Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2.[H-].[Na+].Cl[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[N:7]2[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc2[nH]c(C)cc12
Reactant: ClCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1cc(C)n2Cc1cccc2ccccc12
Reaction time: 0.67 h
Yield: 97.1 %

Procedure:
4-Methoxy-2-methyl-1H-indole (644 mg, 4 mmol) was dissolved in 10 mL of DMF and 160 mg (4 mmol) of 60% NaH/mineral oil was added. After 0.67 hours, 707 mg (4 mmol) of 1-(chloromethyl)naphthalene was added. After 5 hours, the mixture was diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate was washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 1.17 g (97% yield) of 4-methoxy-2-methyl-1-[(1-naphthalenyl)methyl]-1H-indole.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:16][C:15]=1[B:28]1[O:32]C(C)(C)C(C)(C)[O:29]1.B(OC(C)C)(OC(C)C)OC(C)C>C1COCC1>[F:13][C:14]1[C:15]([B:28]([OH:29])[OH:32])=[CH:16][C:17]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:18][N:19]=1
Reactant: CC(c1cnc(F)c(B2OC(C)(C)C(C)(C)O2)c1)N1CCOCC1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(c1cnc(F)c(B(O)O)c1)N1CCOCC1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
To a solution of diisopropylamine (Aldrich) (0.640 mL, 4.57 mmol) in THF (10 mL) at −40° C. in 100 mL 3-neck round-bottom flask was added butyllithium solution, 1.6 m in hexanes (Aldrich) (2.85 mL, 4.57 mmol) dropwise via the addition funnel After the addition, it was continued to stir at −40° C. for 20 min then cooled to −78° C. To this reaction mixture was added 4-(1-(6-fluoropyridin-3-yl)ethyl)morpholine (Example 339 step 3) (0.800 g, 3.81 mmol) in THF (10 mL) dropwise via the addition funnel It was continued to stir at −78° C. after the addition. After 1 h, triisopropyl borate (Aldrich) (1.309 mL, 5.71 mmol) was added into the reaction mixture dropwise via the addition funnel After the addition, it was continued to stir at −78° C. for 20 min then removed the cooling bath and slowly warmed up to rt and stirred for 1 h. The reaction mixture was quenched with 1N NaOH (15 mL). The aqueous layer was extracted with EtOAc (2×15 mL)—the organic layer was discard; the aqueous layer was acidified to a pH of about 5 to 6 using 5 N HCl. The resulting mixture was extracted with EtOAc (2×15 mL) and CHCl3 (2×15 mL). The combined organic layers were dried over MgSO4 and concetrated to afford the product as a light brown amorphous solid (780 mg). MS (ESI pos. ion) m/z: 255.1. 1H NMR (400 MHz, CDCl3) δ ppm 1.38 (dd, J=11.44, 6.75 Hz, 3H) 2.36 (d, J=4.30 Hz, 2H) 2.45-2.60 (m, 2H) 3.35-3.47 (m, 1H) 3.63-3.77 (m, 4H) 8.15 (dd, J=9.00, 2.35 Hz, 1H) 8.19-8.27 (m, 2H) 8.33 (d, J=9.00 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:19](O)=[O:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(Cl)CCl>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[N:23]1([NH:22][C:19]([C:10]2[CH:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)=[O:20])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NN1CCCCC1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 0 °C
Yield: 24.7 %

Procedure:
5,6-Diphenyl-pyrazine-2-carboxylic acid (500 mg, 1.81 mmol) from Preparation A, step (a), was dissolved in DCM (4 ml) and DMF (150 μl). DMAP (22 mg, 0.18 mmol) and 1-aminopiperidine (218 mg, 2.17 mmol) were added and the solution was cooled to 0° C. A slurry of EDC (1.99 mmol, in 2 mL DCM and 100 μl DMF) was added dropwise. The reaction mixture was stirred at 25° C. After 17 hours additional 1-aminopiperidine (40 mg, 0.40 mmol) and EDC (76 mg, 0.40 mmol) was added, and the mixture was stirred for an additional 3 hours. The crude was diluted with DCM (5 ml) and washed with a saturated solution of NaHCO3. The organic phase was dried (MgSO4), filtered and evaporated. Flash chromatography (SiO2, ethyl acetate:hexane 2:1) gave the subtitle compound (160 mg, 25%) as a white solid.
Reaction SMILES: C([O:5][C:6]1[C:9](=[O:10])[C:8](=O)[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1)CCC.[OH-].[NH4+:31].O>CO>[NH2:31][C:8]1[C:9](=[O:10])[C:6](=[O:5])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1
Reactant: [NH4+]
Reactant: CCCCOc1c(NCCCOc2cccc(CN3CCCCC3)c2)c(=O)c1=O
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1c(NCCCOc2cccc(CN3CCCCC3)c2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 41 h
Yield: 77 %

