Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24].C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>>[Cl:10][C:6]1[CH:5]=[C:4]([F:11])[C:3]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:2]([NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:33]=2[F:32])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NC(=O)c1ccc(F)cc1F
Yield: 80.2 %

Procedure:
3-(2-Amino-4-chloro-6fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)pyrimidinedione (2.0 g, 5.4 mmol) and triethylamine (0.66 g, 6.5 mmol) were dissolved in anhydrous tetrahydrofiuran (30 ml) and stirred under ice cooling. To this solution was slowly added 2,4-difluorobenzoyl chloride (0.96 g, 5.4 mmol) and solution refluxed for 2 hr. Another batch of 2,4-difluorobenzoyl chloride (0.19 g, 1.1 mmol) was added and solution refluxed for 2 hr. Solvent was removed in vacuo and the product purified by column chromatography on silica gel using hexane-ethyl acetate (3:1) as the eluent to afford the title compound (2.2 g).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]#[CH:11])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[C:12]([O:15][CH:16]([CH2:21][O:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:17][N:18]=[N+:19]=[N-:20])(=[O:14])[CH3:13].CCN(C(C)C)C(C)C>C1COCC1.[Cu]I>[C:12]([O:15][CH:16]([CH2:21][O:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:17][N:18]1[CH:11]=[C:10]([CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[N+:1]([O-:3])=[O:2])[N:20]=[N:19]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(CN=[N+]=[N-])COS(=O)(=O)c1ccc(C)cc1
Reactant: C#CCn1ccnc1[N+](=O)[O-]
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)OC(COS(=O)(=O)c1ccc(C)cc1)Cn1cc(Cn2ccnc2[N+](=O)[O-])nn1
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of 2-nitro-1-(prop-2-ynyl)-1H-imidazole (0.2 gm, 1.32 mmol) and 1-azido-3-(tosyloxy)propan-2-yl acetate (0.41 gm, 1.32 mmol) in THF (2.5 mL), was treated with CuI (0.025 gm, 0.132 mmol) and DIPEA (0.3 mL, 1.46 mmol) at room temperature. After stirring the reaction mixture for overnight, silica was added, solvent evaporated under reduced pressure and purified by chromatography on silica gel (MeOH/CH2Cl2, 1/10) to give the 1-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-3-(tosyloxy)propan-2-yl acetate (0.5 gm, 81%) as white solid. 1H NMR (CDCl3, 400 MHz) δ: 7.76-7.78 (m, 3H), 7.35-7.39 (m, 3H), 7.15 (br, 1H), 5.68 (d, J=5.6 Hz, 2H), 5.27-5.32 (m, 1H), 4.56-4.67 (m, 2H), 4.19 (dd, J=4.0, 11.2 Hz, 1H), 4.08 (dd, J=4.0, 11.2 Hz, 1H), 2.46 (s, 3H), 1.97 (s, 3H); Mass Spec (lo-res): Calc'd for C18H20N6O7S: 464.11; found: 465.1 (M+H+).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](O)=[O:9])=[CH:3][CH:2]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([N:19]([O:20][CH3:21])[CH3:18])=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A mixture of 2-(biphenyl-4-yl)acetic acid (1 g, 4.7 mmol), N,O-dimethylhydroxylamine hydrochloride (458 mg, 4.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (900 g, 4.7 mmol), hydroxybenzotriazole (635 mg, 4.7 mmol), and triethylamine (1.42 g, 14.1 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. When TLC indicated that 2-(biphenyl-4-yl)acetic acid was consumed, the reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE: EtOAc=8:1) to afford 2-(biphenyl-4-yl)-N-methoxy-N-methylacetamide (1.0 g, yield 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.[OH-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: BrCc1ccccc1
Reactant: OCc1ccc(Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: OCc1ccc(Cl)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-Chloro-2-(hydroxymethyl)phenol (for a preparation see Intermediate 14)(1.51 g, 9.54 mmol) in ethanol (20 ml), was added sodium hydroxide (5.25 ml, 10.5 mmol). To the mixture was added a solution of benzyl bromide (1.14 ml, 9.54 mmol, Aldrich) in ethanol (30 ml) dropwise. The reaction was stirred under nitrogen overnight at ambient temperature. The solvent was removed in vacuo to leave an aqueous suspension. The suspension was diluted with water (50 ml) and dichloromethane (40 ml). The phases were separated and the aqueous phase extracted with dichloromethane (30 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (20 ml) and the solvent removed in vacuo to leave a white solid (1.52 g). The residue was loaded in dichloromethane and purified on silica 100 g using 0-50% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (1.32 g);
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1I.[N:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[N:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1[C:15]1[CH:16]=[N:11][CH:12]=[N:13][CH:14]=1
Reactant: OB(O)c1cncnc1
Reactant: N#Cc1nccc(I)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1nccc(-c2cncnc2)c1F
Temperature: 85 °C
Yield: 68.3 %

