Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[C:24]([N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32])(=[O:26])[CH3:25]>>[C:24]([N:27]1[CH2:31][CH2:30][N:29]([C:2]2[CH:3]=[N:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[N:6][CH:7]=2)[C:28]1=[O:32])(=[O:26])[CH3:25]
Reactant: Cc1cnc(N2CCN(C(=O)c3ncc(Br)cn3)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2cnc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)nc2)C1=O
Yield: 8.7 %

Procedure:
Using (5-bromopyrimidin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (376 mg) described in Preparation Example 229 and 1-acetylimidazolidin-2-one (192 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (37 mg) was obtained.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][C@H:3]2[CH2:6][NH:7][CH2:8][C@@H:2]12.Br[C:17]1[CH:18]=[C:19]([CH3:24])[C:20]([Cl:23])=[N:21][CH:22]=1>>[Cl:23][C:20]1[N:21]=[CH:22][C:17]([N:7]2[CH2:6][C@H:3]3[C@H:2]([N:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[CH2:8]2)=[CH:18][C:19]=1[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CNC[C@H]21
Reactant: Cc1cc(Br)cnc1Cl
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)OC(C)(C)C)[C@@H]3C2)cnc1Cl
Yield: 41 %

Procedure:
The product from Example 15E and 5-bromo-2-chloro-3-methyl pyridine were processed as described in Example 1E to provide the title compound (41% yield). MS (DCI/NH3) m/z 338/340 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:7][C:8]=1[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH3:20])=[CH:15][CH:14]=1)=[O:12])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Br[CH2:41][C:42]([O:44]CC)=[O:43]>CN(C)C=O.O>[CH:1]([C:4]1[N:5]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=2)[S:7][C:8]=1[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:20])[CH2:41][C:42]([OH:44])=[O:43])=[CH:15][CH:14]=1)=[O:12])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CNc1ccc(C(=O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CCC(=O)c1ccc(N(C)CC(=O)O)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 122.6 %

Procedure:
The obtained 3-[4-Isopropyl-2-[4-(trifluoromethyl)phenyl]thiazol-5-yl]-1-(4-methylaminophenyl)propan-1-one (40 mg, 0.0931 mmol) and diisopropylethylamine (80 μL, 0.462 mmol) were dissolved in anhydrous dimethylformamide (2 mL). Ethyl bromoacetate (66 mg, 0.393 mmol) was added to the solution. The mixture was stirred at 110° C. for 16 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate to remove the solvent. The obtained residue was purified by silica gel column chromatography with hexane/chloroform (7:3, v/v) to give the desired compound (56 mg) as yellow crystalline product (yield 47%).
Reaction SMILES: CO.C[O:4][C:5](=O)[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[C:8]([Cl:14])[CH:7]=1.[BH4-].[Na+].C(O)(C)(C)C>O>[Cl:12][C:10]1[CH:11]=[C:6]([CH:7]=[C:8]([Cl:14])[C:9]=1[NH2:13])[CH2:5][OH:4]
Reactant: COC(=O)c1cc(Cl)c(N)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CO
Solvent: O
Product: Nc1c(Cl)cc(CO)cc1Cl
Yield: 92.7 %

Procedure:
Methanol (400 ml) was added dropwise over 2 hours to a mixture of methyl-3,5-dichloro-4-aminobenzoate (110 g), NaBH4 (142.5 g) and t-butanol (1.1 L). At the end of the addition, the mixture was refluxed 3 hours, cooled, then H2O (1.2 L) was carefully added. The resulting layers were separated and the organic phase was washed with H2O (2×200 mL), separated, dried (MgSO4), filtered and evaporated to afford the desired product (89 g), mp 110-112° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:35]=[CH:34][C:25]4[O:26][C:27]([F:33])([F:32])[O:28][C:29]([F:31])([F:30])[C:24]=4[CH:23]=3)=[O:20])=[C:14](SC)[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[CH:38]1C=C(Cl)C=C(C(OO)=O)C=1.[S:49]([O-:53])([O-])(=[O:51])=S.[Na+].[Na+]>C(Cl)Cl.C1COCC1>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:35]=[CH:34][C:25]4[O:26][C:27]([F:32])([F:33])[O:28][C:29]([F:30])([F:31])[C:24]=4[CH:23]=3)=[O:20])=[C:16]([S:49]([CH3:38])(=[O:53])=[O:51])[CH:17]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)c(SC)c2)ccn1
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)c(S(C)(=O)=O)c2)ccn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 46.1 %

