Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.O[CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])=[CH:12][CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: Oc1ccc(-c2nc3ccccc3o2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCOc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 24 h

Procedure:
To a mixture of 4-(benzoxazol-2-yl)phenol (0.3 g; 1.4 mmol), N-(2-hydroxyethyl)phthalimide (0.27 g; 1.4 mmol), triphenylphosphine (0.56 g; 2.1 mmol) and THF (5 ml) is added diisopropyl azodicarboxylate (0.42 ml; 2.1 mmol). The reaction is stirred 24 hours, diluted with ethyl acetate, washed with H2O, 2N HCl, NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to dryness. The residue is purified by gradient elution column chromatography using CH2Cl2 and 1% MeOH/99% CH2Cl2 to yield N-[2-[4-(benzoxazol-2-yl)phenoxy]ethyl]phthalimide which is used directly in Step D.
Reaction SMILES: [C@@H:1]1([O:11][CH2:12][CH2:13][N:14]([CH2:24][CH2:25][O:26][C@@H:27]2[O:35][C@@H:34]([CH3:36])[C@@H:32]([OH:33])[C@@H:30]([OH:31])[C@@H:28]2[OH:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[OH-].[Na+].Cl>O>[C@@H:27]1([O:26][CH2:25][CH2:24][N:14]([CH2:13][CH2:12][O:11][C@@H:1]2[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[O:35][C@@H:34]([CH3:36])[C@@H:32]([OH:33])[C@@H:30]([OH:31])[C@@H:28]1[OH:29]
Reactant: COC(=O)CCCCCN(CCO[C@@H]1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O)CCO[C@@H]1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@@H]1O[C@@H](OCCN(CCCCCC(=O)O)CCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Reaction time: 16 h

Procedure:
To a solution of methyl 6-(bis{2-[(α-L-fucopyranosyl)oxy]ethyl}amino)hexanoate (45 mg, 0.086 mmol) in water (10 mL) was added NaOH (0.086μL, 0.086 mmol, 1.0 M). After stirring for 16 hours, the reaction mixture was neutralized with 0.01 M HCl and the resulting solution was lyophilized to yield the title compound. UPLC Method B: m/e=512.2866 [M+1]; Rt=1.709 min.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[I:9][CH2:10][C:11](O)=[O:12].C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[I:9][CH2:10][C:11]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:12]
Reactant: O=C(O)CI
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(CI)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.7 %

Procedure:
N-Hydroxysuccinimide (1 g, 8.7 mmole), iodoacetic acid (8.7 mmole, 1.6 g), and DCC (8.7 mmole, 1.7 g) were added to 250 mL of EtOAc and the mixture was stirred at room temperature for 5 hours. The mixture was filtered and the filtrate concentrated to dryness in vacuo. The residue was crystallized from ethanol to yield 1.74 g (71%) of white crystals, mp 148-150° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.C([N-]C(C)C)(C)C.[Li+].C([C:27]([O:29][CH3:30])=[O:28])#N>O1CCCC1>[O:1]=[C:2]1[CH2:3][CH:4]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]([CH2:6][CH2:5]2)[CH:8]1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)C#N
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1C(=O)CC2CCC1N2C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 88 %

Procedure:
Tetrahydrofuran (55.5 mL) was added to a flask containing tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10 g, 0.0444 mol). At −78° C., lithium diisopropylamide (24.4 mL, 0.0488 mol) was added dropwise to the reaction. The reaction was allowed to stir for 1 hr, then methyl cyanoformate (4.226 mL, 0.05326 mol) was added dropwise at −78° C. The reaction was let to stir for 5 hrs at room temperature. The reaction was quenched using saturated ammonium chloride solution. Some of the tetrahydrofuran was removed in vacuo. The remaining THF and ammonium chloride mixture was extracted using ethyl acetate three times. The combined ethyl acetate layers were washed with water and dried over sodium sulfate. The solution was filtered, was concentrated, and was purified using flash chromatography (0-100% ethyl acetate in hexane). A yellow oil was recovered (88% yield).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([O-:13])=[O:12]>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:17]([C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc([N+](=O)[O-])c1

