Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH:17]([N-]C(C)C)(C)C.[Li+].IC>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: CCOC(=O)Cc1cc(F)cc2ccoc12
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)c1cc(F)cc2ccoc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A solution of 1.09 gm (4.90 mMol) ethyl 2-(5-fluorobenzofur-7-yl)acetate in 5 mL tetrahydrofuran was cooled to −78° C. To this solution were slowly added 6.1 mL (6.13 mMol) lithium diisopropylamide (1.0 M in tetrahydrofuran) and the mixture was stirred at −78° C. for 1 hour. To this solution were then added 0.76 mL (12.25 mMol) iodomethane and the mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was then diluted with ethyl acetate and the resulting solution washed sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The remaining organic phase was concentrated under reduced pressure and the residue subjected to flash silica gel chromatography, eluting with hexane containing 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.723 gm (62%) of the desired compound.
Reaction SMILES: C([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[CH:7]=[CH:6][C:5]=1O)C=C.ClC1C=CC=[C:23]([C:27](OO)=[O:28])C=1.C(Cl)(Cl)Cl.[C:35](=[O:38])([O-])[O-:36].[K+].[K+]>O>[O:18]=[C:9]1[C:8]2[CH:7]=[CH:6][C:5]3[O:28][CH:27]([C:35]([OH:36])=[O:38])[CH2:23][C:4]=3[C:17]=2[O:16][C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(O)ccc2c(=O)c3ccccc3oc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)C1Cc2c(ccc3c(=O)c4ccccc4oc23)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.8 %

Procedure:
A mixture of 4-allyl-3-hydroxy-9-oxo-9H-xanthene (10 g), m-chloroperbenzoic acid (21 g) and chloroform (1,000 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (40 g) and water (1,000 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (2,000 ml) and, to the stirred solution, a mixture of chromium trioxide (9 g), water (40 ml) and concentrated sulfuric acid (15 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 4 g of 1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 283°-286° C. This compound showed a mass spectrum having a molecular ion peak at m/e 282.
Reaction SMILES: Cl[S:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:4])=[O:3].[CH2:17]([NH2:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)C(C)C)(C)C.Cl>ClCCl>[CH2:17]([NH:23][S:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:4])=[O:3])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCN
Reactant: CCOC(=O)CCCCCCCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCNS(=O)(=O)CCCCCCCC(=O)OCC
Temperature: 25 °C
Reaction time: 22 h
Yield: 95 %

Procedure:
Ethyl 8-chlorosulfonyl-octanoate (No. 6804260; 692.3 mg, 2.56 mmol) was dissolved in dichloromethane (4.0 mL), and a solution of hexylamine (310.5 mg, 3.07 mmol) in dichloromethane (3.0 mL) and N,N-diisopropylethylamine (668 μL, 3.84 mmol) were added in order. The mixture was stirred at room temperature for 22 hours. After completing the reaction, the mixture was neutralized by adding 1 M hydrochloric acid, and extracted with dichloromethane. The organic layer was washed with water and a saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The resulting residue was then purified with SP1 (SiO2 cartridge, 25% ethyl acetate/n-hexane, Rf=0.5) to obtain ethyl 8-hexylsulfamoyl-octanoate (No. 6804262; 818.3 mg, 95% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1([C:12](=[C:14]2C(=O)OC(C)(C)[O:16][C:15]2=O)[OH:13])[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:7]1[C:15](=[O:16])[CH:14]=[C:12]([OH:13])[C:8]21[CH2:11][CH2:10][CH2:9]2)=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(C(O)=C2C(=O)OC(C)(C)OC2=O)CCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)C=C(O)C12CCC2

Procedure:
{1-[(2,2-Dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidene)-hydroxy-methyl]-cyclobutyl}-carbamic acid tert-butyl ester (1.2 g, 3.5 mmol) is refluxed in ethyl acetate for 4 hours. The solvent is removed in vacuo and the resulting residue is crystallized from ether. 1H-NMR (400 MHz; DMSO-d6): 12.5 (s, 1H), 4.73 (s, 1H), 2.87 (dt, 2H), 2.35-2.25 (m, 2H), 1.85 (quint, 2H), 1.51 (s, 9H); LC-MS (m/z, ES−): 238 (M−H), Retention time: 2.24 mins (LC-MS method 3)
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[OH-].[Na+].[Cl:12][CH:13]([Cl:18])[C:14](OC)=O>C(O)C>[Cl:12][CH:13]([Cl:18])[C:14]1[N:9]=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1
Reactant: COC(=O)C(Cl)Cl
Reactant: Nc1cccc[n+]1N
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ClC(Cl)c1nc2ccccn2n1
Reaction time: 4 h

