Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:10]=1[Cl:11].ClC1C=C(Br)C=CC=1Cl.C(OCC)C.[CH3:27][N:28]1[CH2:33][CH:32]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1>C(OCC)C.[Cu]I.O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:32]2[CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: CCOC(=O)C1=CCN(C)CC1
Reactant: Clc1ccc(Br)cc1Cl
Agent: [Cu]I
Agent: II
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C)CC1c1ccc(Cl)c(Cl)c1
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a suspension of magnesium (10.76 g) in diethyl ether (110 mL) was added a trace amount of iodine. About one-tenth of a solution of 3,4-dichlorobromobenzene (100 g) in diethyl ether (110 mL) was added slowly at 35-40° C., and the mixture was vigorously stirred until the reaction started. When the reaction started, the rest of the 3,4-dichlorobromobenzene/diethyl ether solution was added slowly while cooling the reaction mixture to 35-40° C. When all was added, the mixture was stirred at 40° C. for 1 hr, and then cooled to 0° C. To the reaction mixture was added copper(I) iodide (12.6 g), and the compound (56.2 g) obtained in step 1 was slowly added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, and at room temperature for 1 hr. The reaction mixture was poured into water (40 mL), diethyl ether (500 mL) was added, and the precipitate was removed by decantation. The reaction mixture was washed with aqueous ammonium chloride solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20% ethyl acetate/hexane→2.5% aqueous ammonia/17.5% methanol/ethyl acetate) to give crude ethyl 3-(3,4-dichlorophenyl)-1-methylpiperidine-4-carboxylate (cis/trans mixture) (75.5 g) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[CH3:21][S:22][CH2:23]CCl>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:21][S:22][CH3:23])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: CSCCCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
5.85 G. of 1-amino-2-nitro-4-thiocyanatobenzene is treated in 20 ml. dimethylformamide under nitrogen at 20°-25° with 1.14 g. sodium borohydride. After 1 hour 10 ml. of methylthioethylchloride is added and the mixture stirred overnight, diluted with water and extracted with chloroform. The dried chloroform solution is passed through a silica gel column, then evaporated to dryness to afford 1-amino-2-nitro-4-methylthioethylthiobenzene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[Cl:22][CH2:23][CH2:24][NH2:25]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:25][CH2:24][CH2:23][Cl:22])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCCCl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.8 %

Procedure:
To a solution of 4-fluoro-3-nitro-benzoic acid methyl ester (10.0 g, 0.0502 mol) in dry DMF (100 mL) was added with stirring potassium carbonate (59.0 g, 0.43 mol) followed by 2-chloroethylamine hydrochloride (8.7 g, 0.075 mol) and the mixture was stirred for 15 h at ambient temperature. The reaction mixture was diluted with ice water (500 mL) and the solid precipitated was filtered, washed with water and dried under vacuum to get a yellow solid (12.7 g, 98%). MS-ESI m/z 259 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([CH2:10][O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:3]=1.[BH4-].[Na+].CC(C)=O.C(Cl)(Cl)Cl>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH2:10][O:11][CH2:12][C:13]([F:16])([F:14])[F:15])[N:3]=1
Reactant: O=Cc1cc(COCC(F)(F)F)nc(Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CCO
Product: OCc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.8 %

