Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:10]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][C:11]=3[NH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1.CC(C)=O.C(Cl)(Cl)Cl.[NH4+].[OH-]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C@@H:10]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][C@H:11]3[NH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: Fc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Fc1ccccc1-c1cccc2c1[C@@H]1CCNCC[C@H]1N2
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of 10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.49 g, 1.74 mmol) in THF (6 mL) was added dropwise to 1.5 M borane-THF complex (6 mL, 9 mmol) and stirred at room temperature for 1.25 hours. The excess borane was quenched with H2O and the mixture was added to TFA at 0° C. After 0.3 hours the reaction was diluted with H2O and concentrated in vacuo. The residue was diluted with H2O, made basic with 15% NaOH and extracted three times with CH2Cl2. The extracts were dried over MgSO4 and concentrated in vacuo to give a white solid which was passed through a column of silica gel with 1:19 acetone/CHCl3 with 1% NH4OH to give 0.25 g (51%) of a light brown solid as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.38-7.33 (m, 2H), 7.21-7.10 (m, 3H), 6.69 (d, J=7.7Hz, 2H), 3.89 (dt, J=11.0 Hz, 3.5Hz, 1H), 3.60-3.53 (m, 1H), 3.18-3.12 (m, 1H), 2.94-2.88 (m, 1H), 2.83 (m, 1H), 2.74-2.72 (m, 1H), 2.21-2.16 (m, 1H), 1.97-1.87 (m, 1H), 1.67 (m, 1H), 1.26 (m, 1H); MS m/z 283.2 (M++H).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl.O>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH2:16][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(C(=O)N2CCN(C3CC3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-cyclopropyl-piperazine-1-carbonyl)-benzaldehyde (56.0 g) in 1,2-dichloroethane (550 mL) was added morpholine (37.8 mL) dropwise over 5 min. The mixture was cooled to 10° C. and was treated with NaBH(OAc)3 (64.3 g) in portions over 1 h. After a further 2 h, the mixture was warmed to room temperature, and a water bath was used to keep the temperature below 20° C. After 18 h, water (60 mL) was added while the temperature was kept under 20° C. by the addition of small amounts of ice. After 20 min, the mixture was basified to pH˜10 with 1 N NaOH (450 mL) and the mixture was stirred for 10 min. The layers were separated, and the organic layer was washed with 1 N NaOH (150 mL). The combined aqueous layers were extracted with CH2Cl2 (200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated to yield the title compound as pale yellow viscous oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:13][CH2:12][CH:9]([CH:10]=[CH:11]1)[CH:8]1[CH:4]2[CH2:5][N:6](CC2C=CC=CC=2)[CH2:7]1>[Pd]>[NH2:1][CH2:2][C:3]12[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13]1)[CH:8]1[CH:4]2[CH2:5][NH:6][CH2:7]1
Reactant: NCC12C=CC(CC1)C1CN(Cc3ccccc3)CC12
Agent: [Pd]
Product: NCC12CCC(CC1)C1CNCC12

Procedure:
7.4 g (27.5 mmol) of 1-aminomethyl-4-benzyl-4-azatricyclo[5.2.2.02,6 ]undec-8-ene are hydrogenated in 100 ml of tetahydrofuran using 1.5 g of palladium/active charcoal at 100° C./100 bar. The catalyst is filtered off with suction and the residue is distilled.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])(=[O:22])=[O:21])=[CH:16][CH:15]=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:12][S:13]([C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])(=[O:22])=[O:21])=[CH:18][CH:19]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(S(=O)(=O)N2CCCC2=O)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(S(=O)(=O)N2CCCC2=O)cc1
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
A solution containing 2.41 g of m-chloroperbenzoic acid in 48 cm3 of methylene chloride is added to 3.4 g of 1-(4-methylthiobenzene-sulphonyl)pyrrolidin-2-one prepared as in Example 4 in solution in 34 cm3 of methylene chloride, at a temperature not exceeding 25° C. After agitation at ambient temperature for 30 minutes, the reaction medium is then treated with a 10% aqueous solution of sodium sulphite. The organic phase is separated off, washed with a 5% aqueous solution of sodium bicarbonate, then with water. After drying, the solvent is evaporated off under reduced pressure, and the residue is crystallized from 95% ethanol. 1.70 g of expected product is obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[C:14](C)=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:40][C:41]1[C:42]([OH:50])=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1.C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=C(C)C=CC=5O)C=CC=4)N=C3C=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:43]5[CH:44]=[CH:45][CH:46]=[C:41]([F:40])[C:42]=5[OH:50])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(Br)c4)cn23)CC1
