Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C@H:12]([OH:16])[CH2:13][CH:14]=[CH2:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>O1CCCC1>[CH2:21]([O:20][CH:19]([O:23][CH2:24][CH3:25])[CH2:18][O:16][C@H:12]([CH2:13][CH:14]=[CH2:15])[CH2:11][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:22]
Reactant: C=CC[C@@H](O)COCc1ccccc1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 98.8 g, 2.47 mol) in tetrahydrofuran (1 L) at room temperature was added drop-wise over 30 minutes a solution of (2R)-1-(benzyloxy)pent-4-en-2-ol (C1) (190 g, 0.988 mol) in tetrahydrofuran (500 mL), while the reaction temperature was maintained below 30° C. After 30 minutes, a solution of 2-bromo-1,1-diethoxyethane (390 g, 1.98 mol) in tetrahydrofuran (500 mL) was added drop-wise. The reaction mixture was stirred at room temperature for 1 hour, then the temperature was gradually increased to 70° C. and the reaction mixture was left to stir at 70° C. for 18 hours. It was then cooled to room temperature, subsequently cooled in an ice bath, and quenched by slow addition of ice/water (200 mL), while keeping the internal reaction temperature at approximately 18° C. The mixture was partitioned between saturated aqueous sodium chloride solution (1 L) and ethyl acetate (1 L), and the organic layer was washed with saturated aqueous sodium chloride solution (1 L), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was effected by filtration through a pad of silica (Gradient: 0% to 20% ethyl acetate in heptane) to afford the product as an orange oil. Yield: 257 g of 60% purity, approximately 500 mmol, 51% yield and 57.76 g of 90% purity, approximately 170 mmol, 17% yield. 1H NMR (400 MHz, CDCl3), product peaks only: δ 7.26-7.38 (m, 5H), 5.78-5.90 (m, 1H), 5.02-5.13 (m, 2H), 4.61 (t, J=5.3 Hz, 1H), 4.55 (s, 2H), 3.48-3.74 (m, 9H), 2.31-2.37 (m, 2H), 1.22 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:12]([OH:14])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.N1([C:27](=O)[C:26]2N(C)C=N[C:21]=2N(C)C1=O)C.C1(C)CCC(C(C)C)C(O)C1>O.C(O)C>[CH:26]([O:13][C:12](=[O:14])[C@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)[NH2:2])([CH3:27])[CH3:21]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: CC1CCC(C(C)C)C(O)C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
HCl (70 g) and tyrosine (7 g) were dissolved in water (1 L). Caffeine (50 g), ethanol (100 ml) and menthol (20 g) were added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[N+]([O-])([O-])=O.[NH4+].[Ce].[Ce].[Cl:17]N1C(=O)CCC1=O>C(#N)C>[Cl:17][C:7]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: FC(F)(F)c1n[nH]cc1Cl
Yield: 143.6 %

