Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1.O[C:24]1[CH:37]=[CH:36][C:27]2[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=2[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:24]2[CH:37]=[CH:36][C:27]3[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=2)[CH:16]=1
Reactant: Cc1cc(O[C@@H]2CCOC2)cc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@@H]5CCOC5)cc4C)c3)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 85.7 %

Procedure:
(R)-(2′,6′-Dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 2c (143 mg, 0.48 mmol), methyl (S)-2-(6-hydroxyl-2,3-dihydrobenzofuran-3-yl)acetate (100 mg, 0.48 mmol) and triphenylphosphine (189 mg, 0.72 mmol) were dissolved in 20 mL of dichloromethane. The reaction solution was cooled down to 0° C., followed by addition of diisopropyl azodicarboxylate (146 mg, 0.72 mmol). The reaction solution was warmed up to room temperature and stirred for 12 hours. The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound methyl 2-((S)-6-((2′,6′-dimethyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 2d (201 mg, yield 85.9%) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:26])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[N:6]2[C:12](=[O:25])[CH:13]([NH:14][C:15](=[O:24])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:5]2[S:4]1.[CH3:27][OH:28]>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[CH3:27][O:28][C:3]1([CH3:26])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[N:6]2[C:12](=[O:25])[CH:13]([NH:14][C:15](=[O:24])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:5]2[S:4][CH2:2]1
Reactant: CO
Reactant: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1(C)CBr
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)OC
Reaction time: 2 h

Procedure:
Methyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate (0.88 g) was dissolved in methylene chloride (13 ml) containing methanol. To the solution was added silver fluoroborate (0.45 g), and the mixture was stirred for 2 hours. After the reaction, the reaction mixture was filtered and the filtrate was washed with a dilute sodium bicarbonate aqueous solution and then with water. The solution was dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (25 g) and eluted with chloroform. The elute was separated into fractions of each about 20 ml and the seventh to tenth fractions were collected. The solvent was distilled off to give Methyl 3-methoxy-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (0.60 g).
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[CH3:16][C@@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH:18]1([C@H:17]([N:24]2[C:11](=[O:12])[C:6]3[C:7](=[C:2]([F:1])[C:3]([F:15])=[C:4]([F:14])[C:5]=3[F:13])[C:8]2=[O:10])[CH3:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: ClC(Cl)Cl
Product: C[C@H](C1CCCCC1)N1C(=O)c2c(F)c(F)c(F)c(F)c2C1=O
Temperature: 180 °C
Yield: 63.8 %

Procedure:
220 mg of tetrafluorophthalic anhydride and 127 mg of (R)-α-methylbenzylamine were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 1.5 hours. After cooled, the reaction product was dissolved in chloroform, purified by silica gel column chromatography (eluent; methylene chloride:methanol=30:1 v/v), recrystallized from a mixed solvent of n-hexane-ethyl acetate, to obtain 210 mg of the desired product as a colorless powder. Yield: 64%. m.p. 147-148° C.; [α]20D=−5.13° (C=0.658 AcOEt); MS(EI+) 329(M)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])/[C:5](=[N:7]/[OH:8])/[NH2:6].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:21]([C:20]3[CH:24]=[CH:25][C:17]([NH2:16])=[CH:18][CH:19]=3)[O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(N)cc3)n2)cc1Cl
Temperature: 150 °C
Yield: 50.6 %

