Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[S-:19][C:20]#[N:21].[K+].FC(F)(F)S(O)(=O)=O.O>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]#[N:21])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: N#C[S-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#CSCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 0.67 h
Yield: 65.7 %

Procedure:
To a mixture of 7-aminocephalosporanic acid (40 g) and potassium thiocyanate (15.7 g) in acetonitrile (200 ml) was added dropwise trifluoromethanesulfonic acid (40 ml) below 15° C. under cooling in an ice-bath and stirring, which was continued for 30 minutes at 5° to 15° C. and for 40 minutes at ambient temperature. The reaction mixture was poured into cold water (400 ml) and stirred for 30 minutes. The resulting precipitate was filtered, washed with water and acetone and dried to give 7-amino-3-cyanothiomethyl-3-cephem-4-carboxylic acid (26.2 g), mp. 175° to 180° C. (dec.).
Reaction SMILES: C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C(O)=O.C(=O)([O-])[O-].[K+].[K+].BrCCCCCCC[C:43]([N:45]=[N+]=[N-])=[O:44].[CH:48]([C:51]1[CH:57]=[CH:56][CH:55]=[C:54]([CH:58]([CH3:60])[CH3:59])[C:52]=1[NH2:53])([CH3:50])[CH3:49]>O.C(Cl)(Cl)Cl.CN(C=O)C>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:45][C:43]([NH:53][C:52]1[C:51]([CH:48]([CH3:50])[CH3:49])=[CH:57][CH:56]=[CH:55][C:54]=1[CH:58]([CH3:60])[CH3:59])=[O:44]
Reactant: O=C(O)CCCCCCCBr
Reactant: [N-]=[N+]=NC(=O)CCCCCCCBr
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCCCCCCCBr
Reaction time: 3 h
Yield: 74.2 %

Procedure:
DPPA (123 mg, 0.45 mmols) was added to a DMF (1 ml) solution of 8-bromooctanoic acid (100 mg, 0.45 mmols) and potassium carbonate (68 mg, 0.49 mmols), and stirred at room temperatures for 3 hours. The reaction mixture was diluted with water, and extracted with ether. The organic layer was washed with water, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. A chloroform (2 ml) solution of the resulting 8-bromooctanoic acid azide (95 mg, 0.38 mmols) was heated under reflux for 30 minutes, to which was added a chloroform (1 ml) solution of 2,6-diisopropylaniline (68 mg, 0.38 mmols), and heated under reflux for further 15 hours. After the reaction, the solvent was evaporated, and the residue was purified through preparative thin-layer chromatography (developer: chloroform/methanol=20/1) to obtain 112 mg (yield: 63%) of N-(7-bromoheptyl)-N′-(2,6-diisopropylphenyl)urea as colorless powdery crystals.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C([O-])(O)=O.[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>C1COCC1.C(O)C>[Cl:17][C:18]1[N:23]=[C:22]([NH:11][C:7]2[CH:6]=[C:5]3[C:10]([C:2]([CH3:1])=[N:3][NH:4]3)=[CH:9][CH:8]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1n[nH]c2cc(N)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1n[nH]c2cc(Nc3ccnc(Cl)n3)ccc12
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a stirred solution of 3-methyl-6-aminoindazole (2.71 g, 0.015 mol) and NaHCO3 (1.26 g, 0.045 mol) in THF (15 mL) and ethanol (60 mL) was added 2,4-dichloropyrimidine (6.66 g, 0.045 mol) at room temperature. After the reaction was stirred for four hours, the suspension was filtered and washed thoroughly with ethanol. The filtrate was concentrated under reduced pressure, and the resulting solid was washed with ether to remove excess pyrimidine to yield 3.5 g (89% yield) of N-(2-chloro-4-pyrimidinyl)-N-(3-methyl-1H-indazol-6-yl)amine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([N:11]([CH2:28][C:29]1[CH:30]=[C:31]([NH:35]C(=O)OC(C)(C)C)[CH:32]=[CH:33][CH:34]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]2[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=2)[CH:14]=1)(=[O:10])[CH3:9].FC(F)(F)C(O)=O>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([N:11]1[CH2:28][C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[NH:35][C:22]2=[N:21][C:20](=[C:25]([Cl:26])[CH:24]=[N:23]2)[NH:19][C:15]2=[CH:14][C:13](=[CH:18][CH:17]=[CH:16]2)[CH2:12]1)(=[O:10])[CH3:9]
