Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1F)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccccc1F)C2
Yield: 69.2 %

Procedure:
A mixture of 7-(2-fluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.35 g), aminoguanidine hydrochloride (0.16 g), concentrated hydrochloric acid (0.21 ml), water (0.21 ml) and ethanol (40 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate, and to the mixture was added sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid (3 ml), and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give 7-(2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 59) (0.33 g) as colorless crystals.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:17])[CH2:16][CH2:15][CH2:14]1)[N:8]([CH3:18])[C:7]2=[O:19].[CH3:20][C@@H:21]1[C:25]2[NH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][C:24]=2[C:23](=[O:38])[NH:22]1>>[CH3:18][N:8]1[C:7](=[O:19])[C:6]2[C:11](=[C:2]([C:27]3[NH:26][C:25]4[C@@H:21]([CH3:20])[NH:22][C:23](=[O:38])[C:24]=4[CH:28]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]1[NH:12][C:13]1([CH3:17])[CH2:16][CH2:15][CH2:14]1
Reactant: Cn1c(NC2(C)CCC2)nc2c(I)cccc2c1=O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(NC5(C)CCC5)nc34)[nH]c21
Yield: 54.6 %

Procedure:
This compound (169 mg, 54% yield) as a brown solid was prepared according to the procedure described for Example 448, using 8-iodo-3-methyl-2-((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (711) (303 mg, 0.82 mmol) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (215 mg, 0.82 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.27 (1H, br.), 8.00 (1H, dd, J=7.6, 1.4 Hz), 7.85 (1H, dd, J=7.8, 1.4 Hz), 7.66 (1H, s), 7.15 (1H, t, J=7.7 Hz), 6.98 (1H, s), 6.81 (1H, s), 4.60 (1H, q, J=6.5 Hz), 3.41 (3H, s), 2.38 (2H, m), 2.14 (2H, m), 1.88 (2H, m), 1.67 (3H, s), 1.40 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 378.2 (M+H)+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[N:5]1([CH2:17][CH:18]=[O:19])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[O:16][CH:15]=[CH:14][C:12]3=2)[CH:7]=[N:6]1.[Cl-].[NH4+]>O1CCCC1>[N:5]1([CH2:17][CH:18]([OH:19])[CH2:1][CH3:2])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[O:16][CH:15]=[CH:14][C:12]3=2)[CH:7]=[N:6]1
Reactant: O=CCn1ncc2ccc3occc3c21
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)Cn1ncc2ccc3occc3c21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under argon atmosphere, 5 ml of 1.0 M tetrahydrofuran solution of ethylmagnesium bromide was diluted with 5 ml of tetrahydrofuran, a tetrahydrofuran (5 ml) solution of 0.30 g of (1H-furo[2,3-g]indazol-1-yl)acetaldehyde was added dropwise, and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layers were combined, washed with brine and then dried with anhydrous magnesium sulfate. After removal of the solvent, the residue was purified by a silica gel column chromatography to give 0.29 g of 1-(1H-furo[2,3-g]indazol-1-yl)-2-butanol.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:3]1=[O:34].S([O-])(O[O-])(=O)=[O:36].[K+].[K+].OOS([O-])=O.[K+]>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:36])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:3]1=[O:34]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3ccccn3)n(Cc3cccc4ccccc34)cc21
Reactant: O=S(=O)([O-])O[O-]
Agent: O=S([O-])OO
Agent: [K+]
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)c3ccccn3)n(Cc3cccc4ccccc34)cc21