Procedure:
An acetonitrile solution (20 ml) of 3-trifluoromethyl-1H-pyrazole (0.5 g), dicerium ammonium nitrate (1.0 g) and N-chlorosuccinimide (0.7 g) was refluxed for 3 hours. After cooling, the reaction solution was washed with saturated aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride. After drying an organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure to obtain 4-chloro-3-trifluoromethyl-1H-pyrazole (0.9 g).
Reaction SMILES: O1CCN(CC[N+]#[C-])CC1.[C:11]([C@H:14]([C@@H:26]([CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28])[CH2:15][N:16]1[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[N:18]([CH3:24])[C:17]1=[O:25])([OH:13])=O.[OH:41][N:42]1C=CC=CC1=O.C[Si](C)(C)ON>C(Cl)Cl>[CH:36]1([CH2:35][C@H:26]([C@@H:14]([C:11](=[O:13])[NH:42][OH:41])[CH2:15][N:16]2[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[N:18]([CH3:24])[C:17]2=[O:25])[C:27]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:28])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CN1C(=O)N(C[C@H](C(=O)O)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reactant: O=c1ccccn1O
Agent: C[Si](C)(C)ON
Agent: [C-]#[N+]CCN1CCOCC1
Solvent: ClCCl
Product: CN1C(=O)N(C[C@H](C(=O)NO)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
0.78 g of 2-morpholino-ethyl isocyanide was added at 22° to a suspension of 2.11 g of 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl)piperidine from Example 11 and 0.61 g of N-hydroxy-2-pyridone in 21 ml of methylene chloride and the mixture was stirred for 3 hrs. The solution was treated with 0.58 g of O-trimethylsilyl-hydroxylamine and stirred for 2 hrs. The reaction mixture was washed with saturated NaHCO3 solution and with water and evaporated. The residue was dissolved in 20 ml of t-butyl methyl ether and 0.23 ml of water, stirred for 11/2 hrs. at 22°, the suspension was diluted with 10 ml of hexane, filtered and the residue was dried at 22°/11 mbar, there being obtained 1.82 g (83%) of pure 1-[3-cyclopentyl-2(R)-[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-ethyl]propionyl]piperidine I, MS (EI): 436 (40%).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH:10]=[CH:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-:3])=[O:2].CO.C(=O)([O-])[O-].[K+].[K+].CC(C)(O)[C:26]#[N:27]>O1CCCC1>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH:10]([C:26]#[N:27])[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1C=CCCc2ccc([N+](=O)[O-])cc21
Reactant: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1CCc2ccc([N+](=O)[O-])cc2C(=O)C1
Temperature: 90 °C

Procedure:
A mixture of 50 g of 3-nitro-8,9-dihydro [5H] benzocycloheptene-5-one, 1200 ml of methanol, 120 ml of tetrahydrofuran, 100 ml of a 10% aqueous potassium carbonate and 50 ml of acetone cyanhydrin under nitrogen was refluxed for an hour in a bath at 90° C. and the mixture was concentrated to about 200 ml under reduced pressure. The mixture was cooled to 20° C. and was extracted with methylene chloride. The organic phase was washed with water, dried and distilled to dryness under reduced pressure. The 58 g of brown oil residue were crystallized from 50 ml of methanol and the mixture was vacuum filtered to obtain 46 g of 3-nitro-5-oxo-6,7,8,9-tetrahydro [5H] benzocycloheptene-7-carbonitrile with a melting point of 107° C. and then 120° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:21])=[O:14])=[CH:11][CH:10]=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)c1ccc(OCc2ccccc2)cc1
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1

Procedure:
In the synthesis of an alcohol to be reacted with the ester (v), 4-benzyloxybenzoic acid (vi) is first reacted with a halogenating agent such as oxalyl chloride to obtain 4-benzyloxybenzoyl chloride (vii).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].O=S(Cl)[Cl:16]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-fluoro-4-nitrobenzoic acid (30 g, 162.0 mmol) in toluene (500 mL) was added SOCl2 (35 mL, 486 mmol). The reaction was heated to 110° C. at which point the reaction became homogeneous. The reaction was stirred at 110° C. for 3 h. The reaction had not gone to completion so an additional portion of SOCl2 (10 mL) was added. The reaction was stirred for an additional 3 h. A small amount of stalling material remained thus a final portion of SOCl2 (10 mL) was added and the reaction was heated for 2 h. The resulting green solution was cooled to room temperature and allowed to stand over night. The reaction mixture was filtered and concentrated in vacuo. Toluene (300 mL) was added to the resulting oil and removed under reduced pressure (2×). The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:17][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:18].[Na].[N-:20]=[N+:21]=[N-:22].[Cl-].[NH4+]>CN(C)C=O.N1C=CC=CC=1>[CH3:1][C:2]1[S:17][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]4[NH:22][N:21]=[N:20][N:16]=4)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1sc2nc3ccc(C#N)cn3c(=O)c2c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1sc2nc3ccc(-c4nnn[nH]4)cn3c(=O)c2c1C

