Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2.CS(O[CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)(=O)=O>O1CCCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)[N:12]=[CH:11]2
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Brc1ccc2[nH]ncc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3cc(Br)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of potassium tert-butoxide (37.25 g) in tetrahydrofuran (1000 mL) was added 5-bromoindazole (54.52 g), and the mixture was stirred at room temperature for 15 minutes. To the reaction solution was added tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (98.74 g), and the reaction solution was heated at reflux for 1 day. Then, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 as the eluting solvent) to give Compound Q17 (45.68 g).
Reaction SMILES: C[Li].[CH3:3][CH:4]([CH2:6][CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C:15]3[CH2:16][CH2:17][C:18]4[C@:23]([C:25]=3[CH2:26][CH2:27]2)([CH3:24])[CH2:22][CH2:21][C:20](=[O:30])[CH:19]=4)[CH2:13][CH2:12]1)[CH3:10])[CH3:5].[Cl-].[NH4+]>C(OCC)C>[CH3:5][CH:4]([CH2:6][CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C:15]3[CH2:16][CH2:17][CH:18]4[C@:23]([C:25]=3[CH2:26][CH2:27]2)([CH3:24])[CH2:22][CH2:21][C:20](=[O:30])[CH2:19]4)[CH2:13][CH2:12]1)[CH3:10])[CH3:3]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C=C1CC3
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)CC1CC3
Reaction time: 0.5 h

Procedure:
0.85 ml of a methyllithium solution (1.6 N, in diethyl ether) are added to a suspension of 130 mg cuprous iodide in diethyl ether at 0° C. The resulting mixture is stirred for one hour before a solution of 130 mg cholesta-4,8-dien-3-one in 1 ml diethyl ether is added. After being stirred for 30 minutes the reaction mixture is poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous sodium sulphate and filtered. After evaporation of the solvent the residue is chromatographed with mixture of hexane and ethyl acetate to give 80 mg-5-methyl-5, cholest-8-en-3-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][C:20](Cl)=[O:21].Cl.[CH3:24][NH2:25]>C(Cl)Cl.[OH-].[Na+]>[CH3:24][NH:25][C:20](=[O:21])[CH2:19][O:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:8][O:9][C:10]=2[C:2]=1[Cl:1]
Reactant: CN
Reactant: O=C(Cl)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CNC(=O)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Reaction time: 18 h

Procedure:
A solution of 4.0 g of {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetyl chloride in methylene chloride is added dropwise to a solution of 0.9 g of methylamine hydrochloride in 50 ml methylene chloride and 25 ml of 15% sodium hydroxide solution at 0° C. After 18 hr at room temperature the reaction mixture is acidified, filtered, and the filtrate partitioned. The aqueous solution is washed with methylene chloride. The organic solutions are combined, washed with saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solution gives N-methyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide, mp 164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25](OC)=[O:26])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][CH2:25][OH:26])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2CCCO)o1
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a mixture of methyl 3-[2-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propoxy]phenyl]propionate (400 mg) and tetrahydrofuran (10 ml) was added gradually lithium aluminum hydride (40 mg) under ice-cooling, and the resulting mixture was stirred for 1 hour. Sodium sulfate decahydrate (400 mg) was carefully added to the reaction mixture, which was filtered. The residue on the filter paper was washed with ethyl acetate. The filtrate was concentrated, and hexane was added to the residue to give crystals of 4-(4-chlorophenyl)-5-[3-(2-(3-hydroxypropyl)phenoxy)propyl]-2-(2-methyl-1-imidazolyl)oxazole (264 mg, 65%). Recrystallization from ethyl acetate-hexane gave colorless prisms. Melting point 119-120° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)[C:13](SCCC4CC4)=[N:12]3)[CH2:10][CH:9]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:34].[I-].N.CCO>>[NH2:34][C:13]1[N:14]([CH2:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: O=C1N(CCC2CC2)C(SCCC2CC2)=NC12CC(c1ccccc1)Oc1ccc(Br)cc12
Agent: N
Agent: [I-]
Solvent: CCO
Product: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CCC1CC1
Yield: 23.9 %

