Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1Br.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:24][C:25]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH:12]=1)=[O:33]
Reactant: COC(=O)c1ccncc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccncc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 14 h
Yield: 85.8 %

Procedure:
PdCl2(PPh3)2 (0.7 g, 1.03 mmol, 0.05 eq.) was added to a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (6.3 g, 20.5 mmol, 1.0 eq.) in THF (120 mL) under nitrogen. To this was added 3-bromoisonicotinic acid methyl ester (4.4 g, 20.5 mmol, 1.0 eq.). This was followed by the addition of a solution of Na2CO3 (8.7 g, 82.1 mmol, 4.0 eq.) in water (41 mL). The resulting solution was stirred for 14 hours while the temperature was maintained at reflux in an oil bath. The resulting solution was diluted with EtOAc (100 mL), and washed with saturated aqueous NaCl (2×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:10) to yield 3′,6′-dihydro-2′H-[3,4′]bipyridinyl-4,1′-dicarboxylic acid 1′-t-butyl ester 4-methyl ester (5.6 g) as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31](/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38])=[CH:32][CH:33]=4)[N:28]([CH3:40])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.C([O-])=O.[NH4+].O1CCCC1>[Pd].C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:32][CH:33]=4)[N:28]([CH3:40])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)(=[O:15])=[O:16])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(/C=C/C(=O)O)ccc23)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(CCC(=O)O)ccc23)cc1

Procedure:
10% Palladium-on-carbon (10 mg) was added to a stirred solution of (E)-3-[3-{1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-6-indolyl]-2-propenoic acid (the compound of Example 58, 80 mg, 0.14 mmol) and ammonium formate (64 mg, 0.5 mmol) in a 1:1 mixture of tetrahydrofuran and ethanol (10 ml total). The mixture was stirred at reflux for 48 h. cooled, filtered through Arbocel™ and concentrated. The grey foam was purified by flash column chromatography (elution with 98% dichloromethane/2 % methanol) giving the product as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[Mg].[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:21](=O)[CH2:22][CH2:23][CH2:24][CH:25]=2)[CH2:16][CH2:15]1)[CH2:12][CH3:13].Cl.C([O:30]CC)C>>[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH2:21][CH2:22][C:23]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([F:1])[CH:3]=3)([OH:30])[CH2:24][CH:25]=2)[CH2:16][CH2:15]1)[CH2:12][CH3:13]
Reactant: CCC[C@H]1CC[C@H](C2=CCCCC2=O)CC1
Reactant: Fc1cc(Br)ccc1Cl
Reactant: CCOCC
Agent: Cl
Agent: [Mg]
Product: CCC[C@H]1CC[C@H](C2=CCC(O)(c3ccc(Cl)c(F)c3)CC2)CC1

Procedure:
A solution of 6.7 of 3-fluoro-4-chlorobromobenzene in 30 ml of anhydrous diethyl ether was added dropwise under stirring at 10°-15° C. to 0.66 g of magnesium metal powder, followed by reaction at room temperature for 1 hour so that a Grignard reagent was formed. After 4.8 g of trans-4-propylcyclohexylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 1-(trans-4-propylcyclohexyl)-4-(3-fluoro-4-chlorophenyl)-4-hydroxycyclohexene was obtained as a crude reaction product.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[O:6][C:7]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:8]=2[CH:9]=1)C.C(O)=O>O>[CH:4]([C:5]1[O:6][C:7]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:3]
Reactant: CCOC(OCC)c1cc2ccc(C(=O)OC)cc2o1
Solvent: O
Solvent: O=CO
Product: COC(=O)c1ccc2cc(C=O)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Methyl 2-(diethoxymethyl)-1-benzofuran-6-carboxylate (2.71 g, 9.7 mmol) is treated drop-wise with formic acid (20 ml, 530 mmol) and water (5.5 ml). The reaction is stirred overnight at RT, diluted with water (50 ml), and the brown slurry is filtered. The cake is dried overnight to afford 1.86 g (94%) of methyl 2-formyl-1-benzofuran-6-carboxylate as an amber solid. 1H NMR (400 MHz, DMSO-d6): δ 3.91, 8.03, 8.28, 9.92 ppm.
Reaction SMILES: B(F)(F)F.[CH3:5]COCC.[CH3:10][C:11]1[C:12](=[O:23])[O:13][CH2:14][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1.BrC[CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28].[Mg]>O1CCCC1.CCOCC>[CH2:27]([CH:26]([CH2:29][CH3:30])[CH2:10][C@@:11]1([CH3:5])[C:12](=[O:23])[O:13][CH2:14][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:16]1)[CH3:28]
Reactant: CCOCC
Reactant: CCC(CC)CBr
Reactant: CC1=N[C@@H](c2ccccc2)COC1=O
Agent: FB(F)F
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(CC)C[C@]1(C)N[C@@H](c2ccccc2)COC1=O
Temperature: -20 °C
Reaction time: 0.83 h