Procedure:
To N-methyl-4-[3-(methylthio)-4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)-amino]carbonyl}amino)phenoxy]pyridine-2-carboxamide (150 mg, 0.28 mmol) in anhydrous 1:1 v/v DCM/THF (3.0 mL) at 0° C. was added mCPBA (162.7 mg, 0.61 mmol, 2.2 eq, and the reaction mixture was stirred at RT for 17 h. The reaction mixture was poured into aqueous saturated sodium thiosulfate solution and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 73.3 mg (46.1%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 10.31 (s, 1H), 8.81 (q, J=5.4 Hz, 1H), 8.71 (s, 1H), 8.55 (d, J=5.7 Hz, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.15 (d, J=2.4 Hz, 1H), 7.70 to 7.59 (m, 3H), 7.47 (s, 1H), 7.45 (d, J=6.9 Hz, 1H), 7.21 (dd, J=5.4, 2.4 Hz, 1H), 3.37 (s, 3H), 2.79 (d, J=5.1 Hz, 3H); MS LC-MS (M+H)+=571.1, RT=3.81 min; m.p. 222-223.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[Cl:11].CCO.[Cl-].[NH4+].O>C1COCC1.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[Cl:11]
Reactant: O=[N+]([O-])c1ccc(Br)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Br)c(Cl)c1
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
To a solution of 1-bromo-2-chloro-4-nitrobenzene (1.0 g, 4.23 mmol) in THF (7.24 mL) was added EtOH (7.24 mL) followed by ammonium chloride (0.339 g, 6.34 mmol) in water (7.23 mL, 401 mmol) and iron (0.945 g, 16.92 mmol). The reaction mixture was heated at 60° C. in a sealed tube. After 3.5 hours, the reaction mixture was allowed to cool to room temperature and the heterogeneous mixture filtered through a disposable fritted funnel. The filter cake was washed with EtOAc. The solution was concentrated to half-volume, then diluted with EtOAc (10 mL) and 1 N NaOH (10 mL). Layers were separated. Aqueous phase was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford the title compounds as a tan solid. The crude material was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][C:24]=1[F:37])[CH2:2][CH2:3][CH3:4].[N+](=[CH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N-].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+]>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]#[N:36])=[CH:25][C:24]=1[F:37])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Reaction time: 0.5 h

Procedure:
To a mixture of 4′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (2.14 g), rhodium(I) acetate (0.57 g) and toluene (30 mL) was added dropwise a solution of ethyl diazoacetate (2.30 g) in toluene (10 mL) at 70° C., and the mixture was stirred at the same temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (1.24 g, 49%).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].S(=O)(=O)(O)[OH:8].[CH2:12]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])O>O>[C:15]([NH:14][CH2:12][CH:3]([C:1]([NH2:2])=[O:8])[C:4]([OH:6])=[O:5])(=[O:18])[CH:16]=[CH2:17]
Reactant: N#CCC(=O)O
Reactant: O=S(=O)(O)O
Reactant: C=CC(=O)NCO
Solvent: O
Product: C=CC(=O)NCC(C(N)=O)C(=O)O
Reaction time: 1.5 h

