Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:57]1([CH2:62][C@H:63]2[CH2:67][CH2:66][CH2:65][NH:64]2)[CH2:61][CH2:60][CH2:59][CH2:58]1.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:64]1[CH2:65][CH2:66][CH2:67][C@@H:63]1[CH2:62][N:57]1[CH2:61][CH2:60][CH2:59][CH2:58]1)=[O:6])[C:11]([NH:13][C@H:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CN[C@@H](CN2CCCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CN2CCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 11 %

Procedure:
Prepared analogously to Example 1g from (1S)-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and (2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidine in tetrahydrofuran. Yield: 11%; C26H29Cl2N5O2 (514.454); mass spectrum: (M+H)+=514/516/518 (chlorine isotope).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C@H:3]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(C(C)C)C(C)C.[C:30](C1CC(=O)NC1=O)([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>CN(C)C=O>[CH2:33]([O:32][C:30]([NH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C@H:3]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N
Reactant: O=C1CC(C(=O)OCc2ccccc2)C(=O)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 105.1 %

Procedure:
To a solution of (3R,4R)-di-tert-butyl 4-aminopyrrolidine-1,3-dicarboxylate (Org. Biomol. Chem. 2004, 2, 2763-2776) (765 mg, 2.67 mmol) and Hunig's base (465 uL, 2.67 mmol) in N,N-dimethylformamide (5 mL) was added Cbz succinimide (665 mg, 2.67 mmol). The mixture was stirred for 3 hours and partitioned between EtOAc and water. The organic layer was washed repeatedly with brine, dried (Na2SO4) and concentrated to a clear oil (1.18 g, quantitative yield). MS (DCI/NH4) m/z=438 (M+NH4)+.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:14]([CH3:17])[C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1)([OH:3])=O.[OH2:22]>C(Cl)Cl.C(OCC)(=O)C>[O:3]=[C:1]1[C:13]2[CH:12]=[CH:11][C:10]([CH:14]([CH3:17])[C:15]([NH2:16])=[O:22])=[CH:9][C:8]=2[CH2:7][CH2:6][C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]1=2
Reactant: CC(C#N)c1cccc(CCc2ccccc2C(=O)O)c1
Reactant: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C(N)=O)c1ccc2c(c1)CCc1ccccc1C2=O
Temperature: 100 °C

Procedure:
2-[3-(2-Carboxyphenethyl)phenyl]propionitrile (26 g.) is added to polyphosphoric acid (135 g.) [prepared from orthophosphoric acid (d = 1.7; 430 g.) and phosphorus pentoxide (500 g.)] and the emulsion obtained is heated for 1 hour at 100°C. After cooling, the reaction mixture is taken up in water (200 cc.) and methylene chloride (200 cc.). The organic layer is decanted, washed with a saturated solution of sodium bicarbonate (2 × 100 cc.) and then with water (2 × 100 cc.) and is finally dried over anhydrous sodium sulphate (50 g.). After evaporation of the solvent under reduced pressure (20 mm.Hg) at 60°C., the oil obtained is taken up in ethyl acetate (80 cc.). The product which crystallises is filtered off to give 2-(5-oxo-10, 11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionamide (6 g.), melting at 175°C. After recrystallisation from ethanol, the product melts at 181°C.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.I[CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]>>[CH2:9]([O:8][P:1]([CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12])(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: C=CCCCI
Reactant: CCOP(OCC)OCC
Product: C=CCCCP(=O)(OCC)OCC
Temperature: 130 °C

