Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2](=[NH:12])(OCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>CO.[OH-].[Na+]>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:2](=[NH:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(CN)OC
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(CNC(=N)c1ccccc1)OC
Reaction time: 72 h
Yield: 104.5 %

Procedure:
(EX-1A) A solution of ethyl benzimidate hydrochloride (92.25 g, 496.9 mmol) in 300.0 mL dry methanol (1.68 M) was cooled to ca 0° C. and added a solution of aminoacetaldehyde dimethyl acetal (73.10 mL, 670.9 mmol) in dry methanol (75.0 mL, 9.0 M) drop wise at such a rate the temperature was kept below 5° C. The resulting solution was allowed to stir for 3 days with the temperature being maintained below 5° C. The reaction mixture was then concentrated under reduced pressure to give a yellow oil. The residue was dissolved in 1 N NaOH (750 mL) and extracted with dichloromethane (4×250 mL). The organic solutions were combined, dried (MgSO4), and concentrated to give 108.13 g crude N-(2,2-dimethoxyethyl)benzamidine as a yellow oil. The crude N-(2,2-dimethoxyethyl)benzamidine (108.13 g, 519.2 mmol) in dry methanol (125.0 mL, 4.2 M) was added dimethyl methoxymethylenemalonate (94.13 g, 540.5 mmol) in one portion at room temperature. The resulting mixture was heated to approximately 100° C., where the solvent was slowly distilled off over a two hour period. The resulting dark brown solution was allowed to cool to room temperature and was diluted ethyl acetate (1 L). The organic solution was washed with saturated NH4Cl (2×500 mL) and brine (1×500 ml). The organic solution was dried (MgSO4), filtered and concentrated. Purification of the crude product by MPLC (25% ethyl acetate/hexane) gave pure methyl 1-(2,2-dimethoxyethyl-2-phenylpyrimidin-6(1H)-one-5-carboxylate (EX-1A) in 73% yield as a tan oil: 1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 7.59-7.49 (m, 5H), 4.86 (t, J=5.5 Hz, 1H), 4.16 (d, J=5.4 Hz, 2H), 3.95 (s, 3H), 3.32 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 165.9, 164.6, 159.3, 158.2, 134.6, 130.9, 128.93, 128.78, 114.9, 101.9, 56.0, 55.1, 52.7, 49.1; HRMS (ES) calcd for C16H19N2O5 319.1294, found 319.1288.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([N:16]([CH3:25])[C:17]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.Cl.NC(N)=N.[CH2:35](OC(=O)C1(CCCC1)N(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)C)[CH3:36].O>CS(C)=O>[CH2:35]([O:23][C:22](=[O:24])[C:17]1([CH2:21][CH2:20][CH2:19][CH2:18]1)[N:16]([S:13]([C:9]1[CH:8]=[C:7]2[C:12]([C:3]([Cl:2])=[CH:4][N:5]=[C:6]2[NH:26][C:27]([NH2:29])=[NH:28])=[CH:11][CH:10]=1)(=[O:14])=[O:15])[CH3:25])[CH3:36]
Reactant: CN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Reactant: CCOC(=O)C1(N(C)S(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCCC1
Agent: Cl
Agent: N=C(N)N
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1(N(C)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Temperature: 50 °C
Yield: 54.8 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(methyl)cycloleucine hydrochloride ##STR91## NaH (31 mg, 80% dispersion in mineral oil, 1.04 mmol) was added to a solution of guanidine hydrochloride (164 mg, 1.67 mmol) in DMSO (4 ml), and the solution heated at 50° C. for 1 h. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-(methyl)cycloleucine ethyl ester (180 mg, 0.42 mmol) in DMSO (2 ml) was added, and the reaction heated at 80° C. for 3 h. The cooled reaction mixture was poured into water, and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), and evaporated in vacuo. The residual yellow oil was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880 NH3 (90:10:1) as eluant, and recrystallised from EtOAc to afford N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(methyl)cycloleucine ethyl ester (105 mg, 0.23 mmol) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][OH:25])[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CN=C1.[C:31]([Si:35]([CH3:38])([CH3:37])Cl)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C.C(OCC)(=O)C>[Si:35]([O:25][CH2:24][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][C:10]1=[O:23])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)(c2ccc(Cl)c(Cl)c2)C(=O)C1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(CO[Si](C)(C)C(C)(C)C)(c2ccc(Cl)c(Cl)c2)C(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution (20 mL) of tert-butyl 7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-6-oxo-1,4-oxazepane-4-carboxylate (1.27 g) in DMF were added imidazole (266 mg) and tert-butyldimethylchlorosilane (540 mg), and the mixture was stirred at room temperature for 3 hr. The reaction solution was diluted with ethyl acetate, the mixture was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.35 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C([O:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1)=[CH2:13])C>C1COCC1.O>[Br:1][CH2:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1ncccc1OC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccnc1C(=O)CBr
Reaction time: 0.25 h
Yield: 54 %

