Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[CH2:7].C([SiH](CC)CC)C.C(OCC)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH3:7])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: C=Cc1ccc(OC)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCc1ccc(OC)c(OC)c1
Temperature: 60 °C
Yield: 41.4 %

Procedure:
In a 5 mL flask opened to the air, to a clear solution of 3,4-dimethoxystyrene (100 μL, 0.755 mmol) in benzene (0.8 mL) was added triethylsilane (240 μL, 0.816 mmol). The flask was placed in a 60° C. bath and iodo[bis(triphenylphosphine)]dioxorhenium(V) (32 mg, 0.037 mmol) was added. The resulting brown solution was heated at 60° C. for 12 hours. The crude reaction mixture was directly applied to a SiO2 column and chromatographed eluting with 4:1 hexanes:diethyl ether to afford 3,4-dimethoxyethylbenzene (52 mg, 57% yield) as a colorless liquid. The reaction was repeated using pent-2-enal and t-butyl acrylate as the electrophilic reactants, as indicated in the first two schemes above (wherein “TES” represents triethylsilyl).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][NH2:9])[CH2:4][CH3:5])[CH3:2].Cl[C:11]1[C:24]2[C:23](=O)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:21]=3)[S:16][C:15]=2[C:14]([N+:34]([O-:36])=[O:35])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][N:8]1[C:11]2[CH:12]=[CH:13][C:14]([N+:34]([O-:36])=[O:35])=[C:15]3[S:16][C:17]4[CH:18]=[CH:19][C:20]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:21][C:22]=4[C:23]([C:24]=23)=[N:9]1)[CH3:2]
Reactant: O=c1c2cc(OCc3ccccc3)ccc2sc2c([N+](=O)[O-])ccc(Cl)c12
Reactant: CCN(CC)CCNN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)Sc1ccc(OCc3ccccc3)cc1-2
Yield: 61.1 %

Procedure:
A mixture of 1.2 g (0.0091 mol) of 2-(diethylaminoethyl)hydrazine, 2.7 g (0.0069 mol) of 1-chloro-4-nitro-7-phenylmethoxy-9H-thioxanthen-9-one, and 0.97 g (0.0069 mol) of powdered K2CO3 in 30 ml of xylene was reacted and 2.0 g of the product was isolated as described in Example 58.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH2:15]1OCCOCCOCCOCCOCCOC1.CI.[H-].[Na+]>CN(C=O)C>[N+:11]([C:8]1[CH:7]=[CH:6][C:5]([CH:4]([CH3:15])[C:3]([O:2][CH3:1])=[O:14])=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 697.9 %

Procedure:
A mixture of (4-nitro-phenyl)-acetic acid methyl ester (3.0 g, 15 mmol), 18-crown-6 (396 mg, 1.5 mmol), and methyl iodide (3.74 mL, 60 mmol) were combined in DMF (50 mL) and cooled to 0° C. Sodium hydride (660 mg, 16.5 mmol) was added. The solution was stirred with warming to room temperature overnight. The solution was partitioned between ethyl acetate and water. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to provide 2.19 g (70%) of the title compound. MS (DCI) m/e 210 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:10]1[C:15]2[C:14](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:10][S:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)(=[O:8])=[O:7])[CH:13]=[CH:12][CH:11]=1
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)c1nccs1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc2cccnc12)c1nccs1
Yield: 15 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoqunoline (250 mg, 1.73 mmol), thiazole-2-sulfonyl chloride (Intermediate 444) (413 mg, 2.25 mmol), pyridine (2 ml), DMAP (cat.) and DCM (2 ml) gave the title compound (110 mg, 15%), after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][S:11][C:10]=2[C:14]([O:16]C)=[O:15])=[O:7])=[C:4]([F:21])[CH:3]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][S:11][C:10]=2[C:14]([OH:16])=[O:15])=[O:7])=[C:4]([F:21])[CH:3]=1
Reactant: COC(=O)c1sccc1NC(=O)c1cc(F)c(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccsc1C(=O)O)c1cc(F)c(Cl)cc1F
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 3-[(4-chloro-2,5-difluorobenzoyl)amino]thiophene-2-carboxylate, MeOH, THF and 1M sodium hydroxide (NaOH) solution (aq) was stirred for two hours at 85° C. to give 3-[(4-chloro-2,5-difluorobenzoyl)amino]thiophene-2-carboxylic acid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[C:26]=1[F:27])(=O)=O.O1CCOCC1.B([C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH3:49])[C:42]([OH:44])=[O:43])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O>[F:27][C:26]1[C:11]2[C:12]([C:22](=[O:25])[NH:23][CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[O:14][C:10]=2[CH:9]=[CH:8][C:7]=1[C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH3:49])[C:42]([OH:44])=[O:43]
Reactant: COc1ccc(C(=O)O)cc1B(O)O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)c(F)c12
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3OC)c(F)c12
Temperature: 85 °C
Yield: 35.4 %