Reactant: OB(O)c1cccc(F)c1O
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)ccc5O)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cccc(F)c5O)c4)cn23)CC1

Procedure:
Prepared from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate and (3-fluoro-2-hydroxyphenyl)boronic acid in 100% following the same procedure as (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′-hydroxy-5′-methyl-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 616.20.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([C:11]([CH3:17])([CH3:16])[C:12]([F:15])([F:14])[F:13])[CH:3]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:16])([CH3:17])[C:12]([F:13])([F:14])[F:15])[N:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CC(C)(c1cc(Br)c([N+](=O)[O-])cn1)C(F)(F)F
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(c1cc(Br)c(N)cn1)C(F)(F)F
Temperature: 85 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
To a mixture of 4-bromo-5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine (50 mg, 0.160 mmol) in EtOH (10 mL) was added tin(II) chloride dihydrate (180 mg, 0.799 mmol). The mixture was stirred at 85° C. for 16 h. Then the mixture was added to an aqueous NaHCO3 solution. The mixture was extracted with EA (50 mL×2). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=2:1, Rf=0.5) to yield a light yellow solid of 4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-amine (30 mg, 0.090 mmol, 56.4% yield): 1H NMR (400 MHz, CD3OD): δ 8.05 (s, 1H), 7.58 (s, 1H), 1.56 (s, 6H). ES-LCMS m/z 283.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]([C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[NH:1][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:5]
Reactant: Nc1ccccc1C(=O)c1ccccc1Cl
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 38.3 %

Procedure:
Under nitrogen atmosphere, 44.4 g (0.192 mole) of 2-amino-2'-chlorobenzophenone was added in four portions at 15 min intervals to a stirred melt (130°-135° C.) of 33.5 g (0.211 mole) of 2-chloro-3-nitropyridine. Heating was continued for 30 min at 130°-125° C. and for 45 min at 145° C. The reaction mixture was cooled to 110° C. and 200 ml of hot toluene was added. To the cooled mixture (room temperature) 100 ml of 10% aqueous sodium hydroxide was added and stirring was continued for 15 min. The toluene layer was separated and washed three times with 75 ml portions of water, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in 300 ml of methylene chloride and the solution was stirred with 100 g of fluorisil for 30 min. The mixture was filtered, rinsing the fluorisil filter-cake several times with methylene chloride. The combined filtrates were treated in the same manner with an additional 100 g of fluorisil. The methylene chloride was separated by filtration and concentrated in vacuo. The residue was crystallized from ethyl acetate-cyclohexane to give 26.0 g of a bright yellow solid, m.p. 119° C. A second crop (7.0 g) was obtained from the filtrate and recrystallized from isopropyl ether, m.p. 118°-119° C. The total yield amounted to 49% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[NH:29])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[N:31]#[C:32]Br>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[N:29][C:32]#[N:31])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: N#CBr
Reactant: CS(=N)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=NC#N)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 27.5 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl sulfoximide (50 mg, 0.000108 mol) and DMAP (14.5 mg, 0.000216 mol) in DCM (1 mL) was added cyanogen bromide (23 mg, 0.000216 mol) at 25° C. Reaction mixture was stirred at 25-30° C. for 18 hr and then diluted with DCM (10 mL). Organic layer was washed with dil.HCl. Drying over sodium sulfate and evaporation afforded 20 mg of titled compound in 37% yield.