Procedure:
A 500 ml. reactor equipped with mechanical stirrer, nitrogen inlet, condenser, thermometer and addition funnel is charged with 102.0 grams (1.2 equivalents) of cyanoacetic acid and 225.0 grams (2.2 equivalents) of concentrated sulfuric acid. Stirring is begun and nitrogen is blanketed over the stirred solution. The reactor is then placed in a water bath to provide temperature control. Upon dissolution of the cyanoacetic acid, the solution temperature is adjusted to 25° C. and 101.0 grams (0.6 equivalents) of a 60 percent by weight active aqueous solution of N-methylol acrylamide is added dropwise through the addition funnel while agitation continues. The rate of addition and water bath temperature are adjusted so that the reacting materials are maintained at 30° C.±2° C. The addition takes approximately 1.5 hours. After completion of the N-methylol acrylamide addition, the reacting materials are maintained at 30° C.±2° C. with agitation for an additional 1.5 hours for the completion of the reaction.
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4]1)C.[Br:15]N1C(=O)CCC1=O>>[Br:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[N:7][N:3]([CH3:1])[N:4]=2)=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1nnc(-c2ccc(C)cc2)n1
Product: Cn1nnc(-c2ccc(CBr)cc2)n1

Procedure:
As depicted in Scheme 5, Intermediate (M), for example, 5-(4-methylphenyl)-1,2,3,4-tetraazole, was prepared by reacting an appropriate toluonitrile, for example para-toluonitrile, with sodium azide at elevated temperature in an appropriate solvent. Intermediate (M) was then alkylated with an appropriate iodoalkane under basic conditions, affording the corresponding alkylated tetraazole (N), for example, 2-ethyl-5-(4methylphenyl)-1,2,3,4-tetraazole. Intermediate (N) was in turn brominated with, for example, N-bromosuccinimide at elevated temperature in an appropriate solvent, providing the corresponding bromomethyl derivative (O), for example, 5-[4-(bromomethyl)phenyl]-2-ethyl-1,2,3,4-tetraazole. Intermediate (O) was then reacted with ethyl isonipecotate under basic conditions in an appropriate solvent, providing the corresponding ester (P), for example, ethyl 1-{[4-(2-ethyl-1,2,3,4-tetraazol-5-yl)phenyl]methyl}piperidine-4-carboxylate, which was in turn converted to its piperidinecarboxylic acid (Q) by reacting it with aqueous sodium hydroxide in an appropriate solvent, affording, for example, 1-{[4-(2-ethyl-1,2,3,4-tetraazol-5-yl)phenyl]methyl}piperidinecarboxylic acid. Intermediate (Q) was then reacted with, for example, N,O-dimethylhydroxylamine hydrochloride and diethylcyanophosphonate, under basic conditions at reduced temperature in an appropriate solvent, yielding the corresponding piperidine carboxamine (R), for example, 1-{[4-(2-ethyl(1,2,3,4-tetraazol-5-yl))phenyl]methyl}(4-piperidyl)-N-methoxy-N-methylcarboxamide. Intermediate (R) was reacted with a Grignard Reagent, for example, 4-trifluoromethoxyphenylmagnesium bromide, in an appropriate solvent, affording the corresponding ketone (S), for example, 1-{[4-(2-ethyl(1,2,3,4-tetraazol-5-yl))phenyl]methyl}(4-piperidyl)4-(trifluoromethoxy)-phenyl ketone. The ketone (S) is then halogenated with, for example, phosphorous oxychloride in an appropriate solvent, yielding the corresponding halogen compound (S1), for example, {4-[chloro(1-{[4-(2-ethyl(1,2,3,4-tetraazol-5-yl))phenyl]methyl}(4-piperidyl))methyl]phenoxy}trifluoromethane. Intermediate (S1) is in turn reacted with, for example, an appropriate phenol, such as 4-(trifluoromethoxy)phenol in an appropriate solvent, providing the corresponding phenoxy derivative, a compound of formula I, for example, 1-[(1-[[4-(2-ethyl(1,2,3,4-tetraazol-5-yl))phenyl]methyl}(4-piperidylidene))[4-(trifluoromethoxy)phenyl]methoxy]-4-(trifluoromethoxy)benzene. Example 11, set forth below provides a detailed procedure for this synthesis.