Procedure:
From 0.43 g (0.0017 mol) of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile (Example 32), 0.33 g (0.0051 mol) of sodium size azide and 0.3 g (0.0056 mol) of ammonium chloride in 80 ml of dimethylformamide, following the procedure of Example 34, there is obtained 0.14 g of 2,3-dimethyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one with pyridine (1:0.6); mp 292°-294° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].CCN(CC)CC.Cl>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:13]=[CH:12]/[C:11]([OH:15])=[O:14])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(I)ccc1Br
Reactant: C=CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(/C=C/C(=O)O)ccc1Br
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-4-iodo-2-methoxybenzene (L. A. Hasvold et al, US 2004/0254159, EXAMPLE 57B) (33.45 g, 107 mmol) in MeCN (100 mL) was added acrylic acid (9.61 g, 133 mmol), Et3N (37.2 mL, 267 mmol) and palladium acetate (719 mg, 3.2 mmol). The reaction mixture was heated to 90° C. for 40 minutes, cooled to RT and poured into 2.4 L 1M HCl. After stirring for 30 minutes, the solid was filtered, heated to reflux in EtOH (230 mL), allowed to cool to RT and stirred overnight. The solid was filtered and washed with 1:1 EtOH hexane (50 mL) to give desired product. LRMS ESI+ (M+H)+257.0.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: [Br-]
Reactant: CC(C)c1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)c1cc(Br)ccc1O
Yield: 179.9 %

Procedure:
First, 20.4 g of 2-isopropylphenol and 750 ml of chloroform were charged into a reaction vessel, and 80 g of tetra-n-butylammonium tribromide was added at room temperature (about 20° C. ) with stirring and the mixture was stirred at room temperature for additional 24 hours. To the reaction solution, 750 ml of a saturated sodium sulfite solution was added, and the mixture was shaken vigorously to concentrate the chloroform layer. To the residue, 500 ml of diethyl ether and 500 ml of 10% hydrochloric acid were added, and the mixture was shaken vigorously. The ether layer was dried over anhydrous magnesium sulfate and concentrated to give 32 g of 4-bromo-2-isopropylphenol (yield, 100%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:13]OC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:13])[N:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CON(C)C(=O)c1cccnn1
Solvent: C1COCCO1
Product: CC(O)c1cccnn1
Temperature: 150 °C
Reaction time: 0.58 h
Yield: 328.8 %

Procedure:
A suspension of compound 2 (20 mg, 0.049 mmol) and Lawesson's Reagent (20 mg, 0.049 mmol) in anhydrous dioxane (1 mL) was stirred at 150° C. for 35 min in a CEM microware reactor. The mixture was concentrated in vacuo, and the residue was purified by prep-TLC to give compound 3 (20 mg, 96%) as a yellow solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:13]OC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C1(C)C=CC=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:13])[N:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CON(C)C(=O)c1cccnn1
Solvent: Cc1ccccc1
Product: CC(O)c1cccnn1
Temperature: 130 °C
Yield: 248.7 %

Procedure:
To a solution of compound 2 (68 mg, 0.149 mmol) in dry toluene (2 mL) was added Lawesson's reagent (91 mg, 0.224 mmol) under N2. The reaction mixture was heated in a CEM microwave reactor at 130° C. for 1 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (petroleum ether:EtOAc=3:1) to give compound 3 (46 mg, 66%) as a white solid.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.Cl.[NH2:13][OH:14].C(N(CC)CC)C>CO>[C:9]1(=[N:13][OH:14])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH2:11]1
Reactant: O=C1CCCc2ccccc21
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: ON=C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 108.7 %

