Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[C:6]([CH:11]([CH3:16])[C:12]([O:14]C)=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Li+]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[OH:1][CH:2]1[C:10]2[C:5](=[C:6]([CH:11]([CH3:16])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)C(C)c1cccc2c1CCC2O
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1cccc2c1CCC2O
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.3 %

Procedure:
Methyl 2-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)propanoate (2 g, 0.0091 mol) was dissolved in tetrahydrofuran (18 mL). Lithium hydroxide solution (18 mL, 0.018 mol, 1M) was added to it and the reaction mixture was stirred at ambient temperature for 5 hours. TLC (in 60% ethyl acetate in hexane, Rf=0.1) showed complete consumption of starting material. Tetrahydrofuran was removed under reduced pressure and the residue was diluted with water (100 mL). The aqueous part was washed with ethyl acetate (2×100 mL) and acidified with hydrochloric acid (1N, 25 mL). The compound was extracted with ethyl acetate (3×50 mL). The combined organic part was washed with water (2×50 mL) and brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford desired compound (1.6 g, 85% yield).
Reaction SMILES: CO.[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)OCC[O:18]2)[CH:12]=1)([CH3:10])[C:6]([O:8][CH3:9])=[O:7].Cl>O>[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:18])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=1)([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(C)(SC)c1cccc(C2(c3ccccc3)OCCO2)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)C(C)(SC)c1cccc(C(=O)c2ccccc2)c1
Yield: 95 %

Procedure:
Methanol (10 ml) and 1 ml of water were added to 2.52 g of methyl α-methylthio-α-[m-(2phenyl-1,3-dioxa-2-cyclopentyl)phenyl]propionate, and 0.2 ml of conc. hydrochloric acid was added. The mixture was heated for 20 minutes under reflux. After cooling, 20 ml of water was added, and the mixture was extracted with 50 ml and 10 ml respectively of methylene chloride. The extract was washed twice with 10 ml of water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was chromatographed on a column of silica gel using methylene chloride as an eluent to afford 2.10 g of methyl α-methylthio-α-(m-benzoylphenyl)-propionate as a colorless oil in a yield of 95%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[F:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Fc1cccc2cn[nH]c12
Product: CCOC(=O)Cn1cc2cccc(F)c2n1

Procedure:
The title compound was prepared according to the method described for Preparation 93 using 7-fluoro-1H-indazole and ethyl bromoacetate to afford the title compound as an off-white solid in 35% yield, 175 mg.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[SH2:10].[OH-].[Na+].[OH-].[Na+].CO>CO>[SH:10][CH2:1][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[OH:9]
Reactant: S
Reactant: c1ccc(C2CO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OC(CS)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
1-mercapto-2-phenyl-2-ethanol was prepared from 1000 grams of styrene oxide, 567 grams of H2S and 10 mL of a 20 weight % NaOH solution in methanol. These reactants were pumped into a 1 gallon autoclave reactor and heated from 28° C. to 59° C. during a 1-hour period while the pressure rose from about 350 psig to about 500 psig. At the end of the 1-hour period an additional 20 mL of the NaOH in methanol solution was charged to the autoclave and the reaction mixture was reheated to about 60° C. (at 490 psig) during a 2 hour period. Thereafter, 50 mL of the NaOH/methanol solution was charged to the autoclave and the entire reaction mixture was heated to about 100° C. (at 490 psig) during a period of 50 minutes. Then 50 mL of methanol was added to the autoclave and heating at about 100° C. (400 psig) continued for about 1 hour. 1353 grams of the product, 1-mercapto-2-phenyl-2-ethanol, were recovered.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:19]=2)[CH2:10][C:11](=[O:17])[CH2:12][O:13]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([C:7]#[C:8][CH:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:19]=2)[CH2:10][C:11](=[O:17])[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(C#Cc2ccccc2)CC(=O)COC(C)=O)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(C#Cc2ccccc2)CC(=O)CO)cc1OC1CCCC1
Reaction time: 3.5 h
Yield: 24.9 %

