Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[N:18][OH:19])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=C1CC2CCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
4.85 g (22.56 mmol) of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one was dissolved in 60 ml of ethanol. 3.13 g (45 mmol) hydroxylamine hydrochloride was then added followed by 1.8 g (45 mmol) of NaOH in 15 ml of water. The mixture was refluxed for 20 hrs and was cooled to ambient temperature. The solvent was removed in vaccuo. The residue was diluted with ethyl acetate and washed with water and the organic layer was dried over sodium sulfate. The solvent was removed to give 4.28 g of product as a light yellow solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C@@H:16]1[C:11]([CH2:12][C:13](=[O:20])[CH2:14][CH2:15]1)=[CH:10][C@H:9]3[CH3:21].C[C@@H]1C=C2[C@H](CCC(=O)C2)[C@@H]2[C@@H]1[C@H]1[C@@](CC2)(C)C(=O)CC1.C(O)(=O)C.O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@H]1C(CC(=O)CC1)=C[C@H]3C>>[CH3:21][C@@H:9]1[CH:10]=[C:11]2[C@H:16]([CH2:15][CH2:14][C@H:13]([OH:20])[CH2:12]2)[C@@H:17]2[C@@H:8]1[C@H:5]1[C@@:3]([CH2:19][CH2:18]2)([CH3:4])[C@@H:2]([OH:1])[CH2:7][CH2:6]1
Reactant: C[C@@H]1C=C2CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]21
Agent: C[C@@H]1C=C2CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@@H]21
Solvent: CC(=O)O
Product: C[C@@H]1C=C2C[C@@H](O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]21

Procedure:
Following essentially the same procedure but substituting 17β-hydroxy-7α-methyl-estr-5-en-3-one or 7α-methyl-estr-5-en-3,17-dione for the 17β-hydroxy-7α-methyl-estr-5-en-3-one acetate above, also results in the preparation of the desired 7α-methyl-estr-5-ene-3β,17β-diol.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH:2]([CH3:4])[CH3:3].C(N(C(C)C)C(C)C)C.Cl[C:27](=[O:49])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][O:38][C:39]2[CH:48]=[CH:47][CH:46]=[CH:45][C:40]=2[C:41]([O:43][CH3:44])=[O:42])=[CH:32][CH:31]=1>C(#N)C>[CH2:1]([N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=1)[C:27](=[O:49])[CH2:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][O:38][C:39]2[CH:48]=[CH:47][CH:46]=[CH:45][C:40]=2[C:41]([O:43][CH3:44])=[O:42])=[CH:34][CH:35]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)N(Cc2ccc(C(F)(F)F)cc2)CC(C)C)cc1
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
N-Isobutyl-N-[4-(trifluoromethyl)benzyl]amine (0.172 g, 0.746 mol) was dissolved in dry acetonitrile under N2 and N-ethyl-N,N-diisopropylamine (0.371 g, 2.867 mmol) was added. The mixture was stirred for 30 min and methyl 2-{2-[4-(2-chloro-2-oxoethoxy)phenyl]ethoxy}benzoate (0.200 g, 0.573 mmol) was added. The solution was stirred over night at room temperature. The crude was purified by flash chromatography (started with isocratic heptane/EtOAc 50/50 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation to give 0.242 g of methyl 2-{2-[4-(2-{isobutyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]ethoxy}benzoate (yield 77.6%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]2[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=2[C:10]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:24][CH:23]=1)=[O:21].C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]2[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=2[C:10]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[CH:24][CH:23]=1)=[O:21]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3OC)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccccc2O)sc2cc(O)ccc12
Yield: 48.5 %

