Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)O)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([O:22][Si](C)(C)C)=[C:19](C)[CH3:20].C([O-])([O-])=O.[K+].[K+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:19]([CH3:20])[C:18]([O:17][CH3:16])=[O:22])=[CH:4][CH:3]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: OC(c1cccc(F)c1)c1ccc(Br)s1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C(C)C(c1cccc(F)c1)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of (5-bromo-thiophen-2-yl)-(3-fluoro-phenyl)-methanol (2 g, 6.96 mmol) and (1-methoxy-2-methyl-propenyloxy)-trimethyl-silane (2.23 g, 13.92 mmol) in dichloromethane (20 ml) at 0° C. was added a solution of titanium tetrachloride in dichloromethane (1M solution, 7.7 ml, 7.66 mmol) slowly. After being stirred at 0° C. for 10 minutes and room temperature overnight, the reaction mixture was poured into an iced aqueous solution of K2CO3. The solution was extracted with dichloromethane. The organic layer was washed, dried (MgSO4) and concentrated to give the crude product. The crude product was purified by silica gel flash chromatography using 10% ethyl acetate in hexanes to give methyl 3-(5-bromothiophen-2-yl)-3-(3-fluorophenyl)-2-methyl-propanoate as a viscous yellow oil (1.74 g, 70% yield). HPLC Rt: 3.97 min.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[OH:11][NH2:12]>C(O)C.C(OCC)(=O)C>[NH2:2][C:1](=[N:12][OH:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: NO
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(N)=NO
Temperature: 25 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
tert-Butyl cyanoacetate (1.0 g) was dissolved in ethanol (10 mL), and aqueous hydroxyamine solution (50%, 0.5 mL) was added dropwise under ice-cooling. After stirring at room temperature for 5 hr, the mixture was diluted with ethyl acetate, and washed with brine, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and ethyl acetate-hexane was added. The resulting precipitate was collected by filtration to give the object product (820 mg, 67%).
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([N+:24]([O-])=O)=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)[C:3](=[O:11])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>[Pd].C1COCC1.CCO>[NH2:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:14]([CH2:13][CH2:12][N:2]([CH3:1])[C:3](=[O:11])[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17]2
Reactant: [H][H]
Reactant: CN(CCN1CCCc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(CCN1CCCc2cc(N)ccc21)C(=O)Oc1ccccc1

Procedure:
A suspension of phenyl methyl(2-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethyl)carbamate (500 mg, 1.41 mmol) and palladium on activated carbon (10%, 75 mg, 0.07 mmol) in a 1:1 mixture of THF/EtOH (20 mL) was stirred under a balloon of hydrogen for 4.5 hours. The suspension was filtered through a pad of celite. The filter pad was rinsed with 25 mL methanol and the filtrate was concentrated to give a dark viscous oil. The crude product was used without further purification (460 mg, quantitative). 1H-NMR (CDCl3) δ 7.39-7.34 (m, 2H), 7.22-7.17 (m, 1H), 7.12-7.08 (m, 2H), 6.61-6.42 (m, 3H), 3.61-3.45 (m, 4H), 3.26 (t, J=6.0 Hz, 2H), 3.20 (brs, 2H), 3.13 and 3.06 (2×s, 3H), 2.70 (t, J=6.3 Hz, 2H), 1.96-1.87 (m, 2H). MS (ESI): 326.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][NH:9][C:5]2=[N+:6]([O-])[CH:7]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[CH:11][C:4]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc(F)cc2cc[nH]c21
Product: Fc1cnc2[nH]ccc2c1Cl