Procedure:
To a solution of 1-butoxy-2-[3-(3-piperidinomethylphenoxy)propylamino]-1-cyclobutene-3,4-dione [prepared in Example 2] (4.06 g, 0.01014 mole) in methanol (40 mL) was added 14M aqueous ammonium hydroxide (1.5 mL, 0.021 mole). The mixture was stirred at ambient temperature for 41 hours. Water (40 mL) was added and stirring was continued for 10 minutes. The precipitate was collected by filtration, washed with methanol:water (1:1) (20 mL), and dried in vacuo to give 2.68 g (77.0% yield) of the title compound. A sample purified by chromatography showed spectral data identical to that of an authentic sample.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([O:7][CH3:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:8][O:7][C@H:6]1[C@H:2]([O:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:3][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5]1
Reactant: CO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
(+/−)-Trans-Benzyl 3-hydroxy-4-methoxypyrrolidine-1-carboxylate (7.7 g, 30.6 mmol) and N,N-dimethylpyridin-4-amine (0.374 g, 3.06 mmol) were dissolved in DCM (75 mL). Cooled to 0 deg. Celsius and added 4-methylbenzene-1-sulfonyl chloride (8.76 g, 46 mmol) and triethylamine (6.41 ml, 46.0 mmol). The reaction was stirred to warm to RT overnight. The solvent was removed and the residue was passed thru a pad of silica to give the product, (+/−)-Trans-benzyl 3-methoxy-4-(tosyloxy)pyrrolidine-1-carboxylate (10.3 g, 25.4 mmol, 83% yield).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:8])[C:4]([CH3:7])([OH:6])[CH3:5].CCN(C(C)C)C(C)C.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH:22]=[CH:21][N:20]=1>CN1CCCC1=O.O>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:2][C@@H:3]([CH3:8])[C:4]([CH3:7])([OH:6])[CH3:5])[N:24]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(Nc2ccnc(Cl)n2)cc1
Reactant: C[C@H](N)C(C)(C)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(Nc2ccnc(N[C@@H](C)C(C)(C)O)n2)cc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
(3S)-3-Amino-2-methyl-butan-2-ol HCl (1.00 mg, 7.16 mmol; prepared using the method of Konno et. al., Chem. Pharm. Bull. 1997, 45, 185) is dissolved in N-methyl-pyrrolidinone (10 mL). Hunig's base (1.62 mL, 9.30 mmol) is added followed by (2-chloropyrimidin-4-yl)-(4-methoxyphenyl)-amine, 1, (789 mg, 3.35 mmol) and the solution warmed to 140° C. After 24 hours, the reaction mixture is cooled to room temperature and diluted with water (100 mL) and the mixture extracted three times with CH2Cl2 (100 mL). The combined organic layers are washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified over silica (100% CH2Cl2 to 5% to 10% MeOH/CH2Cl2) to afford 564 mg (46% yield) of the desired product as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=5.8 Hz, 1H), 7.20 (d, J=9.0 Hz, 2H), 6.87 (d, J=9.0 Hz, 2H), 5.87 (d, J=5.8 Hz, 1H), 4.00-3.90 (m, 1H), 3.80 (s, 3H), 2.83 (s, 3H), 1.25 (s, 3H), 1.18 (d, J=7.3 Hz, 3H), 1.17 (s, 3H); MS (ESI) m/z 303 (M+1).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][CH2:8][P:9]([O:14][CH2:15][CH3:16])(=[O:13])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([O:7][CH2:8][P:9]([O:14][CH2:15][CH3:16])(=[O:13])[O:10][CH2:11][CH3:12])=[O:4]
Reactant: CCOP(=O)(CO)OCC
Reactant: CC(Br)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(COC(=O)C(C)Br)OCC
Reaction time: 20 h
Yield: 32.3 %