Procedure:
A solution of 24 g of 1,2-diaminopyridinium iodide and 6.6 g. of sodium hydroxide in 200 ml of ethanol was stirred at 50°-60° C. for 1 hour. To the reaction mixture was added 17.2 g of methyl dichloroacetate and the mixture was refluxed with stirring for 4 hours. The mixture was concentrated under reduced pressure, water was added and extracted with chloroform.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16][OH:17])[C:11]([NH:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[Li]CCCC.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16][O:17][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[C:11]([NH:13][CH3:14])=[O:12])=[CH:18][CH:19]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC(=O)N(CCO)CCOc1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)N(CCOc1ccc(C#N)cc1)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 12.7 %

Procedure:
To a well-stirred solution of 1-[2-(4-cyanophenoxy)ethyl]-1-(2-hydroxy-ethyl)-3-methylurea (6.6 g, 0.0257 mol; see step (i) above) in dry THF (70 mL) was added n-BuLi (2.85 N, 1.766 g, 0.0276 mol) at −78° C., dropwise under a nitrogen atmosphere. After stirring at the same temperature for 45 min, p-toluenesulfonyl chloride (5.25 g, 0.0276 mol) in dry THF was added (drop by drop) and the reaction mixture was then stirred at −40° C. for 2 h. The reaction was quenched with 50 mL water and warmed to room temperature. The product was extracted with ethyl acetate, washed with brine solution and dried over sodium sulfate. Solvent evaporation under reduced pressure, followed by column chromatography over silica gel (using 15-25% methanol in chloroform) yielded 1.36 g of the title compound as a brown gummy liquid.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:23]=2[N:24]=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: COc1ccc2nc(C)sc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2nc(CBr)sc2c1
Temperature: 25 °C
Yield: 47 %

Procedure:
17.4 mg of dibenzoyl peroxide were added to a solution of 0.8 ml of 2-methyl-6-methoxybenzothiazole and 1.05 g of N-bromosuccinimide in 20 ml of carbon tetrachloride at room temperature and the resulting mixture was stirred under reflux for 5 hours. At the end of this time, the mixture was allowed to cool to room temperature and then extracted with methylene chloride. The resulting extract was washed consecutively with a saturated aqueous sodium sulfite solution, water and an aqueous sodium chloride solution and then dried over sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using an 8:1 by volume mixture of hexane and ethyl acetate, to give 649.3 mg (yield 47%) of the title compound as a solid having a melting point of 78° to 81° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])[CH2:2][CH3:3].[S:14]([O:19]C)([O:17][CH3:18])(=[O:16])=[O:15]>ClCCCl>[CH3:18][O:17][S:14]([OH:19])(=[O:16])=[O:15].[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](=[NH:9])[O:8][CH3:18])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(N)=O
Reactant: COS(=O)(=O)OC
Solvent: ClCCCl
Product: CCCOc1ccccc1C(=N)OC
Product: COS(=O)(=O)O
Yield: 26.4 %

Procedure:
To a warm, stirred solution of 2-n-propoxybenzamide (896 g., 5.0 moles) in 1,2-dichloroethane (5 l) was added dimethyl sulfate (950 ml., 10.0 moles) over a period of about 0.5 hour. The mixture was stirred and heated under reflux for 17 hours. The solvent was removed. The residual oily solid was collected by filtration, washed with ethyl acetate and dried to give methyl 2-n-propoxybenzimidate methyl sulfate (403 g.), m.p. 79°-82°. The combined filtrate and washings were stored at 0° for 18 hours and gave a second crop (503 g.) of benzimidate, m.p. 81°-83°. A slurry of the methyl 2-n-propoxybenzimidate methyl sulfate (906 g.) in ethanol (1 l) was added to ethanol ( 4 l) which had previously been saturated with gaseous ammonia. The mixture was stored at room temperature for 17 hours. The mixture was filtered. The filtrate was evaporated to dryness to give 2-n-propoxybenzamidine methyl sulfate (872 g., 60%), m.p. 86°-88°.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:41]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>O1CCCC1.O>[F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][N:5]([S:47]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)(=[O:49])=[O:48])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)N2CCOCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (324 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 121 mg) at room temperature, and the mixture was stirred for 10 min. 15-Crown-5 (664 mg) was added, morpholine-4-sulfonyl chloride (250 mg) was added and the mixture was further stirred for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2) to give the title compound as a colorless oil (yield 370 mg, 78%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[CH3:17][N:18]([CH3:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>O1CCOCC1>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:22]2[CH:23]=[CH:24][C:19]([N:18]([CH3:28])[CH3:17])=[CH:20][CH:21]=2)=[CH:4][N:3]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)c1ccc(-c2cnc(N)c([N+](=O)[O-])c2)cc1
Temperature: 110 °C
Yield: 66 %