Procedure:
1H NMR (CDCl3) δ=5.8 (m, 1H), 5.0 (m, 2H), 3.2 (t, 2H), 2.2 (sq, 2H), 1.8 (sq, 2H). Triethyl phosphite (400 mL, 2.3 mol, 3.5 eq.) was added to the 1-iodo-4-pentene, and the mixture was heated to 130° C. for three hours. Diethyl ethyl phosphonate was removed by fractional vacuum distillation, revealing the desired 4-pentenyl phosphonic acid diethyl ester which was used without further purification. 1H NMR (CDCl3) δ=5.7 (m, 1H), 4.8 (m, 2H), 4.0 (m, 4H), 2.0 (sq, 2H), 1.7 (m, 4H), 1.2 (t, 6H). 31P NMR (CDCl3) δ=33.3.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N:11]2[CH2:16][CH2:15][C:14]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:24])[CH3:10])[CH:6]=[CH:7][CH:8]=1>CN(C=O)C.CCOC(C)=O>[OH:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N:11]2[CH2:16][CH2:15][C:14]([CH3:23])([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:13][C:12]2=[O:24])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@H](C)N2CCC(C)(c3ccccc3)OC2=O)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](c1cccc(O)c1)N1CCC(C)(c2ccccc2)OC1=O
Temperature: 170 °C
Yield: 87 %

Procedure:
A mixture of 3-((S)-1-(3-methoxyphenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one Isomer 1 (0.1240 g, 0.381 mmol) and EtSNa (0.2115 g, 2.51 mmol) in DMF (2 mL) was heated at 170° C. for 2.5 h under nitrogen. The mixture was diluted with EtOAc, washed with 1 N aq HCl. The aqueous phase was extracted with EtOAc (2×). The combined organic phase was dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 3-((S)-1-(3-hydroxyphenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (0.1036 g, 87%). LC-MS Method 1 tR=1.49 min, m/z 312 (MH+); 1H NMR (400 MHz, CDCl3) δ 7.59-7.53 (m, 1H), 7.40-7.28 (m, 5H), 7.19-7.15 (m, 1H), 6.98 (m, 1H), 6.83-6.75 (m, 2H), 5.74 (q, J=7.1 Hz, 1H), 2.80-2.67 (m, 2H), 2.30-2.25 (m, 1H), 2.09-2.01 (m, 1H), 1.62 (s, 3H), 1.25 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.C(N(CC)CC)C.[CH:22]1([C:25]2[CH:26]=[C:27]([NH2:30])[NH:28][N:29]=2)[CH2:24][CH2:23]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:30][C:27]2[NH:28][N:29]=[C:25]([CH:22]3[CH2:24][CH2:23]3)[CH:26]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Clc1ncc(-c2ccccc2)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1ncc(-c2ccccc2)c(Nc2cc(C3CC3)n[nH]2)n1
Yield: 60 %

Procedure:
To 2,4-Dichloro-5-phenyl-pyrimidine (187 mg, 0.83 mmol) and triethylamine (255 μL, 1.83 mmol) in ethanol (25 mL) was added 5-Cyclopropyl-2H-pyrazol-3-ylamine (142 mg, 1.16 mmol) and the solution was heated to 80 C for 14 h. The solvent was removed in vacuum, and the title compound was obtained by flash chromatography (0-2% methanol in dichloromethane) to give: 150 mg (60% yield). HPLC tr=6.68 min (87%), LCMS m/e 312.1 (M+H), 310.0 (M-H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[N-:21]=[N+:22]=[N-:23].[Na+].O.C([O-])(O)=O.[Na+]>CS(C)=O>[N:21]([CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1)=[N+:22]=[N-:23]
Reactant: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CBr)c2F)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CN=[N+]=[N-])c2F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
2-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (2.00 g, 5.32 mmol) and sodium azide (0.346 g, 5.32 mmol) were combined in DMSO (10 mL) and stirred 16 h at 25° C. at which time TLC indicated complete conversion (10% Et2O/hexanes). Water (150 mL) and saturated aqueous NaHCO3 (30 mL) were added and the mixture stirred vigorously for 30 min. The resultant precipitate was filtered off, washed with water, and air dried to give 2-{[3-(azidomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (1.76 g, 5.21 mmol, 98% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (d, J=0.73 Hz, 1H), 7.96 (d, J=0.73 Hz, 1H), 7.48-7.60 (m, 2H), 4.60 (s, 2H).
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=O.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:1]([CH2:4][CH:5]2[C:9]3[C:10]([C:16]([NH:18][C:19]4[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=4[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=3[O:7][CH2:6]2)=[O:3])=[CH:30][CH:29]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)NCc1ccc(Cl)cc1
Yield: 58 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.20 g) obtained in Example 9 and 4-chlorobenzylamine to give Compound 30 (0.15 g, 58%) as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(OCC)(=O)C>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[O:11][CH:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:13]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: Cc1ccc(O)c(Cl)c1
Reactant: COC(=O)Cc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(Oc1ccc(C)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
To a suspension of 0.282 g (7.04 mmol) of a 60% oil dispersion of sodium hydride in DMF was added 1.00 g (7.04 mmol) of 2-chloro-4-methylphenol and the mixture was stirred under an N2 atmosphere at room temperature. After 10 minutes, a solution of 1.94 g (8.45 mmol) of methyl 2-bromophenylacetate dissolved in 10 mL of DMF was added and the reaction was stirred an additional 1.5 hours. The reaction was then diluted into ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 4% ethyl acetate/hexane to afford 1.70 g (83%) of the title compound.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]1[C:18]2[C:13](=[CH:14][C:15]([OH:23])=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=2)[NH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO.O>[CH2:3]([C:10]1[C:18]2[C:13](=[CH:14][C:15]([OH:23])=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[NH:12][N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc2c(Cc3ccccc3)n[nH]c2cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c(Cc3ccccc3)n[nH]c2cc1O
Reaction time: 3 h