Procedure:
Prepared from the compound of Example 20, 3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(2-pyridinyl)thio]-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione and potassium peroxymonosulphate (commercially sold under the trade mark "OXONE") following the method of Example 8 c).
Reaction SMILES: CC([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:11][CH:12]=1)(C)C.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:6][C:7]1[CH:8]=[C:9]([C:13](=[O:19])[CH2:14][CH2:15][C:16]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[O:18])[CH:10]=[CH:11][CH:12]=1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)CCC(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN1CCN(C(=O)CCC(=O)c2cccc(O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Under nitrogen, to a solution of the product of Step 1 (490 mg, 2.52 mmol) in DMF (10 mL), was added 1-methylpiperazine (505 mg, 5.04 mmol), HOBT (1.02 g, 7.6 mmol), HBTU (950 mg, 2.5 mmol), followed with 4-methylmorpholine (770 μL, 7.6 mmol). This mixture was then stirred at rt overnight. The reaction mixture was concentrated and the residue was purified with reverse phase HPLC (5% MeCN/H2O→50% MeCN/H2O), to afford the title compound as white solid (572 mg, 82%). MS (ES+) m/e 277 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:8][NH:7][N:6]=1)=[O:4].[H-].[Na+].O.[CH2:20]1COCC1>>[CH3:1][O:2][C:3]([C:5]1[NH:6][NH:7][N:8]([CH3:20])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4]
Reactant: C1CCOC1
Reactant: COC(=O)c1n[nH]nc1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C1=C(c2ccc(F)cc2)N(C)NN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
5-(4-Fluoro-phenyl)-2H-[1,2,3]triazole-4-carboxylic acid methyl ester (2.21 g, 10 mmol) in THF (10 ml) was added drop-wise to an ice-cooled slurry of sodium hydride (0.42 g, 60% dispersion in mineral oil, 10 mmol) in THF (45 ml), under argon. After stirring at room temperature for 1 h, the reaction mixture was heated at 80° C. for 16 h. Water was added to the cooled mixture and the product was extracted with diethyl ether (2×). The combined organics were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 10-50% ethyl acetate-pentane) afforded 5-(4-Fluoro-phenyl)-1-methyl-2H-[1,2,3]triazole-4-carboxylic acid methyl ester (763 mg, 33%) and the title compound (943 mg, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][C:17]2[C:18]([N:23]=1)=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:7].[H-].[Na+].I[CH3:34]>CN(C=O)C>[CH3:30][O:29][C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:26]=1[O:27][CH3:28])[C:6]([N:8]([CH3:34])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][C:17]2[C:18]([N:23]=1)=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:7]
Reactant: CI
Reactant: COc1cc(C(=O)Nc2ccccc2-c2nc3ncccc3o2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C)c2ccccc2-c2nc3ncccc3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3,4,5-trimethoxy-N-(2-oxazolo[4,5-b]pyridin-2-yl-phenyl)-benzamide (0.03 g, 0.1 mmol) in 3 mL of DMF was added sodium hydride (60% dispersion in mineral oil, 0.006 g, 0.2 mmol). The mixture was stirred at RT for 30 minutes, becoming homogeneous. To this was then added iodomethane, drop wise (0.040 g, 0.3 mmol, 0.02 mL). After an additional hour at RT, the reaction was quenched with water and then partitioned between saturated NH4Cl and EtOAc. The organic layer was washed with brine and dried over MgSO4. The crude product was purified by silica chromatography, 0-5% methanol/dichloromethane. The desired product was isolated as a yellow solid. (Calc'd for C23H21N3O5: 419.44, [M+H]+ found: 420.1)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].[OH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][C:11]1[O:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][C:7]=1[CH2:6][O:5][C:4]1[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=1[CH2:2][O:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccccc1COc1cccc(CC(=O)O)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
A mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.21 g), methyl 2-(3-hydroxyphenyl)acetate (0.60 g), anhydrous potassium carbonate (0.65 g) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (1.37 g, 88%) of 2-[3-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 104-105° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[N:12][C:13]2[NH:14][CH2:15][CH2:16][CH2:17][C:18]=2[CH:19]=1.[C:21]([N:29]=C=O)(=[O:28])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:21]([N:14]1[C:13]2[N:12]=[CH:11][C:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:2])=[O:20])=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:28])[NH2:29]
Reactant: COC(=O)c1ccncc1-c1cnc2c(c1)CCCN2
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: NC(=O)N1CCCc2cc(-c3cnccc3C(=O)O)cnc21
Yield: 54.7 %

Procedure:
To a solution of 3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-isonicotinic acid methyl ester (131 mg, 0.49 mmol) in DCM (30 mL) is added benzoyl isocyanate (107 mg, 0.73 mmol). The mixture is heated to reflux for 3 hrs. The solvent is then removed and the residue is dissolved in anhydrous MeOH (10 mL). Then K2CO3 (180 mg, 1.3 mmol) is added and the mixture is heated to reflux for 0.5 h. After cooling down, the organic solvent is evaporated. The residue is dissolved in water and washed with DCM. The water layer is separated and purified by neutral preparative HPLC to give 80 mg of 3-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-isonicotinic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:5]2[C:6]3[O:10][CH:9]=[CH:8][C:7]=3[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: COc1cc(Br)c2occc2c1
Product: COc1cc(C2(O)CCN(Cc3ccccc3)CC2C)c2occc2c1
Yield: 53.8 %