Procedure:
4-Chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine can be obtained as in example 4 stage 4(b) but starting from 1.7 g of 5-fluoro-1H-pyrrolo[2,3-b]pyridine 7-oxide in 10 cm3 of phosphorus oxychloride. In this way, 1.3 g of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine is obtained as a solid with the following characteristics:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[CH2:21]([N:25]=[C:26]=[O:27])[CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[CH2:21]([NH:25][C:26]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:27])[CH2:22][CH2:23][CH3:24]
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: CCCCN=C=O
Solvent: ClCCl
Product: CCCCNC(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (198 mg, 714 μmol, Example 87, Step 3) in DCM (2.0 mL) was added n-butyl isocyanate (88 μL, 785 μmol). The resulting mixture was then stirred at RT for overnight. Then, the solvent was removed and the residue was mixed with silica gel. The solid mixture was the purified by silica gel flash column chromatography using ISCO instrument (solid loading, 0%-400% EtOAc/hexane) to give the title compound as a colorless solid. MS (ESI, positive ion) m/z: 377 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14](=[O:16])[CH3:15])=[CH:10][NH:11]2)=[CH:7][CH:6]=1.C(C1C2C(=CC=C(OC(F)(F)F)C=2)N([CH2:35][C:36]([OH:38])=[O:37])C=1)(=O)C>>[C:14]([C:9]1[C:8]2[C:12](=[CH:13][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:17])=[CH:6][CH:7]=2)[N:11]([CH2:35][C:36]([OH:38])=[O:37])[CH:10]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)Cc1ccc2c(C(C)=O)c[nH]c2c1
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: COC(=O)Cc1ccc2c(C(C)=O)cn(CC(=O)O)c2c1

Procedure:
was prepared from (3-acetyl-1H-indol-6-yl)-acetic acid methyl ester in a similar manner as described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. Brown solid. MS: 290 [M+H]+; tR (HPLC conditions k): 2.83 min.
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:13](=[O:16])[N:12]4[N:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=[C:11]4[NH:10][C:9]=3[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH2:34]([O:33][C:31]([CH2:30][CH2:29][CH2:28][N:10]1[C:9]2[C:8](=[O:26])[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:15][C:14]=2[C:13](=[O:16])[N:12]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=[C:11]12)=[O:32])[CH3:35]
Reactant: O=C1c2[nH]c3cc(-c4ccccc4)nn3c(=O)c2CN1C1CCCCC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCCn1c2c(c(=O)n3nc(-c4ccccc4)cc13)CN(C1CCCCC1)C2=O
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of 100 g (2.87) mmole) of 6-cyclohexyl-4,7-dihydro-2-phenyl-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-dione (see preparation 1), 0.82 ml. (5.7 mmoles), of ethyl 4-bromobutyrate and 0.41 g., 3.0 mmole of potassium carbonate in 11 ml. of -dimethyl-sulfoxide (DMSO) was stirred at 50° C. for 16.5 hours. Then 35 ml. of water was added and the mixture was suction filtered. The collected solid was washed with more water and air dried. The crude solid was recrystallized from 95% ethanol (100 ml), reflux cooled to room temperature, affording 1.11 g (84% yield) of the titled compound as very fine white needles, m.p. 195°-196° C. 1H NMR (CDCl3, δ) 8.06 (d, 2H, phenyl-H (ortho), 7.45 (m, 3H, phenyl-H), 6.70 (s, 1H, pyrazole-H, 4.74 (t, 2H, J=Hz, 4-NCH 2), 4.37 (s, 2H, lactam CH2), 4.16 (q, 2H, J=7 Hz, OCH2), 4.15 (m, 1H, 6-NCH), 2.49 (t, 2H, CH2CO2C2H5), 2.23 (m, 2H, CH2), 1.15-1.95 (m, 10H, cyclohexyl CH2), 1.26 (t, 3H, J"7 Hz, CH3.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH3:2].O[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:11]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCN(CC)CCCCCCO
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCCCCCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.3 %

Procedure:
A mixture of 2.17 g of 6-diethylamino-1-hexanol (J. Chem. Soc. 1942, 428), 1.52 g of 4-hydroxy-benzaldehyde and 3.3 g of triphenylphosphine in 100 ml of tetrahydrofuran was treated slowly at 20° with a solution of 1.97 g of diethyl azodicarboxylate. After the dropwise addition the mixture was stirred at room temperature for a further 5 hours. The reaction mixture was then evaporated in a rotary evaporator. The residue was chromatographed on 400 g of neutral aluminium oxide (activity grade III) with hexane:ethyl acetate 7:3). There were obtained 2.22 g (64%) of 4- [[6-(diethylamino)hexyl]oxy]benzaldehyde as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29]/[C:30](=[N:33]/[H])/[NH:31]O)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]>CS(C)=O>[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[N:31]=[C:8]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=3)[O:10][N:33]=2)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCCc2noc(-c3cc(Cl)ccn3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 10.9 %

