Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.[C:8]([C:10]1[C:11](F)=[N:12][CH:13]=[CH:14][CH:15]=1)#[N:9]>CN(C=O)C>[CH:3]1([O:7][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:8]#[N:9])[CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCC1
Reactant: N#Cc1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1OC1CCC1
Reaction time: 1 h

Procedure:
NaH 60% dispersion in mineral oil (100 mg, 2.5 mmol) was added to a rt solution of cyclobutanol (0.13 mL, 1.6 mmol) in DMF (1.5 mL). After stirring for 1 h, 3-cyano-2-fluoropyridine (150 mg, 1.23 mmol) was added and the brown suspension was stirred at rt for 1 h. The rxn mixture was quenched with water and extracted with DCM (2×). The combined org. layers were dried (MgSO4), filtered and concentrated in vacuo to yield 2-cyclobutoxynicotinonitrile as an orange oil. LC-MS B: tR=0.76 min; [M+H]+=175.21. 1H NMR (DMSO) δH: 8.43 (m, 1H), 8.26 (dd, J1=7.6 Hz, J2=1.9 Hz, 1H), 7.17 (dd, J1=7.6 Hz, J2=5.0 Hz, 1H), 5.25 (m, 1H), 2.43 (m, 2H), 2.13 (m, 2H), 1.82 (m, 1H), 1.66 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[CH:3]=1.[CH2:9]([OH:14])[CH2:10][CH2:11][C:12]#[CH:13]>C(N(CC)CC)C.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.[Cu]I>[OH:14][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:4]1[CH:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][OH:14])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCCO
Reactant: Brc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCCCC#Cc1cccc(C#CCCCO)c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
1,3-Dibromobenzene (7.48 g, 31.71 mmol), 4-pentyn-1-ol (6.40 g, 76.10 mmol), and bis(triphenylphosphine)palladium(II) dichloride (445 mg, 0.63 mmol) was stirred in triethylamine (150 mL) under nitrogen for 5 min. Copper(I) iodide (61 mg, 0.32 mmol) was added and the mixture was stirred for 18 hrs at 75° C. The mixture was cooled to room temperature and filtered through a celite pad, rinsed with ethylacetate. The combined filtrate was evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (chloroform:methanol 20:1) to afford 7.24 g of the title compound. Yield: 94%. 1H NMR (300 MHz, CDCl3) δ 1.85 (m, 4H), 2.53 (t, J=6.9 Hz, 4H), 3.81 (t, J=6.0 Hz, 4H), 7.16-7.31 (m, 3H), 7.42 (t, J=1.2 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 16.2, 31.6, 61.9, 80.6, 90.0, 124.0, 128.3, 130.8, 134.7 ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12].C[O:16][C:17]([C@H:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.Cl>>[CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[C@H:7]([NH:10][C:17]([C@H:19]([NH2:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:16])[C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12]
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: COC(=O)[C@H](N)c1ccccc1
Agent: Cl
Product: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O

Procedure:
Under the condition similar to that of Example 15, 6-aminopenicillanic acid is reacted with D-α-phenylglycine methyl ester hydrochloride using the mycelium obtained in the procedure of Example 15 to produce 0.08 g of Ampicillin when determined by microbiological assay.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=O.[CH3:13][O:14][C:15]1[CH:43]=[CH:42][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([NH2:25])[C:22]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][C:33]([CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:34][C:28]=4[N:27]=3)=[N:21]2)=[CH:17][CH:16]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH:25][C:23]1[C:22]([C:26]2[NH:30][C:29]3[CH:31]=[CH:32][C:33]([CH2:35][N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:34][C:28]=3[N:27]=2)=[N:21][N:20]([CH2:19][C:18]2[CH:42]=[CH:43][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:24]=1)=[O:6]
Reactant: COc1ccc(Cn2cc(N)c(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)n2)cc1
Reactant: COc1cccc(F)c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(NC(=O)c3c(F)cccc3OC)c(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)n2)cc1
Yield: 116.8 %