Procedure:
(Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (1 g, 4.37 mmol), 4-aminobenzoic acid (0.660 g, 4.81 mmol), HOBT (0.737 g, 4.81 mmol), DCC (0.992 g, 4.81 mmol) and DIEA (1.680 ml, 9.62 mmol) were combined in a microwave vial. The reaction mixture was heated in the microwave for 20 minutes at 150° C. The reaction mixture was filtered to remove the urea formed in the reaction and the solvent was removed in vacuo. The crude material was purified by FCC (50% ethyl acetate/heptane) to afford 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline (729 mg, 2.211 mmol, 50.6% yield) as an off white solid: LCMS (Table A, Method b) 3.00 min, (M+H)+ 330.13.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.ClS([N:15]=[C:16]=O)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:16]#[N:15])=[CH:5][NH:6]2
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Brc1cccc2[nH]ccc12
Solvent: CC#N
Product: N#Cc1c[nH]c2cccc(Br)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 4-bromoindole (5 g, 25.5 mmol) in acetonitrile (50 ml) was added dropwise chlorsulfonylisocyanate (2.37 ml, 27.3 mmol) over a 5 minute period. The reaction mixture was stirred at 0° C. for 2 hours, and TEA (3.77 ml, 27.0) was added dropwise over a 10 minute period. The reaction mixture was allowed reach room temperature overnight, poured into ice/water mixture (200 ml), and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, concentrated, and purified by flash chromatography to afford 4-bromo-1H-indole-3-carbonitrile LVII as an off-white solid (4.9 g, 87% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:6][C:5](=[O:14])[CH2:4][CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O>CO>[C:15]1([CH:3]2[CH:2]([NH:1][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[O:23][CH3:22])[CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:6][C:5](=[O:14])[CH2:4]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccccc1C=O
Reactant: NC1C(c2ccccc2)CC(=O)NC1c1ccccc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1CNC1C(c2ccccc2)CC(=O)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
Under a nitrogen atmosphere in a round bottom flask were placed 500 mg (1.9 mmol) of 5 -amino-4,6-diphenyl-2-oxopiperidine and 5 mL of methanol. To the system was added 1 g of 3 Å molecular sieves, and the pH of the mixture was adjusted to 4.5 using methanol saturated with hydrogen chloride. To this system was added 284 mg (2.1 mmol) of 2-methoxybenzaldehyde, and the mixture was stirred at room temperature overnight. The mixture was filtered through diatomaceous earth (Celite (trademark)), the filter cake was rinsed well with methanol and the filtrate was concentrated with a rotary evaporator. The residue was partitioned between saturated aqueous sodium bicarbonate and chloroform, the layers were separated and the aqueous phase was extracted with three portions of chloroform. The combined chloroform extracts were dried (sodium sulfate) and concentrated, and the residue was subjected to flash column chromatography (30 g of silica gel) using 3:97 methanol/chloroform as the eluant to obtain 115 mg of 4,6-diphenyl-5-(2-methoxybenzylamino)-2-oxopiperidine.
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]([O:15]C)=[O:14])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[O:11][CH3:12].[OH-].[Na+]>CO>[F:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[O:11][CH3:12]
Reactant: COC(=O)c1cc2ccsc2c(OC)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(F)c(C(=O)O)cc2ccsc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.6 %

Procedure:
In 30 mL of 90% aqueous solution of methanol is dissolved 5.90 g of methyl 6-fluoro-7-methoxybenzo-[b]thiophene-5-carboxylate, to which is added 1.18 g of sodium hydroxide. The mixture is stirred at ambient temperature for 6 hours. The reaction mixture is concentrated under reduced pressure, the residue is mixed with water and hexane, and the aqueous layer is separated. The aqueous layer is adjusted to pH 1 with 6 mol/L hydrochloric acid, and the deposited crystal is collected by filtration, washed with water and dried. Thus, 5.20 g of 6-fluoro-7-methoxybenzo[b]thiophene-5-carboxylic acid is obtained as a light brown-colored crystalline product.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH2:12])[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[N:13]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH2:12])[N:3]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Nc1cc2ccccc2c(Br)n1
Reactant: C1COCCN1
Product: Nc1cc2ccccc2c(N2CCOCC2)n1
Yield: 92 %

Procedure:
1-Bromo-3-aminoisoquinoline is reacted with an equimolar quantity of morpholine as described in Example 1 to give 1-morpholinyl-3-aminoisoquinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:28][CH2:29][CH2:30][N:31]2[C:35](=[O:36])[C:34]3=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]3[C:32]2=[O:41])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 100 °C

