Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26](OC)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.C1C[O:34][CH2:33]C1.CO>[OH-].[Na+]>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH2:8][CH2:7][C:6]([S:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=3[O:34][CH3:33])(=[O:21])=[O:22])([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]2)=[CH:14][CH:15]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(Br)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1S(=O)(=O)C1(C(=O)O)CCN(Cc2ccc(Br)cc2)CC1

Procedure:
1-(4-Bromo-benzyl)-4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (16.5 g, 33.3 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 6.18 g (40%); tan solid; mp 215° C.; MS: 469.7 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=2)[CH2:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>C(O)C.[Pd]>[CH2:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=CCC(NC(=O)Cc2ccc(O)c(OC)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCC1CCC(NC(=O)Cc2ccc(O)c(OC)c2)CC1
Yield: 80.6 %

Procedure:
The compound (180 mg) of Example 1 was dissolved in ethanol (7 ml), 10% palladium/carbon (50 mg) was added to the solution, and the mixture was hydrogenated at 25° C. The catalyst was removed by filtration from the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was purified by a silica gel chromatography (eluent: chloroform) to give 146 mg of the desired compound (cis:trans=1:4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][CH2:9][C:10]2[C:14]([C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[CH:17]=[O:18])=[C:13]([CH3:23])[O:12][N:11]=2)=[CH:5][CH:4]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1>C1COCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:17]([C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[C:14]2[C:10]([CH2:9][O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][CH:24]=3)=[N:11][O:12][C:13]=2[CH3:23])[OH:18])=[CH:29][CH:28]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COc1ccc(COCc2noc(C)c2-c2ccccc2C=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(COCc2noc(C)c2-c2ccccc2C(O)c2ccc(Cl)cc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a round bottomed flask was added 2-(3-((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)benzaldehyde (94 mg, 0.279 mmol) and THF. The solution was cooled to −78° C. before addition of (4-chlorophenyl)magnesium bromide solution (418 μl, 1M in THF, 0.418 mmol) and the reaction stirred at −78° C. for 30 min. The solution was quenched via the addition of water and warmed to room temperature. The aqueous was extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (4-chlorophenyl)(2-(3-((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)phenyl)methanol. LC/MS m/z 450 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[OH:11].[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:12]([O:14][C:15](=[O:19])/[CH:16]=[C:17](/[O:11][C:3]1[C:4]([F:10])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[F:1])\[CH3:18])[CH3:13]
Reactant: CC#CC(=O)OCC
Reactant: COc1ccc(F)c(O)c1F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C=C(\C)Oc1c(F)ccc(OC)c1F
Yield: 76.1 %

Procedure:
To a stirred mixture of 2,6-difluoro-3-methoxy-phenol (5.00 g, 0.031 mol) and ethyl-2-butynoate (7.00 g, 0.062 mol) in tetrahydrofuran (40 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.76 g, 0.031 mol) in tetrahydrofuran (10 mL) slowly. After addition was complete the mixture was stirred at reflux overnight. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue purified by ISCO column chromatography (Teledyne Isco RediSep Flash Column 120 g, 0% to 15%) ethyl acetate/hexanes which afforded (E)-3-(2,6-difluoro-3-methoxy-phenoxy)-but-2-enoic acid ethyl ester (6.42 g, 76%) as a colorless oil.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([C@:32]([OH:45])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:27]1)[NH:5][C@@H:6]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:7][N:8](C)[C:9](OCC[Si](C)(C)C)=O)#[N:2].[N+](CC)(CC)(CC)CC.[F-]>CC#N>[C:1]([N:3]=[C:4]([N:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([C@:32]([OH:45])([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:27]1)[NH:5][C@@H:6]([CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH2:7][NH:8][CH3:9])#[N:2]
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=NC#N)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Product: CNC[C@H](CC1CCCCC1)NC(=NC#N)N1CCC[C@@H]([C@@](O)(CCCCOC)c2ccccc2)C1
Yield: 15.3 %

