Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:15](=O)[C:14]3[C:9](=[C:10]([OH:18])[CH:11]=[CH:12][C:13]=3[OH:17])[C:7](=O)[C:5]=2[CH:6]=1.[BH4-].[Na+]>>[C:13]1(=[O:17])[C:14]2[C:9](=[CH:7][C:5]3[C:4]([CH:15]=2)=[CH:3][CH:2]=[CH:1][CH:6]=3)[C:10](=[O:18])[CH:11]=[CH:12]1
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Agent: [BH4-]
Agent: [Na+]
Product: O=C1C=CC(=O)c2cc3ccccc3cc21
Yield: 94.9 %

Procedure:
To a dried 100 mL-round-bottom flask equipped with stirring bar and serum cap, was added 1 g (MW 240.21; 0.0042 mol) of quinizarin (3). The compound was dried under vacuum, and then maintained under argon. Methanol (distilled over Mg), 20 mL, was added via syringe. The solution was stirred to dissolve the quinizarin and then cooled over an ice-water bath equipped with a thermometer. To it, 0.638 g (MW 38; 0.0168 mol) of sodium borohydride was added. The resulting mixture was stirred at 0° C. for 1 hour. The progress of the reaction was monitored by TLC (using hexanes: ether 1:1 as the eluant). The reaction was quenched by adding carefully 11 mL of 6 N HCl dropwise at 0° C. over a period of 10 minutes. Orange solids precipitate. The solids were collected by filtration over a fritted filter funnel, and washed several times with distilled water to remove the acid. The solid was then dried under vacuum and recrystallize from acetone-ether to give 0.83 g (95% yield) of yellow crystals, mp 204-206° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=2)[CH:3]=1.[N:16]1([CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>C(O)CCC>[O:29]=[C:25]1[NH:26][CH2:27][CH2:28][N:24]1[CH2:23][CH2:22][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=3)[CH:3]=2)[CH2:18][CH2:17]1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Reactant: O=C1NCCN1CCN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: N#Cc1cnc(Nc2cc(N3CCN(CCN4CCNC4=O)CC3)ncn2)s1

Procedure:
35-1 (0.25 g, 1.06 mmol), 44-4 (0.21 g, 1.06 mmol) and DIEA (0.69 g, 5.32 mmol) were heated at 150° C. for 3 hours in n-butanol. Upon cooling the precipitate was filtered off, washed with n-butanol and ethyl ether and then dried to afford 44-5. Hi-Res MS: calc: 400.1663 found: 400.1633. 1H-NMR (CD3OD): 8.38(s, 1H); 7.99(s, 1H); 6.14(s, 1H); 3.65(m, 4H); 3.55(m, 2H); 3.39(m, 2H); 3.35(t, 2H); 2.59(complex, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:13]2[N:14]([CH2:23][O:24][CH2:25][CH3:26])[C:15](=[O:22])[NH:16][C:17](=[O:21])[C:18]=2[CH2:19][CH3:20])C(=O)C)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C[O-].[Na+].[NH4+].[Cl-]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:13]2[N:14]([CH2:23][O:24][CH2:25][CH3:26])[C:15](=[O:22])[NH:16][C:17](=[O:21])[C:18]=2[CH2:19][CH3:20])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCOCn1c(N(C(C)=O)c2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCOCn1c(Nc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Reaction time: 4 h
Yield: 70.3 %

