Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[C:13]1([CH:19]([C:25]2[C:26](=[O:35])[C:27]([CH3:34])=[C:28]([CH3:33])[C:29](=[O:32])[C:30]=2[CH3:31])[CH2:20][CH2:21][C:22](O)=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(N(CC)CC)C>[N:8]1([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:22](=[O:23])[CH2:21][CH2:20][CH:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:25]3[C:26](=[O:35])[C:27]([CH3:34])=[C:28]([CH3:33])[C:29](=[O:32])[C:30]=3[CH3:31])=[CH:7][CH:6]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: CC1=C(C)C(=O)C(C(CCC(=O)O)c2ccccc2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C)C(=O)C(C(CCC(=O)Nc2ccc(-n3ccnc3)cc2)c2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.2 %

Procedure:
To a solution of 1-(4-aminophenyl)imidazole(0.71 g), 4-phenyl 4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)butanoic acid(1.25 g), ,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.85 g) and 1-hydroxybenzotriazole(0.85g) in DMF(8 ml) was added triethylamine(0.7 ml) and the mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into ice water and the precipitate was filtered and dissolved in chloroform-methanol. This solution was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by column chromatography on silica gel (chloroform: methanol=100:3) to obtain the title compound (0.82 g, amorphous).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](OC)=[O:25].Cl.[OH-].[NH4+:32]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:25])[NH2:32]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C(F)(F)F
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C(F)(F)F
Yield: 49 %

Procedure:
A solution of the 9-[(2-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (310 mg, 0.77 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 25 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 145 mg (49%) of the 9-[(2-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.6-7.2 (m, 6H), 6.85 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.25 (d, 1H, J=8 Hz), and 5.8 (s, 2H). IR (KBr, cm−1) 3460, 3360, and 1589. MS (ES) m/e 383, 385.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.C(N)CN.[N+:17]([CH3:20])([O-:19])=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[C:7]([CH2:20][N+:17]([O-:19])=[O:18])[CH2:6][CH2:5]2)=[CH:10][CH:11]=1
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCc2cc(Br)ccc2C1
Solvent: NCCN
Product: O=[N+]([O-])CC1=Cc2ccc(Br)cc2CC1
Temperature: 75 °C

Procedure:
Charged 900 g of 6-bromo-2-tetralone, 1.9 L of nitromethane and 37 g of ethylenediamine in 10 L flask. Heated the mixture liquid to 75° C. in a vessel under N2 for 24 hours to complete the reaction. When the reaction was complete, distilled out the excess nitromethane under reduce pressure. Introduced 200 g of silica gel to the residue with cooling. Hexane (10 L×3) was used to extracted, filtered and the hexane layer combined. On cooling, crystals were formed. About 500 g of 7-bromo-1,2-dihydro-3-(nitromethyl)naphthalene was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[S:10][C:5]2=[N:4][CH:3]=1.[OH-].[Na+].C1C[O:20][CH2:19][CH2:18]1>C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:19]([O:20][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[S:10][C:5]2=[N:4][CH:3]=1)[CH3:18]
Reactant: COC(=O)c1cc2nc(Cl)cnc2s1
Reactant: C1CCOC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cnc2sc(C(=O)O)cc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of methyl 2-chlorothieno[3,2-b]pyrazine-6-carboxylate 22 (100 mg, 0.437 mmol) in THF (1.8 mL) and ethanol (1.2 mL) was added 2N sodium hydroxide (1.09 mL, 2.19 mmol). The reaction was stirred overnight at 50° C. The reaction mixture was poured in citric acid solution and the resulting precipitate was collected, washed with water and dried to give crude 2-ethoxythieno[2,3-b]pyrazine-6-carboxylic acid (60 mg, 61%). (m/z)=225 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[C:22]#[N:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C(Cl)Cl.C1C(=O)N([Br:34])C(=O)C1>CCOCC>[Br:34][C:19]1[S:18][C:17]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:21]([C:22]#[N:23])[CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3sccc3C#N)c(C)nc12
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C#N)c(C)nc12
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of 2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophene-3-carbonitrile (0.83 g, 2.56 mmol) and CH2Cl2 (10 mL) is added NBS (0.48 g, 2.69 mmol). The solution is stirred for 1 hour, diluted with Et2O (100 mL), washed with water (3×100 mL), brine (100 mL), dried (MgSO4) filtered and concentrated to furnish the title compound (1.03 g, 2.55 mmol, >99%). 1H NMR (CDCl3) δ 0.86 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.56 (s, 3H), 2.60 (s, 3H), 3.24-3.32 (m, 1H), 6.76 (s, 1H), 7.30 (s, 1H). LC/MS (m/z): calcd. for C18H19BrN4S (M+H)+: 404.4; found: 404.1.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:11]3[N:12]=[CH:13][C:14]([C:15]#[N:16])=[C:10]3[NH:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[F:25])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:26]>CS(C)=O>[NH2:9][C:10]1[N:11](/[C:7](=[N:6]/[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)/[C:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[F:25])=[O:26])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: O
Reactant: COc1ccc(-c2[nH]c3c(C#N)cnn3c2NC2CCCC2)c(F)c1
Solvent: CS(C)=O
Product: COc1ccc(C(=O)/C(=N\C2CCCC2)n2ncc(C#N)c2N)c(F)c1
Reaction time: 48 h
Yield: 15.4 %

