Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:23][O:24][C:25]1[CH:66]=[CH:65][C:28]([CH2:29][N:30]2[C:34]3=[N:35][CH:36]=[CH:37][C:38]([O:39][C:40]4[CH:45]=[CH:44][C:43]([NH:46][C:47]5[N:62]=[CH:61][CH:60]=[CH:59][C:48]=5[C:49]([NH:51][C:52]5[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=5)=[O:50])=[CH:42][C:41]=4[F:63])=[C:33]3[C:32](I)=[N:31]2)=[CH:27][CH:26]=1>CS(C)=O.O.C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:30]2[C:34]3=[N:35][CH:36]=[CH:37][C:38]([O:39][C:40]4[CH:45]=[CH:44][C:43]([NH:46][C:47]5[N:62]=[CH:61][CH:60]=[CH:59][C:48]=5[C:49]([NH:51][C:52]5[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=5)=[O:50])=[CH:42][C:41]=4[F:63])=[C:33]3[C:32]([NH:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[N:31]2)=[CH:65][CH:66]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(Nc5ncccc5C(=O)Nc5ccc(F)cc5)cc4F)ccnc32)cc1
Reactant: CN1CCC(N)CC1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(Nc5ncccc5C(=O)Nc5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 11.7 %

Procedure:
A 25 mL round-bottomed flask was charged with Cu(I)I (0.0108 g, 0.0568 mmol), 1-methylpiperidin-4-amine (0.0973 g, 0.852 mmol), K2CO3 (0.196 g, 1.42 mmol), L-Proline (0.0131 g, 0.114 mmol) and DMSO (2.5 mL). The reaction mixture was stirred for 5 minutes and 2-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(4-fluorophenyl)nicotinamide (0.200 g, 0.284 mmol) in DMSO (2.5 mL) was added. The reaction mixture was heated to 100° C. for 18 hours. The reaction mixture was cooled to ambient temperature and DCM and water (10 mL) were added. The organic layer washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography, eluting with EtOAc to provide the product (23 mg, 11%). LRMS M−1 (691.2) observed.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.O.C(OCC)(=O)C>[CH2:13]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH3:10])=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of methyl (2S)-5-pyrrolidone-2-carboxylate (80 g) in tetrahydrofuran (900 ml) was added sodium hydride (60% in oil, 23.5 g) by portions. After the addition, the reaction mixture was heated to 60° C., and benzyl bromide (69.8 ml) was added dropwise thereto. After 3 hours, the reaction mixture was cooled to room temperature and water (100 ml) was added dropwise thereto. The reaction mixture was poured into a mixture of ethyl acetate (2 l) and water (800 ml). The organic layer was separated, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (2 l) eluting with a mixture of hexane and ethyl acetate (1:1→1:2, V/V) to give methyl (2S)-1-benzyl-5-pyrrolidone-2-carboxylate (100.8 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:15][O:16]CC)[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[C:5]([CH3:19])=[C:4]([CH3:20])[N:3]=1.ClCCl.B(Br)(Br)Br>CO>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:15][OH:16])[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[C:5]([CH3:19])=[C:4]([CH3:20])[N:3]=1
Reactant: CCOCc1nc2c(Cl)nc(C)c(C)c2n1CC(C)C
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(Cl)c2nc(CO)n(CC(C)C)c2c1C
Temperature: 0 °C
Yield: 68 %