Procedure:
2-Chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine-4-carbaldehyde (0.6 g, 2.36 mmol) was dissolved in ethanol (20 mL). Sodium borohydride (0.134 g, 3.54 mmol) was added and the mixture was stirred at rt for 10 min. Acetone (5 mL) was added and mixture was stirred for 10 min. Chloroform (20 mL) was added and the mixture was filtered through a pad of silica. The solvents were evaporated and the residue was purified by column chromatography on silica eluting with a gradient of methanol in DCM to give the title compound 0.35 g (58%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]4[CH2:30][CH2:29]4)[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:36][OH:37].N1C=CC=CC=1.CO>>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:36][OH:37])=[C:24]([CH:28]4[CH2:29][CH2:30]4)[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NO
Reactant: CCOc1nc(C2CC2)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CCOc1nc(C2CC2)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
Compound A (1.21 g, 2.60 mmol), hydroxylamine hydrochloride (181 mg, 2.6 mmol), pyridine (10 mL, 100 mmol), and MeOH (10 mL, 300 mmol) were combined and stirred at room temperature overnight. Additional hydroxylamine hydrochloride (20 mg) was added and the mixture evaporated to dryness. The solids were dissolved in DCM (50 mL), washed with water (2×20 mL) and saturated aqueous NaCl (10 mL), dried over Na2SO4, and evaporated to dryness to afford compound B as a white solid (1.0 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][C:5]2=[C:7]([C:13]([O:15]C)=[O:14])[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:4]2[O:3]1>C(O)C.[OH-].[Na+]>[CH3:1][C:2]1([CH3:17])[CH2:6][C:5]2=[C:7]([C:13]([OH:15])=[O:14])[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:4]2[O:3]1
Reactant: COC(=O)c1ccc(OC)c2c1CC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)O)c2c1OC(C)(C)C2
Yield: 90.8 %

Procedure:
5.5 g of methyl 2,3-dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carboxylate are stirred at 60° C. for 2 h in a mixture of 150 ml of ethanol and 50 ml of 2N NaOH. The ethanol is distilled off, the residue is taken up in the water and the solution is adjusted to a pH of 4 with 2N HCl. The product which is precipitated hereby is filtered off with suction, washed with water and dried. 4.7 g of the title compound of m.p. 147-149° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]3[C@H:15]4[C@H:25]([CH2:26][CH2:27][C@:10]23[CH3:11])[C@:23]2([CH3:24])[C@H:18]([N:19]([CH3:29])[C:20](=[O:28])[CH2:21][CH2:22]2)[CH2:17][CH2:16]4)=[CH:6][CH:5]=1)([O-])=O.[ClH:32]>CO.C(O)C.O=[Pt]=O>[ClH:32].[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]3[C@H:15]4[C@H:25]([CH2:26][CH2:27][C@:10]23[CH3:11])[C@:23]2([CH3:24])[C@H:18]([N:19]([CH3:29])[C:20](=[O:28])[CH2:21][CH2:22]2)[CH2:17][CH2:16]4)=[CH:30][CH:31]=1
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](Oc5ccc([N+](=O)[O-])cc5)CC[C@H]4[C@@H]3CC[C@@H]12
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](Oc5ccc(N)cc5)CC[C@H]4[C@@H]3CC[C@@H]12

Procedure:
17β-(4-nitrophenoxy)-4-methyl-5α-4-azaandrostan-3-one (938 mg, 2.2 mmole) in MeOH (70 ml) was hydrogenated at 40 psi in the presence of PtO2 (400 mg) for 90 mins. To the resulting mixture was added 5% conc. HCl in absolute ethanol (4 ml) under N2, and then the mixture was filtered through a pad of celite. The filtrate was concentrated, vacuum dried, and then triturated with CH2Cl2 -hexane to give the title product, mp. 307°-310° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][CH:5]1[CH2:12][CH:11]2[CH:7]([C:8]([OH:25])=[C:9]([C:14]3[C:19]([CH2:20][CH3:21])=[CH:18][C:17]([CH3:22])=[CH:16][C:15]=3[CH2:23][CH3:24])[C:10]2=[O:13])[CH2:6]1.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>ClCCl>[CH3:28][C:27]([CH3:30])([CH3:29])[C:26]([O:13][C:10]1[CH:11]2[CH:7]([CH2:6][CH:5]([CH:4]=[N:3][O:2][CH3:1])[CH2:12]2)[C:8](=[O:25])[C:9]=1[C:14]1[C:15]([CH2:23][CH3:24])=[CH:16][C:17]([CH3:22])=[CH:18][C:19]=1[CH2:20][CH3:21])=[O:31]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1cc(C)cc(CC)c1C1=C(O)C2CC(C=NOC)CC2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(C)cc(CC)c1C1=C(OC(=O)C(C)(C)C)C2CC(C=NOC)CC2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
0.104 g (0.31 mmol) of 5-(2,6-diethyl-4-methylphenyl)-6-hydroxy-4-oxo-1,2,3,3a,4,6a-hexahydropentalene-2-carbaldehyde O-methyloxime (compound I-a-13 according to the invention), 0.040 g (0.34 mmol) of pivaloyl chloride and 92 mg (0.91 mmol) of triethylamine in 8 ml of dichloromethane are stirred at room temperature for 2 h. The mixture is poured onto ice, taken up in dichloromethane, washed with water, dried (magnesium sulphate) and concentrated using a rotary evaporator. Chromatography on silica gel (mobile phase ethyl acetate/hexane v:v=25:75) gives 107 mg of the title compound as a colourless oil.
Reaction SMILES: C1N(P(N2CC2)(NC(C2C(I)=CC=CC=2)=O)=O)C1.[CH3:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH:25]=[CH2:26].I[C:28]1[C:36]2[C:31](=[CH:32][C:33]([CH:37]=[O:38])=[CH:34][CH:35]=2)[N:30]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[N:29]=1>>[CH3:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1/[CH:25]=[CH:26]/[C:28]1[C:36]2[C:31](=[CH:32][C:33]([CH:37]=[O:38])=[CH:34][CH:35]=2)[N:30]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[N:29]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1nccn1C
Agent: O=C(NP(=O)(N1CC1)N1CC1)c1ccccc1I
Product: Cn1ccnc1/C=C/c1nn(COCC[Si](C)(C)C)c2cc(C=O)ccc12
Yield: 17 %

