Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][SH:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:36][CH:35]=2)=[CH:27][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][S:17][CH:19]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][S:41]([CH3:44])(=[O:42])=[O:43])=[CH:38][CH:39]=3)=[CH:27][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: SCCc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C(Cl)Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1)SCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
2-[4-(Benzyloxy)phenyl]ethanethiol (334 mg, 1.4 mmol), methyl 2-chloro-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoate (394 mg, 0.95 mmol) and potassium carbonate (189 mg, 1.4 mmol) were dissolved in 14 ml dry DMF and stirred under nitrogen atmosphere at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in toluene. The organic phase was washed (water, brine), dried (MgSO4) and evaporated. Futher purification by preparative HPLC using a gradient of CH3CN/5% CH3CN-waterphase containing 0.1M NH4OAc gave 477 mg of the desired product (yield 75%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([N:13]([CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2.CN(C)CC>CCCCCC.C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([N:13]([CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2
Reactant: CCCN(CCc1cccs1)[C@@H]1CCc2cccc(OC)c2C1
Agent: CCN(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCN(CCc1cccs1)[C@@H]1CCc2cccc(O)c2C1

Procedure:
Synthesis worked according to the preparation of A7-1 when using 21 mg (0.06 mmol) (R)—N-(8-methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine ((R)-A5-1: R═OMe, Cy=2-thienyl). Flash chromatography was done using hexane/ethyl acetate 40/10 in the presence of 0.5% (v/v) dimethylethylamine to achieve compound 1a.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:42])[CH2:27][CH2:28][C:29]([F:41])([F:40])[C:30]([F:39])([F:38])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33].[BH4-].[Na+]>CO>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:42])[CH2:27][CH2:28][C:29]([F:40])([F:41])[C:30]([F:38])([F:39])[C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35]
Reactant: CN(CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
160 mg of 11β-fluoro-3-hydroxy-7α-{5-[methyl-(3,3,4,4,5,5,6,6,6-nonafluoro-hexyl)-amino]-pentyl}-estra-1,3,5(10)-trien-17-one is dissolved in 5 ml of methanol and mixed with 28 mg of sodium borohydride. After 30 minutes of stirring at room temperature, the batch is added to saturated common salt solution, extracted with methylene chloride, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a methylene chloride-MTBE gradient and an ethyl acetate-acetone gradient, 105 mg of 11β-fluoro-7α-{5-[methyl-(3,3,4,4,5,5,6,6,6-nonafluoro-hexyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol is obtained as a foam, [α]D=+43° (c=0.5 in CHCl3).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH2:21]([S:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH3:22]>>[CH2:21]([S:23]([C:26]1[CH:31]=[C:30]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:1])[CH3:20])[CH:29]=[CH:28][CH:27]=1)(=[O:24])=[O:25])[CH3:22]
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc3c(c2)C(C)(C)CC3=O)c1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-(ethylsulfonyl)phenyl boronic acid according to the procedure described in example 21. MS m/z 329; HRMS: calcd for C19H20O3S+H+, 329.12059; found (ESI, [M+H]+), 329.1217.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N:17]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[OH:27]>>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N+:17]=2[O-:27])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CO
Reactant: [O-][n+]1nc(NCCCCN2CCOCC2)nc2cc3c(cc21)CCC3
Product: [O-][n+]1nc(NCCCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCC3

