Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][CH:16]=2)[CH:10]=[CH2:11].CO>ClCCl>[Br:1][CH2:11][CH:10]1[O:22][C:21]2[C:20]3[CH:19]=[C:18]([O:23][CH3:24])[CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[CH2:9]1
Reactant: C=CCc1cnc2ccc(OC)cc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc3c(c2c1)OC(CBr)C3
Temperature: 10 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
N-Bromosuccinimide (1.19 g, 6.69 mmol, 1.2 eq) is added at 10° C. to a stirred solution of 3-allyl-6-methoxy-quinolin-4-ol (1.20 g, 5.57 mmol, 1.0 eq) in dichloromethane (120 mL) and the resulting mixture is stirred at 10° C. for 1 hour. The reaction mixture is then successively washed with water (50 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 80:1, v/v) to afford 2-bromomethyl-8-methoxy-2,3-dihydro-furo[3,2-c]quinoline as a light yellow solid (1.2 g, 73% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C([O:22][C:23]([C:25]1[CH:26]=[N:27][N:28]2[C:33]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:32](Br)[CH:31]=[N:30][C:29]=12)=[O:24])C.[Li+].[OH-].Cl>[Pd].O1CCOCC1.O1CCCC1.C(OCC)(=O)C>[CH:34]1([C:33]2[N:28]3[N:27]=[CH:26][C:25]([C:23]([OH:24])=[O:22])=[C:29]3[N:30]=[CH:31][C:32]=2[C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cnn2c(C3CCCCC3)c(Br)cnc12
Agent: [Pd]
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CSc1ccc(-c2cnc3c(C(=O)O)cnn3c2C2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
A mixture of 14 mg (0.085 mmol) of 4-methylsulfanyl-phenylboronic acid, 2 mg (0.0028 mmol) of Pd catalyst, and 45 mg (0.213 mmol) of potassium phosphate was placed into a 4 mL vial. To this mixture 25 mg (0.077 mmol) of 6-bromo-7-cyclohexyl-pyrazolo[1,5-α]pyrimidine-3-carboxylic acid ethyl ester in 1.5 mL of 1,4-dioxane was added, the resulting mixture was flushed with argon and stirred at 80° C. (oil bath) overnight. The reaction mixture was then diluted with ethyl acetate, filtered through a small pad of Celite, and evaporated (savant) to give a residue (crude coupling product). This residue was dissolved in 1 mL of tetrahydrofuran (THF) and treated with 0.5 mL (0.5 mmol) of 1 M LiOH solution, and the resulting mixture was stirred at rt overnight. Since analysis by thin layer chromatography (TLC) revealed that the reaction was not complete, the mixture was then shaken at 55° C. (sand bath) for 15 h. The reaction mixture was diluted with ethyl acetate, and acidified with 1 M HCl solution to pH=2. The organic layer was separated and concentrated (savant) to give a residue which was purified via reverse-phase chromatography (using Gilson) to afford (after lyophilization) 14 mg (56% overall yield) of 7-cyclohexyl-6-(4-methylsulfanyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (472) as a solid as indicated by 1H NMR; LC-MS—calcd for C20H21N3O2S [M++H]+: 368.14, found: 368.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br.Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: BrCc1ccccn1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: Br
Product: O=[N+]([O-])c1cc(OCc2ccccn2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 2-Bromomethyl-pyridine hydrobromide salt using the conditions described in Example 10C to provide 2-(4-Chloro-3-nitro-phenoxymethyl)-pyridine which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1Br.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>CCOCC.CCCCCC.O1CCCC1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:15]([OH:20])[OH:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CSc1ccccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1ccccc1B(O)O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 1-methylthio-2-bromobenzene (5 g) in dry ether (30 ml) was stirred at 0° C. and 1.63M n-butyllithium in hexane solution (16.6 ml) was added dropwise over a period of 15 minutes. The reaction mixture was stirred at 0° C. for 1.5 hours and then transferred to a cold (-78° C.) solution of triisopropyl borate (7.4 ml) in tetrahydrofuran (40 ml) over 40 minutes. After stirring for 1 hour at -78° C., the reaction mixture was allowed to warm to room temperature overnight. The suspension was poured into dilute 2M hydrochloric acid (40 ml) and the layers were separated. The aqueous phase was extracted with ether (2×80 ml) and the combined organic phases were washed with brine, dried with magnesium sulfate, evaporated and washed with petroleum ether (2×20 ml) to afford 2-methylthiophenyldihydroxyborane.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[OH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[C:4]([O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: OCCCN1CCCCC1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Diketene (1.48 mL, 19.2 mmol, 1.30 equiv) was added to a solution of 1-(3-hydroxypropyl)piperidine (2.12 g, 14.8 mmol, 1.00 equiv, Leonard, N. J.; Musker, W. K. J. Am. Chem. Soc. 1960, 82, 5148) in toluene (30 mL), and the mixture was stirred under argon for 72 hours at room temperature. Removal of solvent gave 3.52 g (100%) of light brown, viscous oil, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:27]=[O:28])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=3)[CH2:16][CH2:17][CH2:18][N:11]21>O1CCCC1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=4)[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:27]([OH:28])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ncc(Cl)cc1Cl
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ncc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 100 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 51 μL, 0.153 mmol) was added to a stirred solution of 9-chloro-1-(3,5-dichloropyridin-2-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (53.7 mg, 0.141 mmol) in tetrahydrofuran (1.0 mL) at 0° C., and the mixture was stirred at 0° C. for 50 min. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the title compound as a colorless solid (57.8 mg, 0.141 mmol, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([CH:23]([C:29]([CH3:31])=O)[C:24](OCC)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:24](=[O:25])[C:23]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:29]([CH3:31])[NH:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Reactant: NNC1CCN(Cc2ccccc2)CC1
Product: Cc1[nH]n(C2CCN(Cc3ccccc3)CC2)c(=O)c1Cc1ccccc1
Yield: 60.2 %

