Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:11][NH:10][CH:9]=[N:8][CH2:7]1)=[O:5].N12CCCN=C1CCCCC2.[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:24]1([C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:8]2[CH2:7][CH:6]([C:4]([O:3][CH3:2])=[O:5])[CH2:11][N:10]=[CH:9]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CN=CNC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C

Procedure:
1,4,5,6-Tetrahydro-5-methoxycarbonylpyrimidine hydrochloride (I.49 g, 8.3 mmol), 1,8 diazabicyclo [5.4.0] undec-7ene, (hereinafter diazabicycloundecene and/or DBU), (2.5 mL, 16.6 mmol), and tritylchloride (2.32 g, 8.3 mmol) were suspended in anhydrous DMF (20 ml) with stirring under nitrogen at room temperature. After 18 hours stirring the suspension was evaporated in vacuo and the residue chromatographed (silica, chloroform/methanol, 9:1) to yield 2.28 g (rf=0.15, 71%) white crystalline solid identified by 300 MHz nmr and ms m/z=384.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[CH:23]=[C:24]([CH3:41])[CH:25]=[C:26]2[C:31]=1[O:30][CH:29]([C:32]([F:35])([F:34])[F:33])[C:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:27]2.N1C=CN=C1.[I:47]I>C(Cl)Cl>[I:47][CH2:21][C:22]1[CH:23]=[C:24]([CH3:41])[CH:25]=[C:26]2[C:31]=1[O:30][CH:29]([C:32]([F:35])([F:34])[F:33])[C:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:27]2
Reactant: CCOC(=O)C1=Cc2cc(C)cc(CO)c2OC1C(F)(F)F
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2cc(C)cc(CI)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
The suspension, of polymer bound triphenylphosphine (0.29 g, 0. 88 mmole), in anhydrous CH2Cl2 (5 mL) was cooled to 0° C. (ice bath) and stirred for 15 minutes. The ethyl 8-(hydroxymethyl)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 605b, Step 1 (0.20 g, 0.63 mmole), imidazole (0.06 g, 0.88 mmole) and iodine (0.19 g, 0.76 mmole) were added to above suspension, which was allowed to stir for 15 minutes at 0° C. The mixture was warmed to room temperature and stirred for an additional 3 hours. The resulting mixture was filtered through a plug of celite and condensed in vacuo to give an oil. The oil was purified by flash chromatography (silica gel) with 50% methylene chloride in hexane to give a light yellow oil (0.14 g, 79%): GCMS m/z 426.00 (M+). 1H NMR (CDCl3/400 MHz) 7.64 (s, 1H), 7.11 (s, 1H), 6.94 (s, 1H), 5.79 (q, 1H, J=7.0 Hz), 4.44 (m, 2H), 4.31 (m, 2H), 2.24 (s, 3H), 1.33 (m, 3H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[C@@H:5]([OH:10])[C@H:4]1[OH:11].[Cl:12][C:13]1[C:18]([NH2:19])=[C:17](Cl)[N:16]=[CH:15][N:14]=1>C(O)C>[NH2:19][C:18]1[C:17]([NH:2][C@@H:3]2[CH2:7][C@H:6]([CH2:8][OH:9])[C@@H:5]([OH:10])[C@H:4]2[OH:11])=[N:16][CH:15]=[N:14][C:13]=1[Cl:12]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Solvent: CCO
Product: Nc1c(Cl)ncnc1N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
A mixture of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (16.9 g, 45.1 mmol) and 4,6-dichloropyrimidin-5-amine (5.7 g, 35 mmol) in ethanol (45 mL) was evenly distributed amongst three tubes and subjected to microwave conditions (CEM apparatus, 300 W max, 150° C. max, 250 psi max, 3 min ramp, 30 min hold) to afford brown solutions; HPLC/LC MS indicated conversion to the desired product. The three reaction mixtures were combined and concentrated in vacuo to afford the crude title compound as a dark brown oil, which was concentrated from toluene (2×30 mL) and carried on without purification: MS (ESI+) for C10H15ClN4O3 m/z 275.0 (M+H)+; MS (ESI−) for C10H15ClN4O3 m/z 273.0 (M−H)−.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH2:14][CH:15]([P:24]([O:29]CC)(=[O:28])[O:25]CC)[P:16]([O:21]CC)(=[O:20])[O:17]CC)[C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][CH:9]=[CH:8][CH:7]=2.C[Si](Br)(C)C>>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH2:14][CH:15]([P:16]([OH:21])(=[O:17])[OH:20])[P:24]([OH:28])(=[O:25])[OH:29])[C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCOP(=O)(OCC)C(Cc1cc(SC)c(O)c2ccccc12)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Product: CSc1cc(CC(P(=O)(O)O)P(=O)(O)O)c2ccccc2c1O
Yield: 71 %