Reactant: CC(=O)N(Cc1cccc(NC(=O)OC(C)(C)C)c1)Cc1cccc(Nc2nc(Cl)ncc2Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)N1Cc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc(c2)C1
Temperature: 70 °C
Yield: 31.6 %

Procedure:
A solution of tert-butyl {3-[(acetyl {3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}amino)methyl]phenyl}carbamate trifluoroacetate (10 mg, 16 μmol) in acetonitrile (1.5 mL) was treated with trifluoroacetic acid (75 μL, 0.97 mmol) and heated at 70° C. for 16 h. The reaction mixture was cooled and purified by preparative LCMS to give the desired product (2.5 mg, 32%) as a solid. LCMS for C20H19ClN5O (M+H)+: m/z=380.0. 1H NMR (300 MHz, CD3OD): δ 8.14 (d, J=1.8 Hz, 1H), 7.78 (s, 1H), 7.63-7.61 (m, 1H), 7.40-7.21 (m, 2H), 7.19-7.05 (m, 3H), 6.98-6.96 (m, 1H), 4.71-4.62 (m, 4H).
Reaction SMILES: [O:1]=[CH:2][CH:3]([CH2:5][SH:6])[OH:4].N(CCO)(CCO)[CH2:8][CH2:9][OH:10].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>>[O:10]=[CH:9][CH2:8][C@@H:2]([C@@H:3]([CH2:5][SH:6])[OH:4])[OH:1]
Reactant: OCCN(CCO)CCO
Reactant: O=CC(O)CS
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Product: O=CC[C@H](O)[C@H](O)CS
Temperature: 0 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
The acceptor aldehyde, 3-thioglyceraldehyde (Compound 3), was prepared by the method of Effenberger. [Effenberger Tetrahedron Lett., 33:5157 (1992)]. DERA (400U) was added to a 10 mL solution containing the acceptor aldehyde (100 mM Compound 3) and donor aldehyde (300 mM acetaldehyde), triethanolamine buffer (100 mM, pH 7.3) and EDTA (1 mM). This reaction is shown in Scheme 1. The resulting solution was stirred in the dark for 2 days under a N2 atmosphere. The reaction was quenched by addition of 2 volumes of acetone and cooling to 0° C. for 20 minutes. The precipitated protein was removed by centrifugation. After removal of the solvent under reduced pressure, a 33 percent yield of Compound 4 was obtained (characterized as 2-deoxy-5-thio-1,3,4-tri-O-acetyl-D-erythro-pentose). Compound 4 was purified from the residue by preparative TLC on silica (methanol/chloroform/hexane, 1:90:10).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]1[CH:14]=[C:15]([C:24]([O:26]CC)=[O:25])[C:16](=[O:23])[N:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)[CH2:6][CH2:5]2.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:23]=[C:16]1[N:17]2[C:22]([CH:21]=[CH:20][CH:19]=[CH:18]2)=[C:13]([CH2:12][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:3]=3)[CH2:8]2)[CH:14]=[C:15]1[C:24]([OH:26])=[O:25]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cc(CN2CCc3cc(Br)ccc3C2)c2ccccn2c1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(CN2CCc3cc(-c4ccccc4)ccc3C2)c2ccccn2c1=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 1-[(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)methyl]-4-oxo-4H-quinolizine-3-carboxylate (0.045 g, 0.10 mmol), phenylboronic acid (0.019 g, 0.15 mmol), and 1 N cesium carbonate (0.20 mL, 0.20 mmol) in 1 mL THF under nitrogen was added bis (tri-tert-butyl-phosphine)palladium(0) (10 mol %). The reaction mixture was stirred at 100° C. for 3 hours, then cooled to rt and concentrated in vacuo. To a solution of the resultant brown residue in 1 mL DMSO was added saturated aqueous lithium hydroxide (0.3 mL). After 2 hours, the reaction was filtered and subjected to purification via reverse phase HPLC to provide the title compound which gave a mass ion (ES+) of 411.0. 1H NMR (400 MHz, DMSO) δ 10.2 (br s, 1H), 9.46 (d, J=6.2 Hz, 1H), 8.74 (s, 1H), 8.60-8.56 (m, 1H), 8.32-8.08 (m, 2H), 7.78-7.75 (m, 1H), 7.67-7.65 (m, 2H), 7.57-7.55 (m, 1H), 7.48-7.44 (m, 2H), 7.38 (d, J=7.4 Hz, 1H), 7.32-7.12 (m, 1H), 4.94 (s, 2H), 4.64-4.50 (m, 2H), 3.82-3.38 (m, 2H), 3.18-3.07 (m, 2H).