Procedure:
The title compound was synthesized according to the method of Example A103, utilizing 1-methyl-2-vinyl-1H-imidazole (35 mg, 0.32 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (100 mg, 0.23 mmol). Purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound (15 mg, 74%) as a tan oil (41.6 mg, 47%). 1H NMR (400 MHz, CD3OD) δ ppm 10.09 (s, 1H), 8.22 (t, J=1.00 Hz, 1H), 8.13 (d, J=8.53 Hz, 1H), 7.78 (dd, J=8.53, 1.25 Hz, 1H), 7.68 (d, J=16.06 Hz, 1H), 7.43 (d, J=16.06 Hz, 1H), 7.13 (d, J=1.25 Hz, 1H), 7.05 (d, J=1.00 Hz, 1H), 5.84 (s, 2H), 4.89 9s, 3H), 3.63 (t, J=8.03 Hz, 1H), 0.87 (t, J=8.03 Hz, 2H), −0.10 (s, 9H); MS ESI 383.2 [M+H]+, calcd for [C20H26N4O2Si+H]+ 383.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH2:10]1[N:15]([CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH2:14][CH2:13][N:12]2[CH2:22][CH2:23][CH2:24][CH2:25][CH:11]12>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:15]2[CH2:14][CH2:13][N:12]3[CH2:22][CH2:23][CH2:24][CH2:25][CH:11]3[CH2:10]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CCCN1CCN2CCCCC2C1
Product: O=C(CCCN1CCN2CCCCC2C1)Nc1ccc(Cl)c(Cl)c1

Procedure:
The procedure is as for Example 2 using as substrate 3,4-dichloroaniline and the compound obtained in Step B of Example 2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(OCC)(=[O:24])C>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:13](=[O:24])[CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Into a round-bottom flask, was placed a solution of tert-butyl 4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.4, 515 mg, 1.80 mmol, 1.00 equiv) in ethyl acetate (5 mL). A solution of NaIO4 (963 mg, 4.50 mmol, 2.50 equiv) in water (5 mL) and RuCl3 (74.7 mg, 0.36 mmol, 0.20 equiv) was carefully added. The resulting mixture was stirred overnight at room temperature. The solids were removed by filtration and the filtrate was washed with 2×20 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 432 mg (80%) of the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].C([Li])CCC.C(Cl)(Cl)(Cl)Cl.C(=O)=O.[CH3:26][C:27]([CH3:29])=[O:28]>O1CCCC1.C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[C:8]([C:27]([CH3:29])([CH3:26])[OH:28])[S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: Oc1cc2ccsc2c(Cl)c1Cl
Reactant: CC(C)=O
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 4 h

