Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)c1ccc(Br)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(F)(F)F)cn3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C

Procedure:
A mixture of 100 mg (0.2 mmol) [(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (example 265, c), 68 mg (0.3 mmol) 2-bromo-5-(trifluoromethyl)pyridine and 131 mg (1 mmol) DIPEA in 8 mL acetonitrile was heated to 80° C. for 18 h. The mixture was evaporated and the residue subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 70 mg (54%) of the title compounds as white foam. MS m/e: 639.1 [M+H]F.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]([NH:18][C:12]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([C:3]3[N:4]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:6][C:2]=3[Cl:1])[CH:11]=2)=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(Cl)c2)cc1-c1c(Cl)cnn1C(C)C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 3-chloro-4-fluoro-phenyl isocyanate (0.082 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 56 as a colorless solid (0.052 g, 28%). LCMS m/z (%)=439 M+H+ (37Cl, 29), 437 M+H+ (35Cl, 46), 1H NMR (400 MHz, acetone-d6) δ: 8.764 (bs, 1H), 8.673 (bs, 1H), 8.31-8.28 (m, 1H), 8.110 (d, J=2.72 Hz, 1H), 8.088 (d, J=2.71 Hz, 1H), 7.974 (s, 1H), 7.878 (d, J=2.68 Hz, 1H), 7.828-7.788 (m, 1H), 7.68-7.64 (m, 1H), 7.635-7.563 (m, 1H), 4.668 (m, 1H), 4.246 (s, 3H), 1.874 (d, J=6.61 Hz, 3H), 1.713 (d, J=6.61 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].BrC[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42]Br)=[C:38]([C:44]([F:47])([F:46])[F:45])[CH:37]=2)=[CH:31][C:30]=1C(F)(F)F>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:42][C:39]2[CH:40]=[CH:41][C:36]([O:35][C:32]3[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=3)=[CH:37][C:38]=2[C:44]([F:45])([F:46])[F:47])[N:8]=1)=[O:5]
Reactant: FC(F)(F)c1cc(Oc2ccc(CBr)c(C(F)(F)F)c2)ccc1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2ccc(Oc3ccccc3)cc2C(F)(F)F)n1)c1c(F)cccc1F
Reaction time: 0.5 h

Procedure:
To 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(45 mg, 0.20 mmol) in dry THF (3.0 ml) under nitrogen at room temperature was added 1.0 M lithium bis(trimethylsilyl)amide in THF (0.20 ml, 0.20 mmol) dropwise. The solution was stirred for approximately 30 min and then 4-(bromomethyl)-3-(trifluoromethyl)phenyl ether (67 mg, 0.20 mmol) in THF (2 ml) was added. The solution was stirred for 3 h and then left to stand overnight. The solvent was removed under a stream of nitrogen. To the residue was added aqueous sodium bicarbonate and then the residue extracted with chloroform three times. The combined chloroform extracts were filtered through a hydrophobic frit. The filtrate was concentrated in vacuo. The residue was purified on MDAP (Method B). The appropriate fractions were combined and the residue dried under high vacuum to give the title compound as a thick white gum (72.3 mg); LCMS: (System 4) MH+=474, tRET=3.35 min.
Reaction SMILES: [C:1]([C:3](=[C:7]([S:10][CH3:11])SC)[C:4]([NH2:6])=[O:5])#[N:2].[CH3:12][CH:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)[CH3:14]>CCO>[C:1]([C:3](=[C:7]([NH:25][C:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:17][CH2:16][N:15]([CH:13]([CH3:14])[CH3:12])[CH2:20][CH2:19]2)=[CH:27][CH:26]=1)[S:10][CH3:11])[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: CC(C)N1CCN(c2ccc(N)cc2)CC1
Reactant: CSC(SC)=C(C#N)C(N)=O
Solvent: CCO
Product: CSC(Nc1ccc(N2CCN(C(C)C)CC2)cc1)=C(C#N)C(N)=O

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 4-(4-(2-propyl)-piperazin-1-yl)aniline (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain 2-cyano-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3-(methylthio)acrylamide as a purple powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]1[N:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:20](=[O:29])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)C1C=CC=CC=1>[Pd].CO>[NH2:10][CH2:11][C:12]1[N:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:20](=[O:29])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=C(NCc1nc2ccccc2c(=O)n1-c1ccc(F)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCc1nc2ccccc2c(=O)n1-c1ccc(F)cc1
Yield: 92.8 %

