Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[Si](C)(C)[CH3:22]>CO>[CH:1]1([NH:7][C:8]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:11]([C:12]([O:14][CH3:22])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cnc(NC2CCCCC2)c([N+](=O)[O-])c1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1cnc(NC2CCCCC2)c([N+](=O)[O-])c1
Yield: 89 %

Procedure:
To a solution of intermediate 57 (9.7 g, 32.2 mmol) in methanol (400 mL) was added chlorotrimethylsilane (3 mL) to achieve pH=2. The reaction mixture was heated at strong reflux for 72 h, during which time the pH was monitored and more chlorotrimethylsilane added as necessary to maintain an acidic solution. The reaction mixture was allowed to cool and was then concentrated on a rotary evaporator. The residue was purified by column chromatography (silica gel, 7:2:1 hexanes/dichloromethane/methanol) to afford the crude ester as a yellow solid (9.0 g, 89%). ESI-MS m/e 280.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([N:11]2[CH2:16][CH2:15][C@:14]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:28])[CH3:10])=[CH:5][CH:4]=1)#[CH:2].Br[C:30]1[CH:31]=[CH:32][C:33](=[O:37])[N:34]([CH3:36])[CH:35]=1>>[OH:27][C:24]([CH3:25])([CH3:26])[CH2:23][C@@:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:13][C:12](=[O:28])[N:11]([C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[CH:31]=[CH:32][C:33](=[O:37])[N:34]([CH3:36])[CH:35]=3)=[CH:8][CH:7]=2)[CH3:10])[CH2:16][CH2:15]1
Reactant: C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Reactant: Cn1cc(Br)ccc1=O
Product: C[C@@H](c1ccc(C#Cc2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 3-[(S)-1-(4-ethynyl-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and 5-bromo-1-methyl-1H-pyridin-2-one following a procedure analogous to that described in Example 31. LC-MS (Method 1): tR=3.46 min; Mass spectrum (ESI+): m/z=485 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Cl)/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.CCOC(C)=O>[C:21]1(/[CH:20]=[CH:19]/[CH2:18][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Reactant: ClC/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1OC/C=C/c1ccccc1
Temperature: 60 °C

Procedure:
4-Fluoro-2-nitrophenol (13.5 g, 86 mmol) was dissolved in anhydrous DMF (100 mL) under an N2 atmosphere and treated sequentially with K2CO3 (23.7 g, 172 mmol) and trans-cinnamyl chloride (13.4 g, 87.6 mmol) and heated to 60° C. for 12 h. Upon completion, the reaction was diluted with EtOAc (500 mL), and washed with H2O (3×300 mL) and sat. aq. NaCl (500 mL). The organic layer was dried with MgSO4, filtered and concentrated to yield a yellow solid which was easily recrystallized from EtOAc/hexanes to provide pure 4-fluoro-2-nitrophenyl (2E)-3-phenylprop-2-enyl ether (5-1). 1H NMR (300 MHz, CDCl3) δ 7.61 (dd, J=7.5, 2.5 Hz, 1H), 7.41 (app d, J=7.0 Hz, 2H), 7.34 (t, J=7.5 Hz, 2H), 7.27 (m, 2H), 7.12 (dd, J=9.0, 4.0 Hz, 1H), 6.76 (d, J=16.0 Hz, 1H), 6.37 (dt, J=16.0, 5.5 Hz, 1H), 4.83 (dd, J=5.5, 1.0 Hz, 2H).
Reaction SMILES: O=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.CN.[BH3-][C:23]#[N:24].[Na+]>CCO>[CH3:23][NH:24][CH:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: CN
Agent: [Na+]
Solvent: CCO
Product: CNC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 1.5 h
Yield: 46.2 %