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:19]=[CH:18][C:14](C(O)=O)=[C:13]([F:20])[C:12]=3[Cl:21])=[CH:6][C:5]=12.C([N:24](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.O>CN(C=O)C>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:19]=[CH:18][C:14]([NH2:24])=[C:13]([F:20])[C:12]=3[Cl:21])=[CH:6][C:5]=12
Reactant: O=C(O)c1ccc(Oc2ccn3ncnc3c2)c(Cl)c1F
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Oc2ccn3ncnc3c2)c(Cl)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A vial was charged with 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chloro-2-fluorobenzoic acid (0.090 g, 0.2925 mmol), triethylamine (0.1223 ml, 0.8776 mmol) and DMF (1.5 ml). Diphenylphosphoryl azide (0.1630 ml, 0.7313 mmol) was added. The reaction was stirred at ambient temperature for 3 hours, then water (0.2199 ml, 0.2925 mmol) was added. The vial was sealed and heated to 100° C. for 1 hour, then cooled to ambient temperature and poured into 1 N NaOH/ice. The reaction was extracted with EtOAc, and the organic layer was dried, filtered and concentrated. The residue was purified by flash chromatography, eluting with a gradient from 100% EtOAc to 10% (with 6% NH4OH) MeOH/EtOAc.
Reaction SMILES: [N:1]([S:4]([C:7]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])(=[O:6])=[O:5])=[C:2]=[O:3].[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH2:28])[N:22]=1>ClCCl>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([S:4]([NH:1][C:2]([NH:28][C:23]2[N:22]=[C:21]([O:20][CH3:19])[N:26]=[C:25]([CH3:27])[N:24]=2)=[O:3])(=[O:6])=[O:5])[CH:16]=1
Reactant: COc1nc(C)nc(N)n1
Reactant: COC(=O)c1ccc(OC)cc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)cc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A solution of 119 g of the compound of Example 6 in 100 ml dichloromethane was added over 0.25 hours to a suspension of 57 g of 4-methoxy-6-methyl-1,3,5-triazin-2-amine in 1000 ml dichloromethane. The reaction was heated at reflux for 3 to 4 hours, then stirred overnight at ambient temperature. The reaction mixture was filtered and dried. The crude product was dissolved in 2000 ml boiling dichloromethane, the solution filtered, and the filtrate evaporated in vacuo to give 75 g of the title compound, m.p. 183°-186° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH2:21][CH3:22])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.N1C=CC=CC=1.CCOCC>C1COCC1>[C:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH2:21][CH3:22])[C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(C(=O)O)c1ccc(N)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(C(=O)O)c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
Benzoylchloride (7.84 g, 0.057 mol) was added dropwise to a solution of 2-(4'-aminophenyl)butyric acid (10.0 g, 0.057 mol) and pyridine (4.85 g, 0.061 mol) in 100 mL of THF at 0° C. After 30 minutes the ice bath was removed and the reaction warmed to room temperature. After 1 hour the suspension was diluted with 300 mL of ether, washed with 10% HCl (3×50 mL), saturated NaCl (50 mL), dried over MgSO4 and evaporated to give a brown solid. Trituration with ether afforded 7.54 g (47.7%) of the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](F)[CH:7]=1.[NH2:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: N#Cc1ncc(F)cc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Br)c1
Temperature: 110 °C
Reaction time: 14 h

Procedure:
To a flask were added 3-bromo-5-fluoropyridine-2-carbonitrile (14.8 g, 73.5 mmol), tert-butyl [(1S,2R)-2-aminocyclohexyl]carbamate (15 g, 70 mmol) and DIPEA (49 mL, 280 mmol). The resulting mixture was heated at 110° C. After 14 hours, the reaction mixture was cooled to room temperature, diluted with dichloromethane, absorbed on silica gel, and purified via silica gel chromatography to afford tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate. 1H NMR (600 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.22 (s, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.68 (d, J=7.8 Hz, 1H), 3.78 (s, 1H), 3.62 (s, 1H), 1.64-1.44 (m, 6H), 1.30 (s, 9), 1.14-1.08 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:11][CH2:10][NH:9][C:7]=2[N:8]=1>C(Cl)Cl.CCOCC.O=[Mn]=O>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH:11]=[CH:10][NH:9][C:7]=2[N:8]=1
Reactant: COc1ncc2c(n1)NCC2
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ncc2cc[nH]c2n1
Reaction time: 8 h
Yield: 90 %

Procedure:
MnO2 (1.720 g, 20 mmol) was added to 2-methoxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine in 20 mL of anhydrous CH2Cl2 at room temperature. The mixture was stirred for 8 h, diluted with anhydrous ether (50 mL), and filtered through a pad of Celite. The filtrate was concentrated in vacuo, and the residue was purified on a silica gel column eluting with MeOH/CH2Cl2 (1:9) to give 2-methoxy-7H-pyrrolo[2,3-d]pyrimidine (0.149 g, 90%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[C:26]([F:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.O>[F:33][C:26]1[C:27]([OH:32])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[C:10]([CH3:11])[C:2]=1[CH3:1]
Reactant: Nc1c(F)ccc(O)c1F
Reactant: Cc1cc(-c2ccccc2)cc(C(=O)O)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccccc2)cc(C(=O)Nc2c(F)ccc(O)c2F)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a solution of 2,3-dimethyl-5-phenyl-benzoic acid (315 mg, 1.4 mmol, 1.1 eq) in CH2Cl2 (10 mL) was added oxalyl chloride (530 mg, 4.2 mmol, 3.3 eq) at 0° C. The reaction was allowed to warm to room temperature and stirred for 1 h. The solvent and excess reagent were removed under reduced pressure and the residue that remained dissolved in THF (10 mL) and added dropwise to a mixture of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (184 mg, 1.3 mmol, 1.0 eq) and NaHCO3 (532 mg, 6.3 mmol, 5.0 eq) in THF (8 mL) at 0° C. The reaction was stirred at room temperature for 2 h, water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 20:1 to 10:1, then CH2Cl2:MeOH, 500:1 to 100:1) to give the title compound as a yellow solid (220 mg, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:3]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH3:30])[CH2:24]OS(C)(=O)=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:30][C@@H:23]([NH:22][C:20](=[O:21])[O:19][C:15]([CH3:16])([CH3:18])[CH3:17])[CH3:24])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: Cn1nccc1-c1cc(N)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C[C@@H](COc1ccc(N)cc1-c1ccnn1C)NC(=O)OC(C)(C)C
Yield: 34.6 %

Procedure:
4-Amino-2-(1-methyl-1H-pyrazol-5-yl)phenol (300.00 mg, 1585.5 μmol), methanesulfonic acid 2-(S)-tert-butoxycarbonylamino-propyl ester (602.45 mg, 2378.3 μmol) and Cesium carbonate (1033.2 mg, 3171.0 μmol) were dissolved in acetone, and heated in the microwave at 130 C for 1 hour. The reaction mixture was filtered and the filtrate removed under vacuum. The residue was dissolved in DCM; washed with 1N NaOH (3×) and then removed under vacuum to yield a brownish residue in 34.6% yield. LCMS m/z=347.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.32 Hz, 3 H), 1.38 (s, 9 H), 3.65 (s, 3 H), 3.67-3.77 (m, 3 H), 6.23 (d, J=1.77 Hz, 1 H), 6.84 (s, 1 H), 6.95 (s, 1 H), 7.11 (s, 1 H), 7.44 (d, J=1.77 Hz, 1 H).
