Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH2:15][CH2:16][C:17](OCC)=[O:18])=[N:13][CH:14]=[C:7]1[C:6](=[O:22])[NH:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[N:13][CH:14]=[C:7]1[C:6](=[O:22])[NH:5]2
Reactant: CCOC(=O)CCc1ncc2c(=O)[nH]c3cc(Cl)ccc3n12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2n2c(CCCO)ncc12

Procedure:
Fifty (50) mg of ethyl 3-(7-chloro-4-oxo-4,5-dihydroimidazo-[1,5-a]quinoxalin-1-yl)propanoate as synthesized in Example 176 was dissolved in 5 mL of tetrahydrofuran, and to the solution 8.9 mg of lithium aluminum hydride was added under cooling with ice. After minutes' stirring, the residual lithium aluminum hydride was quenched with ice pieces, and the reaction liquid was extracted with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogencarbonate solution, and with saturated brine by the order stated, and dried over anhydrous sodium sulfate. Distilling the solvent off from the product, 38 mg of the title compound was obtained.
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].CC(C)([O-])C.[K+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C=O)C>[OH:1][CH:2]([CH3:6])[C:3]([O:5][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(O)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C(C)O)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of DL-2 hydroxypropionic acid (9.0 g, 100 mmole) in 100 ml dry DMF was added potassium tert-butoxide (12.34 g, 110 mmole) and the mixture was stirred for one hour at 60° C. 4-methoxybenzyl chloride (18.8 g 120 mmole) was added and the mixture was stirred for eight hours at 60° C. The mixture was evaporated under reduced pressure and 250 ml ethyl acatate was added. The organic phase was washed four times with water. The organic phase was dried with sodium sulfate and concentrated in vacuo. Yield: 16.8 g
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Sb+3:5].[C:6]([O-:9])(=[O:8])[CH3:7].[C:10]([O-:13])(=[O:12])[CH3:11].[OH-:14].[NH4+].[Sb]>O.C(O)(=O)C(O)=O>[C:1]([O-:4])(=[O:3])[C:2]([O-:8])=[O:14].[Sb+3:5].[C:6]([O-:9])(=[O:8])[C:7]([O-:12])=[O:14].[C:10]([O-:13])(=[O:12])[C:11]([O-:3])=[O:14].[Sb+3:5]
Reactant: CC(=O)[O-]
Reactant: [OH-]
Agent: O=C(O)C(=O)O
Agent: [NH4+]
Agent: [Sb+3]
Solvent: O
Product: O=C([O-])C(=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Antimony oxalate solution was prepared by mixing antimony (III) acetate as obtained from Aldrich with a 1 M solution of oxalic acid in deionized water and heating the mixture to 60° C. A concentrated solution of ammonium hydroxide in deionized water was added dropwise to the antimony containing mixture until the solution became homogeneous. At this point, the solution was diluted as-required with oxalic acid solution or deionized water to desired metal concentration. The prepared antimony oxalate solution (3.3% antimony, 290.9 μL) was mixed with deionized water (1149.1 μL) and the resultant diluted solution (120 μL) was added to the supported rhodium-indium product of the first impregnation step and agitated by vibration for 30 minutes at room temperature. The obtained trimetallic material was dried at 120° C. for 2 hours and then calcined in air at 450° C. for 4 hours.
Reaction SMILES: [C@:1]12([CH3:28])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:12][CH:13]([C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[C:14](C)([CH3:16])[CH3:15])=[O:11]>CO>[C@:1]12([CH3:28])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:12][CH:13]([C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[CH:14]([CH3:15])[CH3:16])=[O:11]
Reactant: CC(C)(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Solvent: CO
Product: CC(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Reaction time: 48 h
Yield: 39 %