Procedure:
To a solution of α-tetralone (10 g, 68.5 mmol) in anhydrous MeOH (175 mL), hydroxylamine hydrochloride (7.6 g, 109.6 mmol) and triethylamine (15.3 mL, 109.6 mmol) were added. The mixture was stirred at room temperature for 16 hrs, followed by removal of the solvent in vacuo. The residue was dissolved in DCM, washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to yield crude 3,4-dihydro-2H-naphthalen-1-one oxime (12 g). MS [M+H]+: 162.1; tR=2.03 min. (method 1)
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:12][OH:13]>C(O)C.O>[C:1]1(=[N:12][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCc2ccccc21
Reactant: NO
Solvent: O
Solvent: CCO
Product: ON=C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5 mL (37.5 mmole) 1-tetralone in 25 mL ethanol was added 2.7 mL (40 mmole) of 50% hydroxylamine in water. The reaction mixture was heated under reflux for 2 hrs, then stirred at room temperature for 16 hrs. The solution was concentrated under reduced pressure. The residue was recrystallized from toluene/hexane to give 1-tetralone oxime (3,4-dihydro-2H-naphthalen-1-one oxime), 3.86 g, m.p. 101-102°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.C1C(=O)N([Br:36])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.O>[Br:36][CH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)c(F)c1
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1F
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a solution of 2-fluoro-4-methyl-benzonitrile (1.45 g, 10.7 mmol) in CCl4 (100 mL) was added 1,1′-azobis(cyclohexanecarbonitrile) (0.240 g, 0.982 mmol) and NBS (2.19 g, 12.3 mmol). The mixture was stirred and heated at reflux overnight, and then cooled to room temperature. A solution of Na2S2O3 (5 g) in H2O (100 mL) was added, and the organic layer was collected. The aqueous layer was extracted with CH2Cl2 (3×50 mL), and the extracts were combined and dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified on silica gel column (1:10 EtOAc/hexanes), affording 4-bromomethyl-2-fluoro-benzonitrile as a pale yellow oil (1.49 g, 65%). 1H NMR (CDCl3) δ 4.45 (s, 2H), 7.24-7.30 (m, 2H), 7.60 (dd, 1H, J=6.3, 8.1 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2].[N:13](OC(C)(C)C)=O>C(O)(=O)C.C(OCC)(=O)C>[CH3:2][C:1]1[C:3]2[C:4](=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[NH:5][N:13]=1
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Reactant: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of 10 g (0.06 mol) of 2-ethyl-5-nitroaniline (prepared by nitration of 2-ethylaniline: Bergman and Sand, Tetrahedron 1990, 46, 6085-6112) in 300 ml of glacial acetic acid, at room temperature, was added a solution of 8.98 ml (0.06 mol) of tert-butyl nitrite in 40 ml of acetic acid dropwise over 15 min. After the addition was complete the solution was allowed to stir for 30 min. The acetic acid was removed in vacuo to afford an orange solid. The solid was dissolved in approximately 120 ml of ethyl acetate and washed with 3×100 ml sat. aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed in vacuo to afford 3-methyl-6-nitroindazole as a yellow solid (10.4 g, 98%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH3:14][NH:15][C:16]([C:18]1[CH:22]=[C:21]([CH2:23][OH:24])[O:20][N:19]=1)=[O:17].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:24][CH2:23][C:21]1[O:20][N:19]=[C:18]([C:16](=[O:17])[NH:15][CH3:14])[CH:22]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNC(=O)c1cc(CO)on1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
2.58 g (12.81 mmoles) of 4-nitrophenyl chloroformate are added in small portions to a solution of 2.00 g (12.81 mmoles) of 3-methylcarbamoyl-isoxazol-5-ylmethanol (commercial), 1.52 g (19.21 mmoles) of pyridine and 0.157 g (1.28 moles) of N,N-dimethylaminopyridine in 15 ml of dichloromethane, cooled to about 0° C. The medium is maintained with stirring for 1 hr at 0° C. then for 1 hr at ambient temperature. The precipitate formed is filtered off, then copiously rinsed with diisopropyl ether. After drying under vacuum at about 60° C., 2.6 g of pure product are obtained in the form of a white powder.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C@H:28]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[CH2:38][CH2:39][C:40]([OH:43])([CH3:42])[CH3:41])[C@H:30]([CH3:44])[N:29]1[C:45](=[O:55])[CH2:46][C:47]1[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:54])(C(C)(C)C)(C)C>O1CCCC1.CC(O)C>[Cl:54][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]([Cl:53])[C:47]=1[CH2:46][C:45]([N:29]1[C@@H:28]([CH2:27][OH:26])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[CH2:38][CH2:39][C:40]([OH:43])([CH3:41])[CH3:42])[C@@H:30]1[CH3:44])=[O:55]
Reactant: C[C@H]1c2cccc(CCC(C)(C)O)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C[C@H]1c2cccc(CCC(C)(C)O)c2C[C@H](CO)N1C(=O)Cc1c(Cl)cccc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
Add tetra-n-butylammonium fluoride (651.71 mL, 651.71 mmol, 1M in THF) to a solution of 1-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanone (400 g, 566.71 mmol) in tetrahydrofuran (4 L) at 5° C. in an appropriate vessel. Heat the mixture to 20° C. and stir. After 3 hours, remove 3 L of tetrahydrofuran by concentrating under reduced pressure and dilute the residues with ethyl acetate (2.5 L). Wash the organics with saturated aqueous ammonium chloride (2 L), water (2 L) and brine (2×2 L). Dry the ethyl acetate solution over anhydrous sodium sulfate and concentrate under reduced pressure to give an oil. Dissolve this oil in 2-propanol (2.5 L) and concentrate under reduced pressure to give an oil. Purify by chiral SFC using AS-H column (50×250 mm, 5 micron particle size) eluting with 80% supercritical carbon dioxide and 20% of a 0.2% solution of diethylmethylamine in isopropyl alcohol at 280 g/min to give the title compound (182.8 g, 389.62 mmol). MS (m/z): 450.2 (M+1 (35C1)), 452.2 (M+1 (37Cl)). Optical rotation: [α]20D −39.4° (c=0.95, MeOH).
Reaction SMILES: CCN(C1C=CC2C3(C4C(OC=2C=1)=CC(C)=C(NC1C=CC=CC=1)C=4)OC(=[O:20])C1C3=CC=CC=1)CC.C(O)[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO.[CH3:114][C@@H:115]([C@@H:122]1[C@@:126]2([CH3:142])[CH2:127][CH2:128][CH2:129]/[C:130](=[CH:131]\[CH:132]=[C:133]3\[CH2:134][C@@H:135]([OH:141])[CH2:136][C@H:137]([OH:140])[C:138]\3=[CH2:139])/[C@@H:125]2[CH2:124][CH2:123]1)[CH2:116][CH2:117][CH2:118][CH:119]([CH3:121])[CH3:120].C(Cl)Cl>C(O)C>[CH3:114][C@@H:115]([C@@H:122]1[C@@:126]2([CH3:142])[CH2:127][CH2:128][CH2:129]/[C:130](=[CH:131]\[CH:132]=[C:133]3\[CH2:134][C@@H:135]([OH:141])[CH2:136][C@H:137]([OH:140])[C:138]\3=[CH2:139])/[C@@H:125]2[CH2:124][CH2:123]1)[CH2:116][CH2:117][CH2:118][C:119]([OH:20])([CH3:120])[CH3:121]
Reactant: CCN(CC)c1ccc2c(c1)Oc1cc(C)c(Nc3ccccc3)cc1C21OC(=O)c2ccccc21
Reactant: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Agent: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Solvent: ClCCl
Solvent: CCO
Product: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Reaction time: 48 h