Procedure:
To a small sealed tube was added 4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (64.5 mg, 0.111 mmol), dioxane (6 mL), water (1.200 mL), 3-borono-4-methoxybenzoic acid (26.1 mg, 0.133 mmol), cesium carbonate (54.2 mg, 0.167 mmol) and finally Tetrakis(triphenylphosphine)palladium(0) (2.6 mg, 2.2 μmol). The tube was sealed and the reaction mixture heated at 85° C. for twenty hours. The reaction mixture was cooled to room temperature, pushed through a plug of celite and evaporated to a dark oil under a stream of nitrogen. The residue was triturated with 15 mL of ice water then air dried overnight giving 17.2 mgs (35.4% yield) of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methoxy benzoic acid as a white solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. LCMS rt=2.770 min., m/z 438.3 (M+H), 93% purity.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:15]([O:17]C)=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1(C(Cl)=O)[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)C(C)C)(C)C.[I-].[Na+]>C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([C:15]([OH:17])=[O:16])=[N:11][C:12]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)N1CCCC1
Reactant: COC(=O)c1ncccc1OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1nc(N2CCCC2)ccc1OCc1ccccc1
Yield: 83 %

Procedure:
6.48 g (25 mmol) of methyl 3-benzyloxypicolinate (N-oxide), 6.68 g (50 mmol) of 1-pyrrolidinylcarbonyl chloride, 6.46 g (50 mmol) of N,N-diisopropylethylamine and 7.49 g (50 mmol) of sodium iodide were refluxed under heating for two hours in 120 ml of acetonitrile. The solvent was distilled off, and water was added to the residue. The mixture was extracted with ethyl acetate, washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained mixture was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain the desired product.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:18][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([F:9])([F:20])[F:21]
Reactant: Oc1ccccc1I
Reactant: OCCc1ccccc1C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1CCOc1ccccc1I
Temperature: 25 °C
Yield: 56 %

Procedure:
To a stirred solution of the 2-iodophenol (220.0 mg, 1.0 mmol), the 2-(2-(trifluoromethyl)phenyl)ethanol (228.0 mg, 1.2 mmol), and triphenyl phosphine (314.0 mg, 1.2 mmol) in anhydrous THF (5 mL) at 0° C. was added DEAD (40% in toluene, 1.20 mmol, 0.35 mL) dropwise. The yellow solution was allowed to warm to room temperature and stirring was continued overnite. After evaporating the solvent under reduced pressure the crude residue was dissolved in DCM (15 mL). The organic layer was washed with 10% NaOH (2×10 mL), water and brine. The organic phase was dried (Na2SO4), filtered and evaporated under reduced pressure. The crude residue was purified by column chromatography on silica gel using hexanes/EtOAc as the eluent. The compound was isolated in 56% yield as a white solid. 1H NMR: 3.17 (t, 2H, J=6.8 Hz), 4.22 (t, 2H, J=6.8 Hz), 6.90-7.10 (m, 4H), 7.15-7.23 (m 1H), 7.30-7.45 (m, 2H), 7.74 (dd, 1H, J=7.6, 1.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][S:13][C:14]2[NH:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:12][S:13]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)=[O:31])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Solvent: ClC(Cl)Cl
Product: CCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Yield: 39.5 %