Procedure:
1.4 595 μl of 2 N NaOH are added to a suspension of 112 mg of “A1” in 1.5 ml of methanol, and the mixture is stirred at 60° for 3 hours. The mixture is cooled, 0.7 ml of 2 N HCl is added, the mixture is diluted with water, the precipitate is removed, and the mixture is subjected to conventional work-up, giving 75 mg of 3-benzyl-6-hydroxy-1H-indazole-5-carboxylic acid (“A2”).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[C:19]([S-:21])#[N:20].[K+]>C(O)C.O.Cl>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:5]2[CH:4]=[CH:3][N:20]=[C:19]2[SH:21])=[CH:10][CH:11]=1
Reactant: COc1ccc(CCCNCC(OC)OC)cc1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CCCn2ccnc2S)cc1

Procedure:
A solution of 3.62 g (.014 mole) of N-[3-(4-methoxyphenyl)propyl]aminoacetaldehyde dimethyl acetal and 1.4 g (.0144 mole) of KSCN in 20 ml of ethanol, 5 ml of H2O and 2 ml of concentrated HCl was refluxed for five hours. Fifty ml of H2O was added, the mixture was cooled and a solid was filtered, washed with H2O and dried. Recrystallization from ethanol gave 1-[3-(4-methoxyphenyl)propyl]-2-mercaptoimidazole, 2.4 g (69%), mp 108-109°.
Reaction SMILES: Br[CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1.[O-:14][CH2:15][CH3:16].[Na+]>C(O)C>[CH2:15]([O:14][CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:16]
Reactant: O=c1onc2n1C(CBr)CCCC2
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCC1CCCCc2noc(=O)n21

Procedure:
Ex-37) To the product of Example 37a or the product of Example 15 in ethanol is added an ethanolic solution of sodium ethoxide. After thin layer chromatography indicates the reaction is complete, it is concentrated and the residue partitioned between water and an extraction solvent. The dried organic layer is stripped of all solvent and the residue chromatographed to produce the title material.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:17])[CH2:10][N:11]=[C:12](SC)[S:13][CH3:14].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>O1CCCC1.O>[CH3:7][O:8][C:9]([C:10]1[N:11]=[C:12]([S:13][CH3:14])[O:24][C:23]=1[C:22]1[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=1)=[O:17]
Reactant: COC(=O)CN=C(SC)SC
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1nc(SC)oc1-c1ccc(F)cc1
Reaction time: 0.75 h
Yield: 16.4 %

