Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].CN(C=O)C.CC(C)([O-])C.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>C(=O)=O.CC(C)=O.C(O)(C)(C)C>[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: Fc1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: O=C=O
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=Cc1cc(O)cc(OCc2ccccc2F)c1
Temperature: -30 °C
Yield: 74.5 %

Procedure:
To a clean, dry 1L flask were added 3,5-dihydroxy benzaldehyde (10 g, 70.9 mmole, 1 eq) and anhydrous DMF (70.9 mL). The mixture was cooled to −70° C. in dry ice/acetone bath while stirring under nitrogen gas. A solution of 1 M tert-butoxide in tert-butanol (70.9 mL) was slowly added drop-wise over 30 min. to the solution while the mixture was allowed to warm to −30° C. The mixture was stirred for ten minutes, then 2-fluorobenzylbromide (13.7 g, 70.9 mmole, 1 eq) was added over 10 min at −30° C. The mixture was stirred at −10° C. for one hour prior to warming to room temperature. The mixture was quenched with 200 mL of saturated ammonium chloride solution. This is an exothermic reaction and the mixture warmed to 45° C. The mixture was filtered by suction onto a 150 mL coarse fritted buchner funnel. The filtrate was added to the material on the funnel. The solid is dried and is a tan to off-white solid (13.0 g, 74.4% yield) of a 1:1 mixture of desired mono-adduct (217a) to undesired bis-adduct (217b). Recrystallization of this material from 1-butanol yields clean product (217a) in the filtrate. Alternatively, flash chromatography can be used to obtain pure product. A white solid (5.2 g, 30% overall yield), was obtained of the desired product (217a). 1H NMR (400 MHz, CDCl3) δ ppm 10.04 (s, 1H), 9.87 (s, 1H), 7.56 (dt, 1H, J=2, 8 Hz), 7.41 (m, 1H), 7.25 (dq, 2H, J=2,8 Hz), 7.04 (dd, 1H, J=1.1, 2.4 Hz), 6.92 (dd, 1H, J=1.1, 2.4 Hz), 6.72 (t, 1H, J=2.3 Hz), 5.17 (s, 2H); Calc'd for C14H11FO3(M+H+)=247; Found 247.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](O)(=O)[C:12]1C(=CC=C[CH:20]=1)C(O)=O.[BH4-].[Na+]>CC(C)=O>[CH:12]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])([CH3:20])[CH3:11]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)Nc1ccccc1C(=O)O

Procedure:
To stirred mixture of 2.7 g. of anthranilic acid and 5.4 g. of phthalic acid in 23 ml. of acetone is added 0.7 g. of powdered sodium borohydride over a period of 30 minutes at 20° C.-30° C. The resulting slurry is then stirred at 35°-40° C. for 4 hours, diluted with 25 ml. of chloroform and filtered. The filtrate is concentrated in vacuo and the residue dissolved in 20 ml. of chloroform and treated with 30 ml. of hexane, filtered and the filtrate concentrated in vacuo to obtain a crude solid product which is recrystallized 5 times from cyclohexane to obtain (second crop of fifth recrystallization) N-isopropylanthranilic acid, m.p. 109°-109.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@@H:24]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][C:26](O)=[O:27])=[CH:19][CH:18]=1.CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[NH:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:26](=[O:27])[CH2:25][C@H:24]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:23][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][CH:21]=2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Reactant: c1ccc2[nH]c([C@@H]3CCCNC3)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCC[C@@H](c2nc3ccccc3[nH]2)C1)Cc1ccc(Br)cc1
Reaction time: 0.08 h
Yield: 75.9 %

