Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)/[C:9]1=[O:35])=O)(C)(C)C.[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:52])=[C:41]([CH:43]=[N:44][C:45]([O:47][Si](C)(C)C)=[CH2:46])[CH:42]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:46][C:45](=[O:47])[NH:44][CH:43]3[C:41]3[CH:42]=[C:37]([F:36])[CH:38]=[CH:39][C:40]=3[CH3:52])[C:11]2=[CH:12][CH:13]=1
Reactant: COc1ccc(Oc2ccc(Cl)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)cc1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)cc1
Yield: 2.7 %

Procedure:
In a manner similar to the method described in Example 1e, E/Z-6-chloro-3-[5-chloro-2-(4-methoxy-phenoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (5 g, 10 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (50 mmol) in toluene to give the title compound as a white solid (160 mg).
Reaction SMILES: Cl[CH:2]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:3]1[CH:4]=[C:5]([CH:10]2[O:14]CCO2)[S:6][C:7]=1[CH2:8][CH3:9].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.[I-].[Na+].Cl>O1CCCC1.O.CN(C)C(=O)C>[CH:15]1([CH:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)[C:3]2[CH:4]=[C:5]([CH:10]=[O:14])[S:6][C:7]=2[CH2:8][CH3:9])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCc1sc(C2OCCO2)cc1C(Cl)C1CCCCC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCc1sc(C=O)cc1C(Nc1ccc(C(=O)OC)cc1)C1CCCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a mixture of 2-{4-[chloro(cyclohexyl)methyl]-5-ethylthiophen-2-yl}-1,3-dioxolane (3.08 g) synthesized above, methyl 4-aminobenzoate (2.96 g), sodium iodide (2.98 g) and N,N-dimethylacetamide (60 mL) sodium carbonate (2.08 g) was added, and the mixture was stirred overnight at 100° C. under an argon atmosphere. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to give a yellow oil. To a solution of the obtained oil in tetrahydrofuran (40 mL) was added 1N hydrochloric acid (10 mL), and the mixture was stirred at room temperature for 1 hr. Tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate/hexane) to give the title compound (2.05 g, 54%) as a yellow solid.
Reaction SMILES: [Li+].[Br-].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[CH3:12][C:13]1[CH:21]=[CH:20][C:19]2[N:18]([CH2:22][CH:23]3[CH2:25][O:24]3)[C:17]3[CH2:26][CH2:27][N:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][C:16]=3[C:15]=2[CH:14]=1>>[OH:24][CH:23]([CH2:25][NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=1)[CH2:22][N:18]1[C:19]2[CH:20]=[CH:21][C:13]([CH3:12])=[CH:14][C:15]=2[C:16]2[CH2:29][N:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][CH2:26][C:17]1=2
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)N1CCc2c(c3cc(C)ccc3n2CC2CO2)C1
Agent: [Br-]
Agent: [Li+]
Product: CCOC(=O)N1CCc2c(c3cc(C)ccc3n2CC(O)CNc2cccc(OC)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
Following a literature procedure (Chakraborti, A. K.; Rudrawar, S.; Kondaskar, A. Eur. J. Org. Chem. 2004, 3597-3600) LiBr (0.001 g, 0.010 mmol) and m-anisidine (0.011 mL, 0.102 mmol) were added to ethyl 8-Methyl-5-(oxiran-2-ylmethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.032 g, 0.102 mmol) and stirred vigorously at ambient temperature overnight. Upon completion the reaction was partitioned between EtOAc/H2O, and the organic layer was concentrated to an orange oil. The crude residue was purified by chromatography (SiO2, 0-50% EtOAc/Hexane) to afford the desired product (30 mg, 67%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:13]2[C:21]([Br:26])=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.Cl[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2[CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1.CCN(C(C)C)C(C)C>Cl.O1CCOCC1>[Br:26][C:21]1[C:13]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:10]([C@@H:8]([NH:7][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][N:33]4[CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[CH3:9])=[N:11][C:12]=2[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(Br)c2n1-c1ccccn1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
[(S)-1-(7-Bromo-6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (220 mg, 0.66 mmol) was dissolved in hydrochloric acid in dioxane (15 mL, 4M) and the reaction stirred at RT for 1 h. The reaction mixture was concentrated in vacuo then the residue dissolved in IPA and 6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine (203 mg, 0.85 mmol) and DIPEA (168 μL, 0.99 mmol) added. The reaction mixture was heated at 90° C. for 16 h then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% methanol in EtOAc) to yield the title compound as a white solid (267 mg, 76%). LCMS (Method C): RT=3.01 min, [M+H]+=537+538.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:14]2[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:15]2)=[C:6]2[CH2:13][CH2:12][CH2:11][C:7]2=[N+:8]([O-])[CH:9]=1)([O-:3])=[O:2].[CH3:32][C:33]([O:35]C(C)=O)=[O:34]>>[C:33]([O:35][CH:11]1[C:7]2=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([N:14]3[CH2:19][C@H:18]([C:20]([F:21])([F:23])[F:22])[CH2:17][C@H:16]([NH:24][C:25]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:31])[CH2:15]3)=[C:6]2[CH2:13][CH2:12]1)(=[O:34])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Product: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A mixture of tert-butyl [(3S,5R)-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.100 g, 0.224 mmol) in Ac2O (1.5 mL, 16 mmol) was stirred at 90° C. for 1 h. The solution was allowed to cool to room temperature, then concentrated under reduced pressure at 60° C. The residue was diluted with EtOAc (5 mL), washed quickly with 1N NaOH. The aqueous phase was extracted with EtOAc twice. The combined organic phases were condensed and columned on 20 g silica gel, eluting with 0-50% EtOAc in hexanes to give the sub-title compound as a brown solid (0.085 g, 78%). LCMS calc. for C21H28F3N4O6 (M+H)+ m/z=489.2. found: 489.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:31][CH:30]([NH2:32])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl.C(O)C>[C:21]([O:25][C:26]([N:28]1[CH2:31][CH:30]([NH:32][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=3[F:19])=[CH:6][N:5]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(Cl)nc1N
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CN(C(=O)OC(C)(C)C)C2)nc1N
Temperature: 80 °C