Procedure:
To 10 ml of anhydrous DMF were added 2.8 g of N- Boc-p-hydroxyphenylglycine methyl ester and 1.38 g (1.0 eq) of anhydrous potassium carbonate, followed by addition of 2.68 g (1.0 eq.) of N-(3-bromopropyl)phthalimide. The mixture was heated at 100° C. for 1 hour. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried. Thereafter, the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: 5% ethyl acetate/dichloromethane), to give colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[N:5][N:4]=1)[CH3:2].N([CH2:11][C@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([C:25]3[CH2:26][CH2:27][S:28](=[O:32])(=[O:31])[CH2:29][CH:30]=3)=[C:20]([F:33])[CH:19]=2)[CH2:13]1)=[N+]=[N-].CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl>[O:32]=[S:28]1(=[O:31])[CH2:27][CH:26]=[C:25]([C:21]2[C:22]([F:24])=[CH:23][C:18]([N:14]3[CH2:13][C@H:12]([CH2:11][N:5]4[N:6]=[N:7][C:3]([CH2:1][CH3:2])=[N:4]4)[O:16][C:15]3=[O:17])=[CH:19][C:20]=2[F:33])[CH2:30][CH2:29]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2cc(F)c(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: CCc1nnn[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: ClCCl
Product: CCc1nnn(C[C@H]2CN(c3cc(F)c(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
5-Ethyl-1H-tetrazole (0.164 g, 1.67 mmol), (5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(hydroxymethyl)oxazolidin-2-one (WO 01/81350 A1) (0.30 g, 0.84 mmol), and polystyrene-triphenylphosphine (1.73 mmol/g loading: Argonaut Technologies, Inc. Foster City, Calif. USA, 1.46 g, 2.53 mmol) were dissolved in dry dichloromethane (30 ml). Diisopropylazodicarboxylate (0.33 ml, 1.68 mmol) was added and the mixture was stirred at room temperature for 16 hours. The resin was filtered off and rinsed with dichloromethane. The filtrate was evaporated to dryness and purified by chromatography on silica gel with 10% acetonitrile in dichloromethane. The material obtained after chromatography was precipitated from dichloromethane with diethyl ether to yield the title compound as a white powder (0.26 g, 71%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]1([CH3:19])[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[S:11]1>C(Cl)Cl>[CH3:6][C:5]([C:17]1[CH:16]=[CH:15][C:13]2[S:14][C:10]([CH3:9])([CH3:19])[S:11][C:12]=2[CH:18]=1)=[O:7]
Reactant: CC(=O)Cl
Reactant: CC1(C)Sc2ccccc2S1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)SC(C)(C)S2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
28.9 g of aluminum chloride were added portionwise at 0° C. to 16.8 ml of acetyl chloride in 360 ml of methylene chloride. After an additional 30 minutes at 0° C., a solution of 35.9 g of 2,2-dimethyl-1,3-benzodithiol in 180 ml of methylene chloride was slowly added dropwise and the mixture was stirred at 0° C. for an additional 12 hours and thereafter at 20° C. for 5 hours. Thereafter, the mixture was poured on to ice, extracted with methylene chloride and the extracts were washed neutral with dilute sodium hydroxide solution and water, dried over sodium sulfate and evaporated. After recrystallization from methanol/ water, there were obtained 41.8 g of 2,2-dimethyl-1,3-benzodithiol-5-yl methyl ketone, melting point 75°-76° C. Then, 41.8 g of this ketone were dissolved in 1 l of ethanol, cooled to 0° C. and 7 g of sodium borohydride were added portionwise. Thereafter, the mixture was stirred at 20° C. for 3 hours, evaporated in a vacuum to a large extent, 200 ml of water were added, the mixture was adjusted slowly to pH 4 with 1N sulfuric acid while cooling and extracted three times with ether. The extracts were washed with water, dried and evaporated, and 42.6 g of α,2,2-trimethyl-1,3-benzodithiol-5-methanol were obtained. Thereafter, 39.5 g of this alcohol were reacted with 65.9 g of triphenylphosphine hydrobromide in 500 ml of acetonitrile and worked-up as described in Example 8 and 96.3 g of [1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphonium bromide were obtained. Then, 17.0 g of this phosphonium salt were reacted with methyl 4-formyl-benzoate in analogy to Example 8. After working-up and recrystallization from ethyl acetate/hexane, there were obtained 4.9 g of methyl p-[(E)-2-(2,2-dimethyl-1,3-benzo-dithiol-5-yl)propenyl]benzoate in the form of colorless crystals, melting point 86°-87° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:27])[CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)C(OCC)=O>CS(C)=O.[Cl-].[Na+].O>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:27])[CH2:13][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1
Reactant: CCOC(=O)C(C(=O)c1c(OC)ccc(OC)c1F)c1cccc(OC)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(CC(=O)c2c(OC)ccc(OC)c2F)c1
Temperature: 150 °C
Reaction time: 5 h
Yield: 57.1 %