Procedure:
A solution of (3R)—N′-cyano-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamidine (145 mg, 0.21 mmol) and Et4NF (160 mg, 1.1 mmol) in MeCN (5 mL) was heated at 100° C. in the microwave for 7 min. The reaction mixture was directly submitted to prep HPLC to afford (3R)—N′-cyano-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamidine (16 mg, 14%).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[CH2:11]([O:13][C:14](=[O:45])[CH2:15][C:16]1([CH2:19][CH2:20][C:21]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:36]=2)(C(OCC=C)=O)[C:22]([O:24]CC=C)=[O:23])[CH2:18][CH2:17]1)[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([O:13][C:14](=[O:45])[CH2:15][C:16]1([CH2:19][CH2:20][CH:21]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:40]=2)[C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1)[CH3:12]
Reactant: C=CCOC(=O)C(CCC1(CC(=O)OCC)CC1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CCOC(=O)CC1(CCC(Cc2ccc(C(=O)OC)cc2)C(=O)O)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
At room temperature, a solution of 4.33 ml (31.06 mmol) of triethylamine and 0.89 ml (23.53 mmol) of formic acid in 20 ml of dioxane is added to a solution of 4.58 g (9.41 mmol) of diallyl {2-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]ethyl}[4-(methoxycarbonyl)benzyl]malonate, 173 mg (0.66 mmol) of triphenylphosphine and 42 mg (0.19 mmol) of palladium acetate in 60 ml dioxane. The reaction mixture is then stirred at 100° C. for 2 hours. After complete conversion, the reaction solution is cooled and the solvent is removed under reduced pressure. The residue is then taken up in ethyl acetate and water and acidified with 1 N hydrochloric acid, and the organic phase is separated off. The aqueous phase is extracted three more times with ethyl acetate, and the organic phases are then combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution is concentrated under reduced pressure. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 4:1). This gives 2.68 g (73% of theory, 95% purity) of a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10]([CH3:15])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:28]=[CH:27]2.[Cl-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:34]([C:29]2[CH:28]=[CH:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([Cl:23])[CH:25]=3)[CH:30]=2)(=[O:35])=[O:36])[C:10]([CH3:15])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-3,3-dimethylpiperazine (125 mg) in methylene chloride (3.0 ml) were added triethylamine (90 ml) and 6-chloronaphthalene-2-sulfonyl chloride (167 mg). The resulting mixture was stirred at room temperature for 84 hours. The reaction mixture was diluted with methylene chloride and added with a saturated aqueous solution of sodium chloride to form two layers. The organic layer obtained by separation was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crudely purified product was purified by chromatography on a silica gel column (hexane:ethyl acetate=8:1), whereby the title compound (155 mg) was obtained as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Br:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([CH2:38][C:39](Cl)=[O:40])=[C:33]([F:42])[CH:32]=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:39](=[O:40])[CH2:38][C:34]2[C:33]([F:42])=[CH:32][C:31]([Br:30])=[CH:36][C:35]=2[F:37])=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1c(F)cc(Br)cc1F
Reactant: Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1c(F)cc(Br)cc1F)Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 17.6 %

Procedure:
To a solution of 2-(4-bromo-2,6-difluorophenyl)acetic acid (0.3 g, 1.195 mmol) in sulfurous dichloride (5 mL, 1.195 mmol) was added DMF (9.25 μL, 0.120 mmol). The resulting mixture was stirred at 60° C. After 2 h, LCMS analysis showed the starting material had disappeared and the solvent was removed in vacuo to give 2-(4-bromo-2,6-difluorophenyl) acetyl chloride (0.35 g, 0.832 mmol, 69.6% yield). To a solution of 4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (0.347 g, 1.113 mmol) and Et3N (0.225 g, 2.227 mmol) in DCM (30 mL) was added 2-(4-bromo-2,6-difluorophenyl)acetyl chloride (0.3 g, 1.113 mmol). The resulting mixture was stirred at 25° C. After LCMS analysis showed the starting material had disappeared, the mixture was washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC (PE/EA=3/1) to give N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,6-difluoro phenyl)acetamide (110 mg, 0.196 mmol, 17.6% yield): 1H NMR (400 MHz, CD3OD) δ 7.81 (d, J=2.8 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.32-7.25 (m, 7H), 7.15 (d, J=8.8 Hz, 1H), 4.61 (s, 2H), 4.23 (t, J=4.6 Hz, 2H), 3.84 (t, J=4.6 Hz, 2H), 3.77 (s, 2H); ES-LCMS m/z 546.0 (M+H).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].Cl[Sn](Cl)(Cl)Cl.C(#N)C.C(O[C@@H:26]1[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:58])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:37]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@:27]1([CH3:59])[O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)C1C=CC=CC=1>>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]([CH:26]2[C:27]([O:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([CH3:59])[CH:37]([O:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:47]([CH2:49][O:50][C:51](=[O:58])[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48]2)[C:2](=[O:3])[N:4]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: C[C@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(OC(=O)c2ccccc2)C(OC(=O)c2ccccc2)C(COC(=O)c2ccccc2)OC1n1ccc(N)nc1=O