Procedure:
By the method described in Example 2, the product of Example 9 (560 mg, 1.12 mmol), ethanethiol (0.42 mL, 5.77 mmol), and aluminum chloride (1.05 g, 7.88 mmol) were stirred in anhydrous CH2Cl2 (30 mL) to provide, after chromatography (silica gel, 5-10% methznol in CH2Cl2), 257 mg (49%) of the title product as a yellow foam: 1H NMR d 1.47 (m, 2H), 1.62 (m, 4H), 2.54 (m, 4H), 2.75 (t, J=5.4 Hz, 2H), 4.10 (t, J=5.4 Hz, 2H), 4.87 (br s, 2H), 6.64 (d, J=8.1 Hz, 1H), 6.72-6.85 (m, 4H), 7.02 (m, 1H), 7.25 (m, 2H), 7.47 (d, J=8.9 Hz, 1H), 7.67 (d, J=8.6 Hz, 2H); MS (FD) m/e 473 (M+); Anal. calc'd. for C28H27NO4S: C, 71.01; H, 5.75; N, 2.96. Found: C, 71.27; H, 5.82; N, 3.19.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1>CCOC(C)=O>[C:11]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=[CH:13][CH:14]=[C:9]([NH2:8])[CH:10]=1
Reactant: Brc1ccccc1
Reactant: Nc1cccc(B(O)O)c1
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2ccccc2)c1

Procedure:
Bromobenzene (300 mg, 1.91 mmol) was coupled to 3-amino-phenylboronic acid (355 mg, 2.29 mmol) using Method E. The crude residue was re-dissolved in EtOAc (8 ml) and washed with saturated NaHCO3 (3×8 ml). The organic layer was extracted with 1.2M HCl (1×8 ml) then basified with 6M NaOH until a white precipitate formed. This was then extracted with EtOAc (3×10 ml). The combined organic layers were dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[CH2:10]([O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)[CH3:11].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[CH2:10]([O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])[CH:15]=1)[CH3:11]
Reactant: CCOC(CBr)OCC
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCC(OCC)OCC)c1
Temperature: 120 °C

Procedure:
2-Bromoacetaldehyde diethyl acetal (3 ml, 20 mmol), ethyl-3-hydroxy-benzoate (1.66 g, 10 mmol), potassium carbonate (2.76 g, 20 mmol) and sodium iodide (0.298 g, 2 mmol) were heated at 120° C. in dimethyl formamide (DMF) (15 ml) for 17 hrs. Another batch of 2-bromoacetaldehyde diethyl acetal (3 ml, 20 mmol) was added and the reaction mixture was heated at 120° C. for another 24 hrs. The reaction was cooled to room temperature and all the solvents were evaporated under reduced pressure. The residues were partitioned between dichloromethane (DCM) (200 ml) and water (200 ml). The DCM layer was separated and the aqueous layer was back-extracted with DCM (2×100 ml). All the DCM extracts were combined, dried over MgSO4 and evaporated under reduced pressure. The residue was purified by a column chromatography (4×20 cm). The product was eluted with 100% DCM and the title compound was obtained as a colourless oil (2.21 g, 78.3%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([NH:12][CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:11]=1)[NH:8][C:7]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][OH:24])[N:22]=1)=[CH:6]2.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](O)=[O:31]>>[CH:13]1([NH:12][C:10]2[CH:11]=[C:3]([CH2:2][NH:1][C:30]([C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)=[O:31])[CH:4]=[C:5]3[C:9]=2[NH:8][C:7]([C:18]2[S:19][CH2:20][C@@H:21]([CH2:23][OH:24])[N:22]=2)=[CH:6]3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NCc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CO)CS3)cc2c1
Reactant: O=C(O)c1ccco1
Product: O=C(NCc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CO)CS3)cc2c1)c1ccco1

Procedure:
[(R)-2-(5-aminomethyl-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol prepared in Example 258 and furan-2-carboxylic acid were reacted according to the same procedure as Step B of Preparation 101 to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25])=[CH:17][C:16]=3[CH3:28])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[OH:26][C:24]([CH3:27])([CH3:25])[CH2:23][O:22][C:18]1[CH:17]=[C:16]([CH3:28])[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][O:7][C:6]3[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[CH:30][CH:29]=3)[CH:10]=2)=[C:20]([CH3:21])[CH:19]=1
Reactant: Cc1cc(OCC(C)(C)O)cc(C)c1-c1cccc(COc2ccc(CO)cc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1cc(OCC(C)(C)O)cc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Temperature: 50 °C