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[O:7]1[CH2:12][CH2:11]C(C(O)=O)[CH2:9][CH2:8]1>CN(C=O)C.C(Cl)Cl>[O:7]1[CH2:12][CH2:11][CH:1]([C:2]([Cl:4])=[O:3])[CH2:9][CH2:8]1
Reactant: O=C(O)C1CCOCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCOCC1
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (170 μL, 1.94 mmol) and DMF (2 drops) were added to a solution of tetrahydro-2H-pyran-4-carboxylic acid (84 mg, 0.64 mmol) in DCM (4 mL) and stirred for 1.5 hours. The reaction was concentrated under vacuum affording tetrahydro-pyran-4-carbonyl chloride. This was used with no further purification or analysis.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.Br[CH2:33][CH2:34][CH2:35][CH2:36]Br.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[N+:16]([C:15]1[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([N:1]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:7][CH2:6]2)=[N:11][C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]([F:30])([F:31])[F:29])=[N:13][CH:14]=1)([O-:18])=[O:17]
Reactant: BrCCCCBr
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CCCC2)CC1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]-pyrimidine-2,4-diamine (86 mg, 0.2 mmol) in DMF (1 mL) were added 1,4-dibromobutane (710 μL, 0.59 mmol) and DIPEA (103 μL, 0.59 mmol). The reaction mixture was stirred at 65° C. for 4 h. The reaction mixture was then diluted with EtOAc and washed with saturated NaHCO3 and water (×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 10:1:0.05 CH2Cl2:MeOH:NH4OH as an eluent to afford 60 mg (62%) of the title compound as an off-white solid, m/z 493.3 [M−1]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:13])[CH:12]=1)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]2([CH3:17])[CH3:16])#[CH:2].[CH3:18][O:19][C:20](=[O:49])[C:21]([C:24]1[CH:29]=[CH:28][C:27](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:26][CH:25]=1)([CH3:23])[CH3:22].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20](=[O:49])[C:21]([C:24]1[CH:25]=[CH:26][C:27]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([OH:13])[CH:12]=2)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]3([CH3:17])[CH3:16])=[CH:28][CH:29]=1)([CH3:23])[CH3:22]
Reactant: C#Cc1cc(O)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.057 g, 0.25 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.112 g, 0.37 mmol), triethyl amine (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) and preparative normal phase HPLC using 5% ethyl acetate in hexane as the mobile phase, the title compound was obtained as a brown oil (0.035 g, 35%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[S:12][CH2:13][C:14](=[O:16])[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[N:17]1[C:26]2[C:21](=[N:22][C:23]([CH:27]=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13](=[CH:27][C:23]3[CH:24]=[CH:25][C:26]4[C:21](=[CH:20][CH:19]=[CH:18][N:17]=4)[N:22]=3)[C:14](=[O:16])[N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(NCCc2cccc(F)c2)=N1
Reactant: O=Cc1ccc2ncccc2n1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1N=C(NCCc2cccc(F)c2)SC1=Cc1ccc2ncccc2n1
Temperature: 130 °C
Yield: 36.8 %

