Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:9][C@H:10]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([CH2:23][O:24]CC2C=CC=CC=2)[O:12][C@H:11]1[N:32]1[CH:40]=[N:39][C:38]2[C:33]1=[N:34][C:35]([F:42])=[N:36][C:37]=2[NH2:41])C1C=CC=CC=1>[H][H].[Pd](Cl)Cl>[C@@H:11]1([N:32]2[CH:40]=[N:39][C:38]3[C:33]2=[N:34][C:35]([F:42])=[N:36][C:37]=3[NH2:41])[O:12][C@H:13]([CH2:23][OH:24])[C@@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: [H][H]
Agent: Cl[Pd]Cl
Agent: Cl
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
reacting a mixture of 2-fluoro-9-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)adenine (VI) dissolved in a non-reactive solvent for (VI), with hydrogen and a molar amount of palladium chloride less than (VI) and concentrated hydrochloric acid in a molar excess to (VI) such that the weight of palladium chloride is between about 3 and 15% by weight of (VI) in a sealed vessel at elevated pressure above atmospheric pressure between about 30 and 50 psig to produce (VII) in the reaction mixture;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH:17]([CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](OCC2C=CC=CC=2)=O)[CH2:20]1)=O.C1([SiH3])C=CC=CC=1>C1COCC1.CCOC(C)=O.C([Sn](Cl)(Cl)CCCC)CCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH2:17][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]1)=[O:4]
Reactant: O=CC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)cc1NCC1CCCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.7 %

Procedure:
A suspension of 3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.268 g, 1.15 mmol) and 3-formyl N-Cbz-piperidine (0.284 g, 1.15 mmol) in THF (0.5 mL) was treated with dibutyltin dichloride (17 mg, 0.057 mmol). After 5 min, phenylsilane (156 □L, 1.26 mmol) was added and the mixture was stirred for 6 days at room temperature. The solvent was then evaporated and the residue was purified by silica gel column chromatography using CH2Cl2:hexanes:EtOAc as eluent to provide 3-[(1-Methyl-piperidin-3-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester as an oil (0.2723 g, 51% yield). 1H NMR (CDCl3, 400 MHz): 7.63-7.59 (m, 2H), 7.40-7.28 (m, 9H), 7.18-6.84 (br s, 1H), 5.20 (d, 1H), 5.10 (d, 1H), 4.55 (m, 1H), 4.15 (m, 1H), 3.82 (s, 3H), 3.58-3.40 (m, 2H), 2.90 (t, 1H), 1.88-1.40 (m, 6H).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[CH2:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:20]([O:22][CH3:23])=[O:21])[CH2:24][O:9]2)=[CH:17][CH:18]=1
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(c2ccc(Cl)cc2)CO1
Temperature: 25 °C

