Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-:4])C.[K+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][O:16][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:18]>>[CH3:15][O:16][C:17]([CH:19]1[CH:23]([CH2:24][S:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:22][CH2:21][C:20]1=[O:4])=[O:18]
Reactant: CCCCCCC(=O)OC
Reactant: CC(C)(C)[O-]
Reactant: SCc1ccccc1
Agent: [K+]
Product: COC(=O)C1C(=O)CCC1CSCc1ccccc1
Yield: 78 %

Procedure:
In accordance with the process of Example 16, potassium t-butoxide (336 mg; 3 m mol), benzyl mercaptan (372 mg; 3 m mol) and 2-oxo-bicyclo 3.1.0! hexane-1-carboxylic acid methyl ester (463 mg; 3 m mol) were used in the reaction, and the reaction product was purified by a silica gel column chromatography with ethyl acetate and n-hexane (1.5; 8.5) to obtain 650 mg of 5-benzylthiomethyl-2-oxo-cyclopentanecarboxylic acid methyl ester as an oil.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:4]1([CH:3]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:1](=[O:10])[CH2:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccccc1
Product: O=C1CC(c2ccccc2)c2ccccc2N1

Procedure:
4-Phenyl-3,4-dihydrocarbostyril (CAS #4888-33-9) was prepared in two steps using the procedure described by Conley, R. T.; Knopka, W. N. J. Org. Chem. 1964, 29, 496-497. The starting materials for this preparation were cinnamoyl chloride (Aldrich) and aniline (Aldrich). The title compound was purified by flash chromatography eluting with CH2Cl2/EtOAc (4:1).
Reaction SMILES: C([O:9][C:10]1[CH:15]=[C:14]([I:16])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH:26]([CH3:28])[CH3:27])[CH:19]=2)=[C:12]([I:29])[CH:11]=1)(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>CO.O>[I:16][C:14]1[CH:15]=[C:10]([OH:9])[CH:11]=[C:12]([I:29])[C:13]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH:26]([CH3:27])[CH3:28])[CH:19]=1
Reactant: COc1ccc(Oc2c(I)cc(OC(=O)c3ccccc3)cc2I)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(Oc2c(I)cc(O)cc2I)cc1C(C)C
Reaction time: 24 h
Yield: 96.8 %

Procedure:
A mixture of 3,5-diiodo-4-(4′-methoxy-3′-iso-propylphenoxy)phenyl benzoate (0.10 g, 0.16 mmol) and 1 N NaOH (0.81 mL, 0.81 mmol) in methanol (1.63 mL) was at room temperature for 24 h. The reaction mixture was neutralized with 2 N HCl, diluted with H2O and extracted with CH2Cl2 (10 mL×2). The organic layers were concentrated under reduced pressure and the crude product was purified preparatory TLC with acetone-hexanes (1:4) as mobile phase to afford 3,5-diiodo-4-(4′-methoxy-3′-iso-propylphenoxy)phenol as an off-white solid (0.079 g, 95%): 1H NMR (300 MHz, DMSO-d): δ 9.99 (s, 1 H), 7.28 (s, 2 H), 6.81 (d, J=12.0 Hz, 1 H), 6.67 (d, J=3.0 Hz, 1 H), 6.30 (m, 1 H), 3.72 (s, 3 H), 3.18 (m, 1 H), 1.11 (d, J=6.9 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (7:3); Rf=0.42.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[C:22]([C:26]1[CH:27]=[C:28](O)[CH:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:31]=1)([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[Br:20][C:28]1[CH:27]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=1
Reactant: BrBr
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1