Procedure:
Add N-bromo-succinimide (306 mg, 1.7 mmol) to a stirred solution of 2-(1-ethoxy-vinyl)-3-methoxy-pyridine (305 mg, 1.7 mg) in THF (30 mL) and water (2 mL). Stir for 15 mins. at RT under N2. Adsorb on SiO2 and purify by flash chromatography on silica gel eluting with 0-40% EtOAc/hexanes to afford the title compound (211 mg, 54%).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[S:21]1[C:29]2[CH2:28][CH2:27][NH:26][CH2:25][C:24]=2[CH:23]=[CH:22]1>CN(C)C=O.C(O)C>[S:21]1[C:29]2[CH2:28][CH2:27][N:26]([CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[CH:18][CH:19]=5)[O:14][N:13]=4)[CH:7]=3)[CH2:25][C:24]=2[CH:23]=[CH:22]1
Reactant: c1cc2c(s1)CCNC2
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCc2sccc2C1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=408.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[OH:10]O>ClCCl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: Clc1cncc(Cl)c1Cl
Reactant: OO
Solvent: ClCCl
Product: [O-][n+]1cc(Cl)c(Cl)c(Cl)c1
Reaction time: 15 h
Yield: 74 %

Procedure:
To a stirred solution of 3,4,5-trichloropyridine (1 g, 5.45 mmol) in dichloromethane (20 mL) at 0° C., was added dropwise a 30% hydrogen peroxide solution (1.2 mL, 10.9 mmol). Following the addition, the temperature was allowed to rise to room temperature and was stirred for 15 hours. The reaction mixture was diluted with dichloromethane (50 mL) and was washed with water (10 mL) and then by brine (25 mL×2). The organic phase was dried (Na2SO4), concentrated under vacuum to afford the title product as a white solid (0.8 g, 74% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.78 (2H, s). MS m/z: 197.90 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][CH2:27][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: CN(C)CCCCl
Reactant: Nc1ccc2ncnc(N3CCc4ccc(Cl)cc43)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(C)CCCNc1ccc2ncnc(N3CCc4ccc(Cl)cc43)c2c1
Temperature: 120 °C

Procedure:
4-(6-Chloro-2,3-dihydro-indol-1-yl)-quinazolin-6-ylamine hydrochloride (0.525 g, 1.58 mmol) was combined with 2 mL of freshly distilled 3-dimethylaminopropyl chloride and heated to 120° C. for 1 hour. Yellow liquid was poured off and the remaining red glass was dissolved in water, basified to pH 11 with potassium carbonate, extracted with chloroform (2×50 mL), washed with brine, dried over magnesium sulfate, filtered and stripped to give 0.272 g yellow foam containing starting material and mono- and di-alkylated products. This foam was filtered through silica gel using chloroform, then the product was washed through the silica gel with 40% v/v methanol in chloroform and concentrated in vacuo. The residue was dissolved in methanol, treated with 1N HCl in methanol diluted with diethyl ether, filtered and dried under vacuum to afford a bright yellow solid, 0.0995 g (15%): M.P. 230° C. (dec):LC-MS: 382 (MH+), 384 ((M+2)H+).
Reaction SMILES: [CH2:1]([CH:8]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH2:1]([CH:8]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(CO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC(Cc1ccccc1)C(=O)O
Temperature: 0 °C