Procedure:
A solution of 8.6 g (0.05 mol) of 2-bromo-propionyl chloride in 30 ml of methylene chloride was added dropwise to a mixture which had been cooled to 0°-10° C. and consisted of 8.4 g (0.05 mol) of diethyl hydroxymethanephosphonate, 6.1 g (0.06 mol) of triethylamine and 30 ml of methylene chloride. The reaction mixture was stirred for 20 hours at 10°-20° C., washed with aqueous sodium bicarbonate solution, dried, filtered, and evaporated down under reduced pressure. 4.9 g (32% of theory) of diethyl 2-bromopropionyloxymethanephosphonate were obtained as an oily residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](O)([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:12][CH2:13][C:14]#[N:15].S(=O)(=O)(O)[OH:17]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:15][C:14](=[O:17])[CH2:13][Cl:12])([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1cccc(Br)c1
Reactant: N#CCCl
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)(NC(=O)CCl)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
To a mixture of the 2-(3-bromo-phenyl)-propan-2-ol and (0.76 g, 3.6 mmol) and chloro-acetonitrile (7 mL) was added acetic acid (0.6 mL) and the resulting mixture was cooled to 0° C. Concentrated sulfuric acid (0.6 mL) was added dropwise and the mixture was brought to room temperature and stirred for 17 h. Mixture was poured into ice-water (10 mL) and extracted with ethylacetate. The extracts were combined, dried over magnesium sulfate and concentrated to afford a white solid. M+1=291.
Reaction SMILES: [CH:1]1([CH2:6][C:7](=O)[CH2:8][C:9]([O:11]CC)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:15]([C:18]1[CH:28]=[CH:27][C:21]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=[N+:16]=[N-:17].[O-]CC.[Na+].O>C(O)C>[CH:1]1([CH2:6][C:7]2[N:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=3)[N:16]=[N:17][C:8]=2[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CC(=O)CC1CCCC1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
Ethyl 4-cyclopentyl-3-oxobutyrate (0.781 g, 3.94 mmol, 1.25 eq.) obtained in Example 103a) and 4-azido-N-ethylbenzamide (0.60 g, 3.15 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (298 mg, 3.94 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 50° C. for 12 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid, and extracted with ethyl acetate (35 ml and 30 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether and ethyl acetate were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a pale-yellow powder (971 mg, 2.84 mmol, 90.0%).
Reaction SMILES: [C:1](OCC)(=[O:7])[C:2](OCC)=[O:3].[CH2:11]([O:13][C:14](=[O:21])[CH2:15][S:16][CH2:17][C:18]([O-:20])=[O:19])[CH3:12].O.Cl.[CH3:24][CH2:25]O>>[C:18]([C:17]1[S:16][C:15]([C:14]([O:13][CH2:11][CH3:12])=[O:21])=[C:1]([OH:7])[C:2]=1[OH:3])([O:20][CH2:24][CH3:25])=[O:19]
Reactant: CCO
Reactant: CCOC(=O)CSCC(=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: O
Product: CCOC(=O)c1sc(C(=O)OCC)c(O)c1O
Reaction time: 288 h