Procedure:
To a solution of 2-(3-methyl-4-propoxy-2-pyridyl)methylthiobenzimidazole (1 g) in chloroform (20 ml) was added dropwise over 10 minutes under ice-cooling m-chloroperbenzoic acid (750 mg) dissolved in chloroform (10 ml). The solution was chromatographed directly on a column of silica gel (50 g), which was eluted with ethyl acetatehexane (1:1) and then with 5% methanol-ethyl acetate. From the eluate was removed the solvent. The residue was recrystallized from acetone-ether-hexane to give 415 mg of 2-[3-methyl-4-propoxy-2-pyridyl)methylsulfinylbenzimidazole.4/5H2O as crystals, m.p. 81°-83° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[Cl:18][CH2:19][CH2:20][CH2:21]Br>CC(C)=O>[Cl:18][CH2:19][CH2:20][CH2:21][O:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: ClCCCBr
Reactant: COc1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OC)c(OCCCCl)c1
Yield: 86.2 %

Procedure:
A mixture of 2,5-dimethoxyphenol (29 g, 0.19 mol), K2CO3 (35 g), 3-chlorobromopropane (38.5 g, 0.25 mol) and acetone (250 ml) was stirred and refluxed for 6 hours, and then stirred at ambient temperature for 16 hours. The reaction was filtered, and the filtrate was concentrated to an orange liquid. The liquid was taken up into Et2O, and the organic layer washed with 1N NaOH, H2O, dried (MgSO4) and was concentrated to yield 37.8 g of an orange solid. An 11.7 g sample of this solid was flash chromatographed on silica gel (180 g) with 5% EtOAc/CH2Cl2 as eluent. Concentration of similar fractions gave 7.2 g of white, waxy solid, which was recrystallized from petroleum ether to afford a white solid, m.p. 48°-50° C.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1ccccc1
Temperature: 100 °C

Procedure:
Adenine (1 mmol) in DMF was treated with sodium hydride (1.2 mmol) followed by benzyl bromide (1.2 mmol) at room temperature under nitrogen. The resulting mixture was warmed at 100° C. for 2 h. The cooled reaction mixture was evaporated to dryness. Extraction and chromatography afforded N9-benzyladenine.
Reaction SMILES: [OH-].[Li+].[NH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[CH3:11])[N:7]=[C:6]([C:14]([O:16]C)=[O:15])[C:5]=1[Cl:18]>O.O1CCCC1>[NH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[CH3:11])[N:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]=1[Cl:18]
Reactant: COC(=O)c1nc(C(C)(F)F)cc(N)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(F)(F)c1cc(N)c(Cl)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A solution of lithium hydroxide (159 mg, 1.27 mmol) in water (6 mL) was added to a solution of methyl 4-amino-3-chloro-6-(1,1-difluroethyl)-pyridine-2-carboxylate (159 mg, 0.63 mmol) in tetrahydrofuran (6 mL). The mixture was vigorously stirred at room temperature overnight and was then concentrated to near dryness. After adding water, the reaction mixture was washed once with ethyl acetate to remove unreacted starting material. The aqueous layer was then acidified to pH<3 with 1N HCl and extracted with ethyl acetate. The organic layer was dried (MgSO4), concentrated and the residue triturated with cold hexane to provide 4-amino-3-chloro-6-(1,1-difluoroethyl)-pyridine-2-carboxylic acid (105 mg, 0.44 mmol) as a white solid; 1H NMR (DMSO-d6): δ 7.02 (s, 1H), 6.94 (br.s, 2H), 1.90 (t, 3H).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH2:38][CH2:39][CH3:40])[CH:32]=4)[CH2:28][CH2:27][C:26]([C:41](O)=[O:42])=[CH:25][C:24]=3[CH:44]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH2:38][CH2:39][CH3:40])[CH:32]=4)[CH2:28][CH2:27][C:26]([C:41]([NH:29][C:23]4[CH:24]=[CH:44][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:42])=[CH:25][C:24]=3[CH:44]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccc(OCCC)c2)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cccc(OCCC)c2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (134 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (100 mg) and triethylamine (455 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 4.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 64) (207 mg) as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[F:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:24][CH2:23][CH2:22][CH2:21][F:20])=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cc(Cl)cc2c1Cl
Reactant: NCCCCF
Product: CCOC(=O)c1cnc2c(OC)cc(Cl)cc2c1NCCCCF

