Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:4]([C:17](=[O:30])[N:18]([CH3:29])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)=[CH:5][NH:6][C:7](=[NH:16])[N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]1=[O:15])#[N:3].[OH-].[Na+].C(OCC)C.C(OC(C)C)(C)C>>[CH3:29][N:18]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=1)[C:17]([C:4]1[C:2]([NH2:3])=[N:16][C:7]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]2=[O:15])=[N:6][CH:5]=1)=[O:30]
Reactant: CN(C(=O)C(C#N)=CNC(=N)N1CC(C)(C)NC1=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Product: CN(C(=O)c1cnc(N2CC(C)(C)NC2=O)nc1N)c1cccc(C(F)(F)F)c1
Yield: 32.6 %

Procedure:
2.67 g (6 mmol) of 1-cyano-1-[N-methyl-N-(3-trifluoromethylphenyl)carbamoyl]-2-[imino(4,4-dimethyl-2-oxo-1-imidazolidinyl)methylamino]ethene hydrochloride are heated at 187°-189° C. under vacuum (4-6 mbar) for 10 min in a bath preheated to 190° C. After cooling, the solidified melt was mixed with 5 ml of 2N sodium hydroxide solution. 12 ml of diethyl ether/diisopropyl ether 5:1 were added. Stirring resulted in initial formation of two clear phases, from which crystals separated out. The mixture was stirred while cooling in ice for 1 hour, and the crystals were filtered off with suction, washed with water and taken up in 50 ml of CH2Cl2. The solution which formed was extracted successively three times with 5 ml of 0.5N NaOH each time and twice with 5 ml of water each time, dried over Na2SO4, filtered and evaporated. The residue was triturated with diisopropyl ether, filtered off with suction and dried as in Example 13. 0.82 g (=32.6% yield) of the compound I was obtained, melting point 209°-210° C.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-:8])[CH:3]=1.CN(C1C=CC=CN=1)C.F[P-](F)(F)(F)(F)F.N1C2C=CC=C(O[P+](N(C)C)(N(C)C)N(C)C)C=2N=N1.[CH3:47][CH:48]1[CH2:53][CH2:52][CH2:51][N:50]([CH2:54][C:55]2[CH:56]=[C:57]([CH:63]=[CH:64][CH:65]=2)[O:58][CH2:59][CH2:60][CH2:61][NH2:62])[CH2:49]1>C(#N)C>[CH3:47][CH:48]1[CH2:53][CH2:52][CH2:51][N:50]([CH2:54][C:55]2[CH:56]=[C:57]([CH:63]=[CH:64][CH:65]=2)[O:58][CH2:59][CH2:60][CH2:61][NH:62][C:1]([C:2]2[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:49]1
Reactant: CC1CCCN(Cc2cccc(OCCCN)c2)C1
Reactant: O=C(O)c1ccc[n+]([O-])c1
Agent: CN(C)[P+](Oc1cccc2[nH]nnc12)(N(C)C)N(C)C
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CC1CCCN(Cc2cccc(OCCCNC(=O)c3ccc[n+]([O-])c3)c2)C1

Procedure:
To a suspension of 2.8 g of nicotinic acid 1-oxide, 2.5 g of dimethylaminopyridine, 8.8 g of benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate in 40 ml of acetonitrile, 5 g of 3-[3-(3-methylpiperidinomethyl)phenoxy]propylamine dissolved in 10 ml of acetonitrile are added at 20° C. under stirring. A rising of the temperature up to 30° C. is observed and a solution is obtained which is then stirred 2 hours at room temperature. The mixture is concentrated under reduced pressure, the residue is treated with 20 ml of concentrated sodium hydroxide and extracted 4 times with 40 ml of ethyl acetate. After evaporation of the organic extracts, the residue is purified by chromatography on silica as described in Example 7. Thus, the N-[3-[3-(3-methylpiperidinomethyl)phenoxy]propyl]-3-pyridinecarboxamide 1-oxide is obtained, identical to the product of Example 8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.Br[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]>CN(C)C(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCBr
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCn1ccc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of 4-benzyloxy-1H-pyridin-2-one (1.0 g, 4.97 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.86 mL, 12.43 mmol) and 1-bromo-3-methyl butane (0.715 mL, 5.96 mmol) in N,N-dimethylacetamide (20 mL) was heated at 65° C. for 5 days. The solution was cooled to about 25° C. and partitioned between 10% aqueous ammonium chloride and dichloromethane, the organic layer separated and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 1% methanol in dichloromethane to provide the title compound (0.569 g, 42%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.N1CC[CH2:15][C@H:11]1[C:12](O)=O>CC(C)=O>[CH3:15][C:11]1[CH:12]=[CH:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Nc1ncccc1C=O
Solvent: CC(C)=O
Product: Cc1ccc2cccnc2n1
Temperature: 25 °C
Yield: 641.6 %

Procedure:
To a solution of 2-amino-3-pyridinecarboxaldehyde (from step c, 24.57 g) in acetone (750 mL) was added proline (2.3 g, 20 mmole), then the mixture was heated to reflux. After 48 hr the mixture was cooled to RT, filtered, and concentrated. Flash column chromatography on silica gel (35% acetone/hexanes) gave the title compound (18.5 g, 64% over 3 steps) as an orangish-yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.07 (m, 1 H), 8.10 (m, 2H), 7.40 (m, 2H), 2.80 (s, 3H); MS (ES) m/e 145 (M+H)+.
Reaction SMILES: Cl.[C:2]([O:7][CH2:8][CH2:9][NH2:10])(=[O:6])[C:3]([CH3:5])=[CH2:4].C(N(CC)CC)C.[F:18][C:19]([F:25])([F:24])[S:20](Cl)(=[O:22])=[O:21].CCOCC>C(Cl)Cl>[C:2]([O:7][CH2:8][CH2:9][NH:10][S:20]([C:19]([F:25])([F:24])[F:18])(=[O:22])=[O:21])(=[O:6])[C:3]([CH3:5])=[CH2:4]
Reactant: C=C(C)C(=O)OCCN
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: C=C(C)C(=O)OCCNS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 15 g (0.091 mol) of 2-aminoethyl methacrylate hydrochloride (available from Aldrich) in 250 ml of anhydrous methylene chloride was added 18.4 g of redistilled triethylamine (0.182 mol). After the mixture was stirred at room temperature for 1 hour, 15.3 g trifluoromethane sulfonylchloride (0.091 mol) was added. The resulting mixture was further stirred at room temperature overnight. About 200 ml ether was added. The mixture was filtered to remove the precipitate formed. The filtrate was sequentially washed with 2×100 ml of 5% HCl, 100 ml of saturated NaHCO3, 2×100 ml brine, and then dried over MgSO4. The solvents were removed by rotavap. About 14.5 g of viscous liquid was obtained. The product was further purified by recrystallization from 1:1 hexane/chloroform to give about 12 g white solid (51%) having a melting point of 55-58° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[OH:18]O>C(O)(=O)C>[N+:1]1([O-:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: OO
Agent: N#Cc1cnn2c(-c3cccnc3)ccnc12
Solvent: CC(=O)O
Product: [O-][n+]1ccccc1

Procedure:
A mixture of 4.42 g of 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 50 ml. of glacial acetic acid and 5 ml. of 30% hydrogen peroxide is heated on a steam bath for 2 hours. The mixture is cooled, filtered and the solid recrystallized from acetic acid to give 2.05 g. of the product of the example, m.p. 294°-295° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:11]1(NN)[CH:16]=CC=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:16]=[CH:11][C:12]([CH3:13])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNc1ccccc1
Reactant: NNc1ccc(Cl)c(Cl)c1
Product: Cc1ccn(-c2ccc(Cl)c(Cl)c2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 1 with 3,4-dichlorophenyl hydrazine · HCl substituted for phenyl hydrazine. There was obtained the title compound; HRMS (M+H)+ : calc. 501.055493; found 501.053920.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:6][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1
Reactant: NCc1ccc(F)c(Cl)c1
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CSC(NCc2ccc(F)c(Cl)c2)=N1
Temperature: 0 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