Procedure:
In one synthesis method, depicted in FIG. 1a, the synthesis comprises reacting cytosine, BSA and SnCl4/acetonitrile with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (1) to form 4-amino-1-(3,4-dibenzoyloxy-5-benzoyloxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (2); and reacting (2) with NaOMe/MeOH to provide 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (3), also known as 2-C-methyl-β-D-ribofuranose. The use of cytosine as a starting material rather than benzoyl-cytosine improves the “atom economy” of the process and simplifies purification at later steps.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22]>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH2:21][CH3:22]
Reactant: CCOC(=O)c1ccc(Br)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC)c1
Temperature: 80 °C
Yield: 62.8 %

Procedure:
Ethyl 4-bromo-3-hydroxybenzoate (prepared according to M. I. Dawson et al WO 2003048101; 0.5 g, 2.04 mmol), potassium carbonate (0.84 g, 6.12 mmol) and iodoethane (0.2 mL, 2.45 mmol) were placed in 50 mL DMF and the reaction was heated at 80° C. for 18 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under vacuum to an oil. The oil was purified by column chromatography using EtOAc/hexane (0-50%) as eluent to give the product (0.35 g, 62%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1COCC1>[N:1]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2ccccc2n1
Yield: 60.3 %

Procedure:
A solution of 2-aminopyridine (5.0 g, 53.2 mmol) in THF (150 mL) was treated with ethyl bromopyruvate (10.32 g, 57.0 mmol) at room temperature followed by heating the mixture at reflux for 16 h. The resulting white precipitate was collected by filtration and washed with THF (10 mL). Recrystallization of the solids from boiling EtOH (20 mL) gave ethyl imidazo[1,2-a]pyridine-2-carboxylate (6.10 g, 60% yield). ESI MS: m/z 191 [M+1]+. See, e.g., J. Med. Chem., 2003, 46, 3914-29.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([OH:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:21])[CH:4]([O:20][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1

Procedure:
3-(4-Benzyloxyphenyl)-2-hydroxypropanoic acid methyl ester was reacted with phenol using the same method as in Example 38(c) to give 3-(4-benzyloxyphenyl)-2-phenoxypropanoic acid methyl ester.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][O:12][CH:13]=[CH:14][C:15](=[O:17])[CH3:16].[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.[Cl-].[NH4+]>C1COCC1>[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](=[O:24])[CH2:16][C:15](=[O:17])[CH:14]=[CH:13][O:12][CH3:11])=[CH:21][CH:20]=1
Reactant: COC=CC(C)=O
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=CC(=O)CC(=O)c1ccc(I)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
In a 1 ltr flask is cooled a solution of lithium hexamethyldisilazide (50 ml, 1.5 M) in THF (250 ml) to −75° C. During a period of 1 h is added 4-methoxy-but-3-en-2-one (6 ml). The mixture is stirred for 1 h at −70° C. A solution of 4-iodobenzoylchloride (7.2 g) in THF (250 ml) is added to the above mixture during 1 h at −70° C. The resulting mixture is slowly heated to ambient temperature and stirred for 1 h. Subsequently, the mixture is added to a cold aqueous solution of ammonium chloride and the resulting suspension is extracted with ethyl acetate. The organic phase is extracted twice with an aqueous solution of ammonium chloride, dried over sodium sulfate and evaporated. The crude oily product is transferred to the next step without any further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([OH:10])=[O:9]>CO.[Pd]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)C=Cc1cccs1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCc1cccs1
Reaction time: 18 h

Procedure:
A mixture of 3-thiophene-2-yl-acrylic acid (Intermediate AB) (2.00 g, 0.01299 mol), 10% Pd on C (2.00 g) in methanol (200 mL) was stirred under the atmosphere of H2 (50 PSI) for 18 h. The resulting system was purged with N2 and then filtered through a pad of celite. Organics were dried over MgSO4 and the solvent was removed in vacuo to provide 3-thiophene-2-yl-propionic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C:13](=[O:33])[C@H:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:15]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:46]([O:53][C:54]([NH:56][C@H:57]([C:59]([OH:61])=O)[CH3:58])=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C>C(OCC)(=O)C.C(O)(C)C.[Pd]>[C:1]([O:5][C:6](=[O:34])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C:13](=[O:33])[C@H:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:15][C:59](=[O:61])[C@H:57]([CH3:58])[NH:56][C:54]([O:53][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:55])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)CN1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 36.8 %

