Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][OH:27])=[C:19]([C:28]#[N:29])[CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][O:27][S:31]([CH3:30])(=[O:33])=[O:32])=[C:19]([C:28]#[N:29])[CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(C(=O)Nc2ccc(SCCCO)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c(C(=O)Nc2ccc(SCCCOS(C)(=O)=O)c(C#N)c2)cnn1-c1ccc(Cl)cc1

Procedure:
A solution of 1-(4-chlorophenyl)-N-[3-cyano-4-(3-hydroxypropylthio)phenyl]-5-methylpyrazole-4-carboxamide (1.8 g) and methanesulfonyl chloride (0.5 ml) in pyridine (20 ml) was stirred overnight. To the reaction mixture was added aqueous hydrochloric acid solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform:methanol=50:1) to give 1-(4-chlorophenyl)-N-[3-cyano-4-(3-methanesulfonyloxypropylthio)phenyl]-5-methylpyrazole-4-carboxamide (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[N:29][C:5]2[N:6]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[CH:9][CH:8]=3.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:50][N:51]1[CH2:56][CH2:55][N:54]([CH2:57][CH2:58]O)[CH2:53][CH2:52]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C1COCC1.CO>[Cl:1][C:2]1[CH:30]=[N:29][C:5]2[N:6]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:58][CH2:57][N:54]2[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]2)=[CH:15][CH:14]=1)=[CH:9][CH:8]=3
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(-c3ccc(O)cc3)cc2c2cc(Cl)cnc21
Reactant: CN1CCN(CCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(CCOc2ccc(-c3ccc4c(c3)c3cc(Cl)cnc3n4S(=O)(=O)c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of 4-(3-chloro-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indol-6-yl)phenol (240 mg, 0.55 mmol, 1 equiv.) in anhydrous THF (14 ml), triphenylphosphin (577 mg, 2.2 mmol, 4 equiv.) and 2-(4-methylpiperazin-1-yl)ethanol (397 mg, 2.75 mmol, 5 equiv.) are added. DIAD (445 mg, 2.2 mmol, 4 equiv.) is then added dropwise to the solution which is stirred at room temperature for 12 hours. The mixture is then extracted with a solution of HCl 0.1M (3×10 ml). The aqueous layer is treated with Na2CO3 until pH=9 and then extracted with AcOEt (3×20 ml). The organic layers are dried over MgSO4, filtered and concentrated under reduced pressure. The residue (yellow solid) is purified over silica chromatography (eluted with AcOEt/MeOH 9:1 and then THF/MeOH 9:1) to give the product as a white solid (259 mg, 0.44 mmol) in 80% yield. 1H NMR (300 MHz, CDCl3) δ 8.47 (dd, 2H, J=2.5, 7.7 Hz), 8.17 (d, 1H, J=2.1 Hz), 8.13 (d, 2H, J=7.5 Hz), 8.00 (d, 1H, J=0.9 Hz), 7.76 (dd, 1H, J=1.5, 8.6 Hz), 7.57-7.39 (m, 5H), 7.55 (d, 2H, J=8.6 Hz), 7.01 (d, 2H, J=8.5 Hz), 4.17 (t, 2H, J=5.6 Hz), 2.87 (t, 2H, J=5.6 Hz), 2.70-2.58 (br d, 8H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13](=[NH:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:5]=1.[O-]Cl.[Na+].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:21]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[NH:12][C:6]=2[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:22]
Reactant: COC(=O)c1ccc(OC)c(NC(=N)c2ccc(F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
3-[(4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (10 g, 34.48 mmol) obtained in step 1 was dissolved in 50% methanol and 5% NaOCl (61 ml, 41.38 mmol) was added dropwise thereto at room temperature. After 5 min, Na2CO3 (7.31 g, 68.96 mmol) was added dropwise thereto and refluxed for 5 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate, and the extract was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (5.66 g, 19.65 mmol) in a yield of 57%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9](Br)[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].O.[CH3:15][N:16]1CCCC1=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:15]#[N:16])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: CN1CCCC1=O
Solvent: O
Product: COc1cc(C=O)cc(C#N)c1OC

Procedure:
A mixture containing 2.5 g of 3,4-dimethoxy-5-bromobenzaldehyde and 1.0 g of cuprous cyanide in N-methylpyrrolidone was refluxed for 2 h. Water was added and the solution was extracted with dichloromethane. The solvent was evaporated in vacuo. Yield 1.55 g (81%), m.p. 109°-112° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:12]=2)=[O:9])=[CH:4][N:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)=[N:3][CH:4]=2)=[O:9])=[CH:12][C:13]=1[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1
Reactant: COc1ccc(NC(=O)c2ccc(Br)nc2)cc1N1CCN(C)CC1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(NC(=O)c2ccc(-c3ccncc3)nc2)cc1N1CCN(C)CC1