Procedure:
H2O2 (70%, 3.6 mL, ca. 72 mmol) was added dropwise to a stirred solution of TFAA (10.2 mL, 72 mmol) in DCM (25 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 62 (2.48 g, 7.2 mmol) and TFA (2.8 mL, 36 mmol) in DCM (25 mL) at 0° C. The solution was stirred at 20° C. for 16 h, cooled to 0° C. and made basic with dilute aqueous NH3 solution and stirred vigorously for 30 min. The mixture was extracted with CHCl3 (4×50 mL), the combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 62 (981 mg, 40%) and (ii) 1,4-dioxide 63 (504 mg, 19%) as a red solid: mp (MeOH) 140-141° C.; 1H NMR δ 8.09 (s, 2H, H-5, H-9), 7.32 (br s, 1H, NH), 3.74 (br t, J=4.6 Hz, 4H, 2×CH2O), 3.57-3.63 (m, 2H, CH2N), 3.09 (br t, J=7.5 Hz, 2H, H-6), 3.05 (br t, J=7.5 Hz, 2H, H-8), 2.50-2.55 (m, 4H, 2×CH2N), 2.47 (br t, J=7.1 Hz, 2H, CH2N), 2.20 (p, J=7.5 Hz, 2H, H-7), 1.71-1.79 (m, 2H, CH2), 1.61-1.69 (m, 2H, CH2); 13C NMR δ 155.9, 149.5, 145.8, 137.9, 129.8, 115.7, 111.6, 66.6 (2), 58.1, 53.5 (2), 41.2, 33.4, 32.4, 27.1, 25.5, 23.4; HRMS (FAB+) calcd for C18H26N5O3 (MH+) m/z 360.2036, found 360.2039.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([OH:17])[C:6]=1[CH:7]=O)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C(Br)C1C=CC=CC=1.[CH3:28][N:29](C=O)C>>[NH2:29][CH2:28][CH2:7][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][C:9]=1[OH:17]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc(O)c(C=O)c(C(C)(C)C)c1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)c1cc(O)c(CCN)c(C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1.17 g (5.0 mmol) of 2,4-di-tert-butyl-6-hydroxybenzaldehyde (from Step A of Example 35) in 10 mL of dry DMF was added 0.25 g (10.4 mmol) of powdered sodium hydride and the resulting mixture was stirred for 30 min under a nitrogen atmosphere. Benzyl bromide (1.0 g, 5.9 mmol) was then added and the resulting mixture was stirred for an additional 3 h. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ether and water. The aqueous layer was re extracted with ether and the organic layers were then combined, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0-10% EtOAc-hexane. Combination of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: O1CCOCC1.[ClH:7].[F:8][C:9]1([CH3:22])[CH2:13][CH2:12][CH2:11][CH:10]1[NH:14]C(=O)OC(C)(C)C>ClCCl>[ClH:7].[F:8][C:9]1([CH3:22])[CH2:13][CH2:12][CH2:11][CH:10]1[NH2:14]
Reactant: CC(C)(C)OC(=O)NC1CCCC1(C)F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(F)CCCC1N
Reaction time: 1.5 h
Yield: 95.6 %

Procedure:
A 4 M dioxane solution of hydrogen chloride (6.30 mL, 25.2 mmol) was added to a stirred solution of tert-butyl 2-fluoro-2-methylcyclopentylcarbamate (1.0954 g, 5.04 mmol, from Step 4) in dichloromethane (4 mL) at room temperature. After 1.5 h at room temperature, the solvent was evaporated to give 2-fluoro-2-methylcyclopentanamine hydrochloride (740 mg, 96% yield).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][N:15]1[C:23]([C:24]2[N:25]([CH3:35])[CH:26]=[C:27]([C:29](=O)[C:30]([F:33])([F:32])[F:31])[CH:28]=2)=[C:22]2[C:17]([N:18]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:19](=[O:38])[N:20]([CH3:37])[C:21]2=[O:36])=[N:16]1.C(N(CC)CC)C>CC(N(C)C)=O>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][N:15]1[C:23]([C:24]2[N:25]([CH3:35])[CH:26]=[C:27](/[C:29](=[N:2]/[OH:3])/[C:30]([F:33])([F:32])[F:31])[CH:28]=2)=[C:22]2[C:17]([N:18]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:19](=[O:38])[N:20]([CH3:37])[C:21]2=[O:36])=[N:16]1
Reactant: Cn1cc(C(=O)C(F)(F)F)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Cn1cc(/C(=N/O)C(F)(F)F)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 29.2 %