Procedure:
1.3 g (2.79 mmol) of N-[[N-(benzyloxycarbonyl)-L-phenylalanyl]methyl]-L-proline tert.butyl ester was hydrogenated in a mixture of 10 ml of ethyl acetate and 10 ml of isopropyl alcohol in the presence of 0.39 g of 5% palladium-on-carbon and 1.06 g (5.58 mmol) of toluene-4-sulphonic acid and the product was coupled with 0.62 g (2.78 mmol) of N-(benzyloxycarbonyl)-L-alanine in the presence of 0.572 g (2.78 mmol) of dicyclohexylcarbodiimide, 0.375 g (2.78 mmol) of hydroxybenzotriazole and 0.64 g (5.57 mmol) of N-ethylmorpholine in a manner analogous to that described in Example 1. After working-up and chromatography on silica gel using 3% isopropanol in dichloromethane for the elution there was obtained 0.55 g of N-[[N-[N-(benzyloxycarbonyl)-L-alanyl]-L-phenylalanyl]-methyl]-L-proline tert.butyl ester as a solid; MS: m/e 538 [M+H]+.
Reaction SMILES: C([CH:5]1[CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])([C:11]#[N:12])[CH2:8][CH2:7][C:6]1=[O:20])(OC)=O.C(C1CC(C2C=CC(Cl)=CC=2)(C#N)CCC1=O)(OC)=O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:9]1([C:11]#[N:12])[CH2:8][CH2:7][C:6](=[O:20])[CH2:5][CH2:10]1
Reactant: COC(=O)C1CC(C#N)(c2ccccc2Cl)CCC1=O
Agent: COC(=O)C1CC(C#N)(c2ccc(Cl)cc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: N#CC1(c2ccccc2Cl)CCC(=O)CC1
Yield: 80 %

Procedure:
Following the procedure of Example 1, Part C, but substituting 33.4 gm. (0.115 mole) of 2-carbomethoxy-4-(o-chlorophenyl)-4-cyanocyclohexanone (prepared in Part B, above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone, using 730 ml. glacial acetic acid and 365 ml. 10 percent aqueous sulfuric acid instead of the 660 ml. and 330 ml., respectively, and heating for 48 hours instead of 24 hours there is obtained a residual solid that is recrystallized from a mixture of methylene chloride and technical hexane thus affording 20.54 gm. (80% yield) of 4-(o-chlorophenyl)-4-cyanocyclohexanone having a melting point at 106° to 108° C.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[H-].[Na+].[CH3:20]I>C1COCC1>[OH:1][C@H:2]1[C@H:6]([O:7][CH3:20])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1
Reactant: CI
Reactant: O=C(OCc1ccccc1)N1C[C@@H](O)[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.7 %

Procedure:
To a solution of benzyl (3R,4R)-3,4-dihydroxypyrrolidine-1-carboxylate (3.81 g, 16.1 mmol) in 60 mL THF was added NaH (0.803 g, 20.07 mmol). The reaction mixture was stirred at room temperature for 15 min, CH3I (2.0 mL, 32.2 mmol) was added and stirred at room temperature overnight. The reaction mixture was quenched with H2O (80 mL) and extracted with EtOAc (2×100 mL). The organic layer was dried and concentrated. The residue was purified by flash column chromatography (1˜2% CH3OH in CH2Cl2) to give a white solid (1.12 g, 28%). 1H NMR (CDCl3) δ 7.36-7.29 (5H, m), 5.12 (2H, s), 4.28-4.27 (1H, m), 3.72-3.37 (5H, m), 3.35 (3H, s), 1.95-1.89 (1H, m). ESIMS (MH+): 252.05.
Reaction SMILES: [Cl:1][C@H:2]1[CH2:20][C@@:17]2([CH2:18][CH3:19])[C@@H:13]([C@@H:14]([OH:22])[CH2:15][C:16]2=[O:21])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl>N1C=CC=CC=1>[C:24]([O:22][C@@H:14]1[C@H:13]2[C@H:12]3[C@H:3]([C@H:2]([Cl:1])[CH2:20][C@:17]2([CH2:18][CH3:19])[C:16](=[O:21])[CH2:15]1)[C@@H:4]1[C:9](=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]1)[CH2:10][CH2:11]3)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@]12C[C@H](Cl)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Agent: Cl
Solvent: c1ccncc1
Product: CC[C@]12C[C@@H](Cl)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1.6 g of 11β-chloro-15α-hydroxy-18-methyl-4-estrene-3,17-dione in 5 ml of pyridine is stirred at room temperature under argon with 1.2 ml of acetic anhydride. After 18 hours, the solution is introduced into hydrochloric-acid-containing ice/water. The thus-precipitated product is vacuum-filtered, dissolved in ethyl acetate, and washed with water. Recrystallization of the crude product from isopropyl ether yields 1.0 g of 15α-acetoxy-11α-chloro-18-methyl-4-estrene-3,17-dione, mp 125.0° C.