Procedure:
The methyl 2-benzyl-3-(t-butyldimethylsilyloxy)propionate (3.3 g) was dissolved in 100 ml of methanol, cooled to 0° C. and treated with 50 ml of 30% potassium hydroxide with vigorous stirring. The reaction was then allowed to warm to room temperature over five hours. The reaction was diluted with 200 ml of water, rinsed with diethyl ether, and the aqueous solution was cooled to 0° C. Dichloromethane (100 ml) was added, followed by the slow addition of 260 ml of 1M hydrochloric acid, with stirring. The layers were separated and the aqueous layer was extracted with dichloromethane (3×200 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by radial chromatography (2% to 4% methyl alcohol in chloroform. 4 mm plate) to yield 2.14 9 of the 2-benzyl-3-(t-butyldimethylsilyloxy)propionic acid.
Reaction SMILES: C[O-].[Na+].[CH3:4][S:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N+:15]=[N-:16]>CO.O>[CH3:21][O:20][C:18](=[O:19])[C:17]([N:14]=[N+:15]=[N-:16])=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([S:5][CH3:4])=[CH:7][CH:8]=1
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: CSc1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(=Cc1ccc(SC)cc1)N=[N+]=[N-]
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution of sodium methoxide prepared from Na metal (8.65 g, 0.38 m) in methanol(200 mL) at 0°-5° C., was added a solution of 4-(methylthio)benzaldehyde (12.6 ml, 94.7 mmol) and methyl azidoacetate (44 g, 0.382 mol) in methanol (30 mL). After stirring at the same temperature for 3 hours, the suspension was diluted with H2O (300 mL). The solids were filtered, washed with water and dried under vacuum to provide 19.4 g (82.0%) of methyl-2-azido-3-(4-methylthiophenyl)propenoate as a yellow solid.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C.CCOCC>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[CH:1])([CH3:16])([CH3:15])[CH3:14]
Reactant: C#CC(O)CCCCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CC(CCCCC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a solution of 1-octyn-3-ol (5.0 g, 0.039 mol) in DMF (50 mL) were added tert-butyldimethylsilyl chloride (7.16 g, 0.0475 mol) and imidazole (3.2 g, 0.0475 mol). The resulting solution was stirred at RT for 18 h then diluted with ether (200 mL) and washed with water (2×200 mL), saturated solution of NH4Cl (200 mL), and brine (200 mL). The organic solution was dried over sodium sulfate and concentrated in vacuo to afford the desired compound (9.0 g, 95%) as a colorless oil used in the next step without further purification. Rf 0.9 (EtOAc/hexanes 1/9); 1H NMR (CDCl3) δ 0.09 (s, 3H), 0.12 (s, 3H), 0.89 (s, 9H), 0.85-1.00 (t, 3H), 1.20-1.70 (m, 8H), 2.35 (s, 1H), 4.30-4.35 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([S:28]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][C:6]3[CH:16]=[CH:17][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=3)[N:14]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1
Product: Cc1ccc(S(=O)(=O)Nc2cccc(COc3ccc(C(F)(F)F)cc3)n2)cc1Cl

Procedure:
This material was prepared in analogy to example 1 from 6-(4-trifluoromethyl-phenoxymethyl)-pyridin-2-ylamine (0.08 g) and 3-chloro-4-methyl-benzenesulfonyl chloride (0.074 g) as an off-white solid (0.105 g). MS (ESI−): 455.2 ([M−H]−).
Reaction SMILES: Cl.NO.C([N:7](CC)C(C)C)(C)C.[Br:13][C:14]1[N:19]=[C:18]([NH:20][C:21]([NH:23]C(OCC)=O)=S)[CH:17]=[CH:16][CH:15]=1>CCO.CO>[Br:13][C:14]1[N:19]2[N:7]=[C:21]([NH2:23])[N:20]=[C:18]2[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)NC(=S)Nc1cccc(Br)n1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Nc1nc2cccc(Br)n2n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1:1, 900 mL) is added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20° C.) for 1 h. 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is then added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H2S evolved). After 3 h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition of H2O (250 mL) and filtration. The combined solids are washed successively with H2O (250 mL), EtOH/MeOH (1:1, 250 mL) and Et2O (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. 1H (400 MHz, DMSO-d6) δ 7.43-7.34 (2H, m, 2×aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1:1, M+H+, 100%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:13]=[CH:12]2)C1C=CC=CC=1>CO.ClCCl.[Pd]>[CH2:18]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCn1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCn1ccc2cc(O)ccc21
Reaction time: 12 h