Procedure:
A mixture of 1.52 g 1-benzyl-4-hydrazinopiperidine and 2.0 g of ethyl 2-benzylacetoacetate in 20 mL of xylenes was refluxed for 1 hour. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography (300 mL column). Elution with 0-5% MeOH in dichloromethane gave 1.61 g of product, 1-benzyl-4-(4-benzyl-5-methyl-1H-pyrazol-3(2H)-on-2-yl)-piperidine. ESI-MS 362.2 (M+H); HPLC A: 2.05 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[N+:14]([O-])[O:15][N:16]=2)[C:5]2[N:6]=[C:7]([OH:13])[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1.P(OCC)(OCC)OCC>C(O)C.CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:4](=[N:14][O:15][N:16]=2)[C:5]2[N:6]=[C:7]([OH:13])[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1
Reactant: [O-][n+]1onc2c(Cl)cc3nc(O)c(O)nc3c21
Agent: CCOP(OCC)OCC
Solvent: CCO
Solvent: CN(C)C=O
Product: Oc1nc2cc(Cl)c3nonc3c2nc1O
Yield: 69.9 %

Procedure:
To a solution of 0,6 g (2,4 mmol) 4-chloro-7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline-1-oxide in a mixture of 14 ml ethanol and 3 ml dimethylformamide was added 0,9 ml (5,3 mmol) triethyl phosphite. The mixture was refluxed for 4 h, and then evaporated in vacuo. The residue was stirred with water and then with ether-ethyl acetate (5:1) to give 0,4 g (71%) 4-chloro-7,8-dihydroxy-1,2,5-oxadiazolo-(3,4-f)quinoxaline, m.p. >300° C. NMR (DMSO-d6 +D2O): 7.40 (1H,s).
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[N:11]=[C:5]2[N:4]=1.Br[CH2:20][CH2:21][F:22].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:22][CH2:21][CH2:20][O:18][C:14]1[CH:13]=[C:12]([C:10]2[N:11]=[C:5]3[N:4]=[C:3]([NH2:2])[CH:8]=[CH:7][N:6]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccn2cc(-c3cccc(O)c3)nc2n1
Reactant: FCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1
Temperature: 70 °C
Reaction time: 23 h
Yield: 21.2 %

Procedure:
In a sealed tube 3-(7-aminoimidazo[1,2-a]pyrimidin-2-yl)phenol hydrobromide (800 mg, 2.6 mmol) was combined with DMF (4.0 ml) to give a light brown solution. 1-Bromo-2-fluoroethane (476 mg, 3.75 mmol) dissolved in DMF (4.0 ml) and Cs2CO3 (1.62 g, 4.97 mmol) were added. The reaction mixture was stirred 23 h at 70° C. H2O (50 ml) was added to the reaction mixture and the product was extracted with EtOAc (3×40 ml). After drying over MgSO4, filtration and concentration in vacuum, the crude product (orange oil) was purified by flash chromatography (50 g SiO2—NH2 cartridge, eluent: CH2Cl2 to CH2Cl2/MeOH 95:5) to yield the title compound (150 mg, 21%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=O)=[CH:14]2)=[O:7].C[N:22](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([NH2:22])=[O:20])=[CH:14]2)=[O:7]
Reactant: O=C(O)c1cc2cccc(NC(=O)c3cccs3)c2[nH]1
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)c1cc2cccc(NC(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a mixture of 7-[(2-thienylcarbonyl)amino]-1H-indole-2-carboxylic acid (100 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (63 mg) and N,N-dimethylformamide (5 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (80 mg) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (97 mg, yield 98%) as pale-brown crystals. melting point 289-290° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH2:13][OH:14].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCCCC1.CC(C)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:21]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH:11]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:12][CH2:13][OH:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(O)c(C(CCO)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Solvent: CC(C)=O
Product: Cc1ccc(OCc2ccccc2)c(C(CCO)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 96 %

