KOSiMe3 (18 mg) and the resulting solution was heated at 75° C. for 4 h. The reaction mixture was then quenched with MeOH and concentrated in vacuo. The residue was then purified by HPLC, before dissolving in acetic acid (1 mL) and water (0.33 mL) and heating at 75° for 20 min. The solution was then concentrated in vacuo and azeotroped with MeOH to give the title compound (3.4 mg). LCMS RT=2.45 min. ES+ve 547 (MH)+
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]([CH:21]=[CH2:22])=[O:20]>>[O:20]=[C:19]([CH3:18])[CH2:21][CH2:22][N:12]1[C:11]2[CH:16]=[CH:17][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][C:10]=2[N:14]([CH2:22][CH2:21][C:19](=[O:20])[CH3:18])[C:13]1=[S:15]
Reactant: C=CC(C)=O
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Product: CC(=O)CCn1c(=S)n(CCC(C)=O)c2cc(Cc3ccccc3)ccc21

Procedure:
14.4 g (60 mmoles) of 5-benzyl-benzimidazoline-2-thione amd 45 ml of methylvinylketone are boiled for 4 hours in the presence of 2 drops of 40%, methynolic Triton B solution. Then the reaction mixture is evaporated off. During storage the distillation residue crystallizes. This is recrystallized from 200 ml of ethanol and thus 19.86 g (87%) of title product melting at a temperature of 98°-100° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6](CC2C=C(C)C(C(=O)C3C=CC(C(F)(F)F)=CC=3)=C(Cl)C=2)[N:5]=[N:4][C:3]=1[C:28]([NH2:30])=[O:29].CI.[C:33](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:33][NH:1][C:2]1[NH:6][N:5]=[N:4][C:3]=1[C:28]([NH2:30])=[O:29]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cn2nnc(C(N)=O)c2N)cc(Cl)c1C(=O)c1ccc(C(F)(F)F)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CNc1[nH]nnc1C(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-amino-1-(4-[4-trifluoromethylbenzoyl]-3-chloro-5-methylbenzyl)-1,2,3-triazole-4carboxamide (438 mg, 1.00 mmole), methyl iodide (142 mg, 1.00 mmol), and potassium carbonate (138 mg, 1.00 mmole) in N,N-dimethylformamide (2.0 mL) is stirred 48 hours at ambient temperature, poured into water (15 mL), and filtered. Chromatography provides 1-4-[4-trifluoromethylbenzoyl]-3-chloro-5-methyl-benzyl)-5-methylamino-1,2,3-triazole-4-carboxamide.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][S:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[N:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:21]=[N:22][CH:23]=[C:18]([S:17][CH3:16])[CH:19]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CSc1cncc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (600 mg, 2.419 mmol), 5-(methylthio)pyridin-3-ylboronic acid (429 mg, 2.54 mmol), PdCl2(PPh3)2 (170 mg, 0.242 mmol), sodium carbonate (769 mg, 7.26 mmol), 1,4-dioxane (6.5 mL), and water (1.6 mL) at 95° C. for 2 h. Purification by column chromatography (silica gel, 0-30% EtOAc in hexanes) gave 4-chloro-5,7-difluoro-3-methyl-2-(5-(methylthio)pyridin-3-yl)quinoline. Mass Spectrum (ESI) m/e=337.0 (M+1).
Reaction SMILES: [BH4-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[S@:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH:10]=2)[CH:4]=1.O.CC(C)=O>C(O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][S@:14]2=[O:15])[CH:4]=1
Reactant: O=[S@@]1CCCC=C1c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: O=[S@@]1CCCC[C@@H]1c1cccnc1
Reaction time: 3 h
Yield: 30.6 %

