Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11]>[Pd].O1CCCC1.O>[ClH:1].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: Cc1[nH]cnc1/C=C/C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1[nH]cnc1CCC(=O)O
Reaction time: 19 h
Yield: 81.4 %

Procedure:
60 mg of 10% palladium-on-charcoal are introduced into a solution of 387 mg (2.1 mmol) of (E)-3-(5-methyl-1H-imidazol-4-yl)acrylic acid hydrochloride in 8 ml of 1/1 tetrahydrofuran/water, purged beforehand with nitrogen. The reaction medium is placed under a hydrogen atmosphere and then stirred for 19 hours. After filtering through Celite and rinsing thoroughly with dichloromethane, the recovered filtrate is concentrated under vacuum. The crude residue is taken up in toluene and concentrated again in order to remove the residual water, and is then taken up in a mixture of heptane and diisopropyl ether (80/20) with stirring for about 2 hours. The desired product precipitates and is filtered off under vacuum. 326 mg (83%) of 3-(5-methyl-1H-imidazol-4-yl)propanoic acid hydrochloride are obtained in the form of a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl.CC(=O)[CH2:15][C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][CH2:15][C:16](=[O:18])[CH3:17]
Reactant: ClCCCc1ccccc1CCl
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)CCc1ccccc1CCCCl

Procedure:
A mixture of 258 g (1.27 mol) of 2-(3-chloropropyl)benzyl chloride, 2, 140 g (1.4 mol) of 2,4-pentanedione, 6, 175 g (1.27 mol) potassium carbonate, and 700 ml of absolute ethanol was stirred at reflux for 18 hours. Evaporation of the alcohol gave a residue which was partitioned between ether and water. The organic phase was dried over anhydrous MgSO4, concentrated and the residue distilled to give the chloro ketone 7, 218 g, bp 123°-127° C/0.2 mm.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[O:7]=[C:8]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:9]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13]>CN(C=O)C>[O:7]=[C:8]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:9]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:1])=[O:19])=[CH:20][CH:21]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(C(=O)N1CCCCC1)c1ccc(C=O)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(C(=O)N1CCCCC1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
Oxone (257 mg, 0.42 mmol) was added to a stirred solution of 4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)benzaldehyde (100 mg, 0.35 mmol) in DMF (5 mL) and the resulting mixture was stirred at room temperature for 16 hours. The DMF was removed in vacuo and the resulting residue was purified by flash column chromatography (50% EtOAc/hexane, Rf=0.4) to afford the desired compound as a pale yellow solid (68 mg. 64%). MP=142° C. 1H NMR (400 MHz, CDCl3) 0.86 (t, J=7 Hz, 3H); 1.05 (m, 1H); 1.15 (m, 1H); 1.2-1.6 (multiple signals, 8H); 1.71 (m, 1H); 2.10 (m, 1H); 3.33-3.43 (m, 3H); 3.69 (m, 1H); 3.77 (t, J=7 Hz, 1H); 7.38 (d, J=8.4 Hz, 2H); 8.02 (d, J=8.4 Hz, 2H). 13C NMR (75 MHz, CDCl3) 13.98, 22.68, 24.50, 25.55, 26.16, 30.04, 34.60, 43.32, 46.68, 48.82, 128.04, 130.50, 153.75, 170.59. HRMS (ESI+1 ion) m/z calcd for C18H26NO3 304.1907. found 304.1917.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([C:16]([CH3:28])([CH3:27])[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[O:18])[CH:12]=[CH:13][C:14]=1[F:15])=O)(C)(C)C.Cl.C(=O)([O-])O.[Na+]>>[NH2:8][C:9]1[CH:10]=[C:11]([C:16]([CH3:28])([CH3:27])[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[O:18])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: COc1ccccc1C(=O)C(C)(C)c1ccc(F)c(NC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccccc1C(=O)C(C)(C)c1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
A mixture of 1-(2-methoxyphenyl)-2-methyl-1-propanone (0.58 g), 4-bromo-2-(tert-butoxycarbonylamino)-1-fluoro -benzene (0.94 g), palladium(II) acetate (37 mg), tri(tert -butyl)phosphine tetrafluoroborate (47 mg) and sodium tert-butoxide (0.78 g) in tetrahydrofuran (10 mL) was stirred at 60° C. under an argon atmosphere overnight. To the reaction mixture was added water, and the mixture was stirred for 10 minutes. The mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=95/5−85/15) to give 2-[3-(tert-butoxycarbonylamino)-4-fluorophenyl]-1-(2-methoxyphenyl)-2-methyl-1-propanone (0.91 g). To the obtained 2-[3-(tert-butoxycarbonylamino)-4-fluorophenyl]-1-(2-methoxyphenyl)-2-methyl-1-propanone (0.34 g) was added hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (0.22 g).
Reaction SMILES: [C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[NH2:7].O.[OH:10][CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12](=[N:19][OH:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[NH2:7].[OH:10][C@H:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)/[C:12](=[N:19]/[OH:20])/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ON=C(c1ccccc1)C(O)c1ccccc1
Agent: N[C@@H]1CCCC[C@H]1N
Solvent: O
Solvent: c1ccccc1
Product: O/N=C(\c1ccccc1)[C@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
2.00 g (17.5 mmol) of (1R,2R)-(-)-1,2-cyclohexanediamine of α!D20 =-36.7° (c 4.14, H2O) and 4.00 g (17.6 mmol) of dl-1-hydroxy-2-hydroxyimino-1,2-diphenylethane were added to 10 ml of benzene and then heated and stirred, and the solution was cooled to room temperature. Afterward, the precipitated crystals were collected by filtration and then recrystallized from 30 ml of benzene twice to obtain 2.30 g of (1R,2R)-(-)-1,2-cyclohexanediamine·(R)-(-)-(E)-1-hydroxy-2-hydroxyimino-1,2-diphenylethane. Physical properties of the product are as follows.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[F:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1>>[F:44][C:45]1[CH:46]=[CH:47][C:48]([OH:51])=[C:49]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])[CH:50]=1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Oc1ccc(F)cc1
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(F)ccc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 4-fluorophenol, the title compound was obtained (53%): 1H NMR (300 MHz, CDCl3) δ 9.42-9.14 (br, 1H), 7.53-6.86 (m, 6H), 6.56-6.48 (m, 1H), 4.58-4.28 (br, 1H), 3.79-3.58 (m, 2H), 1.77-1.61 (m, 2H), 1.41-1.24 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 312 (M−17), 352 (M+23).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][C:14](=[O:16])[O:13][C:12](=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][NH2:19]>C1COCC1>[CH3:18][N:19]1[C:14](=[O:16])[CH2:15][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11][C:12]1=[O:13]
Reactant: CN
Reactant: O=C1CC(c2ccc([N+](=O)[O-])cc2)CC(=O)O1
Solvent: C1CCOC1
Product: CN1C(=O)CC(c2ccc([N+](=O)[O-])cc2)CC1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.5 %

