Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:28]1([CH2:34][CH2:35][CH:36]=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.[P:45]([O-:52])([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48]>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:25])[CH3:26])[NH:22][CH:36]([P:45]([O:49][CH2:50][CH3:51])([O:46][CH2:47][CH3:48])=[O:52])[CH2:35][CH2:34][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=CCCc1ccccc1
Reactant: CCOP([O-])OCC
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C(CCc1ccccc1)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
A mixture of 5.90 g of L-leucine benzyl ester p-toluenesulfonate, 2.01 g of 3-phenylpropionaldehyde and 2.09 ml of triethylamine in 100 ml of toluene was heated to reflux in a Dean-Stark apparatus for 2 hours. The mixture was allowed to cool, and then 1.93 ml of diethyl phosphite was added to the mixture. Then the mixture was heated to reflux for 27 hours, and then allowed to cool. The mixture was successively washed with 100 ml of water, 50 ml of 1N hydrochloric acid and 50 ml of a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: ethyl acetate=10: 1, and hexane: ethyl acetate=1: 1) to yield the title compound as a mixture of stereoisomers, a light-yellow oil (1.87 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][C@H:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C@@H:14]([OH:15])[CH3:16])[CH:8]=[CH:7]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: C[C@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](O)Cn1ccc2cc(F)ccc21
Reaction time: 1 h
Yield: 84 %

Procedure:
A suspension of 0.26 g of sodium hydride dispersion in 35 ml of tetrahydrofuran was treated with 0.95 g of 5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 1 ml of (S)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with 7 ml of water. The mixture was diluted with 180 ml of ether, washed twice with 90 ml of water each time and with 50 ml of saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 28 g of silica gel with toluene-ethyl acetate (19:1). There were obtained 1.15 g (84%) of (S)-1-(5-fluoro-indol-1-yl)-propan-2-ol as a light brown oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:4]=1[F:11].FC1C=C(C)C=C(F)C=1>>[F:10][C:5]1[CH:6]=[C:7]([F:9])[CH:8]=[C:3]([CH3:2])[C:4]=1[F:11]
Reactant: Fc1cc(F)c(F)c(CBr)c1
Agent: Cc1cc(F)cc(F)c1
Product: Cc1cc(F)cc(F)c1F

Procedure:
The title compound was prepared from 1-bromomethyl-2,3,5-trifluoro-benzene by a procedure analogous to that for 3,5-difluorotoluene, above. 1H NMR (400 MHz, CDCl3) δppm; MS (APCl, m/z): [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[N:7]=[C:6]1Cl)[C:2]#[C:3][CH3:4].C([O-])(=[O:19])C.[Na+].C(=O)(O)[O-].[Na+].Cl>CS(C)=O.O>[CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[NH:7][C:6]1=[O:19])[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(Cl)nc2nc(Cl)nc(Cl)c21
Reactant: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC#CCn1c(=O)[nH]c2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.7 %

