Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:5][CH2:4][C:3]1=[O:20].[O-2].[Mg+2].[CH3:23][N:24]1[C:30]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:29]=2[CH:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]([C:42](Cl)=[O:43])[CH2:26][C:25]1=[O:45]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]([C:42]([N:27]2[CH:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[N:24]([CH3:23])[C:25](=[O:45])[CH2:26]2)=[O:43])[CH2:4][C:3]1=[O:20]
Reactant: CN1C(=O)CNC(c2ccccc2)c2cc(Cl)ccc21
Reactant: CN1C(=O)CN(C(=O)Cl)C(c2ccccc2)c2cc(Cl)ccc21
Agent: [Mg+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CN(C(=O)N2CC(=O)N(C)c3ccc(Cl)cc3C2c2ccccc2)C(c2ccccc2)c2cc(Cl)ccc21
Yield: 66.2 %

Procedure:
1 g. of 1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one and 1 g. of magnesium oxide are added to a solution of 0.8 g. (2.29 mmoles) of 1-methyl-4-chlorocarbonyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 10 ml. of chloroform, and the mixture is stirred at 40° C. overnight. Thereafter the inorganic salts are filtered off, washed with 10 ml. of chloroform, and the chloroform solution is stirred with 10 ml. of 2n hydrochloric acid. The hydrochloride of the non-reacted base separates. The salt is filtered off, and the filtrate is washed with 5 ml. of 2.5 % aqueous sodium hydrocarbonate solution and with water. The chloroform solution is dried and evaporated. The obtained dry residue is recrystallized from ethanol. 0.91 g. (66.2 %) of di-(1-methyl-2-oxo-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-4-yl)-ketone are obtained; m.p.: 263°-266° C., Rf2 = 0.71.
Reaction SMILES: [OH:1][CH:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:6]=1)[CH2:3][CH3:4].C([O-])(=O)C.[Na+].[O-][Si]([O-])=O.[Mg+2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:6]=[C:5]([C:2](=[O:1])[CH2:3][CH3:4])[O:9][N:8]=2)=[CH:15][CH:14]=1
Reactant: CCC(O)c1cc(-c2ccc(OC)cc2)no1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: O=[Si]([O-])[O-]
Solvent: ClCCl
Product: CCC(=O)c1cc(-c2ccc(OC)cc2)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Added to 160 ml of dichloromethane were 8.07 g (34.6 mmol) of 5-(1-hydroxypropyl)-3-(4-methoxyphenyl)isoxazole prepared in the above procedure (2), 4.83 g (58.9 mmol) of sodium acetate and 12.7 g of "Florisil" (trade mark, Wakojunyaku Inc. ). While the resultant mixture was stirred vigorously, 12.7 g (58.9 mmol) pyridinium chlorochromate were added in small portions. After the mixture was stirred at room temperature for 4 hours, an insoluble material was filtered off and the solvent was distilled off. The residue was recrystallized from n-hexane, whereby 3-(4-methoxyphenyl)-5-propionylisoxazole was colorless crystals.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:13]([F:12])=[CH:14][CH:15]=3)[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(F)cc1
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(F)cc1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 4-fluorobenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.91-2.04 (m, 4H), 2.12 (s, 1H), 2.31 (d, J=14 Hz, 2H), 2.38 (s, 1H), 3.49 (s, 1H), 3.59 (s, 3H), 3.73 (s, 1H), 3.77-3.89 (m, 1H), 4.38 (s, 1H), 7.20 (t, J=9 Hz, 2H), 7.90 (dd, J=9, 5 Hz, 2H); MS (APCI/NH3) m/z 275 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([OH:28])=[C:5]([C:7]2[N:8]=[C:9]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[OH:27])N(C3C=CC(C(O)=O)=CC=3)N=2)[CH:6]=1.C(Cl)(=O)C1C(=CC=CC=1)[OH:32].C(N)(=O)C1C(=CC=CC=1)O>>[OH:28][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[C:7]1[O:27][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:9](=[O:32])[N:8]=1
Reactant: O=C(Cl)c1ccccc1O
Reactant: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Agent: NC(=O)c1ccccc1O
Product: O=c1nc(-c2ccccc2O)oc2ccccc12