Procedure:
Reaction of 18.4 g of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 10 g of 3-nitrobenzaldehyde in an analogous manner to that described in Example 1 gave 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(3-nitrophenyl)-1,8-(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave 22.6 g of pure material as pale yellow crystals of melting point >280° C.,
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]1[C:20](O)=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[OH:21][CH2:20][CH:9]1[CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-3-phenylpiperidine-2-carboxylic acid (416 mg, 1.36 mmol) in THF (2 ml) at 0° C. was added 1M borane-THF complex in THF (4.1 ml, 3.01 mmol). The reaction was warmed to rt and allowed to stir for 18 h. The reaction was cooled to 0° C., quenched with the careful addition of methanol, and concentrated in vacuo to yield tert-butyl 2-(hydroxymethyl)-3-phenylpiperidine-1-carboxylate (82%). HRMS (ES, M+Na) calcd for C17H25NO3: 314.1726, found: 314.1720. 1H NMR (400 MHz, CD3OD) δ 7.34-7.13 (m, 5H), 4.46 (m, 1H), 4.06 (d, J=13.0 Hz, 1H), 3.75 (m, 1H), 3.09 (m, 1.5H), 2.99 (m, 1.5H), 2.06 (m, 1H), 1.82 (m, 2H), 1.59 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.S(=O)(=O)(O)O.[F:16][C:17](I)([F:19])[F:18].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:16][C:17]([F:19])([F:18])[C:6]1[NH:7][C:8]2[C:4](=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])[N:5]=1
Reactant: FC(F)(F)I
Reactant: Nc1ncnc2nc[nH]c12
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: Nc1ncnc2nc(C(F)(F)F)[nH]c12
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
0.13 g (1.0 mmol) of adenine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 ml of a 30% hydrogen peroxide aqueous solution and 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 8-trifluoromethyladenine (19F-NMR yield: 26%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 8-Trifluoromethyladenine was obtained as a white solid (0.02 g, yield: 10%) by preparative thin-layer chromatography.
Reaction SMILES: COC1C=C(C=CC=1OC)C(C1C=CC(OC)=C(OC)C=1)=O.[C:23]1([O:31][CH3:32])[C:24](=[CH:27][CH:28]=[CH:29][CH:30]=1)[O:25][CH3:26].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:37][C:38]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:39]=1[C:40](Cl)=[O:41]>>[Cl:37][C:38]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:39]=1[C:40](=[O:41])[C:29]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:23]([O:31][CH3:32])[CH:30]=1
Reactant: COc1ccccc1OC
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Agent: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2cc(Cl)ccc2Cl)cc1OC

Procedure:
2′,5′-Dichloro-3,4-dimethoxybenzophenone was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (2.15 mL, 15 mmol), aluminum chloride (2.2 g, 16.5 mmol) and 2,5-dichlorobenzoyl chloride (1.9 mL, 15 mmol) with a reaction time of 3 hours at reflux. The crude product was purified by flash column chromatography (silica gel, 2.5% ethyl acetate/methylene chloride) to afford 3.88 g (83%) of the product as a white solid: mp 129–130° C.; 1H NMR (CDCl3) δ 7.65–7.56 (m, 1H), 7.41–7.12 (m, 4H), 6.89–6.81 (m, 1H), 3.96 (s, 3H), 3.94 (s, 3H); 13C NMR (CDCl3) δ 191.1, 154.4, 149.6, 137.9, 132.0, 130.5, 128.7, 128.0, 125.7, 110.2, 56.1, 56.0; Anal. Calcd for C15H12Cl2O3. Theoretical: C, 57.90; H, 3.89. Found: C, 57.58; H, 3.87.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(OCC)=O.Cl.[NH2:37][CH:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1>ClCCl>[CH2:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:46][CH:38]1[NH:37][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:22]
Reactant: COc1ccc(CCNC(=O)CCCCC(=O)O)cc1OC
Reactant: NC1Cc2ccccc2C1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)CCCCC(=O)NC2Cc3ccccc3C2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
6-[2-(3,4-Dimethoxyphenyl)ethylamino]-6-oxohexanoic acid (6.0 g, 0.019 mole) was dissolved in dry dichloromethane (200 ml) and triethylamine (2.28 g, 0.021 mole) added followed by ethyl chloroformate (1.86 ml, 0.019 mole) at 0°. The solution was stirred at 0° for 30 min and a solution of 2-aminoindane hydrochloride (3.3 g, 0.019 mole) and triethylamine (2.52 ml 0.019) in dry dichloromethane (200 ml) added, allowed to warm to room temperature and stirred for a further 18 hr. The reaction mixture was washed with water, dried (MgSO4) and evaporated and the residue recrystallised from methanol to give the sub-title compound as a white solid (6.4 g), mp 162°-4°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:22]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][C:14]=1[CH3:15]>[C].[Pd].O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][C:14]=1[CH3:15])[NH2:22]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(N)cc1F