Procedure:
Boron trifluoride etherate (5.85 ml, 46 mmol) was added slowly to a solution of (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (4.35 g, 23 mmol, see WO-A-02/051983) in tetrahydrofuran at −78° C. The solution was stirred for 50 minutes and then a solution of the Grignard reagent prepared from 3-(bromomethyl)pentane (10.9 g, 66 mmol) and magnesium turnings (2.5 g, 99 mmol) in ether (250 ml) was added over 40 minutes. The reaction mixture was stirred for a further 75 minutes at −78° C. then allowed to warm to −20° C. and quenched with saturated aqueous ammonium chloride (100 ml). More tetrahydrofuran (100 ml) was added and the organic layer was separated from the aqueous layer. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of pentane to pentane:ether (30:70) to afford the title compound as a white solid (3.21 g).
Reaction SMILES: C(O)C.[F:4][C:5]([F:41])([F:40])[C:6]1[CH:39]=[CH:38][C:9]([C:10]([NH:12][C:13]2[N:17]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24](CC4C=CC=CC=4)[CH2:23][CH2:22]3)[C:16]3[CH:34]=[CH:35][CH:36]=[CH:37][C:15]=3[N:14]=2)=[O:11])=[CH:8][CH:7]=1.[H][H]>[Pd].C(O)(=O)C>[F:40][C:5]([F:4])([F:41])[C:6]1[CH:39]=[CH:38][C:9]([C:10]([NH:12][C:13]2[N:17]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:16]3[CH:34]=[CH:35][CH:36]=[CH:37][C:15]=3[N:14]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Nc1nc2ccccc2n1CCCN1CCN(Cc2ccccc2)CC1)c1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(Nc1nc2ccccc2n1CCCN1CCNCC1)c1ccc(C(F)(F)F)cc1
Yield: 63.9 %

Procedure:
To a solution composed of 75 ml. ethanol and 1 ml. glacial acetic acid was added 2-(4-trifluoromethylbenzamido)-1-[3-(4-benzyl-1-piperazinyl)-propyl]benzimidazole (500 mg., 0.96 millimole) and 100 mg. of 10% Pd/C catalyst. The mixture was shaken on a Paar apparatus at about 2 atm. pressure of hydrogen and 40° C. for 2.5 hrs. at which time the reaction was complete. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to yield a white solid, which on trituration under acetone yielded 300 mg. (63.9% yield) of 2-(4-trifluoromethylbenzamido)-1-[3-(1-piperazinyl)propyl]benzimidazole, as a white crystalline solid, m.p. 184°-185° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[C:4]([CH3:17])[CH:3]=1.[I-:18].[Na+].CNCCNC>O1CCOCC1.[Cu]I>[I:18][C:2]1[S:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[C:4]([CH3:17])[CH:3]=1
Reactant: [I-]
Reactant: CCCc1ccc(Cc2sc(Br)cc2C)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCc1ccc(Cc2sc(I)cc2C)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a mixture of 5-bromo-3-methyl-2-(4-propylbenzyl)thiophene (46, 0.86 g, 2.77 mmol), sodium iodide (0.83 g, 5.53 mmol) and copper(I) iodide (0.053 g, 0.277 mmol) in dioxane (5.2 mL) was added N,N′-dimethylethylenediamine (0.060 mL, 0.553 mmol). The resulting mixture was heated to 110° C. and stirred for 16 hours. After cooling to room temperature, the reaction mixture was filtered through a plug of Celite® and then washed with EtOAc (50 mL). The filtrate was washed with brine and dried over MgSO4. The organic phase was evaporated under vacuum to provide 5-iodo-3-methyl-2-(4-propylbenzyl)thiophene 47 (0.95 g, 2.66 mmol, 96%) as a yellow oil, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:14])[S:10][CH:11]=1
Reactant: CCn1ncc(Br)c1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc(Br)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a solution of 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid 156 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (0.18 g, 0.52 mmol) and DIPEA (0.5 mL, 2.86 mmol) in DCM (5 mL) at 25° C. was added PyBrOP (0.29 g, 0.62 mmol) in one portion. After 2 h, the solution was concentrated and purified via column chromatography (silica, 20-60% EtOAc/hexane) affording the title compound (0.281 g, 86%). LC-MS (ES) m/z=632 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C@@H:12]1[NH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:13]1=[O:27].CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:17]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[C:13](=[O:27])[C@@H:12]2[CH3:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1NCCN(CCCN2CCCCC2)C1=O
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H]1C(=O)N(CCCN2CCCCC2)CCN1C(=O)Nc1cccc(Cl)c1
Yield: 82.4 %

