Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1C=C[C:5]2[N:6]([C:8](CC3N(C)C=CN=3)=[C:9](C3C=CC(F)=CC=3)[N:10]=2)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]3[C:40]=2[CH:41]=O)=[CH:28][CH:27]=1.C(N1C=CN=C1)=C>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]3[C:40]=2[CH2:41][C:5]2[N:6]([CH:7]=[CH2:2])[CH:8]=[CH:9][N:10]=2)=[CH:28][CH:27]=1
Reactant: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: C=Cn1ccnc1
Product: C=Cn1ccnc1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and 1-vinyl-1H-imidazole. (34 mg, 18%). m/e+=335 (M+H+). 1H-NMR (400 MHz, CDCl3, δ): 8.28 (d, 1H, D, J=7.0 Hz), 7.66 (d, 2H, D, J=10.2 Hz), 7.61 (d, 1H, D, J=9.2 Hz), 7.46 (d, 2H, D, J=8.5 Hz), 7.19 (t, 1H, D, J=7.9 Hz), 7.08 (d, 1H), 6.96 (d, 1H), 6.80 (t, 1H, D, J=7.0 Hz), 6.46 (m, 1H), 5.03 (m, 1H), 4.62 (m, 1H), 4.56 (s, 2H).
Reaction SMILES: ClC1C=C(NC2N=C(C3C(C4C=C(NC(=O)C5C(F)=CC=CC=5F)C=CC=4)=NN4C=CC=CC=34)C=CN=2)C=CC=1OCCN(C)C.[F:47][C:48]1[CH:53]=[C:52]([N+:54]([O-])=O)[CH:51]=[CH:50][C:49]=1[O:57][CH2:58][CH2:59][O:60][CH3:61]>>[F:47][C:48]1[CH:53]=[C:52]([NH2:54])[CH:51]=[CH:50][C:49]=1[O:57][CH2:58][CH2:59][O:60][CH3:61]
Reactant: COCCOc1ccc([N+](=O)[O-])cc1F
Agent: CN(C)CCOc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1Cl
Product: COCCOc1ccc(N)cc1F

Procedure:
In a procedure analogous to Example 125, 250 mg of the title compound was prepared from 2-fluoro-1-{[2-(methyloxy)ethyl]oxy}-4-nitrobenzene as brown oil. 1H NMR (CDCl3, 400 MHz) δ 3.40 (s, 3H), 3.51 (brs, 2H), 3.67 (d, 2H, J=4.7 Hz), 4.06 (t, 2H, J=4.7 Hz), 6.32 (d, 1H, J=8.6 Hz), 6.41 (dd, 1H, J=12.6 and 2.8 Hz), and 6.8 (t, 1H, J=9.0 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:10][O:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH3:9])=[CH:4][CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[N:10][O:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH3:9])=[CH:6][CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(O)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(C)=NOCCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 54, but using 0.30 g of 5-(4-{2-[1-(4-hydroxyphenyl)ethylideneaminooxy]ethoxy}benzyl)thiazolidine-2,4-dione (prepared as described in Example 51), 0.092 ml of acetic anhydride and 15 ml of pyridine, 0.3 g of the title compound, melting at 133°-135° C., was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@@H:8]([C:9](=O)[NH:10][CH2:11]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH3:18].B.C1COCC1.[ClH:25]>C1COCC1>[ClH:25].[CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@@H:8]([CH2:9][NH:10][CH2:11]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH3:18]
Reactant: COc1ccc2c(c1OC)CC[C@@H]1CNC(=O)[C@@H]21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1OC)CC[C@@H]1CNC[C@@H]21