Procedure:
4.36 g of 2-amino-5-bromo-3-nitropyridine are dissolved in 73 ml of anoxic dioxane under a nitrogen atmosphere. Subsequently, 60 ml of an aqueous sodium bicarbonate solution (2.0 M), 7.3 g of 4-dimethylaminophenyl-boronic acid, and 0.886 g of trans-dichloro-bis(tricyclohexylphosphane)palladium-(II) are added. The reaction mixture is refluxed at 110° C. for 19 hours. Thereafter, the volatile components are removed in vacuo and the remaining residue is redissolved in 1.0 l of a mixture of water/dichloromethane (1:1). The aqueous phase is extracted four times each with 500 ml of dichloromethane. The organic layer is separated, dried using sodium sulfate, and evaporated to dryness to yield a colorless, crude solid. Subsequently, the residue is purified by flash chromatography on silica gel (eluent: dichloromethane/ethanol 50:1) to afford 3.41 g of the title compound as a colorless solid of m.p. 212° C. MS: 259.2 (MH+). TLC: Rf=0.55 (dichloromethane/ethanol 50:1).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[O:14][C:15]4[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][C:16]=4[N:17]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].CO.Cl>O1CCCC1.O>[N:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[O:14][C:15]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][C:16]=4[N:17]=3)[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2oc(N3CCC(N4CCCCC4)CC3)nc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2oc(N3CCC(N4CCCCC4)CC3)nc2c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Methyl 2-(1,4′-bipiperidin-1′-yl)benzo[d]oxazole-5-carboxylate (Example 94, 220 mg, 0.641 mmol) and potassium hydroxide were combined in a mixture of tetrahydrofuran, methanol, and water (9:1:1, 7 mL) and stirred at 40° C. overnight. The mixture was neutralized with concentrated hydrochloric acid, concentrated under reduced pressure, and triturated with chloroform to afford the title compound. MS (ESI+) m/z 330.2 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(N(C(C)C)CC)(C)C.[CH3:23][C:24]1[C:28](C(Cl)=O)=[C:27]([CH3:32])[O:26][N:25]=1>C(Cl)Cl>[CH3:23][C:24]1[C:28]([C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:7])=[C:27]([CH3:32])[O:26][N:25]=1
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1noc(C)c1C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-tert-butyloxycarbonyl-piperazine (4.581 mmol, 0.9 eq) and diisopropylethylamine (5.09 mmol, 1.0 eq) in methylene chloride (5 mL) was added to a 40 mL vial. 3,5-Dimethyl-isoxazole-4-carbonyl chloride (5.09 mmol, 1.0 eq) was added to the vial and the reaction was shaken overnight at room temperature. When the reaction was complete, it was diluted with methylene chloride (5 mL) and washed with 4 mL of 1N hydrochloric acid followed by 4 mL of 10% potassium carbonate. The organic layer was concentrated in vacuo. The crude residue was dissolved in 5 mL of dioxane and 5 mL of 4M hydrochloric acid in dioxane. The reaction mixture was shaken overnight at room temperature then centrifuged. The supernatant was removed and the remaining solid was shaken with hexane then centrifuged. The supernatant was removed, and the solids were collected and dried in vacuo to give (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone. LR-MS: 210.2 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32].Cl>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32])[CH2:23][CH2:24]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: OCCOCCCl
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCNCC4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(CCOCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 100 mg (0.28 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazine and 36 μl (0.33 mmol) of 2-(2-chloroethoxy)ethanol. The product is in the form of the hydrochloride.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][CH:34]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:37](=[O:39])[C:36]1[CH:35]=[CH:34][C:33]([Cl:32])=[CH:41][CH:40]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1
Yield: 95.7 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4a with 88 mg (0.560 mmol) of 4-chlorobenzoic acid, 143 mg (0.561 mmol) bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (210 mg, 80%) is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.44, FD-MS: M+ =565, 567.
Reaction SMILES: Br[C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:22])[C@:16]1([CH3:17])[C:11]([CH2:12][C@@H:13]([CH3:21])[CH2:14][CH2:15]1)=[CH:10][CH2:9]3.[OH-:23].[Na+].Cl>CN(C)C=O.O>[OH:23][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:22])[C@:16]1([CH3:17])[C:11]([CH2:12][C@@H:13]([CH3:21])[CH2:14][CH2:15]1)=[CH:10][CH2:9]3
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](Br)C[C@@H]32)C1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](O)C[C@@H]32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
16α-Bromo-3β-methylandrost-5-en-17-one (1.00 g, 2.74 ,mmol) was dissolved in dimethylformamide (90 mL). Sodium hydroxide (165 mg, 4.1 mmol) in water (10 mL) was added and the solution stirred for 2 h. at room temperature. The solution was poured into 1% HCl (200 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with 5% sodium biocarbonate, water, then dried over magnesium sulfate and filtered. Evaporation gave a pale yellow solid which was chromatographed on flash silica gel and eluted with ether/hexane (10/90). Recrystallization from ether gave 0.54 g (65%) 16α-hydroxy-3β-methylandrost-5-en-17-one mp 166°-168° C.; NMR (DMSO-d6) δ 5.30 (br s, 1H, H-3), 4.38 (t, 1H, 16β-H), 2.0-1.05 (m, complex), 0.98 (s, 3H, C-19 Me), 0.95 (d, J=8 Hz, 3H, C-3 Me), 0.87 (s, 3H, C-18 Me); IR (KBr) 3440, 2900, 1735, 1445, 1365, 1010; MS 302 (m+, 100), 287(24), 274(7), 259(7), 241(7), 230(72), 215(41), 159(31); Anal. Calcd for C20 H30O2 : C, 79.42; H, 9.99. Found: C, 79.24; H, 10.04.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][N:30]=1>>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:24])[CH3:25])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:4][CH:3]=2)=[N:30][CH:31]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Fc1ccc(Br)nc1
Product: C[C@@H](c1ccc(-c2ccc(F)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 2-bromo-5-fluoropyridine in Step 4. LC-MS Method 2 tR=1.363, m/z=390.9; 1H NMR (CDCl3) 1.11 (s, 3H), 1.19 (s, 3H), 1.53 (d, 3H), 2.16-2.30 (m, 4H), 2.32-2.43 (m, 1H), 2.86 (m, 1H), 5.71 (m, 1H), 7.03 (d, 2H), 7.30 (m, 1H), 7.36 (m, 4H), 7.44 (m, 1H), 7.69 (dd, 1H), 7.68 (d, 2H), 8.43 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:19])[NH:11][C:12]([CH3:18])=[CH:13][C:14]=1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:20][C:21]1[S:22][CH2:23][CH2:24][N:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]1[C:10](=[O:19])[NH:11][C:12]([CH3:18])=[CH:13][C:14]=1[C:15]([N:25]1[CH2:24][CH2:23][S:22][C:21]1=[S:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: SC1=NCCS1
Reactant: Cc1cc(C(=O)O)c(OCc2ccccc2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCSC2=S)c(OCc2ccccc2)c(=O)[nH]1
Reaction time: 1 h
Yield: 49.7 %

