Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:40])[C@H:8]([CH2:35][C:36]([F:39])([CH3:38])[CH3:37])[NH:9][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C@H:26]4[CH2:28][C@@H:27]4[C:29]([NH:31][CH:32]4[CH2:34][CH2:33]4)=[O:30])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:11]([F:13])[F:12])[CH2:5][CH2:4]1)#[N:2].[CH3:41][C:42]1[CH:43]=[CH:44][C:45]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:46][CH:47]=1.O>C1COCC1>[CH3:41][C:42]1[CH:43]=[CH:44][C:45]([S:48]([O-:51])(=[O:50])=[O:49])=[CH:46][CH:47]=1.[C:1]([C:3]1([NH:6][C:7](=[O:40])[C@@H:8]([NH2+:9][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C@@H:26]4[CH2:28][C@H:27]4[C:29]([NH:31][CH:32]4[CH2:34][CH2:33]4)=[O:30])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:11]([F:12])[F:13])[CH2:35][C:36]([F:39])([CH3:38])[CH3:37])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc([C@H]3C[C@@H]3C(=O)NC3CC3)cc2)cc1)C(F)F)C(=O)NC1(C#N)CC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(F)C[C@H]([NH2+][C@@H](c1ccc(-c2ccc([C@@H]3C[C@H]3C(=O)NC3CC3)cc2)cc1)C(F)F)C(=O)NC1(C#N)CC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N1-(1-cyanocyclopropyl)-N2-[(1S)-1-(4′-{(1S,2S)-2-[(cyclopropylamino)carbonyl]cyclopropyl}biphenyl-4-yl)-2,2-difluoroethyl]-4-fluoro-L-leucinamide (60 mg, 0.11 mmol) was dissolved in 0.80 mL of THF. TsOH.H2O (21 mg, 0.11 mmol) was dissolved in 0.20 mL of THF and was added to the reaction mixture. It was stirred at room temperature for 30 minutes. Hexanes (∫3 mL) was then added until a precipitate crashed out of solution. It was sonicated for 5 minutes and it was filtered off on a Buchner funnel. The white solid was dried on the pump overnight. It was triturated in diethyl ether (˜5 mL) for 2 h at room temperature and filtered off on a Buchner funnel to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](\[Cl:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12](Cl)=[O:13].[OH:16][CH:17]1[CH2:21][C:20](=[O:22])[C:19]([CH2:23][CH:24]=[CH2:25])=[C:18]1[CH3:26]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](\[Cl:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:16][CH:17]1[CH2:21][C:20](=[O:22])[C:19]([CH2:23][CH:24]=[CH2:25])=[C:18]1[CH3:26])=[O:13]
Reactant: C=CCC1=C(C)C(O)CC1=O
Reactant: COC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: ClC(Cl)Cl
Product: C=CCC1=C(C)C(OC(=O)[C@@H]2[C@H](/C=C(\Cl)C(=O)OC)C2(C)C)CC1=O

Procedure:
(1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-methoxypropenyl]-cyclopropane-1-carboxylic acid chloride and (4S) hydroxy-3-methyl-2-(2-propenyl)-2-cyclopenten-1-one were reacted to obtain (1S) 2-methyl-4-oxo-3-(2-propenyl)-2-cyclopenten-1-yl (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific [α]D20 =+27°±2.5° (c=0.3% in chloroform).
Reaction SMILES: [Br-:1].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N+:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH3:20])([CH3:19])[C:11]=1[CH3:21])([OH:4])=[O:3].[C:22]1([NH:28][CH:29]=NC2C=CC=CC=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO.ClCCl>C(O)(=O)C>[Br-:1].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N+:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH3:20])([CH3:19])[C:11]=1[CH:21]=[CH:29][NH:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:4])=[O:3]
Reactant: CC1=[N+](CCCCCC(=O)O)c2ccccc2C1(C)C
Reactant: C(=Nc1ccccc1)Nc1ccccc1
Agent: [Br-]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(C)C(C=CNc2ccccc2)=[N+](CCCCCC(=O)O)c2ccccc21
Reaction time: 2.5 h