Procedure:
To a solution of 6,7-dichloro-5-hydroxybenzo[b]thiophene in 28 ml of dried tetrahydrofuran at -28° is added 21 ml of 2.5M n-butyllithium, maintaining the temperature below -18°. Following the addition, the carbon tetrachloride-dry ice bath is replaced with an ice-water bath and the mixture is stirred at 0°-5° for about 4 hrs. A solution of 3.3 ml of acetone in 10 ml tetrahydrofuran is added dropwise. After stirring for one hr, the solution is poured onto 100 ml of water and acidified to pH=5-6 with glacial acetic acid. The acidic solution is extracted with ethyl acetate, washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give 3.84 g of 6,7-dichloro-5-hydroxy-α,α-dimethylbenzo[b]thiophene-2-methanol, mp 171°-173°.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[C@@H:13]([OH:21])[C@@H:12]2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[OH:21][CH:13]1[CH:12]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[O:15][C:14]1([CH3:20])[CH3:19]
Reactant: [H][H]
Reactant: CN([C@@H]1c2cc(OCc3ccccc3)ccc2OC(C)(C)[C@H]1O)S(C)(=O)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C1c2cc(O)ccc2OC(C)(C)C1O)S(C)(=O)=O
Yield: 89.3 %

Procedure:
1.0 g (2.6 mmol) of (±)-trans-N-(6-benzyloxy-3-hydroxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide (Example 1) was hydrogenated in 100 ml of THF/methanol (1:1) in the presence of palladium/carbon until the uptake of hydrogen had ended. The catalyst was filtered off and the filtrate was concentrated, giving 0.7 g of N-(3,6-dihydroxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide; m.p. 204-206° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([I:9])[C:3]=1[N:10]=[C:11]=[O:12].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([I:9])[C:3]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)=[O:12]
Reactant: Cc1cc(F)c(N=C=O)c(I)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Product: Cc1cc(F)c(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the crude 1-fluoro-3-iodo-2-isocyanato-5-methylbenzene from description D2, 4-amino-1-N-Boc piperidine (200 mg, 1 mmol), and dichloromethane (3 ml) was stirred at room temperature for 1 h then directly purified by chromatography on silica gel eluting with 0 to 10% methanol in dichloromethane. Further purification by MDAP (mass-directed auto-purification) gave the title compound 300 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][CH:22]1[CH2:24][O:23]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:21][CH:22]2[O:23][CH2:24]2)=[CH:11][C:10]=1[C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1cc(O)ccc1OCc1ccccc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(OCC2CO2)ccc1OCc1ccccc1

Procedure:
Then, using 6.07 g of the compound of Example 18 above, 4.0 ml of chloromethyloxirane, 3.26 g of anhydrous potassium carbonate and 100 ml of methyl methyl ketone, reaction and workup carried out as in 1-A gave about 8.00 g of 1-(4-benzyloxy-3-tert-butylphenoxy)-2,3-epoxypropane as brown oil. Using the epoxy compound thus obtained, 4.82 g of 1-(2-methoxyphenyl)piperazine and 100 ml of dioxane, reaction and workup carried out as in Example 1-A followed by recrystallization from isopropyl ether gave 6.48 g of white crystals, m.p. 133-134° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=[C:13]([Br:12])[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(Br)cc(C(F)(F)F)c1)c1cc(Br)ccc1O
Yield: 73.3 %

