Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[CH2:7])[CH2:5][OH:6].[CH2:8]([O:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1)[C:9]#[C:10][CH3:11].[Cl-].[NH4+]>O1CCCC1>[CH2:8]([O:12][C:13]1[CH:18]=[C:17]([O:6][CH2:5][C:4]([CH3:3])=[CH2:7])[N:16]=[CH:15][N:14]=1)[C:9]#[C:10][CH3:11]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: C=C(C)CO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)COc1cc(OCC#CC)ncn1
Reaction time: 0.17 h
Yield: 31.4 %

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.11 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.16 g of 2-methyl-2-propenol in tetrahydrofuran was added dropwise at 0° C., followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of a solution containing 0.4 g of 4-(2-butynyloxy)-6-chloropyrimidine in tetrahydrofuran, followed by stirring at the same temperature for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.15 g of 4-(2-butynyloxy)-6-(2-methylallyloxy)pyrimidine.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11]C(=O)OCC2C=CC=CC=2)[CH2:4][CH2:3]1>[C].[Pd].C(O)C>[NH2:11][CH2:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]1
Reactant: O=C(NCCCN1CCC(O)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NCCCN1CCC(O)CC1
Reaction time: 8 h
Yield: 93.6 %

Procedure:
Ethanol (200 ml) and palladium carbon (2.5 g) were added to benzyl N-(3-(4-hydroxypiperidino)propyl)carbamate (2.96 g); and the reaction mixture was stirred vigorously under hydrogen atmosphere overnight. Palladium carbon was removed by filtration, and the filtrate was concentrated to yield the title compound (1.5 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[S:9][CH:10]=[CH:11][N:12]=1>C(#N)C>[S:9]1[CH:10]=[CH:11][N:12]=[C:8]1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Brc1nccs1
Solvent: CC#N
Product: c1csc(N2CCNCC2)n1
Temperature: 25 °C
Yield: 25.4 %

Procedure:
Piperazine (3.44 g, 40 mmol) was added to a solution of 2-bromothiazole (1.8 ml, 20 mmol) in acetonitrile (90 ml). The mixture was heated at reflux for 20 h. The reaction was cooled down at RT and the precipitate (disubstituted piperazine) was filtered off. The filtrate was evaporated, the residue was partitioned between water and ethyl acetate, the organic phase was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were extracted with HCl (1 M). The organic phase was discarded, and the aqueous layer was neutralized by addition of NaHCO3 (solid) to pH 8, and then extracted with EtOAc. The organic extracted was dried over sodium sulfate and evaporated, providing 1-thiazol-2-ylpiperazine (intermediate IIIa, 860 mg, 25% yield) as colorless oil. H-NMR (CDCl3): 2.98 (m, 4H), 3.48 (m, 4H), 6.56 (d, 1H, J=3.63 Hz), 7.20 (d, 1H, J=3.63 Hz).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.076 mmol), 4-aminobutyric acid (624 mg, 6.05 mmol), and NaOMe solution (9 mL, 4.54 mmol) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 17 mg of the title compound. MS: (+) m/z 535.33 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10]O)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.O=S(Cl)[Cl:14]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:10][Cl:14])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: COc1cnc(CO)c(Cl)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cnc(CCl)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-chloro-5-methoxy-pyrazin-2-yl)-methanol (100 mg, 0.57 mmol) in DCM (5 mL) was added SOCl2 (5 eq) at room temperature. The mixture is stirred at room temperature for an additional one hour. Solvent and volatile materials are removed in vacuo to dryness to give 110 mg of 3-chloro-2-chloromethyl-5-methoxy-pyrazine as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[NH2:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([NH:24][C:25]([O:27]C(C)(C)C)=[O:26])=[CH:20][CH:21]=2)[CH2:16][N:15]1[C:32]([O:34]C(C)(C)C)=[O:33])=O>C(O)(=O)C>[C:7]([O:27][C:25]([NH:24][C:19]1[CH:18]=[C:17]2[C:22]([CH2:23][CH:14]([C:12]3[NH:11][C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([C:8](=[O:10])[NH2:9])[C:2]=4[N:1]=3)[N:15]([C:32]([O:34][C:17]([CH3:22])([CH3:18])[CH3:16])=[O:33])[CH2:16]2)=[CH:21][CH:20]=1)=[O:26])([CH3:8])([CH3:2])[CH3:6]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C(C(=O)Nc1cccc(C(N)=O)c1N)C2
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C(c1nc3c(C(N)=O)cccc3[nH]1)C2
Reaction time: 2.5 h

