Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([NH:19][C:20]([C:22]3[N:23]=[CH:24][O:25][C:26]=3[C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[O:21])[CH:16]=[N:15]2)[N:4]=1.[H-].[Na+].Br[CH2:37][CH3:38].O>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([N:11]([CH2:37][CH3:38])[CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([NH:19][C:20]([C:22]3[N:23]=[CH:24][O:25][C:26]=3[C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[O:21])[CH:16]=[N:15]2)[N:6]=1
Reactant: COc1cc(OC)nc(NCCn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)n1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CCn1cc(NC(=O)c2ncoc2-c2cccc(C)c2)cn1)c1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled solution of N-(1-(2-((4,6-dimethoxypyrimidin-2-yl)amino)ethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (80 mg, 0.178 mmol) in DMF (1 mL) was added NaH (12 mg, 0.27 mmol). The icebath was removed and the mixture was stirred for 40 min at rt, then 1-bromo ethane (20 uL, 0.25 mmol) was added and stirred for 18 h at rt. To the reaction mixture was added few drops of water and directly purified by prep. HPLC. LC-MS conditions D: tR=1.19 min, [M+H]+=478.3
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[N:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25]1.O.C(Cl)Cl>CS(C)=O.CCOC(C)=O>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[CH2:11][N:10]1[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[N:3]=[C:2]1[N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25]1
Reactant: CCOC(=O)C1CCCNC1
Reactant: Cn1c(=O)c2c(nc(Br)n2Cc2c(F)cccc2Cl)n(C)c1=O
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCN(c2nc3c(c(=O)n(C)c(=O)n3C)n2Cc2c(F)cccc2Cl)C1
Temperature: 100 °C
Yield: 88.3 %

Procedure:
A solution of 8-bromo-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (6.0 g, 0.015 mol) in 30 mL of DMSO was treated with (+/−)-ethyl piperidine-3-carboxylate (11.7 g, 0.075 mol) and heated at 100° C. for 15 h. The reaction was cooled to room temperature and treated with H2O and CH2Cl2. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were washed with H2O, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, Merck 20×20 cm silica gel 60 F254) eluting with 7:3/hexanes:EtOAc to give 6.33 g (88% yield) of the title compound: 1H NMR (CDCl3, 400 MHz) δ 7.20 (dt, 2H, J=8.1, 5.7), 7.14 (t, 1H, J=7.6), 6.98-6.90 (m, 1H), 5.57 (AB quartet, 2H, J=15.7, 5.7), 4.18-4.00 (m, 2H), 3.51 (s, 3H), 3.42 (dd, 1H, J=12.6, 4.0), 3.30 (s, 3H), 3.18 (br d, 1H), 3.06 (dd, 1H, J=12.4, 10.0), 2.91-2.83 (m, 1H), 2.52-2.41 (m, 1H), 2.03-1.92 (m, 1H), 1.75-1.66 (m, 1H), 1.63-1.40 (m, 2H), 1.21 (t, 3H, J=7.1); LRMS (ESI) m/z 478 (M+H+); TLC (hexanes:EtOAc/7:3) Rf=0.20.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:11]([O:13][C:14]([C:16]12O[CH:19]([CH:20]=[CH:21]1)[CH2:18][CH2:17]2)=[O:15])[CH3:12].[Cl-].[NH4+].[O:25]1CCCC1>>[OH:25][CH:20]1[CH2:21][C:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])=[CH:17][CH:18]=[CH:19]1
Reactant: C1CCOC1
Reactant: CCOC(=O)C12C=CC(CC1)O2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Product: CCOC(=O)C1=CC=CC(O)C1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution (10.72 ml, 1.0 mol/l, 10.72 mmol) of lithium hexamethyldisilazide in tetrahydrofuran was added tetrahydrofuran (60 ml), and the mixture was cooled to −78° C. To this solution was added dropwise a solution of 2-15 ethoxycarbonyl-7-oxabicyclo[2.2.1]hept-5-ene (a mixture of exo form:endo form=7:3, 1.64 g, 9.75 mmol, obtained in Reference Example 1) in tetrahydrofuran (12 ml). After the dropwise addition, the mixture was heated to 0° C. and stirred for 1.5 h. To this reaction mixture was added saturated aqueous ammonium chloride solution (50 ml), and the mixture was extracted with chloroform (100 ml). The organic layer was partitioned, washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate. The components having a low boiling point, such as the solvent and the like, were distilled away. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/5 (volume ratio)) to give ethyl 5-hydroxy-1,3-cyclohexadiene-1-carboxylate (1.52 g, 9.06 mmol, yield 93.9).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=[O:6])C=1C#N)#N.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][C:25]2[S:40][C:28]3[N:29]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:30](=[O:35])[N:31]([CH3:34])[C:32](=[O:33])[C:27]=3[C:26]=2[C:41]([N:43]([O:45][CH3:46])[CH3:44])=[O:42])=[CH:16]1>C1COCC1.O>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]([C:25]2[S:40][C:28]3[N:29]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:30](=[O:35])[N:31]([CH3:34])[C:32](=[O:33])[C:27]=3[C:26]=2[C:41]([N:43]([O:45][CH3:46])[CH3:44])=[O:42])=[O:6])=[CH:16]1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CON(C)C(=O)c1c(Cc2c[nH]c3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1c(C(=O)c2c[nH]c3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
DDQ (0.25 g) was added to a stirred solution of the product of example 4 (0.25 g) in THF (9 ml) and water (1 ml). The solution was stirred for a further 2 h and the concentrated in vacuo. The residue was purified by flash silica chromatography eluting with ethyl acetate:isohexane (7:3) to give the title compound as a pale pink solid (0.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH:22]=O.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:14]1[NH:15][C:16]2[C:21]([C:13]=1[CH3:12])=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-2-oxindole (212 mg), 3-methyl-indole-2-carbaldehyde (190 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 5-bromo-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>>[O:31]=[C:26]1[NH:27][C:28](=[O:30])[C:29](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:10]=3)=[CH:7][CH:8]=2)[S:25]1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(-c2cccc(CNC(=O)c3ccccc3)c2)cc1
Product: O=C1NC(=O)C(=Cc2ccc(-c3cccc(CNC(=O)c4ccccc4)c3)cc2)S1
Yield: 90.5 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 1 g (3.2 mmol) of N-(4′-formylbiphenyl-3-ylmethyl)benzamide with 370 mg (3.2 mmol) of 2,4-thiazolidine dione, 1.2 g (93%) of expected product are obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:13][C:14]1[CH:18]=[C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[O:16][N:15]=1>CC#N.C(Cl)Cl.[Br-].C([P+](C)(C)C)CCCCCCCCCCCCCCC>[Cl:24][C:21]1[S:20][C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:18]=2)=[CH:23][CH:22]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: CCCCCCCCCCCCCCCC[P+](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Solvent: ClCCl
Product: Clc1ccc(-c2cc(Cn3ccnc3)no2)s1
Temperature: 70 °C
Reaction time: 3 h
Yield: 115.4 %

Procedure:
To a solution of imidazole (34 mg) in MeCN (3 mL) was added K2CO3 (138 mg), n-hexadecyltrimethylphosphonium bromide (1 mg) and 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (139 mg). The mixture was stirred for 3 h at 70° C. After cooling to RT the reaction mixture was diluted with DCM (5 mL) and filtered. The filtrate was concentrated in vacuo to give crude 5-(5-Chloro-thiophen-2-yl)-3-imidazol-1-ylmethyl-isoxazole (153 mg) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:22])[C:5](=[N:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:23]OC(OC)N(C)C>>[CH3:1][O:2][C:3]1[C:4](=[O:22])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[N:10][N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[CH:23]=1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(=O)OC
Product: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(OC)c1=O