Procedure:
A mixture of 2-fluoro-6-methoxy-benzoic acid (20 mg, 0.12 mmol), 1-(4-methoxy-benzyl)-3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.12 mmol), EDC (116 mg, 0.14 mmol) and HOBt (81 mg, 0.14 mmol) was stirred at room temperature in DMF (2 ml) for 20 h. The mixture was reduced in vacuo and the residue partitioned between EtOAc (5 ml) and water (2 ml) and the organic portion washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc] to give 2-fluoro-6-methoxy-N-[1-(4-methoxy-benzyl)-3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide as a white solid (80 mg, 61%).
Reaction SMILES: C(N(CCCC)CCCC)CCC.[FH:14].[F:15][C:16]1[C:21]([CH:22]2[O:24][CH2:23]2)=[C:20]([F:25])[C:19]([F:26])=[C:18]([F:27])[C:17]=1[F:28]>>[F:14][CH:22]([C:21]1[C:16]([F:15])=[C:17]([F:28])[C:18]([F:27])=[C:19]([F:26])[C:20]=1[F:25])[CH2:23][OH:24]
Reactant: F
Reactant: Fc1c(F)c(F)c(C2CO2)c(F)c1F
Solvent: CCCCN(CCCC)CCCC
Product: OCC(F)c1c(F)c(F)c(F)c(F)c1F
Temperature: 40 °C
Reaction time: 10 h
Yield: 31.9 %

Procedure:
To Teflon vessel containing 4.2 g (22.5 mmol)of tributylamine was cooled in a dry-ice methanol bath, and to this was added dropwise 2.3 g (112.5 mmol) of anhydrous hydrogen fluoride to prepare 6.4 g (22.5 mmol) of n-Bu3N.5HF. To this was added dropwise 3.15 g (15 mmol) of (+)-pentafluorostyrene oxide at 0° C., and was stirred for 10 hours at 40° C. After it was left to cool, the same treatment as that provided in Example 16 gave 1.1 g of (+)-2-fluoro-2-(pentafluorophenyl)ethanol. Its GC purity was 96%, while its [α]D25 was +10.8° (c=0.54, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([Cl:11])=[C:5]2[NH:4][N:3]=1.[N:13]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.S(=O)(=O)(O)O>[Cl:11][C:10]1[CH:9]=[C:8]([CH3:12])[N:7]=[C:6]2[C:2](=[N+:1]=[N-:13])[N:3]=[N:4][C:5]=12
Reactant: O=N[O-]
Reactant: Cc1cc(Cl)c2[nH]nc(N)c2n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cl)c2c(n1)C(=[N+]=[N-])N=N2
Yield: 67.5 %

Procedure:
A solution of 3-amino-7-chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (D7) (0.5 g) in water (13.5 ml) and concentrated sulphuric acid (2 ml) was treated at 0° with a solution of sodium nitrite (0.406 g) in water (2 ml) added dropwise with stirring. On completion of the addition the mixture was stirred at 0° for 20 min before bringing to pH 8 with saturated sodium carbonate. The resulting solid was collected and dried (0.18 g). The filtrate was extracted with chloroform (3×50 ml), the combined extracts dried with magnesium sulphate, filtered and evaporated to dryness to give a yellow solid which was combined with the solid originally collected, m.p. 119°-124° (combined yield 0.5 g). This crude material was recrystallised from cyclohexane to give the title compound as yellow needles (0.358 g, 68%), m.p. 123.5°-125° (decomposition). (Found: C, 43.51; H, 1.88; N, 35.79; Cl, 18.68. C7H4ClN5 requires C, 43.43; H, 2.08; N, 36.17; Cl, 18.31%). Found M+ 193.0154, C7H4ClN5 requires 193.0155.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[OH:15][CH2:16][CH:17]([NH:24][C:25](=[O:29])[C:26](O)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26](=[O:27])[C:25]([NH:24][CH:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][OH:15])=[O:29]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C(=O)NC(CO)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C(=O)NC(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
The mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.256 g; 1.09 mmol), 2-(2-hydroxy-1-phenylethylamino)-2-oxoacetic acid (0.250 g; 1.19 mmol), HATU (0.413 g: 1.09 mmol) and N,N-diisopropylethylamine (0.474 mL; 2.71 mmol) in DMF (5 mL) was stirred at room temperature overnight and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with water and was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) to yield 0.440 g of N1-(2-(5-chloro-1H-indol-3-yl)ethyl)-N2-(2-hydroxy-1-phenylethyl)oxalamide as a white solid.
Reaction SMILES: [CH2:1]1[C:3]([NH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])([C:4]([OH:6])=O)[CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:51]1[CH:55]=[C:54]([C:56]2([NH2:59])[CH2:58][CH2:57]2)[N:53]=[CH:52]1>CN(C=O)C>[CH2:11]([O:10][C:8](=[O:9])[NH:7][C:3]1([C:4](=[O:6])[NH:59][C:56]2([C:54]3[N:53]=[CH:52][O:51][CH:55]=3)[CH2:58][CH2:57]2)[CH2:2][CH2:1]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Reactant: NC1(c2cocn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(C(=O)NC2(c3cocn3)CC2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.1 %