Procedure:
0.5 g (1.55 mmol) 5-benzyloxy-1-heptylindole is dissolved in a Schlenk flask in 10 ml methanol and 4 ml dichloromethane. 0.06 g Pd (10%)/C is added and the mixture is rinsed with nitrogen for 15 minutes. Thereafter, a balloon filled with hydrogen is placed on the Schlenk piston and hydrogenation is carried out at room temperature for 12 h. The batch is filtrated on a frit and the solvent is removed in vacuo. The residue is purified on silica gel by means of column chromatography (flow agent: hexane/ethyl acetate 9:1). The product accrues as an oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@:15](O)([CH2:16][C@@H:17]([O:36][C:37](=[O:39])[CH3:38])[CH2:18][C@@H:19]2[O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].ClCC(O)=O>C(=O)(OCC)OCC>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:36][C:37](=[O:39])[CH3:38])[CH2:18][C@@H:19]2[O:27][C:28](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)C5OCCO5)CC[C@H]4[C@@H]3C=C[C@@]2(O)C1
Agent: O=C(O)CCl
Solvent: CCOC(=O)OCC
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)c2ccccc2)C1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
In 10 ml of diethyl carbonate was dissolved 350 mg of 20-(1,3-dioxolan-2-yl)-3β-acetoxy-1α-benzoyloxypregn-6-en-5α-ol, followed by addition of 0.1 ml of monochloroacetic acid. The mixture was stirred under heating at 100° C. in an atmosphere of argon gas for 10 hours. The reaction mixture was then worked up in the same manner as Example 124 to give 120 mg of 20-(1,3-dioxolan-2-yl)-3β-acetoxy-1α-benzoyloxypregna-5,7-diene showing the following physical properties.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl>[C:18](=[O:19])([O:7][C:6]1[C:5](=[O:8])[CH:4]([CH3:9])[O:3][C:2]=1[CH3:1])[O:20][CH2:21][CH3:22]
Reactant: CCOC(=O)Cl
Reactant: CC1=C(O)C(=O)C(C)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)OC1=C(C)OC(C)C1=O
Yield: 72.5 %

Procedure:
A solution of 2,5-dimethyl-4-hydroxy-3(2H)-furanone (pineapple ketone, 133.0 g, 1.0 mole) and triethylamine (152.0 g, 1.5 moles) in methylene chloride (665 g) is cooled to 5° C. under nitrogen atmosphere. To the cooled solution is added over a period of 2.5 hours, a solution of ethyl chloroformate (127.7 g, 1.18 moles) in methylene chloride (600 g) stirred at 5°-8° C. for two additional hours. The reaction mixture is filtered through a Buchner funnel to remove the triethylamine hydrochloride. The salt is washed with methylene chloride (200 ml). The combined organic layers are washed twice with 100 ml portions of water and dried over sodium sulfate. The solvent is removed in vacuo and the crude product distilled (<0.1 torr) through a Goodloe column to yield 72.5% of ethyl 2,5-dimethyl-3-oxo-4(2H)-furyl carbonate product b.p. 87° C. (0.08 torr), IR (neat film) 2980(M), 1770(S), 1715(S), 1640(S), 1250(S) cm-1, 'H NMR δ 1.58(t,J=8 Hz,3), 1.65 (d,J=7 Hz,3), 2.32 (s,3), 4.45 (q,J=7 Hz,2), 4.75 (q,J=7 Hz,1), and 3.3% of the diadduct, diethyl 2,5-dimethyl-3,4-furyl dicarbonate, b.p. 110° C. (0.08 torr), IR (neat film 2980(M), 1770(S), 1250(S), 'H NMR δ=1.50 (t,J=6 Hz,6) 2.3 (S,6) 4.45 (q,J=8 Hz,4).
Reaction SMILES: CS(O)(=O)=O.CS(O[CH:11]([C:20]([CH3:30])([S:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19])(=O)=O.[I-:31].[Na+]>CC(C)=O>[I:31][CH:11]([C:20]([CH3:30])([S:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19]
Reactant: [I-]
Reactant: Cc1ccc(SC(C)(C)C(Cc2cccc[n+]2[O-])OS(C)(=O)=O)cc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccc(SC(C)(C)C(I)Cc2cccc[n+]2[O-])cc1
Yield: 62.1 %