Procedure:
Hydroxylamine hydrochloride (0.062 g) was added to a solution of 2-[(5-chloro-1H-indol-3-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-3-[1-methyl-4-(trifluoroacetyl)-1H-pyrrol-2-yl]-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.05 g) and triethylamine (0.063 ml) in dimethylacetamide (5 ml) and the mixture heated at 80° C. for 2 hours. Additional hydroxylamine hydrochloride (0.062 g) was added and the reaction continued at 80° C. for another 3 hours. Cooled, concentrated, and the crude residue purified on preparative HPLC to give the title compound (0.015 g). Mass: 574.17 (M+H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH3:13])=[O:12])[CH2:6][CH2:5]1.S(Cl)([Cl:22])=O.[OH-].[Na+]>C(Cl)Cl>[Cl:22][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH3:13])=[O:12])[CH2:6][CH2:5]1
Reactant: CC(=O)C(c1ccccc1)N1CCN(CCO)CC1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)C(c1ccccc1)N1CCN(CCCl)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To 1-(N-β-hydroxyethyl-piperazino)-1-phenylacetone (1 mole) dissolved in methylene chloride (2 liters) is added thionyl chloride (2 moles) dropwise, at 0° C., with stirring. On completion of the addition, the resulting material is left aside 24 hours, at room temperature. The reaction medium is then poured over ice and sodium hydroxide (3 moles) is added thereto. The organic phase is washed with water to neutral pH. It is then dried over sodium sulfate and the solvent is evaporated off, to give a viscous brown oil which is used crude to proceed with the synthesis.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:13]([O:16]C)=[N:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.C1CCCCC=1>CN(C=O)C.CCOC(C)=O.CO.[Pd]>[F:12][C:7]1[CH:6]=[C:5]2[C:10]([N:11]=[C:2]([NH:25][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[C:3]3[N:4]2[C:13](=[O:16])[NH:14][N:15]=3)=[CH:9][CH:8]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1nnc2c(Cl)nc3ccc(F)cc3n12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1=CCCCC1
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc3ccc(F)cc3n3c(=O)[nH]nc23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1.0 g of 4-chloro-8-fluoro-1-methoxy[1,2,4]triazolo[4,3-a]quinoxaline in DMF (12.0 mL) was added 1.36 g of 4-methoxybenzylamine. This solution was stirred at room temperature for 18 hrs. and then diluted with EtOAc and washed with water and saturated lithium chloride. The extracts were dried over sodium sulfate, filtered, and concentrated and the residue was separated by silica gel chromatography to give a yellow solid. This solid was dissolved in MeOH (15 mL) and 160 mg of 10% Pd/C and 0.96 g of cyclohexene were added. This mixture was heated at reflux for 18 hrs., filtered through a pad of diatomaceous earth, and concentrated to provide an off-white solid. MS (M+H)+=340.0.
Reaction SMILES: [C:1]([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].[O:22]=[C:23]1[C:29]([CH3:31])([CH3:30])[CH2:28]C(=O)[CH:25]=[C:24]1[CH3:32]>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[C:12]([O:11][C:9]([O:8][C:1]1[CH:25]=[C:24]([CH3:32])[C:23](=[O:22])[C:29]([CH3:31])([CH3:30])[CH:28]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1=CC(OC(=O)OC(C)(C)C)=CC(C)(C)C1=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 80.9 %