Procedure:
Beginning with 4.0 gm (17.6 mMol) 5-methoxy-7-bromobenzofuran and 3.94 gm (19.4 mMol) 1-benzyl-3-methyl-4-oxo-piperidine, 3.33 gm (54%) of the desired compound were recovered essentially as described in EXAMPLE 3.
Reaction SMILES: O1C2CCCC([NH2:10])C=2C=C1.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1C(=O)[CH2:20][CH2:19][CH2:18]2>>[CH3:11][O:12][C:13]1[CH:22]=[C:17]2[C:16]([CH2:20][CH2:19][CH:18]2[NH2:10])=[CH:15][CH:14]=1
Reactant: COc1cccc2c1C(=O)CCC2
Reactant: NC1CCCc2occc21
Product: COc1ccc2c(c1)C(N)CC2

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 8-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.72, 2.54, 2.74, 2.90, 3.83, 4.34, 6.78, 6.91, 7.13; MS (FAB) m/z (rel. intensity) 164 (MH+, 17), 308 (8), 164 (17), 163 (7), 162 (19), 148 (18), 147 (99), 146 (18), 145 (9), 121 (11), 115 (8). HRMS (FAB) calcd for C10H13NO+H 164.1075, found 164.1071.
Reaction SMILES: [CH2:1]([C:8]([CH2:10][CH3:11])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH:15]=[CH2:16]>>[C:2]1([CH:1]([C:8](=[O:9])[CH2:10][CH3:11])[CH2:16][CH2:15][CH:14]=[CH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCBr
Reactant: CCC(=O)Cc1ccccc1
Product: C=CCCC(C(=O)CC)c1ccccc1

Procedure:
Ethyl benzyl ketone is reacted with 1-bromo-3-butene according to the foregoing details and there is obtained 5-phenyl-oct-1-en-6-one of boiling point 106° C./4 mmHg; nD20 =1.5088.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C:21]([OH:26])([CH3:25])[C:22](O)=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:45])([C:41]([F:44])([F:43])[F:42])[CH2:38][CH2:39][NH2:40]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C:21]([OH:26])([CH3:25])[C:22]([NH:40][CH2:39][CH2:38][C:37]([F:45])([F:36])[C:41]([F:44])([F:43])[F:42])=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCCC(F)(F)C(F)(F)F
Product: CC(O)(C(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-hydroxy-2-methyl-malonamic acid and 3,3,4,4,4-pentafluorobutylamine, the title compound was prepared in the same manner as described for example 1c. Light yellow, viscous oil (88%). MS: m/e=620(M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)[CH:6]=[CH:5][C:4]=1[CH2:14][C:15]([OH:17])=O)=[CH2:2].Cl.[N:19]1([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]3[C:31](=[O:34])[O:32][CH2:33][C:29]=3[CH:28]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)[CH:6]=[CH:5][C:4]=1[CH2:14][C:15]([N:22]1[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]3[C:31](=[O:34])[O:32][CH2:33][C:29]=3[CH:28]=2)[CH2:20][CH2:21]1)=[O:17])=[CH2:2]
Reactant: C=Cc1cc(-n2cnnn2)ccc1CC(=O)O
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: C=Cc1cc(-n2cnnn2)ccc1CC(=O)N1CCN(CCc2ccc3c(c2)COC3=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [2-ethenyl-4-(1H-tetrazol-1-yl)phenyl]acetic acid (43 mg, 0.19 mmol) in 10 mL of anhydrous DCM was added 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (53 mg, 0.19 mmol), EDC (56 mg, 0.28 mmol), HOBt (38 mg, 0.28 mmol), TEA (115 mg, 1.14 mmol) and then stirred at ambient temperature overnight. Then DCM was added and then mixture was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to afford 5-[2-(4-{[2-ethenyl-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 9.0 (s, 1H), 7.75˜7.78 (m, 2H), 7.48˜7.51 (m, 1H), 7.26˜7.31 (m, 3H), 6.76˜6.84 (rn, 1H), 5.7 (d, J=17.2 Hz, 1H), 5.44 (d, J=10.9 Hz, 1H), 5.22 (s, 2H), 3.75 (s, 2H), 3.6˜3.65 (m, 2H), 3.45˜3.48 (m, 2H), 2.86˜2.9 (m, 2H), 2.59˜2.64 (m, 2H), 2.41˜2.5 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)[CH3:2].[OH:21][C:22]1[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:23]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:36][C:34]2[CH:33]=[CH:32][C:23]([C:24](=[O:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:22]([OH:21])[CH:35]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Product: CCOC(=O)C(Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)c(O)c2)cc1)OC