Procedure:
Nocardia autotrophica N-102 in the same BG medium (100 ml/500 ml-Erlenmeyer flask) as used in Example 1 was cultured at 28° C. under the aerobic conditions for 48 hours. To the culture medium were added 10 ml of a 5% aqueous β-cyclodextrin solution (0.01 M phosphate buffer, pH 7.0), a solution of 1% 1-hydroxyvitamin D3 in 1 ml of ethanol (in the amount of 140 mol of β-cyclodextrin relative to 1 mol of 1α-hydroxyvitamin D3) and a solution of 20% Tween 80 in 1 ml of ethanol. After cultivation for a further 2 hours, methylene chloride was added to the flask, and the determination as described in Example 1 was carried out. The peak fraction having a retention time of 3.8 minutes was collected, concentrated to dryness at 40° C. or below under reduced pressure, and applied to HPLC on Zorbax ODS (made by Du Pont Co.) with water-methanol (1:9) as a mobile phase at a flow rate of 1.0 ml/min. After elution, the peak reaction having a retention time of 5.6 minutes was collected, and concentrated to dryness under pressure at 40° C. or below with a nitrogen gas replacement to give 645 μg (64.5% of conversion ratio from the material) of 1α,25-dihydroxyvitamin D3. In case of the same procedure as described above but without β-cyclodextrin, the yield was 350 μg (35% of the conversion ratio from the material).