Procedure:
A 1000 mL three-neck, round-bottom flask was equipped with a mechanical stirrer, a pressure-compensating dropping funnel, and a reflux condenser. A nitrogen gas flow adapter with overpressure valve was attached on top of the reflux condenser. A slight nitrogen flow guaranteed an inert gas atmosphere in the apparatus. The flask was charged with 181 g triphenylphosphine (690 mmol) and 160 mL acetonitrile (HPLC grade). The white suspension was cooled in an ice bath for 15 minutes. While stirring, dropwise addition of 101.5 g bromine (635 mmol) took place within 40 minutes. After bromine addition, the ice bath was removed. 124 g of 3,5-di-tertbutylphenol (601 mmol) and 140 mL acetonitrile were added in one portion. The orange/white suspension converted into an orange solution upon heating. The mechanical stirrer was replaced by an egg-shape stir bar. The solution was stirred at gentle reflux temperature for three hours.
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][OH:14])=[C:10]([CH3:20])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:21])=[N:7]2.CC(C)=[O:24]>O>[Br:1][C:2]1[C:11]([C@H:12]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:13]([OH:24])=[O:14])=[C:10]([CH3:20])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:21])=[N:7]2
Reactant: Cc1ccc2c(Br)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Reactant: CC(C)=O
Solvent: O
Product: Cc1ccc2c(Br)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethanol (38 g, 108 mmol) in acetone (500 mL) was added RuCl3.3H2O (2.83 g, 10.83 mmol) followed by NaIO4 (116 g, 540 mmol) in H2O (400 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product. LCMS-ESI+: calc'd for C17H20BrNO3: 366.1 (M+H+); Found: 366.0 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])(C)C.[CH:17](=[O:19])[CH3:18]>S(=O)(=O)(O)O>[CH3:11][C:9]1[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([CH:1]([C:18]2[CH:1]=[C:5]([CH3:10])[CH:6]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:17]=2[OH:19])[CH3:4])[CH:10]=1
Reactant: CC=O
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(C(C)c2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reaction time: 1 h
Yield: 70.4 %

Procedure:
Into the reactor described in the foregoing Example 1 there are charged 220 g (1.0 g-mol) of 2,6-ditert.butyl-4-methylphenol, 2.2 g of sulfuric acid and 44 g (1 g-mol) of acetaldehyde are fed into the reactor for one hour at the temperature of 125° C. On completion of the reaction, the reaction mass is treated following the procedure described in the foregoing Example 1 to give 124.6 g of 1,1,-bis-(5-methyl-3-tert.butyl-2-hydroxyphenyl)ethane which constitutes 96.4% of theory, as calculated for the reacted 2,6-ditert.butyl-4-methylphenol (conversion of the latter is 73%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.C(O)C>CCCCCC>[CH2:19]([O:18][C:16](=[O:17])[C:15](=[CH:14][NH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:20]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOc1ccc(N)cc1
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ccc(OCC)cc1)C(=O)OCC

Procedure:
The preparation was the same as in example 1. But one equivalent of p-Phenetidine was used instead of p-Anisidine and one equivalent of diethyl ethoxymethylenemalonate was used instead of dimethyl methoxymethylenemalonate. Ethanol was replaced by hexane. 21 g of the title compound was obtained which is a white solid melting at 55-56° C., UV 329 nm (E=802).
Reaction SMILES: C[O:2]C1C=CC(C2[O:8][C:9]3[C:14]([C:15](=[O:17])[CH:16]=2)=[C:13]([O:18][CH3:19])[C:12]([O:20][CH3:21])=[C:11]([O:22][CH3:23])[CH:10]=3)=CC=1.OC1C(C(=O)C=[CH:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:38][CH:37]=2)=C(OC)C(OC)=C(OC)C=1>>[OH:8][C:9]1[C:14]([C:15](=[O:17])[CH3:16])=[C:13]([O:18][CH3:19])[C:12]([O:20][CH3:21])=[C:11]([O:22][CH3:23])[CH:10]=1.[CH2:43]([O:42][C:39]1[CH:40]=[CH:41][C:36]([CH:35]=[O:2])=[CH:37][CH:38]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COc1cc(O)c(C(=O)C=Cc2ccc(OCc3ccccc3)cc2)c(OC)c1OC
Reactant: COc1ccc(-c2cc(=O)c3c(OC)c(OC)c(OC)cc3o2)cc1
Product: COc1cc(O)c(C(C)=O)c(OC)c1OC
Product: O=Cc1ccc(OCc2ccccc2)cc1