Procedure:
A solution of trans-3a,4,5,9b-tetrahydro-6,7-dimethoxy-1H-benz[e]isoindole-1-(2H)-one and 15 mL dry THF was stirred under N2 at 0° as BH3.THF (27.3 mL, 1M solution) was added slowly. The reaction mixture was stirred at reflux for 2.5 hours, was cooled to 0°, and 30 mL methanolic HCl was added cautiously. The solution was stirred at reflux for 1 hour, then was evaporated to dryness. Water was added and the aqueous layer was extracted with ether. After basifying (1N KOH), the aqueous layer was extracted with ether. The combined basic extracts were washed with water, saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated to yield a clear oil which was converted to the HCl salt (ethereal HCl), evaporated, dried (in-vacuo) to obtain a white solid which was triturated with ether to yield 1.03 g cream colored solid, (63%); mp 196°-8°; M+ 233.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)[CH:5]=1.[OH-].[Na+]>CO.C1COCC1.O>[F:19][C:17]([F:18])([F:20])[C:14]1[CH:15]=[CH:16][C:11]([O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:21])=[O:2])=[N:12][CH:13]=1
Reactant: COC(=O)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid methyl ester (285 g, 0.95 mmol) and NaOH (200 mg, 4 mmol) in methanol:THF:water (1:1:1, 3 mL) was stirred at room temperature for 8 h. Solvents were evaporated. Crude mass was taken in water (20 mL), acidified to pH 4.0 and extracted with ethyl acetate to obtain 3-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid was prepared (215 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[C:14](=O)([O-])[O-].[K+].[K+].IC.Cl>CN(C=O)C>[CH3:14][O:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1O
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C(C)=O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A slurry of 1-(2-hydroxy-3-nitrophenyl)ethanone (1.00 g, 5.52 mmol) and potassium carbonate (3.05 g, 22.08 mmol) in DMF (20 mL) was stirred at room temperature for 30 minutes, then iodomethane (1.338 mL, 16.56 mmol) was added dropwise and the resulting mixture was allowed to stir at room temperature overnight. LCMS indicated some un-reacted starting material remained, therefore additional iodomethane (1.338 mL, 16.56 mmol) was added and the mixture was warmed to 50° C. over 2 days. Reaction was quenched by the addition of water to give a solution followed by adjusting the pH with 1N HCl to ˜7. The resulting solution was extracted with ethyl acetate (80 mL×3) and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the product, 1-(2-methoxy-3-nitrophenyl)ethanone (1.05 g, 5.38 mmol, 97% yield) as a tan oil. HPLC (Method N) RT=1.86 minutes.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1>C(O)(C)(C)C>[C:2]([O:4][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1)([CH3:5])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)Oc1ccc([N+](=O)[O-])cn1

Procedure:
To 50 ml. of tert-butanol, there was added potassium tert-butoxide (0.06 mole) and 2-chloro-5-nitropyridine (0.05 mole). A white solid precipitated. The reaction mixture was heated to about 60° for 4 hours. Excess ammonium chloride was added to neutralize excess potassium tert-butoxide. Solvent was removed by evaporation, and the residue was taken up in chloroform, separated, washed with water, dried over magnesium sulfate, and chromatographed on silica gel with a 50:50 mixture of ethyl acetate:toluene. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH:11]=[N:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([NH2:25])=[O:24])=[N:18]3)=[C:4]([O:33][CH3:34])[CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:31])([CH3:32])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:27])[F:28])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([NH2:25])=[O:24])=[N:18]3)=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=Nc1cccc2nc(C(N)=O)ccc12)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)ccc1C(C)(C)CC(O)(CNc1cccc2nc(C(N)=O)ccc12)C(F)(F)F

Procedure:
Analogously to Example 40, 340 mg (0.69 mmol) of 5-[4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylic acid amide is dissolved in 10 ml of methanol and mixed several times with 110 mg (2.89 mmol) of sodium borohydride. After working-up and purification on silica gel with hexane-ethyl acetate (0–100%), 280 mg (82% of theory) of the product is obtained.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1B(O)O>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: COc1ccc(Cl)c(B(O)O)c1
Product: COc1ccc(Cl)c(-c2ccc(N)c(F)c2)c1
Yield: 67.4 %

Procedure:
The title compound (134 mg) was prepared from 4-bromo-2-fluoroaniline (150 mg, 0.79 mmol) and 2-chloro-5-methoxylphenylboronic acid (191 mg, 1.02 mmol) as a colourless liquid.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][NH:8][C:9]([C:11]1[C:12]2[N:13]=[C:14]([O:27]C)[C:15]([O:25]C)=[N:16][C:17]=2[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[CH3:21])=[O:10])(C)(C)C.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[CH3:21][C:20]1[C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]2[NH:16][C:15](=[O:25])[C:14](=[O:27])[NH:13][C:12]=2[C:11]=1[C:9]([NH:8][CH2:7][C:6]([OH:29])=[O:5])=[O:10]
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)NCC(=O)OC(C)(C)C)c2nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1c([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c2c1C(=O)NCC(=O)O
Reaction time: 0.5 h

