Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:5][NH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:16][C:17]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:18]=3[C:19]([O:21]C)=[O:20])[CH:13]=2)[CH2:8]1.[OH-].[Na+].O>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:5][NH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:16][C:17]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:18]=3[C:19]([OH:21])=[O:20])[CH:13]=2)[CH2:8]1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Nc1ccc2c(c1)CC(NCc1ccc(Cl)c(Cl)c1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Nc1ccc2c(c1)CC(NCc1ccc(Cl)c(Cl)c1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.2 %

Procedure:
The methyl benzoate (0.65 g) was dissolved in 10 mL 1:1 THF/MeOH, and this solution was treated with 2 mL 50% NaOH and 1 mL water and stirred at room temperature for 18 hours. When the starting material was no longer observed by mass spec, the mixture was concentrated, the solids were dissolved in ethyl acetate/water 1:1. The layers were separated, and the aqueous layer was extracted with 2×20 mL ethyl acetate. The organic layers were combined and washed with 10 mL 50% saturated NaCl, dried over MgSO4/Na2SO4, filtered, and concentrated. The residual oil was purified by column chromatography (MPLC, silica, gradient 98:2 to 80:20)(CH2Cl2/MeOH+1% NH4OH). Fractions containing the desired product were combined, concentrated, and dried in vacuo overnight to give 2-[2-(3,4-dichlorobenzylamino)-indan-5-ylamino]-5-nitro-benzoic acid (0.38 g, 60% yield). MS (APCI) m/z 470.0 (M+−1). CHN for (C23H19Cl2N3O4·CH2Cl2) calc: C, 55.58, H, 3.94, N, 8.31; found: C, 55.25, H, 3.88, N, 8.32.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>C1(C)C=CC=CC=1.O>[CH2:19]([S:21]([O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)(=[O:23])=[O:22])[CH3:20]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCS(=O)(=O)Oc1cccc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
8.00 g (53.3 mol) of 3-tert-butylphenol and 5.93 g (58.6 mol) of triethylamine were dissolved in 80 mL of toluene followed by dropping in 7.53 g (58.6 mol) of ethanesulfonyl chloride over the course of 10 minutes at 10° C. followed by stirring for 10 minutes at 25° C. and confirming the 3-tert-butylphenol to no longer be present by gas chromatography. The reaction liquid was placed in water and following separation of the organic layer, was washed three times with water, once with saturated aqueous NaHCO3 solution and once with saturated brine followed by drying with MgSO4, concentrating and purifying the resulting residue by vacuum distillation to obtain 12.02 g (yield: 93%) of 3-tert-butylphenyl ethanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:26]([C:33](Cl)=[O:34])=[N:25]1>ClCCl.C(OCC)(=O)C>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:26]([C:33]([N:10]2[CH2:9][CH2:8][CH:7]([O:6][C:5]3[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)=[O:34])=[N:25]1
Reactant: O=C(Cl)c1noc2ccccc12
Reactant: Clc1ccc(OC2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1noc2ccccc12)N1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a solution of 4-(4-chlorophenoxy)piperidine (26 mg, 0.12 mmol), and N,N-diisopropylethylamine (0.086 mL, 0.49 mmol) in dichloromethane (0.5 mL) was added dropwise a solution of benzo[d]isoxazole-3-carbonyl chloride (22 mg, 0.12 mmol) in dichloromethane (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (3 mL) and washed with water (1.5 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (NH-gel, eluting with ethyl acetate) and then preparative LC-MS to give 16.3 mg (37% yield) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4].[C:8]([O:12][C:13](=[O:21])[NH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:8]([O:12][C:13](=[O:21])[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:2][C:3]([CH:5]2[CH2:7][CH2:6]2)=[O:4])[CH2:17][CH2:16]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C(CBr)C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CC(=O)C2CC2)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 104.5 %

Procedure:
2-Bromo-1-cyclopropyl-ethanone (244 mg, 1.44 mmol, 1.0 eq) is added at room temperature to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (300 mg, 1.44 mmol, 1.0 eq) in N,N-dimethylformamide (12 mL), followed by potassium carbonate (200 mg, 1.44 mmol, 1.0 eq). After 4 hours stirring at 60° C., solvent is evaporated and the residue is extracted with dichloromethane (3×30 mL) and water (30 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford [1-(2-cyclopropyl-2-oxo-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a light yellow solid (425 mg, 99% yield).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[C:7]2[CH2:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[CH2:8]2)=[CH:4][CH:3]=1.CO>[Ir].ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[CH2:8]2)=[CH:15][CH:16]=1
Reactant: O=C1CC(=Cc2ccc(F)cc2)CCCN1
Agent: [Ir]
Solvent: CO
Solvent: ClCCl
Product: O=C1CC(Cc2ccc(F)cc2)CCCN1
Yield: 94.5 %