Procedure:
A stirring mixture of the quinazolinone (3) (63 mg, 0.16 mmol), 10% palladium on activated carbon (18 mg) and methanol (4.4 mL) was evacuated using an aspirator pump and filled with hydrogen. Once the starting material had been consumed as monitored by TLC analysis, the mixture was filtered through a Celite pad which was washed with methanol (2×) and concentrated to give the title amine (4) (40 mg, 93%) as a yellow solid:
Reaction SMILES: [Na].[C:2](=[O:7])([O:5][CH3:6])OC.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[O:18]=[C:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)[CH2:17][C:2]([O:5][CH3:6])=[O:7]
Reactant: COC(=O)OC
Reactant: COc1ccc(C(C)=O)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)c1ccc(OC)cc1
Temperature: 93 °C

Procedure:
30.7 g of sodium was added to 300 ml of toluene, and the mixture was heated to 93° C., followed by cooling while vigorous stirring, to give sandy products. To the product, 600 ml of toluene containing 300 g of dimethyl carbonate was added, and further 250 ml of a toluene solution containing 100 g of p-methoxyacetophenone was added dropwise over 2 hours and 15 minutes at 84° to 86° C. After the dropwise addition, the mixture was stirred under heating at 82° to 83° C. for 1.5 hours, and then the solvent was evaporated. To the residue was added 1 l of isopropyl ether, and crystals were collected by filtration and washed with 500 ml of isopropyl ether. These crystals were added to a mixture of ice and ethyl acetate containing 100 g of acetic acid, and extracted with ethyl acetate. The extract was washed with 5 % sodium hydrogen carbonate and then with water, and dried. Subsequently, the solvent was evaporated to obtain 131.6 g of methyl 3-oxo-3-(p-methoxyphenyl)propionate as an oily product.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCc1ccccc1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: c1ccc(CCCN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 1-bromo-3-phenylpropane, to produce the above.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([NH:14][C:15](=[O:17])[CH3:16])=[C:5](OS(C)(=O)=O)[CH2:6][O:7][CH3:8].C(NCC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])/[C:4](/[NH:14][C:15](=[O:17])[CH3:16])=[CH:5]/[CH2:6][O:7][CH3:8]
Reactant: COCC(OS(C)(=O)=O)=C(NC(C)=O)C(=O)OC
Solvent: ClCCl
Solvent: CCNCC
Product: COC/C=C(\NC(C)=O)C(=O)OC