Procedure:
To a stirred mixture of [(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-amino] acetic acid tert-butyl ester (14a) 150 mg (0.37 mmol) and sodium iodide 555 mg (3.7 mmol) in 25 mL acetonitrile is added dropwise chlorotrimethylsilane 0.46 mL (3.7 mmol). After addition was complete, the reaction mixture was refluxed under an atmosphere of nitrogen for 72 hours. The reaction mixture was quenched by pouring into 100 mL water, and the aqueous mixture was concentrated to 10 mL. The residue was mixed with ethyl acetate, and after stirring for 30 minutes, the product precipitated, 35 mg (29%), mp 250° C. (dec.); 1H NMR (DMSO-d6): δ 12.55 (br s, 1H), 8.40 (t, 1H, J=6.3 Hz), 7.84 (s, 1H), 4.07 (d, 2H, J=6.3 Hz), 2.43 (s, 3H); MS (APCI): m/z 323 (M+H). Anal. Calcd. for C12H10N4O7: C, 44.73; H, 3.13; N, 17.39. Found: C, 41.38; H, 3.12; N, 15.79.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31](=[O:34])[NH:32][CH3:33])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[BrH:40].N([O-])=O.[Na+]>C(#N)C.[Cu]Br>[Br:40][C:2]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31](=[O:34])[NH:32][CH3:33])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Br
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
A suspension of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate (1.6 g, 2.70 mmol) in acetonitrile (30 mL) and hydrogen bromide (25 mL, 2.70 mmol) was treated with aqueous sodium nitrite (0.205 g, 2.97 mmol) at 0° C. and the mixture was stirred for 30 min, copper(I) bromide (0.464 g, 3.24 mmol) was added in portions at the same temperature. It was allowed to warm up to room temperature and then heated to 55° C. overnight. The mixture was cooled down to room temperature and partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na2SO4. Concentrated under reduced pressure, the residue was purified by flashing chromatography on silica gel eluted with 0-50% EtOAc in hexane to give the product (0.92 g, 55%) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (q, J=4.23 Hz, 1H) 8.14 (s, 1H) 7.97 (dd, J=8.78, 5.46 Hz, 2H) 7.80 (d, J=2.93 Hz, 1H) 7.75 (d, J=8.78 Hz, 1H) 7.50 (dd, J=8.88, 2.83 Hz, 1H) 7.41 (t, J=8.88 Hz, 2H) 7.22 (s, 1H) 3.84 (s, 3H) 3.44 (s, 3H) 2.84 (d, J=4.68 Hz, 3H) 2.05-2.15 (m, 1H) 0.92-1.05 (br. s, 1H) 0.87 (br. s., 2H) 0.40 (br. s., 1H). LCMS (m/z, ES+)=617 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:18][C:19]#[CH:20])[CH:8]=1)=[O:6].[N:25](COC(=O)NC(C)(C)C)=[N+:26]=[N-:27].[OH-].[Na+]>C(O)(C)(C)C.O.[Cu].O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:18][C:19]2[N:25]=[N:26][NH:27][CH:20]=2)[CH:8]=1)=[O:6]
Reactant: CC(C)(C)NC(=O)OCN=[N+]=[N-]
Reactant: C#CCn1cc(C(=O)c2ccc(C)c(C)c2)c(=O)c2ccccc21
Agent: [Cu+2]
Agent: [Cu]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc(C(=O)c2cn(Cc3c[nH]nn3)c3ccccc3c2=O)cc1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
29 mg (0.092 mmol) of 3-(3,4-dimethyl-benzoyl)-1-prop-2-ynyl-1H-quinolin-4-one 4c (prepared as described by Paine, J. B.; J. Het. Chem. 1987, 351), 19 mg (0.11 mmol) of tert-butyl-carbamic acid azidomethyl ester, 5.0 mg (0.078 mmol) of copper powder, and 2.0 mg (0.008 mmol) of copper(II) sulfate pentahydrate were combined in a mixture of 0.5 mL tert-butanol and 0.2 mL water and stirred at 80° C. for 4 h. Then 70 mg (1.75 mmol) of sodium hydroxide in 1 mL water was added to that mixture and the resultant mixture was stirred at 80° C. for another hour. The mixture was filtered and purified using reverse phase HPLC (mobile phase with a gradient 15-80% acetonitrile in 50 min). Lyophilization of the HPLC fractions containing purified 4d provided 18 mg of a pale yellow product as the trifluoroacetate salt: LC-MSD, m/z for C21H18N4O2, [M+H]+=359.5, HPLC retention time: 1.5 min; 1H NMR (400 MHz, CDCl3): δ 2.25 (s, 3H), 2.3 (s, 3H), 6.7 (s, 2H), 7.1-7.2 (m, 1H), 7.4-7.45 (m, 1H), 7.45-7.5 (m, 2H), 7.75-7.85 (m, 3H), 8.4-8.5 (m, 1H), 8.65 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:9])[CH:8]=CC=CC=1.[CH3:10][O:11][CH:12]([O:20][CH3:21])[CH2:13][NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18].C(Br)C=C>O>[CH2:9]([N:14]([CH2:13][CH:12]([O:11][CH3:10])[O:20][CH3:21])[C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH:3]=[CH2:8]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)NCC(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: O
Product: C=CCN(CC(OC)OC)C(=O)OCC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
20 g of sodium hydride (80% strength in paraffin oil) are initially introduced into 500 ml of toluene and 89 g (0.5 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate are added dropwise at 80° C. The mixture is stirred at 80° C. for one hour and 73 g (0.6 mol) of allyl bromide are then added dropwise in the course of three hours. The mixture is stirred at 80° C. overnight, the salts are dissolved with water and the organic phase is separated off. The aqueous phase is extracted with toluene, the organic phases are dried over potassium carbonate and concentrated and the residue is distilled.
Reaction SMILES: Br[C:2]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:15])[C:6]2=[O:14].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1B(O)O.[OH-].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(COC)OC>[CH3:15][CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][C:13]=3[C:2]=2[C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[CH3:16])[C:6]1=[O:14]
Reactant: Cc1ccc(C)c(B(O)O)c1
Reactant: CC1Cc2c(cc3c(c2Br)CCC3)C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ccc(C)c(-c2c3c(cc4c2CC(C)C4=O)CCC3)c1
Yield: 77 %

