Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[N:21][O:22][CH2:23][CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:30][CH:31]4[S:35][C:34](=[O:36])[NH:33][C:32]4=[O:37])=[CH:38][CH:39]=3)[CH3:18])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc(NS(=O)(=O)c2ccccc2)cc1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(NS(=O)(=O)c2ccccc2)cc1
Yield: 51 %

Procedure:
Following a procedure similar to that described in Example 40(f), 170 mg of 4'-(phenylsulfonylamino)acetophenone were reacted with 197 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:98 by volume mixture of methanol and methylene chloride as the eluent, to give 170 mg of the title compound, melting at 213°-215° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(N(CC)CC)C.[C:20](Cl)(Cl)=[S:21].[NH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][C:29]([N:38]([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>C(Cl)(Cl)Cl>[CH3:39][N:38]([CH3:40])[C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30][CH2:31][CH:26]([CH2:25][NH:24][C:20]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[S:21])[CH2:27][CH2:28]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: S=C(Cl)Cl
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)C1(c2ccccc2)CCC(CNC(=S)NCCc2c[nH]c3ccccc23)CC1
Temperature: -5 °C
Reaction time: 20 h

Procedure:
Tryptamine (320.4 mg, 2 mmole) was dissolved in dry chloroform (10 ml) and combined with triethylamine (533 μl, 4 mmole). The mixture was cooled to −5° C. Thiophosgene (153.3 μl, 2 mmole) was then added dropwise, resulting in the formation of a precipitate. After a reaction time of 18 h at RT, (4-aminomethyl-1-phenyl-cyclohexyl)-dimethylamine (464.74 mg, 2 mmole) dissolved in chloroform (5 ml) was added. After 20 h stirring at RT, the reaction mixture was clear. Working up was performed by washing the batch with saturated NaHCO3 solution (3×5 ml) and water (5 ml). The organic phase was dried with Na2SO4 and evaporated. The product was a mixture of two diastereoisomers. These were purified and separated by column chromatography [silica gel 60 (70 g); eluent: MeOH/EE 1:1 (1500 ml)]. The more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenylcyclohexylmethyl)-3-[2-(1H-indol-3-yl)ethyl]thiourea (266 mg, m.p. 84-87° C., 31%) and also the more polar diastereoisomer of 1-(4-dimethylamino-4-phenylcyclohexylmethyl)-3-[2-(1H-indol-3-yl)ethyl]thiourea (274 mg, m.p. 92-95° C., 32%) were light beige solids.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:8]([CH2:19]Cl)=[CH:7]2.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:19][C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])=[N+:22]=[N-:23]
Reactant: Fc1ccccc1-c1nc2c(Cl)cccc2cc1CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc2cccc(Cl)c2nc1-c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To stirring solution of 8-chloro-3-(chloromethyl)-2-(2-fluorophenyl)quinoline (0.330 g, 1.08 mmol) in DMF was added sodium azide (0.561 g, 8.62 mmol), and the mixture stirred at room temperature. After 3 hours, the mixture was partitioned between CH2Cl2 and H2O. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure: LC-MS (ESI) m/z 313.0 [M+H]+. The crude product was carried on crude without purification for the next step.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:17]=1[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1.CO.[F:20][B-:21]([F:24])([F:23])[F:22].[CH3:25][O+](C)C>ClCCl>[F:20][B-:21]([F:24])([F:23])[F:22].[CH3:25][N+:1]1[N:2]=[CH:3][N:4]2[C:17]=1[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1
Reactant: C[O+](C)C
Reactant: c1ccc2c(c1)c1ccccc1n1cnnc21
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: C[n+]1ncn2c3ccccc3c3ccccc3c21
Temperature: 2 °C
Reaction time: 16 h