Procedure:
U.S. Pat. No. 6,465,504 discloses a process for preparing Deferasirox wherein the process includes reacting salicyloyl chloride with salicylamide at 170° C. to obtain 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, and further crystallization in ethanol to obtain slight yellow color crystals of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one. 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one which is further reacted with 4-hydrazinebenzoic acid in presence of ethanol to give Deferasirox. Major drawback of this process is preparation of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one at high temperature and in the absence of solvent which causes formation of several impurities which is difficult to avoid.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([C:22]([S:25][CH3:26])([CH3:24])[CH3:23])[NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].C[S-].[Na+].S(=O)(=O)(O)[O-].[Na+]>CS(C)=O>[CH3:26][S:25][C:22]([CH3:24])([CH3:23])[C@H:4]([C:3]([OH:27])=[O:2])[NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:14]=1)(=[O:7])=[O:8]
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(C)(C)SC
Agent: C[S-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CSC(C)(C)[C@@H](NS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)O
Temperature: 45 °C
Yield: 95 %

Procedure:
To a solution of S-methyl--N--[4-(phenoxy)benzenesulfonyl]-D-penicillamine methyl ester (0.250 g., 0.610 mmol) in DMSO (3 mL) at room temperature was added sodium thiomethoxide (171 mg., 2.44 mmol) in one portion. The solution was heated at 45° C. for18 hours, and then cooled to 0° C. and acidified to pH=5 using 1N aqueous sodium bisulfate. The mixture was partitioned between ethyl acetate and water, and the organic phase was washed with brine, dried over MgSO4, and concentrated. The residue was purified on silica eluting with 8 to 12% methanol in dichloromethane to give S-methyl--N--[4-(phenoxy)benzenesulfonyl]-D-penicillamine as a white solid in 95% yield: mp 156-158° C.; 1H--NMR (DMSO-d6) δ 1.28 (s, 3H), 1.31 (s, 3H), 1.97 (s,3H), 7.08-7.82 (m, 10H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4]Br.[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1
Reactant: COC(CBr)OC
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC(OC)OC
Temperature: 110 °C
Yield: 34.8 %

Procedure:
Bromoacetaldehyde dimethyl acetal (0.74 ml, 3.1 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (10 g, 3.13 mmol), (prepared as described for the starting material in Example 2), and anhydrous potassium carbonate (2.16 g, 15.6 mmol) in DMF (30 ml). The mixture was stirred and heated at 110° C. for 4 hours, then allowed t6 cool and the volatiles were removed by evaporation. Water was added to the residue and the aqueous mixture was extracted with methylene chloride (×4). The extracts were combined, washed with brine and dried by filtration through phase separating paper. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-7-(2,2-dimethoxyethoxy)-6-methoxyquinazoline (440 mg, 35%).
Reaction SMILES: IC.[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N:11]([CH3:15])[C:12]([NH2:14])=S)=[CH:6][C:5]=1[CH3:16].CO[CH:19](OC)[CH2:20][NH2:21]>CC(C)=O.C(O)C(C)C>[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N:11]([C:12]2[NH:21][CH:20]=[CH:19][N:14]=2)[CH3:15])=[CH:6][C:5]=1[CH3:16]
Reactant: Cc1cc(N(C)C(N)=S)cc(C)c1Br
Reactant: COC(CN)OC
Solvent: CI
Solvent: CC(C)=O
Solvent: CC(C)CO
Product: Cc1cc(N(C)c2ncc[nH]2)cc(C)c1Br
Yield: 28.3 %