Procedure:
A mixture containing 30.0 g (107.5 mmol)) of 4-bromo-2-methyl-3,5,6,7-tetrahydro-2H-s-indacen-1-one, 410 ml of dimethoxyethane, 21.0 g (135.8 mmol) of 2,5-dimethylphenyl boronic acid, 20.0 g (321 mmol) of potassium hydroxide and 72 ml of water was degassed and the flask atmosphere replaced with nitrogen. Stirring was initiated and 0.60 g (2.7 mmol) of palladium acetate and 2.4 g (9.1 mmol) of triphenylphosphine were added. The reaction mixture was stirred at 78° C. for 4 h. After cooling, the mixture was poured into water and the organic phase was separated. The aqueous phase was extracted two times with 200 ml of dichloromethane. The combined organic fractions were dried and solvents removed on a rotoevaporator giving 45 g of crude product. The crude product was dissolved in dichloromethane and filtered through a plug of silica gel to give 24 g of target compound as an oil after evaporation of the solvent (77% yield based on the indacen-1-one starting material).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[N:3]=1.C([O-])(O)=O.[Na+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CCO>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:6]2[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=3)[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Fc1ccc(-c2cc(Cl)nc(Cl)n2)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2,4-dichloro-6-(3-chloro-4-fluoro-phenyl)-pyrimidine (0.12 mol) and NaHCO3 (1.95 g, 0.023 mol) in EtOH at 0° C., add piperazine-1-carboxylic acid tert-butyl ester (0.013 mol). Remove the ice bath and stir at room temperature for 16 h. Concentrate under reduced pressure and partition between EtOAc and brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:50][F:51])[CH2:11][O:12]2)C1C=CC=CC=1.C(O)=O.C(OCC)(=O)C>C(O)C.O1CCCC1.[Pd]>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:50][F:51])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CF)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CF)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
To a suspension of (1S,2S,3S,4R,5S)-2,3,4-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-fluoromethyl-6,8-dioxa-bicyclo[3.2.1]octane (40 mg, 0.06 mmol) and palladium black (40 mg, 0.38 mmol, Aldrich® high surface area) in ethanol (0.5 mL) and tetrahydrofuran (0.1 mL) was added formic acid (0.085 mL, 2.24 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added and the mixture was filtered through a short pad of Celite® and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel using a 4 g redisep silica cartridge (eluting with a gradient of 50 to 100% ethyl acetate in heptane) to afford the title compound as a solid (15.6 mg, 63% yield). (LCMS) 483.0 (M+HCOO−: negative mode). 1H NMR (500 MHz, METHANOL-d4) delta ppm 7.44 (s, 1 H), 7.38 (s, 1 H), 7.37 (s, 1 H), 7.09-7.12 (m, 2 H), 6.80-6.83 (m, 2 H), 4.71 (dd, J=46.59, 10.49 Hz, 1 H), 4.50 (dd, J=48.30, 10.73 Hz, 1 H), 4.19 (dd, J=7.56, 0.98 Hz, 1 H), 4.04 (d, J=0.98 Hz, 2 H), 4.00 (q, J=6.99 Hz, 2 H), 3.80 (dd, J=8.29, 0.98 Hz, 1 H), 3.67 (t, J=8.17 Hz, 1 H), 3.54-3.57 (m, 2 H), 1.37 (t, 3 H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:15][C@H:16]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[CH:18]([CH2:19][CH2:20][C:21]3[C:22]4[C@:30]([CH3:38])([CH2:31][CH2:32][C:33]=32)[C@@H:25]([C@H:26]([CH3:29])[CH:27]=O)[CH2:24][CH:23]=4)[C:17]1([CH3:40])[CH3:39].[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[N:41]1([CH2:29][C@H:26]([C@@H:25]2[C@:30]3([CH3:38])[C:22]([C:21]4[CH2:20][CH2:19][C@@H:18]5[C@:34]([C:33]=4[CH2:32][CH2:31]3)([CH3:37])[CH2:35][CH2:36][C@H:16]([OH:15])[C:17]5([CH3:40])[CH3:39])=[CH:23][CH2:24]2)[CH3:27])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: C1CCNCC1
Reactant: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](CN1CCCCC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Reaction time: 2 h