Procedure:
To a round bottom flask was added Z-1-aminocyclopropane-1-carboxylic acid (150 mg, 0.638 mmol) in DMF (10 ml), followed by the addition of Hunig's base (207 mg, 1.6 mmol) and HATU (270 mg, 0.71 mmol). The reaction mixture was stirred at room temperature for 15 min, followed by the addition of 1-Oxazol-4-yl-cyclopropylamine (200 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo. The residue was purified by prepHPLC to afford 70 mg of [1-(1-oxazol-4-yl-cyclopropylcarbamoyl)-cyclopropyl]-carbamic acid benzyl ester, m/z 343 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11]OC(C1C=NC=C(C(OC)=O)C=1)=O>>[CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:11])=[O:5]
Reactant: COC(=O)c1cncc(C(=O)OC)c1
Reactant: Cc1ncccc1C(=O)O
Product: COC(=O)c1cccnc1C

Procedure:
methyl 2-methylnicotinate was synthesized from 2-methylnicotinic acid following the general procedure as described for dimethylpyridine-3,5-dicarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])OC(=O)[O:9][C:4]=2[CH:3]=1.[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1>CN1C(=O)CCC1>[NH2:20][C:16]1[CH:15]=[C:14]([NH:21][C:6](=[O:11])[C:5]2[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][C:4]=2[OH:9])[CH:19]=[CH:18][CH:17]=1
Reactant: O=c1oc(=O)c2ccc(Cl)cc2o1
Reactant: Nc1cccc(N)c1
Solvent: CN1CCCC1=O
Product: Nc1cccc(NC(=O)c2ccc(Cl)cc2O)c1
Temperature: 110 °C

Procedure:
7-Chloro-benzo[1,3]dioxine-2,4-dione (91) (0.090 g, 0.455 mmol) and benzene-1,3-diamine (397) (0.17 g, 1.57 mmol) were combined and dissolved in NMP (6 mL). The mixture was heated to 110° C. for 2 h. TLC was inconclusive, it was later determined that the desired product had same Rf as the aniline (397). LC-MS indicated complete reaction. The mixture was diluted with MeOH (2 mL) and LiOH (aqueous, 2.0 M, 4 mL). The mixture was stirred for 10 minutes. The solution was diluted with EtOAc (25 mL), washed with water (2×15 mL), saturated aqueous NaHCO3 (2×15 mL) and brine (2×15 mL) via extraction, dried over MgSO4 and concentrated to give a brown oil. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (15–100% EtOAc in hexane) gave the desired product (398) as an off-white solid upon concentration (0.091 g, 0.347 mmol, 76% yield). LC-MS (ESI): (exact mass: 262.05) m/e=263.0 [M+1]+ (100%), 525.3 [2M+1]+ (10%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:8][N:7]=[C:6]([N+:9]([O-:11])=[O:10])[N:5]=1.[CH3:12]I.O>CN(C)C=O>[Br:3][C:4]1[N:8]([CH3:12])[N:7]=[C:6]([N+:9]([O-:11])=[O:10])[N:5]=1
Reactant: CI
Reactant: O=[N+]([O-])c1n[nH]c(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc([N+](=O)[O-])nc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
1.1 g (28.5 mmol) of 60% sodium hydride are added to a solution of 5 g (25.9 mmol) of 5-bromo-3-nitro-1H-[1,2,4]triazole in 80 ml of dimethylformamide, cooled beforehand to 0° C. The reaction medium is stirred for 20 minutes and 8 ml (129.5 mmol) of methyl iodide are then added. After stirring at room temperature for 18 hours, water is added and the reaction medium is extracted with ethyl acetate. The organic phase is washed thoroughly with water, with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 75/25 heptane/ethyl acetate mixture. 3.2 g (60%) of 5-bromo-1-methyl-3-nitro-1H-[1,2,4]triazole are obtained.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.C(OC(=O)C)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[CH:2][C:1]([OH:4])=[O:3]
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccccc1Cl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C=Cc1ccccc1Cl
Temperature: 145 °C
Reaction time: 18 h