Procedure:
MCPBA (35 g, 77%, 156 mmol) was added to a solution of methyl 2-(4-chlorophenyl)-acrylate (20 g, 102 mmol) in CHCl3 (200 mL). The mixture was refluxed for 24 hours. The reaction was cooled to room temperature, diluted with chloroform (200 mL) and washed with 10% Na2S2O3, 10% NaHCO3 and water. The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (9:1) to give methyl 2-(4-chlorophenyl)oxirane-2-carboxylate. Methyl 2-(4-chlorophenyl)oxirane-2-carboxylate (2 g, 9.4 mmol) and ethanol (10 mL) and isopropylamine (1 mL, 11.7 mmol) were added to a 50 mL high pressure bomb. The mixture was heated to 90° C. for 12 hours in the bomb. After cooling, the solvent was removed, and the residue was dissolved in DCM (20 mL) and TEA (2 mL). (Boc)2O (4 g, 23.0 mmol) was added to it. The mixture was stirred at room temperature for 48 hours. The solvent was removed, and the residue was dissolved in THF (20 mL). LiOH (3M, 14 mL) was added to the mixture. The mixture was stirred at room temperature for 16 hours and refluxed for 2 hours. After cooling, the mixture was quenched with 2N HCl (21 mL). The solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (1:1) to give 3-(tert-butoxycarbonykisopropyl)amino)-2-(4-chlorophenyl)-2-hydroxypropanoic acid. LCMS (APCI+) [M−Boc+H]+ 258.1; Rf: 3.66 min.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:9][C:10]1([CH2:13][O:14][Si](C(C)(C)C)(C)C)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.F[Si-2](F)(F)(F)(F)F.[H+].[H+]>O>[CH2:1]([N:8]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:9][C:10]1([CH2:13][OH:14])[CH2:11][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CN(Cc1ccccc1)CC1(CO[Si](C)(C)C(C)(C)C)CC1
Agent: [H+]
Solvent: O
Solvent: CC#N
Product: COC(=O)CN(Cc1ccccc1)CC1(CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a stirred solution of methyl (benzyl{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopropyl]methyl}amino)acetate (4.0 g, 0.010 mol) in ACN (100 mL, 2 mol) was added at RT, fluorosilicic acid in water (2.00 M, 10.6 mL). The resulting mixture was stirred at RT overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3 until the reaction mixture was alkaline and then extracted with EtOAc (2×). The organic extracts were combined and washed with brine, then dried (MgSO4), filtered and concentrated in vacuo to afford the desired product (1.1 g), which was identified by 1H NMR spectroscopy and used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:64]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[S:73](Cl)(=[O:75])=[O:74])([O-:66])=[O:65]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][S:73]([C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][C:67]=3[N+:64]([O-:66])=[O:65])(=[O:74])=[O:75])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg, Example 38) in dry methylene chloride (20 ml) was added diisopropylethylamine (150 μl) followed by 2-nitrobenzenesulonyl chloride (60 mg), then 4-dimethylaminopyridine (27 mg). The yellow solution was stirred at room temperature under nitrogen atmosphere for 4 h, then quenched with sat'd aqueous sodium bicarbonate solution. The organic layer was washed (water, sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4) and the solvent was removed in vacuo. Chromatography on silica gel (2:1 ethyl acetate/hexane) gave 70 mg of the title compound A and 60 mg of the title compound B (Mass, 1H and 13C NMR data were consistent with the structures).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8]O.P(Br)(Br)[Br:16].O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:16]
Reactant: BrP(Br)Br
Reactant: OCCCCOc1cc(Br)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: BrCCCCOc1cc(Br)ccc1Br
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
To a solution of 12.63 g (39 mmol) of 4-(2,5-dibromophenoxy)butan-1-ol in 83 mL of toluene was added 1.65 mL (17.6 mmol, 0.45 equiv) of phosphorous tribromide. The solution was stirred under nitrogen at 90° C. for 2.5 hours. Additional phosphorous tribromide (0.37 mL, 3.9 mmol, 0.10 equiv) and 0.21 ml (11.5 mmol, 0.3 equiv) of water were added, and the mixture was stirred under nitrogen at 90° C. for 8 hours. The mixture was allowed to cool to ambient temperature, 69 mL of 1N NaOH was added dropwise over 30 minutes, and the layers were separated. The aqueous layer was extracted with 25 mL of toluene. The combined organic layer was washed with 25 mL each of water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the product as a cloudy yellow oil suitable for the next step. MS (m+1)=386.1, 385.1, 381.0; 1H NMR (400 MHz, CDCl3) 7.38 (d, 1H, J 8 Hz), 6.98 (m, 2H), 4.05 (t, 2H, J 6 Hz), 3.53 (t, 2H, J 6 Hz), 2.12 (m, 2H), 2.03 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([N:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: C1CSCCN1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCSCC1
Yield: 28 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.1 equivalents of thiomorpholine as secondary amine. The product was purified by preparative TLC (eluent DCM/MeOH 8:2).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[C:3]=1[N+:18]([O-:20])=[O:19].[CH2:21]([N:23]([CH:26](OC)OC)[CH2:24][CH3:25])[CH3:22]>C(N(CC)C=O)C>[CH2:21]([N:23]([CH2:24][CH3:25])[CH:26]=[CH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[C:3]=1[N+:18]([O-:20])=[O:19])[CH3:22]
Reactant: CCN(CC)C(OC)OC
Reactant: Cc1ccc2c(c1[N+](=O)[O-])C(=O)c1ccccc1C2=O
Agent: CCN(C=O)CC
Product: CCN(C=Cc1ccc2c(c1[N+](=O)[O-])C(=O)c1ccccc1C2=O)CC