Procedure:
(R or S)-1-(4-Iodo-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate: (RS)-1-(4-Iodo-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (2.07 g) was dissolved in boiling methanol (100 mL) and left at room temperature for two days. Crystals formed were filtered to yield pure single diastereomer (R or S)-1-(4-iodo-2-nitrophenyl)-2-methyl-1-propyl (1S)-camphanate (0.409 g, 39%). The absolute configuration of the single diastereomer camphanate is not determined. 1H NMR (400 MHz, CDCl3): δ 8.23 (d, 1 H, J=2.0 Hz, Ph-H), 7.89 (dd, 2 H, J=2.0 and 8.4 Hz, Ph-H), 7.30 (d, 1 H, J=8.4 Hz, Ph-H), 6.56 (s, 1 H, Ph-CH), 2.42 (m, 1 H), 2.07 (m, 1 H), 1.94 (m, 1 H), 1.73 (m, 1 H), 1.11, 1.04 and 0.87 (3 s, 9 H, CH3 3), 0.95 (s, 9 H, (CH3)3C).
Reaction SMILES: C([C:3]1([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:8][CH2:7][C:6](C#N)([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#N.C1([Mg]Br)C=CC=CC=1>>[C:6]1([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:8][CH:7]=1
Reactant: N#CC1(N2CCCCC2)CCC(C#N)(N2CCCCC2)CC1
Agent: Br[Mg]c1ccccc1
Product: c1cc(N2CCCCC2)ccc1N1CCCCC1
Yield: 28 %

Procedure:
Referring now to the drawings, and more particularly to FIG. 1, there is shown the synthesis route for preparing the dihydrochloride salt of 1,1'-para-phenylene dipiperidine. The synthesis involves the reaction between cyanide ion, piperidine, and tetrahydroquinone. The resulting yield of 1,4-dicyano-1,4-dipiperidylcyclohexane is approximately 80%. Tetrahydroquinone, cyanide, and piperidine are commercially available from Aldrich Chemical Co. Piperidine can only be obtained in compliance with federal drug enforcement law. The 1,4-dicyano-1,4-dipiperidylcyclohexane is then reacted with a Grignard reagent, phenyl magnesium bromide, which is also available from Aldrich Chemical Co. In this reaction, the Grignard reaction may cause decyanation of the dicyano compound to give a dienanmine structure which undergoes air oxidation in solution to produce 1,1'-para-phenylene dipiperidine free base. The yield is approximately 28% for the Grignard reaction. The structure of 1,1'-para-phenylene dipiperidine was confirmed by classical CHN analytical methods and modern spectral techniques such as IR and NMR. The compounds melting point and spectral properties were consistent with those reported in the literature.
Reaction SMILES: [O-]Cl.[Na+].C([O-])(O)=O.[Na+].[O:9]1[CH:13]2[O:14][CH2:15][CH2:16][CH:12]2[CH:11]([OH:17])[CH2:10]1.[K+].[Br-]>O.CCOC(C)=O.CC1(C)N([O])C(C)(C)CCC1>[O:9]1[CH:13]2[O:14][CH2:15][CH2:16][CH:12]2[C:11](=[O:17])[CH2:10]1
Reactant: OC1COC2OCCC12
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1COC2OCCC12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
In a 250 mL round bottom flask, NaOCl (6.15 g, 14% w/w) was diluted in 100 mL of water. The pH of the solution was adjusted to 9.5 using a 1M NaHCO3 aqueous solution. In a separate 250 mL round bottom flask, hexahydrofuro[2,3-b]furan-3-ol (1 g, 7.7 mmol, 1 eq.) was dissolved in 15 mL of AcOEt at 0° C. Then KBr (91 mg, 0.77 mmol, 0.1 eq.) dissolved in 1 mL of water was added followed by the addition of TEMPO (12 mg, 0.08 mmol, 0.01 eq.). Finally, the NaOCl mixture was added dropwise. After 15 minutes of stirring at 0° C., the mixture was extracted 3 times with 100 mL of AcOEt. The collected organic layers were dried over Na2SO4 and the solvent was evaporated under reduced pressure to afford 950 mg of a white solid, yield: 96%. The resulting tetrahydrofuro[2,3-b]furan-3(2H)-one was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:24])=[N:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH:3]=1.Br[C:26]1[S:34][C:33]2[CH2:32][CH2:31][N:30]([CH2:35][CH3:36])[CH2:29][C:28]=2[CH:27]=1>[F-].[K+].C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:24])=[N:11][CH:12]=[C:13]([C:26]3[S:34][C:33]4[CH2:32][CH2:31][N:30]([CH2:35][CH3:36])[CH2:29][C:28]=4[CH:27]=3)[CH:14]=2)[CH:3]=1
Reactant: CC1(C)OB(c2cnc(F)c(-c3cc(Cl)ncc3N)c2)OC1(C)C
Reactant: CCN1CCc2sc(Br)cc2C1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCc2sc(-c3cnc(F)c(-c4cc(Cl)ncc4N)c3)cc2C1
Temperature: 100 °C
Yield: 47.4 %