Procedure:
A solution of 23.2 g (106.3 mmol) of di-tert.-butyl dicarbonate in 25 ml of tetrahydrofuran was added dropwise to a suspension, stirred at 24° C., of 20.0 g (144.7 mmol) of K2CO3, 20 ml of tetrahydrofuran, 1.1 g (4.2 mmol) of 18-crown-6 and 15.2 g (100 mmol) of ketoisophorone. The suspension was stirred at 60° C. for 5 hours, then the brown reaction mixture was filtered and finally the solvent was evaporated. The brown residue (26.6 g) was dissolved in 200 ml of dichloromethane and the solution was extracted with saturated NaHCO3 solution and with water. The organic phase was dried over Na2SO4, filtered and evaporated. The brown residue (22.6 g) was chromatographed over 150 g of silica gel (n-hexane/ether 2/1). There were obtained 20.4 g (81%) of 4-tert.-butyloxycarbonyloxy-2,6,6-trimethylcyclohexa-2,4-dienone as a yellow oil; anal. calc. for C14H20O4 (252.31): C 66.65, H 7.99; found: C 66.46, H 8.08.1H-NMR (250 MHz, CDCl3): 1.25 (s, 2 CH3 --C(6)); 1.54 (s, (CH3)3C--O); 1.91 (s, CH3 --C(2); 5.88-5.89 (d, H--C(5)); 6.71-6.74 (m, H--C(5)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:36])([CH3:35])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:34])([C@@:13]3([CH3:33])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:47]2[CH2:51][CH2:50][CH:49]([CH2:52][C:53]([O:55][CH3:56])=[O:54])[CH:48]=2)O1>>[NH2:32][C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:33])([CH2:14][CH2:15]2)[C@@:12]2([CH3:34])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:35])([CH3:36])[C:7]([C:47]2[CH2:51][CH2:50][CH:49]([CH2:52][C:53]([O:55][CH3:56])=[O:54])[CH:48]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1
Reactant: COC(=O)CC1C=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC(CC(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 55.7 %

Procedure:
The title compound was prepared as a mixture of diastereomers in 55.7% yield following the method for the preparation of Example 1, Step 1 described above, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and methyl 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-yl)acetate as the reactant. MS: m/e 531.5 (M−16)+, 2.69 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.54 (s, 1H), 5.50-5.44 (m, 1H), 4.73 (s, 1H), 4.60 (s, 1H), 3.67 (s, 3H), 3.14 (t, J=7.0 Hz, 1H), 2.81-2.61 (m, 1H), 2.59-2.27 (m, 5H), 2.16-1.96 (m, 4H), 1.79-1.18 (m, 20H), 1.09-1.02 (m, 11H), 0.96 (s, 3H), 0.85 (s, 3H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([O:12][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:11][CH:10]=2)=[CH:31][CH:32]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(I)cc1
Reactant: Oc1ccc(-n2cncn2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-n3cncn3)cc2)cc1
Yield: 69.3 %

Procedure:
The title compound (130 mg, 80%) was prepared from 4-[1,2,4]triazol-1-yl-phenol (0.7 g, 0.43 mmol) and (R)-2-(4-Iodo-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.23 g, 0.56 mmol) using the procedure of Example 146, step 3.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[CH2:25](Br)[CH2:26][CH2:27][CH3:28]>>[ClH:1].[CH2:25]([N:12]1[CH2:13][CH2:14][C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)[C@H:10]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH2:11]1)[CH2:26][CH2:27][CH3:28]
Reactant: COc1ccc(OC[C@@H]2CNCC[C@H]2c2ccc(F)cc2)cc1
Reactant: CCCCBr
Agent: Cl
Product: CCCCN1CC[C@@H](c2ccc(F)cc2)[C@H](COc2ccc(OC)cc2)C1

Procedure:
(-)-trans-1-butyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxy-methyl)-piperidine hydrochloride M.p. 163-165° C. was prepared exactly as described in Example 1 from (-)-trans-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperidine hydrochloride and butyl bromide by refluxing for 120 hours.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16]C3C=NC=CC=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.Br[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Fc1cc(F)cc(Br)c1
Product: Cc1ccc(Nc2cc(F)cc(F)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a light yellow solid, MS (ISP): m/e=344.0 (M+H+).
Reaction SMILES: B(F)(F)F.CCOCC.O[C:11]1([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][C:14]2[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:13]=2[CH2:12]1.C([SiH](CC)CC)C>C(Cl)Cl.C(O)C.[Pd]>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:13]2[CH2:12][CH:11]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[CH:22]=1
Reactant: CCOC(=O)CC1(O)Cc2ccc(OC)cc2Oc2ccccc21
Agent: [Pd]
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CC1Cc2ccc(OC)cc2Oc2ccccc21
Reaction time: 0.33 h
Yield: 85.9 %