Procedure:
(R)-2-(Piperidin-3-yl)-1H-benzo[d]imidazole (5A) (0.29 mmol, 58 mg) in DMF (15 mL) was added (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (0.32 mmol, 115 mg) and N-methylmorphine (1.16 mmol, 0.13 mL). The reaction mixture was stirred at rtfor 5 min and then added HATU (0.32 mmol, 122 mg) and kept stirring at rt overnight. The reaction mixture was poured into H2O, extracted with EtOAc. The extract was washed with H2O, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by preparative LC/MS (35-60% CH3CN in H2O) to afford tert-butyl (R)-4-((R)-3-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(4-bromophenyl)-4-oxobutan-2-ylcarbamate (5B) (0.22 mmol, 120 mg, two-step yield: 75.9%). ESI-MS: m/z 542.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([C:9]([F:12])([F:11])[F:10])[C:3]([F:8])([F:7])[C:4](Cl)=[O:5].N1C=CC=CC=1.[CH:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH2:21].O>ClCCl>[CH2:23]([O:22][CH:20]=[CH:21][C:4](=[O:5])[C:3]([F:8])([F:7])[C:2]([F:13])([F:1])[C:9]([F:12])([F:11])[F:10])[CH2:24][CH2:25][CH3:26]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=COCCCC
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCOC=CC(=O)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -10 °C
Reaction time: 15 h

Procedure:
With stirring and at −10° C., 21.7 g (93.2 mmol) of heptafluorobutyryl chloride—dissolved in 50 ml of dichloromethane—were added to a mixture of 8.11 g (102 mmol) of pyridine and 9.33 g (93.2 mmol) of butyl vinyl ether in 200 ml of dichloromethane. After the addition, stirring was continued at room temperature for another 15 h. 300 ml of water were then added to the mixture, and the organic phase was separated off, dried and concentrated.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11]([O:13]CC)=O)=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[S:3][C:4]([C:11]([Cl:18])=[O:13])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Product: O=C(Cl)c1sc(Cl)nc1C(F)(F)F

Procedure:
A mixture of 36.0 g (0.1554 mole) of the acid of Example 17 and 171 g (1.437 mole) of thionyl chloride were held at reflux for 6 hours. Excess thionyl chloride was removed under reduced pressure and the residue (38.1 g, 98%) was reacted as described in Examples 19-31.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C@H:15]([N:16]([CH3:33])[C:17](=[O:32])[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[CH2:14][CH2:13][N:12]([C:34]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[O:35])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(CC)CC)C.[C:49](Cl)(=[O:51])[CH3:50].[OH-].[Na+]>C(#N)C.O>[C:49]([N:39]1[CH2:40][CH2:41][CH:36]([C:34]([N:12]2[CH2:13][CH2:14][C@@H:15]([N:16]([CH3:33])[C:17](=[O:32])[C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:21]=[C:20]([C:28]([F:29])([F:31])[F:30])[CH:19]=3)[C@H:10]([C:5]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=3)[CH2:11]2)=[O:35])[CH2:37][CH2:38]1)(=[O:51])[CH3:50]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71 %

Procedure:
To a solution of N-[(3R,4R)-3-(3,4-dichlorophenyl)-1-(piperidin-4-ylcarbonyl)piperidin-4-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide monohydrochloride (0.35 g) obtained in Example 89 and triethylamine (0.24 mL) in acetonitrile (10 mL) was added acetyl chloride (0.080 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, the mixture was made basic with 2N aqueous sodium hydroxide solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 75→100% ethyl acetate/hexane) to give the title compound (0.25 g, 71%) as a white crystal powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.[CH3:18][C:19]([NH2:26])([C:21]1[N:25]=[CH:24][O:23][N:22]=1)[CH3:20]>>[CH3:18][C:19]([NH:26][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:6]=1)=[O:17])([C:21]1[N:25]=[CH:24][O:23][N:22]=1)[CH3:20]
Reactant: O=C(O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1
Reactant: CC(C)(N)c1ncon1
Product: CC(C)(NC(=O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1)c1ncon1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (Example 58 c) and 1-methyl-1-[1,2,4]oxadiazol-3-yl ethylamine (CAN 1153757-41-5) as starting materials, MS (EI): m/e=377.0 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=1.[H-].[Na+].[CH3:11][O:12][C:13](=[O:22])[CH:14](Br)[CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[CH3:11][O:12][C:13](=[O:22])[CH:14]([N:5]1[C:4](=[O:8])[CH:3]=[C:2]([I:1])[CH:7]=[N:6]1)[CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=c1cc(I)cn[nH]1
Reactant: COC(=O)C(Br)CC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(I)cc1=O
Temperature: 0 °C
Yield: 68.3 %