Procedure:
7-(2-Butynyl)-2,6,8-trichloro-7H-purine (1.0 g) was dissolved in dimethylsulfoxide (20 mL), and then sodium acetate (595 mg) and sodium bicarbonate (366 mg) were added to the mixture. This reaction solution was stirred at room temperature for 12 hours, and then 1 N of aqueous hydrochloric acid solution (5.0 mL) and 80 mL of water were added. This reaction solution was stirred at room temperature for one hour, and then a white precipitate was collected by filtration. The white solid obtained was washed with water and t-butyl methyl ether to give the title compound (800 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH:11](Br)[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:21][C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:21]=[C:22]4[N:27]=[CH:26][CH:25]=[CH:24][N:23]4[C:11]=3[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cccc(C(Br)C(=O)c2ccc3c(c2)OCO3)n1
Reactant: Nc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2c(-c3ccc4c(c3)OCO4)nc3ncccn23)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
To a solution of 1-Benzo[1,3]dioxol-5-yl-2-bromo-2-(6-methyl-pyridin-2-yl)-ethanone of Step C (50 mg, 0.12 mmol) in dimethylformamide (1.0 mL) was added 2-aminopyrimidine (15 mg, 1.3 equiv), and sodium hydrogen carbonate (30 mg, 3 equiv). The resulting solution was shaken at 80° C. for 3 hours, diluted with ethyl acetate (2 mL) and water (3 mL). The organic extract was concentrated in vacuo and silica gel chromatography (3:1 hexane/acetone) yielded the title compound (14 mg, 35%). HPLC tR=1.75 min, LCMS 331.2 (M+1).
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1.[O:39]1CCCC1>>[C:1]1([C@H:7]([OH:39])[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Product: O[C@H](CCc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of 1,3-diphenylpropanone (1.07 g; 5.09 mmol) in tetrahydrofuran (10 mL) was cooled to −23° C. and treated with an asymmetric reducing agent, (+)-B-chlorodiisopinocampheyl-borane (1.80 g; 5.60 mmol) in 20 mL THF, and the resulting solution was allowed to stand overnight at −23° C. After evaporating to dryness, the residue was treated with ether (65 mL) and diethanolamine (1.0 g) and stirred for 3 hrs. The mixture was then filtered to remove solids and concentrated, and the residue was purified using gradient elution (5% ethyl acetate/hexane to 10% ethyl acetate) on a silica gel column to obtain 660 mg (61%) of (1R)-1,3-diphenyl-1-propanol as a crystalline white solid, 1H NMR (360 Mhz; CDCl3): d 1.95-2.15 (m, 3H); 2.59-2.78 (m, 2H); 4.65 (dd, 1H, J=5.4, 7.8); 7.14-7.35 (m, 10H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[N:12]2[CH:11]=[N:10][C:9]([C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:8][N:7]=3)=[C:13]2[CH2:14]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Fc1cccc2c1NCc1c(-c3noc(C4CC4)n3)ncn1-2
Agent: CN(C)c1ccccn1
Product: CC(=O)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2cccc(F)c21

Procedure:
A solution of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-6-fluoro-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXIII, EXAMPLE 103, 0.504 g), dimethylaminopyridine (0.03 g) and acetic anhydride (12 ml) is stirred at 100° for 1 hr. After cooling, excess acetic anhydride is removed under reduced pressure and the residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated. Chromatography on silica gel (320 ml) eluting with methanoldichloromethane (2/98) gives a poor separation of the product from the imine byproduct. The imine impurity is successfully removed by taking up the mixture in dichloromethane and allowing the imine to precipitate out. The filtrate is collected, concentrated and the product crystallized from dichloromethane and hexane to give the title compotmd, mp 208.5°-210.0°; MS m/z at 339; IR (mineral oil) 1671, 1503, 1254, 879 and 1204 cm-1 ; NMR (CDCl3) 1.28, 2.38, 2.13, 2.29, 7.16, 7.41 and 8.13 δ.
Reaction SMILES: Cl.[CH:2]1[C:15]2[C:14](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:25])[CH2:23][NH2:24])[CH2:18][CH2:17]3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClC(Cl)C.ClCCl>[O:25]=[C:22]([N:19]1[CH2:20][CH2:21][C:16](=[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:7][C:6]3[C:15]2=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH2:17][CH2:18]1)[CH2:23][NH:24][C:34](=[O:35])[O:36][CH2:37][CH3:38]
Reactant: CCOC(=O)Cl
Reactant: NCC(=O)N1CCC(=C2c3ccccc3Sc3ccccc32)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCOC(=O)NCC(=O)N1CCC(=C2c3ccccc3Sc3ccccc32)CC1
Reaction time: 0.25 h

Procedure:
50 mg (0.134 mmol) of 2-[4-(9H-thioxanthen-9-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride was dissolved in dichloroethane. 41 mg (0.405 mmol) of triethylamine was added to the obtained solution. A solution of 17.5 mg (0.161 mmol) of ethyl chloroformate in 0.5 ml of dichloromethane was added to the resultant mixture. After stirring for 15 minutes, the product was purified by the thin-layer silica gel chromatography (hexane:ethyl acetate=85:100) to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].C[N+]1C=CN([C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]2[CH3:34])=[O:27])C=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]3[CH3:34])=[O:27])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CC1CCCCN1C(=O)n1cc[n+](C)c1
Agent: [I-]
Product: CC1CCCCN1C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(2-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was purified by flash chromatography using a Quad flash 25 (ethyl acetate/heptane (1:6), (71%, white crystals). HPLC-MS m/z=381.1 (M+1), Rt: 5.2 min.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([OH:22])=[C:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)[CH:16]=[CH:15]2.[H-].[Na+].C(OCC)(=O)C>CN1CCCC1=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([O:22][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[C:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)[CH:16]=[CH:15]2
Reactant: COc1ccc2c(O)c(-c3ccc(SC)cc3)ccc2c1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccc(SC)cc3)ccc2c1
Temperature: 25 °C
Yield: 31.9 %