Procedure:
A stirred suspension of sodium borohydride (11.44 g) in ethanol (935 ml) is treated with a solution of crude (R)-6-(3-pyridyl)-3,4-dihydro-2H-thiopyran 1-oxide (116.9 g; prepared as described in Example 10) in ethanol (117 ml) at room temperature under nitrogen. The mixture is stirred for 3 hours and is then treated with water (935 ml) and acetone (93 ml), with cooling. The solution is extracted with dichloromethane (3×800 ml), the combined extracts are washed with aqueous sodium chloride solution (2×800 ml;25% w/v), dried over magnesium sulphate, and evaporated under reduced pressure to give a paste (96.2 g). This paste is recrystallised from a mixture of tert-butyl methyl ether and methyl ethyl ketone, to give (1R,2R)-2-(3-pyridyl)tetrahydro-2H-thiopyran 1 -oxide (36.16 g), in the form of a pale yellow powder, m.p. 121°-126° C., enantiomeric excess 99.6%. [NMR (CDCl3):- 1.6(m, 1H), 1.8(m,2H),2.0(m,1H),2.4(m,1H),2.7(m,2H), 3.2(m,1H),3.5(dd,1H),7.3(m,1H),7.7(dt, 1H), 8.6(m,2H)].
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:9]1[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12]>COCCOC.CN(C)C=O.O>[Cl:18][C:16]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[C:9]([O:4][CH2:3][CH:2]([F:5])[F:1])[N:17]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: O
Product: NC(=O)c1ccc(Cl)nc1OCC(F)F
Reaction time: 1 h
Yield: 97.5 %

Procedure:
2,2-Difluoroethanol (3.51 mL, 55.5 mmol) was added dropwise over 30 minutes to a suspension of NaH (2.22 g, 60% w/w dispersion in oil) in 1,2-dimethoxyethane (40.0 mL) at 14° C. and stirred for 1 hour. A portion of this solution (25 mL, 35 mmol) was added dropwise over 10 minutes to a solution of 2,6-dichloro-nicotinamide (5.30 g, 27.7 mmol) in dimethylformamide (40 mL) at 14° C. The resultant suspension was stirred for an additional 1 hour at 14° C., diluted with water (600 mL) and extracted with EtOAc (3×400 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated to give title compound as a light orange solid (6.39 g, 97%). This was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])=[CH:4][CH:3]=1.[N+:17]([C:20]1[CH:34]=CC(C=CC(OCCCC)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH2:41](O)[CH2:42]CC>[Pd]>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])=[CH:6][CH:7]=2)[CH2:34][CH2:20][NH:17][CH2:42][CH2:41]1
Reactant: CCCCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCOC(=O)CCc1ccc(N)cc1
Reactant: CCCCO
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOC(=O)CCc1ccc(N2CCNCC2)cc1
Reaction time: 120 h

Procedure:
A mixture of 175 g. (0.79 mole) n-butyl 3-(-4-aminophenyl)-propionate (prepared by the hydrogenation of n-butyl 4-nitrocinnamate in the presence of palladiumcharcoal in n-butanol; b.p. 137°-138° C./0.013 mbar), 141.3 g. (0.79 mole) bis-(2-cholorethyl)-amine hydrochloride and 600 ml. n-butanol is maintained at reflux temperature for 48 hours, then 54.5 g. (0.39 mole) powdered potassium carbonate are added thereto and the reaction allowed to continue for a further 120 hours at the boiling temperature. Thereafter, the reaction mixture is suction filtered hot, the filtrate is evaporated in a vacuum and the oil remaining behind is taken up in n-butanol. The sulphate is now precipitated out in the cold by adding concentrated sulphuric acid. It is filtered off with suction, triturated with diethyl ether and dried. Yield 286.8 g. (69% of theory); m.p. 183°-185° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C.C(OCC)(=O)C>ClCCl.[OH-].[NH4+].O>[Cl:1][C:2]1[C:7]([C:8]([NH2:19])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 809.8 %