Procedure:
Following the same method as described in Example 2, 7.36 g (15 mmol) of tetraethyl 2-[3-methylthio-4-hydroxy-1-naphthyl]ethane-1,1-diphosphonate was treated with trimethylsilyl bromide, and then hydrolysis was effected to obtain 4.03 g of the title compound as pale yellow crystals. The yield was 71%.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)=O>>[CH3:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:25]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:24]=2)=[CH:28][CH:29]=1)(=[O:34])=[O:35]
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: CS(=O)(=O)c1ccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)cc1
Yield: 11 %

Procedure:
4-[4-(4-Methanesulfonyl-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (33 mg, 11%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-1-[4-(methylsulfonyl)phenyl]-1-ethanone (available from TCI America) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J=8.3 Hz, 2H), 8.27-8.35 (m, 3H), 8.14 (d, J=7.8 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.79 (t, J=8.4 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.41-7.48 (m, 2H), 3.26 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:18][CH2:17][C@:13]2([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[NH:14][O:15][CH2:16][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[NH2:14][C@@:13]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:17][O:18][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11][C@H:12]1[CH2:16][OH:15]
Reactant: Fc1ccc([C@]23CO[C@@H](COCc4ccccc4)C[C@H]2CON3)c(F)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Temperature: 40 °C
Reaction time: 16 h

Procedure:
(3aR,5R,7aS)-5-[(Benzyloxy)methyl]-7a-(2,4-difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C5) (48.1 g, 133 mmol) was dissolved in acetic acid (444 mL) and treated with zinc powder (113 g, 1.73 mol). The reaction mixture, which had warmed to 40° C., was allowed to cool to room temperature and stir for 16 hours. Insoluble material was removed via filtration through a Celite® pad, and the pad was washed with ethyl acetate (3×500 mL). The combined filtrates were neutralized with saturated aqueous sodium bicarbonate solution (2.5 L), and the aqueous layer was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (1 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the product as a thick yellow oil, which was used in the following reaction without additional purification. Yield: 48.7 g, assumed quantitative. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 7.62-7.80 (br m, 1H), 7.28-7.39 (m, 5H), 6.94-7.06 (m, 1H), 6.83 (ddd, J=12.7, 8.5, 2.6 Hz, 1H), 4.61 (AB quartet, upfield doublet is broadened, JAB=12.2 Hz, ΔνAB=30.5 Hz, 2H), 4.22 (dd, J=11.6, 2.2 Hz, 1H), 3.83-3.92 (br m, 1H), 3.62-3.73 (br m, 1H), 3.56 (dd, J=10.2, 3.5 Hz, 1H), 3.34-3.41 (m, 1H), 2.26-2.43 (br m, 1H, 2.00-2.17 (br m, 1H), 1.65 (ddd, J=14.1, 4.5, 2.5 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][CH:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:21][S:22][C:23]1[C:28]([N:29]=[C:30]=[O:31])=[C:27]([S:32][CH3:33])[CH:26]=[C:25]([CH3:34])[N:24]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:21][S:22][C:23]1[C:28]([NH:29][C:30]([N:9]([CH:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)[CH2:8][C:7]2[CH:19]=[CH:20][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[O:31])=[C:27]([S:32][CH3:33])[CH:26]=[C:25]([CH3:34])[N:24]=1
Reactant: CSc1cc(C)nc(SC)c1N=C=O
Reactant: CC(C)c1ccc(CNC2Cc3ccccc3C2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1cc(C)nc(SC)c1NC(=O)N(Cc1ccc(C(C)C)cc1)C1Cc2ccccc2C1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A solution of 2-(4-isopropylbenzylamino)indane (159 mg, 0.6 mmol) and 2,4-bis(methylthio)-6-methylpyridin-3-yl isocyanate (136 mg, 0.6 mmol) in 3 ml dimethylformamide was heated at 80° C. under nitrogen overnight. The reaction mixture was cooled to room temperature, diluted with 50 ml ethyl acetate and washed with 3×50 ml water, then 50 ml brine, dried (sodium sulfate), filtered and concentrated in vacuo. The solid residue (265 mg) was purified by column chromatography on silica gel (150 g), eluting with 7:3 hexane/ethyl acetate to yield the title compound as a white solid (195 mg, 66% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:19][C@H:20]([C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH:21]([CH3:23])[CH3:22].C(N[C@H](C(O)=O)C(C)C)(OC(C)(C)C)=O.N1CCOCC1>C(Cl)(Cl)Cl.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:19][C@H:20]([C:24]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[O:25])[CH:21]([CH3:22])[CH3:23])=[O:18])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)[C@H](N)C(=O)N1CCOCC1
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1COCCN1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)N1CCOCC1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example DlI above) and 4-(L-valinyl)morpholine (prepared from N-BOC-L-valine (Aldrich) and morpholine (Aldrich) using General Procedure M, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.5 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 98:2 CHCl3/MeOH as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CC(C)=O.CCOCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:31][CH2:30][CH2:29][CH2:28][Br:27])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(Cl)cc1)N1CCc2cc(O)ccc21
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: O=C(Oc1ccc(Cl)cc1)N1CCc2cc(OCCCCBr)ccc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 49.4 %