Procedure:
To a stirred solution of N-(3,5-dimethyl-phenyl)-N-(3-ethoxymethyl-5-ethyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-acetamide (112) (93 mg, 0.26 mmol) in methanol (5 mL), was added sodium methoxide (73 mg, 1.35 mmol). After 4 hrs., the mixture was neutralized with excess NH4Cl and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to afford 58 mg (70%) of a white solid. m.p. 175-176° C.; 1H-NMR (200 MHz, CDCl3) δ 0.93 (3H, t, J=7.5 Hz), 1.26 (3H, t, J=7.1 Hz), 2.19 (2H, q, J=7.5 Hz), 2.27 (6H, s), 3.70 (2H, q, J=7.1 Hz), 5.34 (2H, s), 6.42 (1H, s), 6.46 (2H, s), 6.65 (1H, s), 8.64 (1H, s); m/z (EI) 317 (M+).
Reaction SMILES: C(O[CH2:5]/[CH:6]=[C:7](\[CH3:21])/[CH2:8][CH2:9][C:10]1[C:15]([CH3:16])=[C:14]([OH:17])[C:13]([CH3:18])=[C:12]([CH3:19])[C:11]=1[OH:20])(=O)C.C1(P(C2C=CC=CC=2C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:21][C@@:7]1([CH:6]=[CH2:5])[CH2:8][CH2:9][C:10]2[C:15]([CH3:16])=[C:14]([OH:17])[C:13]([CH3:18])=[C:12]([CH3:19])[C:11]=2[O:20]1
Reactant: CC(=O)OC/C=C(\C)CCc1c(C)c(O)c(C)c(C)c1O
Agent: c1ccc(-c2ccccc2P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Yield: 81.1 %