Procedure:
A mixture of 3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)nitrobenzene (13.6 g), palladium-carbon (5%, 2.0 g) and tetrahydrofuran (THF) (200 ml) was subjected to catalytic hydrogenation under 1 atmospheric pressure at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to yield 3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)aniline as an oily product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH2:21][CH3:22])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:33]([N:34]2[CH2:46][CH2:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[CH:32][C:31]([F:48])=[CH:30][C:29]=1B1OC(C)(C)C(C)(C)O1)(=[O:25])[CH3:24]>>[C:23]([O:26][CH2:27][C:28]1[C:33]([N:34]2[CH2:46][CH2:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[CH:32][C:31]([F:48])=[CH:30][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH2:21][CH3:22])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CCN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Product: CCN1CC(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)C1
Yield: 65 %

Procedure:
Following Example 136e, starting with 250a and 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d, a 65% yield of 250b was obtained. LCMS: (M+H)+ 639
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[N:10]=[CH:9][C:8]1=[O:19])=[O:5])[CH3:2].[OH:20]O.O>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[NH:10][C:9](=[O:20])[C:8]1=[O:19])=[O:5])[CH3:2]
Reactant: OO
Reactant: CCOC(=O)Cn1c(=O)cnc2cc(Cl)cc(Cl)c21
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(Cl)cc(Cl)c21
Yield: 48 %

Procedure:
The above ester, (70 mg, 0.23 mmol) was reacted with 30% H2O2 (0.345 ml) in glacial acetic acid (0.92 ml) at 55° C. for 4.5 h. The mixture was cooled in an icebath and H2O (0.40 ml) was added. The precipitate was filtered off, washed with water and dried to give 35 mg (48%) of the title compound. 1H-NMR (DMSO-d6):δ1.23 (t, 3H), 4.20 (q, 2H), 5.02 (s, 2H), 7.21 (d, 1H), 7.42 (d, 1H), 12.3 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[CH:11]([CH3:13])[CH3:12])[CH2:6]O.P(Br)(Br)[Br:17].O>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[CH:11]([CH3:13])[CH3:12])[CH2:6][Br:17]
Reactant: COc1cc(CO)cc(OC)c1C(C)C
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: COc1cc(CBr)cc(OC)c1C(C)C
Yield: 175.2 %

Procedure:
To 3,5-Dimethoxy-4-i-propylbenzyl alcohol (12.57 g, 59.8 mmol) in dry ether (100 mL) at 0° C. was added PBr3 (3.0 mL, 31.2 mmol) dropwise under nitrogen. The reaction was monitored by TLC. After the reaction was completed (˜4 h), water (180 mL) was added. The organic layer was separated and the aqueous layer was extracted with ether (3×50 mL). The extract was washed with water (20 mL), sat. Na2CO3 (20 mL), water (20 mL) and brine (20 mL), and dried over anhydrous sodium sulfate. Evaporation of the solution yielded pure bromide (14.93 g, 91.4%) as a white solid. 1HNMR (CDCl3, ppm): δ 1.29 (d, J=7.1 Hz, 6H), 3.64 (hept, J=7.1 Hz, 1H), 3.84 (s, 6H), 4.50 (s, 2H), 6.60 (s, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[BH4-].[Na+].Cl>CCO>[OH:1][C@@H:2]1[CH2:5][C@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1
Reactant: CCOC(=O)C1CC(=O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@H]1C[C@@H](O)C1
Reaction time: 1 h

