Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.C([SiH](CC)CC)C.O[CH:18]([C:30]1[CH:39]=[CH:38][C:37]2[C:36]([CH3:41])([CH3:40])[CH2:35][CH2:34][C:33]([CH3:43])([CH3:42])[C:32]=2[CH:31]=1)[C:19]#[C:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1.O>ClCCl>[CH3:40][C:36]1([CH3:41])[CH2:35][CH2:34][C:33]([CH3:42])([CH3:43])[C:32]2[CH:31]=[C:30]([CH2:18][C:19]#[C:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[CH:39]=[CH:38][C:37]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(O)C#Cc3ccc(C(=O)O)cc3)ccc21
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.1 ml (8.1 mmol) of BF3.Et2O (48%) and 50 ml of dichloromethane are introduced into a three-necked flask under a stream of nitrogen. 2.6 ml (16.2 mmol) of triethylsilane are added at −20° C., followed by a solution of 1 g (2.7 mmol) of 4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid in 30 ml of dichloromethane and the mixture is stirred at room temperature for 30 minutes. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified on a column of silica eluted with dichloromethane. After evaporation of the solvents, 780 mg (82%) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid are collected, with a melting point of 167-8° C.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[N:28]=[N:29][N:30]([CH2:32][CH3:33])[N:31]=3)[C:4]=2[CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[CH2:32]([N:30]1[N:29]=[N:28][C:27]([CH2:26][N:5]2[C:4]3[CH:3]=[C:2]([C:38]4[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=4)[S:10][C:9]=3[C:8](=[O:11])[N:7]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[C:6]2=[O:25])=[N:31]1)[CH3:33]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc(F)cc4)cc32)n1

Procedure:
Tert-butyl 4-{6-bromo-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (405 mg, compound B101), (4-fluorophenyl)boronic acid (105 mg), dichlorobis(tricyclohexylphosphine)palladium (28 mg) and aqueous cesium carbonate solution (0.563 ml, 2.0 M) in DME (10 ml) are reacted according to the procedure described in example B55 to afford the title compound after two times purification by flash column chromatography [silica gel, elution gradient: cyclohexane/EtOAc, 100/0 to 50/50 to 30/70 (v/v) and amino phase silica gel elution gradient: cyclohexane/EtOAc, 100/0 to 50/50 to 30/70 (v/v)] as a solid.
Reaction SMILES: CS(C)=O.[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[CH:9]=O.[NH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[SH:23].C(OCC)(=O)C>O>[Br:5][C:6]1[CH:7]=[C:8]([C:9]2[S:23][C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[N:15]=2)[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=Cc1ccc(O)c(Br)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccc(-c2nc3cc(Cl)ccc3s2)cc1Br
Yield: 30.3 %

Procedure:
In a dimethyl sulfoxide (DMSO) (2 mL) solvent, a solution including 3-bromo-4-hydroxybenzaldehyde (163.7 mg, 0.81 mmol) and 2-amino-4-chlorobenzenethiol (100 mg, 0.45 mmol) was refluxed for 1 hour. After cooling, the residual was distributed between ethyl acetate and water, and an organic layer was dried by using MgSO4, filtered, and evaporated under reduced pressure. The resultant residual was added to water, and then, the precipitate was filtered and the filtered product was washed with water and methylene chloride to obtain a solid Compound 95 (46.4 mg, 17.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=2)=[CH:4][CH:3]=1.C([O:22][N:23]=O)(C)(C)C.Cl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=2)=[N:23][OH:22])=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccnc(F)c1)c1ccc(F)cc1
Reactant: CC(C)(C)ON=O
Agent: Cl
Solvent: CCO
Product: O=C(C(=NO)c1ccnc(F)c1)c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethanone (43 g, 0.184 mol) in ethanol (800 mL) at −10° C. was added dropwise t-butylnitrite (24.1 mL, 0.20 mol) over 10 minutes followed by 2.5 M HCl in absolute ethanol (60 mL, 0.15 mol). The reaction temperature was maintained at −5° C. during these additions. After addition was complete, the dry ice bath was removed and the reaction was allowed to warm to RT and stirred overnight. The ethanol was removed under reduced pressure and the residue was diluted with H2O and made basic with saturated NaHCO3. It was extracted with EtOAc, the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was taken up in methanol/isopropanol and mixed with toluene. The methanol/isopropanol mixture was concentrated under reduced pressure and the title compound was recrystallized from hexane/toluene (47.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N+:5]([O-])=[C:4](C)[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CO.[C:26]([O-:29])([O-])=O.[K+].[K+]>ClCCl.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:26]([OH:29])[C:3]=1[CH3:4]