Procedure:
290 mg (1 mmol) 5-Hydroxy-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester in 5 ml acetone were treated with 320 mg (3 mmol) K2CO3 (powdered) and 0.23 ml (2 mmol) 1,4-dibromobutane. The suspension was stirred at 50° C. for 4 h, cooled to RT, and was diluted with ether and water. The aqueous phase was extracted with ether, the organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with hexane/EtOAc 9:1 yielded 210 mg (49%) 5-(4-Bromo-butoxy)-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester as colorless solid, MS: 423 (M, 1Br, 1Cl).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].Br[CH2:7][CH2:8][CH2:9][CH:10](Br)[CH3:11].C([O-])([O-])=O.[Na+].[Na+]>CCO>[CH3:7][C@H:8]1[CH2:9][CH2:10][CH2:11][N:1]1[C@@H:2]([CH3:5])[CH2:3][OH:4]
Reactant: C[C@H](N)CO
Reactant: CC(Br)CCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](CO)N1CCC[C@@H]1C
Temperature: 100 °C
Yield: 8.8 %

Procedure:
A mixture of (S)-2-aminopropan-1-ol (12.5 g, 0.166 mol), 1,4-dibromopentane (42 g, 0.18 mol) and Na2CO3 (53 g, 0.51 mol) in EtOH (800 mL) was heated at 100° C. for 24 h. The mixture was filtered, and the filter cake was washed with EtOH (50 mL). The combined filtrate was concentrated under reduced pressure, and the crude product was purified on a silica gel column (NH4OH/MeOH/DCM=1/6/300) to give (S)-2-((S)-2-methylpyrrolidin-1-yl)propan-1-ol (2.1 g) as a colorless oil and a crude mixture containing (S)-2-((R)-2-methylpyrrolidin-1-yl)propan-1-ol. 1H NMR (DMSO-d6): δ 4.22 (br s, 1H), 3.36 (dd, 1H), 3.22 (dd, 1H), 2.82 (m, 1H), 2.65 (m, 2H), 2.42 (q, 1H), 1.78 (m, 1H), 1.60 (m, 2H), 1.25 (m, 1H), 0.95 (d, 3H), 0.84 (d, 3H); LCMS: 144 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:5][CH2:6][C:7]1[C:11]([C:12](OC)=[O:13])=[C:10]([CH:16]([CH3:18])[CH3:17])[O:9][N:8]=1)([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1.C(OCC)(=O)C>[CH3:4][C:2]([O:5][CH2:6][C:7]1[C:11]([CH2:12][OH:13])=[C:10]([CH:16]([CH3:18])[CH3:17])[O:9][N:8]=1)([CH3:1])[CH3:3]
Reactant: COC(=O)c1c(COC(C)(C)C)noc1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1onc(COC(C)(C)C)c1CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.4 %