Procedure:
A solution of 5-iodopyridazin-3(2H)-one (52 g, 234 mmol) in tetrahydrofuran (1000 mL) was treated with sodium hydride (11.2 g, 280 mmol) at 0° C. The mixture was stirred at 0° C. for 5˜10 min and then stirred at 25° C. for an additional 40˜50 min. At this time, the reaction mixture was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 72.6 g, 281 mmol). The resulting reaction mixture was heated at 50° C. for 18 h and allowed to cool down to 25° C. The reaction mixture was then partitioned between water (500 mL) and methylene chloride (500 mL). The aqueous layer was back extracted with methylene chloride (1×300 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×300 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (8/1 ethyl acetate/petroleum ether) afforded 3-cyclopentyl-2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (60.1 g, 68.3%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24](O)=[O:25])[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][O:29][C:30](=[O:40])[CH:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:32]>CN(C)C=O>[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:32][C:24](=[O:25])[C@H:12]([CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(N[C@H](C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O
Yield: 45.8 %

Procedure:
The process of Example 51 was repeated except that 357 mg (1.00 mmol) of N-benzyloxycarbonyl-(β-benzyl)-L-aspartic acid and 431 mg (2.00 mmol) of D,L-phenylalanine methyl ester hydrochloride were reacted. As a result, a 238 mg amount (yield of 45.8%) of N-benzyloxycarbonyl-(β-benzyl)-L-aspartyl-L-phenylalanine methyl ester having an [α]D20 = -13.2 (C=1.0 dimethylformamide) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.[Cl-].[Na+].O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=[C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:7]2[N:8]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Temperature: 100 °C
Yield: 17.8 %

Procedure:
7-Chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J, 10 g, 55 mmol), phenylboronic acid (7.3 g, 60 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (1.0 g, 1.4 mmol) were mixed in dioxane (120 ml) and saturated NaHCO3 (60 ml). The mixture was then heated at 100° C. for 4 hours. After cooling to room temperature, Brine was added and the mixture was extracted with EtOAc five times. Combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2) to give 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 2.2 g, 18%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ=7.95-7.85 (m, 2H), 7.62-7.50 (m, 3H), 6.70 (s, 2H), 6.22 (s, 1H), 5.81 (s, 1H), 2.24 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[N:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[C:5]2=[N:4][N:3]=1>CO>[CH3:1][C:2]1[N:6]=[C:5]2[N:4]([CH:7]=[N:8][CH:9]=[C:10]2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1
Reactant: Cc1nnc2c(-c3cccc(C(F)(F)F)c3)cncn12
Solvent: CO
Product: Cc1nc2c(-c3cccc(C(F)(F)F)c3)cncn2n1
Reaction time: 168 h