Procedure:
Iodomethane (260 mg, 9.15 mmol) was added to a solution of 1-(4-bromo-3,5-dimethyl-phenyl)-1-methyl-thiourea (500 mg, 1.83 mmol) in acetone (10 ml) with stirring in a nitrogen stream, and the mixture was heated with stirring at 50° C. for two hours. The reaction solution was concentrated under reduced pressure, and a mixture of the resulting residue and aminoacetaldehyde dimethylacetal (250 mg, 2.38 mmol) in iso-BuOH (8.3 ml) was then heated under reflux for four hours. The reaction mixture was concentrated under reduced pressure. Concentrated hydrochloric acid (3 ml) was then added to the resulting residue, and the mixture was heated with stirring at 90° C. for 30 minutes. The reaction mixture was cooled and then adjusted to pH 10 with a 2 N aqueous sodium hydroxide solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-methanol) to give (4-bromo-3,5-dimethyl-phenyl)-(1H-imidazol-2-yl)-methyl-amine (145 mg, 28%).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C@H:6]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[CH:10][CH:9]=1)C.[OH-].[Na+]>CO>[C:4]([CH2:5][C@H:6]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[CH:10][CH:9]=1)([OH:31])=[O:3]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)cc1-c1ccc(C[C@H](CC(=O)O)NC(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a solution of (R)-4-(4-ethoxy-1-(5′-fluoro-2′-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobutanoic acid (Example 2-8: 83 mg, 0.192 mmol) in MeOH (2 mL) is added 1N NaOH (4 mL, 4 mmol) After stirring at room temperature for 2 hours, the crude is concentrated under reduced pressure to remove MeOH and is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-4-(1-carboxy-3-(5′-fluoro-2′-methoxybiphenyl-4-yl)propan-2-ylamino)-4-oxobutanoic acid (58 mg). HPLC retention time=1.46 minutes (condition D); MS (m+1)=404.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.36-2.59 (m, 6 H) 2.84 (dd, J=13.4, 6.3 Hz, 1H) 2.91 (dd, J=13.4, 6.3 Hz, 1 H) 3.75 (s, 3 H) 4.34-4.56 (m, 1 H) 6.95-7.08 (m, 3 H) 7.26 (d, J=8.1 Hz, 2 H) 7.42 (d, J=8.3 Hz, 2 H)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[C:19](Cl)[CH:20]=[CH:21][C:16]=3[C:15](=[O:23])[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC([F:34])=CC=1C(O)=O.C(N1CCC(=O)CC1)C1C=CC=CC=1.C([Li])CCC>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][C:20]([F:34])=[CH:21][C:16]=3[C:15](=[O:23])[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: O=C1OC2(CCN(Cc3ccccc3)CC2)c2cc(Cl)ccc21
Agent: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1OC2(CCN(Cc3ccccc3)CC2)c2ccc(F)cc21

Procedure:
This reaction was performed as described for (i) above using 2-bromo-5-fluorobenzoic acid (2.19 g, 10.0 mmol), 1-benzylpiperidin-4-one (3.78 g, 20.0 mmol), n-butyl lithium (n-BuLi) (20 mL) and THF (20 mL) to give the sub-titled compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].[Cl-].[Li+]>O.CN(C)C=O>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=1[OH:25])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[NH:28][N:27]=[N:26][N:20]=2)=[CH:17][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(OCc2ccc(C#N)cc2)cc(C(C)(C)C)c1O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(OCc2ccc(-c3nnn[nH]3)cc2)cc(C(C)(C)C)c1O
Temperature: 100 °C