Procedure:
Step-3: A solution of tert-butyl 3-((2-amino-3-carbamoylphenyl)carbamoyl)-7-((tert-butoxycarbonyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (70 mg, 0.133 mmol) in acetic acid (2 ml) was heated to 80° C. and stirred for 2.5 h. The reaction mixture was concentrated, neutralized with aq. NaHCO3 and extracted with DCM. The DCM layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. Purification of the crude product by preparative TLC using methanol/dichloromethane (1:15) mixture as eluent afforded tert-butyl 7-((tert-butoxycarbonyl)amino)-3-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): m/z 508.28 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:35])[C@@H:15]([NH:31][C:32](=[O:34])[CH3:33])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]CC3C=CC=CC=3)[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:36][CH2:37][C:38]2([CH3:43])[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:35])[C@@H:15]([NH:31][C:32](=[O:34])[CH3:33])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:36][CH2:37][C:38]2([CH3:43])[CH2:39][CH2:40][CH2:41][CH2:42]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N[C@@H](Cc1cccc(OCc2ccccc2)c1)[C@H](O)[C@H]1CO[C@@H](OCC2(C)CCCC2)CN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)[C@H]1CO[C@@H](OCC2(C)CCCC2)CN1C(=O)OC(C)(C)C
Yield: 98.5 %

Procedure:
Hydrogenate (2R,5R)-5-[(1S,2S)-2-Acetylamino-3-(3-benzyloxyphenyl)-1-hydroxypropyl]-2-(1-methylcyclopentylmethoxy)-morpholine-4-carboxylic acid tert-butyl ester (244 mg) in methanol (15 mL) with 20% palladium hydroxide on carbon (26 mg) at 50 psi hydrogen for 18 hours. Filter and concentrate to give the desired compound (204 mg). MS(ES): m/z=507 [M+H]
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1.Cl.CCOCC>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc(C(=O)O)c(Cl)c1
Agent: B
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(CO)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
as follows: To a solution of 2-chloro-4-methylbenzoic acid (2.18 g; 12.8 mmol) in THF (22 mL) was added dropwise a solution of BH3.THF in THF (25.6 ml; 1.00 mol/l; 25.6 mmol), at 0° C. Upon complete addition the resulting mixture was heated under reflux, for 3 hours. Subsequently, the mixture was cooled to 0° C., 1M aqueous HCl (30 mL) was added dropwise, and the mixture was stirred for 10 min. Et2O (100 mL) was added and the layers were separated. The organic layer was washed with 1M aqueous HCl (2×), 5% aqueous NaHCO3 (2×), and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford (2-chloro-4-methyl-phenyl)-methanol (1.80 g), which was used as such.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]=[CH:6][C:7]1[C:16]([CH3:17])=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:30])[CH:13]=2)[CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]1[C:16]([CH3:17])=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:26])=[O:27])=[CH:21][CH:20]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:30])[CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cc2ccc(F)cc2c(Oc2ccc(S(=O)(=O)CC)cc2)c1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc2ccc(F)cc2c(Oc2ccc(S(=O)(=O)CC)cc2)c1C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 3-[4-(4-ethanesulfonyl-phenoxy)-6-fluoro-3-methyl-naphthalen-2-yl]-acrylic acid ethyl ester (40 mg, 0.09 mmol) in ethyl acetate (3 mL) was added 10% palladium on carbon (4 mg). The resulting mixture was stirred vigorously under a hydrogen (balloon) atmosphere overnight, and then filtered. The filtrate was concentrated in vacuo to give 3-[4-(4-ethanesulfonyl-phenoxy)-6-fluoro-3-methyl-naphthalen-2-yl]-propionic acid ethyl ester (30 mg, 75%) as a yellow solid, which was used for the next step without any further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[C:22]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)=[N:23][NH:24][CH:25]=4)[CH:18]=[CH:17][N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][N:23]1[C:22]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:13][CH:12]=3)[N:20]=2)[CH:25]=[N:24]1
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3)n2)cc1
Reactant: CN(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(-c3ccnc(Nc4ccc(N5CCN(C)CC5)cc4)n3)cnn2CCN(C)C)cc1
Temperature: 0 °C