Procedure:
A solution consisting of 27.6 g (0.098 mol) of mesylate 9, 20.5 ml of diethylamine and 250 ml of methylene chloride was heated at reflux temperature for 2 hrs under an atmosphere of argon. The resultant solution was cooled, concentrated in vacuo and the residue filtered through a column of silica gel (125 g) using ethyl acetate as the eluent. The fractions containing product (as determined by thin layer chromatography) were combined and concentrated in vacuo. Crystallization of the residue from ether/petroleum ether (bp 35°-60°) yielded Z-2-acetamido-4-methoxy-2-butenoic acid methyl ester (4) identical to the material obtained by the previous method (Examples 1 and 2). The mother liquors from the crystallization of 4 were concentrated in vacuo to yield an oil which contained a 1:1 mixture of 4 and E-2-acetamido-4-methoxy-2-butenoic acid methyl ester (5).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:7]=[C:6]([O:16][CH3:17])[CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:17][O:16][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:7]=1
Reactant: COCCCOc1cc(OC)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCOc1cc(CO)cc(OC)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 3-Methoxy-5-(3-methoxy-propoxy)-benzoic acid methyl ester (5 g, 19.7 mmol) and LAH (528 mg, 20 mmol) in THF (110 mL) is stirred under N2 at 0° C. for 3 h. After adding H2O, the reaction mixture is extracted with EtOAc. The combined organic phases are washed with H2O, brine and dried (Na2SO4). Concentration under reduced pressure and silica gel flash chromatography give the title compound as colorless oil. MS: 227 [M+H]+; tR (HPLC, CombiScreen ODS-AM 50×4.6 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 2 min, flow 2.0 ml/min): 2.85 min.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2)([O-:11])=[O:10].C(#N)C>C(Cl)Cl>[Cl:1][C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[CH:20][C:12]=2[N+:9]([O-:11])=[O:10])[NH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
N-Chlorosuccinimide (1.23 g, 9.25 mmol) is added to a solution of 4-nitroindole (1.5 g, 9.25 mmol, Aldrich) in methylene chloride (75 mL). The resulting mixture is heated to reflux for 16 hours. Acetonitrile (10 mL) is added to the mixture and heating is continued for another 16 hours. The reaction is cooled to room temperature and the methylene chloride is removed by rotary evaporation. The residue is taken up in ethyl acetate and washed with water. The ethyl acetate layer is dried over magnesium sulfate, filtered and the solvents removed by rotary evaporation. The crude material is purified via silica gel column chromatography using 30% ethyl acetate/hexane as the eluent. The product containing fractions are combined and the solvents removed by rotary evaporation to yield 1.35 g of 3-chloro-4-nitroindole as an orange solid (74%).
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[OH:6][CH2:7][C:8](=O)[CH3:9]>C(O)C.O=[Pt]=O>[NH:1]([CH:8]([CH3:9])[CH2:7][OH:6])[CH:2]([CH3:5])[CH2:3][OH:4]
Reactant: CC(=O)CO
Reactant: CC(N)CO
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(CO)NC(C)CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Aminopropan-1-ol (5 g, 66.57 mmol) and 1-hydroxypropan-2-one (5.77 g, 77.89 mmol) were dissolved in ethanol (115 mL) and 50 mg of PtO2 was added. The reaction mixture was stirred at 50 psi H2 pressure at room temperature for 24 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was used without further purification in the following step. Crude yield: 79%. 1H NMR (400 MHz, CDCl3) δ 4.45 (bs, 2H), 3.42-3.43 (m, 1H), 3.16-3.22 (m, 4H), 2.65-2.69 (m, 2H) 0.87-0.91 (m, 6H): LCMS m/z 133.99 [M+H]+, tR: 4.077 min.
Reaction SMILES: [N:1]1([CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:5]=[CH:4][N:3]=[CH:2]1.CC(C)=[O:27].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[N:1]1([CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:27])=[O:16])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)=O
Reactant: CCCCCCCCC(CCCCCCCCCO)n1ccnc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCC(CCCCCCCCC(=O)O)n1ccnc1
Reaction time: 3 h
Yield: 84 %

Procedure:
10-(1H-imidazol-1-yl)octadecan-1-ol (210 mg, 0.63 mmol) was dissolved in acetone (5 ml) and water (2.5 ml), then Jones reagent (0.75 ml) was added at 0° C. and stirring continued for 3 h at room temperature. The reaction mixture was concentrated and diluted with water (10 ml), and extracted with DCM (3×10 ml), then the combined organic layers were washed with brine solution, dried on MgSO4 and concentrated. The crude compound was purified by silica gel column (3-5% MeOH in DCM) to give 10-(1H-imidazol-1-yl)octadecanoic acid (185 mg, 84%) as a gummy liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([O:16]C)[CH:12]=[CH:13][CH:14]=3)[C:9](SC(C)(C)C)=[C:8]2[CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])=[CH:4][CH:3]=1.[C:32](O)(=O)CC>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:23][C:24]([CH3:28])([CH3:29])[C:25]([O:27][CH3:32])=[O:26])=[CH:4][CH:3]=1
Reactant: COc1cccc2c1c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Reactant: CCC(=O)O
Product: COC(=O)C(C)(C)Cc1cc2c(O)cccc2n1Cc1ccc(Cl)cc1