Procedure:
A vial containing a mixture of 3-fluoro-4-iodopicolinonitrile (1.25 g, 5.04 mmol), pyrimidin-5-ylboronic acid (1.249 g, 10.08 mmol), and cesium carbonate (3.45 g, 10.58 mmol) in dioxane (Ratio: 2.0, Volume: 10.18 ml) and water (Ratio: 1.000, Volume: 5.09 ml) was degassed with N2 for 5 min, then PdCl2(dppf)-CH2Cl2Adduct (0.218 g, 0.267 mmol) was added. The solution was heated at 85° C. for 17 hr, and then allowed to cool to room temperature. The reaction was quenched with water. The reaction mixture was diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a brown residue. The crude material was purified by MPLC (80 g column, 60 mL/min, 30-100% EtOAc in hexanes) to give the title compound (695 mg, 3.44 mmol, 68.2% yield) as a pink solid. ESI MS (M+H)+=201.1.
Reaction SMILES: C1(=O)[N:5]([CH:6]2[CH2:11][S:10][C@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:18][C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[C:7]2=[O:28])C(=O)C2=CC=CC=C12.CNN>C(Cl)(Cl)Cl>[NH2:5][CH:6]1[CH2:11][S:10][C@H:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:8]([CH2:18][C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])=[O:20])[C:7]1=[O:28]
Reactant: C[Si](C)(C)CCOC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CS[C@@H]1c1ccccc1
Agent: CNN
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)CCOC(=O)CN1C(=O)C(N)CS[C@@H]1c1ccccc1

Procedure:
A solution of the trimethylsilylethyl ester product from part (a) in dry chloroform is treated with N-methylhydrazine according to the procedure of Example 1(d) to give (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethylsilylethyl ester.
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.[CH2:11]([O:13][C:14]([C:16]12[CH2:23][CH2:22][C:19]([NH:24][CH2:25][C:26]([N:28]3[CH2:32][C@@H:31]([F:33])[CH2:30][C@H:29]3[C:34]([NH2:36])=O)=[O:27])([CH2:20][CH2:21]1)[CH2:18][CH2:17]2)=[O:15])[CH3:12].FC(F)(F)C(OC(=O)C(F)(F)F)=O.O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:11]([O:13][C:14]([C:16]12[CH2:23][CH2:22][C:19]([NH:24][CH2:25][C:26]([N:28]3[CH2:32][C@@H:31]([F:33])[CH2:30][C@H:29]3[C:34]#[N:36])=[O:27])([CH2:20][CH2:21]1)[CH2:18][CH2:17]2)=[O:15])[CH3:12]
Reactant: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C(N)=O)(CC1)CC2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccccc1
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 83.7 %