Procedure:
To the suspension of 90 mg (0.211 mMol) of [4-(4-methyl-piperazin-1-yl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 25) in 4.5 mL of THF is added 38 mg (0.426 mMol) of 2-dimethylamino-ethanol (Fluka) and 122 mg (0.465 mMol) of triphenylphosphine (Fluka). The yellowish suspension is cooled to 0° C. and treated with 81 mg (0.465 mMol) of DEAD*. The mixture is stirred without cooling for 17 h, followed by heating for 24 h at 60° C. After cooling to rt, the reaction mixture is filtered and washed with 5 mL of THF. The filtrate is concentrated under reduced pressure and the crude product is purified by repeated chromatography on silica gel, eluting with CH2Cl2/MeOH (9:1) and CH2Cl2/MeOH/H2O 70:30:5 to obtain the title compound as beige crystals.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:13].C[C:15]([O:17][C:18](C)=O)=O.C(OC)(OC)OC>CN(C)C=O>[CH3:1][N:2]1[C:11](=[O:12])/[C:10](=[CH:15]/[O:17][CH3:18])/[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:13]
Reactant: CC(=O)OC(C)=O
Reactant: CN1C(=O)Cc2ccccc2C1=O
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: CO/C=C1/C(=O)N(C)C(=O)c2ccccc21
Temperature: 125 °C

Procedure:
To a stirred mixture of 0.35 g (2.0 mmol) of (N-methyl)isoquinoline-1,3(2H,4H)-dione, 3.2 ml of Ac2O, and 0.80 ml of N,N-dimethylformamide is added 0.44 ml (4.0 mmol) of (MeO)3CH at 25° C. The mixture is stirred at 125° C. for 30 m, cooled, and concentrated under high vacuum. The residue is recrystallized from Et2O-hexane to give 0.20 g of tan solid, mp 145-150° C. (dec); MS (ES+) m/z 218.2 (M+H)+1: Analysis for C12H11NO3: Calcd: C, 66.35; H, 5.10; N, 6.45. Found: C, 65.98; H, 4.99; N, 6.42.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([N+:18]([O-])=O)[CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>[Pd].CO.CCOC(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([NH2:18])[CH:12]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCc1ccc(-c2ccc(N)c(N)c2)cc1
Reaction time: 1 h

Procedure:
4′-Butyl-3-nitro-biphenyl-4-ylamine (117 mg, 3.70 mmol) and 10% Pd/C (10 mg) in 2:1 v/v MeOH/EtOAc (4 ml) is treated to a steady bubbling of H2 (g) for 15 minutes. The reaction is kept under 1 atm of H2 for 1 hour with stirring. The reaction is filtered through Celite and the filtrate concentrated in vacuo to afford 4′-butyl-biphenyl-3,4-diamine: ESMS m/z 241.2 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@H:9]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:8]2)=O.[BH4-].[Li+]>C1COCC1.CO>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@H:9]([NH:14][C:15](=[O:16])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:8]2
Reactant: COC(=O)c1ccc2c(c1)C[C@@H](NC(=O)OCc1ccccc1)C2
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@H]1Cc2ccc(CO)cc2C1)OCc1ccccc1
Reaction time: 8 h