Procedure:
A 500 mL round bottom flask was charged with 4-chloro-2-(ethoxymethyl)-1-isobutyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridine (10.0 g, 33.8 mmol) and dichloromethane (250 mL) under a nitrogen atmosphere. The solution was cooled to 0° C. and boron tribromide (101 mL of 1M in dichloromethane, 101 mmol) was added through an addition funnel over 30 minutes. The reaction mixture was allowed to warm to room temperature and was stirred over night. Methanol was added slowly until no more fizzing occurred, then the solvent was partially removed under reduced pressure. More methanol was added (100 mL) as well as 6N hydrochloric acid (100 mL) and the solution was heated at reflux for 1 hour. The reaction mixture was then allowed to cool to room temperature and stirred over night. The solvent was partially removed under reduced pressure until a solid precipitated, which was isolated by filtration and washed with water, then triturated with ethyl acetate and hexanes to give 6.15 g of (4-chloro-1-isobutyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-2-yl)methanol as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 6-[1-(tert-butoxycarbonyl)piperidin-4-yl]pyridine-2-carboxylate (500 mg) in tetrahydrofuran (5 ml) and water (1.3 ml) is added, at room temperature, lithium hydroxide monohydrate (125 mg). The mixture is stirred at room temperature for 2 h and then admixed with ice-cold 1N HCl solution. The aqueous phase is extracted with ethyl acetate and then the combined organic phases are dried over sodium sulphate. The solids are filtered off and the solvent is distilled off. This gives 6-[1-(tert-butoxycarbonyl)piperidin-4-yl]pyridine-2-carboxylic acid (310 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([Cl:20])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCN(Cc2ccccc2)CC1
Product: O=C(Cl)C1CCN(Cc2ccccc2)CC1
Yield: 99 %

Procedure:
0.33 g (0.0015 mol) of 1-benzylpiperidine-4-carboxylic acid was dissolved in 5 ml of oxalyl chloride for 2 hrs. The excess oxalyl chloride was distilled off. The residue was taken up twice in toluene and concentrated each time. 0.355 g (99%) of 1-benzyl-piperidine-4-carboxylic acid chloride was obtained as a pale beige solid. This was dissolved in 20 ml of toluene, treated with 0.3 ml (0.00224 mol) of triethylamine and 0.184 g (0.00195 mol) of phenol and boiled at reflux for 18 hrs. After removal of the solvent the residue was chromatographed on silica gel with ether/hexane (1:2.5→1:2) as the eluent. 0.315 g (71%) of phenyl 1-benzyl-piperidin-4-carboxylate was obtained as a yellow oil. MS: me/e=296 (C9H22NO2+).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[CH3:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][Mg]Cl>C1COCC1>[CH3:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:4]([C@@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:7]1)=[O:5]
Reactant: COCCCC[Mg]Cl
Reactant: CON(C)C(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Solvent: C1CCOC1
Product: COCCCCC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a stirred solution of (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.37 g, 5.0 mmol) in THF (10 mL) at −20° C., there was added 1.47 M 4-methoxybutylmagnesium chloride in THF (10.2 mL, 15.0 mmol) dropwise to keep the temperature below −20° C. After addition, the resulting solution was warmed to rt and quenched with 1 N aq HCl (10 mL). The organic layer was separated, and the aqueous layer was extracted with ether (3×5 mL). Combined organic layers were washed with satd aq NaHCO3 (10 mL) and brine (5 mL) and dried over Na2SO4. Removal of the solvent under vacuum gave (R)-tert-butyl 2-(5-methoxypentanoyl)morpholine-4-carboxylate (1.41 g, 93%), which was used without purification. MS m/s 324 (M+Na+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]=[O:8].CC1N=C(C2C=NC([C:33]([F:36])([F:35])[F:34])=CC=2)SC=1CO.FC([Si](C)(C)C)(F)F.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:34][C:33]([F:36])([F:35])[CH:7]([C:6]1[S:5][C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)=[N:3][C:2]=1[CH3:1])[OH:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1C=O
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(F)(F)F
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1C(O)C(F)(F)F
Temperature: 25 °C

Procedure:
To an ice cooled solution of 2.0 g 4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazole-5-carbaldehyde (derived from [4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-methanol according to the method described for 4-Methyl-2-(trans-1,4-trifluoromethyl-cyclohexyl)-thiazole-5-carbaldehyde) and 1.09 ml (trifluoromethyl)trimethylsilane in 10 ml tetrahydrofuran were added 100 mg tetrabutylammoniumfluoride. The reaction mixture was stirred at room temperature for thirty minutes. Then 20 ml 2N HCL were added and the mixture stirred at room temperature for thirty minutes. The mixture was extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo to obtain 1.5 g 2,2,2-Trifluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-ethanol as a solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][C@@H:9]([OH:32])[C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[C:33]([O:36][C@H:37]1[C@@H]2O[C@@H]2[C@@]2(C)C(=C[C@@H](O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=[O:35])C>>[C:1]([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][C@@H:9]([O:32][C:33]([O:36][CH3:37])=[O:35])[C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:18][CH2:19][CH2:20][O:21]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Product: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCCO4)CC[C@H]3[C@H]12
Yield: 74.9 %