Reactant: Cc1cc(Cl)c(Cl)c[n+]1[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1c(O)ncc(Cl)c1Cl
Reaction time: 144 h

Procedure:
To a stirred and cooled solution of 4,5-dichloro-2-methyl-pyridine-N-oxide (8.54 g) in dichloromethane (110 ml) at 10°-15°, was added trifluoroacetic anhydride (12 ml) and the reaction mixture allowed to stand 6 days. The solution was cooled to 5°-10°, methanol added dropwise and the mixture stripped. The residue was treated with H2O (70 ml) basified to pH 9-10 (K2CO3) and extracted with chloroform. The extract was dried (K2CO3), stripped and the residue triturated with petrol to give 4,5-dichloro-2-hydroxy- methylpyridine, (6.15 g), m.p. 103°-106°
Reaction SMILES: [CH3:1][CH:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[CH:13]([C:15]([CH3:17])=[O:16])=[CH2:14].C(N(CC)CC)C.C(OC)(C)(C)C.CCCCCCC>C(O)C>[CH3:1][CH:2]1[N:11]([CH2:14][CH2:13][C:15](=[O:16])[CH3:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12]
Reactant: CC1Nc2ccccc2NC1=O
Reactant: C=CC(C)=O
Solvent: CCO
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(=O)CCN1c2ccccc2NC(=O)C1C
Yield: 86.1 %

Procedure:
3-Methyl-3,4-dihydroquinoxalin-2(1H)-one (0.5 g, 3.1 mmol) together with 0.35 ml (4.3 mmol) of methyl vinyl ketone and a catalytic amount of triethylamine were stirred for 20 hours at room temperature in 20 ml of anhydrous ethanol. Silica gel chromatography with methyl tert.-butyl ether/heptane=2:1 gave 620 mg (87%) of the desired product, melting point 108-109° C. (methyl tert.-butyl ether/heptane).
Reaction SMILES: C(O)(=O)C.N1CCCC1.[CH3:10][C:11]([CH3:13])=[O:12].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:32]2[C:37]([OH:38])=[C:36]([CH3:39])[C:35]([CH3:40])=[C:34]([CH:41]=O)[C:33]=2[CH3:43])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][CH:16]=1>O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:32]2[C:33]([CH3:43])=[C:34]([CH:41]=[CH:10][C:11](=[O:12])[CH3:13])[C:35]([CH3:40])=[C:36]([CH3:39])[C:37]=2[OH:38])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][CH:16]=1
Reactant: CC(C)=O
Reactant: CCOC(=O)CCCCCC(c1ccc(F)cc1)c1c(C)c(C=O)c(C)c(C)c1O
Solvent: C1CCNC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCC(c1ccc(F)cc1)c1c(C)c(C=CC(C)=O)c(C)c(C)c1O
Reaction time: 6.5 h

Procedure:
To acetic acid (0.14 ml) were added pyrrolidine (0.2 ml) and acetone (0.26 ml). To this solution was added ethyl 7-(4-fluorophenyl)-7-(3-formyl-6-hydroxy-2,4,5-trimethylphenyl)heptanoate (1.0 g) and the mixture was stirred for 6.5 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl 7-(4-fluorophenyl)-7-[2-hydroxy-5-(3-oxobutenyl)-3,4,6-trimethylphenyl]heptanoate (0.95 g) (Compound 42). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[CH:28][CH:29]=1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4ccccc4OC)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12c and 4-bromoanisole
Reaction SMILES: C([O:3][C:4]([CH2:6][CH:7]1[CH2:16][CH2:15][CH2:14][CH2:13][C:8]21[O:12][CH2:11][CH2:10][O:9]2)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[OH:3][CH2:4][CH2:6][CH:7]1[CH2:16][CH2:15][CH2:14][CH2:13][C:8]21[O:9][CH2:10][CH2:11][O:12]2
Reactant: CCOC(=O)CC1CCCCC12OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCC1CCCCC12OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
Under an argon atmosphere, a solution of (±)-6-(ethoxycarbonylmethyl)-1,4-dioxaspiro[4.5]decane (1.00 g, 4.39 mmol) in diethyl ether (22 ml) was cooled to 0° C. Lithium aluminium hydride (333 mg, 8.77 mmol) was added and the mixture was stirred at room temperature for 3 h. The mixture was cooled to 0° C., quenched with ethyl acetate (10 ml) and 2 M sodium hydroxide solution (50 ml). The mixture was extracted with chloroform (3×50 ml) and the combined organic extracts were dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give the crude product which was purified using flash column chromatography with hexane-ethyl acetate (3:7) to give (±)-6-(2'-hydroxyethyl)-1,4-dioxaspiro[4.5]decane (767 mg, 94% yield) as a colourless oil. Rf 0.30 (hexane-ethyl acetate, 3:7).