Procedure:
A solution of 399 mg (1.70 mmol) of 4-(4-nitro-phenyl)-dihydro-pyran-2,6-dione (as prepared in Example 2, step (b)) in THF (8 mL) was treated with 1.10 mL (2.21 mmol) of 2.0 M methylamine in THF. The mixture was stirred at RT for 45 min, concentrated in vacuo, taken up in 1 N aqueous HCl (10 mL), and extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was taken up in acetic anhydride (7 mL), treated with triethylamine (1 mL) and heated to 80° C. for 1 h. The solvents were removed in vacuo. The residue was taken up in EtOAc (20 mL) and washed successively with 1 N aqueous HCl, saturated aqueous NaHCO3, and water (1×10 mL each). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with 25-50% EtOAc-hexane afforded 348 mg (83%) of the title compound as an off-white solid: 1H-NMR (CDCl3; 400 MHz): δ 8.25 (d, 2H, J=8.8 Hz), 7.40 (d, 2H, J=8.8 Hz), 3.56-3.45 (m, 1H), 3.21 (s, 3H), 3.10-3.01 (m, 2H), 2.88-2.77 (m, 2H).
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=O)[C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:19])[CH:2]=1>O>[CH:5]1[C:6]([C@H:7]2[CH2:8][O:9][C:10]3[CH:11]=[C:12]([OH:18])[CH:13]=[CH:14][C:15]=3[CH2:16]2)=[CH:1][CH:2]=[C:3]([OH:19])[CH:4]=1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Solvent: O
Product: Oc1ccc([C@H]2COc3cc(O)ccc3C2)cc1

Procedure:
Using a substrate solution containing 0.01 mg/ml of daidzein (manufactured by Funakoshi, purity ≧99%) (5 mg of daidzein suspended in 2 ml of special grade methanol and diluted to 50 ml with BHI (brain heart infusion) medium) in lieu of the above water-soluble soya isoflavone material, equol was produced in otherwise the same manner as above. As a result, the amount of equol in the fermentation broth after 96 hours of culture was 17.9±1.4 μg/ml (mean of 5 determinations ±S.D.).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[NH:8]3.[H-].[Na+].Br[CH2:17][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].O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[N:8]3[CH2:17][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]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Cc1nc2cccc3[nH]c(=O)c1n23
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cccc3n(CCCN4C(=O)c5ccccc5C4=O)c(=O)c1n23
Yield: 31.7 %