Procedure:
To a solution of methyl 3-{[(1,1-dimethylethyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolecarboxylate (21.5 g, 84.2 mmol) in tetrahydrofuran (250 mL) at 0° C. was added a 1.5 M solution of diisobutylaluminum hydride in toluene (185 mL, 278 mmol) slowly. The solution was allowed to warm slowly to ambient temperature overnight then was re-cooled to 0° C. and approximately 250 mL of Rochelle's salt was added dropwise followed by approximately 300 mL of ethyl acetate. An additional 250 mL of Rochelle's salt and 500 mL of ethyl acetate were added and the mixture was stirred at 0° C. for approximately 20 minutes and then at ambient temperature for approximately 4 hours. The mixture was filtered. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated, and purified by chromatography (silica gel, 20% ethyl acetate in hexanes) to afford [3-{[(1,1-dimethylethyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methanol (15.2 g, 91%). 1H-NMR (400 MHz, DMSO-d6) δ 4.76 (t, J=5 Hz, 1H), 4.39 (s, 2H), 4.32 (d, J=5 Hz, 2H), 3.24 (septet, J=7 Hz, 1H), 1.21 (d, J=7 Hz, 6H), 1.18 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:15][C:16]2[CH:17]=[C:18]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35]C)[CH:31]=2)[C:19]([NH:21][C:22]2[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=2)=[O:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH2:8][S:7](=[O:13])(=[O:12])[C:6]=2[CH:14]=1.C[Si](I)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[F:1][C:2]1[C:3]([O:15][C:16]2[CH:17]=[C:18]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][OH:35])[CH:31]=2)[C:19]([NH:21][C:22]2[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=2)=[O:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH2:8][S:7](=[O:13])(=[O:12])[C:6]=2[CH:14]=1
Reactant: COC[C@H](C)Oc1cc(Oc2cc3c(cc2F)S(=O)(=O)CCCO3)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3cc4c(cc3F)S(=O)(=O)CCCO4)cc(O[C@@H](C)CO)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.3 %

Procedure:
A solution of 3-[(7-fluoro-5,5-dioxido-3,4-dihydro-2H-1,5-benzoxathiepin-8-yl)oxy]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (100 mg, 0.19 mmol) in acetonitrile (3 mL) was treated with trimethylsilyl iodide (0.138 mL) and stirred at RT under argon for 16 hours. Sodium thiosulphate solution (30 mL) was added and the mixture extracted with ethyl acetate (6×30 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated to give a yellow oil. The oil was chromatographed on alumina, eluting with 0-50% methanol in DCM, to give the desired compound as an orange solid (19 mg). 1H NMR δ (CDCl3): 1.25 (d, 3H), 2.35-2.42 (m, 2H), 2.52 (s, 3H), 3.32-3.41 (m, 2H), 3.46-3.71 (m, 2H), 3.75 (d, 1H), 4.19-4.22 (m, 2H), 4.53-4.57 (m, 1H), 6.78 (d, 1H), 6.80 (t, 1H), 7.18 (s, 1H), 7.35 (s, 1H), 7.80 (d, 1H), 8.18 (s, 1H), 8.37 (s, 1H), 9.50 (s, 1H); m/z 518 (M+H)+, 516 (M−H)−
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[N:30]1C=CC=CC=1.N>C(#N)C>[NH2:30][C:10](=[O:11])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:14])[CH3:13]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: N
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(C)(C)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (CAN: 30992-29-1, 20 g, 98 mmol), di-tert-butyl dicarbonate (CAN 24424-99-5, 27.67 g, 147 mmol) and pyridine (4.6 mL) in acetonitrile (500 mL) was stirred at room temperature for 20 min. Ammonia (10 mL) was added dropwise for 20 min. The resulting reaction mixture was stirred for 4 h. After removal of most of the solvent under reduced pressure, the solid was filtered off and washed with acetonitrile. The solid was brought to dryness under reduced pressure to give the title compound (17.5 g, 88%) as white solid; MS (EI): m/e 225.1 [M+Na]+.
Reaction SMILES: [N+:1]([CH:4]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH2:8][CH:7]=[CH:6][CH2:5]1)([O-:3])=[O:2].[H][H]>C(OCC)(=O)C.[Pd]>[N+:1]([CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)([O-:3])=[O:2]
Reactant: COc1ccc(C2CC=CCC2[N+](=O)[O-])cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCCCC2[N+](=O)[O-])cc1OC
Yield: 91 %