Procedure:
To a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (2.15 g, 8.05 mmol) in EtOH (20 mL) was added 33% methanamine in EtOH (3.7 g, 40.3 mmol), and the mixture was stirred at r.t for 1.5 h. Then NaBH3CN (1.5 g, 24.2 mmol) was added to the mixture. After that the resulting mixture was stirred at r.t overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as brown oil (1.05 g, 46.2%).
Reaction SMILES: [NH2:1][OH:2].[CH2:3]([N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[CH2:12][C:13](=O)[CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[CH2:12][C:13](=[N:1][OH:2])[CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NO
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Solvent: CCO
Product: ON=C1CC2CCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
A 50%-aqueous hydroxylamine solution (182 mg, 2.76 mmol) was added to a solution of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (538 mg, 2.50 mmol) in ethanol (5 ml) at room temperature and stirred at room temperature for 4 hours. The reaction mixture was concentrated and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol) to obtain 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime (516 mg, 90%).
Reaction SMILES: Cl.C(OC(OCC)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21](OCCOC)=[C:22](OC)[CH:23]=3)[N:18]=[CH:17][N:16]=2)[C:7]1=[O:32])C>C(O)C>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][N:16]=2)[C:7]1=[O:32]
Reactant: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCOC)c(OC)cc23)c2ccccc21
Agent: Cl
Solvent: CCO
Product: O=C1Nc2ccccc2C1c1ncnc2ccccc12
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 11.7 %

Procedure:
2M Hydrochloric acid (40 ml, 80 mmol) was added to a solution of 4-(1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (3.7 g, 79 mmol), (prepared as described in Example 2), in ethanol (300 ml) at 80° C. A precipitate rapidly appeared which then went into solution followed after 15 minutes by the formation of a new precipitate. The mixture was stirred for 45 minutes at 80° C., the solid was collected by filtration, washed with ethanol and then ether and dried under vacuum at 65° C. to give 6-methoxy-7-2-methoxyethoxy)-4-(oxindol-3-yl)quinazoline (2.42 g, 84%) as a red orange solid.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br-].[CH:11]1([Zn+])[CH2:14][CH2:13][CH2:12]1>Cl[Pd](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.[Cu]I.O1CCCC1>[CH:11]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccc(I)cc1
Reactant: [Zn+]C1CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Br-]
Solvent: C1CCOC1
Product: O=Cc1ccc(C2CCC2)cc1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a mixture of 4-iodobenzaldehyde (500 mg), bis(triphenylphosphine)palladium(II) dichloride (75.6 mg), copper(I) iodide (24.6 mg) and dehydrated tetrahydrofuran (10.0 mL), cyclobutylzinc bromide (0.5 mol/L, solution in tetrahydrofuran, 6.46 mL) was added and the mixture was stirred in a sealed tube at 60° C. for 14 hours. After cooling to room temperature, the precipitate was removed by filtration through Celite (registered trademark). The filtrate was concentrated under reduced pressure and thereafter purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-90:10) to give the titled compound as a colorless oil (225 mg).
Reaction SMILES: [C:1]1(C2C=CC(C(OC)=O)=CC=2)C=CC=C(C(OC)=O)[CH:2]=1.[C:21]1([C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=1.C(O)CCCO>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:31]12[C:21]3[CH:26]=[CH:25][C:24](=[CH:23][CH:22]=3)[C:27](=[O:28])[O:29][CH2:30][CH2:2][CH2:1][CH2:40][O:39][C:37](=[O:38])[C:34]([CH:35]=[CH:36]1)=[CH:33][CH:32]=2
Reactant: COC(=O)c1ccc(-c2cccc(C(=O)OC)c2)cc1
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)OC)cc2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: OCCCCO
Product: O=C1OCCCCOC(=O)c2ccc(cc2)-c2ccc1cc2
Temperature: 281 °C
Reaction time: 0.13 h