Procedure:
A degassed mixture of 6′-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-[3,4′]bipyridinyl-3′-ylamine (1.99 g, 5.70 mmol), 2-bromo-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.54 g, 6.30 mmol), 1,1′-[bis(diphenylphosphino) ferrocene]dichloropalladium(II) (466 mg, 0.57 mmol) in 1N aqueous potassium fluoride solution (22.5 mL) and acetonitrile (22.5 mL) was heated under microwave irradiation at 100° C. for 30 minutes. The cooled reaction mixture was loaded onto an SCX-2 cartridge (50 g) and eluted with 2N ammonia in methanol to afford impure product as a brown solid. The resultant brown residue was purified by flash chromatography (silica, 40 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as an off-white solid (1.05 g, 47%). 1H NMR (DMSO-D6, 300 MHz): 8.48 (d, J=2.4 Hz, 1H), 8.12 (dd, J=9.0, 2.6 Hz, 1H), 7.89 (s, 1H), 7.36 (s, 1H), 7.21 (s, 1H), 5.54 (s, 2H), 3.45 (s, 2H), 2.86-2.79 (m, 2H), 2.75-2.68 (m, 2H), 2.58-2.51 (m, 2H), 1.08 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[S-:9]C#N.[Na+].BrBr>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[NH2:1][C:2]1[C:7]([SH:9])=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1
Reactant: N#C[S-]
Agent: BrBr
Agent: Cc1cccc(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(S)c(N)n1
Reaction time: 1 h

Procedure:
The intermediate 2-amino-6-methylpyridine is prepared as follows: To a solution of 68 g. (0.63 mole) of 2-amino-6-methylpyridine in about 500 ml. of glacial acetic acid, cooled to 10°-15° C., is added a mixture of 170.2 g. (2.1 moles) of sodium thiocyanate suspended in about 570 ml. of glacial acetic acid. A solution containing 30.5 ml. of bromine in about 60 ml. of glacial acetic acid is then added, and the mixture is stirred at 10°-15° C. for 1 hour and then at 75°-80° C. for 1/2 hour. The solution is filtered, and the solvent is removed from the filtrate under reduced pressure. The residue is recrystallized from isopropyl alcohol containing activated charcoal. The 2-amino-5-methylthiazolo[4,5-b]pyridine thus obtained melts at 150°-160° C. The product is hydrolyzed by refluxing 8 g. of the material in 120 ml. of 20 percent aqueous sodium hydroxide solution for 6 hours. The resulting cloudy solution is filtered, and the filtrate is acidified and reduced to dryness. The residue is extracted with hot ligroin to yield 2-amino-6-methyl-3-pyridinethiol, melting at 133°-138° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[NH:13]C(=O)C.Cl>CCO>[NH2:13][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[CH3:1])[C:9](=[O:12])[NH:8][CH:7]=[CH:6]2
Reactant: CC(=O)Nc1cc2cc[nH]c(=O)c2cc1C
Agent: Cl
Solvent: CCO
Product: Cc1cc2c(=O)[nH]ccc2cc1N
Reaction time: 6 h
Yield: 68 %