Procedure:
(2S,4S)-1-[2-[(4-Ethoxycarbonylbicyclo[2.2.2]-oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide benzenesulfonate (791 mg) was suspended in N,N-dimethylformamide (2.8 mL), and trifluoroacetic acid anhydride (0.22 mL) was added thereto, followed by stirring under ice-cooling for 1 hour. After adding water (14 mL), potassium carbonate (644 mg) was added thereto at a bath temperature of 40° C., followed by ice-cooling and 1 hour of stirring. The precipitate were collected by filtration, washed with water (3 mL) and then blast-dried at 60° C., thereby obtaining a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (441 mg, 84%).
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CCCCCC[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CO[C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[CH2:41][CH2:40][CH2:39][CH2:38]2.C1(C)C(C2C(C)=CC=CC=2)=CC=CC=1>>[CH3:32][C:31]1[CH:26]=[CH:27][C:28]([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:29][CH:30]=1
Reactant: CCCCCCCCCCCCC
Reactant: COc1ccc2c(c1)CCCC2
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1ccccc1-c1ccccc1C
Product: Cc1ccc(-c2ccc3c(c2)CCCC3)cc1
Temperature: 60 °C
Yield: 76 %

Procedure:
In a reaction flask was placed NiCl2(PCy3)2 (61.2 mg, 0.0886 mmol), PCy3 (49.0 mg, 0.175 mmol), tridecane (255 mg, 1.386 mmol, as an internal standard), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (273 mg, 1.683 mmol). The Grignard reagent (1 M in THF, 5.0 mmol) was added to this mixture under a nitrogen atmosphere at room temperature. The resulting solution was warmed to 60° C. for 15 hours. A sample was withdrawn and quenched with an aqueous sodium citrate solution (1 M). The aqueous solution was extracted with ethyl acetate. GC analysis of the organic phase showed the presence of 6-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene (1.272 mmol, 76% yield), bitoluene (0.50 mmol), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (0.357 mmol) in the reaction mixture.
Reaction SMILES: CCCCCC[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].CO[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH2:21][CH2:20][CH2:19]2.C1(C)C(C2C(C)=CC=CC=2)=CC=CC=1>C1(C)C=CC=CC=1.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][C:12]1[CH:7]=[CH:8][C:9]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][CH:11]=1
Reactant: CCCCCCCCCCCCC
Reactant: COc1ccc2c(c1)CCCC2
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccccc1-c1ccccc1C
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc3c(c2)CCCC3)cc1
Temperature: 110 °C
Yield: 29 %

Procedure:
The Grignard reagent (1 M in ether, 5.0 mmol) was placed under vacuum to remove all volatiles. Toluene (5.0 mL) was then added to the Grignard reagent. In a separate reaction flask was placed NiCl2(PPh3)2 (62.0 mg, 0.0948 mmol), tridecane (282 mg, 1.532 mmol, as an internal standard), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (334 mg, 2.059 mmol). The Grignard reagent in toluene was then transferred to this mixture under a nitrogen atmosphere at room temperature. The resulting solution was warmed to 110° C. for 15 hours. A sample was withdrawn and quenched with an aqueous sodium citrate solution (1 M). The aqueous solution was extracted with ethyl acetate. GC analysis of the organic phase showed the presence of 6-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene (0.598 mmol, 29% yield), bitoluene (0.419 mmol), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (1.043 mmol) in the reaction mixture.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.C(Cl)(=O)C([Cl:27])=O>CN(C=O)C.C1COCC1>[ClH:27].[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([Cl:27])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)Cl
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.0 g of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (6.28 mmol) were initially charged in abs. THF, 4 drops of DMF were added and 3.19 g of oxalyl chloride (25.14 mmol) were then added dropwise. The reaction mixture was stirred at RT for 3 h. Another 0.80 g of oxalyl chloride (6.29 mmol) were added, and the reaction was stirred at RT for a further 4 h. The reaction mixture was concentrated and co-evaporated with toluene three times, and the residue was dried under high vacuum. This gave 2.43 g of the title compound (103% of theory).
Reaction SMILES: CO[N:3](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:4]1[NH:5][C:6](=[O:41])[C:7]2[N:8]=[CH:9][N:10]([CH:13](OC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:14][CH:15]([CH2:19][OH:20])[CH2:16][O:17][CH3:18])[C:11]=2[N:12]=1.C(Cl)(=[O:67])CCCCC.N1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>>[C:18]([O:17][CH2:16][CH:15]([CH2:19][OH:20])[CH2:14][CH2:13][N:10]1[CH:9]=[N:8][C:7]2[C:6](=[O:41])[NH:5][C:4]([NH2:3])=[N:12][C:11]1=2)(=[O:67])[CH2:70][CH2:71][CH2:72][CH2:73][CH3:74]
Reactant: c1ccncc1
Reactant: COCC(CO)CC(OC(c1ccccc1)(c1ccccc1)c1ccccc1)n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Reactant: CCCCCC(=O)Cl
Product: CCCCCC(=O)OCC(CO)CCn1cnc2c(=O)[nH]c(N)nc21
Reaction time: 0.33 h
Yield: 38 %