Procedure:
To the suspension of 2-chloro-5-fluoropyridine-3-carboxylic acid (37.0 g, 210.8 mmol) in dichloromethane (555 mL) was added oxalyl chloride (56.2 g, 442.7 mmol) under nitrogen. DMF (1.54 g, 21.08 mmol) was added slowly to the reaction mixture. The mixture was stirred at room temperature for 2 h and dichloromethane was removed under reduced pressure. The residue was dissolved in THF (300 mL) and cooled down to 0° C. by ice bath. Ammonium hydroxide (28-30%, 113.0 mL, 1.8 mmol) was added in one portion. The mixture was stirred for another 15 min. The mixture was diluted into ethyl acetate (300 mL) and water (300 mL) and the phases were separated. The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated in vacuo to afford 29.8 g desired product as white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J=3.0 Hz, 1H), 8.11 (s, 1H), 8.00 (dd, J=8.0, 3.0 Hz, 1H), 7.89 (s, 1H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=1.11 minutes, (M+H) 175.02.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[NH:8][C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)C>C(O)(=O)C>[CH3:14][C:5]1([CH3:15])[C:4]2[CH:3]=[C:2]3[NH:1][C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:12][C:11]3=[CH:10][C:9]=2[NH:8][C:7](=[O:13])[CH2:6]1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Reactant: O=Cc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccccc4)[nH]c3cc21

Procedure:
3.0 g. 6,7-diamino-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-one and 1.5 ml. benzaldehyde were stirred for 20 hours in 50 ml. ethanol and 5 ml. glacial acetic acid. Half of the solvent was removed in a vacuum and the remainder was mixed with 50 ml. water and filtered off with suction. After recrystallisation from ethyl acetate, there were obtained 2.4 g. of the title compound; m.p. 296 -298° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][C@H:7]1[CH2:11][O:10][C:9](=[O:12])[C@@H:8]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][N:29]([CH3:33])[C:30](=[O:31])[O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@@H:8]2[C@@H:7]([CH2:6][C:5]3[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:11][O:10][C:9]2=[O:12])=[CH:15][C:16]=1[O:21][CH3:22]
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc(C[C@H]2C(=O)OC[C@@H]2Cc2ccc(OC)c(OC)c2)ccc1O
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc(C[C@H]2COC(=O)[C@@H]2Cc2ccc(OC(=O)N(C)C)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of (3R,4R)-4-(3,4-dimethoxybenzyl)-3-(4-hydroxy-3-methoxybenzyl)dihydrofuran-2(3H)-one (150 mg, 0.40 mmol, 1.0 eq) in DCM (15 mL) was added TEA (81 mg, 0.81 mmol, 2.0 eq) and DMAP (98 mg, 0.81 mmol, 2.0 eq), followed by N,N-dimethylcarbamoyl chloride (65 mg, 0.60 mmol, 1.5 eq). The mixture was stirred at rt for overnight, then sat. aq. NH4Cl (30 mL) was added. The reaction mixture was extracted with DCM (30 mL×3). The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=1/1, v/v) to afford 4-(((3R,4R)-4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2-methoxyphenyl dimethylcarbamate (110 mg, 61.6%). LRMS (M+H+) m/z calculated 444.2, found 443.9. 1H NMR (CDCl3, 400 MHz) δ 6.97 (d, 1H), 6.73-6.78 (m, 2H), 6.64-6.70 (m, 1H), 6.50-6.55 (m, 2H), 4.12-4.17 (m, 1H), 3.82-3.90 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.11 (s, 3H), 3.00 (s, 3H), 2.97 (d, 2H), 2.49-2.69 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:15]1(/[CH:14]=[CH:13]/[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Br
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccccc1/C=C/c1ccccc1
Yield: 103.9 %

Procedure:
8.9 g (38.9 mmol) of ethyl 2-bromobenzoate, 5.1 g (49.4 mmol) of styrene, 0.18 g (0.8 mmol) of palladium diacetate, 0.48 g (1.6 mmol) of tri-o-tolylphosphine and 5 g (49.1 mmol) of triethylamine were reacted in 90 ml of anhydrous acetonitrile at 100° C. for 23 h. The mixture was then filtered and the filtrate was diluted with ethyl acetate, washed with water, dried and concentrated under reduced pressure. 10.2 g (100%) of the product were obtained.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].CS(O)(=O)=O.[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[K+]>C(COC)OC.C(O)C>[CH2:11]([O:18][C:19]([NH:4][CH2:3][CH2:2][CH2:1][NH2:5])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCCN
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: NCCCNC(=O)OCc1ccccc1
Temperature: 20 °C