Procedure:
A solution of 6-bromo-1′-(2-cyclopropylethyl)-2′-(2-cyclopropylethylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (40 mg, 0.076 mmol), and NH4I (22 mg, 0.153 mmol) in a solution of NH3/EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′-(2-cyclopropylethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (8 mg, 24%). 1H-NMR (MeOD): 0.01 (m, 2H), 0.34 (m, 2H), 0.61 (m, 1H), 1.48 (m, 2H), 2.10 (m, 1H), 2.37 (m, 1H), 3.67 (m, 2H), 5.12 (d, 0.3H), 5.74 (d, 0.7H), 6.70 (m, 1H), 7.00 (m, 1H), 7.31 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>CN(C1C=CN=CC=1)C.ClCCl>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:25]([NH:24][CH2:22][CH3:23])=[O:26])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Reactant: CCN=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)NCC)cc1
Reaction time: 3 h
Yield: 49 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.40 g) obtained in Example 1d) and DMAP (0.34 g) in dichloromethane (14 ml) was added ethyl isocyanate (0.79 ml) at room temperature and the mixture was stirred for 3 hr. The reaction mixture was diluted with dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate), and the obtained product was recrystallized from ethyl acetate-diethyl ether to give the title compound as a white powder (0.12 g, 49%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C@@H:11]([OH:23])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:26][C:27]1[CH:32]=[C:31](Cl)[N:30]=[CH:29][N:28]=1>O1CCCC1>[CH2:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C@@H:11]([O:23][C:31]2[CH:32]=[C:27]([Cl:26])[N:28]=[CH:29][N:30]=2)[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1C[C@@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C1
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(O[C@@H]2C[C@@H](COCc3ccccc3)[C@@H](OCc3ccccc3)C2)ncn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
At 0° C., under a blanket of nitrogen, to a solution of (1R,3S,4S)-3-(benzyloxy)-4-(benzyloxymethyl)cyclopentanol (24) (226.500 g, 725.026 mmol) in tetrahydrofuran (1150 mL) was added NaH, 60% in mineral oil (86.995 g, 2175.1 mmol) portionwise, maintaining a temperature of less than 10° C. A solution of 4,6-dichloropyrimidine (118.81 g, 797.53 mmol) in tetrahydrofuran (1150 mL) was then added over 30 minutes maintaining a temperature of less than 5° C. The mixture was allowed to warm to ambient temperature and stirred for 24 hours. HPLC analysis indicated that the reaction mixture contained 74% starting material. The reaction mixture was quenched with a mixture of water (1150 mL) and saturated ammonium chloride in water (1150 ml), maintaining a temperature of less than 10° C. The tetrahydrofuran layer was separated and concentrated to ˜2 volumes (500 mL). The aqueous layer was extracted twice with ethyl acetate (1150 mL). The organic layers were combined and washed twice with water (1150 mL) and once with saturated sodium chloride in water (1150 mL). The organics were then concentrated. The residue was taken up in tetrahydrofuran (2300 mL) and cooled to 0° C. under a blanket of nitrogen. NaH, 60% in mineral oil (86.995 g, 2175.1 mmol) was added portionwise maintaining a temperature of less than 10° C. Mixture was allowed to warm to ambient temperature and stirred for 16 hours. HPLC analysis indicated reaction was complete. The reaction mixture was quenched with a mixture of water (1150 mL) and saturated ammonium chloride in water (1150 mL). The tetrahydrofuran layer was separated and concentrated to ˜2 volumes (500 mL). The aqueous layer was extracted twice with ethyl acetate (1150 mL). The organic layers were combined and washed twice with water (1150 mL) and once with saturated sodium chloride in water (1150 ml). The organics were then concentrated to give the crude intermediate 4-((1R,3S,4S)-3-(benzyloxy)-4-(benzyloxymethyl)cyclopentyloxy)-6-chloropyrimidine. This crude reaction mixture was taken in to the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](Br)[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1[O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].[CH2:21]=[O:22]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1[O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:21]=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O[Si](C)(C)C
Reactant: C=O
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O[Si](C)(C)C
Yield: 45 %