Procedure:
A solution of ethyl 3-oxocyclobutanecarboxylate (2.90 g, 20.4 mmol, Parkway) in EtOH (30 mL) at ambient temperature was treated with NaBH4 (0.77 g, 20 mmol). The reaction was stirred for about 1 h and then 2 N aqueous HCl was added to adjust the pH to about 2. The reaction was concd in vacuo. The reaction was partitioned with DCM (50 mL) and brine (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered then concd in vacuo. The resulting residue was purified on silica gel (80 g) using 20-40% EtOAc in DCM to give cis-ethyl 3-hydroxycyclobutanecarboxylate (2.75 g, 66%) as a clear oil: 1H NMR (DMSO-d6) δ 5.17 (d, 1H), 4.09-3.99 (m, 2H), 3.99-3.90 (m, 1H), 2.57-2.47 (m, 1H), 2.42-2.29 (m, 2H), 1.98-1.89 (m, 2H), 1.17 (m, 3H).
Reaction SMILES: O[CH:2]1[CH2:9][CH2:8][CH:7]([OH:10])[CH:6]2[N:11]([CH3:12])[CH:3]1[CH2:4][CH2:5]2.[C:13]([C:17]1[CH:18]=[C:19]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:16])([CH3:15])[CH3:14]>C1(C)C(C)=CC=CC=1.CCOCC.[Ti]>[C:13]([C:17]1[CH:18]=[C:19]([CH2:28][CH2:29][C:30]([O:32][CH:3]2[CH2:4][CH2:5][CH:6]3[N:11]([CH3:12])[CH:2]2[CH2:9][CH2:8][CH:7]3[O:10][C:30](=[O:31])[CH2:29][CH2:28][C:19]2[CH:20]=[C:21]([C:24]([CH3:25])([CH3:27])[CH3:26])[C:22]([OH:23])=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:18]=2)=[O:31])[CH:20]=[C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:22]=1[OH:23])([CH3:16])([CH3:14])[CH3:15]
Reactant: CN1C2CCC1C(O)CCC2O
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Agent: [Ti]
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: CN1C2CCC(OC(=O)CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C1CCC2OC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 56.6 %

Procedure:
In a nitrogen atmosphere a stirred mixture of the diol mixture 2,6-dihydroxy-9-methyl-9-azabicyclo[3.3.1]nonane and 2,5-dihydroxy-9-methyl-9-azabicyclo[4.2.1]nonane (4.28 g., 0.025 mole), 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid (15.3 g, 0.055 mole) and 0.7 ml of titanium tetraisopripylate in 100 ml of xylene was heated under reflux in a flask equipped with a Dean-Stark trap for 14 hours. The xylene was evaporated under reduced pressure and the residue thus obtained was dissolved in ether. The ether solution was washed with 5% aqueous sodium hydroxide and then water. The dried (Na2SO4) solution was evaporated under reduced pressure to give an oily residue which was crystallized from petroleum ether. Recrystallization from methanol gave 9.8 g (56.6%) of the title ester, m.p. 107°-109°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Yield: 95 %