Procedure:
A mixture of 1.68 g (5 mmole) of 2,6-di-t-butyl-4[(4-cyanophenyl)methoxy]phenol (from Example 1) 0.97 g (15 mmole) of sodium azide, 0.30 g (15 mmole) of ammonium chloride, 0.21 g (5 mmole) of lithium chloride and 25 ml of N,N-dimethylformamide was heated in a stoppered flask at 100° C. for 16 hours. The reaction mixture was poured into a mixture of ice and water, and was then extracted with chloroform. The chloroform extract was washed with water, dried and evaporated to give the crude product as an oil. The oil was triturated with water to give a solid. The solid was purified by silica gel chromatography eluting with a mixture of methanol/chloroform/acetic acid in a ratio of 5/94.5/0.5 followed by two recrystallizations from a mixture of methanol, chloroform and hexane to give 0.22 g of white 5-[4-(3,5-di-t-butyl-4-hydroxyphenoxymethyl)phenyl]tetrazole, m.p. 235°-237° C. Analysis: Calculated for C22H28N4O2 : %C, 69.4; %H, 7.4; %N, 14.7; Found: %C, 69.0; %H, 7.6; %N, 14.6.
Reaction SMILES: O[C:2]1[C:7]([OH:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[C:16]([OH:18])[C:15]([O:19][CH2:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([OH:29])[CH:13]=1)=[O:11].[CH2:30]([OH:37])[C:31]([NH2:36])([CH2:34][OH:35])[CH2:32][OH:33]>[Ag]=O>[OH:29][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([OH:18])[C:15]=1[O:19][CH2:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]([C:3]1[CH:4]=[CH:5][C:6](=[O:9])[C:7]2([OH:8])[O:37][CH2:30][C:31]([CH2:34][OH:35])([CH2:32][OH:33])[NH:36][C:2]=12)=[O:11]
Reactant: NC(CO)(CO)CO
Reactant: O=C(COc1c(O)cc(C(=O)c2ccc(O)c(O)c2O)cc1O)c1ccccc1
Agent: O=[Ag]
Product: O=C(COc1c(O)cc(C(=O)C2=C3NC(CO)(CO)COC3(O)C(=O)C=C2)cc1O)c1ccccc1
Yield: 40.3 %

Procedure:
The procedure is analogous to that described in Example 8a), but starting with 0.79 g of [2,3,4-trihydroxy-phenyl][3',5'-dihydroxy-4'-(2-oxo-2-phenylethoxy)phenyl] methanone (compound VIIIb described in Example 2), 12.10 g of Tris and 2.30 g of silver oxide (Ag2O). After purification by chromatography on a 30 g silica gel column (diameter: 2.0 cm, height: 60 cm) eluted with an ethyl acetate/methanol mixture (97/3 by volume), 0.40 g of (RS)-5-[3,5-dihydroxy-4-(2-oxo-2-phenylethoxy)-benzoyl]-3,3-bis(hydroxymethyl)-8a-hydroxy-3,4-dihydro-2H-1,4-benzoxazin-8(8aH)-one is obtained in the form of an orange powder melting at around 185° C. (with decomposition).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.[BH4-].[Na+].Cl.O[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(O)C.[Cl-].[Na+].O.O.O1CCCC1>[O:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH:3]([O:10][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=2)[CH2:2]1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: O=C1COc2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OC2COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 3-coumaranone (0.50 g, 3.7 mmol) in ethanol (20 mL) was added sodium tetrahydroborate (0.28 g, 7.5 mmol), and the mixture was stirred at room temperature for 1 hr. 0.5N Hydrochloric acid (10 mL) was added and the mixture was stirred at room temperature for 10 min. Saturated brine was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated. Tetrahydrofuran (10 mL), methyl 4-hydroxybenzenepropanoate (0.46 g, 2.6 mmol), triphenylphosphine (0.98 g, 3.8 mmol) and diethyl azodicarboxylate (0.91 mL, 4.7 mmol) were added to the residue, and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20:1) to give the title compound. yield 17%, oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[O:18][C:19]3[C:25]([C:26](OC)=[O:27])=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:30]>CO>[C:26]([C:25]1[C:19]2[O:18][C:17]([CH:13]3[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:12]3)=[N:21][C:20]=2[CH:22]=[CH:23][CH:24]=1)(=[O:27])[NH2:30]
Reactant: COC(=O)c1cccc2nc(C3CCCN(C(=O)OCc4ccccc4)C3)oc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc2nc(C3CCCN(C(=O)OCc4ccccc4)C3)oc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 57 %

