Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][N:6]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:16][C:15]=1[C:12]#[C:11][C:8]1[CH:9]=[N:10][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[N:6][CH:7]=1
Reactant: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(I)c4)[nH]c3c2)CC1
Reactant: C#Cc1cnc(NC2CC2)nc1
Product: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(C#Cc5cnc(NC6CC6)nc5)c4)[nH]c3c2)CC1

Procedure:
The title compound was synthesized from N-cyclopropyl-5-ethynylpyrimidin-2-amine and 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1 H-benzo[d]imidazole in a manner similar to that described for in Example 1. The title compound was obtained as a brown solid. Mp:160-162° C.; 1H NMR (300 MHz, CDCl3) δ: 8.43-8.45 (2 H, d, J=6.0 Hz), 8.12-8.15 (1 H, d, J=6.0 Hz), 7.58-7.60 (1 H, d, J=6.0 Hz), 7.52 (1 H, s), 7.45-7.47 (1 H, d, J=6.0 Hz), 7.38-7.40 (1 H, d, J=6.0 Hz), 7.15-7.17 (1 H, d, J=6.0 Hz), 5.80 (1 H, s), 3.60 (2 H, s), 2.80 (8 H, brs), 2.59 (3 H, s), 1.35-1.39 (1 H, m), 0.82-0.88 (2 H, m), 0.58-0.60 (2 H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C28H29ClN7: 498.2167. found: 498.2163.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>C(Cl)Cl.[OH-].[K+].CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[Br:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: O=Cc1cc(Br)c2cn[nH]c2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ncc2c(Br)cc(C=O)cc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
To a solution of 4-bromo-1H-indazole-6-carbaldehyde (225 mg, 1 mmol) in CH2Cl2 (10 mL) and aqueous KOH (2 mL, 50% wt) at 0° C. was added TBAB (3 mg, 0.01 mmol) and SEMCl (200 mg, 1.2 mmol). The mixture was stirred at 0° C. for 4 h, warmed to rt and extracted with ethyl acetate (100 mL). The organic phase was washed with water (2×10 mL) and brine (10 mL), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (1:1 EtOAc/Hex) to give the title compound as a pale yellow solid (280 mg, 82%). 1H NMR (400 MHz, CD3OD) δ 10.02 (s, 1H), 8.21-8.19 (m, 2H), 7.80 (s, 1H), 5.78 (s, 2H), 3.70-3.65 (m, 2H), 0.95-0.92 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=2)(=[O:28])=[O:27])[C:5]([CH:8]([OH:24])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=2)(=[O:27])=[O:28])[C:5]([C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:24])=[N:6][CH:7]=1
Reactant: COc1cccc(NC(=O)C(C)(C)C)c1C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COc1cccc(NC(=O)C(C)(C)C)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
A mixture of N-(2-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-hydroxy-methyl}-3-methoxy-phenyl)-2,2-dimethyl-propionamide (0.17 g, 0.33 mmol) and Dess-Martin reagent (0.185 g, 0.44 mmol) in CH2Cl2 (10 mL) at room temperature was stirred for 5 h. A mixture of 10% aqueous Na2S2O3 (10 mL) and saturated aqueous NaHCO3 (10 mL) was then added and the biphasic mixture vigorously stirred for 30 min. The organic phase was then separated and the aqueous portion was extracted with CH2Cl2. The combined organic extracts were washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure and the residue purified by chromatography on silica gel using ethyl acetate-hexane to provide N-{2-[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-3-methoxy-phenyl}-2,2-dimethyl-propionamide: MS m/z 604.0 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].O[CH2:23][CH2:24]/[CH:25]=[CH:26]/[P:27](=[O:36])([O:32][CH:33]([CH3:35])[CH3:34])[O:28][CH:29]([CH3:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:33]([O:32][P:27](/[CH:26]=[CH:25]/[CH2:24][CH2:23][O:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([O:28][CH:29]([CH3:30])[CH3:31])=[O:36])([CH3:35])[CH3:34]
