Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH2:21][OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=Cc1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of (5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)methanol (966 mg, 3.21 mmol) in dichloromethane (16 mL) was added Dess-Martin periodinane (2.04 mg, 4.81 mmol). The reaction mixture was stirred at room temperature for overnight. 20 mL of saturated NaHCO3 solution and saturated Na2S2O3 solution (8:1) was added for quenching the reaction. After stirred for 1 h, the reaction mixture was extracted by EtOAc. The organic layers was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by automatic column chromatography to yield 5-benzyl-2-(2,5-difluorophenyl)oxazole-4-carbaldehyde (898 mg, 94%) as white solid. 1H NMR (CD3Cl, 400 MHz): δ 10.0 (1H, s), 7.70 (1H, m), 7.37-7.31 (3H, m), 7.29-7.25 (2H, m), 7.19-7.14 (2H, m), 4.44 (2H, s). LC/MS (uplc): 300.0, 1.06 min.
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH:3](C)C.[N+](C1C=CC(N2CCN(CCC)CC2)=CC=1)([O-])=O>[Pd]>[CH2:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH3:3]
Reactant: CC(C)CCN1CCN(c2ccc(N)cc2)CC1
Agent: [Pd]
Agent: CCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: CCCN1CCN(c2ccc(N)cc2)CC1

Procedure:
Using the method described above for the synthesis of 4-(4-isopentylpiperazin-1-yl)aniline, treatment of 1-(4-nitrophenyl)-4-propylpiperazine (1.0 g, 4.01 mmol) with H2 and 10% Pd/C provided crude 4-(4-propylpiperazin-1-yl)aniline (0.99 g, 118% recovery due to incomplete removal of the solvent, >80% purity as determined by LC/MS analysis @ UV 254 nm detection,). The crude product is used in the next step without further purification. LCMS-ESI (m/z): calcd for C13H21N3, 219; [M+H]+ found, 220.
Reaction SMILES: [CH:1]1([CH:6]([N:11]2[CH:15]=[C:14]([C:16]3[C:17]4[C:25](=[O:26])[CH2:24][NH:23][C:18]=4[N:19]=[C:20]([OH:22])[N:21]=3)[CH:13]=[N:12]2)[CH2:7][C:8]([NH2:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O.CC#N.O>C(Cl)Cl>[CH:1]1([C@H:6]([N:11]2[CH:15]=[C:14]([C:16]3[C:17]4[C:25](=[O:26])[CH2:24][NH:23][C:18]=4[N:19]=[C:20]([OH:22])[N:21]=3)[CH:13]=[N:12]2)[CH2:7][C:8]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)CC(C1CCCC1)n1cc(-c2nc(O)nc3c2C(=O)CN3)cn1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC[C@H](C1CCCC1)n1cc(-c2nc(O)nc3c2C(=O)CN3)cn1

Procedure:
To a solution of 3-cyclopentyl-3-[4-(2-hydroxy-5-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanamide (0.006 g, 0.02 mmol) in methylene chloride (0.5 mL) containing triethylamine (20 TL, 0.2 mmol) was added trichloroacetyl chloride (20 TL, 0.2 mmol). When the reaction was complete, preparative HPLC-MS (MeCN/H2O containing 0.15% NH4OH) was used to afford purified product (3 mg, 52%). 1H NMR (400 MHz, d6-DMSO): δ 11.39 (br s, 1H), 9.37 (s, 1H), 8.77 (s, 1H), 8.63 (s, 1H), 4.68-4.59 (m, 1H), 3.94 (s, 2H), 3.19-3.15 (m, 2H), 2.42-2.30 (m, 1H), 1.86-1.75 (m, 1H), 1.69-1.20 (m, 6H), 1.18-1.05 (m, 1H); LCMS (M+H)+: 339.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].Br[CH2:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:30][C:29]=1[F:39].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:27][C:28]3[C:33]([F:34])=[CH:32][C:31]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:30][C:29]=3[F:39])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Reactant: NS(=O)(=O)c1cc(F)c(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(N)(=O)=O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
A mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (170 mg, 0.45 mmol, 1.0 eq), 4-(bromomethyl)-3,5-difluorobenzenesulfonamide (155 mg, 0.54 mmol, 1.2 eq) and K2CO3(94 mg, 0.68 mmol, 1.5 eq) in acetone (2.3 mL) was stirred for 30 min. The reaction mixture was filtered, and the filtrate was concentrated and purified (silica, 0-75% EtOAc/Hex) to afford the title compound (252 mg, 96%) as a white solid. MS (EI) m/z 584 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:5][CH:4]=1.C([Mg]Cl)(C)C.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>C1COCC1.CCCCC>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[C:13]([B:24]([OH:29])[OH:25])[CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2cc(I)ccc2Cl)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(B(O)O)ccc2Cl)cc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 145 g (387 mmol) of 2-[(4-methoxybenzyl)oxy]-1-chloro-4-iodobenzene in 1.2 L of anhydrous THF, placed under argon and stirred at −50° C., are added dropwise 220 mL (440 mmol) of a 2N solution of iPrMgCl in THF, while maintaining the temperature between −40 and −50° C. The reaction mixture is allowed to warm to −10° C. and stirring is continued for 1 hour. 94 mL (406 mmol) of triisopropyl borate are then added and the reaction mixture is then allowed to warm slowly to 0° C. After stirring for 2 hours, the mixture is treated with 500 mL of aqueous 5N HCl solution and then extracted with ether (2×600 mL). The organic phase is washed with 2×1 L of water, dried over Na2SO4 and then concentrated under reduced pressure. The residue obtained is solidified in 300 mL of pentane, filtered off on a sinter funnel and washed with 200 mL of pentane. 96 g of [3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]boronic acid are thus obtained in the form of a white solid.
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:19]([O:21]C)=[O:20])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[N:9]=1>C1COCC1.O>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]3)=[CH:14][CH:15]=2)[N:9]=1
Reactant: COC(=O)C1(c2ccc(-c3csc(N)n3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(-c2ccc(C3(C(=O)O)CC3)cc2)cs1

Procedure:
Lithium hydroxide monohydrate (0.24 g, 5.8 mmol) was added to a mixture of methyl 1-[4-(2-amino-1,3-thiazol-4-yl)phenyl]cyclopropanecarboxylate (0.2 g, 0.73 mmol) in THF (3.0 ml) and water (1.0 mL), and the resulting mixture was refluxed for 30 minutes. Then the reaction mixture was concentrated and the residue was adjusted to be acidic (pH=˜3) by 1N HCl aqueous solution. The precipitate framed was filtered and washed with water to afford the desired product. LC-MS: 261.0 (M+H)+,
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccccn2)cc1Cl
Temperature: 0 °C
Yield: 81.4 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 97, 200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then warmed to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-aminopyridine (85 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (202 mg, 81.5%) as a white foam: [α]23589=−41.8° (c=0.098, chloroform); EI-HRMS m/e calcd for C20H23ClN2O3S (M+) 406.1118, found 406.1119.