Procedure:
A suspension of potassium tert-butoxide (1.18 g; 10.52 mmol) in dry tetrahydrofuran (20 ml), cooled at -78 C., under argon, is treated with a solution of N-[bis(methylthio)methylene] glycine methyl ester (1.02 g; 5.26 mmol) in dry tetrahydrofuran (7 ml). After stirring for 45 minutes, it is added a solution of 4-fluorobenzoyl chloride (0.75 g; 6.31 mmol) in tetrahydrofuran (7 ml). After stirring at -78 C. for 20 minutes, it is brought to room temperature and stirred an additional 16 hours. The reaction mixture is diluted with water (30 ml) and extracted with ethyl acetate (70 ml). The aqueous phase is washed with ethyl acetate (20 ml). The combined organic phases are washed with saturated brine (20 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using an ethyl acetate/hexane gradient (10%-70%) affords the product as a white solid (0.23 g; 16%). HNMR (CDCl3): 8.07 (m, 2H), 7.16 (t, 2H, J=8.9 Hz), 3.93 (s, 3H), 2.73 (s, 3H). Mass spectrum: m/e calculated (MH+)=268.3; observed (MH+)=268.1.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH3:9][C:10](=[CH:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:11]>C(Cl)Cl>[CH3:8][CH2:7][O:6][C:4]([CH:3]1[C:14]([CH3:16])([CH3:15])[CH:13]1[CH:12]=[C:10]([CH3:11])[CH3:9])=[O:5]
Reactant: CC(C)=CC=C(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCl
Product: CCOC(=O)C1C(C=C(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl diazoacetate (5.0 g) in methylene chloride (50 mL) was added dropwise to a slurry of the Cu,K-PFIEP[SO3H] catalyst described above (2.0 g) in methylene chloride (100 mL) and 2,5-dimethyl-2,4-hexadiene (8.33 g). After stirring for about 18 h at ambient temperature, the reaction product was isolated by filtering off the catalyst, evaporating the solvent and chromatographing the resulting residue on silica with 10% ethyl acetate and 90% hexane as eluant. The isolated chrysanthemumate had an identical 1H nmr spectrum to a commercial sample. Anal. Calcd. for C12H20O2 : C, 73.43; H, 10.27; Found: C, 74.08; H, 10.58.
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH2:5]([O:7][C:8](=[O:18])[CH:9]([CH:15]([CH3:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:6]>>[CH2:5]([O:7][C:8](=[O:18])[C:9]([CH:15]([CH3:16])[CH3:17])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[OH:2])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Product: CCOC(=O)C(O)(C(=O)OCC)C(C)C
Reaction time: 48 h

Procedure:
400 g (6.3 mols) of 98 % to 100 % nitric acid are placed in a sulphonating flask, and 10 g (0.05 mols) of isopropyl-malonic acid diethyl ester are added dropwise within 15 minutes at room temperature while stirring. The clear solution is allowed to stand at room temperature for 48 hours. Most of the nitric acid is then carefully removed by evaporation on a rotary evaporator under a water pump vacuum, the residue is distributed between an aqueous potassium hydrogen carbonate solution and a sufficient amount of methylene chloride and is worked up in the usual manner. The methylene chloride phases are again extracted with a small amount of water, dried over sodium sulphate, and the solvent is carefully removed by evaporation in a vacuum. The resulting crude product is distilled in a high vacuum and yields isopropyl-tartronic acid diethyl ester having a B.P. of 65°-67° (0.05 mm of Hg), nD20 = 1.4289.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:14])[S:7][C:6]=2[CH:15]=1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)[S:25][C:18]=12.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:14][C:8]1[S:7][C:6]2[CH:15]=[C:2]([O:1][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[CH:23]=[C:24]([C:26]5[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=5)[S:25][C:18]=34)[CH:3]=[CH:4][C:5]=2[C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1c(C)sc2cc(O)ccc12
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1c(C)sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc12
Yield: 61.2 %