Procedure:
2-Bromo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]pyridine-5-carboxamide (0.125 g;0.31 mmol) was stirred with 4-pyridylboronic acid (0.038 g;0.31 mmol), tetrakis(triphenylphosphine)palladium(0) (0.024 g) and anhydrous sodium carbonate (0.036 g;0.34 mmol) in water (5 ml) and DME (5 ml) and the whole heated at reflux under Ar (18 hours). The reaction mixture was poured into 10% Na2CO3 (aq) (20 ml) and extracted into CHCl3. The organic extracts were combined, dried over Na2 SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 5%MeOH/CHCl3 to yield a orange/yellow gum(0.060 g;48%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:15][C:16]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:19]=[C:18]([C:28]([F:31])([F:30])[F:29])[CH:17]=1.C(O)(=O)C>CCCCCC.C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[N:19]=[C:18]([C:28]([F:31])([F:29])[F:30])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: FC(F)(F)c1cc(CBr)n(-c2ccccc2Cl)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(CNc2ccc(Br)cc2)n(-c2ccccc2Cl)n1
Reaction time: 0.17 h

Procedure:
Into a dry, nitrogen-flushed 250 mL round-bottom flask was placed 4.0 g of 4-bromoaniline (23 mmol). After addition of THF (30 mL), the resulting solution was cooled in an ice bath. 14 mL of a 1.6 M solution in hexane of butyllithium (22 mmol) was added dropwise to the 4-bromoaniline solution to afford a beige suspension. After 10 minutes stirring, the cold suspension was treated with 6.0 g of 5-(bromomethyl)-1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole (18 mmol) as a solution in THF (30 mL) via cannula. The flask and cannula were then rinsed with additional THF (10 mL) to insure complete transfer of the bromide. After 1 hour stirring at 0° C., LC/MS analysis showed no remaining 5-(bromomethyl)-1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole, and showed a large peak for the desired product. After 100 min., the reaction was quenched by the addition of 1 mL of acetic acid (18 mmol). The resulting pale suspension was concentrated in vacuo to afford a pale brown foam. The crude product was purified by silica gel flash chromatography using gradient elution from 0% to 70% EtOAc/hexane. Many of the column fractions were impure. Pure fractions were concentrated in vacuo to afford 4-bromo-N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)aniline as a pale yellow oil, yield: 2.35 g (31%); 1H NMR (400 MHz, CDCl3): δ 7.59-7.55 (m, 1H), 7.52-7.45 (m, 1H), 7.44-7.40 (m, 2H), 7.25-7.21 (m, 2H), 6.63 (s, 1H), 6.41-6.37 (m, 2H), 4.20 (br s, 2H), 3.90 (br s, 1H); MS (ESI) m/z 432.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=1)[O:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21])[C:5]2=O.O.[NH2:27][NH2:28]>>[Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[C:6]([C:13]3[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=3)[O:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21])=[CH:7][NH:28][N:27]=2)[CH:3]=1
Reactant: N#CCCCOc1cccc(-c2coc3cc(O)c(Cl)cc3c2=O)c1
Reactant: NN
Solvent: O
Product: N#CCCCOc1cccc(-c2c[nH]nc2-c2cc(Cl)c(O)cc2O)c1

Procedure:
This compounds was synthesised in the same manner as described above. 4-[3-(6-Chloro-7-hydroxy-4-oxo-4H-chromen-3-yl)-phenoxy]-butyronitrile (0.3 g, 0.84 mmol), Hydrazine hydrate (6 ml). The quenched reaction was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a clear oil which was purified by column chromatograpy to give 4-{3-[3-(5-chloro-2,4-dihydroxy-phenyl)-1H-pyrazol-4-yl]-phenoxy}-butyronitrile as a white soild Rf 0.6 ethyl acetate/hexane (70/30).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Br:16][C:17]1[CH:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(N(CC)CC)C>C(#N)C>[Br:16][C:17]1[CH:22]=[C:21]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Br)ncc2[N+](=O)[O-])CC1
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
A solution of 4-(aminomethyl)-1-boc-piperidine (370 mg, 1.73 mmol) in acetonitrile (1 mL) was added over 1 minute to a solution of 2-bromo-4-chloro-5-nitropyridine (373 mg, 1.57 mmol) and triethylamine (0.24 mL, 1.73 mmol) in acetonitrile (5 mL). The solution was stirred for 30 minutes then partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (×3) and the combined organic phases were dried (Na2SO4) and concentrated to give tert-butyl 4-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate as a light brown foam (640 mg, 98%) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][CH:19]1[CH2:23][CH2:22][CH:21]([CH3:24])[NH:20]1>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][N:20]1[CH:21]([CH3:24])[CH2:22][CH2:23][CH:19]1[CH3:18]
Reactant: CC1CCC(C)N1
Reactant: Fc1cc(Br)c(CCl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1CCC(C)N1Cc1cc(F)c(F)cc1Br
Temperature: 80 °C
Reaction time: 16 h

