Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH:46]([OH:50])[CH2:47][CH2:48][CH3:49])[CH2:40][CH2:39]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:50][CH:46]([CH2:45][CH2:44][N:41]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)[CH2:47][CH2:48][CH3:49])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CCCC(O)CCN1CCN(C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCC(CCN1CCN(C)CC1)OC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 56.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-(4-methylpiperazino)-3-hexanol (46 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (48 mg, yield 49%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([N:6]([C:14]2[CH:18]=[CH:17][NH:16][N:15]=2)[C:7]2[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[OH2:23]>>[S:1]1[CH:5]=[C:4]([N:6]([C:14]2[CH:18]=[CH:17][NH:16][N:15]=2)[C:7]2[CH:12]=[C:11]([OH:23])[CH:10]=[CH:9][CH:8]=2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: O
Reactant: Oc1ccc(N(c2cc[nH]n2)c2csc3ccccc23)cc1
Product: Oc1cccc(N(c2cc[nH]n2)c2csc3ccccc23)c1
Yield: 26 %

Procedure:
Prepared in 26% yield from (5-benzo[b]thiophen-3-yl)-1H-pyrazol-3-yl)-3-(methoxy-phenyl)-amine analogous to the procedure for 4-(benzo[b]thiophen-3-yl-1H-pyrazol-3-ylamino)-phenol [Example 2(b)]. 1H NMR (300 MHz, DMSO-d6) δ12.40 (s, 1H), 9.09 (s, 1H), 8.33 (s, 1H), 8.06 (d, 2 H, J=6.9 Hz), 7.98 (s. 1H), 7.42-7.51 (m, 2H), 6.96 (t, 1H, J=7.8 Hz), 6.92 (br s, 1H), 6.71 (br s, 1H), 6.26 (br s, 1H), 6.15 (d, 1H, J=7.5 Hz). Anal. (C17H13N3OS.0.33 H2O) C, H, N, S. Calculated C=65.17; H=4.39; N=13.41; S=10.23; found C=65.30; H=4.40; N=13.05; S=10.19.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[CH:12]=[C:13]([CH2:21]O)[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[Cl:3][CH2:21][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:12]=1
Reactant: OCc1cc(-c2ccccc2)cc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1cc(-c2ccccc2)cc2ccccc12
Reaction time: 15 h

Procedure:
Thionyl chloride (0.78 cc) is added in the course of 10 minutes to a stirred solution, cooled beforehand to 0° C., of 3-phenyl-1-naphthalenemethanol (1 g) in chloroform (20 cc), and the temperature is then allowed to rise to room temperature (approximately 20° C.). The mixture is stirred for 15 hours at this temperature and the solvent evaporated under reduced pressure. 1-Chloromethyl-3-phenylnaphthalene (1.1 g) is obtained, the proton NMR spectrum of which, in deuterated chloroform, shows the following characteristics:
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][C@H:32]([N:39]=[C:40]=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.CN(C=O)C>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C@H:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH3:31])=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: C[C@H](N=C=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1)c1ccccc1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 31.5 mg (0.21 mmol) of (S)-(−)-α-methylbenzyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of methanol and 1 N hydrochloric acid (2:1), again concentrated and dried under high vacuum. 32.5 mg (62.7% of theory) of the title compound are obtained.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:14][C:15]1[CH:16]=[C:17]([NH:23][C@H:24]([C@@H:41]([OH:43])[CH3:42])[C:25]([NH:27][NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[O:26])[CH:18]=[CH:19][C:20]=1[C:21]#[N:22].O>CN(C=O)C>[Si:10]([O:43][C@@H:41]([CH3:42])[C@@H:24]([NH:23][C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[C:15]([Cl:14])[CH:16]=1)[C:25]([NH:27][NH:28][C:29](=[O:40])[C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)=[O:26])([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 68.7 %