Procedure:
Dimethyl 3,4'-biphenyldicarboxylate (5.41 g, 0.0200 mole), 21.62 g (0.0800 mole) of dimethyl 4,4'-biphenyldicarboxylate, 18.24 g (0.200 mole) of 1,4-butanediol and 20 μL of titanium tetraisopropoxide are added to a 100-mL round bottom flask equipped with a paddle stirrer, 15-cm heated Vigreux column, distillation head, condenser and graduated receiver. The apparatus is evacuated and refilled with nitrogen three times. A molten salt bath preheated to 220° C. is raised around the flask and after the monomers have melted, the stirrer is started. Methanol begins to distill and after 20 minutes, 7.0 mL is collected. During the next 27 minutes, the temperature is increased to 281° C. then the pressure is slowly reduced to 1 mm Hg. The excess 1,4-butanediol distills and viscosity of the reaction mass slowly increases. After an additional 8 minutes, the clear colorless polymer melt becomes very viscous and the polymerization is stopped. As it cools, the polymer melt quickly crystallizes to an opaque white solid which is then ground to a course powder. The polymer's inherent viscosity is 1.16 dL/g and its peak melting point is 266° C.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1>[CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([OH:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)c1ccc(OCC2CCCCC2)cc1
Solvent: C1CCOC1
Product: C[C@@H](O)c1ccc(OCC2CCCCC2)cc1
Temperature: -14 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
A solution of 1-(4-(Cyclohexylmethoxy)phenyl)ethanone (1.05 g, 4.5 mmol) in THF (2.5 mL) was added dropwise to a solution of (+)-DIP-Cl 2.3 g 1.59 eq) in THF (7.2 mL) at −55° C. under N2. The reaction mixture was allowed to slowly warm to −14° C. After 18 h, the reaction mixture was warmed to room temperature and concentrated in vacuo. The resulting oil was then diluted with Et2O (50 mL) and treated with diethanolamine (1.5 mL). This mixture was stirred for 3 h and then filtered through Celite to remove the white precipitate. The filtrate was removed in vacuo to give a yellowish oil. Flash chromatography on silica gel eluting with 20:1 to 85:15 hexanes-EtOAc afforded 790 mg of material contaminated with reagent by-products as impurities.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[C:10]=2[O:9]1
Reactant: CNCC1Cc2cccc(Br)c2O1
Reactant: COc1ccc(B(O)O)cc1
Product: CNCC1Cc2cccc(-c3ccc(OC)cc3)c2O1