Reaction SMILES: CON=C1CN([C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[CH:13][CH:12]=2)=[O:10])[C@H](C(OC)=O)C1.FC1C=CC=CC=1C1C=CC(C(O)=O)=CC=1.C(Cl)(=O)C([Cl:47])=O>C1COCC1.CN(C=O)C>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[CH:15]=[CH:16][C:11]([C:9]([Cl:47])=[O:10])=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccc3F)cc2)C1
Agent: O=C(O)c1ccc(-c2ccccc2F)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Method B (e.g. methyl (2S,4EZ)-4-(methoxyimino)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate): To a solution of 2′-fluoro[1,1′-biphenyl]-4-carboxylic acid (69 mg, 0.32 mmol.) in 9 ml THF, were added oxalyl chloride (0.09 mL, 0.99 mmol) and DMF (three drops) under ice cooling. The mixture was stirred for 2 h at rt. The solvent was removed affording the corresponding acyl chloride, 2′-fluoro[1,1′biphenyl]-4-carbonyl chloride. The latter was now dissolved in THF (7 mL) and added slowly on a 0° C. solution containing the free NH-compound from the previous step, e.g. methyl (2S,4EZ)-4-(methoxyimino)-2-pyrrolidinecarboxylate (38 mg, 0.22 mmol), and triethylamine (2eq, 0.44 mmol, 0.06 ml) in THF/DCM 1:1 mixture (12 ml). The reaction mixture was stirred overnight at r.t. Pol-trisamine was added (69 mg, 3.45 mmol/g) in order to scavenge excess of acyl chloride. The mixture was shaken 5 h, filtered and the resulting solution was washed with NH4Cl 20%, brine, and dried over MgSO4. After filtration and evaporation of the solvents, the resulting dark oil (3.26 g) was purified by SPE (SAX sorbent) using neat DCM as eluent. The desired product, e.g. methyl (2S,4EZ)-4-(methoxyimino)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate was obtained as a mixture of two isomers as a white foam in 34% yield (97.3% purity by HPLC).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH:9]2[NH:11][CH:6]1[CH2:7][C@H:8]2[C:12]([O:14][CH2:15]C)=[O:13])(=[O:3])[CH3:2].O=C1CC2(C(OC)=O)N(C(OC(C)(C)C)=O)C1CC2.C(N[C@H]1[C@H](C(OC)=O)CC=CC1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[C:56](Cl)([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:57]>C(Cl)Cl.O>[C:1]([O:4][CH:5]1[CH2:10][CH:9]2[N:11]([C:56]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:57])[CH:6]1[CH2:7][CH:8]2[C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)[C@@H]1CC2NC1CC2OC(C)=O
Agent: COC(=O)C12CCC(C(=O)C1)N2C(=O)OC(C)(C)C
Agent: COC(=O)[C@@H]1CC=CC[C@H]1NC(C)=O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CC2C(OC(C)=O)CC1N2C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
A mixture of ethyl (5R)-2-acetoxy-7-azabicyclo[2.2.1]heptane-5-carboxylate 151b (prepared in analogy to O7-tert-butyl O4-methyl 2-oxo-7-azabicyclo[2.2.1]heptane-4,7-dicarboxylate starting from methyl trans-6-acetamidocyclohex-3-ene-1-carboxylate with procedures reported in the literature: Org. Lett., Vol. 9, No. 7, 2007 p 1235-p 1238) (0.55 g, 2.4 mmol) in DCM (10 mL) and sodium carbonate (0.76 g, 7.2 mmol) in water (3 mL) was added CbzCl (0.61 g, 3.6 mmol) dropwise. After addition, the mixture was stirred for 2 hours, then extracted with DCM. Removal of solvent afforded O7-benzyl O5-methyl 2-acetoxy-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate 151c, which was used in next step without purification. Crude yield: 100%. MS: calc'd (MH+) 362, measured (MH +) 362.