Reactant: O=C1c2ccccc2C(=O)N1c1ncnc2c1ncn2O
Reactant: CC(C)OP(=O)(/C=C/CCO)OC(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OP(=O)(/C=C/CCOn1cnc2c(N3C(=O)c4ccccc4C3=O)ncnc21)OC(C)C
Temperature: 0 °C
Yield: 80.1 %

Procedure:
To a mixture of 9-hydroxy-6-phthalimidopurine (141 mg, 500 μmol), diisopropyl (E)-4-hydroxybut-1-enylphosphonate (110 g, 500 μmol) and triphenylphosphine (197 mg, 750 μmol) in tetrahydrofuran (5 ml) stirred at 0° C. was added diethyl azodicarboxylate (131 mg, 750 μmol). The mixture was then stirred at room temperature for 2 hr. The solvent was removed and the residue purified by column chromatography on silica gel eluting with dichloromethane-methanol (49:1, 16:1) to give (E)-9-[4-(diisopropoxyphosphoryl)but-3-enyloxy]-6-phthalimidopurine as a gum (200 mg, 80%); λmax (EtOH) 273 (14,380) nm; υmax (film) 2970, 1730 1590 1570 1355 1240 and 975 cm-1 ; δH [(CD3)2SO] 1.24 (12H, pseudo t, J 6 Hz, CH(CH3)2), 2.77 (2H, m, CH2), 4 60 (2H, m, CH(CH3)2), 4.66 (2H, t, J 6 Hz, CH2O ), 6.07 (1H, dd, J 17 Hz and 20 Hz, PCH=CH), 6.75 (1H, ddt, J 6 Hz, 17 Hz and 22 Hz, PCH=CH), 8.00-8.25 (4H, m, Ph), 9.00 (1H, s, H-2/H-8), 9.08 (1H, s, H-2/H-8) (Found: M+ 499. 1620. C23H26N5O6P requires M+ 499.1621).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:8][CH3:9])[CH2:7][CH2:6][NH:5][CH2:4]1.Cl[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:27])[C:16]([C:24]([OH:26])=[O:25])=[CH:17][N:18]2[CH:21]2[CH2:23][CH2:22]2)=[CH:13][C:12]=1[F:28]>>[CH:21]1([N:18]2[C:19]3[C:14](=[CH:13][C:12]([F:28])=[C:11]([N:5]4[CH2:6][CH2:7][C:3]([O:8][CH3:9])([O:2][CH3:1])[CH2:4]4)[CH:20]=3)[C:15](=[O:27])[C:16]([C:24]([OH:26])=[O:25])=[CH:17]2)[CH2:22][CH2:23]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: COC1(OC)CCNC1
Product: COC1(OC)CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
Following procedures similar to Step 5 of Example 1, a 0.186 g (1.4 mmol) sample of 3,3-dimethoxypyrrolidine, from Step 4 of Example 1, was reacted with 0.200 g (0.7 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (preparation described by K. Grohe, et al., DE 3142854, May, 1983) at 60° C. under N2 for 188 hours to yield the title compound, mp 224°-226° C.: MS (DCl) M/Z 377 (M+H); NMR d 1.42 (d, 1H), 1.63 (m, 2H), 3.75 (s, 3H), 3.99 (s, 3H), 4.02 (m, 1H), 4.26 (m, 2H), 4.40 (m, 2H), 7.46 (d, 1H, J=7.5 Hz), 8.13 (d, 1H, J=13.5 Hz), 9.19 (s, 1H). Analysis calculated for C19H21FN2O5 ·0.5 H2O: C, 59.21; H, 5.75; N, 7.27. Found: C, 59.70; H, 5.48; N, 7.13.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[CH3:13][CH2:14][CH:15]([NH2:18])[CH2:16][CH3:17]>>[CH2:14]([CH:15]([NH:18][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=1)[CH2:16][CH3:17])[CH3:13]
Reactant: CCC(N)CC
Reactant: O=C(O)C=Cc1ccc(O)cc1
Product: CCC(CC)NC(=O)C=Cc1ccc(O)cc1

Procedure:
N-(1-Ethyl-propyl)-3-(4-hydroxy-phenyl)-acrylamide was prepared in a similar manner as described in example 4 from 4-hydroxy-cinnamic acid and 3-pentylamine. MS (M+H, 234.10).