Procedure:
The title compound was prepared (0.052 g, 23%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 4-methoxyphenylboronic acid (0.188 g, 1.24 mmol). mp 214-217° C.
Reaction SMILES: [CH:1]([NH:4][S:5]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH2:17]([O:19][C:20]([C:22]1[C:23](=[O:45])[C:24]2[CH:29]=[N:28][C:27](S(C)(=O)=O)=[N:26][C:25]=2[N:34]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39]3)[CH:35]=1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[C:23](=[O:45])[C:24]2[CH:29]=[N:28][C:27]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][S:5](=[O:7])(=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])=[CH:15][CH:14]=3)=[N:26][C:25]=2[N:34]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39]3)[CH:35]=1)=[O:21])[CH3:18]
Reactant: CC(C)NS(=O)(=O)CCc1ccc(N)cc1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCS(=O)(=O)NC(C)C)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 2-(4-amino-phenyl)-ethanesulfonic acid isopropylamide (58 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a white solid (50 mg, 36%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.34 (s, 1H), 8.53 (s, 1H), 7.88 (br, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.27 (m, 3H), 7.18 (d, J=7.9 Hz, 1H), 6.94 (br, 2H), 5.88 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.61 (m, 1H), 3.22 (m, 2H), 3.10-2.96 (m, 6H), 2.23 (m, 2H), 1.38 (t, J=7.1 Hz, 3H), 1.25 (s, 3H), 1.22 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(Cl)Cl.CS(C)=O.[CH:14]([Si:17]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[O:18][CH:19]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH2:23][CH:22]([OH:30])[CH2:21][CH2:20]1)([CH3:16])[CH3:15]>O>[CH:34]([Si:17]([CH:14]([CH3:16])[CH3:15])([CH:31]([CH3:33])[CH3:32])[O:18][CH:19]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH2:23][C:22](=[O:30])[CH2:21][CH2:20]1)([CH3:36])[CH3:35]
Reactant: CC(C)[Si](OC1CCC(O)Cc2cccnc21)(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)[Si](OC1CCC(=O)Cc2cccnc21)(C(C)C)C(C)C
Temperature: -60 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
In an oven dried 500 mL round bottom flask was charged with OXALYL CHLORIDE (6.49 mL, 72.9 mmol), CH2Cl2 (150 mL) under N2. The flask was cooled to −60° C. and DMSO (6.90 mL, 97 mmol) was added to the reaction mixture dropwise. After finish addition, the reaction was stirred at −60° C. for 30 min before cannula the 9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-6-ol (8.1557 g, 24.31 mmol) (dissolved in 20 mL CH2Cl2 and rinsed with 20 mL CH2Cl2) to the reaction mixture at −60° C. The reaction was stirred at −55° C. for 40 min before addition of TEA (16.94 mL, 122 mmol). The reaction seems formed a thick suspension. The reaction was stirred for 1 hour and water was added to the reaction mixture. The organic layer was separated and the aqueous layer was extract by CH2Cl2 twice. The CH2Cl2 layer was combined, dried (Na2SO4), filtered and concentrated. Flash column by ethyl acetate in hexane from 25% to 50% gave the product as yellow oil (1.49 g, 18.4%). MS(ESI)[M+H+]=334.30; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.36 (d, J=5.04 Hz, 1 H) 7.46 (d, J=7.55 Hz, 1 H) 7.16 (dd, J=7.55, 4.78 Hz, 1 H) 5.22 (dd, J=4.78, 2.27 Hz, 1 H) 4.66 (d, J=14.35 Hz, 1 H) 3.26 (d, J=14.60 Hz, 1 H) 2.94-3.05 (m, 1 H) 2.42-2.55 (m, 1 H) 2.36 (dd, J=14.10, 5.04 Hz, 1 H) 2.03-2.17 (m, 1 H) 1.03-1.16 (m, 3 H) 0.96-1.00 (m, 9 H) 0.89-0.92 (m, 9 H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:44].C(N(CC)CC)C.[F:52][C:53]([F:59])([F:58])[S:54](Cl)(=[O:56])=[O:55]>ClCCl>[F:52][C:53]([F:59])([F:58])[S:54]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:32])[CH3:31])[CH2:25][CH2:26]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:44])(=[O:56])=[O:55]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Yield: 76.9 %

Procedure:
In a similar manner to Step 1 of Example 299, 4-hydroxy-7-(1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl)isoindolinone (150 mg, 0.240-mmol) was suspended in dichloromethane (6.0 mL), and the suspension was treated with triethylamine (0.167 mL, 1.20 mmol) and trifluoromethanesulfonyl chloride (0.046 mL, 0.43 mmol) under ice-cooling, followed by purification by preparative thin-layer chromatography (chloroform/methanol=13/1) to obtain 4-trifluoromethanesulfonyloxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (139 mg, yield 77%).
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:8]1([Mg]Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[NH4+]>ClCCl.O=[Mn]=O>[C:8]1([CH:3]2[CH2:4][O:5][CH2:6][CH2:7][N:2]2[OH:1])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ON1CCOCC1
Reactant: Cl[Mg]c1ccccc1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: ON1CCOCC1c1ccccc1
Reaction time: 1 h
Yield: 10.2 %

Procedure:
Activated MnO2 (0.65 g, 7.41 mmol) was added to a solution of N-hydroxymorpholine (0.25 g, 2.47 mmol) in dichloromethane (15 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of phenylmagnesium chloride (2.0 M in tetrahydrofuran, 2.47 mL, 4.94 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (15 mL) and dichloromethane (15 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×20 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 25% diethyl ether in hexanes to give the title compound (0.045 g, 11%) as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][O:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:21][CH:22]([F:24])[F:23])(=O)=O>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][O:11][N:10]([CH2:21][CH:22]([F:24])[F:23])[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CONC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CON(CC(F)F)C1=O
Yield: 34.9 %