Procedure:
A solution of 3.35 g of 2-[2-methanesulphonyloxy-3-methyl-3-(4-methylthiophenoxy)butyl]pyridine N-oxide methanesulphonic acid salt and 2.25 g of sodium iodide in 50 ml of acetone was heated under reflux for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between water and dichloromethane and the organic phase was evaporated. The residue was taken up in 50 ml of acetone and heated under reflux for 2 hours with 2.25 g of sodium iodide. The cooled reaction mixture was then evaporated and the residue was partitioned between water and dichloromethane. The organic phase was evaporated and the residue was crystallized from dichloromethane/ethyl acetate to give 1.8 g of 2-[2-iodo-3-methyl-3-(4-methylthiophenoxy)butyl]pyridine N-oxide in the form of a pale yellow solid of melting point 191°-193° C.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:15])([F:14])[C-:5]([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7].CN([S+](N(C)C)N(C)C)C.FC(F)(F)C(=C(F)F)C(F)(F)F.F[Si](C)(C)C>C(#N)C1C=CC=CC=1>[Br:1][C:5]([C:6]([F:9])([F:8])[F:7])([C:10]([F:11])([F:12])[F:13])[C:4]([F:14])([F:15])[F:3]
Reactant: BrBr
Reactant: FC(F)(F)[C-](C(F)(F)F)C(F)(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: C[Si](C)(C)F
Agent: FC(F)=C(C(F)(F)F)C(F)(F)F
Solvent: N#Cc1ccccc1
Product: FC(F)(F)C(Br)(C(F)(F)F)C(F)(F)F
Yield: 81 %

Procedure:
Bromine, 17.25 g (0.108 mol), was added dropwise at 0° to a solution of tris(dimethylamino)sulfonium 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)-2-propanide, prepared by dissolving 33.4 g (0.12 mol) of tri(dimethylamino)sulfonium difluorotrimethylsilicate and 24.0 g (0.12 mol) of perfluoroisobutylene in 75 mL of benzonitrile, then pumping out the by-product fluorotrimethylsilane at reduced pressure. The reaction mixture was evacuated to transfer the volatile reaction product into a cold trap (-78°). Sublimation of the contents of the trap at atmospheric pressure gave 26.11 g (81%) of 2-bromo-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane as a very volatile solid: m.p. (sublimation 49°-51°; 19F NMR (CDCl3) δ -67.6 ppm (s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH2:9].C(N(CC)CC)C.Cl[O-].[Na+].[OH:20][N:21]=[CH:22][C:23]1[N:24]=[C:25]([CH:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:46])[CH2:35][N:36]3[C:40]([CH3:41])=[CH:39][C:38]([C:42]([F:45])([F:44])[F:43])=[N:37]3)[CH2:30][CH2:29]2)[S:26][CH:27]=1.CC1N(CC(N2CCC(C3SC=C(C4C=C(C5C=CC=CC=5)ON=4)N=3)CC2)=O)N=C(C(F)(F)F)C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:20][N:21]=[C:22]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([C:34](=[O:46])[CH2:35][N:36]4[C:40]([CH3:41])=[CH:39][C:38]([C:42]([F:45])([F:43])[F:44])=[N:37]4)[CH2:32][CH2:33]3)[S:26][CH:27]=2)[CH2:9]1
Reactant: C=Cc1ccccc1Cl
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Agent: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(-c3cc(-c4ccccc4)on3)cs2)CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4Cl)C3)cs2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-chloro-2-ethenylbenzene (0.035 g, 0.25 mmol), triethylamine (2.5 mg, 0.025 mmol) and Clorox® aqueous sodium hypochlorite solution (1 mL, 16.1 mmol) in dichloromethane (5 mL) was added 4-[4-[(hydroxyimino)methyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 2, Step C) (0.10 g, 0.25 mmol) in dichloromethane (5 mL) dropwise over 1 h at 0° C. The reaction mixture was allowed to stir for 1 h, then filtered through Celite® diatomaceous filter aid, and concentrated under reduced pressure to give an oil, which was purified by column chromatography on silica gel using 50% ethyl acetate in hexane as eluant to give 73 mg of the title compound as a white foam, melting at 115-122° C. (crystallized from methyl acetate/petroleum ether).