Procedure:
To a suspension of 2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one (38.1 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 130° C. with microwave for 10 min., then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give 2-[2-(3-fluoro-phenyl)-ethylamino]-5-[1,5]naphthyridin-2-ylmethylene-thiazol-4-one as a brown solid (22.3 mg, 36.9%). HR-ES (+) m/e calcd. for C20H15FN4OS: (M+H)+ 379.1024. Found: 379.1024.
Reaction SMILES: CC([N:5]([C@@H:9]([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[C:27]3[C:28]([CH:31]([CH3:33])[CH3:32])=[N:29][O:30][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][C@H:9]([CH2:10][CH3:11])[C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[C:27]3[C:28]([CH:31]([CH3:32])[CH3:33])=[N:29][O:30][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1)=[O:13]
Reactant: CC[C@H](C(=O)Nc1ccc(Oc2cccc3onc(C(C)C)c23)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc3onc(C(C)C)c23)nc1
Reaction time: 2 h

Procedure:
1,1-dimethylethyl((1R)-1-{[(6-{[3-(1-methylethyl)-1,2-benzisoxazol-4-yl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 43, 2.0 mg) was dissolved in dichloromethane (1.0 mL) and, at 0° C., TFA (0.05 mL, 0.65 mmol) was added. The reaction mixture was stirred at that temperature for 2 hours. After removal of the volatiles, the residue obtained was charged on a SCX cartridge and eluted with DCM/MeOH/NH3 (2.0 M in MeOH) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[C:5]([OH:35])[CH:6]=[CH:7][C:8]=2[N:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:23][CH:24]=2)[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1.C[C:37]([CH3:39])=[O:38]>>[CH3:1][C:2]1[C:3]2[CH:4]=[C:5]([OH:35])[CH:6]=[CH:7][C:8]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:21][CH:20]=2)[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1.[CH3:39][C:37]([OH:17])=[O:38]
Reactant: CC(C)=O
Agent: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCN3CCCCCC3)cc2)c2ccc(O)cc12
Product: CC(=O)O
Temperature: 50 °C

Procedure:
Bazedoxifene free base (700 mg) and acetone (8 mL) are mixed and stirred at 45-55° C. to make a clear solution. The solution is filtered followed by addition of seed crystals of bazedoxifene acetate (20 mg) and drop-wise addition of a mixture of acetic acid (0.1 mL) in acetone (1 mL) at room temperature. To the mixture, heptane (40 mL) is added over a period of 15-30 minutes and mixture is stirred for another 30 minutes. The solid so obtained is collected by filtration, washed with heptane (5 mL), and dried by suction. The obtained wet solid is then further dried under vacuum at below 70° C. for about 6-8 hours to afford 850 mg of crystalline bazedoxifene acetate Form D.
Reaction SMILES: N[C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.N([O-])=[O:16].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O.O>[OH:16][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cc2c(cn1)[nH]c1ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
0.75 g of 3-amino-β-carboline are dissolved in 85 ml of 6-molar sulfuric acid and at 0° C. mixed with a solution of 0.435 g of sodium nitrite in 10 ml of water. The reaction mixture is stirred for an hour at 0° C. and then added drop by drop to 320 ml of boiling 2-molar sulfuric acid and then refluxed for another 20 minutes. After standing overnight, the product is neutralized with sodium hydroxide and extracted with a mixture consisting of 10 parts of ethyl acetate and one part of ethanol. The ethyl acetate extract is washed once with water, dried and evaporated. The evaporation residue is recrystallized from dimethylformamide. Thus 0.2 g of 3-hydroxy-β-carboline are obtained
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][C:11]=3[CH:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH2:23].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCCl.CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([NH:23][C:22]4[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:21]=4[F:20])=[O:19])=[CH:13][C:11]=3[CH:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1-c1cc2cc(C(=O)O)ccc2s1
Reactant: Cc1ccc(F)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(F)c(NC(=O)c2ccc3sc(-c4cccnc4N)cc3c2)c1
Temperature: 60 °C

Procedure:
The reaction mixture of 2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid (54 mg, 0.2 mmol, 1 eq), 2-fluoro-5-methylaniline (0.048 mL, 2.1 eq), DMAP (5 mg, 0.2 eq), and EDCI (46.1 mg, 1.2 eq) in anhydrous 1,2-dichloroethane (2 mL) and anhydrous DMF (0.5 mL) was stirred and heated at 60° C. for 1 hour. It was then diluted with ethyl acetate, washed sequentially with aqueous NH4Cl, saturated aqueous NaHCO3, and brine, and finally dried with anhydrous sodium sulfate. The upper, clear solution-layer was decanted, concentrated, and the solid residue was subject to a gradient column chromatography (EtOAc-Hex 1:4 to 1:1) to yield 2-(2-aminopyridin-3-yl)-N-(2-fluoro-5-methylphenyl)-1-benzothiophene-5-carboxamide as a white solid in amount of 39.8 mg.