Reaction SMILES: Cl[C:2](OCCCCCC1OC(=O)ON=1)=O.OCCCOC(=O)C(C)=C.N1C=CC=CC=1.[C:32]([O:37][CH2:38][CH:39]([C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]1[O:53][C:52](=[O:54])[O:51][N:50]=1)=[O:42])C)(=[O:36])[C:33]([CH3:35])=[CH2:34]>O1CCOCC1>[C:32]([O:37][CH:38]([CH3:2])[CH2:39][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]1[O:53][C:52](=[O:54])[O:51][N:50]=1)=[O:42])(=[O:36])[C:33]([CH3:35])=[CH2:34]
Reactant: O=C(Cl)OCCCCCc1noc(=O)o1
Reactant: C=C(C)C(=O)OCC(C)C(=O)OCCCCCc1noc(=O)o1
Agent: C=C(C)C(=O)OCCCO
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: C=C(C)C(=O)OC(C)CC(=O)OCCCCCc1noc(=O)o1
Yield: 97.2 %

Procedure:
In accordance with the procedure of Example 1, 35.34g (0.15 moles) 5-(chloroformyloxypentyl)-1,3,4-dioxazol-2-one is made to react with 21.63g (0.15 moles) hydroxypropylmethacrylate (a 1:1 mixture of 2-hydroxypropyl and 1-methyl-2-hydroxyethylmethacrylate) in 75 ml 1,4-dioxane by adding 11.86g (0.15 moles) pyridine in 65 ml 1,4-dioxane over a 1 hour period at 18-21° C. After work-up, 50.0g of a slightly reddish-brown liquid is obtained which is analyzed by IR and NMR spectroscopy to be a 1:1 mixture of 5-[(2-methacryloyloxy-1-methylethyl)formyloxypentyl]-1,3,4-dioxazol-2-one and 5-[(2-methacryloyloxy-2-methylethyl)formyloxypentyl]-1,3,4-dioxazol-2-one (yield: 97.2%), having the respective structural formulas: ##STR17##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]=[N+]=[N-])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([NH2:15])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N=[N+]=[N-])CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1

Procedure:
The roughly purified product of Intermediate 37 (142 g) was reduced by hydrogenation at room temperature for 9 hours by using 10% Pd/C (7.1 g) and ethyl acetate solution (1.42 l) under hydrogen atmosphere of 1 atm. The palladium catalyst was removed by filtration, and the solvent was evaporated under reduced pressure. Then, the residue was purified by flash column chromatography (chloroform:methanol:triethylamine=100:20:10) to obtain the title compound (45.8 g).
Reaction SMILES: C(Cl)(=O)C1C=CC(C(Cl)=O)=CC=1.[CH3:13][O:14][C:15](=[O:26])[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1.O[Li].O>ClCCl.CO>[CH3:13][O:14][C:15](=[O:26])[C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: [Li]O
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 20.3 g (100 mmol) terephthaloyl chloride in 100 ml dichloromethane was added to 100 ml anhydrous methanol at 0° C. The reaction was left 1.5 h at rt. The reaction mixture was evaporated and the residue was dissolved dichloromethane. The organic phase was washed with saturated NaHCO3 aq. The organic phase was dried and evaporated. Yield 18.3 g (94.2 mmol, 94%). A solution of 18.3 g (94.2 mmol) of terephthalic acid dimethyl ester and 3.96 g (94.2 mmol) LiOH.H2O in anhydrous methanol (did not dissolve completely) was stirred for 5 d at rt. The solvent was evaporated and the product was dissolved in water. The aqueous phase was washed with dichloromethane. The aqueous phase was made acidic with 2 M HCl aq. The product precipitated from the aqueous phase. The product was filtered off and dried in vacuo. The product was dissolved in 1 L dry ethanol, and thereafter 4 l water was added slowly while stirring. The product precipitated slowly overnight at +4°C. The product was filtered and dried in vacuo. Yield 8.61 g (48 mmol, 51%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([OH:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].[CH2:23](OC(=O)C)[CH3:24]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([O:14][CH2:23][CH3:24])=[O:13])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCCCCCC(C(=O)O)S(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Product: CCCCCCC(C(=O)OCC)S(=O)(=O)c1ccc(C)cc1