Procedure:
A mixture of 18.4 g (0.19 mol) of potassium acetate in 70.3 g (0.5 mol) 2-chlorobenzaldehyde is heated to 145° C. Next 76.5 g (0.75 mol) of acetic anhydride is added in 1 hour. After dosing of 0.50 mol of acetic anhydride the mixture became clear. The mixture is stirred at 145° C. during 18 hours. The hot reaction mixture is poured into a mixture of 670 g of 6.4 w/w % aqueous NaOH (1.1 mol, 2.1 eq based on 2-chlorobenzaldehyde) and 200 mL toluene at 80° C. The final pH was 7.4. After separation of the organic phase, the water layer is again extracted with 100 mL of toluene at 80° C. The combined water phases are acidified with 380 g of 25 w/w % H2SO4 to pH 4.6. Crystallization starts at pH 6.4. The mixture is cooled to 25° C. and the product is isolated by filtration, washed with 100 mL of water and dried (vacuo, 50° C.). 3-(2-chloro-phenyl)-acrylic acid was obtained as an off white solid (100.2 g, 0.55 mol, yield 55%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:15]2[C:14](=O)[NH:13][C:12]([S:17][CH3:18])=[N:11][C:10]=2[NH:9][CH:8]=1)(=[O:3])[CH3:2].N.P(Cl)(Cl)([Cl:22])=O>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:15]2[C:14]([Cl:22])=[N:13][C:12]([S:17][CH3:18])=[N:11][C:10]=2[NH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc2[nH]cc(CCOC(C)=O)c2c(=O)[nH]1
Agent: N
Product: CSc1nc(Cl)c2c(CCOC(C)=O)c[nH]c2n1
Temperature: 47.5 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
The above pyrrolopyrimidinone (1.2) (3.7 g, 13.8 mmol) was suspended in phosphoryl chloride (20 ml) and the solution heated at 45-50° C. overnight. The solution was cooled and poured onto ice and stirred for 10 mins and then neutralised with concentrated ammonia solution. The solid was filtered and recrystallised from methanol to give a yellow-brown solid which was chromatographed (CHCl3/2% MeOH) to give the product as a pale brown solid, yield 1.3 g. Unreacted starting material was eluted from the column in CHCl3/5% MeOH, yield 1.44 g. Overall yield 54%. δH ([2H6]-DMSO) 12.24 (1 H, br s, NH), 7.38 (1 H, s, 6-H), 4.26 (2 H, t J 6.8 Hz, OCH2), 3.08 (2 H, t J 6.8 Hz, OCH2CH2), 2.52 (3 H, s, CH3S), 1.98 (3 H, s, CH3CO) ppm. UV λmax (nm) 314 (4800), 254 (28300), 222 (13000). pH 12 λmax 291 (5100), 257 (26700). Accurate mass measurement 285.0339, C11H12CIN3O2S requires 285.0356.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[CH2:8][O:9][C:10]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:11]=2[CH:12]=1.CC(C)([O-])C.[K+].Br[C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(O)(C)(C)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[CH2:8][O:9][C:10]2[CH:16]=[CH:15][C:14]([O:17][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:13][C:11]=2[CH:12]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cn1ccnc1C1=Cc2cc(O)ccc2OC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)C=C(c1nccn1C)CO2
Yield: 68.6 %

Procedure:
A mixture of 4.56 g (0.02 mol) of 3-(1-methyl-1H-imidazol-2-yl)-2H-1-benzopyran-6-ol [m.p. 210°-215° C., prepared following the procedure described in J. Heterocyclic Chem. 23, 1693 (1986)] and 2.3 g (0.02 mol) of potassium tert.butoxide in 100 ml of tert.butanol is heated, under vigorous stirring, at 50° C. for 30'. A solution of 3.9 g (0.02 mol) of ethyl bromoisobutyrate in 10 ml of tert.butanol is rapidly added dropwise and the resulting mixture refluxed for 4 hours. The solvent is evaporated under vacuum and the residue is taken up with H2O (100 ml) and ethyl acetate. The aqueous solution is separated and extracted again with ethyl acetate (2×100 ml). The combined organic layers are washed with brine and dried over Na2SO4. After removal of the solvent under vacuum, the residue is chromatographed over silica gel (eluant chloroform/methanol 95/5) giving 4.7 g of ethyl 2-[3-(1-methyl-1H-imidazol-2-yl)-2H-1-benzopyran-6-yl]oxy-2-methylpropanoate, colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])[S:15][C:8]=23)=[C:4]([F:25])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[O:40]=[C:41]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:42][C:43](O)=[O:44]>CN(C=O)C.CCOC(C)=O>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:43](=[O:44])[CH2:42][C:41]([NH:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[O:40])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:17])[S:15][C:8]=12
Reactant: Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Reactant: O=C(O)CC(=O)Nc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1)Nc1ccccc1
Reaction time: 24 h
Yield: 51 %