Procedure:
3-Chlorophenyl isocyanate (36 mg, 0.23 mmol) was added to a solution of (S)-3-methyl-1-(3-piperidin-1-yl-propyl)-piperazin-2-one (intermediate 20; 52 mg, 0.21 mmol) and 4-methylmorpholine (21 mg, 0.21 mmol) in N,N-dimethylformamide (1 ml), then after 16 h the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloro-methane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (68 mg, 84%). Colorless gum, MS (ISP)=393.2 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH:10](O)[C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[C:3]1([CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2.[ClH:20].O.Cl.Cl>C(O)C>[OH2:17].[ClH:20].[NH2:1][CH:2]1[C:9]2=[CH:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[C:3]1([CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2.[NH2:1][CH:2]1[C:9]2=[CH:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[C:3]1([CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2.[ClH:20]
Reactant: CC12CCCCCC(C(O)c3ccc(O)cc31)C2N
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC12CCCCCC(=Cc3ccc(O)cc31)C2N
Reaction time: 8 h
Yield: 70 %

Procedure:
13-Amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-methanobenzocyclodecen-3,12-diol (0.7 g., 0.002 mole) was dissolved in 20 mL of boiling ethanol. To this solution was added 5 mL ethanol saturated with hydrogen chloride and was allowed to stand overnight. The solvent was evaporated under reduced pressure and the resulting residue was recrystallized from acetone-ethanol (5:1) to afford 400 mg (70% yield) of the title compound as a hydrochloride hemihydrate, mp 216°-218° C.
Reaction SMILES: [ClH:1].[NH:2](C(OC(C)(C)C)=O)[C@H:3]([C:8]([NH:10][C@H:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(OCC)(=O)C>COC(C)(C)C>[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:9])[CH2:4][CH:5]([CH3:6])[CH3:7].[ClH:1]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
Gaseous HCl (10.2 g, 279 mmol) was infused into a mixture of Boc-Leu-Leu-OMe (17.9 g, 50.0 mmol) and ethyl acetate (71.4 g) at 20 to 25° C. After 30 min, t-butyl methyl ether (142.9) was added to the resulting solution followed by a seed crystal. The resulting solid crystalline product was filtered at 0 to 5° C. and dried in vacuo to give H-Leu-Leu-OMe.HCl (14.1 g, 95.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[N:12]=2)=[CH:4][CH:3]=1.[F:27][C:28]([F:33])([F:32])[C:29]([O-:31])=[O:30]>>[OH:31][C:29]([C:28]([F:33])([F:32])[F:27])=[O:30].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2coc(-c3ccc(F)cc3)n2)CC1
Reactant: O=C([O-])C(F)(F)F
Product: Fc1ccc(-c2nc(CN3CCNCC3)co2)cc1
Product: O=C(O)C(F)(F)F