Procedure:
Similar to the preparation of 1c, 1e (4′-benzyloxy-5,6,7-trimethoxyflavone) was prepared from 6-hydroxy-1-(4-benzyloxycinnamoyl)-2,3,4-trimethoxybenzene (6b), which, in turn, was obtained from the reaction of the acetophenone 5 and 4-benzyloxybenzaldehyde. A solution of 1e (500 mg, 1.20 mmol) in 48% HBr (5 mL) and glacial acetic acid (10 mL) was refluxed for 2 h. Then, the reaction mixture was poured onto crushed ice (ca. 100 g). The resulting precipitate was filtered and washed with water. Recrystallization from ethanol furnished compound 1f (305 mg, 85%). 1H NMR (DMSO, 200 M Hz) δ 12.63 (br s, 1H), 10.30 (br s, 1H), 8.70 (br s, 1H), 7.93 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 6.88 (s 1H), 6.78 (s 1H), 3.90 (s, 3H); 13C NMR (DMSO, 50 M Hz) δ 182.2 (s), 163.8 (s), 161.1 (s), 154.3 (s), 149.6 (s), 146.2 (s), 129.9 (s), 128.4 (d, 2C), 121.4 (s), 116.0 (d, 2C), 105.0 (s), 102.5 (d), 91.1 (d), 56.3 (q). The stereochemistry of compound 1f was confirmed by cosy and nosy experiments.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=3)=[N:8][C:7]=12)[CH3:2].Cl.[NH:27]1[CH2:30][CH:29]([C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=3)[NH:34][N:35]=2)[CH2:28]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[CH2:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([C:18]3[CH:25]=[CH:24][C:21]([CH2:22][N:27]4[CH2:28][CH:29]([C:31]5[N:32]=[C:33]([C:36]6[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=6)[NH:34][N:35]=5)[CH2:30]4)=[CH:20][CH:19]=3)=[N:8][C:7]=12)[CH3:2]
Reactant: Cc1cccc(-c2nc(C3CNC3)n[nH]2)n1
Reactant: CCc1cnn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCc1cnn2cc(-c3ccccc3)c(-c3ccc(CN4CC(c5n[nH]c(-c6cccc(C)n6)n5)C4)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
A mixture of 142 mg (0.43 mmol) 4-(3-ethyl-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-benzaldehyde and 314 mg (0.65 mmol, ca 60% pure) 2-(5-azetidin-3-yl-2H-[1,2,4]triazol-3-yl)-6-methyl-pyridine hydrochloride salt in 3.65 mL NMP was treated with 0.146 mL triethylamine and 0.045 mL acetic acid and stirred overnight at rt. The mixture was treated with 101 mg sodium triacetoxyborohydride and stirred overnight at rt. The reaction was partitioned between DCM and saturated sodium hydrogencarbonate solution, the organic phase dried and concentrated in vacuo and the residue purified by preparative reverse phase HPLC to give 49 mg of the title compound contaminated with formic acid.
Reaction SMILES: Cl.[C:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:18]=1.C(N(CC)CC)C.O>O1CCCC1>[C:2]([CH:10]1[CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[N:18]=2)[CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCC(C(=O)c3ccccc3)CC2)nc(-c2ccncc2)cc1=O
Yield: 89 %

Procedure:
A solution of 4-benzoylpiperidine hydrochloride (903 mg, 4.00 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (666 mg, 3.00 mmol) and triethylamine (2.0 ml, 15 mmol) in tetrahydrofuran (30 ml) was refluxed for several hours. After cooling, water was added to the reaction mixture. The precipitate was filtered, washed with water and dried to give the title compound (1.00 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5](SC)=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:16]1C=CC=C(C(OO)=O)C=1.[S:26]([O-:30])([O-])(=[O:28])=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[NH2:1][C:2]1[S:6][C:5]([S:26]([CH3:16])(=[O:30])=[O:28])=[N:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S([O-])([O-])=S
Reactant: CSc1nc(-c2ccccc2)c(N)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1nc(-c2ccccc2)c(N)s1
Temperature: 0 °C
Yield: 26 %