Procedure:
Add 4-fluoro-benzaldehyde (2.20 mL, 20.3 mmol) to a solution of 6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-ol (3.0 g, 10.1 mmol) and 60% sodium hydride (400 mg, 10.1 mmol) in 1-methyl-2-pyrolidinone (30 mL). Heat the reaction to 170° C. for 70 minutes, then cool to ambient temperature. Dilute the reaction with ethyl acetate (200 mL) and wash twice with 5% aqueous lithium chloride (500 mL), brine, 1N aqueous hydrochloric acid, dry with solid magnesium sulfate and chromatograph on silica gel with dichloromethane/hexane mixtures to give 1.29 g of 4-[6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-yloxy]-benzaldehyde (32%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[O:3].CCCCCC.[H-].[Na+].[C:19](=O)([O:23]CC)[O:20][CH2:21][CH3:22]>C1COCC1.C(O)C>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:19]([O:20][CH2:21][CH3:22])=[O:23])=[CH:5][CH:6]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Temperature: 0 °C
Yield: 47.9 %

Procedure:
A solution of 4-fluoroacetophenone (100 g, 7.239 mol) in dry THF (100 ml) was added dropwise over 2.5 hours to a refluxing slurry of hexane-washed NaH (68.3 g, 60% oil dispersion, 1.708 mol) and diethyl carbonate (176.0 ml, 1.453 mol) in dry THF (300 ml). This solution was refluxed an additional 0.5 hours, cooled (0° C.), and a solution of ethanol (50 ml) in dry THF (150 ml) was added to quench the excess NaH. 300 ml of water and 100 ml of acetic acid were added, and this mixture was extracted with ethyl acetate (3×300 ml). The combined organics were washed with saturated NaHCO3 (1×500 ml), washed with brine (2×500 ml), dried (MgSO4), concentrated under reduced pressure, and distilled at 10 mm to yield 146.3 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCO
Product: O=Cc1cc(O)ccc1-c1ccc(Cl)cc1

Procedure:
2-bromo-5-hydroxybenzaldehyde (20 g), 4-chlorophenylboronic acid (17.1 g) and dichlorobis(triphenylphosphine) palladium(II) (1.75 g) were dissolved in 475 mL of a dimethoxyethane:ethanol:2M Na2CO3 solution (7:2:2). The mixture was heated to reflux for 1 hour. The reaction mixture was then diluted with ethyl acetate, washed thoroughly with water and with brine, dried over MgSO4, filtered and concentrated. The resulting solid was slurried in 500 mL of hexane:ether mixture (2:1). The title compound was collected by filtration.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1O>>[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: C[C@@H]1CCCC[C@H]1O
Product: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@@H]1C)C(C)=O
Yield: 8.5 %

Procedure:
Ethyl (Z)-2-hydroxyimino-3-oxobutyrate (3.48 g) was reacted with trans-2-methylcyclohexanol as described in Example 4a, method 3 to give the title compound (0.476 g, 8.5%), as a colourless liquid, νmax (film) 2930, 1740 and 1690 cm-1, δH (CDCl3) 0.95 (3H, d, J 6.9 Hz), 1.34 (3H, t), 1.3-2.1 (9H, m), 2.40 (3H, s), 4.36 (2H, q), and 4.39 (1H, m).
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C@@H:13]([OH:26])[CH2:14][C@:15]4([CH3:25])[C@@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.C[C@@:28]12[C@@:36](O)([C:37](CO)=[O:38])[CH2:35][CH2:34][C@H]1[C@@H]1CCC3[C@@](C)([C@H]1[C@@H](O)C2)C=CC(=O)C=3.C[C@H]1[C@](O)(C(CO)=O)[C@]2(C)[C@H]([C@H]3[C@](F)([C@@H](O)C2)[C@]2(C)C(=C[C:62](C=C2)=[O:63])CC3)C1.Cl(O)(=O)(=O)=[O:82]>ClCCl>[CH3:1][C@@:2]12[C@H:12]3[C@@H:13]([OH:26])[CH2:14][C@:15]4([CH3:25])[C@@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.[CH:37]([CH:36]([CH2:35][CH3:34])[C:28]([O:63][CH3:62])=[O:82])=[O:38]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Solvent: ClCCl
Product: CCC(C=O)C(=O)OC