Procedure:
A light yellow solution of 3-(cyclopentylamino)-2-(2-fluoro-4-methoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (199 mg, 0.586 mmol) in DMSO (100 mL) was stored for several days at RT. After 2 days, it became a light brown solution and this solution was stored for 50 days. Then, it was poured into water (300 mL) and the organic compound was extracted into ethyl acetate (3×50 mL). The combined organic extracts were washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave the crude yellow solid which was purified using an ISCO (80 g) column chromatography eluting with 0-50% ethyl acetate in hexanes. The desired fractions were combined and the solvent was removed under vacuum to isolate 32 mg (15.4% yield) of (E)-5-amino-1-(1-(cyclopentylimino)-2-(2-fluoro-4-methoxyphenyl)-2-oxo ethyl)-1H-pyrazole-4-carbonitrile as an yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.45-1.53 (br m, 4H), 1.53-1.85 (br m, 4H), 3.73 (p, 1H), 3.89, (s, 3H), 6.95-7.10 (m, 2H), 7.72 (s, 1H), 7.92 (t, J=8.5 Hz, 1H), 8.11 (br s, 2H). LC/MS calcd. for C18H18FN5O2 (m/e) 355.371, obsd. 356.2 (M+H, ES+).
Reaction SMILES: O[CH:2]1[O:6][C:5](=O)[CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.O.[NH2:17][NH2:18]>C(O)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:2]=[N:18][NH:17][C:5](=[O:6])[CH:4]=2)=[CH:9][CH:10]=1
Reactant: NN
Reactant: COc1ccc(C2=CC(=O)OC2O)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cn[nH]c(=O)c2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A suspension of 5-hydroxy-4-(4-methoxyphenyl)-5H-furan-2-one (2.00 g, 9.7 mmol) in 15 mL of ethanol was stirred as hydrazine hydrate (0.97 g, 2.0 eq) was added in dropwise. The reaction was stirred at 85° C. overnight, and then the solvent was reduced. The solid was collected and washed with cold EtOH to give 1.7 g (87%) of 5-(4-methoxyphenyl)-2H-pyridazin-3-one: MS m/z 203 (M+H).
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][O:15][CH3:16])[C:8]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[CH:24]1([CH2:27]Br)[CH2:26][CH2:25]1>O>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][O:15][CH3:16])[C:8]=1[O:17][CH2:27][CH:24]1[CH2:26][CH2:25]1
Reactant: COCOc1cccc(Br)c1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cccc(Br)c1OCC1CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To 200 ml of N,N-dimethylformamide solution containing 23.3 g (0.10 mol) of 2-bromo-6-methoxymethoxyphenol (see Synthesis, 2001, 741-744) were added 13.8 g (0.10 mol) of potassium carbonate and 19.5 ml (0.20 mol) of cyclopropylmethyl bromide, and the mixture was stirred at 80° C. for 2 hours. After completion of the reaction, water was added to the reaction mixture, and extracted with toluene. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 24.1 g of the title compound as a colorless oil. (Yield: 84%)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:19][CH:18]=1)=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:15][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:21][CH:22]=1)[CH2:7][CH2:6]2
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Reactant: CC(=O)NC(C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)NC(C)c1ccc(CN2CCc3cc(C(F)(F)F)ccc3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 74 mg (0.37 mmol) 6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline and 70 mg (0.37 mmol) N-(1-(4-Formylphenyl)ethyl)acetamide (example I) in 2 mL THF are added 63 μl (1.1 mmol) AcOH and the reaction mixture is stirred at r.t. for 10 min. The resulting mixture is cooled to 0° C., 117 mg (0.551 mmol) sodium triacetoxyborohydride are added and the reaction mixture is stirred at r.t. for 2 h. After that time, the reaction is quenched by the addition of 200 μL water and purified by HPLC.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([F:30])[C:6]([NH:20][CH:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[CH:21]([NH:20][C:6]1[C:5]([F:30])=[CH:4][C:3]([C:1]([NH2:2])=[O:37])=[C:8]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:7]=1)[CH2:25][C:26]([F:29])([F:27])[F:28]
Reactant: N#Cc1cc(F)c(NC(CC(F)(F)F)C(N)=O)nc1Nc1cnc2ccccc2c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1cc(F)c(NC(CC(F)(F)F)C(N)=O)nc1Nc1cnc2ccccc2c1
Reaction time: 0.33 h