Procedure:
This example describes the preparation of I where n=3 and R1=p-fluorophenyl. In a nitrogen-filled glove box, a Fisher-Porter tube was charged with iridium catalyst prepared as in Example 1 (10 mg, 0.012 mmol) and 3-(p-fluorobenzylidene)caprolactam (250 mg, 1.1 mmol). Methanol (3 mL) and dichloromethane (3 mL) were added and the system was flushed 4 times with hydrogen and pressured to 60 psi (0.5 MPa) H2. After 18 h the reaction mixture was filtered through a short pad of silica. The solvent was removed at reduced pressure to afford 3-(p-fluorobenzyl)caprolactam (230 mg, 92%) as a white crystalline solid. Chiral HPLC analysis (Chiralpak AS, 60% heptane, 39.2% isopropanol, 0.4% trifluoroacetic acid, 0.4% n-hexylamine, 40° C.) indicated that conversion was 100% and the enantiomeric excess was 67%. 19F NMR δ −117.99; 13C NMR δ 28.93, 29.47, 29.94, 36.73, 42.28, 45.65, 115.18 (d, J=21 Hz), 130.81, 136.47, 161.49 (d, J=241 Hz), 179.79; 1H NMR: δ 1.43 (m, 3H), 1.70 (m, 1H), 1.76 (m, 1H), 1.91 (m, 1H), 2.54 (app. dd, 1H), 2.67 (m, 1H), 3.12-3.31 (m, 3H), 6.78 (br s, 1H), 6.96 (m, 2H), 7.14 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH2:14][CH2:15][C:16]([NH2:19])([CH3:18])[CH3:17])[CH:13]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.[OH-].[Na+]>C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH2:14][CH2:15][C:16]([NH2:19])([CH3:17])[CH3:18])[CH:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cn(CCC(C)(C)N)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(N)CCn1cnc(-c2ccc(O)cc2)c1
Temperature: 0 °C
Yield: 54 %

Procedure:
1.0 g (4.00 mmol) 3-[4-(4-methoxy-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamine and 4.00 g pyridine hydrochloride were stirred for 2 h at 200° C. in a sealed reaction vessel in a microwave. The reaction mixture was poured into 40 mL ice water and 40 mL ethyl acetate, the pH of the aqueous phase was adjusted to over 9 with sodium hydroxide solution (2M) and the phases were separated. The aqueous phase was extracted five times with 50 mL ethyl acetate. The combined organic phases were dried over magnesium sulphate and the solvent was eliminated using the rotary evaporator. 0.530 g (2.16 mmol, 54%) 3-[4-(4-hydroxy-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamine were obtained as a colourless solid.
Reaction SMILES: CN(C)C=O.C(OC([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:20]([O:25]CCO)=[N:21][CH:22]=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=O)(C)(C)C.[C:29]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:30]=1.[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([F:56])[CH:50]=1>C1COCC1>[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:29][CH2:30][N:21]2[CH:22]=[CH:23][N:24]=[C:19]([N:16]3[CH2:15][CH2:14][NH:13][CH2:18][CH2:17]3)[C:20]2=[O:25])=[C:51]([F:56])[CH:50]=1
Reactant: Oc1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1c(N2CCNCC2)nccn1CCOc1ccc(Cl)cc1F
Reaction time: 2 h
Yield: 34.9 %