Procedure:
Hydrocortisone or prednisolone or dexamethasone or bethamethasone is reacted with an alkyl formylalkanoate in a solution of dichloromethane in the presence of catalytic amount of perchloric acid to produce the corresponding 17,21-carboxycyclic acetal pregnane derivatives, e.g., when hydrocortisone and methyl formylbutyrate are used the product is (IV) 11β-hydroxy-3,20-dioxo-17,21-(methoxycarbonyl-n-propyl) methylenedioxy-4-pregnene; when prednisolone and methyl formylacetate are used the product is (V) 11β-hydroxy-3,20-dioxo-17,21-(methoxycarbonylmethyl)methylenedioxy-1,4-pregnadiene.
Reaction SMILES: [F:1][CH2:2][C@@H:3]([OH:9])[C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].[C:10](=[O:13])([O-])[O-:11].[Na+].[Na+].C(N1C(=O)CC([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)C1=O)(O)=O>C1COCC1.O>[C:10]([N:5]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:4]([C:6]([OH:8])=[O:7])[C@@H:3]([CH2:2][F:1])[OH:9])([OH:11])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: N[C@H](C(=O)O)[C@H](O)CF
Reactant: O=C(O)N1C(=O)CC(OCc2ccccc2)C1=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H]([C@H](O)CF)N(OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a stirred solution of (2S,3S)-4-fluorothreonine 101 (0.100 g, 0.82 mmol) in THF/H2O (1:1, 5 ml) adjusted to pH 9 using sodium carbonate was added N-carboxybenzyloxysuccinimide (0.308 g, 1.24 mmol). After stirring the solution for 18 hours at room temperature, the solvent was removed in vacuo to give a white residue. The residue was partitioned between ethyl acetate (5 ml) and water (10 ml). The organic layer was separated and aqueous layer further extracted with ethyl acetate (2×5 ml), this organic phase was discarded. The pH of the aqueous layer was adjusted to 3 using 1N HCl. The aqueous layer was extracted with ethyl acetate (4×10 ml), the combined organic layers were dried (MgSO4) and the solvent removed in vacuo to afford N-carboxybenzyloxy-(2S,3S)-4-fluorothreonine 102 as a pale yellow oil (110 mg, 70% yield); 1H (400 MHz, CDCl3) 8.20 (1H, bs, OH, exchange with CH3OD), 6.46, 6.45 and 6.07 (1H, 3×d, J 8.9), 5.10-4.85 (2H, m, CH2Ph), 4.65-4.25 (4H, H-2, H-3 and 4-CH2); 19F (376 MHz, CDCl3) −228.59 and −228.51 (2×dtJ 46,14 due to rotamers).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([O:50][CH3:51])[C:4]=1[CH:5]=[CH:6][CH:7]([S:17]([CH:20]([CH:30]=[CH:31][C:32]1[C:37]([O:38][CH3:39])=[CH:36][C:35]([O:40][CH3:41])=[CH:34][C:33]=1[O:42][CH3:43])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([NH2:29])[CH:22]=1)(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH2:16])[CH:9]=1.[Cl:52][CH2:53][C:54](Cl)=[O:55]>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:51][O:50][C:44]1[CH:45]=[C:46]([O:48][CH3:49])[CH:47]=[C:3]([O:2][CH3:1])[C:4]=1[CH:5]=[CH:6][CH:7]([S:17]([CH:20]([CH:30]=[CH:31][C:32]1[C:33]([O:42][CH3:43])=[CH:34][C:35]([O:40][CH3:41])=[CH:36][C:37]=1[O:38][CH3:39])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([NH:29][C:54](=[O:55])[CH2:53][Cl:52])[CH:22]=1)(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:54](=[O:55])[CH2:53][Cl:52])[CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(C=CC(c2ccc(OC)c(NC(=O)CCl)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)CCl)c2)c(OC)c1
Yield: 88 %