Procedure:
4-Chloro-2-pyridinecarboxylic acid (40 mg, 0.25 mmol) and CDl (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The reaction mixture was purified by MDAP. The product fraction was combined and concentrated to give the title compound as a white solid (13 mg, 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1>[Ni].C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CCCCCC(=O)C=Cc1ccc(Cl)cc1
Agent: [Ni]
Solvent: Cc1ccccc1
Product: CCCCCC(=O)CCc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
15 g of Raney nickel are added to a solution of 100 g (0.423 mol) of 1-(4-chlorophenyl)-1-octen-3-one in 500 ml of toluene and the mixture is stirred for 5 hours at 60° C. under a hydrogen pressure of 70-90 bar in an autoclave. After this the reaction mixture is filtered and concentrated under reduced pressure. 97.3 g (96.4% of theory) of 1-(4-chlorophenyl)-3-octanone are obtained in the form of a colorless oil. ##STR36##
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21](Cl)=[O:22])=[CH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>>[F:24][C:25]([F:34])([F:35])[O:26][C:27]1[CH:28]=[C:29]([NH:30][C:21]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18]=2[CH:19]=[CH:20][C:11]([O:10][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=2)=[CH:12]3)=[O:22])[CH:31]=[CH:32][CH:33]=1
Reactant: NC(=O)c1cc(Oc2ccc3c(C(=O)Cl)cccc3c2)ccn1
Reactant: Nc1cccc(OC(F)(F)F)c1
Product: NC(=O)c1cc(Oc2ccc3c(C(=O)Nc4cccc(OC(F)(F)F)c4)cccc3c2)ccn1

Procedure:
6-(2-carbamoylpyrdin-4-yloxy)-1-napthoyl chloride (step b, 150 mg g, 0.41 mmol) was reacted with 3-trifluoromethoxyaniline 56 μL, 0.41 mmol, Aldrich) under the conditions of Example 421 Step c to furnish the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 468.1 (M+1). Mass Calc'd for C24H16F3N3O4: 467.40.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32])([O-:24])=[O:23]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N+:22]([O-:24])=[O:23])(=[O:32])=[O:33])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-aminopiperidine-1-carboxylic acid tert-butyl ester (400 mg, 200 mmol) in anhydrous dichloromethane (14 mL) under argon was added triethylamine (340 μL, 2.4 mmol) and the solution cooled in an ice bath. 2-Nitrophenylsulfonyl chloride (443 mg, 2.0 mmol) was added and the reaction allowed to stir at rt for 16 h. The crude solution was washed with water (2×30 mL) before removing the solvent in vacuo. The crude material was purified by chromatography using ethyl acetate/petroleum ether (30-60%) as the eluent to give the title compound as an off-white powder. δH (d6 DMSO): 8.43 (2H, m), 8.17 (1H, s), 8.09 (2H, m), 3.80-3.69 (2H, m), 3.31-3.23 (1H, m), 2.86-2.69 (2H, m), 1.63-1.51 (2H, m), 1.39 (9H, s), 1.29-1.17 (2H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]#[N:12])[CH2:6][CH2:5]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[ClH:21]>CCOCC.O>[ClH:21].[NH2:12][CH2:11][CH2:10][N:7]1[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][OH:1])[CH2:9][CH2:8]1
Reactant: N#CCN1CCC(CCO)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: NCCN1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 62 %

Procedure:
The title compound was prepared according to general procedure H described in Scheme 3. 2-(4-(2-Hydroxyethyl)piperidin-1-yl)acetonitrile (1.2 g, 7.13 mmol) was dissolved in ether (5 mL) and added carefully to a slurry of LiAlH4 (8.3 equiv., 2.25 g, 59 mmol) in ether (25 mL) and stirred at RT under Ar for 14 h. The crude reaction mixture containing a white precipitate was cooled to 0° C. and treated dropwise with 10% aqueous NaOH (4 mL) and stirred for 30 min. The cooled mixture was treated with H2O (8.1 mL) to provide a thick precipitate. The mixture was then treated with ether (20 mL), stirred and filtered. The filter cake was washed with ether (5×20 mL). The combined ether layer was concentrated under reduced pressure to provide a concentrated solution in ether/H2O that was acidified to pH 2 with 1 N HCl. The mixture was concentrated under reduced pressure to provide the title compound as a dark yellow oil (923 mg, 62%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[C:17]([C:20]1[CH:28]=[CH:27][C:23]2[NH:24][N:25]=[N:26][C:22]=2[CH:21]=1)(O)=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:17]([C:20]2[CH:28]=[CH:27][C:23]3[N:24]=[N:25][NH:26][C:22]=3[CH:21]=2)=[N:16][N:15]=1
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3nn[nH]c3c2)o1
Yield: 39 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 5-carboxy-benzotriazole instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:20:10 to 20:70:10, 125 mg, 39%) which was obtained as a white solid. MS: m/e 345.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9](Br)[C:8]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:7][C:6]=1[C:17]([F:20])([F:19])[F:18])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[C:8]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:7][C:6]=1[C:17]([F:20])([F:19])[F:18])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(OCC2CC2)nc1C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)c(OCC2CC2)nc1C(F)(F)F
Temperature: 80 °C
Yield: 114.3 %