Procedure:
To a stirred suspension of chloropyrimidine (700 mg, 2.34 mmol, Example 289) in methylene chloride (30 mL), amine (525 mg, 5.64 mmol, Example 318) in ethanol (30 mL) was added and the mixture heated at 80° C. for 4.5 hours. The solvent was removed and the residue was dissolved in ethyl acetate and the mixture was washed successively with 0.5N hydrochloric acid and water. The organic layer was dried with sodium sulfate and concentrated to give a white solid. 1.0 g, 98%. MS (ES) MH+=436.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].ClC(Cl)(Cl)C[O:66][C:67](Cl)=[O:68]>N1C=CC=CC=1.ClCCl>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([O:40][C:5]([CH2:4][CH2:3][CH2:2][C:67]([OH:66])=[O:68])=[O:6])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](OC(=O)CCCC(=O)O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Temperature: -20 °C
Reaction time: 2 h

Procedure:
875 mg of paclitaxel was dissolved in 6 ml of pyridine and 40 ml of dichloromethane. The solution was cooled at −20° C. Three hundred microliters of trichloroethylchloroformate (Troc) (at −20° C.) was added by portions of 100 microliters and the solution was kept at −20°C. for two hours. An additional 100 microliters of Troc was added and the solution was stirred at room temperature for 20 hours. The solvent was evaporated to dryness. The residue was dissolved in 10 ml of dimethylformamide with 1.36 g of glutaric anhydride and 40 mg of dimethylaminopyridine. The solution was stirred at 85° C. for 20 hours. The product was precipitated with 10 volumes of water. The white precipitate was collected on a sintered glass filter and dried. The dried product was then dissolved in 20 ml of methanol:acetic acid (9:1) and 0.5 g of zinc powder was added. The solution was stirred at room temperature for 30 minutes. Zinc was filtered and the filtrate was evaporated to a volume of about 2 ml. 70 ml of dichloromethane was added and the solution was washed twice with 30 ml of 0.01N HCl, once with 30 ml of sodium bicarbonate and once with 50 ml of water. The organic phase was dried with anhydrous sodium sulfate, filtered and evaporated to dryness. This yielded 620 mg of a C7-glutaryl paclitaxel
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13]([OH:15])=O)=[O:5])[CH3:2].Cl.C(N=C=N[CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])C.O[N:29]1[C:33]2C=CC=CC=2N=N1.O>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=[O:15])[NH:29][CH2:33][CH2:27][N:25]1[CH2:24][CH2:23][CH2:22][CH2:26]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
A stirred solution of 2-carboxymethyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.27 g, 6 mmol) in N,N-dimethylformamide (3 ml) and dichloromethane (30 ml) was added with 2-pyrrolidine-1-yl-ethamine (0.83 ml, 6.6 mmol), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (3 g, 12 mmol) and 1-hydroxybenzotriazol (0.9 g, 6 mmol) in the ice/water-bath. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight, then added with cold water (20 ml), extracted with dichloromethane (50 ml×3). The combined organic extracts were washed with saturated sodium bicarbonate solution (50 ml), water (50 ml), brine (50 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-methyl-2-[(2-pyrrolidin-1-yl-ethylcarbamoyl)-methyl]-1H-pyrrole-3-carboxylic acid ethyl ester (1.898 g, 100%) as a brown oil which was used as such.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.Cl[C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Reactant: CCCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCOC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (3 ml) was suspended 60% sodium hydride (20 mg). The compound 1 (124 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, n-propyl chloroformate (200 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-n-propoxycarbonyl-quinoline (compound 8, 96 mg). 1H-NMR data on this compound in deutro-chloroform were as shown below.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C([N-:14]C(C)C)(C)C.[Li+].O.O.O.C([O-])(=O)C.[Na+].N[O:28][S:29]([OH:32])(=O)=O>O1CCCC1>[S:29]([C:9]1[S:10][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=2[CH:8]=1)(=[O:32])(=[O:28])[NH2:14]
Reactant: CC(C)[N-]C(C)C
Reactant: Clc1nccc2sccc12
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1cc2c(Cl)nccc2s1
Temperature: 25 °C
Reaction time: 178 h
Yield: 49 %