Procedure:
To a solution of N2-monomethoxytrityl-9-(4-monomethoxy-trityloxy3-hydroxymethylbut-1-yl)guanine (0.72 g, 0.9 mmol) in pyridine (4 ml) was added hexanoyl chloride (0.38 ml, 2.7 mmol) and the solution was stirred for 20 minutes. The mixture was precipitated in water (40 ml) and the resulting precipitate was stirred in 80% acetic acid (10 ml) at 80° for 45 minutes. The solvent was removed and the residue purified by column chromatography on silica gel eluting with chloroform-methanol mixtures (7:1, 5:1) to afford 9-(4-hexanoyloxy-3-hydroxymethylbut-1-yl)guanine (0.12 g, 38%), m.p. 179-181° C.; νmax 2960, 2930, 1730, 1690, 1630, and 1600 cm−1; δH [(CD3)2SO] 0.84 (3H, t, J 6.9 Hz, CH3), 1.24 (4H, m, CH3(CH2)2), 1.50 (2H, quintet, J 7.3 Hz, CH2CH2CO), 1.6-1.8 (3H, m, 2′-H and 3′-H), 2.26 (2H, t, J 7.3 Hz, CH2CO), 3.40 (2H, t, J 5 Hz, D2O exchange leaves d, CH2OH), 3.9-4.1 (4H, m, 1′-H and CH2OCO), 4.60 (1H, t, J 5.1 Hz, D2O exchangeable, 2-NH2), 7.67 (1H, s, 8-H), and 10.49 (1H, s, D2O exchangeable, 1-H); (Found: C, 52.63; H, 6.91; N, 18.75:%; C16H25N5O4 requires: C, 54.69; H, 7.17; N, 19.93%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])([OH:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Ethyl acetate (1.95 ml, 20 mmol) was added dropwise at −78° C. to 1M solution of LiHMDS in THF (20 ml, 20 mmol). After stirring for 10 min at −78° C., 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.98 g, 20 mmol) in 8 ml of THF was added dropwise at −78° C. and the dry ice/acetone bath was removed to allow the temperature to slowly reach 0° C. At this temperature, the reaction mixture was quenched by addition of 25 ml of H2O and the mixture was extracted twice with Et2O, the organic layers were washed with brine, dried over Na2 SO4 and concentrated on vacuum to give the product as an yellow oil.
Reaction SMILES: [Cl-].C([Al+]CC)C.CCCCCC.[Cl-].[Al+3].[Cl-].[Cl-].[O:17]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:31]1[O:34][CH:32]1[CH3:33]>>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][C@@H:32]([OH:34])[CH3:33])=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1CO1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: CC[Al+]CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Product: C[C@H](O)COc1ccc(Oc2ccccc2)cc1
Yield: 72 %

Procedure:
In Example 2, 0.1 mL of a diethyl aluminum chloride/hexane solution was used in place of anhydrous aluminum chloride, and the color of the catalyst solution changed from brown to dark green by the addition of a diethyl aluminum chloride/hexane solution. Then 4-phenoxyphenol and propylene oxide were added to the dark green catalyst solution to achieve the reaction in the same manner as described in Example 2. Thus (S)-(+)-1-(4-phenoxyphenoxy)-2-propanol was obtained in 72% yield and the optical purity was 87% e.e.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:19]1[O:22][CH:20]1[CH3:21]>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[O:5]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C@@H:20]([OH:22])[CH3:21])=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CC1CO1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: C[C@H](O)COc1ccc(Oc2ccccc2)cc1
Yield: 84 %