Procedure:
Imidazole (3.77 g, 55.44 mol) and TBDMS-Cl (5.01 g, 33.24 mmol) were added sequentially to a pre-cooled (0° C.) solution of N′-((2R,3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoyl)-4-(methylsulfonyl)benzohydrazide (5 g, 11.08 mmol) in DMF (350 mL). The reaction mixture was allowed to warm to room temperature and stirred for 17 h, whereupon the solution was poured into H2O (90 mL). The white precipitate was filtered, washed with H2O (30 mL) and taken up in CH2Cl2 (170 mL) This organic layer was washed with brine (1×50 mL), dried (Na2SO4), filtered and concentrated to provide the title compound (4.3 g, 69%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.8 (br s, 1H), 8.08 (d, J=8.0 Hz, 2 H), 8.04 (d, J=9 Hz, 2 H), 7.53 (d, J=8 Hz, 1H), 6.99 (s, 1H), 6.85 (d, J=8 Hz, 1H), 6.22 (d, J=8 Hz, 1H), 4.43-4.38 (m, 1H), 4.27-4.22 (m, 1H), 1.37 (d, J=7 Hz, 3H), 0.86 (s, 9H), 0.11 (s, 3H) and 0.05 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[F:17][CH:18]([F:21])[CH2:19][OH:20].O>CN(C)C=O>[F:17][CH:18]([F:21])[CH2:19][O:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: OCC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCC(F)F
Temperature: 120 °C
Yield: 85 %

Procedure:
In a microwave tube a mixture of 1-fluoro-2-nitrobenzene (100 mg, 0.7 mmol), potassium carbonate (193 mg, 1.4 mmol), and 2,2-difluoroethanol in N,N-dimethylformamide (2 ml) was heated in a microwave oven at 120° C. for 20 minutes. For the workup, the reactrion mixture was poured into water (5 ml). The precipitated product was filtered and the aqueous layer was extracted with ether. The combined organic layers were dried and evaporated to yield together with the precipitated material 130 mg (85%) of the 1-(2,2-difluoro-ethoxy)-2-nitro-benzene which was sufficiently pure to be engaged in the next step without further purification; (calculated) C8H7F2NO3 [203.15]; (found) [M+H]+=204.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8](S)=[N:9][C:10](C)=[C:5]2[C:4]([C:13]2[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[N:3]1.[CH3:21][NH2:22]>C(O)C.C(OCC)(=O)C>[CH3:21][NH:22][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[C:5]=12
Reactant: Cc1nc(S)nc2c1c(-c1ccc([N+](=O)[O-])o1)nn2C
Reactant: CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ncnc2c1c(-c1ccc([N+](=O)[O-])o1)nn2C

Procedure:
A mixture of 3.0 grams of 1-methyl-4-methyl-mercapto-3-(5-nitro-2-furyl)-1H-pyrazolo [3,4-d] pyrimidine, 50 millitres of a 33% solution of methylamine in ethanol and 20 milliliters of ethyl acetate was heated at reflux for 1hour and cooled. The crystalline product formed was collected, washed with ethanol and dried. Recrystallisation from ehtyl acetate gave 4-methylamino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo [3,4-d]pyrimidine having melting point 280° C. identical to the product obtained in Example 13.
Reaction SMILES: [F:1][S:2]([F:19])([F:18])([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14]O)=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:22]>C1(C)C=CC=CC=1>[Cl:22][CH2:14][C:13]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2]([F:19])([F:18])([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[N:10]=[N:11][N:12]=1
Reactant: OCc1nnnn1-c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: FS(F)(F)(F)(F)c1ccc(-n2nnnc2CCl)cc1
Reaction time: 4 h