Procedure:
To a solution of 4-chlorothieno[3,2-c]pyridine (1.7 g, 10 mmol) in distilled tetrahydrofuran (25 ml), cooled to -70° C. and under a nitrogen atmosphere, was added dropwise 0.7 M lithium diisopropylamide in THF (16 ml, 11 mmol) to give a clear solution. After 178 hour, sulfur dioxide gas was bubbled over the reaction surface and it was gradually let warm to room temperature. The mixture was diluted with diethyl ether and the precipitated lithium sulfinate salt was collected by filtration. This salt (3.1 g) was dissolved in water (25 ml) and sodium acetate trihydrate (5.4 g, 66 mmol) and hydroxylamine-O-sulfonic acid (2.5 g, 22 mmol) were added. After stirring for 18 hours, the precipitated product was collected by filtration, dissolved in ethyl acetate, dried over anhydrous sodium sulfate, filtered through a pad of charcoal and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give 1.23 g (49% yield) purified product.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH2:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[K+].[C:23]([C:25]1[N:26]=[C:27]([C:38]([O-])=[O:39])[N:28]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:29]=1)#[N:24].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][S:16](=[O:19])(=[O:20])[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:38]([C:27]2[N:28]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:29]=[C:25]([C:23]#[N:24])[N:26]=2)=[O:39])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: Nc1ccc(C2CCS(=O)(=O)CC2)cc1C1=CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CCS(=O)(=O)CC2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
To a mixture of 2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-phenylamine (as prepared in the previous step, 122 mg, 0.50 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 3, step (d), 134 mg, 0.44 mmol) and bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBroP) (205 mg, 0.44 mmol) in 5 mL of DMF was added DIEA (209 μL, 1.20 mmol). The resulting mixture was stirred at RT for 18 h under Ar, cooled to RT. Treated with 50 mL of EtOAc, the mixture was washed with H2O (3×10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-3% EtOAc/DCM) gave 161 mg (73%) of the title compound as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 9.69 (s, 1H), 8.29 (d, 1H, J=8.4 Hz), 7.78 (s, 1H), 7.14 (dd, 1H, J=8.4, 2.2 Hz), 7.04 (d, 1H, J=2.2 Hz), 5.95 (s, 2H), 5.83 (m, 1H), 3.66 (t, 2H, J=8.2 Hz), 3.11-3.20 (m, 4H), 2.77 (dddd, 1H, J=12.1, 12.1, 3.2, 3.2 Hz), 2.35-2.47 (m, 2H), 2.17-2.33 (m, 6H), 1.74-1.89 (m, 4H), 0.97 (t, 2H, J=8.2 Hz), 0.00 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C28H38N4O4SSi, 555.2 (M+H), found 555.3.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=1)[C@@H:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2.Br>C(O)(=O)C>[C:27]1([C@H:8]2[CH2:7][CH2:6][C:5]3[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11][C:10]=3[C@H:9]2[C:13]2[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 100 °C