Procedure:
To a suspension of 8.66 g (50 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 100 ml of DMF was added, while stirring under ice-cooling, 2.20 g (55 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added 13.14 g (50 mmol) of N-(3-bromopropyl)phthalimide. The mixture was stirred for 7 hours at 100° C. After cooling, the reaction mixture was poured into water, which was subjected to extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and, the solvent was then distilled off. The residue was crystallized from methylene chloride—ethanol to give 5.72 g of the desired compound (31.7%, pale brown solid substance).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[NH2:19][C@@H:20]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:21]([NH:23][CH3:24])=[O:22]>>[CH3:27][C:26]([CH3:29])([CH3:28])[CH2:25][C@H:20]([NH:19][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:21](=[O:22])[NH:23][CH3:24]
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=402.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH2:14]Br)[O:10][C:9]=2[C:8]([O:16][CH3:17])=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-:19].[Na+].[Na+]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH:14]=[O:19])[O:10][C:9]=2[C:8]([O:16][CH3:17])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(OC)c2oc(CBr)cc12
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(OC)c2oc(C=O)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.7 %

Procedure:
To a well stirred solution of Methyl-2-bromomethyl-7-methoxybenzo[b]furan-4-carboxylate (step 6) (3.1 g, 10.36 mmol) in dimethyl sulfoxide (30.0 mL) was added powdered sodium carbonate (1.64 g, 15.55 mmol) at 90-95° C. and stirred for 2-3 hours. Reaction mixture was cooled to room temperature and diluted with water (300 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×50 mL) and dried over anhydrous sodium sulfate. Removal of solvent gave crude product (2.9 g) as brown viscous oil. Purification by silica gel column using chloroform: ethyl acetate (95:5) as an eluent afforded 2.2 g of pure product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[Li+].[OH-]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1-c1ccn[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(F)ccc1-c1ccn[nH]1
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of methyl 5-fluoro-2-(1H-pyrazol-5-yl)benzoate (415 mg, 1.9 mmol) in EtOH (10 ml) was treated with 4.0 eq of LiOH and stirred and monitored for two hours until the reaction was complete. The reaction mixture was then made to pH=5, and then the solution concentrated under reduced pressure, during which time a ppt formed. The solution was concentrated to minimum volume and cooled in ice, filtered and washed with ice water to give 5-fluoro-2-(1H-pyrazol-5-yl)benzoic acid (172 mg, 44%). 1H NMR (400 MHz, DMSO-d6): 13.03 (s, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.67 (dd, J=8.3, 5.6 Hz, 1H), 7.37 (td, J=8.6, 2.9 Hz, 2H), 6.44 (d, J=2.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30][OH:31])[O:14][CH2:13][CH2:12][N:11]([C:15](=[O:28])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:31][CH2:30][CH2:29][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:14][CH2:13][CH2:12][N:11]([C:15](=[O:28])[C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)[CH2:10]1)(=[O:42])=[O:41]
Reactant: COc1cc(C(=O)N2CCOC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCOC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
388 mg (0.83 mmole) of 2-[2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethanol [prepared as described in step (e) above] were dissolved in 5 ml of methylene chloride, and 126 mg (1.25 mmole) of triethylamine and 0.078 ml (1.01 mmole) of methanesulfonyl chloride were added to the resulting solution. The mixture was then stirred at room temperature for 2 hours. The reaction mixture was then diluted with methylene chloride, after which it was washed with 1 N aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride, in that order. The organic extract was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 1:4 to 0:1 by volume as the eluent, to obtain 424 mg of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[C:7]([OH:13])(=O)[CH2:8][C:9]([OH:11])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][N:2]1[C:7](=[O:13])[CH2:8][C:9](=[O:11])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: CNC(=O)NC
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN1C(=O)CC(=O)N(C)C1=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
276 g (3.14 mol) of 1,3-dimethylurea and 376 g (3.62 mol) of malonic acid were dissolved in 600 ml of glacial acetic acid at 60° to 70° C. To the solution was added 1250 ml of acetic anhydride and the temperature was gradually raised to 90° C. After stirring for 6 hours, the reaction mixture was allowed to stand at room temperature overnight and then the glacial acetic acid and acetic anhydride were distilled off under reduced pressure. The residue was poured into 500 ml of ethanol while it was still hot, the crystals thus-deposited were collected by filtration and refluxed by heating in a mixture of 380 ml of concentrated hydrochloric acid and 400 ml of water for 2 hours. The mixture was allowed to stand under cooling with ice for 6 hours, the crystals thus-deposited were collected by filtration and washed with a small amount of ethanol to obtain 360 g of 1,3-dimethylbarbituric acid.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[N:18]2[CH2:27][C:28]2[C:29]([CH3:34])=[N:30][O:31][C:32]=2[CH3:33])=[C:9]1[CH3:35])(C)(C)C.[OH-].[Na+].Cl>CCO>[CH3:34][C:29]1[C:28]([CH2:27][N:18]2[C:19](=[O:26])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]2[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:36])=[O:5])[C:9]=2[CH3:35])=[C:32]([CH3:33])[O:31][N:30]=1
Reactant: Cc1noc(C)c1CN1C(=O)c2ccccc2C1c1c(C)n(CC(=O)OC(C)(C)C)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1noc(C)c1CN1C(=O)c2ccccc2C1c1c(C)n(CC(=O)O)c2ccccc12
Temperature: 70 °C