Procedure:
The procedure of Example 12 was repeated except that 44.6 mg (0.1 mmole) of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxy-7α-hydroxypregna-5-en-3β-yl acetate was used in lieu of 49.0 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-hydroxypregna-5-en-3β-yl acetate to give 37.8 mg of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate (yield: 75%)
Reaction SMILES: [Cl-].[NH3+:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[NH:12][C:11](=[O:16])[C:10](=[O:17])[NH:9][C:8]=3[C:7]=2[CH:18]=1.CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1>>[N:2]1([C:3]2[CH:4]=[CH:5][C:6]3[CH:15]=[CH:14][C:13]4[NH:12][C:11](=[O:16])[C:10](=[O:17])[NH:9][C:8]=4[C:7]=3[CH:18]=2)[CH:21]=[CH:25][CH:24]=[CH:23]1
Reactant: COC1CCC(OC)O1
Reactant: [NH3+]c1ccc2ccc3[nH]c(=O)c(=O)[nH]c3c2c1
Agent: [Cl-]
Product: O=c1[nH]c2ccc3ccc(-n4cccc4)cc3c2[nH]c1=O

Procedure:
8.8 mmol of 9-ammoniobenzo[f]quinoxaline-2,3(1H,4H)-dione chloride were reacted with 8.8 mmol of 2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[CH3:20]>C1COCC1>[O:7]1[CH2:8][CH2:9][O:10][CH:6]1[CH2:5][CH2:4][CH:16]([C:15]1[CH:18]=[CH:19][C:12]([F:11])=[C:13]([CH3:20])[CH:14]=1)[OH:17]
Reactant: BrCCC1OCCO1
Reactant: Cc1cc(C=O)ccc1F
Agent: II
Solvent: C1CCOC1
Product: Cc1cc(C(O)CCC2OCCO2)ccc1F
Temperature: 63 °C
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
To a suspension of Mg turnings (1.1 g, 0.05 g-at.) and catalytic amount of iodine in 200 mL THF was added dropwise 2-(2-bromoethyl)-[1,3]dioxolane (4.3 g, 0.02 mol) with heating over a period of 30 min. The resulting mixture was stirred for 30 min at 63° C. and then cooled to −30° C. and 4-fluoro-3-methyl-benzaldehyde (3.0 g, 0.02 mol) added slowly as a solution in 50 mL of THF. The temperature was maintained at −30° C. for 1 h and then slowly raised to room temperature over a period of 3 h. The excess Grignard was destroyed by the careful addition of 200 mL saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate (3×100 mL) and the combined organic layers washed with brine (2×50 mL) and dried over Na2SO4. After evaporation of the solvent, the product was isolated by flash column chromatography eluting with 0% to 50% ethyl acetate/hexanes to give 1.6 g of the title compounds as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2([CH2:24][OH:25])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]2=[O:23])=[C:4](O)[CH:3]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[C:9]3([CH2:24][O:25][C:4]=2[CH:3]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]3=[O:23]
Reactant: CCCCCN1C(=O)C(CO)(c2cc(F)c(Cl)cc2O)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C2(COc3cc(Cl)c(F)cc32)c2ccccc21
Yield: 44 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 3-(4-chloro-5-fluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 44% yield: 1H NMR (300 MHz, CDCl3) δ 7.34 (td, 1H), 7.14 (dd, 1H), 7.06 (td, 1H), 6.98 (d, 1H), 6.93 (d, 1H), 6.50 (d, 1H), 4.96 (d, 1H), 4.70 (d, 1H), 3.87-3.63 (m, 2H), 1.81-1.65 (m, 2H), 1.47-1.29 (m, 4H), 0.91 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.2, 156,9, 154.8, 151.6, 142.5, 131.5, 129.4, 128.6, 123.7, 121.7, 121.9, 111.2, 108.9, 80.6, 57.9, 40.5, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 360 (M+1).
Reaction SMILES: [CH:1]12[NH:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:7]2[CH:4]3[CH2:5][CH2:6][CH:1]2[CH:2]([NH:8][C:9]2[C:10]4[CH:11]=[CH:12][N:13]=[CH:14][C:15]=4[CH:16]=[CH:17][CH:18]=2)[CH2:3]3)=[CH:22][CH:21]=1
Reactant: c1cc(NC2CC3CCC2N3)c2ccncc2c1
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc(CN2C3CCC2C(Nc2cccc4cnccc24)C3)cc1