Procedure:
This compound was synthesized from tert-butyl 4-((2-(4-fluorophenyl)oxazol-4-yl)methyl)piperazine-1-carboxylate as described for example 46 step 4 (130 mg, crude) as a trifluoroacetate salt and it was carried through without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (br s, 2H), 8.21 (s, 1H), 8.04-8.01 (m, 2H), 7.42-7.38 (t, J=8.9 Hz, 2H), 3.80 (m, 2H), 3.18 (m, 4H), 2.88 (m, 4H). MS (ESI) m/z: Calculated for C14H16FN3O: 261.13. found: 262.0 (M+H)+
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(Cl)Cl.C(N(CC)CC)C.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[S:38](Cl)(=[O:40])=[O:39]>O>[F:22][C:2]([F:1])([F:21])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:38]([C:34]3[S:33][CH:37]=[CH:36][CH:35]=3)(=[O:40])=[O:39])[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100 mL round-bottomed flask was charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (2.27 g, 6.92 mmol, published PCT patent application no. WO 2006/094842), 20 mL of CH2Cl2 and triethylamine (1.45 mL, 10.4 mmol). To this was added 2-thiophenesulfonyl chloride (1.39 mL, 7.61 mmol, Sigma-Aldrich, St. Louis, Mo.) and the mixture was stirred at room temperature for 2 h. After that time, the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL). The combined extracts were dried (MgSO4) and concentrated. This oil was purified by column chromatography (120 g silica gel, 0 to 50% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (2.35 g) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.70-7.65 (m, 1H) 7.64-7.56 (m, 3H), 7.23-7.18 (m, 1H), 7.02-6.94 (m, 2H), 3.43-3.36 (m, 4H), 3.33-3.25 (m, 4H). m/z (ESI, +ve ion) 475.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.332 μM; GK-GKRP EC50 (LC MS/MS)=0.500 μM.
Reaction SMILES: [N+:1]([C:4]1[N:5]([C:9]([CH2:11][CH2:12][OH:13])=[O:10])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[P:14](Cl)([Cl:17])([Cl:16])=[O:15]>C1COCC1>[P:14]([Cl:17])([Cl:16])(=[O:15])[O:13][CH2:12][CH2:11][C:9]([N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2])=[O:10]
Reactant: O=C(CCO)n1ccnc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C(CCOP(=O)(Cl)Cl)n1ccnc1[N+](=O)[O-]

Procedure:
A solution of 3.0 mmol of 2-(2-nitro-1-imidazoyl)ethanol in 17 ml dry THF is added dropwise over 1 hr to 7.0 mmol phosphorus oxychloride in 5 ml THF at -7° to -2° C. with stirring. The suspension is stirred for another 75 min at 0° C., then allowed to reach room temperature and filtered. The residual powder is washed under a nitrogen flow with THF and the solvent and excess POCl3 removed from the filtrate in vacuo over 1 hr to yield 2-(2-nitro-1-imidazoyl)ethyl phosphorodichloridate as an oil.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][N:3]=[N:2]1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:3]2[N:4]=[C:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:1]=[N:2]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)Cc1nnn[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 3 h
Yield: 78.4 %