Procedure:
1-(5-carboxypentyl)-2,3,3-trimethylindolium bromide (1.77 g, 5 mmol) and N,N′-diphenylformamidine (1.96 g, 10 mmol) were mixed in acetic acid (15 m); the resulting mixture was then heated at reflux. The reaction was monitored by UV/VIS spectroscopy (methanol solution, product absorbance λmax 398 nm) and TLC (silica. Methanol, 20: dichloromethane, 80; product runs as a yellow streak, Rf 0.1-0.25). After 2.5 hrs the orange-red solution was then left to cool over 16 hrs, then the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica. 5-20% methanol/dichloromethane) to give the title compound [1.3] as a yellow-orange foam after drying, 1.5 g (66%).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.[CH2:32]([SH:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=3[N:3]=[C:2]2[S:34][CH2:32][CH3:33])=[CH:13][CH:14]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1nc2c(c(=O)n(CCCOC3CCCCO3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.15 g, 0.29 mmol, intermediate 14) in DMF (10 mL) was added ethanethiol (27 mg, 0.44 mmol) and potassium carbonate (81 mg, 0.58 mmol). The reaction was heated at 80° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 1.912 min; LCMS MH+-THP 409.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([OH:33])[CH:14]([N:19]3[CH2:24][CH2:23][C:22]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([OH:25])[CH2:21][CH2:20]3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>[Pd].C(O)(=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2([OH:25])[CH2:23][CH2:24][N:19]([CH:14]3[CH:13]([OH:33])[C:12]4[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=4)[O:16][CH2:15]3)[CH2:20][CH2:21]2)=[CH:27][CH:28]=1
Reactant: OC1c2ccc(OCc3ccccc3)cc2OCC1N1CCC(O)(c2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1ccc2c(c1)OCC(N1CCC(O)(c3ccc(F)cc3)CC1)C2O
Reaction time: 8 h
Yield: 54.7 %

Procedure:
A mixture of 3R*4S*7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4-ol (0.80 g, 1.78 mmol), 10% palladium on carbon (0.16 g), methanol (40 mL), and acetic acid (0.8 mL) was hydrogenated for 8 hours with a starting pressure of 48.5 psi. The reaction was filtered through celite and the filtrate was concentrated. The residue was stirred vigorously with ether and saturated sodium bicarbonate for 1 hour. The solid was washed with water and ether and dried in vacuo. Recrystallization from ethanol yielded 0.35 g (54%) of 3R*4S*3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4,7-diol as a white solid which had mp 159-160° C.; NMR DMSO∂σ δ7.55-7.47 (m, 2H), 7.11 (t, J=9 Hz, 2H), 7.02 (d, J=8.4 Hz, 1H)k, 6.32 (dd, J=2.3, 8.3 Hz, 1H), 6.15 (d, J=2.3 Hz 1H), 5.10-4.50 (br m with s at 4.63, 3H), 4.23 (dd, J=2.8, 10.3 Hz, 1H), 4.04 (t, J=10.5 Hz, 1H), 2.99 (br d, J=10.8 Hz, 1H), 2.86 (br d, J=10.7 Hz, 1H), 2.73-2.50 (m, 3H), 2.08-1.90 (m, 2H), 1.58 (br d, J=13 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.OC1C=CC(C([O:19][CH2:20][C:21]2[CH:26]=CC=CC=2)=O)=CC=1.C1(C)C(S(OC[C@H]2OC2)(=O)=O)=CC=CC=1.C(C1OC1)Br>>[O:19]1[CH2:20][C@H:21]1[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: BrCC1CO1
Agent: Cc1ccccc1S(=O)(=O)OC[C@@H]1CO1
Product: COC(=O)c1ccc(OC[C@@H]2CO2)cc1
Yield: 90 %

Procedure:
The same procedure of Reference Example 4 was repeated except that methyl 4-hydroxybenzoate was used in lieu of benzyl 4-hydroxybenzoate, and (S)-(+)-glycidyl toluenesulfonate was used in lieu of epibromohydrin to give the title compound (yield 90%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:20])([CH2:18]O)[CH2:16][OH:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:9][CH2:10][CH2:11][Cl:12])[O:17][CH2:16][C:15]([CH3:20])([CH3:18])[CH2:14][O:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)(CO)CO
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)COC(CCCCl)(c2ccc(Br)cc2)OC1