Procedure:
By the procedure described in Example 1(b), 2.6 g (60% of theory) of 2-[(4-methylphenyl)sulfonyl]octanoic acid, MP 111°-123° C. (acetic acid ethyl ester), is obtained from 4.75 g (14.5 mmol) of ethyl 2-[(4-methylphenyl)sulfonyl]octanoate (Example 13) and 32 ml of 1N potash lye.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:18]([OH:20])=[O:19])[CH2:15][CH:16]=[CH2:17])[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1.[N+](=[CH2:31])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:18]([O:20][CH3:31])=[O:19])[CH2:15][CH:16]=[CH2:17])[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1
Reactant: C=CCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O
Reactant: C=[N+]=[N-]
Product: C=CCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)OC

Procedure:
In the manner given in Example 10, a solution of 7-chloro-2-[(1-carboxy-3-butenylidene)hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-3-butenylidene]hydrazino]-5-(o-chlorphenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.Cl[C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1.BrC1C=CC(C=O)=C(F)C=1.BrC1N=CC=CN=1>>[N:11]1[CH:12]=[CH:13][N:14]=[CH:15][C:10]=1[C:2]1[S:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: O=Cc1csc(Br)c1
Reactant: Clc1cnccn1
Agent: Brc1ncccn1
Agent: O=Cc1ccc(Br)cc1F
Product: O=Cc1csc(-c2cnccn2)c1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 15 by substituting 5-bromo-3-thiophenecarboxaldehyde (prepared as described in Chem. Pharm. Bull. 1999, 47,1393) and chloropyrazine, respectively, for the 4-bromo-2-fluorobenzaldehyde and 2-bromopyrimidine of Reference Example 15. MS 191 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P:11]2(=[O:19])[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][O:12]2)=[CH:6][CH:5]=1.[Li+].[OH-]>O1CCOCC1>[CH3:17][C:14]1([CH3:18])[CH2:15][O:16][P:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][CH:6]=2)(=[O:19])[O:12][CH2:13]1
Reactant: COC(=O)c1ccc(CP2(=O)OCC(C)(C)CO2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C)COP(=O)(Cc2ccc(C(=O)O)cc2)OC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(5,5-Dimethyl-2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-ylmethyl)-benzoic acid methyl ester (0.23 g, 0.75 mmol) was made 0.25 M in dioxane and to this stirring solution was added 3 N aq LiOH (0.05 g, 2.26 mmol). The resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated in vacuo and carried directly onto subsequent coupling without further purification: MS: cal'd 285 (MH+), exp 285 (MH+).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:42](=[O:43])[N:12]2[C:13]([C:36]([O:38]CC=C)=[O:37])=[C:14]([CH2:17][N:18]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[S:19]3(=[O:35])=[O:34])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[Na+:73].C(OCC)(=O)C>C(C(CCCC)C(O)=O)C.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl.C(OCC)(=O)C>[O:35]=[S:19]1(=[O:34])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:27][N:18]1[CH2:17][C:14]1[C@H:15]([CH3:16])[C@@H:11]2[C@@H:10]([C@H:8]([OH:7])[CH3:9])[C:42](=[O:43])[N:12]2[C:13]=1[C:36]([O-:38])=[O:37].[Na+:73]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3N=C(c4ccccc4)c4ccccc4S3(=O)=O)[C@H](C)[C@H]12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)O