Procedure:
In the process for the preparation of the novel compound of the general formula (I) according to the aforesaid second aspect of this invention, there is employed as the starting compound such a mono-amino-protected derivative of the α,ω-alkanediamine as represented by the general formula (II) shown hereinbefore. This mono-amino-protected derivative of the formula (II) may be prepared by anyone of known various methods but preferably may be prepared in accordance with the method of Atwell & Denny [see the "Synthesis", page 1032 (1984)]. More specifically, for example, an aqueous solution of propane-1,3-diamine is adjusted to pH 3.8 with methane-sulfonic acid, followed by addition of ethanol. The resulting solution is added dropwise with a solution of benzyloxycarbonyl chloride in dimethoxyethane under stirring at 20° C. At the same time, to the resulting mixture is added an aqueous solution of potassium acetate so that the pH of the reaction mixture is maintained at 3.5-4.5 during the reaction, whereby one of the amino groups of the propane-1,3-diamine can be selectively benzyloxycarbonylated to afford N-(benzyloxycarbonyl)-propane-1,3-diamine in a high yield (see Referential Example 2 given hereinafter).
Reaction SMILES: [NH2:1][C:2](=[CH:4][C:5](=[O:9])[CH2:6][CH2:7][CH3:8])[CH3:3].[C:10](OC)(=[O:13])[C:11]#[CH:12]>CN(C)C=O>[C:5]([C:4]1[CH:12]=[CH:11][C:10](=[O:13])[NH:1][C:2]=1[CH3:3])(=[O:9])[CH2:6][CH2:7][CH3:8]
Reactant: C#CC(=O)OC
Reactant: CCCC(=O)C=C(C)N
Solvent: CN(C)C=O
Product: CCCC(=O)c1ccc(=O)[nH]c1C
Temperature: 25 °C

Procedure:
D-5. 5-(n-Butanoyl)-6-methyl-2(1H)-pyridinone--A mixture containing 22.2 g of 3-methyl-5-n-propylisoxazole [Kashima et al., Bull. Chem. Soc. Japan 46, 310-313 (1973)], 500 mg of platinum dioxide and 200 ml of ethanol was hydrogenated under catalytic hydrogenation conditions for ninety minutes, the catalyst was filtered off and the filtrate was concentrated on a rotary evaporator to yield 18.5 g of colorless residue which solidified on cooling. The residue containing 2-amino-2-hepten-4-one was dissolved in 50 ml of dimethylformamide and to the solution was added 14.8 g of methyl 2-propynoate. The resulting reaction solution was allowed to stand at ambient temperature for thirty minutes (exothermic) and then refluxed for three and one half hours. The dimethylformamide was removed on a rotary evaporator. The remaining dark brown liquid was heated in an oil bath at 195°-200° C. for four hours, cooled to room temperature, crystallized from isopropyl alcohol and dried at 80°-85° C. to produce, as pale yellow flakes, 9.4 g of 5-(n-butanoyl)-6-methyl-2(1H)-pyridinone, m.p. 167°-168° C.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]3([C:15]([O:17]CC)=O)[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl.Cl.[NH:24]1[CH2:28][CH2:27][C:26]2([C:36]3[CH:35]=[CH:34][N:33]=[CH:32][C:31]=3[C:30](=[O:37])[O:29]2)[CH2:25]1>CO>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]3([C:15]([N:24]4[CH2:28][CH2:27][C@@:26]5([C:36]6[CH:35]=[CH:34][N:33]=[CH:32][C:31]=6[C:30](=[O:37])[O:29]5)[CH2:25]4)=[O:17])[CH2:13][CH2:14]3)=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1OC2(CCNC2)c2ccncc21
Reactant: CCOC(=O)C1(c2ccc(N3CCCC3)nc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCCC5)nc4)CC3)C2)c2ccncc21