Procedure:
By proceeding as indicated in the procedure of Preparation VII above, starting with 10 mmol of 3,5-di-t-butyl-4-trimethylsilyloxy-bromobenzene and 15 mmol of HCHO (in the protected form of H2C(OCH3)2), one obtains (yield: 45%) 3,5-di-t-butyl-4-trimethylsilyloxy-benzaldehyde, followed by the expected product, 3,5-di-t-butyl-4-hydroxybenzaldehyde.
Reaction SMILES: [CH:1]([C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH3:14])=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:2].C[Si](C)(C)[C:24]([F:27])([F:26])[F:25].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[NH4+].[Cl-].[Cl-].[Na+].O>[CH3:13][O:12][C:11]1[C:3]([CH:1]([OH:2])[C:24]([F:27])([F:26])[F:25])=[C:4]2[C:8](=[C:9]([CH3:14])[CH:10]=1)[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]=[CH:5]2
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 19-D) (0.44 g, 1.52 mmol) in THF (7.24 mL), trimethyl(trifluoromethyl)silane (0.71 mL, 4.56 mmol) and then TBAF (1M in THF, 4.56 mL, 4.56 mmol) were added at 0° C., and the reaction was stirred at room temperature. After 20 minutes the reaction mixture was diluted with aq. NH4Cl and brine, extracted with EtOAc, and the organic extract was dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-70% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 360.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:12]=[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=S)c1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)Cc1csc(-c2ccc(F)cc2)n1

Procedure:
To a stirred solution of 4-fluorothiobenzamide (8.94 g, 57.6 mmol) in ethanol (70 mL) was added ethyl 4-chloroacetoacetate (7.8 mL, 58 mmol). The reaction was heated at reflux for 4 hours, treated with an addition aliquot of ethyl 4-chloroacetoacetate (1.0 mL, 7.4 mmol) and refluxed for an additional 3.5 hours. The reaction was then concentrated and the residue was partitioned between ethyl acetate (200 mL) and aqueous NaHCO3 (200 mL). The organic layer was combined with a backextract of the aqueous layer (ethyl acetate, 1×75 mL), dried (Na2SO4) and concentrated. The resulting amber oil was purified by flash chromatography using a hexane/ethyl acetate gradient to afford ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate as a low melting, nearly colorless solid (13.58 g, 89%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:14]3[C:15]([OH:19])=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:4][CH:3]=1.[C-:20]#[N:21].[Na+].O>C(#N)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.[Cu]I>[C:20]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:14]3[C:15]([OH:19])=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:4][CH:3]=1)#[N:21]
Reactant: [C-]#N
Reactant: Oc1cccc2occ(CCc3ccc(Br)cc3)c12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(CCc2coc3cccc(O)c23)cc1
Yield: 33.7 %