Procedure:
To a solution of 23 (100 mg, 0.28 mmol), HOBT (49 mg, 0.36 mmol) and EDC (80 mg, 0.41 mmol) in DMF (5 mL) was added 3-oxo-3-(phenylamino)propanoic acid (1) (65 mg, 0.36 mmol). The reaction mixture was stirred for 1 day and was diluted with EtOAc. The resultant solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to provide a residue, which was purified by column chromatography (eluents MeOH—CH2Cl2, 2:98, 5:95) to produce a solid material, which after trituration with EtOAc/hexane afforded 5f as a white solid (74 mg, 51% yield). MS (m/z): 519.2 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:30])[CH3:14])=[CH:8][C:7]=1[CH3:31].CO.[OH-].[Li+].Cl>C1COCC1.O>[CH3:31][C:7]1[CH:8]=[C:9]([O:12][CH:13]([C:15]2[O:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH3:30])[CH3:14])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:32])=[O:2]
Reactant: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1CCC(=O)O
Temperature: 60 °C

Procedure:
3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionic acid methyl ester (0.176 g, 0.393 mmol) is dissolved in 20 mL of a 3:2:1 mixture of THF:MeOH:H2O. Lithium hydroxide (0.050 g, 2.08 mmol) is added and the resulting mixture is heated to 60° C. for 1 hr. The mixture is cooled to room temperature, diluted with 50 mL water and the pH is adjusted to 2–3 with 1M HCl. The product is extracted with two 50 mL portions of ethyl acetate. The combined organic extracts are washed with 50 mL water, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield the title compound, 3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionic acid as a white solid, 0.12 g (71%). MS (M++1) 434.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:16]=[C:17]2[CH2:23][C:22](=[O:24])[NH:21][C:18]2=[N:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:16]=[C:17]3[CH2:23][C:22](=[O:24])[NH:21][C:18]3=[N:19][CH:20]=2)=[CH:5][CH:4]=1
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1Cc2cc(-c3ccc(C(F)(F)F)cc3)cnc2N1
Temperature: 100 °C
Yield: 12.1 %

Procedure:
8.13 g 4-(Trifluormethyl)phenyl-boronic acid, 7.6 g 5-Bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one and 34.9 cesium carbonate were dissolved in a mixture of 14 ml water and 42 ml dimethylformamide. The reaction mixture was degassed with argon and then 2.0 g tetrakis(triphenylphosphine)palladium(0) were added and the mixture heated to 100° C. for two hours. Then 1.0 g 4-(Trifluormethyl)phenyl-boronic acid were added and the mixture stirred for an additional hour. Then 1.0 g 4-(Trifluormethyl)phenyl-boronic acid were added and the mixture stirred for additional three hours at 100° C. The cooled reaction mixture was diluted with 500 ml ethyl acetate and washed with 300 ml water and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting crude material was purified by chromatography on silica gel to obtain 1.2 g 5-(4-Trifluoromethyl-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[O:16]1[C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1>CCOCC>[CH2:9]([O:8][C:5]1[N:6]=[CH:7][C:2]([C:23]2([OH:26])[CH2:24][CH2:25][C:20]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:21][CH2:22]2)=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc(OCc2ccccc2)nc1
Solvent: CCOCC
Product: OC1(c2ccc(OCc3ccccc3)nc2)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from 5-bromo-2-benzyloxy-pyridine (Alfa Aesar) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]1.CCN(CC)CC>CS(C)=O.O>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[N:10]1[CH2:11][CH:8]([C:3]2[C:2]([N:22]3[CH2:27][CH2:26][CH:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1
Reactant: Clc1nccnc1C1CN(c2ccc3ccccc3n2)C1
Reactant: CC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)C1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 2-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-quinoline (80 mg, 0.27 mmol) and 1-piperidin-4-yl-ethanone (WUXI APPTEC) (34.3 mg, 0.27 mmol) in DMSO (5 mL) was added Et3N (54.5 mg, 0.54 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (20 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give 1-{1-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-ethanone (65.8 mg, 0.17 mmol, yield 62.9%).