Procedure:
A mixture of 1-[(3′-{[4-(hydroxymethyl)phenoxy]methyl}-2,6-dimethylbiphenyl-4-yl)oxy]-2-methylpropan-2-ol, manganese dioxide and chloroform was stirred with heating at 50° C. for 20 hours to obtain 4-{[4′-(2-hydroxy-2-methylpropoxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy}benzaldehyde.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][C:15]=3[CH:16]=[CH2:17])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.C(O)C.[Pd]>[CH2:16]([C:15]1[CH:14]=[N:13][N:11]2[CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]([C:18]3[CH:19]=[CH:20][C:21]([CH:22]=[O:23])=[CH:24][CH:25]=3)=[N:9][C:10]=12)[CH3:17]
Reactant: C=Cc1cnn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cnn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
275 mg 4-(6-phenyl-3-vinylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde was dissolved in 10 mL THF and 10 mL ethanol. Pd/C (10% w/w) was added and stirred under H2-atmosphere at room temperature for 1.5 h. The mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by chromatography on silica gel (dichloromethane/ethyl acetate) to yield the desired compound.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].CC1N=C(CC2C3C(C=CC=CC=3)=CC=2C)SC=1>ClC(Cl)C>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[O:13])=[CH:15][CH:16]=1)([O-:7])=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cc1csc(Cc2c(C)cc3cccccc2-3)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
AlCl3 (101 mg, 0.757 mmol) was weighed quickly into an argon-flushed vial. While the vial was being purged with argon, dichloroethane was added slowly. The ensuing mixture was syringed quickly into a round-bottom flask and cooled to 0° C. A solution of 4-nitro benzoyl chloride (70 mg, 0.377 mmol) in dichloroethane was added slowly into the suspension of AlCl3 at O—C. This mixture was stirred at 0° C. for 30 min after which a fresh solution of compound 6 (64 mg, 0.253 mmol) in dichloroethane was added slowly to the reaction mixture being stirred at 0° C. After the reaction was stirred at 0° C. for 30 min, it was brought to room temperature and then stirred for another 30 min. The reaction was quenched by adding ice-cold water slowly. The organic layer was extracted into dichloromethane and washed with water and brine, dried with MgSO4 and purified using flash chromatography (ethyl acetate and hexane). The purified material was dried down into a brown/orange solid. Yield: 45 mg, 44%. 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J=9.84 Hz, 1H), 8.44 (d, J=9.89 Hz, 1H), 8.29 (d, J=8.82 Hz, 2H), 7.86 (d, J=8.81 Hz, 2H), 7.71 (t, J=9.82 Hz, 1H), 7.46 (t, J=9.72 Hz, 1H), 7.29 (t, J=9.93 Hz, 1H), 6.67 (s, 1H), 4.70 (s, 2H), 2.42 (s, 3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.2, 170.3, 152.3, 150.4, 149.5, 146.3, 141.4, 140.2, 138.2, 135.6, 133.7, 130.2, 127.2, 125.0, 124.3, 123.6, 123.3, 113.2, 29.0, 16.9. HRMS (ES) calcd MH+ [C23H19N2O3S]+403.1038. found 403.1106.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[CH2:17][CH2:16][CH2:15][C:6]3=[N:7][N:8]([CH2:11][CH:12]([OH:14])[CH3:13])[C:9]([CH:10]=1)=[C:5]23.N([O-])=[O:19].[Na+].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.O.O>[OH:14][CH:12]([CH3:13])[CH2:11][N:8]1[C:9]2[CH:10]=[C:2]([OH:19])[CH:3]=[C:4]3[C:5]=2[C:6]([CH2:15][CH2:16][CH2:17]3)=[N:7]1
Reactant: CC(O)Cn1nc2c3c(cc(N)cc31)CCC2
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(O)Cn1nc2c3c(cc(O)cc31)CCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
The product from Step D (1.90 g, 8.4 mmol) was dissolved in H2SO4/H2O (1:2, 60 mL) and cooled to 0° C. A solution of NaNO2 (0.64 g, 9.2 mmol) in H2O (2.0 mL) was added dropwise and the resultant dark solution was stirred for 2 h. Water (40 mL) was added to this solution and the mixture was heated to 110° C. for 2 h. After cooling the mixture to room temperature it was carefully neutralized with a saturated aqueous NaHCO3 solution and extracted with ethyl acetate (3×65 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, 50% to 60% gradient of ethyl acetate in hexane) to give a solid (1.2 g, 83%): m.p: 153-155° C.; MS (ES) m/z 233(M+); 1H NMR (CDCl3) δ 9.39 (1H, s), 6.50 (1H, s), 6.34 (1H, s), 4.84 (1H, d, J=4.0 Hz), 4.00 (3H, m), 2.76 (2H, q, j=6.0 Hz), 2.01 (2H, m), 1.01 (3H, d, J=6.0 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:19][CH3:20])[CH3:18])=[CH:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:19]([N:17]([CH3:18])[CH2:16][CH2:15][CH2:14][O:13][C:12]1[CH:21]=[CH:22][C:9]([C:3]2([CH2:2][N:1]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[CH:10][CH:11]=1)[CH3:20]
Reactant: BrCCOCCBr
Reactant: CCN(C)CCCOc1ccc(C2(CN)CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(C)CCCOc1ccc(C2(CN3CCOCC3)CCOCC2)cc1
Temperature: 60 °C
Yield: 56 %