Procedure:
A solution of 1,2,4-triazolo[4,3-f]phenanthridine (A. G. Mikhailovskii, V. S. Shklyaev, Chem. Heterocycl. Comp. 1992, 445) (5.9 g, 27 mmol) in dichloromethane (200 ml) and methanol (20 ml) is admixed under argon at 2° C. with trimethyloxonium tetrafluoroborate (4.3 g, 29 mmol) and stirred at 2° C. for 1 h and at room temperature for 16 h. The resulting precipitate is filtered off and washed with dichloromethane, methanol and petroleum ether. Yield: 5.9 g (69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:33](C1NC=CN=1)(C1NC=CN=1)=[O:34]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][O:32][C:33]4=[O:34])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: OCCNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CC(=O)N(C)C
Product: O=C1OCCN1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
2-({2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl}amino)ethanol (prepared as described in Example 36/27 mg, 0.06 mmol) was dissolved in DMA (0.7 ml) and carbonyl diimidazole (14 mg, 0.09 mmol) was added at −15° C. The temperature was slowly raised to room temperature and the reaction mixture was stirred for 1 hour. The crude mixture was purified by preparative HPLC (column beta-basic, Hypercil 5 μm, 21×100 mm) eluting with a mixture of water and acetonitrile containing 2g/l of ammonium carbonate (gradient) to give the title compound (20 mg, 69%); NMR Spectrum: 3.67-3.71 (m, 4H), 4.29 (t, 2H), 4.44 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.37 (t, 1H), 7.58 (d, 1H), 7.74 (dd, 1H), 7.88 (t, 2H), 8.11 (d, 1H), 8.13 (s, 1H), 8.33 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 482 (MH+).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[C:5]21[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2.O.[NH2:21][CH2:22][C@H:23]([OH:25])[CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:4]3[CH:3]=[CH:2][N:21]([CH2:22][C@H:23]([OH:25])[CH3:24])[C:12]=32)=[CH:7][CH:8]=1
Reactant: Cc1ccc2c(c1)C(=O)C(CC=O)C21CCCCC1
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C21CCCCC1
Reaction time: 0.75 h
Yield: 83 %

Procedure:
A solution of 2.56 g of (RS)-2'-(2-oxoethyl)-5'-methyl-2',3'-dihydro-spiro[cyclohexane-1,1'-[1H]indene]-3'-one and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 2:3). 2.45 g (83%) of (R)-1-[7'-methyl-1',4'-dihydro-spiro[cyclohexane-1,4'-indeno[1,2-b]pyrrole]-1'-yl]-propan-2-ol were obtained as a brown oil.
Reaction SMILES: F[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:43]=[C:42]2[C:38]([CH:39]=[N:40][NH:41]2)=[CH:37][CH:36]=1.CS(C)=[O:46]>>[C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:46].[NH:41]1[C:42]2[C:38](=[CH:37][CH:36]=[C:35]([NH:34][C:2]3[C:7]([C:8]([NH:10][C:11]4[CH:12]=[CH:13][C:14]([C:17]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])([C:22]([F:25])([F:23])[F:24])[C:18]([F:20])([F:19])[F:21])=[CH:15][CH:16]=4)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:43]=2)[CH:39]=[N:40]1
Reactant: CS(C)=O
Reactant: COCCOCCOC(c1ccc(NC(=O)c2cccnc2F)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc2cn[nH]c2c1
Product: COCCOCCOC(c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1)(C(F)(F)F)C(F)(F)F
Product: O=C(O)C(F)(F)F
Temperature: 120 °C

Procedure:
To a suspension of 2-fluoropyridine-3-carbonyl chloride (180 mg, 0.5 mmol, Step B) and NaHCO3 (300 mg) in CH2Cl2 (5 ml), a solution of 4-{2,2,2-trifluoro-1-[2-(2-methoxy)ethoxy]-1-(trifluoromethyl)ethyl}phenylamine (95 mg) was added dropwise, and the suspension was stirred at RT for 1.5 h. Solid inorganic salts were removed via filtration. The filtrate was concentrated to afford (2-fluoro(3-pyridyl))-N-(4-{2,2,2-trifluoro-1-[2-(2-methoxyethoxy)ethoxy]-1-(trifluoromethyl)ethyl}phenyl)-carboxamide as a brown solid. (2-Fluoro(3-pyridyl))-N-(4-{2,2,2-trifluoro-1-[2-(2-methoxyethoxy)ethoxy]-1-(trifluoromethyl)ethyl}-phenyl)carboxamide (240 mg, 0.5 mmol) and 6-amino-indazole (133 mg, 1 mmol) were dissolved in DMSO (2 mL). The solution was heated to 120° C. for 8 h, then partitioned between CH2Cl2 and aqueous NaHCO3 (sat.). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified via preparative HPLC to give a yellow powder as a TFA salt of the title compound. MS: 598 (M+1). Calc'd. for C27H25F6N5O4−597.5.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49][NH:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:48]4[CH2:49][C:50]5[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=5)[CH2:47]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2Cc3ccccc3C2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with 2,3-dihydro-1H-isoindole (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C44H50Cl2N5O3 [(M+H)+] 766.3285, observed 766.3286.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH2:55]([S:57](Cl)(=[O:59])=[O:58])[CH3:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:57]([CH2:55][CH3:56])(=[O:59])=[O:58])[CH2:49][CH2:48]1
Reactant: CCS(=O)(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 45 %