Procedure:
To a solution of crude 2-(5-cyano-3-fluoro-6-(quinolin-3-ylamino)pyridin-2-ylamino)-4,4,4-trifluorobutanamide (180 mg) in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1 mL) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred for 20 min. HOAc (0.5 mL) was added. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (44 mg). MS 437.3 (M+H); UV 202.2, 224.1, 295.2 nm; t 0.482 min.
Reaction SMILES: Br[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1.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>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:16]=[N:15][C:5]4[NH:6][C:7]5[CH:12]=[N:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=5[C:4]=4[CH:3]=3)=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: OCc1cc2c(cn1)[nH]c1ncc(Br)cc12
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(-c3cnc4[nH]c5cnc(CO)cc5c4c3)cc2)CC1
Temperature: 150 °C

Procedure:
A suspension of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-methanol (40.7 mg, 0.146 mmol), 4-(4-methylpiperazin-1-yl)phenylboronic acid pinacol ester (46.4 mg, 0.154 mmol) and bis(triphenylphosphine)palladium(II) dichloride (5.1 mg, 7.3 μmol) in acetonitrile (0.73 mL) and 2N aqueous sodium carbonate solution (0.73 mL) was heated at 150° C. under microwave irradiation for 20 minutes. The cooled reaction mixture was diluted with THF, the solid removed by filtration, and washed with THF and DCM. The combined filtrate was concentrated in vacuo and the resultant residue purified by flash chromatography (silica, 1-15% (2N ammonia methanol) in DCM) to afford the title compound. 1H NMR (DMSO-D6, 400 MHz): 12.46 (s, 1H), 9.76 (s, 1H), 9.07 (d, J=1.8 Hz, 1H), 8.97 (d, J=1.8 Hz, 1H), 8.50 (s, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 4.13 (s, 2H), 3.38-3.30 (m, 8H), 2.89 (s, 3H). LCMS (Method D): RT=5.24 min, M+H+=374.
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[OH:4].[C:29]1([C:40](O)=[O:41])[CH:30]=[CH:31][CH:32]=[C:33]2[CH2:39][CH2:38][CH2:37][CH:36]=[CH:35][C:34]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[CH:2]([NH:1][C:40]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[CH2:39][CH2:38][CH2:37][CH:36]=[CH:35][C:34]=12)=[O:41])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (206 mg, 0.53 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (268 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].C(=O)([O-])[O-].[Na+].[Na+].[C:21](ON1C(=O)CCC1=O)([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>O1CCOCC1.O.O1CCOCC1>[C:21]([NH:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5][C:4]1[CH:11]=[CH:12][C:13]([OH:14])=[C:2]([Cl:1])[CH:3]=1)([O:23][CH2:24][CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:22]
Reactant: N[C@@H](Cc1ccc(O)c(Cl)c1)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(O)c(Cl)c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 5 h

Procedure:
3-chlorotyrosine* (Aldrich 51,244-3)(113.5 g, 526 mmol) was added to a roundbottom flask equipped with a mechanical stirrer and temperature probe. 3-chlorotyrosine was dissolved in a solution of dioxane:water 2:1 (500 mL). Sodium carbonate (55.8 g, 526 mmol) was added, and the solution cooled to 0° C. in an ice bath. Fmoc-OSu (177.5 g, 526 mmol) was dissolved in dioxane (300 mL) and added in one portion to the solution at 0° C. The reaction was stirred for 5 hours at 0° C. The reaction was allowed to warm to room temperature overnight. The reaction was concentrated until a volume of 100 mL was achieved. 0.5 M potassium hydrogensulfate was added until the pH was 3. The pH was determined using pH paper (0-14) that was placed directly into the mixture. The pH was determined by comparison to the chart included with the pH paper. The solution was extracted with ethyl acetate (3×500 mL). The organic layers were combined and washed with water (500 mL) and brine (500 mL). The organic layer was then washed over sodium sulfate and concentrated to a constant eight (under vacuum) to give Fmoc-3-chlorotyrosine as a light beige solid. (204 g, 95% purity by area)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:30][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)=[CH:25][CH:26]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccc(F)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)cc2)nc1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 92.1 %