Procedure:
A suspension of 3-[2-(4-bromophenyl)ethyl]-4-hydroxybenzofuran (0.5 g), sodium cyanide (0.23 g), tetrakis(triphenylphosphine)palladium (0) (91 mg) and copper (I) iodide (30 mg) in acetonitrile (5 mL) was heated for reflux for three days. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give 3-[2-(4-cyanophenyl)ethyl]-4-hydroxybenzofuran (0.14 g). To a solution of hexamethyldisilazane (0.35 mL) in diethyl ether (2 mL) was added n-butyl lithium (2.46 mol/L n-hexane solution 0.7 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added a solution of the 3-[2-(4-cyanophenyl)ethyl]-4-hydroxybenzofuran (0.13 g) in diethyl ether (3 ml), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 2 mol/L hydrochloric acid, and the resulting mixture was washed with diethyl ether twice. The aqueous layer was basified by addition of 2 mol/L aqueous sodium hydroxide solution, and the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with a mixed solvent of dichlorometane and methanol (5/1) (three times), and the extract was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-[2-(4-carbamimidoylphenyl)ethyl]-4-hydroxybenzofuran (0.11 g). This material was dissolved in 1,4-dioxane (5 mL)-1 mol/L aqueous sodium hydroxide solution (5 mL). To the solution was added benzyl chloroformate (0.1 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid (5 mL), and the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (35 mg).
Reaction SMILES: [F:1][C:2]1[C:16]([F:17])=[C:15]2[C:5]([C:6](=[O:30])[C:7]([C:19]([NH:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])=[C:8]([OH:18])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.O>[F:1][C:2]1[C:16]([F:17])=[C:15]2[C:5]([C:6](=[O:30])[C:7]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[C:8]([OH:18])[C:9]32[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C2(CCOCC2)c2c(ccc(F)c2F)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)C2(CCOCC2)c2c(ccc(F)c2F)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
A mixture of t-butyl N-((7,8-difluoro-2-hydroxy-4-oxo-2′,3′,5′,6′-tetrahydro-4H-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (0.13 g, 0.3 mmol) in 3 mL TFA was stirred at room temperature for 1 hour. The mixture was diluted with 100 mL water and a white precipitate was formed to form a suspension. The suspension was stirred for 30 minutes at room temperature, filtered, and washed with 20 mL water. The solid was dried under vacuum at 45° C. for 15 hours to give 0.09 g of the title compound as a white solid. MS m/e: (M+H)+ 368.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.[OH-].[K+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1([OH:18])[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Product: CN1CCC(O)(c2c[nH]c3ccc(Br)cc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-bromoindole (490 g), 1-methyl-4-piperidone (339 mL) and potassium hydroxide (15 g) in IMS (3L) was stirred under nitrogen at room temperature for 24 hrs. The mixture was cooled to 7° and filtered. The filter cake was washed with ethanol (300 mL) followed by water (800 mL) to give an off-white powder which was dried in vacuo at 50° for 24 hr (563.8 g, 73% of theory).
Reaction SMILES: [C:1]1([CH3:35])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([OH:34])[CH2:29][C:30]([O:32]C)=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>CCO.O>[C:1]1([CH3:35])[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([OH:34])[CH2:29][C:30]([OH:32])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)CC(O)CCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCC(O)CC(=O)O)CCC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 7-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)-3-hydroxy heptanoate (step 3)(43 mg, 0.091 mmol) in EtOH (908 μL) was treated with sodium hydroxide (136 μL, 0.272 mmol) and stirred at room temperature for 1 hour. The resulting mixture was diluted with water (2 ml) and acidified to pH 2. The mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried by passing through a phase separator and concentrated under reduced pressure to give an oil. The oil was purified by flash column chromatography using the ISCO combiflash Rf, eluting with 0-50% EtOAc (containing 10% MeOH) in iso-hexane on a 4 g silca cartridge. The product fractions were combined and the solvent removed under reduced pressure to yield the titled compound as a colourless oil;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[K+].[Br-]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([O:11][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[C:7]([O:12][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a solution of ethyl-3,5-dihydroxy benzoate, 3 (16.8 g, 92 mmol) in acetone (350 mL) were added potassium carbonate (27.6 g, 200 mmol) and benzyl bromide (23.8 mL, 200 mmol) and stirred at room temperature for 9 h. Reaction mixture was filtered, concentrated on rotavapor and the crude product purified by column chromatography to afford 8. Yield 24.7 g (74%); mp 63-65° C.; MS (FAB) 363 (M++1); IR (KBr) 1824, 1708; 1H NMR (200 MHz, CDCl3) δ 7.34-7.35 (m, 10H), 7.30 (d, J=2.3 Hz, 2H), 6.79 (t, J=2.2 Hz, 1H), 5.07 (s, 4H), 4.36 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27](=[O:28])[CH2:26][CH:25]([C:29]([OH:31])=O)[CH2:24]3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.Cl.[F:33][C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH:25]([C:29]([N:36]4[CH2:37][CH2:38][C@H:34]([F:33])[CH2:35]4)=[O:31])[CH2:26][C:27]3=[O:28])=[CH:19][CH:18]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)O)CC4=O)cc3)CC2)c(C)c1
Reactant: F[C@H]1CCNC1
Agent: Cl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)N5CC[C@H](F)C5)CC4=O)cc3)CC2)c(C)c1
Yield: 17.9 %

Procedure:
Using 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid (62 mg) described in Example 333 and (S)-3-fluoropyrrolidine hydrochloride (19 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (13 mg) was obtained.