Reaction SMILES: N1C=NC(CC(OCC)=O)=N1.[C:12]1([C:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:19]2[CH:23]=[N:22][C:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[N:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:37]1([C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:19]2[CH:23]=[N:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[N:20]2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCOC(=O)CCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CCOC(=O)Cc1nc[nH]n1
Product: O=C(O)CCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
By a method similar to that in Reference Example 15 and using, instead of ethyl 1H-1,2,4-triazol-3-ylacetate, ethyl 3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propanoate obtained in Reference Example 24, the title compound was obtained as a white powder (175 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(Cc3ccc(OC)cc3)c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 54.2 %

Procedure:
To a solution of commercially available 1H-indole-6-carboxylic acid methyl ester (0.35 g, 2.0 mmol) and 4-methoxybenzyl bromide (0.32 mL, 2.2 mmol) in DMF (2 mL) was added sodium hydride (92 mg, 2.3 mmol). After stirring at room temperature for 3.5 hr, the solution was diluted with water (25 mL) and ethyl acetate (75 mL), the organic layer was washed again with dilute NaHCO3 (25 mL) and then brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1:5) to provide 1-(4-methoxy-phenylmethyl)-1H-indole-6-carboxylic acid methyl ester as a white solid (0.32 g, 54% yield). 1H NMR (400 MHz, DMSO) δ 8.10 (s, 1H), 7.73 (d, 1H, J=3.4 Hz), 7.64 (m, 2H), 7.14 (d, 2H, J=9.0 Hz), 6.88 (d, 2H, J=9.0 Hz), 6.58 (d, 1H, J=3.4 Hz), 5.45 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17](F)=[C:18]([CH:21]=1)[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:17]2[CH:16]=[CH:15][C:14]([Br:13])=[CH:21][C:18]=2[CH:19]=[O:20])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
(3-Hydroxy-phenyl)-acetic acid methyl ester (5 g, 30.1 mmol), 5-bromo-2-fluorobenzaldehyde (3.6 mL, 30.1 mmol), and potassium carbonate (8.3 g, 60.2 mmol) were combined in 1,4-dioxane (40 mL) and stirred at 120° C. for 16 hours. Once no starting material was seen by analytical LCMS and tlc, the mixture was worked-up with 10% aqueous HCl and EtOAc, and the crude material was purified by silica gel chromatography to give the desired product as a colorless oil (5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH3:15])=[O:13])=[CH:6][C:5]2=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.I[CH2:29][CH3:30]>O>[CH2:29]([O:16][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)[CH3:30]
Reactant: CCI
Reactant: COC(=O)c1cc(=O)c2cc(F)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)nc2ccc(F)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
8.0 g (0.036 M) of methyl 6-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylate and 15.0 g (0.108 M) of potassium carbonate are introduced into 80 ml of DMF. The reaction mixture is stirred for 1 hour at 50° C. After addition of 3.0 ml (0.037 M) of iodoethane and heating for 12 hours at 50° C., the reaction medium is poured into 400 ml of demineralized water. A brown solid precipitates out. The solid is filtered off, washed thoroughly with water and then with isopropyl ether, and finally dried under vacuum at 40° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][CH:14]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[CH3:12][S:13]([CH:14]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C(SC)c2ccc(OC)cc2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(c2ccc(OC)cc2)S(C)=O)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 104.7 %

Procedure:
A 50 ml. chloroform solution of 0.014 mole (2.4 grams) of m-chloroperbenzoic acid was slowly added to a stirred, cooled (0° C.), 25 ml. chloroform solution of 3.4 grams (0.0125 mole) of bis(p-methoxyphenyl)methyl methyl sulfide. The solution was kept at 0° C. for 2.5 hours, then warmed to an ambient temperature and maintained there for 2.5 hours, washed with 100 ml. of 10 percent aqueous potassium carbonate solution, 100 ml. of water and dried with Na2SO4. The solvent was removed to give 3.8 grams (105 percent yield) of a pale yellow viscous liquid which crystallized upon standing to an impure, low melting solid (about 90 percent purity) of bis(p-methoxyphenyl)methyl methyl sulfoxide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1.[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(=O)(O)[O-].[Na+]>ClCCl.CO>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:13]2[CH2:14][CH2:15][CH:10]([C:9]3[C:4]4[O:3][CH2:2][O:1][C:5]=4[CH:6]=[CH:7][CH:8]=3)[CH2:11][CH2:12]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: c1cc2c(c(C3CCNCC3)c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-Benzo[1,3]dioxol-4-yl-piperidine (0.680 g, 3.31 mmol,) in dichloromethane (35 ml) and methanol (1 ml) was added at room temperature commercially available trans-tert-butyl-4-(2-oxoethyl)-cyclohexylcarbamate (1.04 g, 4.31 mmol) and the solution was allowed to stir for 120 min. Sodium triacetoxyboron hydride (1.26 g, 5.96 mmol) was added portion wise and the mixture was allowed to stir for 16 h at room temperature. The solution was poured into saturated sodium bicarbonate solution (15 ml) and extracted with dichloromethane (2×20 ml). The combined organic layers were dried (MgSO4) and evaporated. The crude material was purified by flash chromatography on silica gel The crude material was purified by flash chromatography (methanol in dichloromethane 0-10%) to yield trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (1.43 g, 74%), MS (ISP) m/z=431.5 [(M+H)+].
Reaction SMILES: [O:1]=[C:2]([CH3:15])[CH2:3][C:4]([NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5].[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)([O-:18])=[O:17]>C(O)(C)C.C(O)(=O)C.N1CCCCC1>[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[C:3]([C:2](=[O:1])[CH3:15])[C:4]([NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5])([O-:18])=[O:17]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)NCC(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)NCC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 85 %

Procedure:
9.821 g (45.6 mmol) of t-butyl 2-[N-(3-oxobutanoyl)amino]acetate and 6.891 g (45.6 mmol) of 3-nitrobenzaldehyde were suspended in 50 ml of isopropyl alcohol. With addition of 0.331 g (2.28 mmol) of piperidine acetate, the mixture was stirred for 15 hours. The above mixture was ice-cooled for one hour and the precipitated crystals were separated by filtration. The thus obtained crystals were washed with cooled isopropyl alcohol and dried under reduced pressure. The thus obtained crystals were recrystallized from acetonitrile, whereby 13.5 g (85%) of the captioned compound was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14]2[CH:27]=[CH:26][C:17]([CH:18]=[C:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.C(O)(=O)C>CN(C)C=O.[Pd]>[CH3:1][NH:2][C:3](=[O:28])[NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][O:13][C:14]2[CH:27]=[CH:26][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:16][CH:15]=2)=[CH:9][CH:10]=1
Reactant: CNC(=O)Nc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Yield: 58.9 %

Procedure:
1.2 g (3.02 mmole) 5-(4-[2-(4-methylureidophenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was hydrogenated for 18 hours in 100 ml dimethylformamide and 10 ml acetic acid with 1 g Pd/C (10%) as catalyst. The catalyst was filtered off and the solvent was evaporated in vacuo. Ethyl acetate was added and the product was extracted with potassium carbonate in water. A black precipitate was filtered off and the ethyl acetate phase was extracted with more potassium carbonate solution. The water phase was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated in vacuo and recrystallized in methanol to give 0.71 g (yield 59%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([N:15]=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:10]=2)=[CH:5][CH:4]=1.Cl.NO.O.O.O.C([O-])(=O)C.[Na+]>CO.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(CSc2ccnc(N=C(c3ccccc3)c3ccccc3)c2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: O