Procedure:
Methyl 2-(1-(benzyloxycarbonyl)piperidin-3-yl)benzo[d]oxazole-7-carboxylate (180 mg, 0.46 mmol) was added to ammonia in methanol (20 mL) and the mixture was stirred at room temperature for 2 days. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 mL×4), the organic phase was dried with anhydrous sodium sulfate and evaporated under reduced pressure. 100 mg of benzyl 3-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate was obtained. Yield: 57%. LC-MS (ESI) m/z: 380 (M+1)+.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([N:17]3[CH2:25][CH2:24][CH2:23][C@@H:18]3[C:19]([O:21]C)=[O:20])[CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]=1[CH:26]1[C:39]2[C:38](=[O:40])[CH2:37][C:36]([CH3:42])([CH3:41])[CH2:35][C:34]=2[O:33][C:32]2[CH2:31][C:30]([CH3:44])([CH3:43])[CH2:29][C:28](=[O:45])[C:27]1=2.C1COCC1.O.O>C(OCC)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([N:17]3[CH2:25][CH2:24][CH2:23][C@@H:18]3[C:19]([OH:21])=[O:20])[CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]=1[CH:26]1[C:27]2[C:28](=[O:45])[CH2:29][C:30]([CH3:43])([CH3:44])[CH2:31][C:32]=2[O:33][C:34]2[CH2:35][C:36]([CH3:42])([CH3:41])[CH2:37][C:38](=[O:40])[C:39]1=2
Reactant: COC(=O)[C@H]1CCCN1c1cccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1ccc(-c2cccc(N3CCC[C@@H]3C(=O)O)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
Lithium hydroxide (16.9 mg, 403 μmol) was added to a solution of the methyl 1-{6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridin-2-yl}-D-prolinate obtained in Example 15-2 (157 mg, 269 μmol) in a mixed solvent of THF/water (2:1, v/v) (3 mL) at room temperature. The mixture thus obtained was stirred at the same temperature as above for 30 minutes, and was further stirred at 60° C. for 1 hour. Thereafter, water and diethyl ether were added to the reaction solution, and the mixed solution was then extracted with water twice. The resultant was washed with diethyl ether. Thereafter, 1 N hydrochloric acid was added to the water layer thus obtained, so that the pH was adjusted to pH 4 or lower, and the mixed solution was then extracted with ethyl acetate three times. The organic layer thus obtained was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The residue obtained was crystallized from hexane/ethyl acetate to obtain the title compound (107 mg, yield: 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH:26]2OCCO2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[O:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH:35]2[O:31][C:32](=[O:37])[NH:33][C:34]2=[O:36])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: O=C1COC(=O)N1
Reactant: COc1cc(CCCC2OCCO2)ccc1OCc1nc(-c2ccccc2)oc1C
Product: COc1cc(CCCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 18, 2-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-1,3-dioxolan was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[4-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]butyl]-2,4-oxazolidinedione, which was recrystallized from dichloromethane-isopropyl ether to give colorless prisms, m.p.135-136° C.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:14][C:15]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>>[CH3:14][C:15]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cccc(C(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1cccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reaction time: 2 h

Procedure:
tert-Butyl piperazine-1-carboxylate(0.50 g, 2.6 mmol), 2,3-dimethylbenzoic acid (0.44 g, 2.9 mmol), 1-hydroxybenzotriazole (HOBT) (0.45 g, 2.9 mmol) and 1-ethyl-3-(3-dimethylamino- propyl)carbodiimide hydrochloride (EDC.HCl) (0.56 g, 2.9 mmol) were added to dry, degassed dimethylformamide (7 mL). The pH of the reaction was adjusted to 7 with triethylamine, and the reaction stirred for 2 h. The dimethylformamide (DMF) was distilled in vacuo, and the residue partitioned between ethyl acetate and water. The organic phase was washed with 2% aqueous potassium hydrogen sulfate, saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over magnesium sulfate. The crude product was chromatographed on silica gel using 30% ethyl acetate in hexane as eluant. The title compound was obtained as a white solid, NMR (CDCl3, 300 MHz) δ 7.17 (1H, d, J=7 Hz), 7.13 (1H, t, J=7 Hz), 6.98 (1H, d, J=7 Hz), 3.77 (2H, m), 3.51 (2H, m), 3.32 (2H, t, J=5 Hz), 3.19 (2H, m), 2.28 (3H, s), 2.18 (3H, s), 1.45 (9H, s).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][C:34]1[CH:35]=[C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:38])[NH:19][C:9]4[CH:10]=[C:11]([O:14][C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:31]=[C:32]([CH3:37])[N:33]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(OC(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4ccc(OC(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example M193) (230 mg, 0.423 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (97 mg, 54%).