Procedure:
The desired compound was prepared according to the procedure of Example A42, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and ethanesulfonyl chloride as starting materials in 45% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.00 (s, 1H), 9.40 (m, 2H), 8.98 (s, 1H), 8.28 (m, 2H), 8.21 (s, 1H), 7.65 (m, 1H), 7.30 (m, 1H), 7.07 (m, 1H), 3.60 (m, 2H), 2.99 (m, 6H), 2.81 (m, 2H), 2.32 (m, 2H), 1.91 (m, 1H), 1.80 (m, 2H), 1.25 (m, 2H), 1.20 (t, 3H). LCMS for C26H31ClN7O3S (M+H)+: m/z=556.2.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:16]=[C:15]([CH3:30])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH3:14])=[CH:7][CH:6]=1.CN(CCN(C)C)C.[Li]CCCC.CN([CH:47]=[O:48])C>CCOCC>[CH3:30][C:15]1[CH:16]=[C:17]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])[CH:18]=[C:2]([CH3:1])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH3:14])=[C:7]([CH:6]=1)[CH:47]=[O:48]
Reactant: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-methoxymethoxybenzene (2.0 g, 4.66 mmol) in ether was added TMEDA (1.05 mL, 6.99 mmol), followed by nBuLi (2.5 M in THF, 2.8 mL) at −20° C. The reaction mixture was warmed up to 0° C. and stirred for 1 h DMF (0.72 mL, 9.32 mmol) was then added and after stirring at 0° C. for 2 h, the reaction mixture was quenched with a saturated solution of NH4Cl and diluted with EtOAc. The water layer was extracted with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated to give the crude product 5-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-2-methoxymethoxy-benzaldehyde (2.1 g, 98%): 1H NMR (300 MHz, d6-DMSO): δ 10.33 (s, 1H), 7.24 (m, 3H), 6.58 (s, 2H), 5.31 (s, 2H), 3.91 (s, 2H), 3.33 (s, 6H), 1.23 (m, 3H), 1.06 (m, 18H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:9); Rf=0.55.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([OH:15])[C:10]([CH3:14])=[CH:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].CC(C)=O>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][C:9](=[O:15])[C:10]([CH3:14])=[CH:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC=C(C)C(O)CCc1ccccc1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CCC=C(C)C(=O)CCc1ccccc1
Temperature: 85 °C

Procedure:
To a dry 2 liter multi-neck round bottom flask fitted with an air stirrer, nitrogen inlet condenser and an addition funnel 168 g of 65% 1-Phenyl-4-Methyl-4-Hepten-3-ol, 51 g of 98% Aluminum Isopropoxide, (obtained from the Acros Organics) and 200 g of Acetone and 200 g of Toluene were added and stirred. The reaction mixture was slowly heated at reflux to 85° C. The samples were collected every our when the temperature of the reaction mixture was between 70° C. and 80° C. The NMR spectrum of the 1-Phenyl-4-Methyl-4-Hepten-3-one is as follows: 1.0 ppm (t, 3H); 1.8 ppm (s, 3H); 2.2 ppm (m, 2H); 2.9-3.0 ppm (m, 2H); 6.6 ppm (t, 1H) 7.2 ppm (m, 3H); 7.28 ppm (s,1H), 7.3 ppm (s, 1H).
Reaction SMILES: C(O)=O.[CH3:4][N:5]([CH3:36])[C:6](=[O:35])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:10][CH:9]=1.C([Si]([O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH:63]2[CH2:65][O:64]2)=[CH:57][CH:56]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[OH:64][C@H:63]([CH2:62][O:61][C:58]1[CH:59]=[CH:60][C:55]([OH:54])=[CH:56][CH:57]=1)[CH2:65][NH:34][CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][CH:22]2[CH2:21][CH2:20][N:19]([C:17]([NH:16][CH2:15][CH2:14][C:11]3[CH:10]=[CH:9][C:8]([O:7][C:6](=[O:35])[N:5]([CH3:4])[CH3:36])=[CH:13][CH:12]=3)=[O:18])[CH2:24][CH2:23]2)=[CH:31][CH:30]=1
Reactant: CN(C)C(=O)Oc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)C(=O)Oc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 27.2 %

Procedure:
4-{2-[({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}carbonyl)amino]ethyl}phenyl dimethylcarbamate formate (0.47 g, 0.94 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.40 g, 1.0 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.22 g, 0.256 mmol).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.C[Si](C)(C)Cl.[CH3:25][CH:26]([CH:28]([Cl:33])[O:29][C:30](Cl)=[O:31])[CH3:27]>ClCCl>[Cl:33][CH:28]([O:29][C:30]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:31])[CH:26]([CH3:27])[CH3:25]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: CC(C)C(Cl)OC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Reaction time: 0.33 h
Yield: 77.5 %