Procedure:
To a solution of methyl 4-[2-(4-fluorophenyl)-2-oxoethyl]benzoate (1.00 g, 3.67 mmol) dissoved in ethanol (18 ml) was added sodium hydroxide 2M (18 ml). The mixture was refluxed for 15 minutes The reaction was cooled and evaporated to removed ethanol. The aqueous residue was acidified with HCl 2 M and extracted with ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and evaporated to give (0.9 g) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:39]=[CH:38][C:17]([C:18]([NH:20][C:21]3[CH:30]=[C:29]4[C:24]([CH2:25][CH2:26][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]4)=[CH:23][CH:22]=3)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:40]([O:42]C)=[O:41])#[N:2].[OH-].[Na+]>CO.O1CCCC1>[C:34]([O:33][C:31]([N:27]1[CH2:26][CH2:25][C:24]2[C:29](=[CH:30][C:21]([NH:20][C:18]([C:17]3[CH:38]=[CH:39][C:14]([O:13][C:12]4[CH:11]=[C:10]5[C:5]([CH:6]([C:40]([OH:42])=[O:41])[CH2:7][CH2:8][O:9]5)=[CH:4][C:3]=4[C:1]#[N:2])=[CH:15][CH:16]=3)=[O:19])=[CH:22][CH:23]=2)[CH2:28]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc5c(c4)CN(C(=O)OC(C)(C)C)CC5)cc3)c(C#N)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(NC(=O)c3ccc(Oc4cc5c(cc4C#N)C(C(=O)O)CCO5)cc3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
To a stirred solution of tert-butyl 7-(4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (84 mg, 0.14 mmol) in a mixture of methanol (1 mL) and tetrahydrofuran (0.5 mL) was added 2M sodium hydroxide (0.36 mL, 0.72 mmol). The resulting solution was stirred at ambient temperature for 1 hour, then concentrated. The residue was partitioned between ethyl acetate (10 mL) and 1M hydrochloric acid (5 mL). The organic layer was dried over sodium sulfate and concentrated to afford 7-(4-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid as an orange oil (40 mg, 49% yield).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([CH3:34])[CH:15]2[Si:20]([CH:23]1[C:31]2[C:26](=[C:27](Br)[CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH3:33])([CH3:22])[CH3:21]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[C:14]([CH3:34])[CH:15]3[Si:20]([CH:23]2[C:31]3[C:26](=[C:27]([C:4]4[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=4)[CH:28]=[CH:29][CH:30]=3)[CH:25]=[C:24]2[CH3:33])([CH3:22])[CH3:21])=[CH:3][CH:2]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CC1=Cc2c(Br)cccc2C1[Si](C)(C)C1C(C)=Cc2c(Br)cccc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3ccc(C)cc3)cccc2C1[Si](C)(C)C1C(C)=Cc2c(-c3ccc(C)cc3)cccc21
Reaction time: 1 h

Procedure:
In an argon atmosphere, to a solution of 15 mL of THF with 34.0 ml of 0.5 M ZnCl2 (17.0 mmol) in THF, 15.2 ml of 1.0 M p-tolylmagnesium bromide (15.2 mmol) in THF was added at ambient temperature. This mixture was stirred for 1 hour, and, then, 11.7 ml of 0.02 M Pd(PtBu3)2 (0.23 mmol, 4 mol. %) in THF and 2.78 g (5.86 mmol) of 1 were added. The resulting mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 2.79 g (96%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([N:15]2[CH:19]=[CH:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[C:16]2=[O:33])[CH:11]=[CH:12][C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Br:36][CH2:37][CH2:38]Br>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH2:1]([C:8]1[CH:9]=[C:10]([N:15]2[CH:19]=[CH:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[C:16]2=[O:33])[CH:11]=[CH:12][C:13]=1[O:14][CH2:38][CH2:37][Br:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: O=c1n(-c2ccc(Oc3ccccc3)cc2)ccn1-c1ccc(O)c(Cc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1n(-c2ccc(Oc3ccccc3)cc2)ccn1-c1ccc(OCCBr)c(Cc2ccccc2)c1
Temperature: 80 °C

Procedure:
A solution of 1-(3-benzyl-4-hydroxyphenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (233 mg) in 1,2-dibromoethane (1.7 ml) was mixed with sodium hydroxide solution (3N, 0.6 ml) and tetrabutylammonium hydrogen sulfate (12 mg). The mixture was heated at 80° C. for 2 hours. After cooling, the reaction mixture was diluted with dichloromethane and washed with sodium hydroxide solution (1N), hydrochloric acid (1N) and saturated brine. The organic phase was dried over magnesium sulfate and concentrated, and the residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 3:2). The product with the molecular weight of 541.45 (C30H25BrN2O3); MS (ESI): 541 ([M+H]+), was obtained in this way.