Reaction SMILES: Br.[NH2:2][C:3]1[C:8]([CH2:9]Br)=[CH:7][C:6]([Br:11])=[CH:5][N:4]=1.[CH3:12][NH2:13]>C1COCC1>[NH2:2][C:3]1[C:8]([CH2:9][NH:13][CH3:12])=[CH:7][C:6]([Br:11])=[CH:5][N:4]=1
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CN
Agent: Br
Solvent: C1CCOC1
Product: CNCc1cc(Br)cnc1N
Yield: 80 %

Procedure:
A solution of the 2-amino-3-(bromomethyl)-5-bromopyridine hydrobromide salt (prepared above) in 40% aqueous methylamine (50 mL) and THF (50 mL) was stirred at RT overnight in a pressure bottle. The reaction solution was concentrated and extracted with EtOAc (2×100 mL). The combined organic phases were washed with H2O, dried over Na2SO4 and concentrated. Purification on silica gel afforded the title compound (4.25 g, 80%) as a yellow oil: MS (ES) m/e 217 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([F:23])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[ClH:24]>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:23])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][CH2:11]1.[ClH:24]
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H](F)c2ccc(F)cc2F)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(F)c2ccc(F)cc2F)CC1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
(R)-tert-butyl 4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate (2.8 g, 8.50 mmol) was dissolved in EtOAc (20 mL) and HCl (4 M in EtOAc, 21 mL) was added. The reaction mixture was stirred at 23° C. for 2 h. Evaporation of the solvent gave the title compound as its HCl salt (2.1 g, 93%). ESI-MS m/z [M+H]+ 229.9.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([NH2:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:4]=1)#[N:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]#[N:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:31])=[O:32])[CH:4]=1)#[N:2]
Reactant: CC1=C(C(N)=O)C(c2ccc(C#N)cc2S(=O)(=O)c2ccccc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=C(C#N)C(c2ccc(C#N)cc2S(=O)(=O)c2ccccc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
The reaction was carried out under argon. (rac)-4-{4-Cyano-2-[phenylsulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide (137 mg, 253 μmol) was initially charged in dry THF (8 ml), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 121 mg, 507 μmol; 2 eq.) was added and the mixture was stirred at RT for 8 h (HPLC control). The reaction mixture was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a solid (106 mg, 80% of theory).