Procedure:
42.0 g (0.16 mol) of 2-methyl-1-nitroanthraquinone (0.16 mol) and 46.2 g (0.32 mol) of diethylaminodimethoxymethane (0.32 mol) in 150 g of diethylformamide are refluxed for 7 hours. After all the volatiles have been distilled off, the residue is slurried in water and filtered with suction, and the filter residue is dried under reduced pressure. This gives 49.6 g (90.0%) of 2-(2'-diethylaminoethenyl)-1-nitroanthraquinone; melting point: 235°-241° C. (with decomposition).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH3:25][N:26]([CH3:28])[NH2:27]>>[CH3:25][N:26]([CH3:28])[NH:27][C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)nn1C
Reactant: CN(C)N
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NN(C)C)n(C)n1
Yield: 100 %

Procedure:
As described for example 43, 2-methyl-5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (120 mg, 0.37 mmol) was converted using N,N-dimethylhydrazine instead of rac-3-aminotetrahydrofuran, to the title compound (130 mg, 100%) which was obtained as a colorless oil. MS: m/e=356.2 [M+H]+.
Reaction SMILES: CO[C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[OH:11].[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[OH:11])[C:3]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COC(=O)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 55.1 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-propionic acid methyl ester (262.2 mg, 0.82 mmol) and 2-aminothiazole (165 mg, 1.65 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. % , 2.60 mL, 1.81 mmol) was heated to 100° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and filtered through a pad of celite (ethyl acetate as eluent). The filtrate was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 ethyl acetate/hexanes) afforded the 2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-N-thiazol-2-yl-propionamide (174 mg, 54.6%) as a white solid: mp 86-88° C.; EI-HRMS m/e calcd for C17H18Cl2N2O2S (M+Na)+ 407.0358. found 407.0361.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)C(O)(C)C)(=O)C.[CH3:14][CH:15]([OH:18])[C:16]#[CH:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH3:14][CH:15]([O:18][C:4]1[CH:5]=[CH:6][CH:11]=[CH:12][CH:13]=1)[C:16]#[CH:17]
Reactant: C#CC(C)O
Reactant: CC(=O)c1cccc(C(C)(C)O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C#CC(C)Oc1ccccc1
Reaction time: 0.17 h

Procedure:
Phenol 27 (422.9 mg, 4.49 mmol), But-3-yn-2-ol (300 mg, 4.28 mmol) were dissolved in anhydrous THF (10 mL) under N2 atmosphere, at 0° C. was added Ph3P (1.12 g, 4.26 mmol) portion wise, stirred it for 10 min, and then DEAD (894.6 mg, 5.14 mmol) added slowly. The resultant solution was heated up to 70° C. stirred for 20 h. To the reaction mixture water added and extracted with DCM and dried organic layer on MgSO4, filtered, concentrated. Purified by flash chromatography using ethylacetate/n-hexane, 5:95) provided compound 28 (450 mg, 69%) as a solid. 1H NMR (CDCl3, 400 MHz) δ 1.67 (d, J=6.8 Hz, 3H), 2.47 (d, J=2 Hz, 1H), 4.88 (q, J=2 Hz, 1H), 6.97-7.03 (m, 3H), 7.28-7.32 (m, 2H).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:14])[CH:11](Br)[CH3:12])[CH:8]=[CH:9][C:2]1=2.C(O)C.[C:18]1([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:14])[CH:11]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:12])[CH:8]=[CH:9][C:2]1=2
Reactant: NCCCCc1ccccc1
Reactant: CC(Br)C(O)c1ccc2c(c1)CCS2
Solvent: CCO
Solvent: CCOCC
Product: CC(NCCCCc1ccccc1)C(O)c1ccc2c(c1)CCS2

