Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:15]2[CH:16]=[C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1)[CH3:10].C(OC([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]1[C:39](O)=[O:40])=O)(C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:15]2[CH:16]=[C:17]([C:20]3[CH2:21][CH2:22][N:23]([C:39]([C@H:34]4[CH2:35][CH2:36][CH2:37][CH2:38][NH:33]4)=[O:40])[CH2:24][CH:25]=3)[CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1)[CH3:10]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCNCC3)cc21
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a stirred solution of the crude (R)-1-(1-(2,4-dichlorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-benzo[d]imidazole (1.2 g, 3.1 mmol) and (R)-1-(t-butoxycarbonyl)piperidine-2-carboxylic acid (0.71 g, 3.1 mmol) in N,N-dimethylformamide (DMF, 10 mL) at 0° C. under nitrogen was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 1.4 g, 3.7 mmol) and diisoproylethylamine (iPr2NEt, 0.80 g, 6.2 mmol). The reaction mixture was stirred at room temperature for 1 h, and diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10-100% ethyl acetate in hexanes) to afford the desired product (1.5 g, 2.6 mmol, 85%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]#[N:12])=[CH:6][CH:5]=1.[Br:22][CH2:23]Br>CN(C=O)C>[Br:22][CH2:23][C:10]([C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1)([C:11]#[N:12])[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#CC(CCOc1ccccc1)c1ccc(Cl)cc1
Reactant: BrCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CBr)(CCOc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a flask was added 6.1 g. (0.127 mole) of a 50% oil dispersion of sodium hydride. After washing the sodium hydride several times with hexane to remove the mineral oil, 50 ml. of dry DMF was added, then a solution of 30 g. (0.11 mole) of 2-(4-chlorophenyl)-4-phenoxybutanenitrile in 25 ml. of dry DMF was added dropwise at 0° C. The reaction was stirred and allowed to warm to room temperature over 1.5 hours, then 21.2 g. (0.127 mole) of dibromomethane was added dropwise at 15° C. Upon completion of the addition, the reaction was stirred and heated to 50° C. and was complete in three hours. The reaction mixture was cooled to room temperature, diluted with 300 ml. of water, and then extracted three times with 100 ml. portions of methylene chloride. The combined extracts were washed with dilute hydrochloric acid and water, then dried using sodium sulfate. Upon removal of the solvent, 31 g. of 1-bromo-2-(4-chlorophenyl)-2-cyano-4-phenoxybutane was obtained (77% yield).
Reaction SMILES: [I-].C([NH:5][CH2:6][C:7]1[CH:8]=[N+:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)(=O)C.[ClH:14]>>[Cl-:14].[NH3+:5][CH2:6][C:7]1[CH:8]=[N+:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1.[Cl-:14]
Reactant: CC(=O)NCc1ccc[n+](C)c1
Reactant: Cl
Agent: [I-]
Product: C[n+]1cccc(C[NH3+])c1
Product: [Cl-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
A suspension of 3-(acetamidomethyl)-1-methylpyridin-1-ium iodide (26.9 g, 92 mmol) in HCl (6N, 307 mL, 1.84 mol) was heated to 100° C. for 3 h. The solution was concentrated under reduced pressure (bath temp 80° C.). The resulting red oil solidified overnight and was triturated with MeOH and filtered to afford the title compound (8.76 g, 49%) as an off white solid. The filtrate was concentrated to a red oil, which after standing for 4 days, the formed solid was collected and washed with cold MeOH, affording a second crop (6.5 g, 36%). LCMS: Rt=0.11 min, m/z=123.0 (M+) Method 2m_acidic. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (s, 1H) 9.03 (d, J=6.0 Hz, 1H) 8.66 (d, J=8.1 Hz, 1H) 8.45 (brs, 3H) 8.24 (t, J=7.0 Hz, 1H) 4.38 (s, 3H) 4.30 (s, 2H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].S(Cl)([Cl:11])=O.[CH3:13]O>>[ClH:11].[NH2:1][C@H:2]([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH3:13])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: C=CC[C@@H](N)C(=O)O
Product: C=CC[C@@H](N)C(=O)OC
Product: Cl
Reaction time: 16 h
Yield: 100 %