Procedure:
N-(7-Methyl-1-oxo-1,2-dihydro-isoquinolin-6-yl)-acetamide (0.366 g, 1.69 mmol) and conc. HCl (0.5 mL) is heated to reflux in EtOH (0.84 mL). After 6 hours, the mixture is concentrated to dryness, then diluted with water and basified using 1 N NaOH until pH is ca. 10. The aqueous solution is extracted with methylene chloride (4×50 mL) and the organic layers are combined and washed with brine, dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 3% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2 to give the title product (0.200 g, 1.15 mmol) as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:6]=[C:7]([C:10]2[CH:34]=[CH:33][C:13]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH2:28][C:29]([O:31]C)=[O:30])[CH:23]=[CH:22]4)=[C:12]([O:35][CH3:36])[CH:11]=2)[S:8][CH:9]=1)([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[CH:1]([O:4][C:5]1[N:6]=[C:7]([C:10]2[CH:34]=[CH:33][C:13]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH2:28][C:29]([OH:31])=[O:30])[CH:23]=[CH:22]4)=[C:12]([O:35][CH3:36])[CH:11]=2)[S:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)Cn1ccc2cc(OCCCOc3ccc(-c4nc(OC(C)C)cs4)cc3OC)ccc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2nc(OC(C)C)cs2)ccc1OCCCOc1ccc2c(ccn2CC(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
Methyl (5-{3-[4-(4-isopropoxy-1,3-thiazol-2-yl)-2-methoxyphenoxy]propoxy}-1H-indol-1-yl)acetate (Example 56, 204 mg, 0.40 mmol) was dissolved in THF (3 mL) in a round bottom flask, and LiOH.H2O (67 mg, 1.60 mmol) in water (1 mL) was added. The mixture was stirred at rt for 16 h. The solvents were evaporated under reduced pressure and the residue was suspended in small volume of water. The pH of the mixture was adjusted to 3 with 1 N HCl. The aqueous layer was immediately extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated to give 182 mg (91%) of the product as a white solid. 1H NMR (400 MHz, CDCl3) δ: 7.42 (s, 1H), 7.32 (d, 1H), 7.15-7.08 (m, 2H), 7.04 (d, 1H), 6.88 (dd, 1H), 6.82 (d, 1H), 6.52 (d, 1H), 5.96 (s, 1H), 4.85 (s, 2H), 4.70-4.60 (q, 1H), 4.35-4.20 (m, 4H), 3.88 (s, 3H), 2.38-2.28 (m, 2H), 1.42 (d, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C(C1C=CC=CC=1)CCC.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCc1ccccc1
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 61.2 %

Procedure:
To a mixture of 301 mg (purity: 100%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 832 mg (5.52 mmol) of 2-cyclopropyl-6-methylphenol were added normal butylbenzene (2.76 g) and 333 mg (5.65 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 308 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 61%) and 2.9 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.6%) were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:28])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:19][CH2:18]3)[CH3:16])[CH:8]=2)=[CH:4][CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])=[CH:34][CH:33]=1.C(OCC)C.CCCCCC>O1CCCC1>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][CH:17]([N:15]([CH3:16])[C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:42]([NH:41][C:39](=[O:40])[CH2:38][C:35]4[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=4)=[O:43])=[CH:30][CH:29]=3)[CH:12]=[CH:11][N:10]=2)=[O:28])[CH2:18][CH2:19]1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 10.5 h
Yield: 13.5 %