Procedure:
4 gr of 1-(2,3-dihydro-5-benzo[b]thienyl-2-bromo-1-propanol, 100 ml of ethanol and 20 gr of 4-phenylbutylamine are refluxed for 5 hours. The solvent and excess amine are evaporated in vacuo and the residue obtained is treated with ether. The solid is recrystallized from a mixture of methanol and ether, and the corresponding free base is obtained by treatment with a diluted NaOH solution and recrystallized from acetone. 1.05 gr of final product are so obtained.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:42]=[CH:41][C:27]([C:28]([N:30]2[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]([O:38]CC)=[O:37])[CH2:31]2)=[O:29])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22].C(O)C.[OH-].[Na+].Cl>O1CCCC1>[F:44][C:2]([F:1])([F:43])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:30]2[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]([OH:38])=[O:37])[CH2:31]2)=[O:29])=[CH:41][CH:42]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ccc(C(F)(F)F)cn4)cc3C)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(-c2ccc(C(F)(F)F)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a reaction mixture of ethyl (3R)-1-(4-((4,4,4-trifluoro-1-(2-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)phenyl)butyl)amino)benzoyl)piperidine-3-carboxylate (0.100 g), ethanol (0.7 mL) and tetrahydrofuran (0.7 mL) was added 1M aqueous sodium hydroxide solution (0.322 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.055 g).
Reaction SMILES: N#N.[CH:3]1[C:20]2[CH:19]=[CH:18][C:17]3[C:8](=[CH:9][CH:10]=[C:11]4[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[Sn](Cl)(Cl)Cl.ClC[CH:28]([O:31]C(CCl)CCl)CCl>O.ClC1C=CC=CC=1Cl>[CH:3]1[C:20]2[CH:19]=[CH:18][C:17]3[C:8](=[CH:9][C:10]([CH:28]=[O:31])=[C:11]4[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: ClCC(CCl)OC(CCl)CCl
Reactant: c1ccc2c(c1)ccc1c3ccccc3ccc21
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N#N
Solvent: O
Solvent: Clc1ccccc1Cl
Product: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Reaction time: 4 h

Procedure:
A 5 L 3-neck flask fitted with overhead mechanical stirrer, thermometer, condenser and N2 line was charged with chrysene (Eastman Kodak Co., Rochester, NY., 14650, 100 g, 0.438 mol) and o-dichlorobenzene (2.5 L). The liquid was warmed until all the large chunks of solid dissolved (80°) and then cooled quickly to give finely divided crystals. After further cooling with a salt-ice bath to 5°, SnCl4 (Aldrich Chemical Co., Milwaukee, WI, 53201, 98%, 228.2 g, 0.876 mol, 102.4 mL) was added in one portion. No temperature change occurred. The reaction mixture was kept below 5°, and 1,1-dichloromethylmethylether (Aldrich, 70.48 g, 0.613 mol, 55.45 mL) was added dropwise over 1 h. The resulting suspension was warmed slowly to 40°. The reaction mixture was then cooled to 10° and hydrolysed by careful addition of 1 L of cold H2O. After 4 h, the layers were separated and the organic layer filtered, dried with anhydrous Na2SO4 (Mallinckrodt Co., St. Louis, MO, 63147, 100 g) and filtered again. The clear yellow solution was split into 2 portions and each passed through a 500 g plug of SiO2 using PhCH3 as the eluting solvent with 500 mL fractions. This chromatography separated unreacted chrysene (3 g) from the aldehyde and a nore polar product. Fractions containing the aldehyde were combined and the PhCH3 removed. Crystals formed during this process and were removed periodically by filtration. After drying (at 60°) the yield of 6-chrysenecarbaldehyde was 89.46 g (79.7%) mp 167°-169°, (C,H), (lit. 168°, N. P. Buu Hoi, J.-P. Hoffinger, and P. Jacquignon, Bull. Soc. Chim. Fr. 3808 (1968)).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[I-].[K+].Br[CH2:16][C:17]1[CH2:18][O:19][C:20]2[C:25]([CH:26]=1)=[C:24]1[O:27][CH2:28][CH2:29][O:30][C:23]1=[CH:22][CH:21]=2>CN(C)C=O.O>[O:27]1[C:24]2=[C:25]3[C:20](=[CH:21][CH:22]=[C:23]2[O:30][CH2:29][CH2:28]1)[O:19][CH2:18][C:17]([CH2:16][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])=[CH:26]3
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCC1=Cc2c(ccc3c2OCCO3)OC1
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1=Cc2c(ccc3c2OCCO3)OC1
Reaction time: 10 h