Procedure:
To a suspension of (2R)-2-amino-4-pentenoic acid (200 mg, 1.74 mmol) in methanol (6 mL) at 0° C. was added dropwise thionyl chloride (1 mL). The resulting solution was allowed to stir for 16 h before the solvent was removed by evaporation and the product crystallized with diethyl ether. The diethyl ether was removed by evaporation to yield the title compound (287 mg, 1.74 mmol, 100%) as a white solid which had spectral data in agreement with that reported.123 Mp 135-140° C. 1H NMR (CDCl3, 300 MHz): δ 8.70 (bs, 3H, NH3+); 5.89 (m, 1H, H4); 5.32 (d, J=17.3 Hz, 1H, H5a); 5.24 (d, J=10.1 Hz, 1H, H5b); 4.31 (m, 1H, H2); 3.81 (s, 3H, OCH3); 2.87 (t, J=6.3 Hz, 2H, H3). Mass Spectrum (ES, +ve) m/z 130 (100%) [M+]. HRMS calcd for C6H12NO2 130.0868, found 130.0870.
Reaction SMILES: [C:1]([N:5]([CH2:10][CH2:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6](=[O:9])[O:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br-].[CH2:21]1[CH2:25]OC[CH2:22]1>>[C:1]([N:5]([CH2:10][CH2:11][C:12]([OH:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:25][CH:21]=[CH2:22])[C:6](=[O:9])[O:7][CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: COC(=O)N(CCC(=O)c1ccccc1)C(C)(C)C
Agent: [Br-]
Product: C=CCC(O)(CCN(C(=O)OC)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of methyl tert-butyl(3-oxo-3-phenylpropyl)carbamate (2.0 g, 7.6 mmol) in THF (200 mL) was added allymagnesium bromide (1 M, 23 mL, 23 mmol) dropwise at −78° C. under N2. After adding completely, the reaction mixture was stirred at rt overnight. The reaction was quenched with saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC to afford methyl tert-butyl(3-hydroxy-3-phenylhex-5-enyl)carbamate (1.05 g, 46%). 1H NMR (CDCl3): 1.12-1.31 (s, 9H), 1.83-1.91 (m, 1H), 2.05-2.11 (m, 1H), 2.38-2.48 (m, 1H), 2.58-2.63 (m, 1H), 2.93-3.01 (m, 1H), 3.21-3.31 (m, 1H), 3.56 (s, 3H), 5.01-5.12 (m, 2H), 5.45-5.56 (m, 1H), 7.15-7.19 (m, 1H), 7.21-7.36 (m, 4H).
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][C@H:23]([C:32]([O:34][CH3:35])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.O1CCCC1.C(N(CC)CC)C>[C:1]([NH:9][C@H:10]([C:18]([NH:22][C@H:23]([C:32]([O:34][CH3:35])=[O:33])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Reaction time: 3 h
Yield: 73.9 %

Procedure:
In 100 ml of a mixture of chloroform-tetrahydrofuran (2:1), were dissolved 5.39 g of N-benzoylphenylalanine, 4.64 g of methyl tyrosinate hydrochloride, 2.02 g of triethylamine and 2.30 g of N-hydroxysuccinimide and the solution was cooled with ice. To the cold solution, 4.12 g of N,N'-dicyclohexylcarbodimide was added. The mixture was stirred for three hours, then allowed to stand at room temperature overnight. The precipitates were removed by filtration and the filtrate was concentrated. The residue was extracted with ethyl acetate and the extract was washed with 2% hydrochloric acid, 4% sodium bicarbonate and water, then dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroleum ether to give 6.6 g of methyl N-benzoylphenylalanyltyrosinate with a mp. 188°-190° C in a yield of 74%. Analysis, calculated for C26H26O5N2C 69.94, H 5.87, N 6.27, found C 69.56, H 6.01, N 6.39.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=O)[CH3:19])[C:6]=1[O:7][CH:8]([CH3:13])C(OC)=O)=[O:4].Cl.O1CCOCC1>O>[CH3:13][C:8]1[O:7][C:6]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:17][CH:16]=[CH:15][C:14]=2[C:18]=1[CH3:19]
Reactant: COC(=O)c1cccc(C(C)=O)c1OC(C)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc2c(C)c(C)oc12
Reaction time: 1 h
Yield: 46 %

Procedure:
A mixture of 4.42 g of methyl 2-(2-methoxycarbonyl-6-acetylphenoxy)propionate, 20 ml of 6N hydrochloric acid and 20 ml of dioxane is refluxed for 10 minutes, and water is added to the reaction mixture. The aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is dissolved in 30 ml of tetrahydrofuran, and 5.55 ml of oxalyl chloride and a drop of dimethylformamide are added to the solution. The mixture is stirred for 1 hour. The reaction mixture is evaporated to remove solvent and the residue is dissolved in 100 ml of benzene. The solution is added dropwise to a refluxed solution of 6.66 ml of triethylamine in benzene and the mixture is refluxed for 5 hours. The reaction mixture is washed successively with 2% hydrochloric acid and water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=5:1) to give 1.48 g of methyl 2,3-dimethylbenzofuran-7-carboxylate.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[CH2:20][C:21]([CH3:23])=[CH2:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH2:22][C:21]([CH3:23])=[CH2:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=C(C)CCl
Reactant: COc1cccc(NC2CCN(C(C)=O)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)CN(c1cccc(OC)c1)C1CCN(C(C)=O)CC1
Yield: 63.6 %