Procedure:
A solution of 0.35 g. of 3-methyl-8-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-c]pyrimidine in 5 ml. of methanol is allowed to stand at room temperature. The rearrangement is monitored by thin layer chromatography and is substantially complete after 7 days. The precipitated product is collected by filtration to give 0.14 g. of the product of the example, m.p. 114°-116° C.
Reaction SMILES: Cl[Si](C)(C)C.[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2[CH2:20][CH2:21][S:22][C:8]1=2.ClN1C(=O)CCC1=O>N1C=CC=CC=1>[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2[CH:20]=[CH:21][S:22][C:8]1=2
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)SCC3
Agent: C[Si](C)(C)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Product: O=C(O)c1ccc2nc3ccsc3c(=O)n2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (2.35 ml, 0.018 mol) is added to a cooled (ice bath) solution of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid (4.5 g, 0.018 mol) in pyridine (35 ml) under nitrogen. The mixture is stirred at ice bath temperature for 1 hour and then allowed to warm at room temperature. N-chlorosuccinimide (2.44 g, 0.018 mol) is added and the mixture is heated at 95° C. for 20 minutes. The mixture is cooled, diluted with ice water (5 ml) and stirred for 15 minutes. The precipitate is filtered, washed with boiling acetone and dried to give the product (3.5 g.) mp 335° C. (dec).
Reaction SMILES: [F:1]/[C:2](=[CH:8]\[C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][C:18]([CH2:20][CH2:21][C:22]3[S:23][CH:24]=[C:25]([CH:27]([CH3:29])[CH3:28])[N:26]=3)=[CH:19][C:12]2=[N:11][C:10]=1[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)/[C:3]([O:5]CC)=[O:4].[OH-].[Li+]>O1CCCC1.CO.O>[F:1]/[C:2](=[CH:8]\[C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][C:18]([CH2:20][CH2:21][C:22]3[S:23][CH:24]=[C:25]([CH:27]([CH3:29])[CH3:28])[N:26]=3)=[CH:19][C:12]2=[N:11][C:10]=1[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)/[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)/C(F)=C/c1c(N2CCOCC2)nc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C(\F)C(=O)O)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
The ethyl (Z)-2-fluoro-3-{8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (28 mg) obtained in (B) was dissolved in tetrahydrofuran (2 ml) and methanol (0.5 ml), added with a solution of lithium hydroxide(5 mg) in water (0.5 ml), and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with water and washed with ether. Then, the aqueous layer was made acidic with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (26 mg) as yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[CH:25]1[CH:30]=[C:29]2[CH:31]=[CH:32][C:33]([OH:46])=[C:34]([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][C:36]=3[OH:45])[C:28]2=[CH:27][CH:26]=1>>[CH:41]1[CH:40]=[C:39]2[CH:38]=[CH:37][C:36]([OH:45])=[C:35]([C:34]3[C:28]4[C:29](=[CH:30][CH:25]=[CH:26][CH:27]=4)[CH:31]=[CH:32][C:33]=3[OH:46])[C:44]2=[CH:43][CH:42]=1.[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:13]2[NH:21][C:20]3[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]=3[N:14]=2)=[O:24])=[N:4][CH:3]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1

Procedure:
In a later publication in Tetrahedron Asymmetry 11 (2000), 1729-1732 the inventors of the above mentioned Chinese patent application reported the resolution of omeprazole using (S)-BINOL. An inclusion complex of (S)-BINOL and (S)-omeprazole was obtained as a grey-blue complex with 90.3% e.e. by mixing racemate omeprazole and (S)-(−)-BINOL in the mole ratio 1:1.5, in a solvent mixture of benzene:hexane (v/v=4:1) at 110° C. The inclusion complex obtained was further purified by recrystallization in benzene:hexane (v/v, 1:1) and separated on a silica gel column to yield (S)-(−)-omeprazole with 98.9% e.e. and 84.1% overall yield. The (S)-(−)-omeprazole so obtained was recrystallized in water to obtain as a white powder with 99.2% e.e.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH:24]=[O:25])([CH2:18][CH2:19]2)[O:16][CH2:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH2:24][OH:25])([CH2:18][CH2:19]2)[O:16][CH2:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Temperature: -78 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a −78° C. solution of 110C compound (35 mg, 0.10 mmol) in DCM (2 mL) was added DIBAL-H (0.16 mL of a 1M solution in toluene; 16 mmol) and the solution was stirred at −78° C. for 2 h. The reaction was quenched with sat′d aq. NaH4Cl and CELITE® (200 mg) was added. The mixture was stirred at rt for 30 min, then was filtered through a 1:1 mixture of CELITE® and MgSO4 and concentrated in vacuo to give the title compound (22 mg, 77% yield). LCMS [M+H]+=339.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:36])[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:37][CH3:38])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1.Br[CH2:40][CH2:41][CH:42]=[CH2:43]>>[CH2:43]([N:11]1[C:10]2[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:20]3[C:21](=[O:36])[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])[C:23](=[O:24])[C:19]=3[C:18]=2[C:17]2[CH:16]=[C:15]([O:37][CH3:38])[CH:14]=[CH:13][C:12]1=2)[CH2:42][CH:41]=[CH2:40]
Reactant: C=CCCBr
Reactant: COc1ccc(CN2C(=O)c3c(-c4ccccc4Cl)cc4[nH]c5ccc(OC)cc5c4c3C2=O)c(OC)c1
Product: C=CCCn1c2ccc(OC)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)N(Cc1ccc(OC)cc1OC)C3=O
Yield: 58.4 %