Procedure:
A solution of (+/-)-1-phenyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-5-oxo-6-acetoxyhexyne (130 mg, 0.34 mmol) in MeOH (2 ml) was treated with NaOH (0.1 ml of a 2.5N solution), and the mixture was stirred at 23° for 3.5 hr. The reaction was diluted with H2O, and extracted with Et2O. The extracts were washed with H2O, dried, and the solvent removed. Purification by flash chromatography (silica gel, 50% Et2O in CH2Cl2) gave the titled compound as an oil (32 mg, 28%). 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 2 H), 7.32 (m, 3 H), 6.98 (m, 2 H), 6.86 (d, 1 H), 4.80 (m, 1 H), 4.38 (t, 1 H), 4.32 (d, 1 H), 4.14 (d, 1 H), 3.84 (s, 3 H), 3.00 (d of d, 1 H), 2.86 (d of d, 1 H), 1.68-2.00 (m, 6 H), 1.62 (m, 2 H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.[C:32]([C@H:35]1[CH2:40][CH2:39][C@H:38]([C:41]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:42])[CH2:37][CH2:36]1)(=[O:34])[CH3:33]>C1COCC1.O.C(OCC)(=O)C>[OH:34][C:32]([C@H:35]1[CH2:40][CH2:39][C@H:38]([C:41]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:42])[CH2:37][CH2:36]1)([C:19]1[S:20][C:16]([C:14]2[CH:13]=[C:12]([NH:21][C:22]3[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=3)[CH:11]=[C:10]([CH3:9])[CH:15]=2)=[CH:17][N:18]=1)[CH3:33]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: -78 °C

Procedure:
A flask containing THF (78 mL) was cooled to −78° C. LDA (1.8 M in THF/heptane/ethylbenzene, 21.7 mL, 39.1 mmol) was added followed by a solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (2.63 g, 7.82 mmol) in THF (25 mL). The resulting solution was allowed to stir at −78° C. for thirty minutes. A solution of butyl trans-4-acetylcyclohexanecarboxylate (2.65 g, 11.73 mmol) in THF (10 mL) was added in one portion and the solution was stirred for 1 hour at −78° C. The reaction was then diluted with water and allowed to warm to room temperature. The mixture was then diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford racemic butyl trans-4-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylate. MS ESI calc'd. for C28H34F3N4O3S [M+H]+ 563. found 563. 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.83 (d, J=4.9, 1H), 7.98-7.91 (m, 2H), 7.45 (s, 1H), 7.27 (d, J=4.9, 1H), 7.14 (s, 1H), 5.84 (s, 1H), 3.96 (t, J=6.5, 2H), 2.31 (s, 3H), 2.16-2.06 (m, 1H), 1.99-1.79 (m, 2H), 1.64 (s, 1H), 1.58-1.44 (m, 6H), 1.32-1.18 (m, 6H), 1.04 (d, J=13.1, 1H), 0.85 (t, J=7.4, 3H). rhSyk=+++
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:20])[C:14](=[CH:18][CH:19]=2)C(O)=O)[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].CN(C)C=O.[CH2:26]([Cl:28])[Cl:27]>S(Cl)(Cl)=O>[ClH:27].[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:20])[C:14](=[CH:18][CH:19]=2)[CH2:26][Cl:28])[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCNc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCCNc1cccc(-c2ccc(CCl)c(=O)[nH]2)c1
Product: Cl