Procedure:
2.36 g (12.75 mmol) of potassium phthalimide and also 0.166 g (1 mmol) of potassium iodide are added to a solution of 2.54 g (8.5 mmol) of the brominated compound obtained in Step E in 20 ml of anhydrous N,N-dimethylformamide; the medium is then stirred under argon for 10 hours. The solvent is evaporated in vacuo; the residue obtained is then taken up in water and extracted with dichloromethane. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. Chromatography on a silica column (eluant:ethyl acetate/petroleum ether 10/90) yields the title phthalimide in the form of a white solid.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([CH3:24])[N:14]=2)=[CH:8][C:7]=1[CH3:25])(O)=[O:2].C(N(CC)CC)C.ClC(OC(C)=C)=O.[Si]([O:47][NH2:48])(C(C)(C)C)(C)C>ClCCl>[OH:47][NH:48][C:1]([CH2:4][O:5][C:6]1[C:7]([CH3:25])=[CH:8][C:9]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([CH3:24])[N:14]=2)=[CH:10][C:11]=1[CH3:12])=[O:2]
Reactant: Cc1cc(-c2nn(C)c(=O)c3ccccc23)cc(C)c1OCC(=O)O
Reactant: CC(C)(C)[Si](C)(C)ON
Agent: C=C(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nn(C)c(=O)c3ccccc23)cc(C)c1OCC(=O)NO
Reaction time: 1 h
Yield: 8.3 %

Procedure:
A solution of example 108 (1.15 g) in dichloromethane (30 ml) at 0° C. was treated with triethylamine (0.52 g) followed by isopropenyl chloroformate (0.41 g), and the mixture was stirred for 1 h. O-tert-butyldimethylsilylhydroxylamine (0.50 g) was then added and the mixture was stirred for a further 18 h. The reaction mixture was washed with 10% citric acid (20 ml), saturated sodium bicarbonate (20 ml) and the concentrated to dryness in vacuo. A solution of the residual solid in tetrahydrofuran (30 ml) and water (5 ml) was then treated with a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1 ml) and stirred 1 h. the resultant crude mixture was concentrated on to silica and purified by chromatography, eluting with 5% methanol in dichloromethane, to provide the title compound as a white solid (0.10 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]>C1COCC1>[CH3:5][CH:4]([CH3:6])[CH2:3][CH2:2][NH:1][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)CCN
Solvent: C1CCOC1
Product: CC(C)CCNc1ccccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 59.8 %

Procedure:
A solution of 1-amino-3-methylbutane (1.5 g) in THF (20 ml) was dropped into a solution of 2-fluoronitrobenzene (2.4 g) in THF (20 ml), at 23° under a nitrogen atmosphere. The mixture was stirred at 23° for 3 h, then heated at reflux for 1.5 h. The mixture was allowed to cool to 23°, then concentrated under vacuum to give a crude compound which was purified by flash chromatography (eluting with CH-EA 9:1) to give the title compound as a yellow oil (2.12 g). T.l.c. CH-EA (4:1) Rf=0.79.