Procedure:
To 5-amino-2-(methylsulfanyl)-4-phenylthiazole (302 mg, 1.36 mmol) in dichloromethane (5.0 ml) was added portionwise 3-chloroperbenzoic acid (638 mg, 77% wt, 2.9 mmol) with cooling to 0° C. The mixture was diluted with dichloromethane (3.0 ml) and after 5 min allowed to warm to ambient temperature. After 3 hr a further quantity of 3-chloroperbenzoic acid (305 mg, 77% wt, 1.4 mmol) was added portionwise. After 20 hr the mixture was treated with sodium thiosulfate (2 ml, 1.0 M), poured into saturated aqueous sodium bicarbonate and extracted three times into dichloromethane (total 100 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo to give a dark brown foam. Flash chromatography on silica gel (ethyl acetate/hexanes) yielded pure 5-amino-2-(methylsulfonyl)-4-phenylthiazole (90 mg, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:19])[CH3:18]>>[ClH:1].[ClH:1].[CH:17]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[N:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CCNCC1
Reactant: CC(=O)c1ccc(-c2ccc(Cl)nc2)cc1
Product: CC(=O)c1ccc(-c2ccc(N3CCN(C(C)C)CC3)nc2)cc1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(4-acetylphenyl)pyridine and 1-isopropylpiperazine.
Reaction SMILES: Cl.C[O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]([O:17]C)=[O:16])[CH:9]=1)[NH2:6].[CH:20]1([N:26]2[C:30]3[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[CH:34][C:29]=3[N:28]=[C:27]2[C:38]2[CH:42]=[CH:41][O:40][CH:39]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:4]([CH:5]([NH:6][C:35]([C:33]1[CH:32]=[CH:31][C:30]2[N:26]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:27]([C:38]3[CH:42]=[CH:41][O:40][CH:39]=3)=[N:28][C:29]=2[CH:34]=1)=[O:36])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH:9]=1)[C:15]([OH:17])=[O:16])([OH:3])=[O:19]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: COC(=O)c1cc(C[C@H](N)C(=O)OC)ccc1O
Agent: Cl
Product: O=C(NC(Cc1ccc(O)c(C(=O)O)c1)C(=O)O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
Racemic 3-(carbomethoxy)tyrosine methyl ester hydrochloride (example 119) was coupled to the carboxylic acid of example 2 in the usual manner and saponified to give the title compound of example 121.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:17](=[O:39])[NH:18][C@H:19]([C:28](=[O:38])[NH:29][C:30]1[S:31][CH:32]=[C:33]([C:35](=[O:37])[CH3:36])[N:34]=1)[C@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:35]([C:33]1[N:34]=[C:30]([NH:29][C:28](=[O:38])[C@@H:19]([NH:18][C:17](=[O:39])[C@H:8]([NH2:7])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@H:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:21])[S:31][CH:32]=1)(=[O:37])[CH3:36]
Reactant: COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)Nc2nc(C(C)=O)cs2)[C@@H](C)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc([C@@H](N)C(=O)N[C@H](C(=O)Nc2nc(C(C)=O)cs2)[C@@H](C)c2ccccc2)cc1
Reaction time: 1 h
Yield: 111.3 %

Procedure:
[(R)-[(1S,2S)-1-(4-Acetyl-thiazol-2-ylcarbamoyl)-2-phenyl-propylcarbamoyl]-(4-methoxy-phenyl)-methyl]-carbamic acid tert-butyl ester (3.1 g, 5.2 mmol) was stirred in dichloromethane (50 mL) in an ice-bath. Trifluoroacetic acid (50 mL) was added and the solution was stirred for 1 hour. The reaction mixture was evaporated and the residue was precipitated with hexanes/ether. The mixture was stirred vigorously for 10 minutes and then filtered. The solid was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organic extracts were washed with brine and dried (sodium sulfate). Evaporation of the solvents gave (2S,3S)-N-(4-acetyl-thiazol-2-yl)-2-[(R)-2-amino-2-(4-methoxy-phenyl)-acetylamino]-3-phenyl-butyramide (2.7 g, 90% pure) as a white solid.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].N1C=CC=CC=1.[Cl:11][C:12]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:13]=1[O:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][C:20](=[CH:24][CH2:25][CH3:26])[C:21](Cl)=O)=[CH:17][CH:16]=1.[OH2:34]>C1C=CC=CC=1>[Cl:11][C:12]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:13]=1[O:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]([CH3:21])[CH:24]=[CH:25][C:26]([O:4][CH2:1][CH:2]=[CH2:3])=[O:34])=[CH:27][CH:28]=1
Reactant: CCC=C(Oc1ccc(Oc2ccc(Br)cc2Cl)cc1)C(=O)Cl
Reactant: C=CCO
Reactant: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C=CCOC(=O)C=CC(C)Oc1ccc(Oc2ccc(Br)cc2Cl)cc1

Procedure:
In a mixture of 70 ml of benzene, 2.1 g (0.030 mole) of allyl alcohol and 2.6 g (0.033 mole) of pyridine, 12.5 g (0.03 mole) of [4-(2-chloro-4-bromophenoxy) phenoxy]2-pentenoic chloride obtained in the previous Preparation was added to react them at room temperature. Water was added to the reaction mixture and the benzene phase was washed with water and dehydrated over anhydrous sodium sulfate and benzene was distilled off to obtain 11.5 g of an orange viscous liquid having ND20 :1.5757 (yield 87.3%).
Reaction SMILES: COC[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[O:14][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:12](C(O)=O)[C:11]2=[O:25].C1(P([N:40]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl.O1CCOCC1>C(O)(C)(C)C>[NH2:40][C:12]1[C:11](=[O:25])[C:10]2[C:15](=[C:6]([CH2:5][OH:4])[CH:7]=[CH:8][CH:9]=2)[O:14][C:13]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCOCc1cccc2c(=O)c(C(=O)O)c(-c3ccccc3)oc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: Nc1c(-c2ccccc2)oc2c(CO)cccc2c1=O