Procedure:
The title compound was prepared using methodology from Step A of Example 8 but substituting 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-4-methoxy indol-2-yl]-2,2-dimethylpropanoic acid (Step B of Example 20) for the propanoic acid in Example 8 (Step A).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]([OH:16])[C:8]2[N:9]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:10]=1)=[O:4].[O:18]1[CH:20]2[CH2:21][C:22]3[C:27]([CH:19]12)=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][CH:23]=3.C(N(CC)CC)C>C(O)C.O>[OH:18][C@@H:20]1[CH2:21][C:22]2[C:27](=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][CH:23]=2)[C@H:19]1[O:16][C:7]1[C:8]2[N:9]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:10]=[C:5]([C:3]([N:2]([CH3:1])[CH3:17])=[O:4])[CH:6]=1
Reactant: COc1cccc2c1C1OC1C2
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cn2c1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cccc2c1[C@@H](Oc1cc(C(=O)N(C)C)cn3c(C)c(C)nc13)[C@H](O)C2
Reaction time: 4 h
Yield: 19.3 %

Procedure:
To a solution of 0.8 g (3.4 mmol) 6-(N,N-dimethylamino-carbonyl)-8-hydroxy-2,3-dimethyl-imidazo[1,2-a]pyridine in 16 ml ethanol and 4 ml water are added 1.0 g (6.2 mmol) 1,2-epoxy-7-methoxy-indane and 0.48 ml triethylamine. After 4 h at 30° C., the mixture is cooled down and partitioned between di-chloromethane and saturated aqueous ammonium chloride. The organic layer is separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether:triethylamine (8:1:1) yields 0.26 g (19%) of the title compound as a colourless solid (m.p. 129° C.).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[N:12][C:11]2[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9](=[O:23])[N:8]3[N:24]=[CH:25][N:26]=[C:7]3[C:6]=2[CH:5]=1)(=O)[CH3:2].[CH3:27][C@@H:28]1[O:33][C@H:32]([CH3:34])[CH2:31][NH:30][CH2:29]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(#N)C>[CH3:27][C@H:28]1[CH2:29][N:30]([CH:1]([C:4]2[CH:13]=[N:12][C:11]3[N:10]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[C:9](=[O:23])[N:8]4[N:24]=[CH:25][N:26]=[C:7]4[C:6]=3[CH:5]=2)[CH3:2])[CH2:31][C@@H:32]([CH3:34])[O:33]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(C)=O)cnc32)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(C)N4C[C@@H](C)O[C@@H](C)C4)cnc32)cc1
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
9-Acetyl-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (67 mg, 0.19 mmol), (2S,6R)-2,6-dimethylmorpholine (0.060 ml, 0.49 mmol), acetonitrile (1 ml) and acetic acid (0.020 mL, 0.35 mmol) were combined and stirred for 10 minutes. Sodium cyanoborohydride (18 mg, 0.29 mmol) was added and the mixture was stirred for 3 days at 50° C. The mixture was filtered and purified by preparative HPLC to afford 26 mg (23%) of 266 as a white solid.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Cl[C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>C(O)C>[CH2:2]([O:1][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])[CH3:3]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncccc1C(=O)O
Temperature: 170 °C

Procedure:
A solution of sodium ethoxide (14.2 mL) was added to a solution of 2-chloronicotinic acid (2.00 g) in ethanol (13 mL). The mixture was heated in a sealed vessel at 170° C. for 2 days. After cooling, the mixture was concentrated in vacuo and the residue taken in water and acidified with hydrochloric acid to pH 3. The precipitated solids were collected by filtration and washed with water to obtain the title compound (1.32 g) having the following physical data.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]4=[CH:9][C:8]=3[N:7]=[C:6](Cl)[C:5]=2[N:4]=[CH:3]1.[CH3:20][NH2:21]>CCOC(C)=O>[CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]4=[CH:9][C:8]=3[N:7]=[C:6]([NH:21][CH3:20])[C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2c(Cl)nc3cc4ccccc4cc3c21
Reactant: CN
Solvent: CCOC(C)=O
Product: CNc1nc2cc3ccccc3cc2c2c1ncn2C
Temperature: 80 °C
Yield: 4 %

