Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:15]=[C:16]([CH:33]=[CH:34][C:35]2[CH:96]=[CH:95][C:38]3[C:39]4[C:48]([C:49]5[CH:54]=[CH:53][C:52]([CH:55]=[CH:56][C:57]6[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])=[C:59]([O:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])[CH:58]=6)=[CH:51][C:50]=5[C:37]=3[CH:36]=2)=[N:47][C:46]2[C:41](=[CH:42][C:43]([N+:92]([O-])=O)=[C:44]([N+:89]([O-])=O)[CH:45]=2)[N:40]=4)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.O.Cl[Sn]Cl>O=O>[CH2:1]([O:13][C:14]1[CH:15]=[C:16]([CH:33]=[CH:34][C:35]2[CH:96]=[CH:95][C:38]3[C:39]4[C:48]([C:49]5[CH:54]=[CH:53][C:52]([CH:55]=[CH:56][C:57]6[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])=[C:59]([O:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])[CH:58]=6)=[CH:51][C:50]=5[C:37]=3[CH:36]=2)=[N:47][C:46]2[C:41](=[CH:42][C:43]([NH2:92])=[C:44]([NH2:89])[CH:45]=2)[N:40]=4)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C=Cc2ccc3c(c2)c2cc(C=Cc4ccc(OCCCCCCCCCCCC)c(OCCCCCCCCCCCC)c4)ccc2c2nc4cc([N+](=O)[O-])c([N+](=O)[O-])cc4nc32)cc1OCCCCCCCCCCCC
Agent: Cl[Sn]Cl
Agent: O=O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(C=Cc2ccc3c(c2)c2cc(C=Cc4ccc(OCCCCCCCCCCCC)c(OCCCCCCCCCCCC)c4)ccc2c2nc4cc(N)c(N)cc4nc32)cc1OCCCCCCCCCCCC
Temperature: 70 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
This compound was synthesized according to a modified literature procedure.52 A Schlenk tube was charged with 3,6-Bis-[2-(3,4-bis-dodecyloxy-phenyl)-vinyl]-11,12-dinitro-dibenzo[a,c]-phenazine BRK_III—63A (564 mg, 0.43 mmol) and (970 mg, 4.30 mmol) of SnCl2.2H2O and was subjected to vacuum. Under N2, 30 ml of O2-free ethanol was transferred to the reaction mixture, which was heated at 70° C. The color of the reaction mixture did not change after one hour and TLC did not show the conversion of the starting material. Additional 50 ml of O2-free ethanol was added and the mixture was refluxed for 23 hours. The reaction was allowed to cool down to room temperature and was then dropped over ice. The solution was extracted with 3×150 ml of ether. The ether extracts were combined and were dried over MgSO4 and was filtered. The solvent (solution is blue fluorescent) was evaporated under vacuum to yield 122 mg (23% yield) of brown solid. HRMS-MALDI-TOF (M+H): m/z 1251.9535; calcd for C84H123N4O4, 1251.9539.
Reaction SMILES: [CH:1]([C:4]([CH2:7][OH:8])([F:6])[F:5])([F:3])[F:2].N1C=CC=CC=1.[CH2:15]([S:17](Cl)(=[O:19])=[O:18])[CH3:16].Cl.N1C=CC=CC=1>>[CH:1]([C:4]([CH2:7][O:8][S:17]([CH2:15][CH3:16])(=[O:19])=[O:18])([F:6])[F:5])([F:3])[F:2]
Reactant: CCS(=O)(=O)Cl
Reactant: OCC(F)(F)C(F)F
Agent: Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)OCC(F)(F)C(F)F