Procedure:
The above material of ethyl 1-(6-pyrrolidin-1-ylpyridin-3-yl)cyclopropanecarboxylate was treated with LiOH in methanol to afford the corresponding acid, which was then coupled with 3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one dihydrochloride using procedures analogous to those for example 96 to afford (1R)-1′-{[1-(6-pyrrolidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one. MS (ESI): (M+H)+=405.1
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([NH:20][CH2:21][CH2:22][OH:23])[C:11]=2[Cl:24])[CH:5]=[N:4]1)[CH3:2].[CH:26]([CH:28]=[O:29])=O>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[C:12]([N:20]3[CH2:26][CH2:28][O:29][C:22](=[O:23])[CH2:21]3)[C:11]=2[Cl:24])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(NCCO)c2Cl)c1O
Reactant: O=CC=O
Solvent: Cc1ccccc1
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(N3CCOC(=O)C3)c2Cl)c1O
Reaction time: 24 h

Procedure:
A solution of 0.50 g (1.3 mmol) of 1-ethyl-4-(2-chloro-3-(2-hydroxyethylamino)-4-methylsulfonylbenzoyl)-5-hydroxypyrazole in 20 mL of toluene was heated to 90° C. and treated with 2 mL of 40 percent aqueous glyoxal solution with stirring. The progress of the reaction was monitored by HPLC analysis and additional aliquots of 40 percent aqueous glyoxal solution were added every few hours until the starting material was consumed. After 24 hours, the reaction was complete and the dark solution was decanted from a gummy residue. The residue was extracted with several portions of hot toluene and the organic solutions were combined. The volatiles were removed by evaporation under reduced pressure and the resulting residue was purified by adding a small amount of diethyl ether and collecting the solids present by filtration. More solids were obtained when the diethyl ether solution was concentrated by evaporation. These solids were collected by filtration as well. The solids were combined to obtain 0.39 g (71 percent of theory) of the title compound as a tan powder melting at 198°-202° C.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH2:11][CH2:12][OH:13])[CH2:7][CH2:8][CH3:9].C(#N)C=C.[OH2:18].[O:19]1[CH2:23][CH2:22][CH2:21]C1>CCCCCC>[CH2:6]([O:10][CH2:11][CH2:12][O:13][CH2:21][CH2:22][C:23]([OH:19])=[O:18])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCO
Reactant: C1CCOC1
Reactant: O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C=CC#N
Product: CCCCOCCOCCC(=O)O
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 53 %

Procedure:
2 ml (3.2 mmol, 10 mol %) of a 1.6N solution of butyllithium in hexane are added dropwise, under N2, at 10° C. to a solution of 3.8 g (32 mmol) of 2-butoxyethanol in 2 ml of tetrahydrofuran. The solution is stirred for 5 minutes at 10° C. Then 2.5 ml (38 mmol) of acrylonitrile are added. The reaction mixture is heated to 55° C. and stirred for 2.5 hours at this temperature. Then a further 0.25 ml (3.8 mmol) of acrylonitrile is added and the mixture is stirred for another hour at 55° C. The reaction mixture is cooled to RT and afterwards poured into water. After acidification with 2N HCl (2 ml) and extraction with toluene, the organic phase is washed with an aqueous saturated solution of NaCl, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator. The crude 3-(2-buthoxyethoxy)propionitrile (4.4 g) is taken up in 15 ml of concentrated hydrochloric acid and the solution is heated for 2.5 hours to 80° C. The resultant brown solution is cooled to RT, diluted with water and and extracted once more with ethyl acetate. The organic phases are combined, washed with an aqueous saturated solution of NaCl, dried over MgSO4, concentrated on a vacuum rotary evaporator and dried under a high vacuum, affording 3.2 g (53%) of 3-(2-butoxyethoxy)propionic acid as a pale brown liquid.