To a suspension of 3-chloro-4-fluorobenzylamine (2.5 g, 15.66 mmol) and Rhodanine (2 g, 15 mmol) in acetonitrile (50 mL) was added DIPEA (5.57 mL, 32 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (4.34 g, 16 mmol) was added in two portions within a period of 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 2 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (200 mL) and methanol (500 mL). The combined solvents were removed under the vacuum and the crude residue was diluted with water (150 mL) and ethyl acetate (150 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the partial solvent under the vacuum gave lot of solids. After cooling in the refrigerator, the solids were collected by filtration and washed with cold ethyl acetate. After drying in air, 2.5 g (64% yield) of 2-(3-chloro-4-fluorobenzylamino)-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C10H8ClFN2OS (M+) 258.0030. found 258.0029.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O-]S([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of serine methyl ester hydrochloride (3.0 g, 19.28 mmol) and triethylamine (2.7 mL, 19.28 mmol) in methylene chloride (30 mL) was added benzaldehyde (1 equivalent), followed by 2 g anhydrous MgSO4. The mixture was stirred at room temperature in a sealed flask for 20 hours, and then the solids were filtered away, and the filtrate was evaporated. The residue was redissolved in methanol (50 mL), and sodium borohydride (1 equivalent) was carefully added. The mixture was stirred for 30 minutes, was diluted with methylene chloride, was washed with NaHCO3, and was then dried over magnesium sulfate. The desired title product was obtained as a yellow oil and was used crude. N-4-methoxybenzyl serine methyl ester was made in a similar fashion using anisaldehyde in place of benzaldehyde.
Reaction SMILES: C([Li])CCC.[C:6]1([S:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[CH:17]=[CH:16]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN([CH:27]=[O:28])C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:6]1([S:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[CH:17]=[C:16]2[CH:27]=[O:28])(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
n-Butyllithium (11.9 mL, 19.0 mmol, 1.6M in hexanes) was added to a solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.50 g, 13.6 mmol) in THF (53 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes, and then DMF (4.2 mL, 54.2 mmol) was added. The reaction mixture was warmed up to 0° C. and stirred for 3 hours. It was then treated with saturated aqueous ammonium chloride and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (2.4 g, 62%) as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[O:40]=[C:20]1[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]#[N:10]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: N#Cc1cccc(CBr)c1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: N#Cc1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using α-bromo-m-tolunitrile to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile was obtained (66%) as a colorless solid: mp 173-178° C. (ethyl acetate/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.60-7.63 (m, 3H), 7.44-7.47 (m, 1H), 7.21-7.24 (m, 2H), 7.05 (t, J=7.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 4.93-4.97 (m, 3H), 4.66-4.69 (m, 1H), 4.13-4.17 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.7, 155.3, 144.8, 141.5, 138.4, 137.4, 132.1, 131.8, 131.7, 130.9, 129.9, 129.0, 124.3, 123.9, 120.7, 118.4, 113.1, 111.4, 108.8, 99.5, 80.1, 64.5, 63.9, 58.0, 43.4; MS (ES+) m/z 410.8 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cc(F)ccc2s1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2sc(CBr)nc2c1
Yield: 20.4 %

Procedure:
A mixture of 5-fluoro-2-methyl-1,3-benzothiazole (500 mg, 2.99 mmol), NBS (600 mg, 3.37 mmol) and AIBN (125 mg, 0.76 mmol) in carbon tetrachloride (25 ml) was heated at reflux for 20 hours under nitrogen with stirring. The solution was then concentrated to give a residue which was purified by silica gel column chromatography using 1% ethyl acetate in petroleum ether to afford 2-(bromomethyl)-5-fluoro-1,3-benzothiazole as a yellow solid (150 mg, 20%). 1H NMR (400 MHz, CDCl3): δ 7.81 (dd, J=8.8, 5.2 Hz, 1H), 7.70 (dd, J=9.2, 2.4 Hz, 1H), 7.23-7.16 (m, 1H), 4.80 (s, 2H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CN(C=O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:3][C:4]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of 1.07 g (5.24 mmol) of 2,6-dichlorobenzothiazole in dry DMF (25 mL) was added 2.4 g of potassium carbonate (15.7 mmol) and 0.5 g of piperazine (5.8 mmol). The mixture was stirred at room temperature for 4 h. When the reaction was complete it was partitioned between EtOAc (150 mL) and water (50 mL) and separated. The aqueous layer was extracted with EtOAC (2×100 mL). The combined organic layers were then washed with water (2×25 mL), brine, dried over Na2SO4, and the solvent was removed under reduced pressure to give 1.33 g (100%) of desired product as a white solid. MS (electrospray): exact mass calculated for C11H12ClN3S, 253.04; m/z found, 254.0 [M+H]+.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[C:22]([F:28])[CH:21]=1.[Si]([C:33]([F:36])([F:35])[F:34])(C)(C)C.Cl>C1COCC1>[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]([OH:25])[C:33]([F:36])([F:35])[F:34])=[C:22]([F:28])[CH:21]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Br)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.9 %

Procedure:
TBAF (0.1 ml) was added to a solution of 4-bromo-2-fluoro-benzaldehyde (2.03 g, 10 mmol) and TMSCF3 (20 ml, 12 mmol) in 10 ml THF at 0° C. The formed mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was then treated with 12 ml of 3M HCl and stirred overnight. The product was extracted with ethyl acetate (3×20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 2.4 g of 1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanol (yield: 90%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.ClC1C=C(C=CC=1)C(OO)=[O:15]>C(OCC)(=O)C>[N+:1]1([O-:15])[CH:2]=[CH:3][C:4]2[C:9]=1[NH:8][CH:7]=[CH:6][CH:5]=2
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: [O-][n+]1ccc2ccc[nH]c1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
To a solution of 7-azaindole (84.8 g, 0.72 mol) in ethyl acetate (700 mL) at 0° C. was added a solution of m-chloroperoxybenzoic acid (19.6 g, 1.14 mol) in ethyl acetate (600 mL) over 1.5 h. The resulting solution was stirred at room temperature for 4 h. After cooling to 0° C., the resulting slurry was filtered and the solid was washed with ethyl acetate (3×30 mL), and the filtrate concentrated in vacuo. The residue was treated at 0° C. with an aqueous 30% potassium carbonate solution to pH 9.5˜10.5. This mixture was stirred for 2 h at 0° C., filtered to collect the precipitate and the precipitate washed with water (2×20 mL) and dried in vacuo to afford 7-azaindole N-oxide (77 g, 80%); LC/MS m/e calcd for C7H6N2O [M+H]+ 135.15, observed 134.9.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][CH2:12][C@H:13]([O:17][CH2:18][CH:19]=[N:20][OH:21])[CH2:14][CH:15]=[CH2:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl.O>[CH2:4]([O:11][CH2:12][C@@H:13]1[O:17][CH2:18][C:19]2=[N:20][O:21][CH2:16][C@@H:15]2[CH2:14]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=CC[C@H](COCc1ccccc1)OCC=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: O
Product: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