Procedure:
Using 5-bromosalicylic acid and 3-bromo-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([CH3:25])[C@@H:15]3[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:27])[CH:4]=[CH:5][C:6](=[O:26])[CH:7]=1.C[OH:29]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([CH3:25])[C@@H:15]3[C:16](=[O:19])[C:17]([OH:29])=[O:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:27])[CH:4]=[CH:5][C:6](=[O:26])[CH:7]=1
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@H]1C(=O)CO
Reactant: CO
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: 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@H]1C(=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
One gram of 9α-fluoro-11β,21-dihydroxy-16α-methyl-1.4-pregnadiene-3,20-dione is dissolved in 125 ml. of methanol and combined with a solution of 250 mg. of copper(II) acetate in 125 ml. of methanol. The mixture is stirred for 15 minutes at room temperature while passing air therethrough, and then is combined with methylene chloride, washed with 5% ammonium chloride solution and water, and concentrated under vacuum. The thus-obtained product is dissolved in 50 ml. of methanol. The solution is mixed with 165 mg. of potassium cyanide, 1.0 ml. of acetic acid, and 5 g. of manganese(IV) oxide and agitated for 30 minutes at room temperature. Then the mixture is filtered, the filtrate diluted with methylene chloride, washed with water, dried, and concentrated under vacuum. The residue is chromatographed over a silica gel column, recrystallized from acetone/hexane, and the methyl ester of 9α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadiene-21-oic acid is thus produced, m.p. 215° C.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[C@H:21]([S:22][CH2:23][C:24]=1[CH2:25][Cl:26])[C@H:20]([NH:27][C:28](=[O:67])/[C:29](=[N:44]\[O:45][C@@H:46]([CH2:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1)=[O:48])/[C:30]1[N:31]=[C:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[S:33][C:34]=1[Cl:35])[C:19]2=[O:68])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:77])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH:1]([O:14][C:15]([C:17]1[N:18]2[C@H:21]([S@:22](=[O:77])[CH2:23][C:24]=1[CH2:25][Cl:26])[C@H:20]([NH:27][C:28](=[O:67])/[C:29](=[N:44]\[O:45][C@@H:46]([CH2:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=1)=[O:48])/[C:30]1[N:31]=[C:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[S:33][C:34]=1[Cl:35])[C:19]2=[O:68])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)C[S@@](=O)[C@H]23)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a solution of (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(2-(((6R,7R)-2-((benzhydryl oxy)carbonyl)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoethylidene)amino)oxy)succinate (27.5 g, 27.2 mmol) in Dichloromethane (DCM) (IL) at −40° C. was added dropwise a solution of m-CPBA (6.40 g, 28.6 mmol) in Dichloromethane (DCM) (200 mL) over 10 min. The mixture was stirred at the same temperature over 30 min. LCMS indicated completion of the reaction. The mixture was treated with 15% aq. Na2S2O3 (200 mL). The organic solution was separated and washed with 5% NaHCO3 (400 mL), brine (400 mL), dried (Na2SO4), filtered, and concentrated (temperature of the water bath should not be too high—apx. 25° C.). The residue was purified by CombiFlash automated silica gel chromatography (220 g column), eluting with EtOAc/Hexanes (0-60%) to afford (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(2-(((5R,6R,7R)-2-((benzhydryloxy)carbonyl)-3-(chloromethyl)-5-oxido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoethylidene)amino)oxy)succinate (27.5 g, 25.4 mmol, 94% yield) as a light yellow foaming solid. LCMS: (M+H)+: 1026.3
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.[NH2:37][CH:38]([C:52](=[O:64])[NH:53][CH2:54][CH2:55][NH:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C:39](=[O:51])[NH:40][CH2:41][CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].C(N(C(C)C)C(C)C)C.C(OCC)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([NH:37][CH:38]([C:52](=[O:64])[NH:53][CH2:54][CH2:55][NH:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C:39](=[O:51])[NH:40][CH2:41][CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:29])[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)C(N)C(=O)NCCNC(=O)OC(C)(C)C
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: Cn1ncc(NC(=O)NC(C(=O)NCCNC(=O)OC(C)(C)C)C(=O)NCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 88 %

Procedure:
To a suspension of phenyl N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (949 mg) and di-tert-butyl 7-amino-6,8-dioxo-2,5,9,12-tetraazatridecanedioate (968 mg) in dehydrated chloroform (4 ml) was added N-ethyldiisopropylamine (0.342 ml), and the mixture was stirred under reflux for 5 hours. To the reaction mixture was added diethyl ether. The resulting precipitate was collected by filtration and dried in vacuo to give di-tert-butyl 7-[({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)amino]-6,8-dioxo-2,5,9,12-tetraazatridecanedioate (1.38 g) as a solid.