Procedure:
Reaction of carbazole (287) (260 mg, 0.51 mmol) prepared as described in example 297 with 4-bromo-1-butene (155 □L, 1.53 mmol) according to procedure described in example 298 gave carbazole (289) (173 mg, 58%) as a yellow powder, mp 161–164° C. 1H NMR δ [(CD3)2SO] 8.50 (d, J=2.6 Hz, 1H), 7.89 (s, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.60–7.46 (m, 4H), 7.31 (dd, J=9.0, 2.6 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H), 6.57 (d, J=2.3 Hz, 1H), 6.44 (dd, J=8.4, 2.3 Hz, 1H), 5.84 (m, 1H), 4.96–4.86 (m, 2H), 4.68 (s, 2H), 4.60 (t, J=6.9 Hz, 2H), 3.89 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H), 2.54 (partially obscured m, 2H). Found: C, 70.23; H, 5.15; N, 4.91. C34H29ClN2O5 requires: C, 70.28; H, 5.03; N, 4.82.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O:17][B:18](OC(C)C)[O:19]C(C)C)(C)C.C([Li])(C)(C)C.[OH-].[Na+]>C1COCC1.O>[CH3:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:18]([OH:19])[OH:17])=[CH:3][CH:4]=2)[N:12]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1nc(-c2ccc(Br)cc2)no1
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(B(O)O)cc2)no1
Temperature: -100 °C
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
A solution of 3-(4-bromophenyl)-5-methyl-1,2,4-oxadiazole (1.0 g) in dry THF (8 ml) containing triisopropylborate (3.5 ml, 2.82 g) was cooled to -100° C. under nitrogen, and treated cautiously with tert-butyllithium (8.82 ml, 1.7M solution). The temperature was maintained between -90° C. and -105° C. during addition. The mixture was stirred at -100° C. for 20 mins after complete addition, and then allowed to warm to -30° C. The mixture was treated slowly with water (5 ml) and allowed to warm to room temperature, 2N sodium hydroxide (50 ml) was added and the basic aqueous layer washed with dichloromethane (2×50 ml). The aqueous layer was acidified with 2N hydrochloric acid (60 ml) and extracted with dichloromethane (4×50 ml, containing 20% methanol). The combined, dried extracts were concentrated in vacuo to give the title compound as a pale yellow solid (500 mg). m.p . 266°-268° C.
Reaction SMILES: [NH:1]([C:8]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH:18]=[CH:17][C:9]=1[C:10]([O:12]C(C)(C)C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[NH:1]([C:8]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH:18]=[CH:17][C:9]=1[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(CCc2ccc(C(=O)OC(C)(C)C)c(Nc3ccccc3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(CCc2ccc(C(=O)O)c(Nc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-anilino-4-(2-(3-methoxyphenyl)ethyl)benzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residue was refined in reversed-phase silica gel column chromatography [eluent; 65-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-anilino-4-(2-(3-methoxyphenyl)ethyl)benzoic acid 4.2 mg of a white solid.