Procedure:
A mixture of ethyl 3-(2-fluoro-3,6-dimethoxyphenyl)-2-(3-methoxyphenyl)-3-oxopropanoate (7.8 g, 20.7 mmol) in DMSO (75 mL) and brine (7.5 mL) was stirred at 150° C. for 5 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (1:10 EtOAc/petroleum ether) to give the title compound (3.6 g). 1H NMR (CDCl3): δ 7.24-7.15 (m, 1H), 6.90 (t, 1H), 6.84-6.75 (m, 3H), 6.56 (dd, 1H), 4.08 (s, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=3)[N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:29])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:9]([N:14]1[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=2)=[C:12]2[C:7](=[CH:8][CH:9]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:10](=[O:29])[NH:11]2)[C:6]([OH:36])=[C:5]1[C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)C1=C(O)C2=CC(c3ccccc3)C(=O)NC2=C(c2cncc(F)c2)N1Cc1ccccc1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
A mixture of 1-benzyl-8-(5-fluoro-pyridin-3-yl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (32 mg, 0.067 mmol), β-alanine (593 mg, 6.7 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (5-80% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 14 mg of the title compound as a light yellow solid. MS: (+) m/z 539.29 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.NC1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+:27]1[CH:32]=CC=C[CH:28]=1>>[N:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:32]=[N:27][CH:28]=1
Reactant: c1cc[nH+]cc1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: c1ccc2ncncc2c1

Procedure:
With reference to Scheme 1 following, the present compounds are generally prepared by reaction of indole 1 and Meldrum's acid 2 and an aldehyde RCHO (formaldehyde, R=H) in the presence of proline [Diane S. Farlow, Michael E. Flaugh, Sharon D. Horvath, Edward R. Lavagnino, and Paul Pranc, Organic Preparations and Procedures Int. 13(1), 39 (1981)] to provide condensation adduct 3 which can be converted directly using Route C to quinazoline I by reaction with an o-aminobenzanilide 4 in the presence of pyridinium p-toluenesulfonate (PPTS) in refluxing pyridine. Alternatively, via Route A condensation adduct 3 can be decarboxylated in aqueous pyridine in the presence of copper powder to provide the intermediate indolylpropionic acid 5. The latter reacts with a methyl anthranilate 6 to form ester 7. Hydrolysis of ester 7 provides the corresponding carboxylic acid 8 which reacts at elevated temperature with an aniline hydrochloride via Route D or with an aniline in the presence of PPTS [Route E] to provide quinazoline I. Intermediate acid 8 can be prepared directly from adduct 3 by reaction with an anthranilic acid 9 in refluxing pypidine [Route B]. ##STR2##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:19]([OH:21])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1>>[NH:36]1[C:35]([NH:34][C:19]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])=[CH:12][CH:13]=3)[N:5]=2)=[O:21])=[N:39][N:38]=[N:37]1
Reactant: CCN(CC)c1ccc(-c2cc(C)cc(C(=O)O)n2)cc1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCN(CC)c1ccc(-c2cc(C)cc(C(=O)Nc3nnn[nH]3)n2)cc1
Yield: 65.5 %