Procedure:
A 10-L four-neck flask was equipped with a refluxing pipe and a dropping funnel to serve as a reactor. To the flask were added HCF2CF2CH2OH (445.35 g; 3.37 mol) and pyridine (306.31 g; 3.88 mol) in an ice bath, and the mixture was stirred. Using the dropping funnel, ethanesulfonyl chloride (411.4 g; 3.20 mol) was dropped, with care for heat generation. The reaction solution changed its color gradually to milky white as pyridine hydrochloride was produced. After the end of the reaction, the reaction solution was washed with a 1 N HCl aqueous solution. The washed solution was separated to collect an organic layer.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:42]3[N:41]=[CH:40][N:39]=[C:29]([NH:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:43][CH2:44][CH:45]([OH:48])CO)[C@@H:21]1[OH:49])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:42]3[N:41]=[CH:40][N:39]=[C:29]([NH:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:43][CH2:44][CH:45]=[O:48])[C@@H:21]1[OH:49])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OCC(O)CO)[C@@H]1O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OCC=O)[C@@H]1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.2 %

Procedure:
Compound 112 (5.59 g, 8.17 mmol) was dissolved in dry CH2Cl2 (40.42 mL). To this NaIO4 adsorbed on silica gel (Ref. J. Org. Chem. 1997, 62, 2622-2624) (16.34 g, 2 g/mmol) was added and stirred at ambient temperature for 30 minutes. Reaction monitored by TLC (5% MeOH in CH2Cl2). Reaction mixture was filtered and the filtrate washed thoroughly with CH2Cl2. Dichloromethane layer evaporated to get the aldehyde 113 (5.60 g) that was used in the next step without purification. Rf 0.3 (5% MeOH in CH2Cl2)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:28])[C:8]1=[O:29])=[O:5])[CH3:2].[Cl-].[CH2:31]([O:38][NH3+:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])(=O)C.[Na+]>CCO.O>[CH2:31]([O:38][N:39]=[CH:22][C:19]1[CH:20]=[CH:21][N:17]([C:14]2[CH:15]=[C:16]3[C:11]([NH:10][C:9](=[O:28])[C:8](=[O:29])[N:7]3[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][C:13]=2[C:24]([F:26])([F:27])[F:25])[CH:18]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: [NH3+]OCc1ccccc1
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=O)c3)cc21
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=NOCc4ccccc4)c3)cc21
Yield: 82.8 %

Procedure:
1.1 g (2.7 mmol) of the compound of Example 70, 0.86 g (5.4 mmol) of O-benzylhydroxylammonium chloride and 0.44 g (5.4 mmol) of sodium acetate in 4.5 ml of EtOH/H2O (1:2) were refluxed for 30 minutes. The ethanol was then removed under reduced pressure, and the precipitate was filtered off with suction and recrystallized from ethanol to yield 1.15 g (84%) of the product. The 1H-NMR shows that an E/Z mixture is present. Melting point 142°-147° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH2:27][C:28]2[N:29]=[N:30][NH:31][CH:32]=2)=[CH:21][CH:20]=1.[S:33](=[O:37])(=[O:36])([OH:35])[OH:34].C(O)(C)C>C(O)(C)C.O>[S:33]([OH:37])([OH:36])(=[O:35])=[O:34].[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH2:27][C:28]2[NH:29][N:30]=[N:31][CH:32]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(CNCc4c[nH]nn4)cc3)c(F)c2)C(=O)O1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CNCc4cnn[nH]4)cc3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
To a stirred suspension of N-[3-(2-Fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (49 mg, 0.11 mmol) in 4:1 isopropanol/water (0.8 mL) was added dropwise 0.5 M sulfuric acid in isopropanol (0.65 mL, 0.33 mmol). The mixture was then stirred for 2 h and the solvent removed under reduced pressure to give the title compound as an amorphous off-white solid which was characterized by XRPD. FIG. 7 shows a characteristic X-ray powder diffraction (XRPD) pattern of amorphous N-{[(5S)-3-(2-fluoro-4′-{[(1H-1,2,3-triazol-5-ylmethyl)amino]methyl}biphenyl-4-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide monosulfate.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:3].C([N-]C(C)C)(C)C.[Li+].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:33])[CH2:27][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1.CCOCC>O1CCCC1>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([OH:33])([C:2]([CH3:3])([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:1])[CH2:27][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1
Reactant: CC(C)c1ccncn1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(c1ccncn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 2.7 %