An aqueous solution of sodium hypochlorite (14.5% solution, 600 mL) was added drop-wise to a 0° C. solution of 2-{[(2R)-1-(benzyloxy)pent-4-en-2-yl]oxy}-N-hydroxyethanimine (C3) (224 g from the previous step, ≦0.759 mol) in dichloromethane (1 L), while the internal temperature was maintained below 15° C. After completion of the addition, the reaction mixture was left to stir at 0° C. for 1.5 hours, then diluted with water (1 L) and dichloromethane (500 mL). The aqueous layer was extracted with dichloromethane (2×500 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (500 mL), water (500 mL) and again with saturated aqueous sodium chloride solution (500 mL). They were subsequently dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 25% ethyl acetate in heptane) afforded the product as a colorless oil. The indicated relative stereochemistry of compound P1 was assigned based on nuclear Overhauser enhancement studies, which revealed an interaction between the methine protons on carbons 3a and 5. Yield: 85.3 g, 345 mmol, 45% over 2 steps. LCMS m/z 248.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.27-7.40 (m, 5H), 4.77 (d, J=13.5 Hz, 1H), 4.54-4.65 (m, 3H), 4.22 (dd, J=13.5, 1 Hz, 1H), 3.79 (dd, J=11.7, 8.0 Hz, 1H), 3.69-3.76 (m, 1H), 3.57 (dd, half of ABX pattern, J=10.1, 5.9 Hz, 1H), 3.49 (dd, half of ABX pattern, J=10.1, 4.3 Hz, 1H), 3.39-3.5 (m, 1H), 2.20 (ddd, J=12.9, 6.5, 1.6 Hz, 1H), 1.51-1.62 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([O:14][CH2:15][CH:16]=[N:17][OH:18])[CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[O-].[Na+]>ClCCl.O>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:14][CH2:15][C:16]2=[N:17][O:18][CH2:13][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[C@H](COCc1ccccc1)OCC=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1

Procedure:
A solution of 2-{[(2R)-1-(benzyloxy)pent-4-en-2-yl]oxy}-N-hydroxyethanimine (C4) (7.12 g, 28.6 mmol) in dichloromethane (168 mL) was placed in a room temperature water bath. Triethylamine (0.299 mL, 2.14 mmol) was added, followed by addition of bleach (aqueous sodium hypochlorite solution, 6.15%, 71 mL, 59 mmol) at a rate slow enough to maintain the internal reaction temperature between 22° C. and 25.5° C. Upon completion of the addition, the reaction mixture was diluted with water and extracted three times with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 0% to 35% ethyl acetate in heptane) provided the product as a yellow oil. The indicated relative stereochemistry of compound P1 was assigned based on nuclear Overhauser enhancement studies, which revealed an interaction between the methine protons on carbons 3a and 5. Yield: 5.65 g, 22.8 mmol, 80%. LCMS m/z 248.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.51-1.63 (m, 1H), 2.17-2.24 (m, 1H), 3.40-3.52 (m, 1H), 3.49 (dd, half of ABX pattern, J=10.2, 4.2 Hz, 1H), 3.57 (dd, half of ABX pattern, J=10.2, 5.8 Hz, 1H), 3.68-3.77 (m, 1H), 3.79 (dd, J=11.8, 8.1 Hz, 1H), 4.23 (dd, J=13.5, 1.2 Hz, 1H), 4.54-4.65 (m, 3H), 4.77 (d, J=13.5 Hz, 1H), 7.27-7.39 (m, 5H).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([OH:8])([CH3:7])[CH3:6])=[O:3].[OH:9][CH2:10][C:11]([C@H:13]([C@@H:15]([C@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])=[O:12].Cl[O-].[Na+]>O.[Ni](Cl)Cl>[CH3:1][C:2]([CH2:4][C:5]([OH:8])([CH3:7])[CH3:6])=[O:3].[CH2:19]([OH:20])[C@H:17]([OH:18])[C@@H:15]([OH:16])[C@H:13]([OH:14])[C:11]([C:10]([OH:3])=[O:9])=[O:12]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl[Ni]Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)CC(C)(C)O
Solvent: O
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 1 h

Procedure:
For a comparison, the same reaction vessel as above the inside of which was under atmospheric pressure was placed in water at 75° C., and the aqueous solutions of diacetone-L-sorbose, nickel chloride and sodium hypochlorite were fed into the reaction vessel in the same manner as above. The reaction temperature was found to rise temporarily to 85°-90° C., and then lowered to 75 ° C. The reaction concluded in 60 minutes. The resultant reaction mixture was worked up in the same manner as above, to provide diacetone-2-keto-L-gulonic acid.