Procedure:
In Example 2, 29 mg of tetraisopropoxy titanium was used in place of anhydrous aluminum chloride, and the color of the catalyst solution changed from brown to slightly greenish brown by the addition of tetraisopropoxy titanium. Then 4-phenoxyphenol and propylene oxide were added to the slightly greenish brown catalyst solution to achieve the reaction in the same manner as described in Example 2. Thus (S)-(+)-1-(4-phenoxyphenoxy)-2-propanol was obtained in 84% yield and the optical purity was 95% e.e.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]3[N:11]=[C:12]([S:21][CH3:22])[N:13]=[C:14]([O:17][CH2:18][CH2:19][CH3:20])[C:15]=3[N:16]=2)[CH:5]=[C:4]([CH3:23])[C:3]=1[OH:24].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>CN(C)C=O>[C:36]([O:35][C:33](=[O:34])[CH2:32][O:24][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]2[O:9][C:10]3[N:11]=[C:12]([S:21][CH3:22])[N:13]=[C:14]([O:17][CH2:18][CH2:19][CH3:20])[C:15]=3[N:16]=2)=[CH:5][C:4]=1[CH3:23])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCCOc1nc(SC)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1nc(SC)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12

Procedure:
To a solution of 2.00 g of 2,6-dimethyl-4-(5-methylsulfanyl-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl)-phenol in 20 ml of N,N-dimethylformamide was added 3.20 g of potassium carbonate, followed by 0.93 ml of tert-butyl bromoacetate. The mixture was reacted for 1 h at 60° C., then allowed to cool and poured onto water. The resulting precipitate was collected by filtration with suction and dried in vacuo. 2.45 g of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][C:3]=1[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NS(C)(=O)=O)ccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.7 %

Procedure:
To a stirred solution of 4-bromo-3-methylaniline (3.32 g, 17.8 mmol) in dry dichloromethane (150 ml) was added triethylamine (4.96 ml, 35.6 mmol), followed by methanesulphonyl chloride (1.52 ml, 19.6 mmol). The complete reaction mixture was stirred at room temperature under Ar for 18 hours. The mixture was then washed with water, saturated potassium carbonate solution, and finally brine. The organic layer was dried (Na2SO4) and concentrate din vacuo to afford a creamy orange solid. This was dissolved in dichloromethane and shaken with 10% sodium hydroxide solution. The aqueous layer was separated and acidified to pH 6 using concentrated hydrochloric acid. This solution was then extracted using chloroform. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford the title compound as a white solid (1.35 g, 30%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O>[Si:23]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-tert-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (970 g) in N,N-dimethylformamide (1000 mL) was added imidazole (591 g) at 0° C. Upon dissolution of the imidazole, tert-butyldimethylsilyl chloride (652 g) was added at 0° C. The reaction was stirred for 16 hours at room temperature, cooled to 0° C., and quenched with water (2.25 L). The mixture was extracted with ethyl acetate (4×), and the combined organic layer was washed with brine (3×), dried over magnesium sulfate, filtered, and concentrated to give 1-tert-butyl 2-methyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate. The residue was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.CN(C)[CH:19]=[O:20].O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:3]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:5]=[CH:6][C:7]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccccc1Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccc(C(F)(F)F)c1Cl

Procedure:
A solution of 0.6 mole of 2-chlorotrifluoromethylbenzene in 1 l of tetrahydrofuran is cooled to -65° C. and 0.58 mole of butyllithium dissolved in hexane is added. The mixture is maintained at the same temperature for 2 hours and a mixture containing 44 ml of dimethylformamide and 200 ml of tetrahydrofuran is then added dropwise. The reaction medium is allowed to return to ambient temperature, 600 ml of water are added, extraction is then carried out with ethyl ether followed by evaporation to dryness. The product is distilled to purify.