Procedure:
Thionyl chloride (1.72 g, 14.4 mmol) was added to a stirred solution of {1-[4-(pentafluoro-λ6-sulfanyl)phenyl]-1H-tetrazol-5-yl}methanol (Intermediate 44, 3.50 g, 11.6 mmol) in toluene (40 mL), SOCl2 at room temperature. The reaction mixture was stirred for 4 hr at reflux. The reaction mixture was concentrated under vacuum. The residue was diluted with DCM and washed with ice-water, saturated aq NaHCO3 and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude compound. This was purified by column chromatography (100-200 mesh silica gel), eluted with 20%-30% EtOAc/pet-ether to give the title compound as a brown gum (3.50 g).
Reaction SMILES: [CH3:1][C:2]1([CH2:13][NH:14]C(=O)OCC2C=CC=CC=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:1][C:2]1([CH2:13][NH2:14])[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC1(CNC(=O)OCc2ccccc2)Cn2cc([N+](=O)[O-])nc2O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CN)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of benzyl (2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)carbamate prepared in Example 200 (190 mg, 0.57 mmol), trifluoroacetic acid (4 ml) and methylene chloride (5 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the residue was treated with diethyl ether to afford 2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethylamine trifluoroacetate (120 mg, yield 67%) as a light yellow powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[H-].[Na+].CS(C)=O.Cl[CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([O-])=[O:24]>O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH2:21][CH3:20])[C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: CC(C)(CCCl)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(C)(C)C(=O)n1cnc2c1c(=O)[nH]c(=O)n2C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
This example illustrates a synthesis of 1-(11,10-Oxidoundecanyl)-3-methyl-7-methylpivalylxanthine (inventive compound no. 1412). A mixture of 3-methylxanthine (Aldrich, 1.00 g, 6.0 mmol), sodium hydride (145 mg, 6.0 mmol) and dimethyl sulfoxide (20 mL) was stirred until homogeneous (0.5 hours). Chloromethylpivalate (865 mL, 904 mg, 6.0 mmol) was added and the reaction stirred for 18 hours. The reaction mixture was poured into water (70 mL) and then extracted with 25% ethano/dichloromethane (4×60 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum to a volume of 40 mL. This solution was cooled in icewater, whereupon a thick white precipitate formed. The solid was filtered off under suction and dried under vacuum to yield 1.43 g (90% yield) 3-methyl-7-(methylpivaloyl)xanthine (inventive compound no. 1404).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[S:12][CH:11]=[C:10]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C1COCC1>C(OCC)(=O)C>[C:25]([O:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[S:12][CH:11]=[C:10]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: NS(=O)(=O)c1csc(C(=O)c2ccc(O)cc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(C(=O)c2cc(S(N)(=O)=O)cs2)cc1
Temperature: 25 °C

Procedure:
58 mg (0.20 mmol) of 5-(4-hydroxybenzoyl)-3-thiophene sulfonamide, 81 mL (1.0 mmol) of pyridine and 94 mL (1.0 mmol) of acetic anhydride were added to 4 mL of THF. The reaction was stirred at rt for 1 1/4 h and then diluted with ethyl acetate. The organic phase was washed with water (2×) followed with brine. The solution was dried over MgSO4 and the solvent removed under vacuum. Flash chromatography utilizing 1:1 hexane/ethyl acetate as the eluant recovered 51 mg of 5-(4-acetoxybenzoyl)-3-thiophene sulfonamide as tan color crystals.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:11](=[O:13])[CH3:12])\[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].O[CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH2:17][CH2:16]1>>[N+:31]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:21]([C@H:18]2[CH2:19][CH2:20][C@H:15]([O:1]/[N:2]=[C:3](/[C:11](=[O:13])[CH3:12])\[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5])[CH2:16][CH2:17]2)=[O:22])=[CH:30][CH:29]=1)([O-:33])=[O:32]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1CCC(O)CC1
Reactant: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Product: CC(=O)/C(=N/O[C@H]1CC[C@H](C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)C(=O)OC(C)(C)C