Procedure:
In the same manner as described in Example 1-(1), 4-methyl-6-(4-diethylaminophenyl)-2-pyridinecarboxylic acid (1.0 g), carbonyldiimidazole (1.0 g) and 5-aminotetrazole (0.32 g) are reacted to give N-(5-tetrazolyl)-4-methyl-6-(4-diethylaminophenyl)-2-pyridinecarboxamide (0.81 g). M.P. 254°-256° C. (decomp.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][Mg]Cl)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][C:5](=[O:9])[CH2:6][CH2:7][CH:8]2[NH:4][C:3](=[O:10])[CH2:2][CH2:1]2)=[CH:14][CH:13]=1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: Fc1ccc(C[Mg]Cl)cc1
Product: O=C(CCC1CCC(=O)N1)Cc1ccc(F)cc1
Yield: 104.9 %

Procedure:
Analogous to the procedure described for Example 1A, Step A, tetrahydro-pyrrolizine-3,5-dione (1.41 g, 10.1 mmol) was reacted with 4-fluorobenzylmagnesium chloride (0.25M in Et2O, 50 mL, 12.5 mmol) over 5 h. Purification by medium pressure chromatography (2% MeOH in CH2Cl2) provided 5-[4-(4-fluoro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (2.64 g). 1H NMR (CDCl3) δ7.18 (m, 2H), 7.03 (m, 2H), 6.34 (m, 1H), 3.70 (s, 2H), 3.62 (m, 1H), 2.54 (t, 2H), 2.34–2.15 (m, 3H), 1.82–1.61 (m, 3H).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([N:21]2[C:10](=[O:12])[CH2:9][C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CCO
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Yield: 40.2 %

Procedure:
According to General Procedure A; ethyl benzoylacetate (12.2 mL, 71.2 mmol, 1.1 equ.) in ethanol (130 mL) was treated at 0° C. with phenylhydrazine (7.00 g, 71.2 mmol, 1.0 equ.) to give 1,3-diphenyl-1H-pyrazol-5(4H)-one (6.75 g, 28.6 mmol, 44%) after purification by column chromatography on silica gel (hexanes:ethyl acetate; 4:1) and crystallization (ethanol) as a white off solid. 1H-NMR (400 MHz) DMSO: 11.84 (s, 1H), 7.84-7.82 (d, 4H), 7.50-7.40 (m, 4H), 7.34-7.27 (m, 2H), 6.02 (s, 1H), 13C-NMR (100 MHz) DMSO: 154.2, 150.0, 139.3, 133.8, 129.3, 129.0, 128.2, 126.1, 125.5, 121.5, 85.5; LC/MS-MS: 237.0→77.1 m/z; GS1 and GS2 at 30, DP=81, CE=68, CXP=4, tR=4.15 min.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.S(Cl)(Cl)=O.[CH2:19](O)[CH2:20][CH3:21]>>[OH:1][C:2]1[C:11]([C:12]([O:14][CH2:19][CH2:20][CH3:21])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: CCCO
Solvent: O=S(Cl)Cl
Product: CCCOC(=O)c1cc2ccccc2cc1O
Temperature: 120 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
2-Hydroxy-naphthalene-3-carboxylic acid (2 g) was dissolved in 1-propanol (10 ml) to prepare a solution. The solution was brought to 0° C., and thionyl chloride (1.16 ml) was gradually added dropwise. The mixture was stirred at 120° C. for 2 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give propyl 2-hydroxy-3-naphthoate (2.15 g, yield 88%).