Procedure:
200 mg of 1-bromo-2-chloromethyl-4,5-difluorobenzene are dissolved in 5 ml of acetonitrile. 540 mg of caesium carbonate and 152 μl of 2,5-dimethylpyrrolidine are added, and the mixture is stirred at 80° C. for 16 h. After cooling to 25° C., the mixture is filtered, and the filtrate is evaporated to dryness. The residue is taken up in 5 ml of ethyl acetate, the solution is washed with 5 ml of 2N sodium hydroxide solution, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness, after which the product is isolated as oil.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N:21]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[C:23]([C:29](O)=[O:30])=[N:22]2)=[CH:16][C:15]=1[CH3:32].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.ClCCCl.CN(C=O)C>[CH2:1]([NH:8][C:29]([C:23]1[C:24](=[O:28])[NH:25][C:26](=[O:27])[N:21]([C:17]2[CH:18]=[C:19]([CH3:20])[C:14]([O:13][C:12]3[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:10]([Br:9])[CH:11]=3)=[C:15]([CH3:32])[CH:16]=2)[N:22]=1)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(Oc2c(C)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2C)cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(C)cc(-n3nc(C(=O)NCc4ccccc4)c(=O)[nH]c3=O)cc2C)cc1Br

Procedure:
To a solution of benzylamine (6 μmol) in 10% DMF/DCE were added sequentially 10% DMF/DCE solutions of 2-[4-(3-bromo-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (5 μmol) and N-methylmorpholine (6 μmol). A DMF solution of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.5 μmol) and the resulting solution was shaken for 4 h at room temperature. The reaction was concentrated at 60° C. in a vacuum oven overnight. HPLC and LCMS shows complete conversion to the title compound of Step A. MS Calc.: 550.1; Found: 549.0 (M−1).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:5][C:4]=1[CH3:19])=O.C1(P(=[CH:39][C:40]([O:42][CH3:43])=[O:41])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[C:16]([NH:15][C:12]1[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:6]2[S:7][C:3](/[CH:1]=[CH:39]/[C:40]([O:42][CH3:43])=[O:41])=[C:4]([CH3:19])[CH:5]=2)[N:11]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1nc(CCc2cc(C)c(C=O)s2)cs1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1sc(CCc2csc(NC(C)=O)n2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
To a solution of N-{4-[2-(5-formyl-4-methylthiophen-2-yl)ethyl]-1,3-thiazol-2-yl}acetamide (468.0 mg, 1.590 mmol) in chloroform (4.7 ml) was added dropwise a solution of methyl (triphenyl phosphoranylidene)acetate (797.4 mg, 2.385 mmol) in chloroform (2 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Merck 9385 60 g, ethyl acetate:dichloromethane=1:8) to give methyl (2E)-3-(5-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}-3-methylthiophen-2-yl)-2-propenoate (591.6 mg, containing triphenylphosphineoxide) as a pale-yellow solid.
Reaction SMILES: CO.C[O:4][C:5](=[O:30])[C:6]1[C:11]([NH:12][C:13](=[O:29])[CH:14]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=[N:8][CH:7]=1.[OH-].[Na+]>O>[CH2:22]([O:21][C:19]([NH:18][CH:14]([CH:15]([CH3:17])[CH3:16])[C:13]([NH:12][C:11]1[C:6]([C:5]([OH:30])=[O:4])=[CH:7][N:8]=[CH:9][CH:10]=1)=[O:29])=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cnccc1NC(=O)C(NC(=O)OCc1ccccc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)Nc1ccncc1C(=O)O
Reaction time: 1 h
Yield: 99 %