Solvent: CO
Product: COc1ccc(CSc2ccnc(N)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-methoxybenzylthio)-2-chloropyridine (12 g, 45.2 mmol) and diphenylmethanimine (8.7 ml, 52.0 mmol) were dissolved in toluene (300 mL). The solution was evacuated and purged with nitrogen. Pd(OAc)2 (0.51 g, 2.3 mmol), rac-Binap (1.41 g, 2.26 mmol), and NaOtBu (6.1 g, 63.2 mmol) were added. The mixture stirred under N2 at 100° C. for 90 minutes. After cooling to ambient temperature, the mixture was quenched with water and the material was extracted with EtOAc, dried, and concentrated to afford the 4-(4-methoxybenzylthio)-N-(diphenylmethylene)pyridine-2-amine crude intermediate (18.5 g). The crude imine was dissolved in MeOH (200 mL) and hydroxylamine hydrochloride (11.0 g, 158 mmol) and sodium acetate trihydrate (30.7 g, 226 mmol) were added. The reaction was stirred at ambient temperature for 2 hours, then diluted with 1N HCl and extracted with EtOAc. The aqueous layer was basified to pH 9 and extracted with EtOAc. This second EtOAc layer was dried and concentrated to provide 4.7 g of the desired product. An additional 4.3 g of product was isolated by concentrating the first EtOAc layer extraction and purified via flash chromatography (70% EtOAc/hexanes) to provide the desired product (Total yield: 9.0 g, 80%) was isolated as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([CH:14]3[C:18](=[O:19])/[C:17](=[CH:20]/[CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)/[CH2:16][C:15]3=[O:27])[CH:9]=2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([CH:14]3[C:18](=[O:19])[CH:17]([CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:16][C:15]3=[O:27])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)C/C(=C\C2CCOCC2)C1=O
Agent: [Pd]
Solvent: CCO
Product: Cc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)CC(CC2CCOCC2)C1=O
Reaction time: 4 h
Yield: 48.5 %

Procedure:
To a solution of 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-4-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-cyclopentane-1,3-dione (88 mg, 0.22 mmol) in ethanol (2 ml) was added 5% palladium on carbon (9 mg) and the reaction stirred under an atmosphere of hydrogen at a pressure of 2 bar for 4 hours. The crude reaction mixture was filtered through a pad of Celite and purified by preparative mass-directed HPLC to give 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-4-(tetrahydro-pyran-4-ylmethyl)-cyclopentane-1,3-dione (43 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([O:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:33]([C:31]1[N:32]=[C:20]2[N:19]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:16]=3)[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][N:21]2[N:30]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(Oc5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4nc(Oc5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 6-8 (24 mg, 0.04 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 6-9.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.CCCCCC.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#C[Si](C)(C)C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
Under argon stream, 3.53 ml (25 mmol) of trimethylsilylacetylene was dissolved in 25 ml of tetrahydrofuran and cooled to -78° C. Into the solution was added dropwise 145.9 ml (24 mmol) of butyllithium-hexane solution, and the reaction was carried out with stirring for 30 minutes. Then, 6.5 ml (24 mmol) of tributyltin chloride was added dropwise, and the reaction was carried out with stirring for 22 hours, while elevating gradually the temperature of the reaction mixture to room temperature. After the reaction, the solvent was evaporated and the residue was distilled under reduced pressure (0.6 mm Hg, 100°-102° C.) to obtain 4.84 g of a transparent liquid (yield: 52.2%).