Procedure:
A mixture of (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Step A and 2,4-dihydroxybenzophenone were allowed to react under the Standard Procedure I to get to title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][O:11][C:10]([CH3:15])([CH3:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:21](=[O:23])=[O:22].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH3:14][C:10]1([CH3:15])[O:9][CH:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:21]([OH:23])=[O:22])[CH2:13][CH2:12][O:11]1
Reactant: O=C=O
Reactant: CC1(C)OCCC(c2cccc(Br)c2)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OCCC(c2cccc(C(=O)O)c2)O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A 1 g portion of 4-(3-bromophenyl)-2,2-dimethyl-1,3-dioxane was dissolved in 18 ml of THF solution and cooled to −78° C., and then 2.35 ml of hexane solution containing 1.57 M n-butyl lithium was added dropwise thereto spending 1 hour. After completion of the dropwise addition, this was further stirred for 30 minutes. After adding excess amount of carbon dioxide thereto at −78° C., the mixture was risen to room temperature. The reaction solution was mixed with ammonium chloride aqueous solution and extracted 10 times with chloroform-methanol (5:1), the organic layer was dried with sodium sulfate and concentrated, and then the thus formed residue was purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 550 mg (63%) of 3-(2,2-dimethyl-1,3-dioxan-4-yl)benzoic acid (Reference Example 15-1). FA: 237
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].C(N(CC)CC)C.[N:14]([C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1)=[C:15]=[O:16]>ClCCCl>[CH3:5][C:2]1([CH3:6])[C:3](=[NH:4])[N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:18]=2)[C:15](=[O:16])[NH:1]1
Reactant: CC(C)(N)C#N
Reactant: N#Cc1ccc(N=C=O)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=N
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 47.3 %

Procedure:
To a solution of compound 9 (641 mg, 7.62 mmol) and triethylamine (168 mg, 1.66 mmol) in 1,2 dichloroethane (8.4 mL) at 0° C. under argon was dropwise added a solution of the isocyanate 8a (1.54 g, 7.28 mmol) in 1,2 dichloroethane (3.5 mL). The solution was stirred at 0° C. for 35 min and the ice bath was then removed and stirred at room temperature for an additional 30 min. The solution was then evaporated to dryness and purified by flash chromatography using EtOAc/Hexane (6:4) as an eluant to give pure compound 10a (1.02 g, 47%). 1H NMR (300 MHz, Acetone-d6) δ: 1.54 (m, 6H), 7.45 (broad s, 1H), 8.12 (d, 1H, J=8.46 Hz), 8.29 (dd, 1H, J1=6.90 Hz, J2=1.61 Hz), 8.46 (s, 1H), 8.51 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccn1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]c(COCc2ccccc2)n1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ncccn2)c(COCc2ccccc2)n1
Yield: 41 %

Procedure:
As described for Example 63, 4-(2-benzyloxymethyl-1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (60 mg, 0.17 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (30 mg, 41%) which was obtained as an off-white solid. MS: m/e=424.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>O>[Cl:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1c(Cl)cccc1Cl
Reactant: Nc1ccc(CCO)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(Cl)cccc1Nc1ccc(CCO)cc1
Temperature: 160 °C
Yield: 72 %

Procedure:
A mixture of 2,6-dichloronitrobenzene (Norman, M. H.; Chen, N.; et al. PCT Int. Appl., WO 9940091 (1999), Spada, A. P.; Fink, C. A.; Myers, M. R. PCT Int. Appl., WO 9205177 (1992), 6.3 g, 32.8 mmol), 4-aminophenylethyl alcohol (4.9 g, 36 mmol) and sodium acetate (3.2 g, 39.3 mmol) was placed in a sealed tube and heated at 160° C. for 3 h. After cooling, the mixture was poured into water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 2N aqueous NaOH (100 mL) and brine (100 mL), then dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 4.57 g (72%) of the title compound as a red oil: 1H-NMR (CDCl3) δ 7.09-7.28 (6H, m), 6.91 (1H, dd, J=2.0, 7.1 Hz), 3.87 (2H, t, J=6.6 Hz), 2.86 (2H, t, J=6.6 Hz).