Procedure:
Diethyl oxalate (6.58 g, 45 mmol) was added to 2,2′ thiobisacetate ethyl ester (4.66 g. 23 mmol) to produce a yellow-orange solution. A solution of Na (1.56 g, 68 mmol) in EtOH (24 mL) was added to produce a white/yellow precipitate, this was mixed well for 10 minutes. H2O (50 mL) was added to the reaction mass with cooling in an ice bath. Concentrated HCl was added dropwise until acidified. This was allowed to stand in the refrigerator for 12 days. At this point a cold filtration was done to isolate a white solid.
Reaction SMILES: Cl.[CH2:2]([NH2:8])[C:3]1[O:7][CH:6]=[CH:5][CH:4]=1.[S-:9][C:10]#[N:11].[NH4+].O.C(OCC)(=O)C>BrC1C=CC=CC=1>[CH2:2]([NH:8][C:10]([NH2:11])=[S:9])[C:3]1[O:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#C[S-]
Reactant: NCc1ccco1
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Brc1ccccc1
Product: NC(=S)NCc1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
Furfurylamine hydrochloride (33.46 grams, 0.250 moles) and ammonium thiocyanate (38.14 grams, 0.501 moles) in 71 ml bromobenzene were heated under nitrogen at reflux temperature for 20 minutes and then cooled to room temperature. The reaction mixture was mixed with a solution of 125 ml water and 100 ml ethyl acetate and left at room temperature overnight. The mixture was then diluted to give 500 ml ethyl acetate and 350 ml water and the aqueous layer separated. The organic layer was washed with water and dried over sodium sulfate. After filtration, the organic layer was evaporated to dryness and bromobenzene removed under vacuum. The resulting solids were ground in a mortar and pestle and the fine particles stirred in diethyl ether to remove residual bromobenzene. The solids were then filtered, washed with diethyl ether and vacuum dried over phosphorus pentoxide, yielding 12.06 grams (30%) of N-furfurylthiourea, m.p. 80°-91° C. Recrystallization from benzene gave yellow needles, m.p. 98°-100° C.
Reaction SMILES: [CH:1]1C=CC=CC=1.[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1.CCCCCC.[C:25]([O:28][CH2:29][CH3:30])(=[O:27])[CH3:26]>>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[C:26]([CH3:1])[C:25]([O:28][CH2:29][CH3:30])=[O:27])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1
Reactant: c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(C)=Cc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
Into 200 ml of benzene, 10.0 g (53.8 mmol) of 4-chloro-2-nitrobenzaldehyde (manufactured by Aldrich Chemical Co., Inc.) and 18.1 g (50.0 mmol) of Wittig reagent (carbethoxyethylidene triphenylphosphorane, manufactured by Aldrich Chemical Co., Inc.) were dissolved; and the mixture was stirred at ordinary temperature for one night. After the completion of the reaction was verified by TLC, the reaction liquid was concentrated, whereby a crude product was obtained. This crude product was refined by a column chromatography (aminopropyl-modified silica gel (Fuji Silysia Chem. Co., NH-DM); developing solvent: hexane/ethyl acetate=1/1), whereby 13.1 g of the aimed compound were obtained as a crystal (yield: 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([C:25]([CH:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)O)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([N:37]=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]1[O:15][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:37]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (2R)-N-benzyloxycarbonylproline (5 g) in CH2Cl2 (50 ml) were added benzoin (4.5 g), 1-ethyl 3-(3-dimethylaminopropyl)carbodiimide (3.9 ml), and dimethylaminopyridine (2.6 g) at room temperature under N2. After being stirred for 12 hours at room temperature, the solvent was evaporated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The obtained compound and CH3COONH4 (8.2 g) were dissolved in acetic acid (50 ml) and the mixture was stirred for 4 hours at 100° C. After the solvent was removed, the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (2R)-1-benzyloxycarbonyl-2-(4,5-diphenyloxazol-2-yl)pyrrolidine (4 g).
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)=[O:4].[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[C@@H:13]([O:19][C:20](=[O:37])[C:21]([OH:36])([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12]2>C(Cl)(Cl)Cl>[Br-:1].[OH:36][C:21]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:20]([O:19][C@@H:13]1[CH:14]2[CH2:15][CH2:16][N+:11]([CH2:2][C:3](=[O:4])[NH:5][C:6]3[CH:10]=[CH:9][O:8][N:7]=3)([CH2:18][CH2:17]2)[CH2:12]1)=[O:37]
Reactant: COc1ccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1
Reactant: O=C(CBr)Nc1ccon1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(O)(C(=O)O[C@H]2C[N+]3(CC(=O)Nc4ccon4)CCC2CC3)c2ccccc2)cc1
Product: [Br-]
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a stirred solution of bromo-N-isoxazol-3-yl-acetamide (Intermediate Ai) (0.057 g, 0.278 mmol) in dry chloroform (1 ml) heated to 50° C. is added hydroxy-(4-methoxy-phenyl)-phenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Intermediate O) in chloroform (1 ml). The reaction mixture is stirred at 50° C. for 6 hours after which time, the titled product is detected by LC-MS. (M+ 492.3)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)[NH:8][C:7](=[O:23])[CH2:6][CH2:5]2.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+].O>CN(C)C=O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[O:12][CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[NH:8][C:7](=[O:23])[CH2:6][CH2:5]3)=[CH:27][CH:26]=1
Reactant: O=C1CCc2cc(Br)c(OCc3ccc(C(=O)O)cc3)cc2N1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCc2cc(-c3ccc(Cl)cc3)c(OCc3ccc(C(=O)O)cc3)cc2N1
Reaction time: 0.08 h
Yield: 66.7 %