Procedure:
80 ml of an aqueous solution of NaOH (30% wt./vol.) and 10.6 g (0.033 moles) of tetrabutylammonium bromide (TBABr) were added to a suspension of 3-(2-hydroxy-5-methylphenyl)-3-phenylpropanol of the formula (VIII) (80 g, 0.330 moles) in toluene (320 ml). The internal temperature was adjusted to 50° C., 45.5 ml (0.396 moles) of benzyl chloride were added dropwise in approx. 1 h and the course of the reaction was monitored by means of TLC (eluent: cyclohexane/acetone: 70/30) until the substrate had completely disappeared. After 7 h, the reaction mixture was cooled to ambient temperature and the aqueous phase was removed. The organic phase was washed with water (3×100 ml), was then evaporated under a vacuum to remove the solvent and to obtain 104 g of 3-(2-benzyloxy-5-methylphenyl)-3-phenylpropanol (IV) as a yellow-brown oil (yield 96%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[C:18]([CH3:29])[CH:17]=1)[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C.ClCl>O1CCCC1.ClCCl.CO>[C:31]([NH:1][CH2:2][CH:3]([NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[C:18]([CH3:29])[CH:17]=1)[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(=O)NC(CN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: ClCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NCC(NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 62 %

Procedure:
Prepared analogously to Example 124 from N-[2-amino-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, acetic anhydride, and triethylamine in tetrahydrofuran. Yield: 62%; Rf value: 0.16 (silica gel; dichloromethane/methanol=19:1); C24H26ClN5O3 (467.95); mass spectrum: (M+H)+=468/470 (chlorine isotope) and (M−H)-=466/468 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:6](=[O:13])[NH:5][C:4](=[O:14])[CH:3]=1.Cl.[N:16]([O-])=[O:17].[Na+]>O>[NH2:1][C:2]1[N:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:6](=[O:13])[NH:5][C:4](=[O:14])[C:3]=1[N:16]=[O:17]
Reactant: Nc1cc(=O)[nH]c(=O)n1C1CCCC1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1c(N=O)c(=O)[nH]c(=O)n1C1CCCC1
Reaction time: 1 h

Procedure:
12.4 g (0.064 mol) of 6-amino-1-cyclopentyl-2,4-(1H,3H)-pyrimidinedione (XIV) was suspended in 200 ml water. To this was added 14 ml of 5N HCl and 4.8 g of NaNO2 (0.07 mol) which was dissolved in water. The reaction mixture was stirred for 1 hour and washed with water. Yield 12.9 g (90%) (XV) NMR.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:32])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C@H:22]([OH:29])[C:23]([O:25][CH:26](C)C)=[O:24])=[CH:15][C:14]=2[O:30][CH3:31])[N:10]=1.O>Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:32])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C@H:22]([OH:29])[C:23]([O:25][CH3:26])=[O:24])=[CH:15][C:14]=2[O:30][CH3:31])[N:10]=1
Reactant: COc1cc(CCC[C@H](O)C(=O)OC(C)C)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Solvent: O
Product: COC(=O)[C@@H](O)CCCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 91.1 %