Procedure:
This material was prepared from the reaction of methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (200 mg, 0.90 mmole) with 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (188 mg, 0.75 mmole) and Cs2CO3 (1.22 g, 3.75 mmole) in a manner as previously described for example 1 to give a yellow solid (200 mg, 51%). 1H NMR (DMSO-d6, 300 MHz) δ8.52 (1H, d, J=5.46 Hz), 8.38 (1H, d, J=9.04 Hz), 8.02 (1H, d, J=2.26 Hz), 7.89 (1H. s), 7.40 (2H, s), 7.02 (1H, s), 6.73 (1H, d, J=5.46 Hz), 3.98 (3H, s), 3.91 (3H, s), 2.82 (3H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:47][CH2:46]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 60 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (57 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (83 mg, 0.108 mmol, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.35 (s, 1H), 8.44 (s, 1H), 8.19 (d, J=5.31 Hz, 1H), 8.09 (d, J=2.20 Hz, 1H), 7.76 (dd, J=8.52, 2.11 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.33-7.44 (m, 3H), 7.27 (d, J=8.61 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.93 (t, J=6.87 Hz, 1H), 6.67 (d, J=2.38 Hz, 1H), 6.51 (d, J=5.31 Hz, 1H), 6.48 (dd, J=8.79, 2.56 Hz, 1H), 3.97 (s, 3H), 3.79 (s, 3H), 3.30-3.35 (m, 2H), 3.11-3.20 (m, 4H), 3.03 (s, 3H), 2.74 (t, J=6.78 Hz, 2H), 2.52-2.62 (m, 4H). MS (ESI): 769 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19]CC2C=CC=CC=2)=[CH:8][CH:7]=1>CO.CN(C)C=O.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(NC(=O)CCCCCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(NC(=O)CCCCCO)cc1
Reaction time: 24 h
Yield: 24.4 %

Procedure:
[4-(6-Benzyloxyhexanoylamino)-phenoxy]-acetic acid methyl ester 57 (24 grms, 62.33 mmol) was dissolved in a mixture of methanol (200 ml) and dimethyl formamide (50 ml) in a pressure vessel. Palladium on carbon (5%, 15 g) was added and the mixture stirred under an atmosphere of hydrogen (4 kg) for 24 hours. Catalyst was removed by filtration, and the solvents distilled off under vacuum. Crude 58 was purified by column chromatography on silica gel using chloroform as eluant to get pure 58 (4.5 g, 24.4%) as a white powder with an m.p. between 87.5-90.4° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[K+].[C:8]([C:10]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=CC([O-])=O)#[N:9]>C(Cl)Cl>[C:8]([C:10]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[CH:1][C:2]([Cl:4])=[O:3])#[N:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#CC(=CC(=O)[O-])c1cccs1
Agent: [K+]
Solvent: ClCCl
Product: N#CC(=CC(=O)Cl)c1cccs1
Yield: 94.8 %

Procedure:
To a stirring solution of oxalyl chloride (81.17 mL, 0.93 mol) in CH2Cl2 (350 mL) was added 3-cyano-3-thiophen-2-yl-acrylic acid potassium salt 21 (100 g, 0.45 mol) portion-wise over 20 min. An additional 250 mL of CH2Cl2 were added to assist stirring. The slurry was stirred at room temperature for 30 min and was then filtered. The potassium chloride salts were washed with copious CH2Cl2. Collected organic rinses were combined and solvent removed under vacuum to afford 84.3 g of 22, which was carried on to the next step without further purification.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([CH3:25])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(C)c1OC
Temperature: 160 °C
Yield: 18.5 %

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61, 0.332 g), potassium methyltrifluoro borate (0.0675 g), palladium chloride dppf adduct with DCM (0.066 g) and cesium carbonate (0.786 g) in THF (9 ml) and water (1 ml) was sealed in a microwave vial and degassed. The mixture was then heated in the microwave at 160° C. for 30 minutes. After cooling, the mixture was dried (MgSO4) and filtered through Celite, and the pad was washed with ethyl acetate. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-50% to give ethyl 6-(benzenesulphonylmethyl)-2-methoxy-3-methylbenzoate (0.05 g) as a colourless gum.