Procedure:
8-Methoxymethoxymethylflavone-3-carboxylic acid was reacted with diphenylphosphoryl azide and then with t-butanol. The resultant product was hydrolyzed with aqueous hydrochloric acid-dioxane to give 3-aminoflavone-8-methanol.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[N:13][C:14]=1Cl>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[N:13][C:14]=1[O:7][CH2:6][CH:3]1[CH2:5][CH2:4]1
Reactant: OCC1CC1
Reactant: O=C(O)c1ccc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccc(Cl)c(OCC2CC2)n1
Temperature: 95 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
Sodium hydride (CAN 7646-69-7, 60% w/w, 1.05 g, 26 mmol) was added to cyclopropylmethanol (CAN 2516-33-8, 7.5 g) at 0° C. and the mixture was stirred for 1 h. 5,6-Dichloro-pyridine-2-carboxylic acid (1 g, 5 mmol) was added and the mixture was heated to 95° C. for 3 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and adjusted to pH=3.0 by hydrochloric acid (3 N). The solution was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (3×30 mL) and brine (2×40 mL) and evaporated to dryness to give the crude product (0.35 g, 25%), which was used in the next step without further purification, MS (EI): m/e=228.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O.C(O)(C(F)(F)F)=O>>[CH:13]1([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH2:2][NH:1]1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 9.4 %

Procedure:
This product was prepared using the same procedure as for intermediate 1 with tryptamine (2.8 g, 17.4 mmol), 4-formylbenzoic acid, methyl ester (2.87 g, 1.1 equiv.) and TFA (2.7 mL, 2 equiv.) to give the title compound (0.5 g, 9%) as white crystals after recrystallization from isopropanol:H2O.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:12](=[O:21])[NH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1.[N+:22](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C=O)C>[NH2:22][N:13]1[C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=2[Cl:3])[C:12]1=[O:21]
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=c1[nH]c(C(F)(F)F)ccc1-c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nn1c(C(F)(F)F)ccc(-c2ccc(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
10 ml of DMF was added to 0.10 g of 60% sodium hydride, and 0.72 g of 3-(2,4-dichlorophenyl)-6-trifluoromethyl-2(1H)-pyridone was added thereto under cooling with ice, followed by stirring further at room temperature for 30 minutes. Then, 0.47 g of 2,4-dinitrophenoxyamine was added thereto at room temperature. Then, the mixture was stirred at 50° C. for 1 hour to complete the reaction. After completion of the reaction, the reaction solution was washed with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off to obtain a crude product. This crude product was purified by silica gel column chromatography to obtain 0.50 g (yield: 68%) of the desired product. Melting point: 98-100° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(C(C)C)CC)(C)C.[NH2:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[C:38]1([CH:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:30][C:6]([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[O:8])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(O)c1c[nH]cn1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC(c1ccccc1)c1ccccc1)c1c[nH]cn1
Temperature: 35 °C
Reaction time: 48 h

Procedure:
A mixture of 11.7 g of 4-imidazolecarboxylic acid, 18.7 g of 1,1'-carbonyldiimidazole, 20 ml of diisopropylethylamine and 600 ml of DMF was heated at 35° C. for approximately 18 hours. Twenty milliters of aminodiphenylmethane were added and the solution stirred at 35° C. for approximately 21/2 days The mixture was concentrated in vacuo and the residue added to 400 ml of water. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated n vacuo. Two crystallizations from hot ethyl acetate/hexane provided 11 grams of the desired titled intermediate, m.p. 201°-202° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][C@H:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH:6]1[O:8][CH2:7]1.[NH3:18].CO>>[CH3:1][CH:2]([CH3:17])[CH2:3][C@H:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH:6]([OH:8])[CH2:7][NH2:18]
Reactant: N
Reactant: CC(C)C[C@@H](CC1CO1)NC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)C[C@@H](CC(O)CN)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 36 h

Procedure:
(S)-[3-Methyl-1-(2,3-epoxypropyl)butyl]carbamic acid, 1,1-dimethylethyl ester (3.6 g., 15.7 mmole) is added to a solution of saturated ammonia/methanol (100 ml.) and stirred for 36 hours at room temperature. The reaction mixture is concentrated into a solid residue of 3.8 g. of (1S)-[3-methyl-1-(3-amino-2-hydroxypropyl)butyl]carbamic acid, 1,1-dimethylethyl ester; m.p. (76°) 90-92°.