Procedure:
5-Bromo-6-cyclopropylmethoxy-2-trifluoromethyl-nicotinic acid ethyl ester (0.3 g, 0.81 mmol) was dissolved in dioxane (1.6 mL). To this solution was added with stirring [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CH2Cl2 (33 mg, 0.04 mmol), 4-chlorophenylboronic acid (197 mg, 1.2 mmol) and sodium carbonate solution (2M, 1.2 mL). This mixture was heated to 80° C. for 5 h and cooled to room temperature. Water (150 mL) was added, the phases were separated and the water mixture was extracted with ethylacetate. Organic phases were pooled, dried with MgSO4 and the volatiles removed in vacuo. The residue was purified by flash chromatography on silica (dichloromethane/methanol, 4:1) to give the title compound (0.37 g) as light yellow oil; MS (ISP) 400.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])[CH:8]=2)[CH:3]=[CH:2]1.B(OB=O)=O.[Br:23][C:24]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:25]=1[CH:26]=O.B(OCCCC)(OCCCC)OCCCC.C(N)CCC.Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[Br:23][C:24]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:25]=1/[CH:26]=[CH:15]/[C:14](=[O:16])[CH2:13][C:12](=[O:17])/[CH:11]=[CH:10]/[C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1
Reactant: CC(=O)CC(=O)C=Cc1ccc2cc[nH]c2c1
Reactant: O=Cc1cc(O)ccc1Br
Agent: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: O=BOB=O
Solvent: CCCCN
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(/C=C/c1ccc2cc[nH]c2c1)CC(=O)/C=C/c1cc(O)ccc1Br
Reaction time: 1 h
Yield: 20.1 %

Procedure:
6-(1H-Indol-6-yl)hex-5-ene-2,4-dione (19.4 mg, 85 μmol) and boron trioxide (11 mg, 0.16 mmol) was placed in a 20 mL reaction vessel, and dissolved in 0.4 mL of ethyl acetate. To the stirring mixture at 80° C. was added a solution of 2-bromo-5-hydroxybenzaldehyde (23 mg, 0.11 mmol) and tri-n-butyl borate (25 μL, 93 μmol), sequentially. After the reaction mixture was stirred for 2 h at the same temperature, n-butylamine (10 μL, 0.10 mmol) was added with additional stirring for 1 h. The reaction mixture was treated with a 1:1 solution (1 mL) of 1N HCl and brine at room temperature, and was stirred at 50° C. for 5 min to 1 h (if necessary, the reaction mixture was neutralized by saturated NaHCO3 aqueous solution). The organic layer was purified directly by silica gel column chromatography (eluting with hexane/ethyl acetate or chloroform/methanol) to obtain the title compound (7.0 mg, 19%) as a solid.
Reaction SMILES: [CH:1](=[O:8])[CH:2]1[CH:7]=[CH:6][CH2:5][CH2:4][CH2:3]1.[CH2:9]=[O:10]>>[C:2]1([CH2:9][OH:10])([CH2:1][OH:8])[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7]1
Reactant: C=O
Reactant: O=CC1C=CCCC1
Product: OCC1(CO)CC=CCC1