Reaction SMILES: [Na].Cl[C:3]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20]>CO.[Cu]>[Cl:12][C:9]1[CH:8]=[C:4]([C:3]([O:19][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:20])[CH:13]=2)=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: Cc1cccc(O)c1
Agent: [Cu]
Agent: [Na]
Solvent: CO
Product: Cc1cccc(Oc2ccc(Cl)cc2C(=O)O)c1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
Sodium (2.41 g) was dissolved in methanol and the solution placed under dry oxygen-free nitrogen. 2,5-Dichlorobenzoic acid (10 g), m-cresol (30 g) and activated copper powder (0.5 g) were added and the methanol removed by distillation. The temperature was increased to 180° with vigorous stirring and this temperature was maintained for 3 hours. The solution was cooled and steam distilled to remove the excess phenol. The resulting solution was filtered, cooled to room temperature and acidified with hydrochloric acid to give an oil. The oil slowly solidified; it was filtered off, dried, and washed with petroleum ether (30°-40° ). It was recrystallised at -10° from diethyl ether/petroleum ether (30°-40° ) to give, as a grey solid, the title compound (4.5 g), mp 124°-125° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[CH:19]([NH:21][CH2:22][CH2:23][O:24][CH2:25]C)[CH3:20])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)CCCCCCCCC>CN(C1C=CN=CC=1)C.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[CH:19]([NH:21][CH2:22][CH2:23][O:24][CH3:25])[CH3:20])=[CH:4][CH:3]=1
Reactant: CCOCCNC(C)c1nc2ccccc2c(=O)n1-c1ccc(F)cc1
Agent: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COCCNC(C)c1nc2ccccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of 130 mg 3-(4-fluorophenyl)-2-[1-(2-ethoxy-ethylamino)-ethyl]-3H-quinazolin-4-one (VI) (0.381 mmol, 1.00 equiv), 59 μL triethylamine (0.419 mmol, 1.10 equiv), and 2 mg DMAP (16 μmol, 0.04 equiv) dissolved in 3 mL 1,4-dioxane at room temperature was added 79 μL neat decanoyl chloride (0.381 mmol, 1.00 equiv); a colorless precipitate developed. The reaction mixture was stirred overnight at room temperature then concentrated in vacuo to remove the dioxaxie. The resulting concentrate was partitioned between dichloromethane and aqueous saturated sodium bicarbonate solution (20 mL each). The separated aqueous layer was extracted again with dichloromethane (15 mL) and the combined organic extracts dried over sodium sulfate, filtered, and concentrated in vacuo to yield a yellow, glassy oil. The crude product was purified by chromatography on silica gel (2.5 cm o.d.×10 cm h) eluting with a gradient of 20 to 25% ethyl acetate in hexane. Fractions containing product at Rf=0.84, 5% methanol in chloroform, were combined and concentrated in vacuo to afford 120 mg of a colorless solid. m.p. 71.4° C. 1H NMR (d6-DMSO; T=140° C.) δ 0.90 (t, 3H, J=7.2 Hz), 1.18–1.44 (m, 14H), 1.44 (d, 3H, J=7.2 Hz), 1.98–2.08 (m, 2H), 3.11 (s, 3H), 3.33–3.52 (m, 4H), 5.11 (br q, 1H, J=6.0 Hz), 7.32 (br m, 3H), 7.49 (br m, 1H), 7.55 (ddd, 1H, J1=1.2 Hz, J2=7.6 Hz, J3=8.0 Hz), 7.73 (d, 1H, J=8.0 Hz), 7.85 (ddd, 1H, J1=1.2 Hz, J2=7.2 Hz, J3=8.4 Hz), 8.15 (dd, 1H, J1=1.6 Hz, J2=8.0 Hz) ppm. At room temperature, compound exists as a mixture of cis/trans amide rotamers, ca. 1:1 determined by integration of characteristic 1H NMR peaks (CDCl3, T=25° C.) at δminor 4.78 (q, 1.0H, J=7.2 Hz) and δmajor 5.33 (q, 1.2H, J=7.2 Hz) ppm. MS (ESI+) 496.4 [MH]+
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:17][NH2:18]>>[OH:1][C:2]1[C:3]([CH3:15])=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:17][N:18]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: NN
Reactant: Cc1c(O)cccc1C(=O)CCC(=O)O
Solvent: O