Procedure:
To a solution of ethyl 5-tetrazolylacetate (1 g) (Lofquist et al. J. Amer. Chem. Soc. (1958), 80, 3908) in pyridine (6 mL) was added triphenylmethyl chloride (2.2 g) and the resulting solution allowed to stir for 3 h. The solvent was evaporated and the product crystallized from ether/hexane to give ethyl 3-triphenylmethyltetrazol-5-ylacetate as a white solid (2 g); TLC: Rf =0.5, ether:hexane (50:50).
Reaction SMILES: [CH2:1]([NH2:8])C1C=CC=CC=1.Cl.CN.[C:12]([C:15]1[S:19][C:18]([N:20]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=3)[C:29]([OH:31])=O)[C:21]2=[O:35])=[N:17][C:16]=1[CH3:36])(=[O:14])[CH3:13]>>[C:12]([C:15]1[S:19][C:18]([N:20]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=3)[C:29]([NH:8][CH3:1])=[O:31])[C:21]2=[O:35])=[N:17][C:16]=1[CH3:36])(=[O:14])[CH3:13]
Reactant: CC(=O)c1sc(N2CCN(Cc3cccc(C(=O)O)c3)C2=O)nc1C
Reactant: NCc1ccccc1
Agent: CN
Agent: Cl
Product: CNC(=O)c1cccc(CN2CCN(c3nc(C)c(C(C)=O)s3)C2=O)c1
Yield: 85 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with methylamine monohydrochloride to react with 3-((3-(5-acetyl-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoic acid, the title compound was obtained as a white powder in 85% yield: 1H NMR (300 MHz, CDCl3) δ 7.73-7.62 (m, 2H), 7.42-7.34 (m, 2H), 6.32 (br s, 1H), 4.51 (s, 2H), 4.13-4.04 (m, 2H), 3.49-3.41 (m, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.60 (s, 3H), 2.45 (s, 3H); MS (ES+) m/z 373.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6](C(OC(C)(C)C)=O)[CH2:7][CH3:8])[CH3:2].[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)CN(CC)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNCC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 30.8 g (113 mmole) of N-[(1,1-dimethylethoxy)carbonyl]-N-ethylglycine ethyl ester in 50 mL dichloromethane at 3° C. is treated with 200 mL of 1:1 (volume/volume) trifluoroacetic acid in dichloromethane. The reaction mixture is stirred for 2 hours while warming to ambient temperature. The reaction mixture is concentrated in vacuo and the residual highly mobile oil is subjected to high vacuum to give the desired compound (55.2 g), which is used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:11]=[CH:10][C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH:13]([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].O>CS(C)=O>[CH3:3][N:4]1[CH:11]=[CH:10][C:8](=[O:9])[N:7]([CH2:21][CH2:20][CH2:19][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C:5]1=[O:6]
Reactant: Cn1ccc(=O)[nH]c1=O
Reactant: C=CCCCC(Br)CCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCn1c(=O)ccn(C)c1=O
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
This example illustrates a synthesis of 1-Methyl-3-(8,9-oxidononyl)uracil (inventive compound no. 1804). Sodium hydride (365 mg, 16 mmol) was added to a stirring solution of 1-methyluracil (2.00 g, 16 mmol) in dimethyl sulfoxide (40 mL). After 15 minutes, 6-bromo-1-nonene (3.26 g, 16 mmol) was added and the mixture stirred for 3 days. The reaction was then poured into water (50 mL) and extracted with dichloromethane (3×60 mL). The combined organic layers were washed with water (50 mL), and aqueous saturated salt solution (30 mL) was then dried over sodium sulfate. The solvent was evaporated under vacuum to yield 3.72 g (94%) 1-methyl-3-(8-nonenyl)uracil (inventive compound no. 1817) as a colorless oil which solidified upon standing.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12](=[O:16])[CH2:13][CH2:14]Cl)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(C=CC(O)=CC=1)O.C(N(CC)CC)C>O1CCOCC1.C(Cl)(Cl)Cl>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12](=[O:16])[CH:13]=[CH2:14])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)CCCl)CC1
Agent: Oc1ccc(O)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CC(=O)[C@H]1CC[C@H](CCCCC)CC1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
12.23 g of 1-(trans-4-pentylcyclohexyl)-3-chloropropan-1-one and 112 mg of hydroquinone were dissolved in 120 ml of absolute dioxan in a sulphonation flask with stirrer, thermometer, reflux condenser, dropping funnel and nitrogen gasification [in an analogous manner to Chem. Ber. 109 (1976) 3426 and 111 (1978) 2825] and 12.6 g of triethylamine were added dropwise within 10 minutes. The mixture was subsequently stirred at 80° C. for 3.5 hours, cooled to 15° C., the precipitated triethylamine hydrochloride was filtered off under suction, back-washed with 50 ml of dioxan and the solvent was evaporated on a rotary evaporator. The oil obtained was taken up in 100 ml of chloroform, washed firstly with 100 ml of 5% sodium hydrogen carbonate solution and then with 100 ml of water (the aqueous phases were each extracted with a small amount of chloroform), dried over sodium sulphate and freed from solvent. The oily 1-(trans-4-pentylcyclohexyl)-2-propen-1-one obtained was further processed without additional purification.