Procedure:
Formula 507 where R1, R3 and R4 are H; R6 is Isopropyl; R6′ is H; W, Y and Z are —C═; and X is —N═: To a solution of MeOH and H2O (2:1, 150 mL) and 4-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-nicotinic acid methyl ester (10.5 g, 27.2 mmol) was added sodium hydroxide (2.18 g, 54.5 mmol). The mixture was stirred for 1 hour, after which silica gel (20 g) was added into the solution. After letting this mixture stir for 10 minutes, the silica gel was filtered off and the solvents were evaporated under reduced pressure. The corresponding carboxylic acid of Formula 507, 4-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-nicotinic acid (10.0 g, 99%) was obtained in sufficient purity to be carried forward for use in the next step. MS (Cl) M/E: 372.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17]CC4C=CC=CC=4)[CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](CN3CCCC3)=[C:28]([O:38][CH3:39])[CH:27]=2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+:43]>C1COCC1.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:43]3[CH2:4][CH2:3][CH2:2][CH2:7]3)=[C:28]([O:38][CH3:39])[CH:27]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(Cc2c(-c3ccc(N)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: C1CCOC1
Product: COc1cc(Cc2c(-c3ccc(N)cc3)sc3cc(O)ccc23)ccc1N1CCCC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
2-(4-Aminophenyl)-6-benzyloxy 3-[3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl]benzo[b]thiophene (103 mg) in THF (4.0 mL) was treated with a solution of ammonium formate (25% in H2O, 2.0 mL) and 10% palladium on carbon (100 mg) sequentially at ambient temperature. The resulting mixture was stirred at ambient temperature under argon for 21 h before filtered through diatomaceous earth followed by rinsing with dichloromethane and methanol. The filtrate was extracted with dichloromethane (20 mL×3) from water (30 mL). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:10:85) afforded the product (80 mg).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:6][C:7](Cl)=[O:8])[CH:4]=[CH2:5].[CH3:10][O:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][N:17]2[C@H:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:19]([C@H:28]([OH:30])[CH3:29])[C:18]2=[O:31])=[CH:14][CH:13]=1>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][N:17]2[C@H:20]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C@@H:19]([C@H:28]([O:30][C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[O:8])[CH3:29])[C:18]2=[O:31])=[CH:32][CH:33]=1
Reactant: C=CCOC(=O)Cl
Reactant: COc1ccc(CN2C(=O)[C@H]([C@@H](C)O)[C@H]2C(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(Cc2ccc(OC)cc2)[C@@H]1C(=O)OC(C)(C)C

Procedure:
At 0°, 24 ml of 1N NaOH, 820 mg of tetrabutylammonium bisulphate and 1 ml of chloroformic acid allyl ester are added to a solution of 2 g of (3S,4S)-1-(p-methoxybenzyl)-3-[(1R)-1-hydroxyethyl)-4-tert.-butoxycarbonyl-2-azetidinone in 24 ml of methylene chloride and the whole is stirred vigorously. After a reaction time of 20 and 40 minutes, further portions (each of 1 ml) of chloroformic acid allyl ester are added. The reaction mixture is diluted with methylene chloride, the aqueous phase is separated off and the organic layer is washed in succession with 5% aqueous citric acid and 8% aqueous NaHCO3 solution and then dried and concentrated by evaporation. After purifying by chromatography, the pure, amorphous title compound is obtained.
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[OH:37]>>[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.[CH3:27][C:26]([OH:37])=[O:25]
Reactant: CO
Agent: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCN3CCCCCC3)cc2)c2ccc(O)cc12
Product: CC(=O)O
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Crystalline bazedoxifene free base (5 g) is charged in methanol (100 mL) heated at reflux temperature to make a clear solution. The solution is filtered and cooled to 25-30° C. followed by addition of acetic acid (0.82 g). The reaction mixture is stirred for ˜1 hour followed by addition of seed crystals of Form D (250 mg). The reaction mixture is allowed to cool to 0-5° C. at which point water (200 mL) is slowly added over a period of 2 hours. The reaction mixture is maintained under stirring for another 1 hour at 0-5° C. The solid is collected by filtration and washed with water (10 mL), and dried under vacuum at about 90° C. to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:52])[CH2:3][CH2:4][N:5]([CH2:49][CH2:50][OH:51])[C:6]([C@:8]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:42])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:41]=[CH:40][C:33]([C:34]([O:36]CCO)=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7].[OH-].[Na+]>O1CCOCC1.O>[CH3:52][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH2:49][CH2:50][OH:51])[C:6]([C@:8]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:42])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:41]=[CH:40][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N(CCO)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OCCO)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N(CCO)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C
Yield: 88.8 %

Procedure:
A mixture of 2-hydroxyethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(dimethylamino)ethyl)(2-hydroxyethyl)carbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (6 mg, 8.37 μmol) and sodium hydroxide (0.042 mL, 0.042 mmol) in dioxane (1 mL) was heated up at 78° C. for 3 hours. The solution was diluted with water and filtered. The clear solution was purified by prep HPLC to provide the title compound as a white solid (5 mg, 84%). LCMS: m/e 673.58 (M+H)+, 2.08 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.55 Hz, 2H), 5.43-5.31 (m, 1H), 4.78 (d, J=1.53 Hz, 1H), 4.66 (s, 1H), 4.26-4.13 (m, 2H), 3.90-3.78 (m, 2H), 3.75-3.63 (m, 4H), 3.30 (s, 6H), 3.20-3.07 (m, 1H), 2.60-2.45 (m, 1H), 1.74 (s, 3H), 2.26-1.22 (m, 21H), 1.08 (s, 3H), 1.07 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H).