Procedure:
(S)-methyl-2-(benzyloxycarbonylamino)-2,3-dihydro-1H-indene-5-carboxylate (15.37 mmol, 5.00 g) was dissolved in THF (50 mL) and the vessel purged with nitrogen. Lithium Borohydride (2M, 30.7 mmol, 15.37 mL) was added dropwise followed by methanol (30.7 mmol, 0.985 g). The solution was stirred at room temperature for 6 h before additional lithium borohydride (2M, 15.35 mmol, 7.69 mL) was added. Stirring was continued overnight. A further amount of lithium borohydride was added (2M, 15.35 mmol, 7.69 mL) and stirring continued for 1 h. The reaction was quenched with MeOH then water and concentrated to a light brown residue. This was partitioned between EtOAc (150 mL) and 1N HCl (150 mL) and the phases mixed and separated. The aqueous layer was twice extracted with ethylacetate and combined organics dried, filtered and concentrated to give a brown gum which was dissolved in MeOH (100 mL) and stirred with activated carbon. Filtration through a dicalite pad followed by concentration and purification on silica eluting with 0-2% MeOH/DCM gave (S)-benzyl 5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-ylcarbamate as a beige solid (2.2, 48%). 1H NMR (400 MHz, CDCl3) δ 1.66 (t, 1H) 2.81 (m, 2H) 3.28 (m, 2H) 4.52 (bs, 1H) 4.65 (d, 2H) 4.95 (bs, 1H) 5.09 (bs, 2H) 7.15-7.37 (bm, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]I)[C:7]=2[CH:14]=1.[CH:15]([C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2)([CH3:17])[CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][N:31]3[CH2:32][CH2:33][N:28]([C:26]4[CH:27]=[C:18]([CH:15]([CH3:17])[CH3:16])[CH:19]=[C:20]5[C:25]=4[N:24]=[CH:23][CH:22]=[CH:21]5)[CH2:29][CH2:30]3)[C:7]=2[CH:14]=1
Reactant: CC(C)c1cc(N2CCNCC2)c2ncccc2c1
Reactant: COc1ccc2occ(CCI)c2c1
Product: COc1ccc2occ(CCN3CCN(c4cc(C(C)C)cc5cccnc45)CC3)c2c1

Procedure:
8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-isopropyl-quinoline was prepared by generally following the procedure outlined in example 21, step 6, starting from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-isopropyl-8-piperazino quinoline (255 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil. Yield: 90 mg (20%); (M+H): 430; 1HNMR (400 MHz, CDCl3): δ 8.83˜8.12 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H), 8.08˜804 (dd,J1=1.8 Hz, J2=1.8 Hz, 1H), 7.75˜6.70 (m, 7H), 3.84 (s, 3H), 3.50˜2.86 (m, 12H), 2.90˜3.01 (m, 1H), 1.34˜1.33 (d, 7 Hz, 6H).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[C:7]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].OS([O-])(=O)=O.[K+]>C1(C)C=CC=CC=1>[CH2:33]([O:32][C:30]([C:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][Si:13]([C:26]([CH3:27])([CH3:29])[CH3:28])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)C1CCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc2C1O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2CC1
Reaction time: 1 h
Yield: 130.4 %

Procedure:
To a solution of 1-hydroxy-2-ethoxycarbonyl-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (5.9 g) in toluene (100 ml) was added KHSO4 (2.0 g). The mixture was stirred for 1 hour under reflux, and then the cooled solution was washed with sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give 2-ethoxycarbonyl-5-t-butyldiphenylsilyloxy-3,4-dihydronaphthalene (7.4 g).
Reaction SMILES: C1CO[C:3]([CH3:10])([CH2:4][CH2:5][CH2:6][C:7]([CH3:9])=[CH2:8])[O:2]1.C(=O)(O)[O-].[Na+]>CC(C)=O.Cl>[CH3:9][C:7]([CH2:6][CH2:5][CH2:4][C:3](=[O:2])[CH3:10])=[CH2:8]
Reactant: C=C(C)CCCC1(C)OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)CCCC(C)=O
Yield: 70.8 %