Procedure:
To 10 mmol of 4-nitro-5-(3,4-dimethoxyphenyl)cyclohexene in 100 mL of ethyl acetate was added 200 mg of 10% palladium on carbon. The resulting suspension was shaken at 50 psi of hydrogen on a Parr Apparatus for one hour. The catalyst was removed by filtration through Celite® diatomaceous earth and the filtrate evaporated to dryness in vacuo to give a 91% yield of the desired product based on 1H NMR.
Reaction SMILES: Cl[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[CH:3]=1.[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1>ClCCl.[Cl-].[Cl-].[Zn+2]>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:18][C:2]2[CH:8]3[CH2:9][CH:5]([CH2:6][CH2:7]3)[C:4](=[O:10])[CH:3]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: O=C1C=C(Cl)C2CCC1C2
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(OC1=CC(=O)C2CCC1C2)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A mixture of 500 mg of 4-chlorobicyclo[3.2.1]oct-3-en-2-one (Preparation Example P2), 440 mg of ZnCl2, 400 mg of 4-chlorobenzoic acid, 1.05 g of diisopropylethylamine and 5 ml of toluene is stirred at room temperature under a nitrogen atmosphere at reflux temperature for 6 hours. After cooling, the reaction mixture is then diluted with dichloromethane and washed with 5% aqueous sulfuric acid and 5% aqueous sodium hydroxide. After concentration of the organic phase to dryness by evaporation, 0.6 g of 4-(4-chlorophenyl-carbonyloxy)-bicyclo[3.2.1]oct-3-en-2-one is obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([N:23]([CH:30]([CH3:32])[CH3:31])[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=S)=[O:22])=[CH:3]1.CN(C=[O:37])C>>[O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([N:23]([CH:30]([CH3:32])[CH3:31])[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:37])=[O:22])=[CH:3]1
Reactant: CC(C)NC(=S)N(C(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Reactant: CN(C)C=O
Product: CC(C)NC(=O)N(C(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C

Procedure:
1-[3-oxo-androst-4-ene-17β-carbonyl]-1,3-diisopropylthiourea m.p. 180°-183° C., [α]D +146° (C=1, DMF).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:21]O>>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([O:6][CH3:21])=[O:5]
Reactant: COc1cc(C(=O)O)c(Cl)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1Cl
Yield: 71 %

Procedure:
A solution of 2-chloro-5-methoxy-4-nitrobenzoic acid (1 mmol) and concentrated sulfuric acid (0.02 mmol) in methanol (200 mL) was heated to reflux for 42 hours. The solvents were evaporated under reduced pressure then the residue partitioned between EtOAc (25 mL) and water (25 mL). The separated aqueous phase was extracted with EtOAc (3×25 mL), then the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound (71%) as a solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].C([Li])CCC.[Cl:20]N1C(=O)CCC1=O.O>C1COCC1>[Cl:20][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc2c(cc1Br)C(C)(C)CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1Cl)C(C)(C)CC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-5-methoxy-1,1-dimethyl-indan (2.00 g, 7.84 mmol) in THF (30 mL) at −78° C. was slowly added n-butyllithium (4.0 mL, 2.5 M in hexane). The resulting solution was stirred at −78° C. for 0.5 h and a solution of N-chlorosuccinimide (1.26 g, 9.40 mmol) in THF (30 mL) was added. After an additional 2 h at −78° C., the reaction was warmed to room temperature, poured into water (50 mL) and extracted with ethyl acetate (2×70 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (2% ethyl acetate/heptane) afforded the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C@H:26]([C:32]#[C:33][CH3:34])[CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=2)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH:15]([O:19][C:20]2[CH:21]=[CH:22][C:23]([C@H:26]([C:32]#[C:33][CH3:34])[CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:25]=2)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC#C[C@H](CC(=O)OC)c1ccc(OC2CCc3cc(-c4cccc(OCC)c4)ccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#C[C@H](CC(=O)O)c1ccc(OC2CCc3cc(-c4cccc(OCC)c4)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 59.3 in THF/MeOH (1:1, 2 mL), was treated with 2N NaOH aqueous solution (1 mL) and stirred for overnight at room temperature. The reaction mixture was acidified with aqueous 4N HCl and extracted with EtOAc to obtain 59, which was purified by preparative HPLC, eluting with 5˜95% ACN in water containing 0.1% TFA. MS ESI (neg.) m/e: 439.1 (M−H). 1HNMR (MeOD-d4) δ 7.65 (br, 1H), 7.48 (s, 1H), 7.38 (d, 1H, J=7.02 Hz), 7.32 (t, 1H, J=7.12 Hz), 7.18 (d, 1H, J=6.57 Hz), 7.14 (s, 1H), 7.06 (m, 2H), 6.99-6.86 (m, 2H), 6.78 (m, 1H), 4.79 (m, 1H), 4.12 (q, 2H, J=6.50 Hz), 3.86 (m, 1H), 3.15-3.01 (m, 2H), 2.54-2.42 (m, 2H), 2.03 (m, 1H), 1.74 (ss, 3H), 1.42 (t, 3H, J=6.74 Hz).