Procedure:
3-benzyloxy-4-carboxy-6-methyl-2(1H)-pyridinone (5.39 g, 21.1 mmol) was dissolved in dry THF (200 ml). Then 2-mercaptothiazoline (2.71 g, 23.2 mmol) and DMAP (0.25 g, 2.0 mmol) were added and the solution stirred under an atmosphere of N2 for 1 h. Then dicyclohexylcarbodiimide (DCC, 5.12 g, 25.3 mmol) was added in small portions at intervals split over 3 hrs. The reaction was left to stir for 16 h, and then left to stand at 0° C. for a further 24 h. The dicyclohexylurea (DCU) was removed by filtration, and the solvents removed. The remaining residue was dissolved in CH2Cl2, filtered and purified by a gradient flash silica column (2-6% CH3OH in CH2Cl2). The solvents were removed from the appropriate fractions by rotary evaporation, and the residue recrystallized from acetone, yielding yellow crystals (3.78 g, 56%). 1H NMR (CDCl3, 300 MHz): δ=7.32-7.47 (m, 5H, aromatic Bn), 5.98 (s, 1H, CH), 5.34 (s, 2H, Bn CH2), 4.34 (t, J=7.3 Hz, 2H, CH2), 2.92 (t, J=7.3 Hz, 2H, CH2), 2.34 (s, 3H, CH3) ppm. Anal. Calcd (Found) for C17H16N2O3S2: C, 56.65 (56.50); H, 4.47 (4.51); N, 7.77 (7.70). FAB-MS (+): m/z: 361[M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]([NH2:21])[CH2:19][OH:20])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:22](=O)(OCC)OCC.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]4[CH2:19][O:20][CH2:22][NH:21]4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)OCC
Reactant: CN1CCC(c2c[nH]c3ccc(CC(N)CO)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(CC4COCN4)cc23)CC1
Temperature: 130 °C
Yield: 66 %

Procedure:
A mixture of the product from step (f) (1.6 g), diethyl carbonate (0.71 g) and potassium carbonate (0.08 g) was heated at 130° C. for 5 hours. The mixture was cooled, taken up in methanol and the insoluble potassium carbonate filtered off. The filtrate was evaporated in vacuo and the residue eluted through a silica column using DCM/EtOH/NH4OH (30:8:1) as eluant to give a colourless foam which was crystallised from isopropanol/ether to give the desired product as a colourless crystalline solid (1.1 g), mp 191°-192° C. 1H NMR and microanalysis as for product of Synthetic Example 4.