Procedure:
6-[m-(Propylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid (1.0 g.) is added to 10 ml. thionyl chloride containing 10 drops of dimethylformamide. Solution soon occurs and after a half hour a new solid appears. The mixture is diluted with methylene chloride and the 6-[m-(propylamino)phenyl]-1,2-dihydro-2-oxonicotinyl chloride hydrochloride collected and washed with methylene chloride.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CN1CCCC1=O.[Cl-].[Na+].O>[N:14]1([C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=3[N:3]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: O=[N+]([O-])c1cccc2[nH]c(Cl)nc12
Reactant: c1c[nH]cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cccc2[nH]c(-n3ccnc3)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of 2-chloro-4-nitro-1H-benzimidazole (300 mg) in N-methyl-2-pyrrolidone (4 ml) was added imidazole (517 mg) and the mixture was stirred at 80° C. for 8 hours. The reaction mixture was poured into brine and extracted with a mixture of chloroform and methanol. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol (100-0-30-1) to give 2-(1-imidazolyl)-4-nitro-1H-benzimidazole (175 mg).
Reaction SMILES: C1([CH:7]([S:12]C(C2C=CC=CC=2)C=C(C)C)[CH:8]=[C:9]([CH3:11])[CH3:10])C=CC=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[CH:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:10][C:9]1([CH3:11])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[S:12][CH2:7][CH2:8]1
Reactant: c1ccccc1
Reactant: CC(C)=CC(SC(C=C(C)C)c1ccccc1)c1ccccc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1(C)CCSc2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 15.48 g (86.824 mmol) of phenyl-3-methylbut-2-enylsulfide (from Example 1) in 160 ml benzene were added successively 12.6 g (88.767 mmol) of phosphorus pentoxide and 11 ml of 85% phosphoric acid. This solution was refluxed with vigorous stirring under argon for 20 hours, then cooled to room temperature. The supernatant organic layer was decanted and the syrupy residue extracted with 3×50 ml ether. Organic fractions were combined and washed with water, saturated NaHCO3 and saturated NaCl solutions and then dried (MgSO4). Solvent was removed in vacuo and the residue purified by kugelrohr distillation (80° C., 0.5 mm) to give the title compound as a pale yellow oil. PMR (CDCl3) :δ 1.30 (6H, s), 1.90-1.95 (2H, m), 2.95-3.00 (2H, m), 6.96-7.00 (2H, m), 7.04-7.07 (1H, m), 7.30-7.33 (1H, m).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[NH2:25])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:33][C:34]1[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:35]=1[C:36](Cl)=[O:37].CCOC(C)=O>C1COCC1>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][C:16]=2[NH:25][C:36](=[O:37])[C:35]2[CH:39]=[C:40]([I:43])[CH:41]=[CH:42][C:34]=2[F:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cc(I)ccc1F
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2N)C1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(I)ccc2F)C1
Reaction time: 48 h

Procedure:
In a vial, (R)-2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)benzenamine (.517 g, 1.4 mmol) was taken up in THF. Triethylamine (0.29 ml, 2.1 mmol) and 2-fluoro-5-iodobenzoyl chloride (0.43 g, 1.5 mmol) were added. The vial was sealed and the reaction stirred for 48 h. The reaction mixture was poured into EtOAc/1N NaOH. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was treated with hexanes and passed through a Redi-Sep® pre-packed silica gel column (40 g) eluting with 0-10% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)—N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluoro-5-iodobenzamide as a white foam.
Reaction SMILES: [CH3:1][NH2:2].[N:3]([C:6]1[CH:7]=[C:8]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:9]=[CH:10][CH:11]=1)=[C:4]=[O:5]>O1CCCC1.C(OCC)(=O)C>[CH3:1][NH:2][C:4]([NH:3][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:7]=1)=[O:5]
Reactant: CC1(C)OB(c2cccc(N=C=O)c2)OC1(C)C
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reaction time: 0.08 h