Procedure:
A mixture of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine (12 g, 28 mmol), acetic acid (75 mL), and 48% HBr (75 mL) was heated at 100° C. for 15 h. The solution was cooled and the resulting white precipitate was collected by filtration. The hydrobromide salt (9.6 g, 69%) was dissolved in CHCl3 /MeOH and was stirred with satd NaHCO3 (aq). The layers were separated and the aqueous layer was further extracted with CHCl3 /MeOH. The combined organic layers were dried (MgSO4), filtered, and concentrated to yield product as an off-white foam. 1H NMR (250 MHz, CDCl3): δ7.04 (m, 3H), 6.74 (m, 2H), 6.63 (d, J=8.3 Hz, 2H), 6.50 (m, 3H), 6.28 (d, J=8.6 Hz, 2H), 4.14 (d, J=4.9 Hz, 1H), 3.94 (t, J=5.3 Hz, 2H), 3.24 (dd, J=12.5, 4.1 Hz, 1H), 2.95 (m, 4H), 2.78 (m, 4H), 2.14 (m, 1H), 1.88 (m, 4H), 1.68 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[Cl:10])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Cl:29].[O-]CC.[Na+]>C(O)C>[Cl:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[Cl:10])=[CH:6][CH:7]=1
Reactant: Oc1ccc(C(=C(Cl)c2ccccc2)c2ccccc2)cc1
Reactant: ClCCCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: ClCCCCCOc1ccc(C(=C(Cl)c2ccccc2)c2ccccc2)cc1

Procedure:
Combine (E and Z)-1-[(4-hydroxy)phenyl]-1,2-diphenyl-2-chloro-ethylene (2.3 g, 7.5 mmol) and 5-bromo-1-chloropentane (2.78 g, 15.0 mmol) in ethanol (40 mL). Add a solution of sodium ethoxide in ethanol (11.12 mL, 0.67M, 7.5 mmol). Heat to reflux under an inert atmosphere. After 24 hours concentrate in vacuo. Chromatograph on silica gel eluting with 1/7 ethyl acetate/hexane. Concentration of the product containing fractions to give the title compound which is taken on to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]([NH2:7])=[NH:6])=[NH:3].CO[C:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]=1>C(O)C>[NH2:6][C:5]1[N:4]=[C:2]([NH2:1])[N:3]=[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:10][NH2:11])[N:7]=1
Reactant: COC1=NCCCCC1
Reactant: N=C(N)NC(=N)N
Solvent: CCO
Product: NCCCCCc1nc(N)nc(N)n1

Procedure:
A mixture of biguanide (1.05 g.), 4,5,6,7-tetrahydro-2-methoxy-3H-azepine (1.27 g.) and ethanol (50 ml.) was heated under reflux for 18 hours, cooled and the solid that crystallised was collected to give 2,4-diamino-6-(5-aminopentyl)-1,3,5-triazine which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[CH:7]=O)[CH3:2].[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])/[CH:7]=[N:16]/[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC(C)C
Reactant: N#Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1cc(/C=N/c2ccc(C#N)cc2)ccc1OC(C)C
Yield: 86.9 %

Procedure:
A mixture of 3-ethoxy-4-isopropoxybenzaldehyde (1.78 g, 8.55 mmol), 4-aminobenzonitrile (1.01 g, 8.55 mmol), and 5 g 4 A molecular sieves in 20 mL toluene was refluxed with azeotropic removal of water for 2 h. The mixture was filtered and concentrated to afford 2.29 g of Intermediate 1.1 as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH:9]1([N:6]2[C:7](=[O:8])[C:2]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:3][C:4]([C:14]([O:16][CH3:17])=[O:15])=[CH:5]2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: c1cn[nH]c1
Reactant: COC(=O)c1cc(Br)c(=O)n(C2CCCC2)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-n2cccn2)c(=O)n(C2CCCC2)c1
Temperature: 100 °C

Procedure:
A mixture of methyl 5-bromo-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate (300 mg, 1.00 mmol), pyrazole (23 mg, 0.34 mmol), K2CO3 (99 mg, 0.72 mmol), CuI (9.1 mg, 0.048 mmol), N1—N2-dimethylethane-1,2-diamine (5 uL, 0.048 mmol) in toluene (3 mL) was heated to 100° C. for 17 h. The mixture was brought to RT and quenched with saturated NH4Cl, brine, dried over MgSO4 and chromatographed on silica gel using 3:1 hexanes:ethylacetate to afford the title compound as a white solid. MS m/z: 288 (M+1).