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12]C=1.[C-:16]1([N:21]2[C:25](=[O:26])[NH:24][NH:23][C:22]2=[O:27])[CH:20]=[CH:19][CH:18]=[CH:17]1.[CH-]1C=CC=C1.[Fe+2:33]>O1CCCC1>[C-:16]1([N:21]2[C:22](=[O:27])[N:23]=[N:24][C:25]2=[O:26])[CH:17]=[CH:18][CH:19]=[CH:20]1.[CH-:12]1[CH:13]=[CH:14][CH:15]=[CH:10]1.[Fe+2:33]
Reactant: O=c1[nH][nH]c(=O)n1-[c-]1cccc1
Reactant: Ic1ccccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1N=NC(=O)N1[c-]1cccc1

Procedure:
With reference to EXAMPLE 1-2, 4.5 mg (0.014 mmol) of iodobenzene diacetate was added to a mixture of 5 mg (0.017 mmol) of 4-ferrocenylurazole and 0.25 mL of tetrahydrofuran at room temperature, followed by stirring for an hour. Thus, the tetrahydrofuran solution of 4-ferrocenyl-1,2,4-triazoline-3,5-dione was obtained. A tetrahydrofuran (0.25 mL) solution of 1 mg (0.0025 mmol) of alfacalcidol prepared in accordance with the method described in Japanese Patent Publication (KOKAI) No. 48-62750, Tetrahedron Lett., 1973, 2339 and Tetrahedron, 30, 2701 (1974) was added to the solution obtained. The mixture was stirred at room temperature for an hour. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:2) to give 1 mg (57%) of the titled alfacalcidol/4-ferrocenyl-1,2,4-triazoline-3,5-dione adduct (ALF-FTAD) as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([OH:29])[C:5]1[N:6]([CH3:28])[C:7](=[O:27])[C:8]2[C:13]([C:14]=1[C:15]1[C:16]([CH3:25])=[C:17]3[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=[C:10]([OH:26])[CH:9]=2>C(OC(C)=O)(C)(C)C.O>[CH4:1].[CH3:1][O:2][C:3](=[O:30])[CH:4]([O:29][C:8]([CH3:13])([CH3:9])[CH3:7])[C:5]1[N:6]([CH3:28])[C:7](=[O:27])[C:8]2[C:13]([C:14]=1[C:15]1[C:16]([CH3:25])=[C:17]3[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=[C:10]([OH:26])[CH:9]=2
Reactant: COC(=O)C(O)c1c(-c2ccc3c(c2C)CCCO3)c2ccc(O)cc2c(=O)n1C
Solvent: O
Solvent: CC(=O)OC(C)(C)C
Product: C
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccc(O)cc2c(=O)n1C
Yield: 85 %

Procedure:
To a solution of Hydroxyl-[7-hydroxy-2-methyl-4-(5-methyl-chroman-6-yl)-1-oxo-1,2-dihydro-isoquinolin-3-yl]-acetic acid methyl ester (600 mg, 1.465 mmol) in t-BuOAc (10 ml) was added HClO4 (512 mg, 5.12 mmol). The resultant mixture was stirred at RT under N2 for 2 h. The reaction mixture was diluted with water and extracted with EA (50 mL*3), dried over sodium sulfate and concentrated to dryness. The mixture was purified by chromatography column on silica gel to afford the title product (300 mg, 44%). LCMS (10-80 AB—2MIN.M): Rt=1.308, purity=96%, M+1=466.