Procedure:
Treatment of the product of part (i) (2.46 g) with lithium diisopropylamide (0.02 mole) in dry tetrahydrofuran followed by 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (4.49 g) according to the method of Example 3 gave the title compound, (0.185 g), m.p. 126°-127° (from ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:23]3[CH:24]=[CH:25][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:27][CH:28]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: CCS(=O)(=O)c1ccc(Br)cc1
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Product: CCS(=O)(=O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 1-bromo-4-ethanesulfonyl-benzene. White solid. MS (ESI): 497.0 MH+).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.[C:14]1([C:20]2[C:28]3[C:27]([N:29]4[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]4)=[N:26][CH:25]=[N:24][C:23]=3[S:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:2]([OH:1])[CH2:3][NH:35][CH:32]2[CH2:33][CH2:34][N:29]([C:27]3[C:28]4[C:20]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[CH:21][S:22][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:30][CH2:31]2)=[CH:7][CH:8]=1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Reactant: OCc1ccc(OCC2CO2)cc1
Product: OCc1ccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)cc1
Yield: 19 %

Procedure:
Synthesis followed SP6 (4 h), using 120 μmol (4-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give the title compound with 19% yield upon purification by prep. HPLC (reversed phase).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:26])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH2:27]([O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:14]([NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)=[O:26])=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Cc1ccc(O)c([N+](=O)[O-])c1)Nc1cccc(C2CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)Nc1cccc(C2CCCCC2)c1

Procedure:
A mixture of N-(3-cyclohexylphenyl)-4-hydroxy-3-nitrophenylacetamide (the compound of Example 29) (300 mg), benzyl bromide (287 mg), potassium carbonate (500 mg) and acetone (10 ml) is heated under reflux for 18 hours. After cooling, water is added to the mixture, and the mixture is extracted with ethyl acetate. The organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give 4-benzyloxy-N-(3-cyclohexylphenyl)-3-nitrophenylacetamide (320 mg). This product is dissolved in ethanol (5 ml), and thereto are added reduced iron (200 mg), ammonium chloride (80 mg) and water (5 ml), and the mixture is heated under reflux for one hour. The reaction solution is filtered through Celite, and the filtrate is concentrated, and the residue is dissolved in chloroform. The organic layer is washed with water, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (240 mg).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25]C(=O)C)[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[C@@H:6]1[S:17][CH2:18][C@@H:19]([OH:25])[C@H:20]([OH:21])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccccc1O[C@@H]1SC[C@@H](O)[C@H](O)[C@H]1O
Yield: 67.7 %

Procedure:
If the procedure described in Preparation LXXXIV is followed starting from 0.85 g (2.05.10-3 mol) of 2-nitrophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 0.1 ml of a solution of sodium methylate in methanol (8% w/v of Na), reacted in 50 ml of methanol for 30 min, 0.4 g (yield: 68%) of the expected product is obtained after precipitation in ether and lyophilization.
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][C:11]([CH2:14][CH2:15][O:16][C:17]([NH:19][C:20]2[C:21](=[O:46])[N:22]([CH2:32][C:33]([NH:35][CH:36]([CH:43]([CH3:45])[CH3:44])[C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[O:34])[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[O:18])=[CH:12][N:13]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:9]1[S:10][C:11]([CH2:14][CH2:15][O:16][C:17]([NH:19][C:20]2[C:21](=[O:46])[N:22]([CH2:32][C:33]([NH:35][CH:36]([CH:43]([CH3:44])[CH3:45])[C:37](=[O:42])[C:38]([F:40])([F:41])[F:39])=[O:34])[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[O:18])=[CH:12][N:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCCc2cnc(NC(=O)OC(C)(C)C)s2)c1=O)C(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCCc2cnc(N)s2)c1=O)C(=O)C(F)(F)F
Reaction time: 3 h
Yield: 60.2 %