Product: Cc1c(O)cccc1C1=NNC(=O)CC1

Procedure:
3-(3-hydroxy-2-methylbenzoyl)propionic acid was cydised with hydrazine hydrate in a similar manner to that described in Example 3 (i) to give 6-(3-hydroxy-2-methylphenyl)-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]3[C:20](=[O:28])[NH:19][C:18](=[O:29])[N:17]([CH3:30])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([O:41]CC)=[O:40]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]3[C:20](=[O:28])[N:19]([CH2:38][C:39]([OH:41])=[O:40])[C:18](=[O:29])[N:17]([CH3:30])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CC(=O)O)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[3-Methyl-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (70 mg) and potassium carbonate (28 mg) were dissolved in N,N-dimethylformamide (1.5 ml), and ethyl bromoacetate (22 μl) was added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was concentrated by distillation, and ethanol (1.5 ml) and 2 N sodium hydroxide aqueous solution (0.5 ml) were added to the resulting residue. The reaction mixture was stirred at room temperature for 3 hours, diluted with water, and neutralized with 2 N hydrochloric acid. After the mixture was extracted with ethyl acetate, the organic layer was concentrated by distillation to give 75 mg of 4-[1-carboxymethyl-3-methyl-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. Then, the resulting 4-[1-carboxymethyl-3-methyl-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (10 mg) was dissolved in trifluoroacetic acid (0.5 ml), and the reaction mixture was stirred at room temperature for 30 minutes. After the solvent was removed by distillation, a half of the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as eluent to give 5.9 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:11]=[CH:10][C:7]=1[CH:8]=O.[S:27]=[C:28]1[NH:32][C:31](=[O:33])[CH2:30][S:29]1>C1C=CC=CC=1>[Br:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:11]=[CH:10][C:7]=1[CH:8]=[C:30]1[S:29][C:28](=[S:27])[NH:32][C:31]1=[O:33]
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1OCc1ccccc1Br
Solvent: c1ccccc1
Product: O=C1NC(=S)SC1=Cc1ccc(OCCN2CCOCC2)cc1OCc1ccccc1Br

Procedure:
2-(2-Bromobenzyloxy)-4-(2-morpholin-4-yl-ethoxy)benzaldehyde (43 mg, 0.102 mmol) obtained in step 4 was dissolved in benzene and reacted with 2-thioxothiazolidin-4-one in the same manner as in step 2 of Example 1 to afford the object compound (yellowish solid, 25 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([N:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH3:18])=[O:16])[CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CCOC(C)=O.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:12])[CH2:14][C:15]([N:17]([CH3:18])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccccc1CN(C)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1CN(C)C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
Treat the acid from Step 4 (9.3 g) in EtOAc (100 mL) with 1,1'-carbonyldiimidazole (4.62 g) and DMAP (345 mg), stir the resulting solution at room temperature for 15 min., then heat at 50° C. for 1 h. Cool the reaction mixture to 0° C. and treat with a solution of NaBH4 (3.45 g) in H2O (50 mL), warm slowly to room temperature and stir for 12 h. Dilute the reaction mixture with EtOAc (250 mL) and wash with 1N HCl (1×100 mL) and H2O (1×100 mL), dry over MgSO4, filter and concentrate under reduced pressure to yield a crude oil (13 g). Chromatograph on silica gel, eluting with 5% CH3 OH/CH2Cl2 to give 3,4-dichloro-β-(2-hydroxyethyl)-N-methyl-N-[(2-methoxyphenyl) methyl]benzenepropanamide (8.7 g). HRMS (FAB, M+H+): m/e cal'd for [C20H24NO3Cl2 ]+ 396.1133; found 396.1124.