Procedure:
The crude product of step b) was dissolved in 3 mL EtOH and treated with 0.5 mL of 1 M NaOH. After heating to 70° C. for 1 h, the reaction was cooled, acidified with 1 M HCl and extracted into DCM. The extracts were concentrated and the title compound was purified by preparative LCMS to give the title compound. 1H NMR (DMSO-d6) δ 7.84-7.81 (m, 1H), 7.56-7.46 (m, 2H), 7.25 (d, J=8.1 Hz, 1H), 7.19-7.16 (m, 1H), 6.93 (t, J=7.5 Hz, 1H), 6.69 (t, J=7.5 Hz, 1H), 6.39 (d, J=7.8 Hz, 1H), 3.73 (s, 1H), 4.85 (d, J=15.2 Hz, 1H), 4.52 (d, J=17.1 Hz, 1H), 4.51 (d, J=17.1 Hz, 1H), 3.51 (d, J=15.3 Hz, 1H), 2.35 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H); MS: ESI (negative): 428.6 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17]CC)=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
To a solution of ethyl 2-(4-(4-Fluorobenzoyl)piperidin-1-yl)acetate (52.7 g, 180 mmol) in ethanol (300 mL) was added sodium hydroxide solution in water (1.8 M, 300 mL). The mixture was stirred at ambient temperature for 24 h then neutralized with HCl (37%) until pH 5˜7. The solvent was evaporated under reduced pressure, dissolved with methanol and methylene chloride, and filtered. The resulting solution was evaporated to give the title compound as a white solid (47.7 g, >99% yield). 1H NMR (400 MHz, CD3OD) δ 8.11 (dd, J=8.8, 5.3 Hz, 2H), 7.26 (t, J=8.8 Hz, 2H), 3.57-3.85 (m, 5H), 3.21 (t, J=11.0 Hz, 2H), 1.96-2.18 (m, 4H). MS m/z 266.3 (M+1), retention time=0.87 min.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:5]=[C:6]([C@@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:19]=[CH:18]3)[C@@H:11]([NH2:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)[CH3:3].C([O:34][CH2:35][C:36](Cl)=[O:37])(=O)C>>[CH2:2]([C:4]1[CH:5]=[C:6]([C@@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[N:19]=[CH:18]3)[C@@H:11]([NH:13][C:35](=[O:34])[CH2:36][OH:37])[CH3:12])[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Agent: Cl
Product: CCc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CO)c1

Procedure:
The title compound was prepared analogous to the method described in Example 21 starting from (1R,2S)-1-(3-ethylphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine hydrochloride (22a) (50 mg, 0.12 mmol), and Acetoxyacetyl chloride (14 μL, 0.13 mmol). Yield 37 mg (70%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:23](Br)[CH:24]([CH3:26])[CH3:25]>>[C:1]([C:5]1[CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:10]=1[O:11][CH2:23][CH:24]([CH3:26])[CH3:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CBr
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)c(O)c(C(C)(C)C)c1
Product: COC(=O)c1cc(-c2ccc(C)cc2)c(OCC(C)C)c(C(C)(C)C)c1
Yield: 95 %

Procedure:
In a manner similar to that of Example 1c, by reacting 1.57 g (5.3 mmol) of methyl 5-tert-butyl-6-hydroxy-4′-methyl-3-biphenylcarboxylate with 1.14 mL (10.5 mmol) of isobutyl bromide. A yellow oil is obtained (m=1.8 g; yield=95%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=O.[C:13]([O:17][C:18](=[O:25])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])([CH3:16])([CH3:15])[CH3:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:13]([O:17][C:18](=[O:25])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:11][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Cn1c(C=O)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(CNCCCCNC(=O)OC(C)(C)C)nc2ccccc21

Procedure:
Using General Procedure B, reaction of 1-methyl-1H-benzoimidazole-2-carbaldehyde and (4-amino-butyl)-carbamic acid tert-butyl ester in CH2Cl2 with NaBH(OAc)3 gave {4-[(1-methyl-1H-benzoimidazol-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a sticky white foam. 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.54-1.64 (m, 4H), 1.80-1.82 (m, 2H), 2.67-2.75 (m, 2H), 3.12-3.13 (m, 2H), 3.82 (s, 3H), 4.06 (s, 2H), 7.23-7.30 (m, 2H), 7.31-7.38 (m, 1H), 7.70-7.76 (m, 1H).