Procedure:
To a solution of 4-((6-bromo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoic acid (100 mg, 0.27 mmol) and 4-chlorophenyl boronic acid (62 mg, 0.40 mmol) in N,N-dimethylformamide (2.0 mL) in a Biotage microwave vial was added sodium bicarbonate (200 mg, 2.38 mmol) and water (0.50 mL). The reaction mixture was stirred for 5 minutes under an atmosphere of dry N2. Pd(PPh3)4 (10 mg, 0.009 mmol) was added, and the resulting mixture was sealed and subjected to microwave irradiation at 130° C. for 8 minutes. The mixture was cooled, diluted with ethyl acetate (5 mL), filtered through celite, washed with 10% N,N-dimethylformamide in ethyl acetate (40 mL), transferred to a separation funnel, and the organic phase was washed with 1N sodium carbonate (20 mL), 30% ammonium chloride (20 mL) and brine (30 mL), dried and the solvent removed under reduced pressure. The crude product was purified by preparative HPLC with a gradient acetonitrile/water (5-98%) to afford 4-((6-(4-chlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoic acid (72 mg, 0.18 mmol, 66%). LCMS mz 408.0 (M+H), 430.0 (M+Na), anal HPLC >96% in purity, 1H NMR (400 MHz; dmso-D6) δ10.1 (σ, 1H), 7.95 (d, J=8.2 Hz, 2H); 7.55 (d, J=9.0 Hz, 2H); 7.48 (m, 4H); 7.18 (s, 1H); 6.69 (s, 1H); 5.15 (s, 2H); 2.87 (m, 2H); 2.47 (m, 2H).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[CH3:10]>>[CH:15]1[CH:16]=[CH:17][C:12](/[CH:9]=[CH:10]/[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:13][CH:14]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccccc1
Product: O=C(/C=C/c1ccccc1)c1ccccc1

Procedure:
The compound was not synthesised according to the procedure of Example 1. Instead, an aldol condensation of equimolar amounts of benzaldehyde and acetophenone were first of all carried out to give 1,3-diphenylpropenone:
Reaction SMILES: O=[C:2]1[N:21]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2=[N:6][C:7]([C:10]3[CH:11]=[N:12][N:13]4[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=34)=[CH:8][CH:9]=[C:4]2[NH:3]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(OCC)OCC>CCO>[O:25]1[CH2:24][CH2:23][CH:22]([N:21]2[C:5]3=[N:6][C:7]([C:10]4[CH:11]=[N:12][N:13]5[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=45)=[CH:8][CH:9]=[C:4]3[N:3]=[CH:2]2)[CH2:27][CH2:26]1
Reactant: N#Cc1ccn2ncc(-c3ccc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: N#Cc1ccn2ncc(-c3ccc4ncn(C5CCOCC5)c4n3)c2c1
Temperature: 145 °C
Reaction time: 2.5 h
Yield: 41 %

Procedure:
To a suspension of the compound obtained in example 2 section d (33.6 mg, 0.1 mmol) in EtOH (1.5 mL), citric acid (2 mg, 0.1 mmol) and triethyl orthoformate (340 μL, 2 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 145° C. and 270 W for 2.5 hours. The crude residue was cromategraphed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 14.2 mg of the desired product (41% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[C:12]1(=O)[CH2:15][CH2:14][CH2:13]1.N1CCCC1>>[OH:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][C:12]1([CH2:15][CH2:14][CH2:13]1)[CH2:10][C:9]2=[O:11]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: O=C1CCC1
Solvent: C1CCNC1
Product: O=C1CC2(CCC2)Oc2ccc(O)cc21

Procedure:
The title compound was prepared from 2′,5′-dihydroxyacetophenone (10 g, 65.724 mmol) and cyclobutanone (13.29 ml, 131.44 mmol), in the presence of pyrrolidine (10.79 ml) by similar procedure as described in Step 1 of Intermediate 1 to give 10 g of the product; 1H NMR (300 MHz, CDCl3) δ 1.63-1.73 (m, 2H), 1.84-1.95 (m, 2H), 2.05-2.15 (m, 2H), 2.23-2.33 (m, 2H), 6.85 (d, J=8.7 Hz, 1H), 7.06 (d, J=9.0 Hz, 1H), 7.33 (s, 1H).