Procedure:
A solution of (E)-5-(2,5-dihydroxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl acetate (125 mg; 0.43 mmol), (R)-6,6'-dimethyl-2,2'-bis(diphenylphosphino-1,1'-biphenyl (7 mg, 3%) and π-allylpalladium chloride dimer (2.3 mg, 1.5%) in tetrahydrofuran (2 ml) was held at 65° C. for 12 hours. After cooling the solvent was removed and the residue was purified on 3 g of silica gel with hexane/ethyl acetate (99:1). After crystallization from pentane there was obtained 81 mg of (S)-3,4-dihydro-2,5,7,8-tetramethyl-2-vinyl-2H-[1]-benzopyran-6-ol. O.P. 53%.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH2:16][CH2:17][OH:18])[CH:8]3[N:9]=2)=[C:5]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:4]=[CH:3]1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.CCCCCC>N1C=CC=CC=1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:18][CH2:17][CH2:16][N:11]2[CH:8]3[N:9]=[C:10]4[C:6]([N:7]3[N:13]([CH3:14])[C:12]2=[O:15])=[C:5]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:4]=[CH:3][N:2]4[NH2:1])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1C(=O)N(CCO)C2N=C3C(=C(c4ccco4)N=CN3N)N21
Solvent: c1ccncc1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)OCCN2C(=O)N(C)N3C4=C(c5ccco5)N=CN(N)C4=NC23)cc1
Temperature: 26 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
A mixture of 5-amino-8-(2-furyl)-3-(2-hydroxyethyl)-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one obtained in step 6 (3.5 g, 11 mmol), p-toluene sulphonylchloride (5.2 g, 27 mmol) were taken in pyridine (30 ml) and stirred at 25-27° C. for 16 hours. To the reaction mixture hexane (100 ml) was added and solid obtained was filtered off and washed with water (100 ml) followed by hexane (100 ml) to obtain 2-[5-amino-8-(2-furyl)-1-methyl-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl 4-methylbenzenesulfonate (4.1 g, 78%) as a brown solid.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:20]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:7]=1.[OH-].[Na+]>C1COCC1>[C:22]1([C:21]2[C:14]3[C:13]([NH:12][C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=4)[O:5][CH2:4][C:3]([OH:34])=[O:2])=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Dissolve 50 mg (0.111 mmol) of 3-[(5,6-diphenylfuro[2,3-d]pyrimidin-4-yl)amino]phenoxyacetic acid methyl ester in 2 ml of THF, add 0.33 ml of 1N sodium hydroxide solution at RT and stir at 50° C. for 1 h. Cool to RT and remove the THF under reduced pressure. Add water to the residue and then, with ice cooling, 1N hydrochloric acid. Filter off the precipitated solid, wash repeatedly with water and dry under reduced pressure. 39.4 mg (81.3% of theory) of the target compound are obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Cl[C:16]1[C:25]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:31]([O:33][CH2:34]C)=[O:32])[CH:22]=2)[N:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:28]([N:26]([CH3:27])[C:25]1[C:16]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=3[CH:8]=2)=[N:17][CH:18]2[CH:23]([N:24]=1)[CH:22]=[C:21]([C:31]([O:33][CH3:34])=[O:32])[CH:20]=[CH:19]2)([CH3:30])[CH3:29]
Reactant: CCOC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C1=CC2N=C(N(C)C(C)C)C(c3cc4cc(OC)ccc4o3)=NC2C=C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of 5-methoxybenzofuran-2-ylboronic acid (275.0 mg, 1.43 mmol) in dioxane (5.0 mL) was added ethyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140.0 mg, 0.48 mmol), K3PO4 (302.0 mg, 1.43 mmol) and Pd(PPh3)4 (27.5 mg, 0.02 mmol) and water (3 drops) with stirring for 1 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)amino)-2-(5-methoxybenzofuran-2-yl)-4a,8a-dihydroquinoxaline-6-carboxylate as a light yellow solid (150.0 mg, 73%).
Reaction SMILES: I[CH3:2].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH:21]([OH:23])[CH3:22])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:13][CH2:12]1.[H-].[Na+]>O1CCCC1>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH:21]([O:23][CH3:2])[CH3:22])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:13][CH2:12]1
Reactant: CI
Reactant: CC(O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
Iodomethane (6.0 μL, 0.10 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (40 mg, 0.10 mmol) and sodium hydride (60% dispersion in mineral oil; 6.7 mg, 0.15 mmol) in tetrahydrofuran (1 mL) at 0° C. After 2 h, the mixture was allowed to warm to ambient temperature. Additional iodomethane (6.0 μL, 0.10 mmol) and sodium hydride (60% dispersion in mineral oil; 2.2 mg, 0.05 mmol) were added every 1.5 h over a total of 4.5 h, after which the reaction was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (16 mg). MS 422.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1)#[N:2].[CH2:16]([O:18][C:19](=[O:29])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]O)[CH:22]=1)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:16]([O:18][C:19](=[O:29])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:13]2[C:12](=[O:15])[CH:11]=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:14]2)[CH:22]=1)[CH3:17]
Reactant: CCOC(=O)Nc1cccc(CO)c1
Reactant: N#Cc1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(C#N)cc3)ccc2=O)c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
15 g (76 mmol) of 6-(4-cyanophenyl)-2H-pyridazin-3-one, 22.2 g (114 mmol) of ethyl(3-hydroxymethylphenyl)carbamate and 29.9 g (114 mmol) of triphenylphosphine are dissolved in 250 ml of THF. Under a nitrogen atmosphere, the reaction mixture is cooled to 0° C., 18 ml (174 mmol) of diethyl azodicarboxylate are slowly added dropwise, and the reaction mixture is stirred at room temperature for 72 h. The reaction mixture is evaporated to dryness. 200 ml of isopropanol are added to the residue, and the mixture is stirred for 15 h. The precipitate is filtered off with suction, washed with isopropanol and dried in vacuo.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:10][C:11](C)([O-])[CH3:12].[K+].O1CCCC1.C(Br)C#C.C(=O)(O)[O-].[Na+].N>CN(C)C=O>[CH2:12]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[C:11]#[CH:10]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: N
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C#CCn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1H-benzimidazole (1.0 g, 8.46 mmol) in N,N-dimethylformamide (12 mL) was added a 1M solution of potassium tert-butoxide in tetrahydrofuran (8.04 mL, 8.04 mmol). The solution was stirred at room temperature for about 10 min, before propargyl bromide (0.940 mL, 8.46 mmol) was added dropwise. The solution was stirred at room temperature for about 30 min, poured into a cooled saturated aqueous solution of sodium bicarbonate and was extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated under vacuum to provide Example 648. MS (DCI-NH3): m/z 157 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1