Reaction SMILES: [Br-].[Mg+2].[Br-].[C:4]([O:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[O:23]C)[N:14]=[CH:13]1)(=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6]>N1C=CC=CC=1>[C:4]([O:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[OH:23])[N:14]=[CH:13]1)(=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: COc1cccc2ncn(COC(=O)C(C)(C)C)c(=O)c12
Agent: [Br-]
Agent: [Mg+2]
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCn1cnc2cccc(O)c2c1=O
Temperature: 120 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Magnesium bromide (7 g, 38 mmol) was added to a solution of (5-methoxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate (7.4 g, 25.5 mmol) in pyridine (25 ml). The mixture was stirred at 120° C. for one hour. After cooling, the solvents were evaporated under high vacuum. Diluted acetic acid (15 ml in 100 ml water) was added. The precipitated solid was filtered, washed with water and dried under high vacuum in the presence of P2O5 to give (5-hydroxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate as a white solid (6.33 g, 90%); NMR Spectrum (CDCl3) 1.23 (s, 9H), 5.93 (s, 2H), 6.99 (d, 1H), 7.22 (d, 1H), 7.68 (t, 1H), 8.21 (s, 1H); Mass spectrum MH+ 277.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][CH2:10]O)=[CH:7][O:8][C:4]=2[CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[N:36]1([C:42]2[CH:43]=[CH:44][CH:45]=[C:46]3[C:51]=2[N:50]=[CH:49][CH:48]=[CH:47]3)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C>N1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][CH2:10][N:39]3[CH2:40][CH2:41][N:36]([C:42]4[CH:43]=[CH:44][CH:45]=[C:46]5[C:51]=4[N:50]=[CH:49][CH:48]=[CH:47]5)[CH2:37][CH2:38]3)=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: OCCc1coc2cc(Cl)ccc12
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc2c(CCN3CCN(c4cccc5cccnc45)CC3)coc2c1
Reaction time: 48 h

Procedure:
To a stirred solution of 2-(6-chloro-1-benzofuran-3-yl)ethanol (980 mg, 5 mmol) in anhydrous pyridine (20 ml), p-toluenesulfonyl chloride (1.14 g, 6.0 mmol) was added. The reaction mixture was kept at 0° C. for 48 hrs and quenched with ice cold water. The reaction mixture was extracted with chloroform, washed well with water and dried over anhydrous MgSO4. It was filtered and concentrated. The crude product obtained was taken to next step without any purification. A mixture of tosylate (350 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino-quinoline (213 mg, 1 mmol) was heat at 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by eluting it initially with 70% ethyl acetate:hexane and then with 5% methanol:ethyl acetate. 8-{4-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as a yellow oil. Yield: 120 mg (30%); (M+H): 392; 1HNMR (400 MHz, CDCl3):δ 8.82˜8.81 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H); 8.40˜8.20 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.46˜6.92 (m, 8H); 3.50˜2.70 (m, 12H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:33]=[CH:32][C:19]([CH2:20][CH:21]([C:27]([O:29]CC)=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1.O.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH2:25]([O:24][C:22]([CH:21]([CH2:20][C:19]1[CH:32]=[CH:33][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:17][CH:18]=1)[C:27]([OH:29])=[O:28])=[O:23])[CH3:26]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diethyl 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylmalonate (4.60 g, 10.2 mmol) obtained in Example 55 was dissolved in a mixed solvent of ethanol (50 ml) and tetrahydrofuran (25 ml), and the mixture was stirred at room temperature for 18 hr. The solvent was evaporated to give a crude solid. Water (20 ml) and 1N sodium hydroxide (30 ml) were added to dissolve said crude solid. 1N Hydrochloric acid was added at 0° C., and the mixture was extracted three times with ethyl acetate (30 ml). The extracted organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness to give a crude title compound (4.7 g), which was purified and concentrated by silica gel column chromatography (developing solvent; chloroform:methanol=100:1→50:1) to give the title compound. This compound was dissolved in 1N sodium hydroxide (10 ml) and washed twice with ethyl acetate (30 ml). 1N Hydrochloric acid (15 ml) was added to the aqueous layer, and the mixture was extracted three times with ethyl acetate (30 ml). The extracted organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness to give the title compound (2.91 g, yield 67%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([O:15]CC3C=CC=CC=3)=[O:14])=[CH:11][CH:10]=2)[CH2:4][O:3]1>[Pd].CO>[CH3:1][C:2]1([CH3:25])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](COc2ccc(C(=O)OCc3ccccc3)cc2)O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC[C@@H](COc2ccc(C(=O)O)cc2)O1