Procedure:
A mixture of ethyl 3-[3-(4-fluorophenyl)-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (950 mg), 2-chloromethylquinoline hydrochloride (600 mg), potassium carbonate (700 mg) and N,N-dimethylformamide (15 ml) was stirred at 60° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-(4-fluorophenyl)-1-[4-(2-quinolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1210 mg, yield: 92%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1.[Na+].[I-]>CN(C=O)C.O>[CH:23]1([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=3)[CH2:6][CH2:5]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc(N2CCNCC2)nc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN(C3CCCC3)CC2)nc1
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To a solution of 2.21 g of methyl 6-piperazinylnicotinate (compound 6), 3.18 g of sodium carbonate and 1.64 g of cyclopentyl bromide in 50 ml of DMF was added a catalytic amount of NaI. The mixture was heated to 120°-130° C. and stirred for 4 hours. The resulting mixture was poured into 150 ml of water and extracted with ethyl acetate. The extract was washed twice with water, and once with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated. Purification of the concentrate by column chromatography (silica gel; ethyl acetate) afforded 1.73 g of methyl 6-(4 -cyclopentyl-1-piperazinyl)nicotinate (yield 60%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([CH2:46][CH2:47][CH2:48][S:49]([NH2:52])(=[O:51])=[O:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][CH2:47][CH2:48][S:49]([NH2:52])(=[O:51])=[O:50])[CH2:41][CH2:42]3)=[O:36])[C@@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(N)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 2) was reacted with 3-piperazin-1-yl-propane-1-sulfonic acid amide dihydrochloride (example 55) to give the title compound. HR-MS (ES, m/z) calculated for C35H46Cl2N7O4S [(M+H)+] 730.2704, observed 730.271.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.O[CH2:12][CH2:13]/[CH:14]=[CH:15]/[P:16](=[O:25])([O:21][CH:22]([CH3:24])[CH3:23])[O:17][CH:18]([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][CH2:13]/[CH:14]=[CH:15]/[P:16]([O:21][CH:22]([CH3:23])[CH3:24])([O:17][CH:18]([CH3:19])[CH3:20])=[O:25]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(C)OP(=O)(/C=C/CCO)OC(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OP(=O)(/C=C/CCn1cnc2c(Cl)ncnc21)OC(C)C
Temperature: 0 °C
Yield: 37.2 %

Procedure:
To a mixture of 6-chloropurine (414 mg, 2.67 mmol), diisopropyl (E)-4-hydroxybut-1-enylphosphonate (630 mg, 2.67 mmol) and triphenyl phosphine (1.05 g, 4.00 mmol) in dry tetrahydrofuran (30 ml) stirred at 0° C. was added diethyl azodicarboxylate (0.70 g, 4.02 mmol). The mixture was allowed to warm to room temperature and stirred for 27.5 hr. The solvent was removed and the residue Was purified by column chromatography on silica gel eluting with dichloro-methane-methanol (24:1, 13:1) to give (E)-6-chloro-9-[4-(diisopropoxyphosphoryl)but-3-enyl]purine as a white solid (0.37 g, 37%), m.p. 105° C.; λmax (EtOH) 266 (9,260)nm; υmax (KBr) 3435, 2980, 1590, 1560, 1330, 1230 and 1210 cm-1 ; δH (CDCl3) 1.25 (12H, dd, J 6 Hz and 21 Hz, CH(CH3)2), 2.88 (2H, m, CH2), 4.45 (2H, t, J 7 Hz, CH2N), 4.55 (2H, m, CH(CH3)2), 5.68 (1H, dd, J 17 Hz and 20 Hz PCH=CH), 6.70 (1H, ddt, J 7 Hz, 17 Hz and 22 Hz, PCH=CH), 8.10 (1H, s, H-2/H-8), 8.77 (1H, s, H-2/H-8); FABMS (thioglycerol) 373 (MH+) (Found: C, 48.40; H, 6.03; N, 14.81%. C15H22ClN4O3P requires C, 48.33; H, 5.95; N, 15.03%).