Procedure:
To a solution of 2,4,6trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in toluene, chloroacetyl chloride (10 mmol) in dioxane (10 mL) was added and the solution was refluxed for 2 h. The solution was cooled and the solvent was removed in a rotary evaporator to give 2,4,6-trimethoxystyryl-3-chloroacetamido-4-methoxybenzylsulfone in 88% yield. M.p. 163-165° C. NMR (DMSO-d6) δ 3.83(s, 3H), 3.84(s, 6H), 3.85(s, 3H), 4.14(s, 2H), 4.22(s, 2H) 6.08 (s, 2H), 7.11-7.20(d, 1H vinylic), 6.90-8.33(m, aromatic), 8.89(s, 1H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([O:5][C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[O:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:7]1)=[O:4].[N+](C1C=CC=CC=1)([O-])=O.[F:43]C(F)(F)C([O-])=O.[Na+].FOC(F)(F)F>FC(Cl)(Cl)Cl>[F:1][C:2]([F:32])([F:33])[C:3]([O:5][C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@:20]2([F:43])[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[O:25][C:26](=[O:31])[C:27]([F:29])([F:30])[F:28])[CH2:7]1)=[O:4]
Reactant: O=C([O-])C(F)(F)F
Reactant: C[C@]12CC[C@H](OC(=O)C(F)(F)F)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)C(F)(F)F)CC[C@@H]12
Agent: FOC(F)(F)F
Agent: [Na+]
Solvent: FC(Cl)(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: C[C@]12CC[C@@]3(F)[C@@H](CC[C@H]4C[C@@H](OC(=O)C(F)(F)F)CC[C@@]43C)[C@@H]1CC[C@@H]2OC(=O)C(F)(F)F
Yield: 39.4 %

Procedure:
A well-stirred solution of 3β, 17β-di(trifluoroacetoxy)-5α-androstane (2.5 g, 5.15 mmole, prepared by treatment of 5α-androstane-3β,17β-diol with trifluoroacetic anhydride in pyridine), nitrobenzene (800 mg, 6.5 mmole) and sodium trifluoroacetate (10 g, 73.5 mmole) in fluorotrichloromethane (45 ml) was treated with trifluoromethyl hypofluorite (8.5 mmole) at -20° for 2.5 hours, air being admitted to the reaction vessel during this time. Thereafter the solution was purged with nitrogen and the solvent was removed in vacuo. The residue was dissolved in chloroform and the resulting solution was washed with aqueous sodium bicarbonate and water and was then dried, whereafter the product was chromatographed on silica gel (125 g). Elution with chloroform:hexane (3:7) gave unreacted starting material (308 mg), while subsequent elution with chloroform:hexane (7:13) gave 3β,17β-di(trifluoroacetoxy)-9α-fluoro-5α-androstane (1.02 g), which crystallized from hexane as prisms (917 mg) m.p. 140°-142°; [α] 24D - 22° (c 1.47, CHCl3). (Found C,55.10; H,5.78; F,26.35%;m/e 502. C33H29O4F7 requires C,54.97; H,5.82; F,26.47%; M+ 502).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:36]=[CH:35][C:20]([C:21]([N:23]([CH3:34])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31]C=O)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([C:44]([CH2:46][NH:47][CH3:48])=[O:45])[CH2:40][CH2:39]1.[C:49]([BH3-])#N.[Na+]>CO.C(O)(=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:34])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:48][N:47]([CH3:49])[CH2:46][C:44]([N:41]4[CH2:40][CH2:39][N:38]([CH3:37])[CH2:43][CH2:42]4)=[O:45])=[O:22])=[CH:35][CH:36]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCC=O)cc2)cc1
Reactant: [BH3-]C#N
Reactant: CNCC(=O)N1CCN(C)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCN(C)CC(=O)N3CCN(C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.7 %

Procedure:
To a mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(formylmethoxy)phenyl]benzamide (400 mg) and 4-methyl-1-(N-methylamino)methylcarbonylpiperazine (143 mg) in a mixture of methanol (15 ml) and acetic acid (0.5 ml) was added sodium cyanoborohydride (52.4 mg) and the mixture was stirred at ambient temperature for 4 hours. The solution was diluted with ethyl acetate (30 ml) and washed successively with saturated aqueous sodium hydrogen carbonate, water and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column (chloroform:methanol:conc. ammonia=10:1:0.1) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[2-[N-methyl-N-(4-methylpiperazin-1-yl)carbonylmethylamino]ethoxy]phenyl]benzamide (310 mg) as a colorless amorphous.