Procedure:
A mixture of N-(l-acetylpiperidin-4-yl)-3-methoxyaniline (2.0 g), 3-chloro-2-methylpropene (10 ml) and potassium carbonate (5.0 g) in dimethylformamide (50 ml) was reacted at 80° C. for 6 hr. Then the reaction mixtures were concentrated under reduced pressure and partitioned between ethyl acetate and water. The ethyl acetate layer was washed successively with water and brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/hexane system) to give the title compound (1.55 g) as a yellow oil (yield: 63.6%).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:21]=[CH:20][C:16](C(O)=O)=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:29])C=CC=CC=1.CC[N:41]([CH2:44]C)CC.N#N>CN(C=O)C>[N:41]([C:16]1[CH:20]=[CH:21][C:13]([C:3]2[C:4]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[NH:1][N:2]=2)=[CH:14][CH:15]=1)=[C:44]=[O:29]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: CN(C)C=O
Product: O=C=Nc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1

Procedure:
To a solution of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoic acid 1 (5.8 g, 20.99 mmol) in DMF (200 mL) were added diphenylphosphoryl azide (5.22 mL, 23.09 mmol) and Et3N (3.35 mL, 23.09 mmol). The reaction mixture was heated to about 80° C., for about 4 h, until no more N2 gas evolution was observed. The off-white precipitation was filtered off and washed with EtOAc (3×5 mL) and Et2O (3×5 mL). The solid was dried under vacuum to give quantitative yield of 2 that was used in the next step without further purification. Mp 338-339° C. IR (KBr) 2132, 1723,1582,1520
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]1[CH2:12][N:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]([CH2:17][OH:18])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl.C1CCCCC1>[CH2:23]([O:18][CH2:17][CH:10]1[CH2:9][CH2:8][CH:7]([CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][N:11]1[S:13]([CH3:16])(=[O:15])=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OCC1CCC(CO)N(S(C)(=O)=O)C1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(C)(C)OCC1CCC(COCc2ccccc2)N(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
(6-ring): To a solution of (2RS,5RS)-(5-tert-butoxymethyl-1-methanesulfonyl -piperidin-2-yl)-methanol (2.80 g) in dichloromethane (20 ml) and cyclohexane (30 ml) was added benzyl 2,2,2-trichloroacetimidate (3.03 g) and trifluoromethanesulphonic acid (0.2 ml). The reaction mixture was stirred 1 h at room temperature, poured onto a saturated sodium bicarbonate solution and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:3 and 1:2 as eluents to obtain (2RS,5RS)-2-benzyloxymethyl-5-tert-butoxymethyl-1-methanesulfonyl-piperidine (3,6 g) as a syrup, MS: 369 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][NH:10][C:4]=2[CH:3]=1.CS(O)(=O)=O.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl.O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][N:10]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: Clc1cc2[nH]nc(I)c2cn1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Clc1cc2c(cn1)c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
At r.t. to a suspension of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (0.55 g, 2.0 mmol) in methylene chloride (6 mL) and tetrahydrofuran (3 mL) was added methanesulfonic acid (20 μL, 0.4 mmol), followed by dihydropyran (0.54 mL, 5.9 mmol) (Aldrich, Cat. #: D106208). The mixture was stirred at r.t. overnight. Then, it was stirred at 60° C. for 4 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.72 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[C:29]1[C:34]([N+:35]([O-:37])=[O:36])=[C:33]([NH:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:32]=[C:31]([CH3:43])[N:30]=1)(=O)=O>C1(C)C=CC=CC=1>[CH2:39]([NH:38][C:33]1[CH:32]=[C:31]([CH3:43])[N:30]=[C:29]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:34]=1[N+:35]([O-:37])=[O:36])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCNc1cc(C)nc(OS(=O)(=O)C(F)(F)F)c1[N+](=O)[O-]
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCNc1cc(C)nc(N(Cc2ccccc2)Cc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 97.4 %

Procedure:
Dibenzylamine (1.04 g, 5.28 mmole), triethylamine (0.53 g, 5.28 mmole), 4-butylamino-6-methyl-3-nitro-2-pyridinyl trifluoromethanesulfonate (1.72 g, 5.28 mmole) and toluene (45 mL) were combined and heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature then filtered through a layer of silica gel. The silica gel was eluted with methylene chloride. The combined organic filtrates were evaporated to provide 2.08 g of an oily semisolid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:29])[CH2:12][CH2:13][C@@H:14]2[C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)[CH2:6]1.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31].O.C(OCC)(=O)C>N1C=CC=CC=1>[S:30]([O:1][CH2:2][CH2:3][S:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:29])[CH2:12][CH2:13][C@@H:14]2[C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)[CH2:6]1)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@]12CC[C@H](SCCO)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCS[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Yield: 97.4 %