Procedure:
Methyl amine (2.0 M in THF) was added to a solution of 2-(3-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.49 g, 2.0 mmol) and in tetrahydrofuran (6.0 mL) at 0° C. The mixture was stirred at this temperature for 5 min, then at r.t. for 2 h. The mixture was diluted with ethyl acetate, washed with water, 1N HCl aq. and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the desired product which was directly used in next step without further purification. LCMS (M+H)+: m/z=277.1
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:13]#N)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[C:16]1([Mg]Cl)[CH:21]=[CH:20]C=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][N:2]([CH3:15])[C:3]1([C:13]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1
Reactant: Cl[Mg]c1ccccc1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 g 8-dimethylamino-1,4-dioxaspiro[4.5] decane-8-carbonitrile were dissolved in 300 ml tetrahydrofuran, 143 ml 2.0 molar phenyl magnesium chloride solution in THF were added under a nitrogen atmosphere and stirred overnight at ambient temperature. To work up the mixture, 100 ml ammonium chloride solution (20% by weight) were added with ice cooling, the phases were separated, the aqueous phase was extracted twice with 250 ml diethylether in each case, the combined organic phases were dried over sodium sulfate, filtered, concentrated and substantially freed from solvent residues under vacuum. The crude dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]dec-8-yl)amine (34.5 g) obtained was stirred for 48 hours with a mixture of 83 ml concentrated hydrochloric acid (32% by weight) and 48 ml water at ambient temperature without further purification. Subsequently the reaction mixture was first washed three times with 50 ml diethylether in each case, then alkalized by addition of 100 ml sodium hydroxide solution (32% by weight) with ice cooling, extracted three times with 100 ml dichloromethane in each case, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and substantially freed of solvent residues under vacuum. 18.8 g 4-dimethylamino-4-phenylcyclohexanone were obtained.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8]([C:11](=[CH:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>>[CH:1]1([S:4]([C:5]2[CH:6]=[CH:7][C:8]([C:11](=[CH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:10]=2)=[O:32])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CC1CCOCC1)c1ccc(SC2CC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCOC(=O)C(=CC1CCOCC1)c1ccc(S(=O)C2CC2)cc1

Procedure:
Partial oxidation of ethyl 2-(4-cyclopropylsulfanylphenyl)-3-(tetrahydropyran-4-yl)acrylate (see Preparation 22, 3.14 g, 9.44 mmol) with mCPBA, employing the protocol described above in Preparation 18, furnished ethyl 2-(4-cyclopropanesulfinylphenyl)-3-(tetrahydropyran-4-yl)acrylate: m/z (ES+)=349.2 [M+H]+. Sanctification of this ester (1.15 g, 3.3 mmol), using the procedure described in Preparation 25, afforded the title compound: m/z (ES+)=641.4 [2M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])N.[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14](=[O:16])N>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:16])=[O:7].[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:7])=[O:16]
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: N[C@@H](CC(=O)O)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O
Temperature: 95 °C

Procedure:
10 mM L-glutamine or 10 mM L-asparagine in 0.1 M potassium phosphate pH 7.0, respectively, were preheated to 37° C. The resulting assay was started by addition of 50 μl native or 10 μl recombinant enzyme in a total reaction volume of 150 μL and stopped after 10-20 min by addition of 20 μL 3% TCA or by heating at 95° C. for 10 min. A control experiment was carried out without amino acids. Formation of product was followed using HPLC. One unit of enzyme activity was calculated as the amount of enzyme required to produce 1 μM glutamic acid or aspartic acid respectively, at 37° C. per minute.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].Br[C:11]1[CH:12]=[CH:13][C:14]([Cl:21])=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1>>[CH3:7][N:6]([CH2:5][CH:4]1[CH2:14][CH:13]([C:11]2[CH:12]=[CH:13][C:14]([Cl:21])=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:12]2[C:1](=[CH:2][CH:15]=[CH:16][CH:11]=2)[O:3]1)[CH3:8]
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Reactant: CCOC(=O)CN(C)C
Product: CN(C)CC1CC(c2ccc(Cl)c(C(F)(F)F)c2)c2ccccc2O1