Procedure:
This compound is prepared by hydrolysis of 23j using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:31])[CH2:14][C:15]([O:17][CH:18]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH3:19])=[O:16]>CC(OC)(C)C.CC(C)=O.O>[CH3:12][CH:13]([CH3:31])[CH2:14][C:15]([O:17][CH:18]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH3:19])=[O:16]
Reactant: CC(C)CC(=O)OC(C)OC(=O)ON1C(=O)CCC1=O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: CC(C)CC(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (900 mg, 6 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl 3-methylbutanoate (800 mg, 2.8 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 19 (200 mg, 21% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.88-0.97 (m, 8H), 1.22-1.38 (br. m, 3H), 1.42 (d, J=5.2 Hz, 3H), 1.71-1.74 (m, 2H), 1.90-2.02 (br. m, 3H), 2.1-2.2 (br. m, 3H), 2.85 (t, J=6.4 Hz, 2H), 6.69 (q, J=5.6 Hz, 1H), 7.48 (t, J=6.0 Hz, 1H), 12.01 (br. s, 1H). MS (ESI) m/z 352.15 (M+Na)+; 328.14 (M−H)−.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][C:9]1[C:10]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C=Cc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(O)c(CCc2ccccc2)n1
Yield: 81.8 %

Procedure:
1.2 g of 3-benzyloxy-6-methyl-2-styrylpyridine was dissolved in 20 ml of methanol. 684 mg of 10% palladium carbon was added thereto, and the mixture was to hydrogenated. The atmosphere in the reaction system was replaced by nitrogen and the catalyst was filtered off. The filtrate was evaporated, to give 695 mg of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[NH:6]1.[H-].[Na+].[CH2:23](I)[CH2:24][CH3:25]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[N:6]1[CH2:23][CH2:24][CH3:25]
Reactant: CCCI
Reactant: COC(=O)CC1NC(=O)N(Cc2ccc(C)cc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)N(Cc2ccc(C)cc2)C(=O)C1CC(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
A 0° C. solution of compound [1-(4-methyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester (1.60 g, 5.8 mmol) in DMF (28 mL) is treated with sodium hydride (60% dispersion, 0.25 g, 6.4 mmol) and warmed to room temperature and stirred under N2 for 15 minutes. The resultant mixture is cooled to 0° C. and then treated with 1-propyl iodide (1.08 g, 6.4 mmol) and then warmed to room temperature and stirred for 30 minutes. The reaction is quenched with aqueous 1 N HCl (28 mL) and then worked up extractively with EtOAc and water. The organic layer is dried i and the solvent removed to give crude product that is purified by flash chromatography using a gradient of 10:1 to 1:1 hexanes:EtOAc to afford 1.40 g (76%) [1-(4-methyl-benzyl)-2,5-dioxo-3-propyl-imidazolidin-4-yl]-acetic acid methyl ester. 1H NMR. MS (ES+) Calc'd for C17H23N2O4 (M+1) 319. Found m/z 319 (100%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.[F:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=O)=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:15]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:24][CH:23]=2)[CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C1CCCNC1
Reactant: Nc1ccc(F)cc1
Agent: Cl
Product: Fc1ccc(NC(c2ccc(F)cc2)C2CCCNC2)cc1