Procedure:
A solution of 6,6-ethylenedioxy-2-methyl-hept-1-ene (12.2 g) in acetone (300 ml) and 10% hydrochloric acid (12 ml) is stirred at room temperature for 1.5 hours. The reaction is neutralized to pH 7 with a sodium bicarbonate solution and the resulting solids are filtered. The acetone is removed in vacuo and the residue is partitioned between ether and brine. The ether extract is dried (Na2SO4) and evaporated in vacuo to give 2-methyl-6-oxo-hept-1-ene as a pale yellow liquid (6.4 g), nmr (CDCl3,δ) 1.7 (br s, CH3 --C=), 2.12 (s, CH3C=O), 2.4 (t, J=6 Hz, CH2C=O), 4.69 (br s, 2H, H2C=C).
Reaction SMILES: C(O[C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18])C.[Br:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(OC(=O)C)C>CS(C)=O>[Br:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18]
Reactant: Nc1ccccc1Br
Reactant: CCOc1c(Nc2ccc([N+](=O)[O-])cc2O)c(=O)c1=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1c(Nc2ccc([N+](=O)[O-])cc2O)c(Nc2ccccc2Br)c1=O
Temperature: 25 °C
Yield: 18.7 %

Procedure:
A solution of 3-ethoxy-4-(2-Hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione (0.39 g, 1.4 mmol) and 2-bromoaniline (0.36 g, 2.09 mmol) in 2 mL DMSO was heated at 110° C. for overnight. The reaction mixture was cooled to room temperature, and ethylacetate was added, and a precipitate formed. The filtrate was partitioned between ethylacetate and water. The organic layer was dried over sodium sulfate and concentrated. Titration from acetone and hexanes gave 106 mg (19%) of 3-(2-bromoanilino)-4-(2-hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione. LCMS(H+) 404
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8](=[O:32])[CH2:9][CH2:10][CH2:11][CH:12](Br)[CH:13]1[O:30][C@H:16]2[CH2:17][C@@H:18]([OH:29])[C@H:19](/[CH:20]=[CH:21]/[C@@H:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C@H:15]2[CH2:14]1)[CH2:2][CH3:3].C1CCN2C(=NCCC2)CC1.Cl.P([O-])([O-])([O-])=O>>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8](=[O:32])[CH2:9][CH2:10][CH2:11]/[CH:12]=[C:13]1/[CH2:14][C@@H:15]2[C@@H:19](/[CH:20]=[CH:21]/[C@@H:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C@H:18]([OH:29])[CH2:17][C@@H:16]2[O:30]/1)[CH2:2][CH3:3]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OCCOCCC)O[C@H]2C[C@H]1O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2C/C(=C/CCCC(=O)OCCOCCC)O[C@H]2C[C@H]1O
Yield: 68.5 %

Procedure:
235 mg of (13E)-(5RS,6RS,9α,11α,15S)-5-bromo-6,9-epoxy-11,15-dihydroxyprost-13-enoic acid 2-propoxyethyl ester (prepared as described in Example 5) and 0.8 ml of DBU were stirred at 50°-60° C. for 3 hours under a nitrogen atmosphere. The solution obtained was cooled to 0°-5° C., 4 ml of 1 N hydrochloric acid and 4 ml of a phosphate buffer with a pH of 6.86, cooled to 0°-5° C., were added and the mixture was extracted with diethyl ether. The extract was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on Florisil using as eluent a mixture of ethyl acetate and n-hexane (1:4) containing 0.1% v/v of triethylamine to give 136 mg of the title compound having the following physical characteristics.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br.[OH:14][C:15]1[CH:19]=[C:18]([N:20]2[C:28]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[N:22]=[CH:21]2)[S:17][C:16]=1[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:20]1([C:18]2[S:17][C:16]([C:29]([O:31][CH3:32])=[O:30])=[C:15]([O:14][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[O:3][C:2]([F:13])([F:12])[F:1])[CH:19]=2)[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[N:22]=[CH:21]1
Reactant: FC(F)(F)Oc1ccccc1CBr
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
110 mg of 2-(trifluoromethoxy)benzyl bromide is added to a mixture of 100 mg of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and 59.7 mg of potassium carbonate in 3 ml anhydrous DMF. The mixture is stirred for 14 h at room temperature. Ice water is added and the organic phase is extracted with dichloromethane. The organic phase is poured on a phase separator and the solvent is removed under vacuum. The residue is dissolved in 2 ml of dichloromethane and filtered through a short plug of silica gel (eluent: hexane/ethyl acetate 1/1 (v/v) to 0/100 (v/v)) to yield the title compound.