Procedure:
Reaction of Intermediate 29 with 4-methylbenzaldehyde affords the title compound.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([S:43][C:44]3[N:48](COCC[Si](C)(C)C)[N:47]=[N:46][CH:45]=3)=[CH:39][CH:38]=2)O1>>[NH:48]1[C:44]([S:43][C:40]2[CH:41]=[CH:42][C:37]([C:2]3[N:7]4[CH:8]=[C:9]([CH2:11][CH2:12][C:13]5[CH:22]=[CH:21][C:20]6[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:4][CH:3]=3)=[CH:38][CH:39]=2)=[CH:45][N:46]=[N:47]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Reactant: CC1(C)OB(c2ccc(Sc3cnnn3COCC[Si](C)(C)C)cc2)OC1(C)C
Product: c1ccc2nc(CCc3cn4c(-c5ccc(Sc6cnn[nH]6)cc5)cnc(N5CCOCC5)c4n3)ccc2c1

Procedure:
The title compound 36 was prepared from compound 3a and compound 63c using the methods described in Example 1, Step G. Subsequently, the SEM group was removed using the methods described in Example 37, Step C. 1H-NMR (400 MHz CDCl3) δ (ppm): 3.22-3.32 (m, 2H), 3.35-3.43 (m, 2H), 3.83 (br. s., 4H), 4.14 (br. s., 4H), 7.17-7.30 (m, 3H), 7.31-7.39 (m, 4H), 7.48-7.59 (m, 1H), 7.73 (br. s., 1H), 7.76-7.88 (m, 2H), 8.01 (d, J=8.6 Hz, 1H), 8.10 (d, J=8.6 Hz, 1H). Mass Spectrum LCMS, ESI (pos.) Calcd. for C29H26N8OS: 535.0 [M+H]. found 535.6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:39])[CH2:10][N:11]([C:13](=[O:38])[C@:14](C(OC(C)(C)C)=O)([CH2:16][CH2:17][CH2:18][CH:19]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[NH2:20])[NH2:15])[CH3:12].[ClH:41]>C(OCC)(=O)C>[ClH:41].[CH3:1][O:2][C:3](=[O:40])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:39])[CH2:10][N:11]([C:13](=[O:38])[C@H:14]([CH2:16][CH2:17][CH2:18][CH:19]([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[NH2:20])[NH2:15])[CH3:12]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CN(C)C(=O)[C@@](N)(CCCC(N)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCN1C(=O)CN(C)C(=O)[C@@H](N)CCCC(N)C(=O)OCc1ccccc1