Procedure:
The title compound is prepared from 4-fluoroaniline and 3-(4-fluorobenzoyl)piperidine hydrochloride according to the procedure of Example 31.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[CH:4]=1.S(Cl)([Cl:21])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:21][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2cc(CO)ccc2c(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc2cc(CCl)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Hydroxymethyl-5,6,7-trimethoxynaphthalene (781 mg) was dissolved in chloroform (6 mL), and thionyl chloride (561 mL) was added dropwise to the solution. After stirring at room temperature for 5 hours, the reaction mixture was poured into ice water, and sodium hydrogencarbonate was added to adjust the pH of the reaction mixture to 8 to conduct extraction with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:25][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(OCCc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, phenethyl alcohol and DBU in dioxane. ES-MS m/e (%): 318 (M{37Cl}+H+, 33), 316 (M{35Cl}+H+, 100).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[CH2:15][C:16](Cl)=[O:17]>O1CCCC1.O>[CH2:10]([O:9][C:1]1[O:8][CH2:15][C:16](=[O:17])[C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1=C(OCC)OCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl malonate (8.0 mL, 0.052 mol) was added dropwise to a solution of sodium hydride (60% w/w in oil, 4.2 g, 0.11 mol) in anhydrous tetrahydrofuran (130 mL) that cooled with ice bath. The mixture was refluxed for 7 min. The reaction mixture was cooled with ice bath, chloroacetyl chloride (4.2 mL, 0.052 mol) was added dropwise to the reaction mixture and stirred for 1 h then stirred at 45° C. for 1 h. Cooled to ambient temperature, the reaction mixture was diluted with water, and extracted with chloroform for 4 times. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel(chloroform/methanol) to afford ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (5.0 g, y. 48%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[CH3:18][C:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20].C1OCCOCCOCCOCCOCCOC1.[NH:45]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:46]([C:63]([OH:65])=[O:64])[CH2:47][C:48]1[N:52]=[CH:51][N:50]([S:53]([C:56]2[CH:62]=[CH:61][C:59]([CH3:60])=[CH:58][CH:57]=2)(=[O:55])=[O:54])[CH:49]=1.[CH:73]1([CH2:79][C@@H:80]([CH:82]=[O:83])[NH2:81])[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1.C(O)(=O)C.[Cl-].[NH4+]>C1COCC1>[NH:45]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:46]([C:63]([OH:65])=[O:64])[CH2:47][C:48]1[N:52]=[CH:51][N:50]([S:53]([C:56]2[CH:57]=[CH:58][C:59]([CH3:60])=[CH:61][CH:62]=2)(=[O:55])=[O:54])[CH:49]=1.[CH:73]1([CH2:79][C@H:80]([NH-:81])[C@@H:82]([OH:83])[CH2:18][C:19](=[O:20])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1
Reactant: CC(=O)C1CCCCC1
Reactant: N[C@H](C=O)CC1CCCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: [NH-][C@@H](CC1CCCCC1)[C@@H](O)CC(=O)C1CCCCC1
Reaction time: 0.17 h

Procedure:
To a 0.5N potassium bis-trimethylsilylamide solution in toluene (9.2 ml, 4.60 mmol, 2.5 eq) is added dropwise at -78° C. cyclohexyl methyl ketone (0.58 g, 4.60 mmol, 2.5 eq) in THF (9 ml) with stirring under a nitrogen atmosphere over 10 minutes. After 20 minutes stirring at the same temperature, 18-crown-6 (1.216 g, 4.60 mmol, 2.5 eq) in THF (10 ml) is dropwise added to the mixture over two minutes. Further, the dipeptidealdehyde [14a] (1.0 g, 1.83 mmol) in THF (10 ml) is dropwise added over 15 minutes at -78° C., and the mixture is stirred for one hour at the same temperature. The reaction is quenched by adding a solution of acetic acid (0.60 g, 10 mmol, 5.5 eq) in THF (10 ml) and after the addition of saturated aqueous ammonium chloride (30 ml) the mixture is extracted with ethyl acetate (50 ml×3). The organic layer is washed with saturated aqueous sodium chloride, dried over MgSO4, concentrated to dryness in vacuo, and purified with silica gel chromatography (Lobar column, CH2Cl2 :MeOH=95:5) to obtain Boc-His(Ts)-1(S)-cyclohexylmethyl-2(S)-hydroxy-4-oxo-4-cyclohexyl-butylamide [10b] (0.18 g, 15%) in amorphous powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[N:18]=[C:19]2[N:23]([C:24]=1[C:25](O)=[O:26])[CH:22]=[CH:21][S:20]2>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:25]([C:24]2[N:23]3[C:19]([S:20][CH:21]=[CH:22]3)=[N:18][C:17]=2[CH3:16])=[O:26])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Reactant: Cc1nc2sccn2c1C(=O)O
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)OC(C)(C)C

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (acidic): tR=0.84 min; [M+H]+=377.1. 1H-NMR (CDCl3): δ=0.54 (bs, 1H); 0.80-0.86 (m, 1H); 1.50 (s, 9H); 1.51-1.58 (m, 1H); 1.77 (bd, J=11.8 Hz, 1H); 2.53-2.61 (m, 1H); 2.68 (s, 3H); 3.17-3.24 (m, 1H); 3.59-3.69 (m, 2H); 4.39-4.45 (m, 1H); 6.84 (d, J=4.3 Hz, 1H); 7.79 (bs, 1H); 8.27 (d, J=4.4, 1H).