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of methyl 4-methoxy-3-oxo-2-{[3-(trifluoromethyl)phenyl]hydrazono}butanoate (14.0 g, 44 mmol) in N,N-dimethylformamide dimethyl acetal (100 mL) was refluxed for 4 h. After cooling to room temperature, the precipitate was collected by filtration and washed with hexane/AcOEt (3/1) to give the title compound (12.9 g, 89% yield) as off-white crystals: mp 169-170° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.98 (3H, s), 3.99 (3H, s), 7.66-7.74 (2H, m), 7.83-7.89 (2H, m), 7.95 (1H, s). Anal. Calcd for C14H11F3N2O4: C, 51.23; H, 3.38; N, 8.53. Found: C, 51.15; H, 3.47 N, 8.60.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[C:9]=1[S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCc1cc2ccccc2o1
Solvent: ClCCl
Solvent: O
Product: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4.35 g. (0.025 mol.) of 2-n-butylbenzofuran in 25 ml. of methylene chloride was added a solution of 5.16 g. (0.025 mol.) of 4-methoxybenzenesulfonyl chloride in 50 ml. of methylene chloride. The resulting solution was cooled to 0° and 6.9 g. (0.026 mol.) of stannic chloride was added dropwise. The reaction mixture was stirred for 30 minutes in the cold, for 1.5 hours at ambient temperature, then refluxed for ca. 60 hours. The mixture was poured into 200 ml. of water and stirred for 5 minutes. The layers were separated and the organic phase was extracted three times with water. Sodium hydroxide solution (ca. 1%) was added to the organic layer and it was stirred at ambient temperature for 1 hour. The layers were separated and the organic phase was washed three times with water and once with a saturated sodium chloride solution, dried (MgSO4) and evaporated to dryness to give a residue which was chromatographed on a silica gel "dry column" with 9:1 methylene chloride-ether as eluant to give 2-n-butyl-3-(4-methoxyphenylsulfonyl)benzofuran.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C@H:10]([CH2:19]O)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9](=[O:21])[C@H:10]([CH2:19][Br:23])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CBr)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The N-Boc-serine benzyl ester was brought up in dichloromethane (170 mL) and treated with carbon tetrabromide (26.37 g, 79.51 mmol, 1.2 eq.), and triphenylphosphine (25.20 g, 96.08 mmol, 1.45 eq.) and the solution was stirred at 0° C. for 30 min. The volatiles were then evaporated in vacuo and the residue was triturated with ether (1000 mL). The solid that separated out was filtered off and organic layer was evaporated in vacuo to get the crude product. The crude material was purified by flash chromatography on silica gel to get N-Boc-β-bromoalanine benzyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29])([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[C:5]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29])([CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1F
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
3-(4-Benzyloxy-phenyl)-2-(2-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester (12.8 g, 31.34 mmol) is dissolved in ethanol (500 mL), treated with 10% palladium on carbon (6.0 g), and stirred under an atmosphere of hydrogen for 90 minutes. The suspension is filtered through celite and concentrated to provide 2-(2-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (9.65 g, 97%). The title compound is separated by chiral chromatography (Column OJ, 40% IPA in heptane, 1 mL/mmin, 240 nm UV. 1H NMR (400 MHz, CDCl3): δ 7.13 (d, 2H, J=8.0 Hz), 7.07-7.02 (m, 1H), 6.98-6.88 (m, 3H), 6.74 (d, 2H, J=8.0 Hz), 6.05 (s, 1H), 4.20 (q, 2H, J=6.9 Hz), 3.24, 3.16 (ABq, 2H, J=13.4 Hz), 1.39 (s, 3H), 1.23 (t, 3H, J=6.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:4]2[N:5]([CH2:12][CH2:13][N:14]=2)[C:6](=[O:11])[C:7]=1[NH:8][CH:9]=O.[C:23](OC(=O)CC)(=O)[CH2:24]C>N1C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:3]2[C:2]3[N:1]=[C:9]([CH2:23][CH3:24])[NH:8][C:7]=3[C:6](=[O:11])[N:5]3[CH2:12][CH2:13][N:14]=[C:4]23)=[CH:17][CH:18]=1
Reactant: NC1=C(NC=O)C(=O)N2CCN=C2N1Cc1ccc(Cl)cc1
Reactant: CCC(=O)OC(=O)CC
Solvent: c1ccncc1
Product: CCc1nc2c([nH]1)C(=O)N1CCN=C1N2Cc1ccc(Cl)cc1

Procedure:
A mixture of 25.00 g. (0.078 mol) of the product of Procedure 2 and 50 ml. dry pyridine in 50 ml. (0.388 mol) of propionic anhydride was heated at reflux for 3 hr. Upon cooling, a white solid precipitated. CH3CN was added, and the white solid filtered and air-dried to give crystals, mp 278.0°-279.0° (corr.). The material may be recrystallized from DMF-i-PrOH.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(O)=O>CC1C=CC(S(N[C@@H]([C@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.C(N(CC)CC)C.CO>[OH:12][C@H:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: O=CO
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
Into 1 ml of methanol were dissolved 7 mg (0.01 mmol) of [RuCl2(p-cymene)]2 and 8 mg (0.02 mmol) of (R,R)-TsDPEN to prepare a solution, and to the solution was dropwise added 2 mg (0.02 mmol) of triethylamine, followed by stirring for 0.5 hour at room temperature. To the reaction solution was dropwise added a solution prepared by dissolving 364 mg (2.2 mmol) of phenylpyruvic acid into 4 ml of methanol, and 1.2 ml (8.9 mmol) of triethylamine was furthermore dropwise added thereto. The bath was heated up to a temperature of 40° C., and then 0.25 ml (6.7 mmol) of formic acid was dropwise added over 1 hour, followed by stirring for 2 hours at a bath temperature of 40° C. Upon completion of the reaction, the solvent was distilled off under reduced pressure. Thereto was added 2 ml of water, and then concentrated hydrochloric acid was gradually dropwise added under ice cooling; thus, pH of the solution was adjusted to 2. Extraction was performed twice with 20 ml of ethyl acetate, and then the organic phase was washed with 2 ml of a saturated aqueous solution of sodium chloride, followed by concentration under reduced pressure. As a result, 370 mg (yield 99%, 94% ee) of (2R)-hydroxy-3-phenylpropanoic acid was obtained.
Reaction SMILES: [CH2:1](Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH2:1]([C:10]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCc1ccccc1
Reactant: O=C1CCCCC1
Product: OC1(CCc2ccccc2)CCCCC1
Yield: 96 %

Procedure:
Since TmI2(DME)x exhibits such high reactivity at room temperature, its viability at reduced temperature is examined. In these reactions, TmI2(DME)x is added as a DME solution by syringe using a saturated stock solution generated in situ from Tm and I2. Phenethyl iodide reacts smoothly at −22° C. in 10 minutes to form phenethylcyclohexanol in 96% yield (entry f). The reaction of phenethyl bromide with cyclohexanone at 0° C. produces a 96% yield of phenethylcyclohexanol in 20 minutes (entry g), while reaction at −22° C. gave a 94% yield in 60 minutes (entry h). Phenethyl chloride reacts at 0° C. to give a 90% yield after 1 hour (entry j). This variation of reaction time as a function of temperature could be used to control regiochemistry in sequenced reactions.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].O1CCOCC1>>[ClH:23].[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:11]2([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2cccnc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)C1(c2cccnc2)CCNCC1

Procedure:
Prepare by the method of example 20.10 using 1-tert-butoxycarbonyl-4-(pyridin-3-yl)-piperidine-4-carboxylic acid amide (3 mmol) and HCl in dioxane (40 mmol, 4N) to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=3)=[CH:14][CH:13]=2)=[N:8]1)=[O:4].[NH2:28][CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1.C1COCC1.CO>C(O)(=O)C>[CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:28][CH:29]4[CH2:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30]4)[CH:19]=3)=[CH:16][CH:17]=2)=[N:8]1)=[O:4]
Reactant: CC(C)(C)C(=O)OCn1cnc(-c2ccc(-c3cccc(C=O)c3)cc2)n1