Procedure:
As described in Example 4, Step A, (3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.30 g) was alkylated with 2,2-difluoroethyl trifluoromethanesulfonate (0.35 g). to afford the title product as a white solid (138 mg); 1H-NMR (CDCl3, 400 MHz): 6.05 (tt, 1H), 5.10 (m, 1H), 4.90 (m, 1H), 4.35 (dt, 2H), 4.20 (dd, 1H), 1.50 (s, 9H); along with the O-alkylated product (179 mg): 1H-NMR (CDCl3, 400 MHz): 5.95 (tt, 1H), 4.80 (m, 1H), 4.60 (m, 1H), 3.80-4.10 (m, 3H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]([OH:10])=[O:9])[CH:3]=1.S(Cl)(Cl)=O.[CH3:15]O>>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]([O:10][CH3:15])=[O:9])[CH:3]=1
Reactant: Nc1cc(CC(=O)O)n[nH]1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(N)[nH]n1
Reaction time: 18 h
Yield: 48 %

Procedure:
(5-amino-1H-pyrazol-3-yl)acetic acid (3.02 g, 0.022 mmol) in methanol (32 ml) was added to a mixture of methanol (32 ml) and thionyl chloride (3.15 ml) at 0° C. The resulting mixture was stirred for 18 hours, evaporated and the residue purified by chromatography on silica gel, eluting with methanol:ammonia:dichloromethane (9:1:90), to yield methyl (5-amino-1H-pyrazol-3-yl)acetate (1.58 g, 48% yield):
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)c2ccccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(O)c2ccccc12
Yield: 73.6 %

Procedure:
2.23 g (6.62 mmol) of (4-benzyloxy-naphthalen-1-yloxy)-acetic acid ethyl ester was dissolved in 20 ml of tetrahydrofuran and hydrogenated over 0.5 g of 10% of palladium on charcoal as catalyst at ambient temperature and atmospheric pressure. Filtering off the catalyst and evaporating the solvent yielded 1.2 g of the title compound as light brown solid.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[C:61]([O:69][CH2:70][C@@H:71]([OH:83])[CH2:72][C:73](=[O:82])[CH2:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])(=O)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:61]([O:69][CH2:70][C@H:71]([OH:83])[CH2:72][C@@H:73]([OH:82])[CH2:74][C:75]([O:77][C:78]([CH3:79])([CH3:80])[CH3:81])=[O:76])[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(=O)c1ccccc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@@H](O)COCc1ccccc1
Temperature: 30 °C
Reaction time: 24 h
Yield: 92.3 %

Procedure:
To 40 ml of a culture solution of E. coli HB101 (pNTCMG1) prepared in the same manner as in Example 6, 3 g of glucose, 6 mg of NADP, 4 g of tert-butyl (S)-6-benzoyloxy-5-hydroxy-3-oxohexanoate and 1.6 g of toluene were added. The reaction solution was stirred at 30° C. for 24 hours while adjusting the pH of the reaction solution to pH 6.5 by adding 5 M sodium hydroxide dropwise. After completion of the reaction, the reaction solution was extracted with toluene. The solvent was removed and then an extracted material was analyzed. As a result, tert-butyl (3R,5R)-6-benzyloxy-3,5-dihydroxyhexanoate having an excess rate of a diastereomer of 99.7% d.e. was obtained in a yield of 92.3%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.Cl[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH3:21])[C:13](=[O:22])[CH2:12][N:11]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:21][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:10]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[N:11][CH2:12][C:13]1=[O:22]
Reactant: CN1C(=O)CN=C(Cl)c2ccccc21
Reactant: CC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1CCN(C2=NCC(=O)N(C)c3ccccc32)CC1
Temperature: 25 °C

Procedure:
4-Methyl piperidine (1.56 g) was added to a solution of crude 5-chloro-1,2-dihydro-1-methyl-3H-1,4-benzodiazepin-2-one hydrochloride (0.005 mol) in dichloromethane (50 ml) cooled in ice. After warming to room temperature, sodium bicarbonate solution (20 ml) was added. The organic phase was separated, dried (Na2SO4) and evaporated to give an orange oil which was purified by column chromatography on silica with CH2Cl2 ∆CH2Cl2 :MeOH 95:5 as eluant to afford product.