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:36]=[CH:35][N:34]([CH2:37][CH2:38][OH:39])[N:33]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8]([NH:31][C:32]2[CH:36]=[CH:35][N:34]([CH2:37][CH2:38][OH:39])[N:33]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reactant: Nc1ccn(CCO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: O=C(Nc1ccn(CCO)n1)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (50 mg, 0.15 mmol, prepared as in Example 1) in methylene chloride (5 mL) and N,N-dimethylformamide (1 drop) cooled to 0° C. was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 88 μL, 0.18 mmol) and stirred at 0° C. for 10 min. After this time, the reaction mixture was warmed to room temperature and then stirred for another 25 min. After this time, the reaction mixture was then concentrated in vacuo and the residue taken up in methylene chloride (2 mL) and added dropwise to a separate reaction flask containing a mixture of 2-(3-amino-pyrazol-1-yl)-ethanol (28 mg, 0.22 mmol) and 2,6-lutidine (32 μL, 0.29 mmol) in methylene chloride (5 mL) cooled to 0° C. The resulting reaction mixture was then allowed to warm to room temperature and stirred for 16 h. After such time, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then extracted with methylene chloride (3×15 mL). The organic layers were then washed with a 1N aqueous hydrochloric acid solution (10 mL), dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate concentrated in vacuo. The crude material was purified via automated flash chromatography (4 g silica gel column, 60-95% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (57 mg, 86%) as a white foam: [α]29D=−28.5°, (c=0.26, methylene chloride); HR-ES(+) m/e calcd for C22H25N4O3F3 [M+H]+ 451.1952, observed 451.1950; 1H NMR (300 MHz, DMSO-d6) δ ppm 10.91 (s, 1H), 8.01 (t, J=8.50 Hz, 2H), 7.69-7.81 (m, 1H), 7.56 (d, J=2.27 Hz, 1H), 6.40 (d, J=2.27 Hz, 1H), 4.97-5.13 (m, 2H), 4.85 (t, J=5.29 Hz, 1H), 4.71 (d, J=18.51 Hz, 1H), 4.02 (t, J=5.67 Hz, 2H), 3.69 (q, J=5.67 Hz, 2H), 0.99-2.12 (m, 11H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[O:11])=[CH:7][C:6]=2[CH:28]=1.[C:29]1([N:35]2[CH2:40][CH2:39][NH:38][C@@H:37]([CH3:41])[CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:14]([NH:16][CH2:17][C:18]([N:38]3[CH2:39][CH2:40][N:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:36][C@@H:37]3[CH3:41])=[O:20])=[O:15])=[O:11])=[CH:7][C:6]=2[CH:28]=1
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccn1)NC(=O)c1cc2cc(Cl)ccc2o1
Reactant: C[C@H]1CN(c2ccccc2)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccccc2)CCN1C(=O)CNC(=O)[C@H](Cc1ccccn1)NC(=O)c1cc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [[(2S)-2-[[(5-chloro-1-benzofuran-2-yl)carbonyl]amino]-3-(2-pyridyl)propanoyl]amino]acetic acid (150 mg), (S)-1-phenyl-3-methylpiperazine (79 mg), 1-hydroxy-benzotriazole (55 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (79 mg) in N,N-dimethylformamide (3 ml) was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (15 ml), and washed successively with saturated aqueous sodium hydrogencarbonate solution, water, and brine. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol 10:1) to give the title compound as a colorless amorphous solid.