Procedure:
10 g (38.2 mmol) of 4′-bromo-4-chlorobutyrophenone, 4 g (38.2 mmol) of 2,2-dimethyl-1,3-propanediol and 200 mg (1 mmol) of p-toluenesulfonic acid monohydrate were heated under reflex in benzene for 3 days to conduct the azeotropic dehydration. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After the extraction with ethyl acetate, the extract was washed with water and saturated aqueous common salt solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[O:14]1[CH:18]([CH2:19][OH:20])[CH:15]1[CH2:16][OH:17]>>[CH2:1]([NH:13][CH:18]([CH:15]([OH:14])[CH2:16][OH:17])[CH2:19][OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: OCC1OC1CO
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNC(CO)C(O)CO

Procedure:
Dodecylamine (185 g, 1.0 mole) was charged into a 500 ml round bottom flask equipped with a stirrer, thermometer (with temperature controller) and powder dropping funnel. Then 2,3-epoxy-1,4 butandiol (26 g, 0.4 moles) was placed in the dropping funnel. The mixture was stirred and heated while epoxide was being added so that suitable dissolution and reaction could occur. Upon completion of such addition the temperature of the reaction mixture was 100° C. The resulting mixture was stirred for 3 hours at 100° C. and distilled with a molecular still at 125° C. and <1 mm to remove excess dodecylamine. The resultant non-volatile product was cooled to give a light tan solid whose IR and NMR spectra were consistent with the formula ##STR8## where n=1.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[C:3]=1[C:4]([NH:6][CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8](O)=[O:9])=[O:5].C(N(C(C)C)CC)(C)C>C1COCC1>[NH2:1][C:2]1[C:3]2[C:4](=[O:5])[NH:6][CH:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8](=[O:9])[NH:22][C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(N)c1C(=O)NC(Cc1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cccc2c1C(=O)NC(Cc1ccccc1)C(=O)N2
Temperature: 50 °C
Reaction time: 17 h

Procedure:
88 mg (0.3 mmol) 2-(2,6-diamino-benzoylamino)-3-phenyl-propionic acid are dissolved in 2 ml THF, combined with 143 mg (0.9 mmol) 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride and 103 μl (0.6 mmol) diisopropyl-ethylamine and stirred for 17 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:34][O:35][C:36](=O)[O-:37]>C(Cl)Cl>[CH3:34][O:35][C:36]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([NH:9][C:10]2([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:2][CH2:3]1)=[O:37]
Reactant: O=C([O-])OCCl
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCN(C(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
Subsequently, 0.98 ml (2.83 mmol) of the phenylmethyl 1-[N-(piperazine-1-carbonyl)amino]cyclohexanecarboxylate and 0.39 ml (2.83 mmol) of triethylamine were dissolved in 20 ml of anhydrous methylenechloride and then 0.21 ml (2.83 mmol) of chloromethylcarbonate was added to the above prepared mixture and stirred for 12 hours at the room temperature. The reaction solution was successively washed with 1N hydrochloric acid, saturated sodium hydrogen-carbonate solution and saturated brine, and dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby 1.12 g of phenylmethyl 1-[N-[4-(methoxycarbonyl)piperazine-1-carbonyl]amino]cyclohexanecarboxylate was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C.[F:16][C:17]1[CH:18]=[C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[CH:20]=[CH:21][C:22]=1[CH:23]=O.[S-2].[Na+].[Na+]>CO.O.Cl>[F:16][C:17]1[CH:18]=[C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[CH:20]=[CH:21][C:22]=1[C:23]1[NH:11][C:10]2[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=2[N:1]=1
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: COc1cccc(-c2ccc(C=O)c(F)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(-c2ccc(-c3nc4c(C(=O)O)cccc4[nH]3)c(F)c2)c1
Temperature: 70 °C