Procedure:
Boron trifluoride etherate (0.48 mL, 3.9 mmole) was added to a solution of ethyl (±)-10,11-dihydro-10-hydroxy-3-methoxydibenzo[b,f]oxepine-10-acetate (690 mg, 1.95 mmole) and triethylsilane (0.62 mL, 3.9 mmole) in dry CH2Cl2 at 0° C. under argon. After 20 min, the reaction was quenched with 5% NaHCO3, and the mixture was extracted with CH2Cl2. Drying (MgSO4) and concentration gave a yellow oil. This was dissolved in absolute ethanol (20 mL) and 10% Pd/C (413 mg, 0.39 mmole) was added. The mixture was hydrogenated for 3 hr at 50 psi on a Parr hydrogenation apparatus. The catalyst was removed by filtration through celite®, and the filtrate was concentrated to afford the title compound (523 mg, 86%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ7.18-6.58 (m, 7 H), 4.18-4.08 (m, 2 H), 3.80 (s, 3 H), 3.80-3.74(m, 1 H), 3.40-3.30 (dd, 1 H). 2.98-2.84 (dd, 1 H), 2.74-2.62 (dd, 1 H), 2.60-2.52(m, 1 H), 1.32-1.20 (t, 3 H).
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][N+:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].[BH4-].[Na+]>CO.CCOC(C)=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: CCC[n+]1ccc(-c2ccc([N+](=O)[O-])c(OC)c2)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN1CC=C(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To 4-[3-(methyloxy)-4-nitrophenyl]-1-propylpyridinium iodide (5.7 g, 14.24 mmol) in 75 mL of MeOH at 0° C. was added, NaBH4 (1.62 g, 42.73 mmol) over 1 h. The mixture was allowed to come to rt over 2 h. The solvent was reduced to approximately 20 mL and then diluted with EtOAc, washed with conc. NaHCO3, dried (Na2SO4), filtered, rotovaped down, and purified by flash chromatography to give the title compound of step C (3.33 g, 12.05 mmol, 85%). 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (d, J=8.42 Hz, 1H), 7.02 (s, 1H), 6.99-7.02 (m, 1H), 6.19 (ddd, J=3.43, 1.92, 1.79 Hz, 1H), 3.95 (s, 3H), 3.20 (q, J=2.81 Hz, 2H), 2.72 (t, J=5.68 Hz, 2H), 2.54-2.60 (m, 2H), 2.41-2.48 (m, 2H), 1.54-1.64 (m, 2H), 0.94 (t, J=7.42 Hz, 3H).
Reaction SMILES: [OH:1][C@H:2]([CH3:11])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[Si:17]([O:1][C@H:2]([CH3:11])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CCOC(=O)CCC[C@@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C
Yield: 87.8 %

Procedure:
A solution of ethyl 5(R)-hydroxyhexanoate 3 (1.80 g, 11.24 mmol), imidazole (2.3 g, 33.8 mmol), and t-butyldimethylsilyl chloride (2.54 g, 16.85 mmol) in 30 mL of DMF was stirred at 23° C. overnight (19 h). The solvent (DMF) was then removed in vacuo and aqueous saturated sodium bicarbonate (100 mL) was added followed by ethyl acetate (100 mL). The layers were separated and the aqueous layer was re-extracted with 100 mL of EtOAc. The combined organic layers were washed with water, brine, and dried over anhydrous sodium sulfate. Flash column chromatographic purification on 30 g of silica gel yielded 2.71 g (88%) of TBDMS-ether 4 (G.C. purity of 99+A %); 1H NMR (CDCl3): 0.04 (s, 6H), 0.91 (s, 9H), 1.18 (d, J=6 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.42 (m, 2H), 1.65 (m, 2H), 2.39 (t, J=7.5 Hz, 2H), 3.79 (m, J=6 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:12]([Mg]Br)[CH3:13]>>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH2:12][CH3:13]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CC[Mg]Br
Product: CCC(O)(CCCl)c1ccccc1

Procedure:
1-chloro-3-phenylpentan-3-ol was prepared from 3-chloro-1-phenylpropan-1-one and ethylmagnesium bromide following a procedure analogous to that described in Preparation 1 Method 1 Step 2.