Procedure:
1,1′-Azobis(N,N-dimethylformamide (TMAD; 0.217 g, 1.26 mmol) was added to a stirred mixture of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-pyrazinyloxy]ethanol (0.324 g, 1.00 mmol), triphenylphosphine (0.324 g, 1.23 mmol) and 4-chloro-fluorophenol (0.217 g, 1.48 mmol) in THF (1 mL) at room temperature. After 2 h, the reaction mixture was concentrated and the crude N-t-BOC derivative of the title compound was N-deprotected with TFA/dichloromethane/H2O (45:50:5). Purification by chromatography on silica gel using EtOAc/toluene (4:6) as eluent gave 0.123 g (35%) of the title compound as a yellow oil. HRMS m/z calcd for C16H18ClFN4O2 (M)+ 352.1102, found 352.1098.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH2:14].[CH3:15][O:16][C:17]1[CH:28]=[CH:27][C:20]([CH:21]([OH:26])[C:22](OC)=[O:23])=[CH:19][CH:18]=1>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][C:22](=[O:23])[CH:21]([C:20]1[CH:27]=[CH:28][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[OH:26]
Reactant: COC(=O)C(O)c1ccc(OC)cc1
Reactant: COc1ccc(CCN)c(Cl)c1OC
Solvent: CCOC(C)=O
Product: COc1ccc(C(O)C(=O)NCCc2ccc(OC)c(OC)c2Cl)cc1
Yield: 69.4 %

Procedure:
16.86 g of (2-chloro-3,4-dimethoxyphenyl)ethylamine obtained in step 4 was reacted with 15.33 g of methyl 4-methoxymandelate obtained in step 5 at 130° to 140° C. in a nitrogen gas atmosphere for 1.5 hour. After cooling, the reaction mixture was dissolved in 30 ml of ethyl acetate and purified by silica gel chromatography. After development with ethyl acetate/n-hexane (1/1) and then with ethyl acetate, 20.6 g (69%) of N-(2-chloro-3,4-dimethoxyphenylethyl)-4-methoxymandelamide was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14]C1CO1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1.F[C:34](F)(F)[C:35]([OH:37])=O.[OH-:40].[Na+].O>C(Cl)Cl>[CH3:25][C:23]1[CH:24]=[C:19]([O:18][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH2:14][CH:35]([OH:37])[CH2:34][OH:40])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[C:20]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[N:21][C:22]=1[CH3:26]
Reactant: O=C(O)C(F)(F)F
Reactant: [OH-]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1OCC1CO1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,3′]bipyridine (compound 348) (92 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was then brought to 0° C. Trifluoroacetic acid (1 ml) was added to the solution, and the mixture was stirred at 0° C. for 30 min. The mixture was then stirred at room temperature for 5 hr. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (34 mg, yield 36%).
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][C:11]=1[CH2:18][N:19]1[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[CH2:21][O:20]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl.C(OCC)(=O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH:17][C:27]([CH3:28])=[O:29])=[CH:12][C:11]=1[CH2:18][N:19]1[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[CH2:21][O:20]1
Reactant: CC1(C)CON(Cc2cc(NN)ccc2Cl)C1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NNc1ccc(Cl)c(CN2OCC(C)(C)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
Triethylamine (0.6 g, 0.0055 mole) was added to a stirred solution of 2-[(2-chloro-5-hydrazinophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone hydrochloride (1.5 g, 0.005 mole) in methylene chloride (50 ml), followed by the dropwise addition of acetic anhydride (0.6 g, 0.0055 mole). Upon completion of addition, the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with water (3×50 ml). The dried (magnesium sulfate) organic layer was concentrated under reduced pressure. The residue was recrystallized from ethanol-water to yield 0.95 g of 2-[[2-chloro-5-(methylcarbonylhydrazo)phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone as a yellow solid; m.p. 178°-180° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.Cl.[CH2:23]([NH2:25])[CH3:24]>CO.C(Cl)Cl>[CH2:23]([NH:25][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:24]
Reactant: CCN
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCNCc1ccc2[nH]c(C(N)=O)c(Sc3ccccc3)c2c1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) with ethylamine hydrochloride (23.9 mg, 0.30 mmol) as described in General Procedure X to afford lad (53.0 mg, 60.4%) as an ivory colored solid, tlc Rf=0.1 (10% MeOH/CH2Cl2-0.2% Et3N), m/z obs=326 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:13]4)=[CH:10][CH2:9][C:8]1=[CH:7][C:6](=[O:28])[CH2:5][CH2:4]2.C(Cl)(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:42])C=1.[OH-].[K+]>C(OCC)(=O)C.C(O)(=O)C>[OH:42][C@:11]12[CH:10]=[CH:9][C:8]3[C@:3]([CH2:2][OH:1])([CH2:4][CH2:5][C:6](=[O:28])[CH:7]=3)[C@H:20]1[CH2:19][CH2:18][C@@:16]1([CH3:17])[C@H:12]2[CH2:13][CH2:14][C@@H:15]1[O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@H]2C3=CCC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)O[C@H]1CC[C@H]2[C@@]3(O)C=CC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@]12C