Procedure:
tert-Butyl (Z)-2-(hydroxyimino)-3-oxobutyrate (7.36 g) was treated with 4-nitrobenzyl 4-hydroxycyclohexanecarboxylate as described in Example 4, Method 3 to give the title compound (5.1 g, 29%) as a gum. νmax (film) 2950, 1740, 1695, and 1525cm-1, δH (CDCl3) 1.53 (9H, s), 1.62 (3H, m), 1.82 (1H, m), 2.14 (4H, m), 2.37 (3H, s), 2.45 (1H, tt, J 3.7 Hz, 10.7 Hz), 4.26 (1H, tt, J 3.8, 9.8 Hz), 5.22 (2H, s), 7.51 (2H, d), and 8.24 (2H, d). δC (CDCl3) 25.2, 26.2, 28.1 (3C), 29.8, 41.6, 64.7, 82.7, 84.0, 123.8 (2C), 128.3 (2C), 143.3, 147.7, 150.7, 160.6, 174.5 and 193.0. [Mass spectrum (ammonia) MNH4+ (466)].
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[S:6][CH:7]=1.CO>[O-2].[Mn+4].[O-2].C(Cl)(Cl)Cl>[CH:2]([C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:11])[CH3:12])[S:6][CH:7]=1)=[O:1]
Reactant: CC(C)C(=O)Nc1nc(CO)cs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1nc(C=O)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
A mixture of N-[4-(hydroxymethyl)-1,3-thiazol-2-yl]-2-methylpropanamide (520 mg), manganese (IV) oxide (2.26 g), methanol (0.5 ml) and chloroform (5 ml) was stirred at ambient temperature for 18 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The crystalline residue was collected and washed with diisopropyl ether to give N-(4-formyl-1,3-thiazol-2-yl)-2-methylpropanamide (365 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl>[Si:17]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: OCCc1ccncc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccncc1
Temperature: -78 °C
Yield: 97.9 %

Procedure:
4-(2-Hydroxyethyl)pyridine (8.1 g, 65.8 mmol) and triethylamine (10.1 mL, 66 mmol) were dissolved in CH2Cl2 (100 mL) and cooled to −78° C. To this solution, tert-butyl-dimethylsilyl chloride (11.0 g, 66 mmol) was added. The mixture was allowed to warm to room temperature overnight. The mixture was placed directly on a bed of SiO2 and eluted with 100:0-10:1 CH2Cl2:methanol to provide 4-[2-(tert-Butyldimethylsilyloxy)ethyl]pyridine (15.3 g, 97%).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[C:23]1([Si:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>C1C=CC=CC=1>[C:37]1([Si:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:1][CH2:2][C@@:3]23[C@@H:20]4[C@H:11]([C@H:12]5[C@@:16]([CH2:18][CH2:19]4)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]5)[CH2:10][CH2:9][C:8]2=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]3)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H]1CCC2=O

Procedure:
A solution of 19-hydroxy-4-androstene-3,17-dione, triphenylchlorosilane and pyridine contained in 100 ml of benzene is refluxed for a period of 18 hours. The resulting suspension is filtered and concentrated in vacuo to a yellow oil. The oil is placed on a silica gel chromatographic column packed in chloroform which is further eluted with chloroform. The chloroform eluant is evaporated to dryness in vacuo and the residue is recrystallized from methanol to yield 19-triphenylsiloxy-4-androstene-3,17-dione.
Reaction SMILES: [OH2:1].C[N+]1([O-])CC[O:6]CC1.[CH3:10][C:11]([S:20]([CH2:23][CH:24]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])(=[O:22])=[O:21])([C:13]([N:15]1[CH2:19][CH:18]=[CH:17][CH2:16]1)=[O:14])[CH3:12]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[OH:1][CH:17]1[CH:18]([OH:6])[CH2:19][N:15]([C:13]([C:11]([S:20]([CH2:23][CH:24]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])(=[O:21])=[O:22])([CH3:10])[CH3:12])=[O:14])[CH2:16]1
Reactant: CC(C)(C(=O)N1CC=CC1)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Product: CC(C)(C(=O)N1CC(O)C(O)C1)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.7 %