Procedure:
The reaction mixture consequently formed was filtered. The filtrate was concentrated under a vacuum. The residue of the concentration was dissolved in 50 ml of ethyl acetate and the resultant solution was filtered. The filtrate was washed with an aqueous 10% citric acid solution, an aqueous 5% sodium hydrogen carbonate solution, and water sequentially in the order mentioned and dried with anhydrous sodium sulfate. The dried substance was distilled under a vacuum to expel the solvent. The residue was solidified with n-hexane to afford 5.05 g of α-tertiary butyloxycarbonyl-ε-benzyloxycarbonyl-L-lysyl-sarcosyl-L-proline methyl ester (melting point 45° to 48° C., yield 79%). This ester was dissolved in 80 ml of a solution prepared by dissolving dry hydrogen chloride gas in ethyl acetate and adjusting the concentration to 3.5N and then left standing for reaction at room temperature for one hour.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:14][NH:13][C:12](=[O:15])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:1][C:2]2[CH:3]=[C:4]([CH:10]3[CH2:14][NH:13][C:12](=[O:15])[CH2:11]3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1ccc(C2CNC(=O)C2)cc1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2CNC(=O)C2)cc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.3 %

Procedure:
A mixture of 4-(3-hydroxy-4-methoxyphenyl)-2-pyrrolidone (63 mg, 0.3 mmol), 4-chlorophenylboronic acid (61 mg, 0.45 mmol), copper (II) acetate (54 mg, 0.3 mmol), triethylamine (152 mg, 1.5 mmol), dichloromethane (3 ml) and small amount of molecular sieves is allowed to stir at ambient temperature. After 18 hours, the mixture is filtered over celite and the filtrate is concentrated under vacuum. The resulting residue is dissolved in 30 ml of ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. Purification by flash column chromatography (ethyl acetate/hexane 1:1 to methanoudichloromethane 3:97) gives 26 mg (27%) of 4-(3-(4-chlorophenyloxy)-4-methoxyphenyl)-2-pyrrolidone: 1H NMR (300 MHz, CDCl3) δ 7.24 (d, J=9.2 Hz, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.95(d, J=8.4 Hz, 1H), 6.87 (s, 1H), 6.83(d, J=9.2 Hz, 2H), 5.83 (b, 1H), 3.80 (s, 3H), 3.72 (t, J=8.4 Hz, 1H), 3.65-3.62 (m, 1H), 3.34 (t, J=8.4 Hz, 1H), 2.68 (dd, J=16.8, 8.8 Hz, 1H), 2.41 (dd, J=16.8, 9.2 Hz, 1H).
Reaction SMILES: C(O)[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].OCC([C@H]([C@H](CO)O)O)=O.[OH-].[Na+]>>[O:7]=[CH:2][C@H:3]([C@H:4]([C@H:5]([CH2:6][OH:8])[OH:20])[OH:21])[OH:22]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: O=C(CO)[C@@H](O)[C@@H](O)CO
Agent: [Na+]
Agent: [OH-]
Product: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Reaction time: 18 h

Procedure:
Cellulomonas gerida (JCM1490) strain was inoculated at a concentration of 1% to 18 L of a medium containing 2.0 g/L of sucrose, 5.0 g/L of yeast extract, 5.0 g/L of soybean peptides, 5 g/L of NaCl, 3 g/L of K2HPO4, 1 g/L of KH2PO4 and 15 g/L of L-ribose (pH 7.0) contained in a 30-L jar. The seed culture was obtained beforehand by culturing the bacterium in the same medium contained in a flask with a baffle at 30° C. for 18 hours with shaking at 160 rpm. The conditions in the jar were controlled to be 300 rpm, 1 vvm and 30° C., and the culture was performed for 18 hours. The obtained culture broth in which the culture was completed was centrifuged to collect the cells. The cell pellet was added with 1.8 L of glycine-HCl buffer (50 mM, pH 8.5) and homogenously suspended in the buffer. Then, the suspension was added with 60 mL of toluene and stirred vigorously for 15 minutes. 1.2 L of the toluene-treated cells prepared as described above was added to 12.5 L of the crude L-ribulose solution obtained in 2), and the reaction was performed at 30° C. for 24 hours while gently stirring the mixture so that the mixture should become uniform. During the reaction, pH was controlled to be 8.5 with 1 N NaOH. The obtained mixture after the reaction was centrifuged to remove the cells, and passed through a precision membrane filter with a pore size of 0.22 μm to obtain 12 L of transparent crude L-ribose solution. The concentration of L-ribose was 30 g/L, and the concentration of L-ribulose was 13 g/L.