Procedure:
38 mg sodium tris(acetoxy)borohydride were added to a solution of 42 mg (20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-al and 10 μl piperidine in 3 ml tetrahydrofuran at room temperature. The mixture was stirred for two hours, poured into saturated sodium bicarbonate solution, extracted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 15 mg (20S)-20-[(piperidin-1-yl)methyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].OC1C=CC=CC=1C(C1C=CC=CC=1O)=O.C(OC=C)(=O)CC.[CH:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[O:47]C=C)=[O:40])=[CH2:31]>C1(C)C=CC=CC=1>[CH:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[OH:47])=[O:40])=[CH2:31]
Reactant: C=COc1ccccc1C(=O)c1ccccc1OC=C
Agent: C=COC(=O)CC
Agent: O=C([O-])[O-]
Agent: O=C(c1ccccc1O)c1ccccc1O
Solvent: Cc1ccccc1
Product: C=COc1ccccc1C(=O)c1ccccc1O
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (3.81 g, 5.7 mmol) and sodium carbonate (24.9 g, 0.23 mol)) in toluene (280 ml) were added 2,2′-dihydroxybenzophenone (0.19 mmol) and vinyl propionate (0.75 mol), followed by stirring at 100° C. in an atmosphere of argon gas for 10 hours. The reaction mixture was analyzed by gas chromatography to find that bis(2-vinyloxyphenyl) ketone [i.e., bis(2-vinyloxyphenyl)methanone] and 2-hydroxyphenyl 2-vinyloxyphenyl ketone [i.e., 2-hydroxyphenyl(2-vinyloxyphenyl)methanone] were formed in yields of 82% and 5%, respectively, with a conversion from 2,2′-dihydroxybenzophenone of 99%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:14]=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][NH2:17]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][NH:17][CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1(c2cccc(F)c2)CCCCC1
Reactant: CN
Product: CNCC1(c2cccc(F)c2)CCCCC1
Yield: 45.2 %

Procedure:
The title compound was prepared from the above 1-(3-fluorophenyl)cyclohexane-carbaldehyde (103 mg, 0.5 mmol) and methylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to General Procedure H2.The crude product was purified by silica gel column chromatography (MeOH/CH2Cl2, MeOH from 0% to 15%) to give 1-(1-(3-fluorophenyl)cyclohexyl)-N-methylmethanamine (50 mg, 45%). 1H NMR (CDCl3): 1.28-1.52 (m 4H), 1.54-1.60 (m, 2H), 1.69-1.76 (m, 2H), 2.12-2.18 (m, 2H), 2.28 (s, 3H), 2.61 (s, 2H), 7.45-7.48 (m, 2H), 6.87-6.92 (m, 1H), 7.08 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.27-7.32 (m, 1H). 13C NMR (CDCl3) 22.4, 26.8, 34.9, 37.5, 42.6, 64.6, 112.7, 112.9, 114.2, 114.4, 122.8, 129.9, 130.0, 162.2, 164.7.ESI MS m/z 222.