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A 500 mL high-pressure flask was charged with palladium on carbon (0.300 g, 0.282 mmol), then MeOH (200 ml) was added, followed by (R)-benzyl 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoate (6.17 g, 18.02 mmol). The resulting suspension was allowed to shake under an atmosphere of hydrogen (35 Psi) at ambient temperature for 2 hrs. The mixture was filtered through Celite® and the colorless filtrate was concentrated to afford (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoic acid as white solid (4.45 g, 17.64 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[CH2:15]=[O:16]>O>[OH:16][CH2:15][N:9]1[C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13]
Reactant: C=O
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Solvent: O
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1CO

Procedure:
A stirred mixture composed of 6-nitro-2H-1,4-benzoxazin-3(4H)-one (5.82 g), 37% formaldehyde aqueous solution (28.5 ml) and water (5.4 ml) is refluxed for 2 hours, and cooled. The resultant solid is collected by filtration, washed with water, ethanol, ether and n-hexane successively, and dried to obtain 4-hydroxymethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (5.19 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH:16]3[CH2:21][C:20]([CH3:23])([CH3:22])[NH:19][C:18]([CH3:25])([CH3:24])[CH2:17]3)[N:12]=[C:11]([NH:26][CH:27]3[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]3)[N:10]=2)[CH2:5][C:4]([CH3:38])([CH3:37])[NH:3]1.[CH2:40]=[O:41].[OH-].[Na+]>C(O)(=O)C.O>[CH3:33][C:31]1([CH3:34])[CH2:32][CH:27]([NH:26][C:11]2[N:10]=[C:9]([NH:8][CH:6]3[CH2:5][C:4]([CH3:38])([CH3:37])[NH:3][C:2]([CH3:39])([CH3:1])[CH2:7]3)[N:14]=[C:13]([N:15]([CH:16]3[CH2:17][C:18]([CH3:24])([CH3:25])[NH:19][C:20]([CH3:22])([CH3:23])[CH2:21]3)[CH2:40][OH:41])[N:12]=2)[CH2:28][C:29]([CH3:36])([CH3:35])[NH:30]1
Reactant: CC1(C)CC(Nc2nc(NC3CC(C)(C)NC(C)(C)C3)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CC(Nc2nc(NC3CC(C)(C)NC(C)(C)C3)nc(N(CO)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
54.3 g of 2,4,6-tris-(2,2,6,6-tetramethyl-4-piperidylamino)-1,3,5-triazine are dissolved in 200 ml of glacial acetic acid. After addition of 20 ml of 36% formaldehyde solution, the reaction mixture is stirred for 18 hours at room temperature, then diluted with water, made strongly alkaline with concentrated sodium hydroxide solution and extracted with toluene. The toluene solution is dried over sodium sulphate and concentrated in vacuo. Crystallisation of the residue yields 2,4-bis-(2,2,6,6-tetramethyl-4-piperidylamino)-6-(2,2,6,6-tetramethyl-4-piperidyl-methylolamino)-1,3,5-triazine in the form of colourless crystals with a melting point of 201°-202° C.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:31])[NH:10][CH:11]([CH2:25][C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)[C:12]([NH:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:24][C:22]1[CH:21]=[CH:20][C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]3[O:7][C@@H:6]3[C:4]([OH:5])=[O:3])=[O:31])[CH2:25][C:26]3[N:27]=[CH:28][NH:29][CH:30]=3)[S:16][C:17]=2[CH:23]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)NC(Cc1c[nH]cn1)C(=O)Nc1nc2ccc(F)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(Nc1nc2ccc(F)cc2s1)[C@H](Cc1c[nH]cn1)NC(=O)[C@H]1O[C@@H]1C(=O)O
Yield: 76.7 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 18e (153 mg, 0.32 mmol); LiOH (7.7 mg, 0.32 mmol); THF/MeOH/H2O (3.5 mL: 1.5 mL: 1.5 mL); yielded 31a as a white solid (103 mg, 71.5%). 1H NMR (DMSO-d6, 400 MHz): δ 14.55 (bs, 1H); 14.36 (bs, 1H); 9.18-9.02 (m, 1H): 7.93-7.91 (m, 1H); 7.79-7.75 (m, 1H); 7.44 (s, 1H); 7.31-7.29 (t, 1H); 4.96-4.91 (q, 1H); 3.72-3.71 (d, 1H, J=1.62 Hz); 3.51-3.50 (d, 1H, J=1.62 Hz); 3.29-3.16 (m, 2H). %). 13C NMR (DMSO-d6, 100 MHz): 169.50, 168.51, 165.84, 165.84, 159.82, 157.53, 157.44, 145.02, 133.67, 132.68, 132.57, 128.56, 121.63, 117.01, 114.40, 114.16, 108.27, 108.00, 52.67, 52.19, 51.34, 26.20. ESI-HRMS (m/z): [M+H+] calcd. for C17H14FN5O5S: 420.0773, observed: 420.0777.