Procedure:
To a mixture containing gabapentin (1.71 g, 10 mmol) and triethylamine (3.06 mL, 22 mmol) in dichloromethane (150 mL) was added trimethylchlorosilane (1.4 mL, 11 mmol) and the resulting mixture was stirred until clear (about 20 min). A solution containing 1-chloro-2-methylpropylchloroformate (1.27 mL, 11 mmol) in dichloromethane (10 mL) was then added at 0° C. and stirred at room temperature for 60 min. The reaction mixture was washed with 10% citric acid (30 mL) and the organic layer separated. The aqueous layer was further extracted with ether (3×20 mL) and the combined organic phases were dried over MgSO4 and then concentrated in vacuo. Chromatography of the residue on silica gel, eluting with hexane: ethyl acetate (1:4) gave 2.37 g (77%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.04 (d, J=6.4 Hz, 3H), 1.06 (d, J=6.4 Hz, 3H), 1.36-1.53 (m, 10H), 2.15 (m, 1H), 2.34 (s, 2H), 3.24 (m, 2H), 5.39 (t, 1H), 6.32 (d, J=5.6 Hz), 1H). MS (ESI) m/z 306.34 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([Cl:32])[CH:31]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:28]2[CH:27]=[C:26]([Cl:25])[CH:31]=[C:30]([Cl:32])[CH:29]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2cc(Cl)cc(Cl)c2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) from 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester (see Example 1(a)) and 3,5-dichlorophenylboronic acid, followed by ester hydrolysis in accordance with the procedure described in Example 35, Method 3, step (b).
Reaction SMILES: [CH:1]1([CH:7]([CH2:18][C:19]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=O)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.C[N:31](C)C=O>>[CH:1]1([C:7]2[CH:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:31]=[C:9]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC(CC(=O)c1ccco1)C1CCCCC1)c1cccc(O)c1
Reactant: CN(C)C=O
Solvent: CC(=O)O
Product: Oc1cccc(-c2cc(C3CCCCC3)cc(-c3ccco3)n2)c1
Temperature: 100 °C

Procedure:
A mixture of 3-cyclohexyl-1-(3-hydroxyphenyl)-5-(furan-2-yl)-1,5-pentanedione on Wang resin (2.7 g, 1.90 mmol), NH4OAc (1.7 g), and AcOH (1.7 mL) in dimethylformamide (30 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 3-(4-cyclohexyl-6-furan-2-yl-pyridin-2-yl)-phenol; 1H NMR (DMSO-d6) d 1.42 (m, 4 H), 1.71 (m, 2 H), 1.85 (m, 4 H), 2.64 (m, 1 H), 6.67 (dd, J=3.3, 1.5 Hz, 1 H), 6.85 (dd, J=8.1, 1.8 Hz, 1 H), 7.18 (d, J=3.3 Hz, 1 H), 7.29 (m, 1 H), 7.57 (m, 3 H), 7.63 (s, 1 H), 7.85 (s, 1 H), 9.54 (s, 1 H); IR (KBr) 1607 cm−1 ; MS [M+H]+ m/z=320. Anal. calcd for C21H21NO2.0.6 C4H8O2: C, 75.52; H, 6.94; N, 3.77; Found: C, 75.72; H, 6.72; N, 3.55.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)=[O:7])([CH3:4])[CH3:3].[OH:28]O.[OH-].[Na+]>CO.ClCCl.O>[CH3:4][C:2]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17]2([O:28][CH:18]2[C:19](=[O:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)=[O:7])([CH3:1])[CH3:3]
Reactant: OO
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A solution of N-(1,1-dimethylethyl)-3-oxoandrost-4-ene-17β-carboxamide (4.77 g, 12.8 mmole) in methanol (55 mL) and dichloromethane (11 mL) was cooled to 12° C. and treated in one portion with 30% aqueous hydrogen peroxide (3.3 mL) followed by dropwise addition of an aqueous sodium hydroxide solution prepared by dissolving sodium hydroxide (0.38 g) in water (2.2 mL). After one hour, the cooling bath was removed and the reaction was stirred for an additional 3 hours. Most of the solvent was then removed in vacuo. The residue was dissolved in dichloromethane and purified by flash chromatography (hexane-20% ethyl acetate and hexane-40% ethyl acetate) to give N-(1,1-Dimethylethyl)-4,5-epoxy-3-oxoandrostane-17β-carboxamide (3.3 g, 66.2%) as a solid foam. This material was a mixture of the 4α,5α- and 4β,5β-isomers and it was used as is in further reactions.