Procedure:
832 mg (6.16mmol) of 4-methylmorpholine 4-oxide monohydrate and 10 ml of an osmium tetroxide solution [1.0 g of osmium tetroxide and 1 ml of tert-butyl hydroperoxide (70% in water) in 199 ml of tert-butanol]were added at room temperature to a solution of 935 mg (2.05 mmol) of benzyl rac-α-[[[1-methyl-1-(3-pyrrolin-1-ylcarbonyl)ethyl]sulfonyl]methyl]hydrocinnamate in 30 ml of acetone and 10 ml of water. The reaction mixture was stirred at room temperature for three days. Subsequently, the solvent was evaporated under reduced pressure, the residue was poured into 80 ml of ice-cold 10% citric acid solution and extracted with 240 ml of ethyl acetate. The organic extracts were washed twice with 80 ml of water each time and the combined aqueous phases were back-extracted twice with 80 ml of ethyl acetate each time. The combined ethyl acetate extracts were dried over magnesium sulphate and evaporated under reduced pressure. For purification, the crude product (1.1 g) was chromatographed on 80 g of silica gel with a 1:4 mixture of toluene and ethyl acetate as the eluent. There were obtained 750 mg of benzyl (RS)-α-[[[1-[[(3RS,4RS)-3,4-dihydroxy-1-pyrrolidinyl]carbonyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamate as a colourless oil, MS: 490 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][CH:9]1[CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[CH3:42][C:43]([Si:46](Cl)([CH3:48])[CH3:47])([CH3:45])[CH3:44]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([O:13][Si:46]([C:43]([CH3:45])([CH3:44])[CH3:42])([CH3:48])[CH3:47])=[CH:10][CH:9]1[CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(=O)CC1CCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)=CC1CCNC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 83.9 %

Procedure:
To a pre-cooled (−78° C.) solution containing 6 (400 mg, 1.10 mmol) in THF (10 mL) was added 1M NaHMDS/THF (2.43 mL) in a dropwise fashion. After 45 min, a solution containing TBSCl (348 mg, 2.31 mmol) in THF (5 mL) was added to the heterogeneous reaction mixture. After 30 min, the homogeneous reaction mixture was quenched with saturated aqueous NH4Cl. The solution was diluted with EtOAc and the layers were separated. The organic phase was washed with brine then dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (4:1 hexanes/EtOAc) to afford 440 mg (83%) of 7 as a white foam. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ7.26 (m, 5H), 5.87 (m, 0.25H), 5.70 (m, 0.25H), 5.48 (m, 0.5H), (app dd, J=16.4, 12.8 Hz, 2H), 4.92 (m, 0.3H), 4.55 (br s, 0.7H), 4.49 (m, 0.7H), 4.39 (m, 0.3H), 3.99 (m, 0.2H), 3.92 (m, 0.4H), 3.86 (br s, 0.4H), 3.76 (m, 1H), 3.28 (m, 0.5H), 3.13 (m, 0.5H), 3.03 (m, 0.5H), 2.92 (m, 0.5H), 1.78 (m, 1H), 1.64 (m, 1H), 1.38 (s, 9H), 0.85 (s, 9H), 0.11 (s, 6H) ppm. Mass spectrum, m/z [499.2] (M+Na)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:20][C@H:19]1[CH2:34][OH:35])=[O:17])([CH3:14])([CH3:13])[CH3:12].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[CH2:20][C@@H:19]1[CH:34]=[O:35])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1C=O
Reaction time: 0.17 h
Yield: 101.8 %

Procedure:
Under nitrogen atmosphere, to a solution of oxalyl chloride (1.64 ml) in dichloromethane (34 ml) under −65° C., was added dropwise a solution of dimethyl sulfoxide (2.0 ml) in dichloromethane (15 ml) and stirred for 10 minutes at the same temperature. A solution of (2S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (3.29 g) in dichloromethane (24 ml) was dropped into the above solution over 5 minutes under −65° C. The reaction mixture was stirred at the same temperature for 15 minutes, then stirred at −45° C. for 90 minutes. Triethylamine (7.85 ml) was added to the solution under −40° C., and the mixture was stirred at 0° C. for 20 minutes. The mixture was poured into saturated aqueous ammonium chloride (100 ml). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give (2R)-2-formylpiperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (3.33 g) as a colorless syrup.