Procedure:
A solution of 2 g. of 19-hydroxy-17β-pivaloxyandrosta-4,7-dien-3-one in 2000 ml. of carbon tetrachloride was left to stand with 1.5 g. of meta-chloroperbenzoic acid for two and a half days, whereupon an additional 0.5 g. of meta-chloroperbenzoic acid was added. After five days the solution was repeatedly extracted with 2% aqueous potassium hydroxide until the extracts were alkaline. The solution was then extracted with water and evaporated. The residue obtained was treated with 9 ml. of 0.2 N methanolic potassium hydroxide for 30 minutes. Then 9 ml. of 0.2 N acetic acid in ethyl acetate was added and the mixture was concentrated at reduced pressure. Recrystallization of the residue combined with thick layer chromatography yielded 7-hydroxy-8,19-oxido-17β-pivaloxyandrost-4-en-3-one, mp. 211°-212° C. λ max 246 mμ, 8α,19-dihydroxy-17β-pivaloxyandrost-4,6-dien-3-one, mp 202°-203° C., λ max 280 mμ, as well as 8β,19-dihydroxy-17β-pivaloxyandrost-4,6-dien-3-one, mp. 218°-220° C., λ max 282 mμ. The structure of these compounds was confirmed by ir and nmr spectroscopy.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([CH3:24])[N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].Cl[CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31]>C(O)(C)C.[OH-].[Na+].O>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([CH3:24])[N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[O:26][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(CC(C)C)cc(C)n3)n2)cc(C)c1O
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(CC(C)C)cc(C)n3)n2)cc(C)c1OC[C@@H](O)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.4 %

Procedure:
To a solution of 2-ethyl-4-[5-(4-isobutyl-6-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (41 mg, 0.116 mmol) in isopropanol (3 mL) and 3 N aq. NaOH (0.4 mL), (S)-3-chloro-1,2-propanediol (66 mg, 0.577 mmol) is added. The mixture is stirred at 65° C. for 16 h before another portion of (S)-3-chloro-1,2-propanediol (66 mg, 0.577 mmol) and 3 N aq. NaOH (0.4 mL) is added. Stirring is continued at 65° C. for 24 h. The mixture is cooled to rt, diluted with water, and repeatedly extracted with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC using DCM:methanol 9:1 to give the title compound (16 mg) as a colourless oil; LC-MS: tR=1.02 min, [M+H]+=426.17.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.CCOCC.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].CCN(CC)CC>C1COCC1>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:18]
Reactant: Nc1cccnc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccnc1
Reaction time: 1 h

Procedure:
To a solution of pyridin-3-ylamine (20 g, 212.49 mmol, CAS RN 462-08-8) in a mixture of THF:Et2O (175 mL; 2.5:1 v/v) was added slowly a solution of pivaloyl chloride (26 mL, 212.5 mmol, CAS RN 3282-30-2) in THF (50 mL) and Et3N (44 mL, 318.7 mmol) at 0° C. and left stirring at that temperature for 1 h. After the completion of reaction, the reaction mixture was filtered, and the filtrate was evaporated in vacuo. The crude filter cake was washed with n-hexane to yield the title compound. Colorless crystalline solid (32 g, 85%). MS (ESI): m/z=179.4 [M+H]+.
Reaction SMILES: [F:1]C1C=CC(CO)=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)O[C:21](=O)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2)=O.[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([NH:43][CH:44]3[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]3)=[CH:38][CH:39]=[N:40]2)=[CH:35][CH:34]=1.C(O)(=O)C.C([BH3-])#N>ClCCl>[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([NH:43][C@H:44]3[CH2:45][CH2:46][C@@H:47]([NH:50][CH2:21][C:20]4[CH:15]=[CH:16][CH:17]=[C:18]([F:1])[CH:19]=4)[CH2:48][CH2:49]3)=[CH:38][CH:39]=[N:40]2)=[CH:35][CH:34]=1
Reactant: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Reactant: OCc1ccc(F)cc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1cccc(CN[C@H]2CC[C@@H](Nc3ccnc4cc(Cl)ccc34)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4-fluorobenzyl alcohol (9.2 mg, 0.073 mmol) was added Dess-Martin periodinane (31.0 mg, 0.073 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 0.5 hour and was added to a mixture of N-(7-chloroquinolin-4-yl)-cyclohexane-1,4-diamine (20 mg, 0.073 mmol), acetic acid (0.008 mg, 0.13 mmol) and MP-cyanoborohydride (51 mg, 0.219 mmol, Argonaut Technologies) in dichloromethane (5 mL). The mixture was stirred at room temperature for 18 hours, filtered and concentrated under reduced pressure to provide the τιτλεδ compound. MS(ESI) m/e 384 (M+H)+; 1H NMR (500 MHz, DMSO-D6) δ ppm 8.91 (br.s, 2 H), 8.75 (d, 1 H), 8.61 (d, 1 H), 7.97 (d, 1 H), 7.81 (dd, 1 H), 7.52 (dd, 1 H), 7.42 (d, 1 H), 7.37 (d, 1 H), 7.29 (td, 1 H), 4.25 (br.s, 2 H), 4.09 (br.s, 2 H), 1.76-2.13 (m, 8 H).
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:10]([OH:12])=O)[CH3:9])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].N1C=CC=CC=1.[OH2:19].[O:20]1[CH2:24]C[CH2:22][CH2:21]1>>[CH2:21]([O:20][C:24](=[O:19])[C:10](=[O:12])[CH:8]([NH:7][C:1](=[O:6])[CH2:2][CH:3]([CH3:4])[CH3:5])[CH3:9])[CH3:22]
Reactant: O
Reactant: C1CCOC1
Reactant: CC(C)CC(=O)N[C@@H](C)C(=O)O
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)C(C)NC(=O)CC(C)C