Procedure:
To 2-[3-[2-(2-tert-butoxycarbonylaminothiazol-5-yl)ethoxycarbonylamino]-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.9 g) in methylene chloride (5 mL) was added trifluoroacetic acid (1 mL), and the resulting solution was allowed to stir for 3 h. The solvents were evaporated and the residue chromatographed, eluting with methanol:methylene chloride (5:95), to give the title compound (0.46 g); MS: m/z=566(M+1).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([O:10]C(=O)C)[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:38]#[N:39])=[N:18][C:19]=3[NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:7][C@@H:6]1[CH2:40][O:41]C(=O)C)(=O)C.N>[Pd].C(O)C>[NH2:39][CH2:38][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@H:8]2[C@H:9]([OH:10])[C@H:5]([OH:4])[C@@H:6]([CH2:40][OH:41])[O:7]2)=[C:19]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:18]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Agent: N
Solvent: CCO
Product: NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
10% Palladium on carbon (200 mg) was added to a solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-{2-cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}tetrahydro-3-furanyl acetate (Preparation 1) (1.9 g, 3.2 mmol) in a saturated solution of ammonia in ethanol (100 ml). The reaction mixture was stirred under an atmosphere of hydrogen (414 kPa, 60 psi) for 16 hours at room temperature. The solids were removed by filtration through Arbocel (Trade Mark) and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume increasing to 80:20:2 by volume). This gave the title compound as a solid (770 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:7][C@:8]12[CH2:25][CH2:24][C@H:23]3[C@@H:13]([CH2:14][CH2:15][C:16]4[C@:21]3([CH3:22])[CH:20]=[CH:19][C:18](=[O:26])[CH:17]=4)[C@@H:12]1[CH2:11][CH2:10][C:9]2=[O:27].C[Si](Cl)(C)C>C(Cl)Cl.CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:20]1[C@@:21]2([CH3:22])[C:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:8]2([CH3:7])[C@H:12]3[CH2:11][CH2:10][C:9]2=[O:27])=[CH:17][C:18](=[O:26])[CH2:19]1
Reactant: C=CCCCBr
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@]12C(=CC(=O)C[C@@H]1CCCCCBr)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.25 h
Yield: 8 %

Procedure:
Cp2ZrHCl (206 mg, 0.80 mmol, 2.0 eq.) was added to a stirred, room temperature, solution of 5-bromo-1-pentene (0.12 mL, 1.0 mmol, 2.5 eq.) in CH2Cl2 (0.40 mL) under an argon atmosphere. After stirring for about 15 min, the resulting clear yellow solution was transferred via syringe over about 1 min to a clear colourless stirred solution of CuOTf-ligand complex (30.0 mg, 0.040 mmol, 0.10 eq.) in Et2O (2.0 mL) under an argon atmosphere. The resulting dark mixture was allowed to stir for an additional 10 min before 1,4-androstadiene-3,17-dione (114.0 mg, 0.40 mmol, 1.0 eq.) and TMSCl (0.26 mL, 2.00 mmol, 5.0 eq.) were added sequentially dropwise via syringe. Stirring at room temperature was continued arbitrarily for 15 h before the reaction was quenched by the addition of Et2O (ca 3 mL) and NH4Cl (1 M aq., ca 1.5 mL). The mixture was partitioned between the aqueous and Et2O layers and the former phase was extracted with Et2O (3×10 mL). The combined organic phase was washed with NaHCO3 (sat. aq., ca 10 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash column chromatography of the yellow residue (10:30:60 EtOAc/DCM/petrol; SiO2) gave major diastereomer (3) (+)-1α-(5-Bromopentyl)-4-androstene-3,17-dione (107 mg, 0.24 mmol, 60%) and minor diastereomer (3a) (+)-1α-(5-Bromopentyl)-4-androstene-3,17-dione (14 mg, 0.032 mmol, 8%). Diastereomeric ratio (4.8:1) was determined by integration of 1H NMR spectra.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([CH2:23][C:24]2[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=2)[C:6]2[CH:7]=[C:8]([C:10]3([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)OCC[O:11]3)[O:9][C:5]=2[C:4]=1[O:32][CH3:33].Cl>C(O)C>[NH2:30][C:27]1[N:26]=[C:25]([NH2:31])[C:24]([CH2:23][C:21]2[C:6]3[CH:7]=[C:8]([C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:11])[O:9][C:5]=3[C:4]([O:32][CH3:33])=[C:3]([O:2][CH3:1])[CH:22]=2)=[CH:29][N:28]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)c2cc(C3(c4ccccc4)OCCO3)oc2c1OC
Agent: Cl
Solvent: CCO
Product: COc1cc(Cc2cnc(N)nc2N)c2cc(C(=O)c3ccccc3)oc2c1OC