Procedure:
A solution of 2,3-diaminobenzoic acid (0.15 g, 0.824 mmol) in methanol (2 mL) was acidified with acetic acid (0.5 mL) To this mixture was added a solution of 3-fluoro-3′-methoxy-biphenyl-4-carbaldehyde (0.2466 g, 1.0695 mmol) in methanol followed by a solution of cupric acetate (0.183 g, 0.919 mmol) in water (4 mL). The resulting mixture was stirred vigorously and heated to 70° C. for 5 minutes and then filtered hot. The precipitate was washed with water and dissolved in ethanol (5 mL) containing 0.5 mL conc. HCl. A solution of sodium sulphide (0.082 g, 1.0512 mmol) in water was added. The reaction mixture was kept acidic by adding 2-3 drops of conc HCl. The reaction mixture was filtered hot to remove copper sulfide. The pH of the solution adjusted to 4 and diluted with water. The precipitate formed was filtered, washed with water and dried. The residue obtained was purified by column chromatography using 5% methanol in dichloromethane to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33][CH3:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33][CH3:34])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1SC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CSc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Allyl (rac)-4-[4-cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (750 mg, 1.54 mmol) was dissolved in THF (10 ml), and morpholine (201 mg, 2.308 mmol) was added. The reaction solution was saturated with argon (argon was passed through the solution for 30 min). Tetrakis(triphenylphosphine)palladium(0) (7.47 mg, 0.006 mmol) was then added, and the mixture was stirred at RT overnight. Since HPLC showed little conversion, more tetrakis(triphenylphosphine)palladium(0) (7.47 mg, 0.006 mmol) was added and the mixture was stirred at RT for a further 3 h. The content of the flask was then filtered through kieselguhr and the residue was washed with THF. The filtrate was concentrated under reduced pressure and the residue was recrystallized from diethyl ether (15 ml). The crystals were filtered off with suction and dried under high vacuum. This gave 663 mg (96% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([S:9][CH2:10][C:11]3[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][N:12]=3)=[N:8][C:4]=2[CH:3]=1.C([O-])(O)=[O:24].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[Na+].C(OC)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([S:9]([CH2:10][C:11]3[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][N:12]=3)=[O:24])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])O
Reactant: COc1ccnc(CSc2nc3cc(Cl)ccc3[nH]2)c1OC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: COC=O
Product: COc1ccnc(CS(=O)c2nc3cc(Cl)ccc3[nH]2)c1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5-chloro-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (645 mg, 0.0019 mol) was dissolved in 25 ml CH2Cl2 and mixed with NaHCO3 (323 mg, 0.0038 mol) dissolved in 10 ml H2O. The stirred mixture was cooled to 0° C. and treated with MCPBA (84%, 389 mg, 0.0019 mol) dissolved in 6 ml CH2Cl2. After reacting for 10 min the layers were separted and the aqueous layer extracted with 5 ml CH2Cl2. The organic layers wcre combined and extracted with 20 ml water containing NaOH (154 mg, 0.0038 mol). The latter aqueous layer was collected (residual CH2Cl2 distilled off on the rotavapor) and treated with two portions of HCOOCH3 (2×118 μl, 0.0038 mol).
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)C=CC=CC=1.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][C:20]=2[O:19][CH2:18]1>>[N:15]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[NH:9][C:8]([N:30]1[CH2:31][CH2:32][N:27]([CH2:26][C:24]2[CH:23]=[CH:22][C:21]3[O:17][CH2:18][O:19][C:20]=3[CH:25]=2)[CH2:28][CH2:29]1)=[O:16]
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: O=C(Nc1ncccn1)Oc1ccccc1
Product: O=C(Nc1ncccn1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
The title compound was prepared from pyrimidin-2-yl-carbamic acid phenyl ester and 1-benzo[1,3]dioxol-5-ylmethyl-piperazine. 1H NMR (400 MHz, CDCl3): 8.46 (d, J=5.3 Hz, 2H), 7.31 (br s, 1H), 6.85-6.83 (m, 2H), 6.72-6.68 (m, 2H), 5.89 (s, 2H), 3.56 (br s, 4H), 3.45 (bs, 2H), 2.48 (br s, 4H).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].N[C:6]1[CH:7]=[C:8]2[CH2:16][C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[CH2:14][CH2:13][C@@H:12]([OH:25])[C:9]2=[N:10][CH:11]=1.C=O.[C:28](O)(=O)C>C(#N)C>[F:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C@@H:15]1[CH2:14][CH2:13][C@@H:12]([OH:25])[C:9]2=[N:10][CH:11]=[C:6]([N:2]([CH3:1])[CH3:28])[CH:7]=[C:8]2[CH2:16]1