Procedure:
To a solution of 0.90 g of 3β-(2-hydroxyethylthio)-17β-(3-furyl)-5β-androstan-14β-ol, in 9 ml of dry pyridine, 0.64 g of tosylchloride were added. After 5 hrs 10 ml of water and 50 ml of ethyl acetate were added. The organic phase was washed with water, dried over anhydrous sodium sulfate to give 1.2 g of 3β-(2-tosyioxyethylthio)-17β-(3-furyl)-5β-androstan-14β-ol as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(#N)C.CCOCC>[CH3:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[CH:20]=[N:1]2
Reactant: COC(OC)OC
Reactant: Cc1cccc(N)c1C(=O)NC1CCC(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: Cc1cccc2ncn(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (0.60 g, 2.2 mmol), trimethyl orthoformate (3 mL, 26.8 mmol), and p-toluene sulfonic acid (0.060 g) in acetonitrile (20 mL) was heated to reflux for 30 hours. The mixture was cooled to room temperature. To the mixture, water (75 mL) and ether (20 mL) were added, and the resulting mixture was stirred for 2 hours. The suspension was filtered and washed with water and ether (50 mL each) to give 3-(5-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (0.28 g, 47% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 3.08 min (99%); mp: 262-264° C.; 1H NMR (DMSO-d6) δ 2.09-2.16 (m, 1H, CHH), 2.62-2.84 (m, 6H, CH2, CH3, CHH), 5.42 (brs, 1H, NCH), 7.32 (d, J=7 Hz, 1H, Ar), 7.52 (d, J=8 Hz, 1H, Ar), 7.69 (t, J=8 Hz, 1H, Ar), 8.30 (s, 1H, CH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ22.35, 22.62, 30.88, 58.00, 119.81, 125.36, 129.57, 133.72, 140.15, 147.08, 149.07, 160.21, 169.91, 172.33, 172.44; LCMS: MH=272; Anal. Calcd. for C14H13N3O3: C, 61.99; H, 4.83; N, 15.49. Found: C, 61.67; H, 4.40; N, 15.41.
Reaction SMILES: CCN=C=NCCCN(C)C.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1.[CH:21]1([NH:26][C:27]2[C:32]([C:33](O)=[O:34])=[CH:31][N:30]=[C:29]([S:36][CH3:37])[N:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl>[N:12]1([C:33]([C:32]2[C:27]([NH:26][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:28][C:29]([S:36][CH3:37])=[N:30][CH:31]=2)=[O:34])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CSc1ncc(C(=O)O)c(NC2CCCC2)n1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CSc1ncc(C(=O)n2nnc3ccccc32)c(NC2CCCC2)n1
Reaction time: 1 h
Yield: 53.9 %

Procedure:
EDCI (7.690 g, 40.26 mmol) and benzotriazole (4.796 g, 40.26 mmol) were added to a suspension of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid (10.186 g, 40.26 mmol) in DCM (250 mL), at RT, and the reaction mixture was stirred for 1 h. The resulting mixture was washed 3 times with water; the combined aqueous extracts were extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure to give a crude oil. This material was triturated with hot tert-butyl methyl ether and the mixture was left to stand overnight. The white solid which formed was collected by filtration to give 7.698 g (54% yield) of benzotriazol-1-yl-(4-cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl)-methanone.
Reaction SMILES: [O:1]=[C:2]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:27]([CH2:28][CH2:29][C@:7]12[CH3:8])[C@:20]1([CH2:21][O:22]C(=O)CC)[C:15](=[CH:16][C:17](=[O:30])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)[CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[OH:22][CH2:21][C@@:20]12[C@@H:27]3[C@H:12]([C@H:9]4[C@@:7]([CH2:29][CH2:28]3)([CH3:8])[C@@H:6]([O:5][C:2](=[O:1])[CH2:3][CH3:4])[CH2:11][CH2:10]4)[CH2:13][CH2:14][C:15]1=[CH:16][C:17](=[O:30])[CH2:18][CH2:19]2
Reactant: CCC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)CC)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@]12C

Procedure:
A solution of 11 g of 17β,19-bis(1-oxopropoxy)androst-4-en-3-one in 2 liters of methanol is treated with 2.5 g of sodium carbonate in 250 ml of water and refluxed for one hour after which the reaction mixture is poured into 10 liters of water, and the solid collected by filtration. The solid is dissolved in methylene chloride, dried over magnesium sulfate, filtered and the solvent removed. The residue is crystallized from acetone-hexane yielding 6 g of 19-hydroxy-17β(1-oxopropoxy)androst-4-en-3-one. M.P. 160°-162° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[O:2]1[C:6]2[CH2:7][N:8]([C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)CCCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.18 g (1.1 mmol) of 4-phenylbutyric acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate=10/1 to 5/1) to yield the desired product.