Procedure:
The process of example 4 was repeated using N,N-dimethylglycine ethyl ester in place of N,N-dimethylalanine ethyl ester in part (a), and using 5-bromo-2-chlorobenzotrifluoride in place of 4-bromochlorobenzene in part (c) to yield the title compound which was isolated as the hydrochloride salt.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C@H:12]1[C@@H:17]([NH2:18])[C@H:16]2[CH2:19][C@@H:13]1[CH2:14][CH2:15]2)=[O:11])[CH3:8].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:7]([O:9][C:10]([C@H:12]1[C@@H:17]([NH:18][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C@H:16]2[CH2:19][C@@H:13]1[CH2:14][CH2:15]2)=[O:11])[CH3:8]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: O=C1CCCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NC1CCCC1
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
Cyclopentanone (0.12 mL, 1.38 mmol) was added to a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 230 mg, 1.26 mmol) in anhydrous methanol (10 mL) at 25° C. under a nitrogen atmosphere. After stirring for 10 min, glacial acetic acid (0.5 mL) and sodium cyanoborohydride (260 mg, 3.15 mmol) were added sequentially, and the resulting mixture was stirred at 50° C. for 30 min. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, (1S,2R,3S,4R)-3-cyclopentylamino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (237 mg, 0.94 mmol, 75%), as a yellow oil. LC-MS (ESI) calcd for C15H25NO2 251.19, found 252.0 [M+H+].
Reaction SMILES: [CH2:1]([N:8]([C:15]([C:17]1([CH2:20][NH:21][C:22]([O:24]C(C)(C)C)=O)[CH2:19][CH2:18]1)=[O:16])[C@H:9](C(OC)=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C@@H:9]([CH3:10])[C:22](=[O:24])[NH:21][CH2:20][C:17]2([CH2:19][CH2:18]2)[C:15]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](C)N(Cc1ccccc1)C(=O)C1(CNC(=O)OC(C)(C)C)CC1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C(=O)NCC2(CC2)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.8 g (7.2 mmol) 2-1 in 75 mL CH2Cl2 and 5 mL TFA was allowed to stir at room temperature overnight. The solvents were removed by rotary evaporation, the residue was basified with saturated aqueous Na2CO3, and extracted with three portions of 2:1 CHCl3/EtOH. The organic extracts were concentrated, redissolved in CH2Cl2, filtered and concentrated to provide a brown oil. This material was dissolved in 75 mL of toluene, cooled to 0° C. and 8.4 mL (16.9 mmol) of a 2 M solution of AlMe3 in toluene was added dropwise. The reaction was allowed to slowly warm to room temperature overnight with stirring. An additional 2 mL of AlMe3 was added and stirring was continued for an additional 24 h. The reaction was cooled to 0° C., carefully quenched with 100 mL of 1M HCl, and extracted with 3 portions of EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to provide 2-2 as a white taffy. Data for 2-2: LC/MS: rt=1.38 min; m/z (M+H)=258.1. found; 258.1 required.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH:18](C)C.O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:18][C:6]1[N:5]([CH2:4][CH:3]=[O:2])[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: COC(=O)c1cccc2nc(C(C)C)n(CC(OC)OC)c12
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2nc(C)n(CC=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a stirred solution of methyl 1-(2,2-dimethoxyethyl)-2-isopropyl-1H-benzo[d]imidazole-7-carboxylate from Step A above in methylene chloride were added water and trifluoroacetic acid and the reaction was stirred at room temperature for 2 h and then heated at reflux for 3.5 h. The reaction mixture was concentrated under reduced pressure to remove the excess trifluoroacetic acid, diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 2-methyl-1-(2-oxoethyl)-1H-benzo[d]imidazole-7-carboxylate (0.4 g, 56%): 1H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.81 (dd, J=8.0, 1.5 Hz, 1H), 7.67 (dd, J=7.5, 1.0 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 5.38 (s, 2H), 3.84 (s, 3H), 2.47 (s, 3H); MS (ESI+) m/z 233 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[N:10]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:19][C:18]=1[O:32][CH2:33][CH2:34][F:35])[C:9]2=[O:36])=[O:5])C.C[O-].[Na+]>CO>[F:35][CH2:34][CH2:33][O:32][C:18]1[CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:21]=[CH:22][C:17]=1[N:10]1[C:9](=[O:36])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([O:3][CH3:1])=[O:5])[CH:7]=2)[N:12]=[C:11]1[CH3:16]
Reactant: CCOC(=O)c1ccc2nc(C)n(-c3ccc(OCCCN4CCCC4)cc3OCCF)c(=O)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2nc(C)n(-c3ccc(OCCCN4CCCC4)cc3OCCF)c(=O)c2c1

Procedure:
6-ethoxycarbonyl-3-{2-fluoroethoxy-4-[3-(1-pyrrolidinyl)propoxy]-phenyl}-2-methyl-4(3H)-quinazolinone synthesized in Example 205 was treated by sodium methoxide in dry methanol, and the title compound was thus obtained.