Reactant: Nc1cnc2c(c1)C[C@H](c1cccc(F)c1F)CC[C@H]2O
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)c1cnc2c(c1)C[C@H](c1cccc(F)c1F)CC[C@H]2O
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
SODIUM CYANOBOROHYDRIDE (242 mg, 3.86 mmol) was added to the Acetonitrile (2 mL) solution of (6R,9R)-3-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (56 mg, 0.193 mmol) and FORMALDEHYDE (1 mL, 13.43 mmol) at rt. The reaction was stirred at room temperature for 4 hours. ACETIC ACID (0.5 mL, 8.73 mmol) was added to the reaction mixture (Caution: heat generation was observed to cause acetonitrile reflux) and the reaction was stirred overnight. Volatile was removed mostly via vacuum and the crude was added NaOH (1N), extracted with ethyl acetate twice. The ethyl acetate layer was dried (Na2SO4), filtered and concentrated. Flash column by methanol in CH2Cl2 from 0 to 4% gave the desired product (27.6 mg, 45%). MS (ESI)[M+H+]=319.35.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:7]=1
Reactant: NCCc1ccc(O)cc1
Reactant: Clc1ccnc(Cl)n1
Solvent: CN(C)C=O
Product: Oc1ccc(CCNc2nccc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
2,4 dichloropyrimidine (1.49 g) was dissolved in DMF along with diisopropylethylmine (1.29 g) and tyramine (1.37 g.) The mixture was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water and the organic layer washed with 1 N HCl followed by saturated NaHCO3 and brine. The solvent was removed and the residue subjected to flash chromatography (ethyl acetate as eluent.) 4-[2-(4-Chloro-pyrimidin-2-ylamino)-ethyl]-phenol eluted first and was isolate as a minor product (15% yield.) LC-MS showed the product had the expected M+H+ of 250.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[O:9][C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]1([N:7]2[C:11]([CH3:12])([C:10]([O:13][CH3:14])=[O:9])[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:23][C:8]2=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1oc(=O)n(-c2ccccc2)c1C
Reactant: O=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1(C)C(c2ccccc2)OC(=O)N1c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, in 3 ml of methylene chloride was dissolved 102.6 mg (0.5 mmol) of 3-phenyl-4-methyl-5-methoxy-2(3H)oxazolone, and after the solution was cooled to −78° C., 53.1 mg (0.5 mmol) of benzaldehyde and 0.5 ml (0.05 mmol) of a methylene chloride solution containing 0.1 M-trimethylsilyl triflate were added to the solution and the mixture was reacted under stirring for 1.0 hour. After the temperature of the mixture was raised up to the room temperature, 15 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the resulting reaction mixture and the mixture was extracted with 15 ml of methylene chloride. The organic layer was washed twice with 15 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained concentrated residue was applied to silica gel column chromatography (eluent, hexane:ethyl acetate=10:1 (volume ratio)) to obtain 146.8 mg (0.47 mmol) of diastereomer mixture crude product of 3-phenyl-4-methyl-4-methoxycarbonyl-5-phenyl-2-oxazolidinone as pale yellowish liquid. A diastereomer ratio thereof was 72/28 according to 1H-NMR. Yield based on 3-phenyl-4-methyl-5-methoxy-2(3H)oxazolone was 94.3%.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:5])C.[CH:16]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:18])[CH3:17].Br[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=1>>[CH:16]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=4)[CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[CH:22][CH:21]=1)([CH3:18])[CH3:17]
Reactant: CCOC(=O)c1cc2ccc(Br)cc2[nH]1
Reactant: CC(C)Oc1ccc(Br)cc1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Product: CC(C)Oc1ccc(-c2ccc3cc(C(=O)O)n(-c4ccc(OC(C)C)cc4)c3c2)cc1

Procedure:
The title compound was prepared in accordance with Example 1, using 6-bromoindole-2-carboxylic acid ethyl ester, 4-isopropoxyphenylboronic acid and 4-bromo-1-isopropoxybenzene.