Procedure:
Isopropyl (S)-(-)-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]-2-hydroxypentanoate (3.55 g) was dissolved in methanolic HCl (5%, 100 ml). The solution was stirred for 10 hours at room temperature, which was poured into water, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:1), was obtained methyl (S)-(+)-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]-2-hydroxypentanoate (3.03 g, 91%). Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p.80-81° C. [α]D +3.03° (c=1. 0, CHCl3)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[CH2:4][CH2:5][CH2:6][CH:7]([Se]C1C=CC=CC=1)[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1.OO.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3](=[O:45])[CH2:4][CH2:5]/[CH:6]=[CH:7]/[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(C(CCCC(=O)OC)[Se]c3ccccc3)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(/C=C/CCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 560 mg of (13E)-(5RS,6RS,9α,11α,15S)-5-phenylseleno-6,9-epoxy-11,15-bis(tetrahydropyran-2-yloxy)prost-13-enoic acid methyl ester (prepared as described in Example 6) in a mixture of 6 ml of ethyl acetate and 3 ml of tetrahydrofuran was added 0.5 ml of 30% hydrogen peroxide and 100 mg of sodium bicarbonate, and the reaction mixture was then stirred for one hour. Afterwards it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium carbonate, water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of benzene and ethyl acetate (6:1) as eluent to give 380 mg of the title compound having the following physical characteristics:
Reaction SMILES: [CH:1]([C:4]1[O:5][C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:7][C:8]=1[CH:9]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])([CH3:3])[CH3:2].[CH3:34][NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39]>>[CH:1]([C:4]1[O:5][C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=2)=[CH:7][C:8]=1[CH:9]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:20])=[CH:17][CH:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])([CH3:2])[CH3:3]
Reactant: CC(C)CC(Oc1ccc(C(=O)O)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C(C)C
Reactant: CCOC(=O)CCNC
Product: CC(C)CC(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C(C)C
Yield: 22.8 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(1-{2-isopropyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-methylbutoxy)benzoic acid (170 mg) as well as ethyl 3-(methylamino)propanoate (58 mg) to give the title compound (46 mg, 23%) as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.[NH:18]1[CH2:22]CC[CH2:19]1.CN(C)[C@@H]1CCNC1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:22])[CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12
Reactant: C1CCNC1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Agent: CN(C)[C@@H]1CCNC1
Product: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
Following the procedures described above for the compound 21 (example 5f, steps 1-3) but substituting pyrrolidine in the step 3 for (R)—N,N-dimethylpyrrolidin-3-amine, title compound 24 was obtained as a white solid (58% yield). MS (m/z): 310.0 (M+H).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:18])[N:5]([C:7]2[CH:12]=[N:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[C:9](=[O:17])[CH:8]=2)[CH:6]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[CH:27])[CH:21]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][C:2]2[N:3]=[C:4]([CH3:18])[N:5]([C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[C:9](=[O:17])[CH:8]=3)[CH:6]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COCCn1ncc(-n2cc(I)nc2C)cc1=O
Reactant: C#Cc1cccc(Cl)c1
Product: COCCn1ncc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)cc1=O

Procedure:
The title compound, yellow crystalline solid, MS: m/e=369.2, 370.9 (M+H+), was prepared in accordance with the general method of example 21a from 5-(4-Iodo-2-methyl-imidazol-1-yl)-2-(2-methoxy-ethyl)-2H-pyridazin-3-one and 1-chloro-3-ethynyl-benzene.
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[F:19][C:20]([F:40])([F:39])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:36][C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=3)[O:28]2)=[CH:23][CH:22]=1>>[F:40][C:20]([F:19])([F:39])[C:21]1[CH:22]=[CH:23][C:24]([CH:27]2[CH2:36][CH:35]([OH:37])[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=3)[O:28]2)=[CH:25][CH:26]=1
Reactant: O=C1CC(c2ccc(C(F)(F)F)cc2)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1ccc2c(c1)C(O)CC(c1ccc(C(F)(F)F)cc1)O2

Procedure:
2-(4-Trifluoromethylphenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 860 mg of 2-(4-trifluoromethylphenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.86 (s, 1H), 7.77 (d, 2H, J 8.3 Hz), 7.68 (d, 2H, J 8.3 Hz), 6.89 (d, 1H, J 2.9 Hz), 6.63 (d, 1H, J 8.7 Hz), 6.56 (dd, 1H, J 8.7, 2.9 Hz), 5.45 (d, 1H, J 7.0 Hz), 5.26 (d, 1H, J 11.2 Hz), 4.90 (m, 1H), 2.32 (m, 1H), 1.85 (m, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])C.S(Cl)(Cl)=O>>[CH2:7]([NH:8][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])[CH:6]([CH3:10])[CH3:4]
Reactant: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Solvent: O=S(Cl)Cl
Product: CC(C)CNC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (100 mg, 0.44 mmol) (from Example 11) and thionyl chloride (2M in DCM, 5 mL) was heated to reflux for 2 hours. The reaction was concentrated, the residue was then stirred with isobutyl amine (excess) in DCM at room temperature for 2 hours. The reaction was diluted with DCM, washed with water, dried and concentrated. The residue was purified on a silica gel column to give the titled compound as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>C1COCC1>[NH2:4][CH2:3][CH:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[OH:1]
Reactant: N#CC(O)c1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)c1cccc2ccccc12
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of hydroxy(1-naphthalenyl)acetonitrile (1.67 g, 9.14 mol) in THF (90 mL) at 0° C. was added dropwise a solution of LAH-THF (1M, 11 mL, 11 mmol). After 2 hrs, the solution was quenched by sequential addition of H2O (0.42 mL), 6N NaOH (6M, 0.32 mL) and H2O (1.6 mL). The resulting precipitate was filtered and the filtrate was concentrated and used directly yielding the title compound (0.897 g, 4.8 mmol, 53%) as a clear oil: LCMS (ES) m/z 188 (M+H)+.