Procedure:
A mixture of 1-methyl-4-chlorobenzo(g)imidazo(4,5-c)quinoline (Preparation 19 in Example 11) (130 mg, 0.49 mmol) and MeNH2 (2.0M/THF, 1.5 mL, 2.92 mmol) was heated in a pressure tube at 80° C. for 18 hours. After the reaction mixture was cooled to RT, it was diluted with EtOAc (100 mL), washed with sat'd NaCO3 (50 mL), and brine. The organic layer was dried over MgSO4, filtered and evaporated in vacuo. The crude material was submitted to flash chromatography (5% MeOH/EtOAc) affording the title compound as a pale white solid (5.2 mg, 4%). 1H NMR (CDCl3): 8.44 (s, 1H), 8.35 (s, 1H), 7.94 (d, J=8.3, 1H), 7.90 (d, J=8.3, 1H), 7.72 (s, 1H), 7.46 (m, 1H), 7.40 (m, 1H), 5.95 (b, 1H), 4.28 (s, 3H), 3.31 (s, 3H). (ESI) m/z (M+H)+=263.14. Inhibition of IKK-1 activity was measured using the assay of Example 2, where the inhibitory potential of the compound of Example 16 resulted in an IC50 of 0.80 μM.
Reaction SMILES: [CH2:1](I)[CH3:2].[C:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([OH:26])[C:23]([OH:25])=[O:24])=[C:17]([Cl:27])[CH:16]=2)=[CH:6][CH:5]=1.Cl>CN(C=O)C>[C:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:26][CH2:1][CH3:2])[C:23]([OH:25])=[O:24])=[C:17]([Cl:27])[CH:16]=2)=[CH:6][CH:5]=1
Reactant: CCI
Reactant: O=C(O)C(O)Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1Cl)C(=O)O
Temperature: 50 °C

Procedure:
Ethyl iodide (0.6 mmol, 0.05 mL) was added to a solution of 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-hydroxy-propionic acid (Step A) and Ag2O (0.09 mmol, 21 mg) in DMF (0.5 mL). The mixture was heated at 50° C. for 24 hours. The mixture was warmed to room temperature, and 1N HCl was added until pH 3. The aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated. The crude was purified by chromatography on silica gel (CH2Cl2) to afford the title compound. 1H-NMR (CDCl3, 300.15 MHz): δ 7.56–7.51 (m, 4H), 7.44–7.39 (m, 2H), 7.30 (t, 1H, J=7.3), 7.20 (d, 1H, J=8.5), 6.99 (d, 2H, J=8.7), 6.95 (d, 1H, J=2.4), 6.77 (dd, 1H, J=8.5, 2.4), 4.21–4.13 (m, 5H), 3.64–3.54 (m, 1H), 3.44–3.34 (m, 1H), 3.29 (dd, 1H, J=14.1, 4.2), 3.01 (dd, 1H, J=14.1, 8.7), 2.28 (qn, 2H, J=6.0), 1.12 (t, 3H, J=6.9).
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH2:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(S(CC(CC1C=CC=CC=1)C(OCC)=O)(=O)=O)(C)(C)C>>[CH:1]1([CH2:4][S:5]([CH2:8][C@@H:9]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)CC1CC1
Agent: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Product: O=C(O)[C@H](Cc1ccccc1)CS(=O)(=O)CC1CC1

Procedure:
This compound was prepared analogously to Example 1d) by the enzymatic hydrolysis of ethyl (RS)-α-[[(cyclopropylmethyl)sulphonyl]methyl]hydrocinnamate which, in turn, was prepared analogously to the synthesis of ethyl (RS)-α-[(tert-butylsulphonyl)methyl]hydrocinnamate described in EPA 0236734 by replacing tert-butylthiol by cyclopropylmethylthiol, MS: 282 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([NH:9][CH2:23][C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1cccnc1
Reactant: COc1ccccc1Oc1cccc(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1cccc(NCc2cccnc2)c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of 3-(2-methoxyphenoxy)aniline (269 mg, 1.25 mmol) and pyridine-3-carboxaldehyde (107 mg, 1.00 mmol) was refluxed in methanol (2.5 mL) for 2 h, then cooled on an ice bath to 5° C. Sodium borohydride (95 mg, 2.5 mmol) was added and the mixture was warmed to room temperature, stirred for 2 h, concentrated in vacuo, and taken up in dichloromethane. The resultant suspension was filtered, the filtrate concentrated in vacuo, and the residue chromatographed on silica gel (eluted with 2% methanol/dichloromethane) to give N-(3-(2-methoxyphenoxy)phenyl)pyrid-3-ylmethylamine.