Procedure:
To a solution of 3-[4-(4-aminophenoxy)-pyridin-2-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (154 mg) in tetrahydrofuran (5.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 3.73 ml) at room temperature, followed by stirring at room temperature for 10.5 hrs. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing a target compound were concentrated to give a residue, to which diethyl ether (1 ml) and hexane (1 ml) were added to give a precipitate. The precipitate was filtered off, and dried under aeration to provide the titled compound (29.8 mg, 13.5%) as white powder.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3]/[CH:4]=[CH:5]/[Sn](CCCC)(CCCC)CCCC.C(OCC)C.C[Li].[Cu]C#N.[Cl-].[Li+].[Si:36]([O:43][CH:44]1[CH2:48][C:47](=[O:49])[C:46]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])=[CH:45]1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].[Cl-].[NH4+]>O1CCCC1>[CH3:59][O:58][C:56](=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][C@@H:46]1[C@@H:45](/[CH:5]=[CH:4]/[CH2:3][C:2]([OH:1])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:44]([O:43][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])[CH2:48][C:47]1=[O:49]
Reactant: CCCCC(C)(O)C/C=C/[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)CCCCCCC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC(C)(O)C/C=C/[C@H]1C(O[Si](C)(C)C(C)(C)C)CC(=O)[C@@H]1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
Into a dry flask was placed a solution of [(4RS, 1E)-4-hydroxy-4-methyl-1-octenyl]tri-n-butyltin (973 mg, 2.26 mmol) in dry tetrahydrofuran (5 ml) under nitrogen atmosphere and the mixture was cooled to 0° C. The solution was dropped with 5.7 ml (4.97 mmol) of a diethyl ether solution of methyllithium (0.88 mol/liter), warmed to room temperature and stirred for 2 h. After cooling to −78° C., the mixture was added with a previously prepared solution of copper (I) cyanide (215 mg, 2.4 mmol) and lithium chloride (102 mg, 2.4 mmol) in dry tetrahydofuran (3 ml) by using a cannula, and stirred for 1 h. The reaction liquid was dropped with boron trifluoride ether complex (283 μl, 2.26 mmol), stirred for 10 min and added with a solution of (±) methyl 7-(3-tert-butyldimethylsilyloxy-5-oxo-1-cyclopentenyl)heptanoate (500 mg, 1.4 mmol) in dry tetrahydrofuran (2 ml) was rapidly added. After stirring for 30 min, 20 ml of a saturated aqueous ammonium chloride/aqueous ammonia (9:1) was added, and stirring was continued for 20 min, letting the temperature rise gradually to room temperature. This mixture was extracted with ethyl acetate (70 ml) two times, and the combined organic layer was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo to remove solvent. The residue was purified by silica gel column chromatography [ethyl acetate/hexane (1/5)] to give 590 mg (85% yield) of (±)-methyl(16RS, 13E)-11-tert-butyldimethylsilyloxy-16-hydroxy-16-methyl-9-oxoprost-13-en-1-oate as a colorless oil. The spectral data of IR and 1H NMR were identical with those of the example 2.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([C:12]2[CH:16]=[C:15]([CH2:17][NH:18][C:19](=[O:25])[C:20]([O:22]CC)=[O:21])[O:14][N:13]=2)=[CH:4][C:3]=1[C:26]([CH3:29])([CH3:28])[CH3:27]>ClCCl>[OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([C:12]2[CH:16]=[C:15]([CH2:17][NH:18][C:19](=[O:25])[C:20]([OH:22])=[O:21])[O:14][N:13]=2)=[CH:4][C:3]=1[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C(=O)NCc1cc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)no1
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2cc(CNC(=O)C(=O)O)on2)cc(C(C)(C)C)c1O

Procedure:
5.0 g (0.012 mol) of the product from Example 50 were hydrolyzed in analogy with Example 4b). The product, arising as an oil, was isolated by extraction with dichloromethane, washing with water and NaCl solution, drying and concentrating. The remaining amorphous product was crystallized from tert-butyl methyl ether/petroleum ether. Yield: 3.4 g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][N:6]=1.[C:12](OC(=O)C)(=O)[CH3:13]>>[OH:1][CH2:2][CH2:3][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[N:11]=[C:12]1[CH3:13]
Reactant: Nc1cccnc1NCCO
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2cccnc2n1CCO
Yield: 59 %

Procedure:
2-(2-Hydroxyethylamino)-3-aminopyridine (3.4 g) was dissolved in acetic anhydride (140 ml) and stirred at reflux for 15 hours. The reaction mixture was cooled and the excess of reagent removed under reduced pressure. The dark brown oil was dissolved in ethanol (100 ml), 2N sodium hydroxide (50 ml) was added and the mixture was stirred for 15 minutes. The solution was acidified to pH5 using 2N hydrochloric acid and the solvents removed under reduced pressure. The residue was chromatographed over silica eluting with 10% methanol in ethyl acetate to yield the title compound (2.32 g, 59%) as a foam.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH2:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[CH:15][CH:14]=1>O1CCCC1>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][NH:11][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[S:21])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CC(=O)N1CCC(CN)CC1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(CNC(=S)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A mixture of 3.1 parts of 1-acetyl-4-piperidinemethanamine, 3.4 parts of 1-chloro-4-isothiocyanatobenzene and 90 parts of tetrahydrofuran was stirred for 3 hours at room temperature. The reaction mixture was evaporated, yielding 6.5 parts (99.7%) of N-[(1-acetyl-4-piperidinyl)methyl]-N'-(4-chlorophenyl)thiourea as a residue (intermediate 14).