Agent: CCCCC(CC)C(=O)[O-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(CN3N=C(c4ccccc4)c4ccccc4S3(=O)=O)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The product from step 1 (26 mg, 0.043 mmol), triphenylphosphine (4.0 mg, 0.015 mmol), 0.5M sodium 2-ethyl-hexanoate in ethyl acetate (0.095 mL, 0.048 mmol), and 0.5M 2-ethyl-hexanoic acid in ethyl acetate (0.095 mL, 0.048 mmol) were dissolved in 1:1 dichloromethane-ethyl acetate (1.5 mL). Tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. The mixture was diluted with diethyl ether and extracted with water (2 mL). The aqueous extracts were purified by preparative layer chromatography on a 1 mm×20 cm×20 cm RPSF plate, using 3:1 water-acetonitrile as the developing solvent. The product band was located by UV, removed and eluted with 4:1 acetonitrile-water. The eluent was concentrated under vacuum to remove the acetonitrile and lyophilized to afford the title compound (9.7 mg) as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[C:5]2[CH2:6][N:7]([C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[OH:18])[C:8](=[O:11])[C:9]=2[CH:10]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=O)=O.O>ClCCl>[Br:1][C:2]1[C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[C:5]2[CH2:6][N:7]([C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[O:18][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C:8](=[O:11])[C:9]=2[CH:10]=1
Reactant: O=C1c2cc(Br)c3ccccc3c2CN1[C@H]1CCCC[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCCC[C@@H]1N1Cc2c(cc(Br)c3ccccc23)C1=O
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-2-[(1S,2S)-2-hydroxycyclohexyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one (see Example 1, 2.00 g, 5.55 mmol) in 15 mL of dichloromethane at 0° C. was added 2,6-lutidine (1.29 mL, 11.1 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (1.91 mL, 8.33 mmol). The mixture was warmed to ambient temperature and after 15 hr, was treated with water. The mixture was extracted 2× with ethyl acetate and the combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-40% ethyl acetate in hexanes, to provide 5-bromo-2-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one that gave a mass ion (ES+) of 475.1 for [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=C(C3C=NC=CN=3)C=[CH:20][N:19]=2)=[CH:12][CH:11]=1.N1C=CN=CC=1C(=O)C.[CH3:40][C:41]1[S:42][C:43]([C:47](=O)[CH3:48])=[C:44]([CH3:46])[N:45]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=[C:47]([C:43]3[S:42][C:41]([CH3:40])=[N:45][C:44]=3[CH3:46])[CH:48]=[CH:20][N:19]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Reactant: CC(=O)c1sc(C)nc1C
Agent: CC(=O)c1cnccn1
Product: Cc1nc(C)c(-c2ccnc(NCc3ccc(C(=O)Nc4ccccc4N)cc3)n2)s1

Procedure:
Title compound was obtained according to the scheme 6 similarly to the compound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone as the starting material 1-(2,4-dimethyl-thiazol-5-yl)-ethanone (Table 11). Characterization of the title compound is provided in the Table 12.
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].C(OCOC)(=O)C.[C:13]([O:16][C@:17]1([C@:41]2([CH3:42])[C@H:27]([C@H:28]3[C@H:38]([CH2:39][CH2:40]2)[C@:36]2([CH3:37])[C:31](=[CH:32][C:33](=[O:43])[CH2:34][CH2:35]2)[CH2:30][CH2:29]3)[CH2:26][CH2:25]1)[C:18](=[O:24])[CH2:19][O:20][C:21](=[O:23])[CH3:22])(=[O:15])[CH3:14]>C(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O>[C:13]([O:16][C@:17]1([C@:41]2([CH3:42])[C@H:27]([C@H:28]3[C@H:38]([CH2:39][CH2:40]2)[C@:36]2([CH3:37])[C:31](=[CH:32][C:33](=[O:43])[CH2:34][CH2:35]2)[C:30]([CH3:1])=[CH:29]3)[CH2:26][CH2:25]1)[C:18](=[O:24])[CH2:19][O:20][C:21](=[O:23])[CH3:22])(=[O:15])[CH3:14]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CC(=O)[O-]
Agent: COCOC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Under argon, a suspension of 0.5 g of sodium acetate in 60 ml of anhydrous chloroform, 2 ml of distilled phosphorus oxychloride, and 15 ml of methoxymethyl acetate is agitated for 30 minutes at a bath temperature of 60° C. After adding 2.0 g of 17α,21-diacetoxy-4-pregnene-3,20-dione, the mixture is further stirred for 3 hours at 70° C. and worked up analogously to Example 1. The dark crude product is purified on 200 g of silica gel with a hexane-ethyl acetate gradient (0-40% ethyl acetate), yielding 1.15 g of 17α,21-diacetoxy-6-methyl-4,6-pregnadiene-3,20-dione, mp 213°-215° C.