Procedure:
Ethyl oxalyl chloride (212 g) was added dropwise with stirring to a solution of isovalerylalanine (136 g) and pyridine (186.5 g) in anhydrous tetrahydrofuran (500 ml) at a rate sufficient to initiate refluxing. The reaction mixture was stirred and heated at reflux for 5 hours. The cooled reaction mixture was treated with water (1000 ml) and extracted with ethyl acetate (4×400 ml). The combined organic extracts were washed with water (3×200 ml) and dried (anhydrous sodium sulphate). Removal of solvent provided a yellow syrup which was evaporated with benzene (2×200 ml) to yield the isomeric enol esters of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:16][CH2:17][CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1.[Cl:35]CCl.Cl>C(OCC)C>[ClH:35].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N(CCN[C@@H](CC(=O)O)Cc1c[nH]c2ccccc12)CCc1ccccc1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: O=C(O)C[C@@H](Cc1c[nH]c2ccccc12)NCCNCCc1ccccc1
Reaction time: 1 h

Procedure:
Combine 2-[(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino]-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine (1.64 g, 3.53 mmol) and dichloromethane (30 mL). Slowly pass hydrogen chloride gas through the solution for 20 minutes. Stir for 1 hour. Add diethyl ether (150 mL) to form a solid. Filter and dry under vacuum to give the title compound. Elem. Anal. calculated for C22H27N3O2 .0.75 H2O: C, 58.70; H, 6.98; N, 9.14. Found: C, 58.71; H, 6.98; N, 9.14.
Reaction SMILES: [OH:1][C:2]1[C:3]([C@@H:10]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]2[OH:12])=[N:4][NH:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:19](OC(=O)C)(=[O:21])[CH3:20]>CO>[OH:1][C:2]1[C:3]([C@@H:10]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]2[OH:12])=[N:4][N:5]([C:19](=[O:21])[CH3:20])[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1[nH]nc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1O
Solvent: CO
Product: CC(=O)n1nc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(O)c1C(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.0 g. of 4-hydroxy-3-β-D-ribofuranosylpyrazole-5-carboxamide in 20 cc. of anhydrous methyl alcohol was stirred and cooled to 0°C. To the cold stirred solution was added 5 cc. of acetic anhydride dropwise over about 10 minutes. The reaction mixture was stirred for about 1 hour while the temperature was allowed to increase to about 25°C. The solvent was removed under reduced pressure to provide an oily residue which was dissolved in 25 cc. of 50 percent methanol-toluene. Again the solvent was removed under reduced pressure. This procedure was repeated three times to insure complete removal of any excess acylating agent. After the final solvents were totally removed, 4-hydroxy-3β-D-ribofuranosyl-N1 -acetylpyrazole-5-carboxamide remained as a white solid.