Procedure:
To a stirred solution of 3-{4-[4-(aminomethyl)tetrahydro-2H-pyran-4-yl]phenoxy}-N-ethyl-N-methylpropan-1-amine (500 mg, 1.6 mmol) and bis(2-bromoethyl)ether (345 mg, 1.5 mmol) in anhydrous acetonitrile (50 mL) was added potassium carbonate (450 mg, 3.3 mmol). The mixture was heated to 60° C. overnight then concentrated in vacuo. The crude product was partitioned between dichloromethane (50 ml) and water (50 ml), the aqueous phase was extracted with dichloromethane (25 ml) and the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude material was carried out with flash chromatography (silica gel, dichloromethane/methanol/aqueous ammonia 100:0:0 to 96:4:0.4) to afford the title compound as a clear colourless oil (315 mg, 0.84 mmol, 52%). 1H NMR (400 MHz CDCl3) δ 1.05 (t, 3H), 1.82-1.93 (m, 2H), 1.92-2.00 (m, 2H), 2.08-2.20 (m, 6H), 2.25 (s, 3H), 2.39 (s, 2H), 2.40-2.50 (q, 2H), 2.50-2.59 (m, 2H), 3.48-3.60 (m, 6H), 3.70-3.80 (m, 2H), 4.00 (t, 2H), 6.86 (d, 2H), 7.20 (d, 2H). LRMS APCI+ m/z 377 [MH]+. HRMS ESI+ m/z 377.2792 [MH]+.−
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][CH:14]=3)=[CH:10][CH:11]=2)[N:6]([CH3:26])[C:5]1=[O:27].[H][H]>[Pd].CCO>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH2:14][CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:18]3)=[CH:10][CH:11]=2)[N:6]([CH3:26])[C:5]1=[O:27]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CCCN(C(=O)OC(C)(C)C)C3)nc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round bottom flask containing tert-butyl 5-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-3,6-dihydropyridine-1(2H)-carboxylate (17-27) (1 g, 2.497 mmol), was added EtOH (25 mL) & Palladium on Carbon (10% by weight on carbon) (0.25 g, 0.2349 mmol). A balloon containing hydrogen gas was then attached and purged 3× with vacuum/hydrogen. The reaction mixture was permitted to stir at room temperature for 1 hour, then purged 3× with vacuum/nitrogen, diluted with EtOH, filtered & concentrated to yield tert-butyl 3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]piperidine-1-carboxylate (18-1). LRMS (M+H)+: observed=403.3, calculated=403.5.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:10]1[C:14]2([CH2:19][CH2:18][CH:17](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>CN(C)C=O>[O:9]([CH:17]1[CH2:18][CH2:19][C:14]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:15][CH2:16]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(OC2CCC3(CC2)OCCO3)cc1
Reaction time: 2 h

Procedure:
440 mg of 60% sodium hydride in mineral oil (0.12 mmole) were stirred in 9 ml absolute dimethylformamide under a nitrogen atmosphere. 1.1 g (0.12 mmole) phenol were added, followed by 3.1 g (10 mmole) toluene-4-sulphonic acid-1,4-dioxaspiro[4.5]dec-8-yl ester (Gray et al., J. Org. Chem., 35, (1970), 1525-1533), dissolved in 6 ml dimethylformamide. The batch was stirred for 2 hours at a temperature between 80° C. and 85° C. After cooling, the batch was poured on to ice and extracted with ether, and the solution was washed with dilute aqueous sodium hydroxide solution and dried over sodium sulphate. After evaporating off the solvent, the crude product was purified with diisopropyl ether via a silica gel column. 1.27 g (54% theoretical) of compound (25) were obtained as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1.S(Cl)([Cl:18])=O>>[Cl:18][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:9][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Oc2ncccn2)cc1
Product: ClCc1ccc(Oc2ncccn2)cc1