Procedure:
The further reaction of the tetrahydrobenzaldehyde with surplus formaldehyde to form 3-cyclohexene-1,1-dimethanol and its derivatives has already been reported by H. E. French and D. M. Gallagher in J. Amer. Chem. Soc. 64, pages 1497-99 (1942). ##STR10##
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:25][C:26]1[CH:27]=[C:28]([CH:42]=[C:43]([CH3:45])[CH:44]=1)[C:29]([C:31]1[NH:36][C:35](=[O:37])[NH:34][C:33](=[O:38])[C:32]=1[CH:39]([CH3:41])[CH3:40])=[O:30].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:25][C:26]1[CH:27]=[C:28]([CH:42]=[C:43]([CH3:45])[CH:44]=1)[C:29]([C:31]1[N:36]([CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:4]=2)[C:35](=[O:37])[NH:34][C:33](=[O:38])[C:32]=1[CH:39]([CH3:40])[CH3:41])=[O:30]
Reactant: Cc1cc(Cl)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CC(=O)Nc1cc(CO)ccn1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Cn2c(C(=O)c3cc(C)cc(Cl)c3)c(C(C)C)c(=O)[nH]c2=O)ccn1
Yield: 31.9 %

Procedure:
N-(4-Hydroxymethyl-pyridin-2-yl)-acetamide (166 mg, 1 mmol) was dissolved in chloroform (10 ml) and cooled in an ice bath under nitrogen atmosphere. With stirring, triethylamine (210 μl, 1.5 mmol) was added and methanesulfonyl chloride (90 μl, 1.2 mmol) was added dropwise. After stirring for 1.1 hr., the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo for ca. 20 min. and mixed with 6-(3-Chloro-5-methyl-benzoyl)-5-isopropyl-1H-pyrimidine-2,4-dione (306 mg, 1 mmol), powdered anhydrous potassium-carbonate (138 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol). DMF (5 ml) was then added to the mixture at room temperature and stirred for ca. 4 hr. After evaporation of DMF, the residue was dissolved in methanol-chloroform (1:9) and filtered through celite pad. The filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (2:1)) to afford 145 mg (32%) of a white solid. m.p. 241-243° C.; 1H NMR (200 MHz, CDCl3) δ 1.17 (3H, d, J=6.7 Hz), 1.23 (3H, d, J=6.7 Hz), 2.19-2.40 (7H, m), 4.63 (1H, d, J=16.7 Hz), 5.03 (1H, d, J=16.7 Hz), 6.83 (1H, d, J=5.3 Hz), 7.38 (1H, s), 7.46 (1H, s), 7.58 (1H, s), 7.99 (1H, s), 8.30 (1H, d, J=5.3 Hz), 9.89 (1H, s), 12.34 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[Cl:28])[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(S(N)(=O)=O)C=CC=CC=1.ClC([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[Cl:28])[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)NCCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: NS(=O)(=O)c1ccccc1
Product: C[C@H](CCCNC(=O)Oc1ccccc1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 82 %

Procedure:
4-chloro-N-(2,5-dichlorophenyl)-N-[4-[[(phenoxy)carbonyl]amino]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[(R)-1-methyl (acetylamino)butyl]benzenesulfonamide by reacting 4-chloro-N-[2,5-dichlorophenyl]-N-[R]-]-methyl-4-aminobutyl]benzenesulfonamide with phenyl chloroformate. Yield=82%; MS (ESI+), 541 (M+H)+.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[I:7].[OH-].[K+].Br[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1>C1COCC1>[I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:6]=1[I:7]
Reactant: Ic1nc[nH]c1I
Reactant: BrCc1ccc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Ic1ncn(Cc2ccc3ccccc3c2)c1I

Procedure:
4,5-diiodoimidazole (5.0 mmol) and KOH (5.0 mmol) were placed in a round bottom flask with 50 mL THF. The mixture was brought to reflux and stirred 0.5 h until KOH was consumed. 2-bromomethylnapthalene (5.0 mmol) was added and the solution was stirred at reflux for 17 hours. KBr was removed by vacuum filtration and the filtrate was collected. The volatiles were removed by rotary evaporation to give 4,5-diiodo-1-(naphthalen-2-ylmethyl)-1H-imidazole as a off white solid. 4,5-diiodo-1-(naphthalen-2-ylmethyl)-1H-imidazole was dissolved in acetonitrile in a round bottom flask. The solution was brought to reflux and excess iodomethane was added. The reaction was stirred at reflux for overnight after which time it was cooled. The resulting yellow precipitate was collected by filtration and analyzed. 1H NMR (300 MHz, d6-DMSO): δ 3.88 (s), 5.64 (s), 7.47-7.60 (m), 7.89-8.02 (m), 9.57 (s) ppm.