Reactant: NC1Cc2ccccc2C1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)OCn1cnc(-c2ccc(-c3cccc(CNC4Cc5ccccc5C4)c3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3-(3′-formyl-4-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate (0.081 g, 0.22 mmol; I-X-17) and 2-aminoindane (0.045 mL, 0.35 mmol) in 1:1 THF/MeOH (2 mL) was added acetic acid (0.12 mL) and MP-BH3CN (ca. 0.67 mmol, Note 1). The mixture was stirred at room temperature overnight, resin was remove by filtration (THF wash) and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc/5% Na2CO3, layers were separated and the aqueous layer was extracted with EtOAc. Combined organics were washed (water, brine), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/CH2Cl2), affording the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.20 (s, 9H), 2.84 (dd, J=15.6, 6.4 Hz, 2H), 3.20 (dd, J=15.6, 7.1 Hz, 2H), 3.68-3.75 (m, 1H), 3.93 (s, 2H), 6.09 (s, 2H), 7.08-7.23 (m, 4H), 7.31-7.38 (m, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.63 (s, 1H), 7.69 (d, J=8.3 Hz, 2H), 8.19 (d, J=8.3 Hz, 2H), 8.37 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[C:13]([C:16]1[S:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:9]([O:8][C:6]1[N:5]=[C:4]([S:11][CH3:12])[N:3]=[C:2]([C:19]2[S:20][C:16]([C:13](=[O:15])[CH3:14])=[CH:17][CH:18]=2)[CH:7]=1)[CH3:10]
Reactant: CCOc1cc(Cl)nc(SC)n1
Reactant: CC(=O)c1ccc(B(O)O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ccc(C(C)=O)s2)nc(SC)n1
Temperature: 80 °C
Yield: 27.9 %

Procedure:
The crude product of Preparation 27, 4-chloro-6-ethoxy-2-methylsulfanylpyrimidine, (525 mg, 2.56 mmol) was dissolved in DMF (4 mL). To this solution was added 5-acetyl-2-thiopheneboronic acid (523 mg, 3.08 mmol), PdCl2dppf (209 mg, 0.26 mmol), potassium carbonate (1.06 g, 7.69 mmol) and water (0.4 mL). The reaction mixture was heated at 80° C. under nitrogen atmosphere for overnight. The reaction mixture was cooled and poured into 30 mL of water and was then extracted with diethyl ether (20 mL×3) three times. The ether layer was separated and dried with anhydrous MgSO4 and concentrated in vacuo. The resulting crude product was purified by flash silica column chromatography (20% ethyl acetate in hexane) to give product 1-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-ethanone (210 mg, 28% yield over two steps). 1H-NMR (CDCl3): δ 7.67 (m, 2H), 6.68 (s, 1H), 4.46 (q, J=7.1 Hz, 2H), 2.60 (s, 3H), 2.59 (s, 3H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].[OH2:25]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:24][C:8]1[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:19]=2)=[O:25])=[N:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: O
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C

Procedure:
In an embodiment, the process comprises contacting 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]thio]-1H-benzimidazole (rabeprazole sulfide) with a chiral reagent in an organic solvent and water followed by addition of titanium isopropoxide. A base is added to this reaction mass followed by an oxidizing agent to obtain dexrabeprazole. The so-obtained dexrabeprazole may then be reacted with the alcoholic solution of magnesium chloride to form dexrabeprazole magnesium hydrate. Alternatively, the dexrabeprazole obtained after reaction with the oxidizing agent is converted to a salt, suitably the potassium salt, and the salt of dexrabeprazole is reacted with the alcoholic solution of magnesium chloride to form dexrabeprazole magnesium hydrate.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[N+](C)([O-])=O>[CH3:9][C:10]1[CH:11]=[C:12]([C:13]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:14])[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2cccc(C)c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To commercially available nitromethane (5 ml) were added commercially available anisole (541 mg), commercially available 3-methylbenzoyl chloride (773 mg) and commercially available scandium(III) trifluoromethanesulfonate (49 mg), and the admixture was stirred at 60° C. overnight. The reaction mixture was partitioned between water and chloroform, and the chloroform layer was dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/acetone to obtain 635 mg of the title compound (yield: 56%).