Procedure:
hydrochloride (107 mg, 25%) was obtained as a yellow solid after crystallisation from ethanol by reacting a solution of 5-[6,7-dimethoxy-2-(2-phenyl-[1,3]dioxolan-2-yl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine (440 mg, 0.981 mmol) in ethanol with 6 N HCl for 16 h at r.t.
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:15](OC)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.CO>C1COCC1>[NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C@H:2]([CH:15]=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C[C@@H](C=O)NC(=O)OCc2ccccc2)ccc1O
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of Z-Tyr(3-tBu)-OMe (3.30 g, 8.57 mmol) in THF (200 ml), diisobutyl aluminum hydride (1.0 M toluene solution) (42.9 ml, 42.9 mmol) was added dropwise at −78° C. over 15 min. After stirring for 1 hour, the mixture was mixed with methanol and a saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:2), giving the titled compound (2.18 g, 72%).
Reaction SMILES: [F:1][C:2]([F:15])([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])[CH:3]([F:5])[F:4].[O:16]([C:23]1[CH:24]=[C:25]([NH:29][CH2:30][CH:31](O)[C:32]([F:35])([F:34])[F:33])[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[O:16]([C:23]1[CH:24]=[C:25]([N:29]2[CH2:30][CH:31]([C:32]([F:33])([F:34])[F:35])[O:11][CH:10]2[C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:2]([F:15])([F:1])[CH:3]([F:4])[F:5])[CH:8]=2)[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC(CNc1cccc(Oc2ccccc2)c1)C(F)(F)F
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Solvent: Cc1ccccc1
Product: FC(F)C(F)(F)Oc1cccc(C2OC(C(F)(F)F)CN2c2cccc(Oc3ccccc3)c2)c1
Yield: 91.7 %

Procedure:
A toluene solution (5 mL) of 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (0.45 g, 2.0 mol) and N-(3-phenoxyphenyl)-3-amino-1,1,1-trifluoro-2-propanol (0.60 g, 2.0 mmol) was refluxed in the presence of molecular sieves and Znl2 (˜5 mg) for 18 h under N2. The reaction mixture was filtered to remove the sieves, and the filtrate was diluted with ethyl acetate. The organic layer was washed with brine. dried (MgSO4) and evaporated to give 0.92 g (92%) of the desired 3-(3-phenoxyphenyl)-2-[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-5-(trifluoromethyl) oxazolidine product as a colorless oil. The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ˜10) in the 1H NMR spectrum. HRMS calcd. 502.1253 [M+H]+, found: 502.1220.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([C:17]([F:20])([F:19])[F:18])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:24]=1[NH2:25]>>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:6]2[C:5]([C:17]([F:20])([F:19])[F:18])=[CH:4][N:3]=[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([N:30]4[CH2:35][CH2:34][CH:33]([N:36]5[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]5)[CH2:32][CH2:31]4)=[CH:29][C:23]=3[O:22][CH3:21])[N:7]=2)=[CH:9]1
Reactant: FC(F)(F)c1cnc(Cl)nc1-c1c[nH]c2ccccc12
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(C(F)(F)F)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole (INTERMEDIATE 4) and 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27).