Procedure:
In a first step as depicted in Scheme 1, an appropriately substituted alcohol, for example, the known compound (4-pyrimidin-2-yloxyphenyl)methan-1-ol, is halogenated with, for example thionyl chloride, to afford the corresponding 2-[4-(chloromethyl)phenoxy]pyrimidine (A). Intermediate (A) is then reacted under basic conditions with an appropriately substituted cyclic amine derivative, for example, the known compound 4-piperidone hydrochloride monohydrate, to afford the corresponding 1-[(4-pyrimidin-2-yloxyphenyl)methyl]piperidin-4-one (B). A mixture of intermediate (B) and an appropriately substituted haloalkyl derivative, for example bis(trifluoromethoxyphenyl)bromomethane, is reacted in the presence of n-butyl lithium, to afford the corresponding 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-[(4-pyrimidin-2-yloxyphenyl)methyl]piperidin-4-ol (I-A). Intermediate (I-A) is then oxidized, with for example hydrogen peroxide, in an appropriate solvent, to form an N-oxide, a compound of formula I-C. In a separate synthesis, intermediate (I-A) is reacted with a thiohalide, for example (dimethylamino)sulfur trifluoride, to provide halogen-derived compounds of formula I-D, wherein X is, for example fluorine. Examples 1 and 3, set forth below, provide detailed methods to how compounds of formula I (-A, -C and -D) shown in Scheme 1 were prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH2:24][CH3:25])=[CH:4][CH:3]=1.Cl.[NH2:27][CH2:28][C:29]([NH2:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:31][C:29](=[O:30])[CH2:28][N:27]=3)[C:9]=2[CH2:24][CH3:25])=[CH:6][CH:7]=1
Reactant: NCC(N)=O
Reactant: CCc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: Cl
Product: CCc1c(C2=NCC(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Compound 26 was synthesized from 4c (1.0 g, 2.53 mmol) and 2-amino-acetamide hydrochloride (5k) (0.56 g, 4.56 mmol) as a white solid (0.81 g, 73%) in a manner similar to that described in Example 53. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, 1H), 7.31 (d, 2H), 7.30˜7.27 (m, 2H), 7.07 (d, 2H), 4.35 (d, 2H), 2.77 (q, 2H), 1.20 (t, 3H); ESMS m/z: 433.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Reactant: ClCCN1CCCC1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCCC1)CN2c1ccccc1Cl

Procedure:
The title compound, MS: m/e=603.0 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 1-(2-chloroethyl)-pyrrolidine hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:21]([NH2:23])=[O:22].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:31](C)=O.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:31])[CH2:17][CH2:16]3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:21]([NH2:23])=[O:22]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)c1cc2c(C3CCNCC3)cccc2n1Cc1cccc(F)c1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN1CCC(c2cccc3c2cc(C(N)=O)n3Cc2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(3-Fluoro-benzyl)-4-piperidin-4-yl-1H-indole-2-carboxylic acid amide (50 mg, 0.14 mmol) in CH2Cl2 (5 ml) were added formaldehyde (20 μl, 0.24 mmol, 37% in H2O solution) and NaBH(OAc)3 (74 mg, 0.35 mmol). After stirring at room temperature for 4 hours, the reaction mixture was added to a saturated solution of sodium bicarbonate, followed by a mixture of CH2Cl2/H2O. The organic fraction was separated, washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo to give 1-(3-Fluoro-benzyl)-4-(1-methyl-piperidin-4-yl)-1H-indole-2-carboxylic acid amide as a brown oil. This oil was dissolved in 4 ml ethanol, and 2 M ethanolic hydrochloric acid solution (1 ml) was added. The reaction mixture is heated at 100° C. for 20 minutes, then cooled to room temperature, and 14 mg of 1-(3-Fluoro-benzyl)-4-(1-methyl-piperidin-4-yl)-1H-indole-2-carboxylic acid amide hydrochloride salt was collected. MS: 366 (M+H)+.