Procedure:
4,6-Dichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.836 mmol) was treated with 4-fluorobutylamine following general procedure B to afford 6-Chloro-4-(4-fluoro-butylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (185 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (105 mg) following general procedure E. The above ethylamide (100 mg, 0.28 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 9-chloro-3-ethyl-1-(4-fluoro-butyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (54 mg). LCMS: m/z 380 [M+1]+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(OC(=O)C)(=O)C.[Br:16]Br>C(O)(=O)C>[Br:16][C:5]1[CH:4]=[CH:3][C:2]([NH2:7])=[C:1]([NH2:8])[CH:6]=1
Reactant: BrBr
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1ccc(Br)cc1N
Temperature: 65 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
In 64 ml of acetic acid, 8.0 g of o-phenylene diamine was dissolved, to which 15.3 ml of acetic anhydride was added drop-wise under cooling. Then the mixture was heated for 30 minutes in an oil bath at 65° C. After cooling to room temperature, a solution of bromine (4.6 ml bromine in 16 ml acetic acid) was quickly added, followed by heating for 40 minutes in an oil bath at 50° C. About 10 minutes after adding bromine, crystals started to precipitate. The reaction mixture was cooled to room temperature, and poured into 300 ml ice water containing 4.0 g sodium hydrogen sulfite. The resulting white precipitates were collected by filtration, washed with water and dried under reduced pressure (14.0 g; yield 70%). Into a 150 ml solution of water:methanol (2:1) containing 33.6 g potassium hydroxide, the white solid was dissolved and heated with stirring for 12 hours in an oil bath at 75°-80° C. After cooling the reaction mixture, and adding 400 ml water thereto, the mixture was extracted with 100 ml ether five times. The ether phase was washed with 200 ml of saturated salt water two times, and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) so as to obtain compound 13 as colorless crystals (5.5 g, total yield 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[C:9]1[S:13][C:12]([CH3:14])=[N:11][CH:10]=1.C([N:24]=[C:25]=[S:26])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:25]([NH2:24])=[S:26])[CH:6]=[CH:7][C:8]=1[C:9]1[S:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: COc1cc(N)ccc1-c1cnc(C)s1
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(N)=S)ccc1-c1cnc(C)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a solution of 3-methoxy-4-(2-methyl-thiazol-5-yl)-phenylamine (100 mg, 0.45 mmol) in tetrahydrofurane (4 mL) was added drop wise under stirring and under an atmosphere benzoyl isothiocyanate (67.7 ul, 0.48 mmol). The reaction was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The residue was dissolved in methanol (6 mL) and a solution of potassium carbonate (188 mg, 1.36 mmol) in water (3 mL) was added. The resulting suspension was stirred at room temperature over night. The precipitate was filtered off, washed with water and diethyl ether to yield the title compound as a pale yellow solid (113 mg, 89%). MS ISP (m/e): 280.1 (100%) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.82 (s, 1H, NH), 8.02 (s, 1H), 7.62 (d, 1H), 7.40 (s, 1H), 7.01 (s, 1H), 3.87 (s, 3H), 2.64 (s, 3H).
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C@@H:7]1[CH2:11][C@H:10]([C:12]#[N:13])[C@@H:9]([O:14][CH3:15])[CH2:8]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(O)(=O)C>C1COCC1>[OH:6][C@@H:7]1[CH2:11][C@H:10]([C:12]#[N:13])[C@@H:9]([O:14][CH3:15])[CH2:8]1
Reactant: CO[C@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CO[C@H]1C[C@H](O)C[C@@H]1C#N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88.5 %

Procedure:
A solution of (1S,2R,4S) and (1R,2S,4R)-4-(tert-butyl-diphenyl-silanyloxy)-2-methoxy-cyclopentanecarbonitrile (3.86 g, 10.17 mmol) in THF (20 ml) was added to a solution of TBAF (20.3 ml, 20.3 mmol, 1M solution in THF) and acetic acid (1.2 ml, 20.9 mmol) in THF (50 ml) at 0° C. After the addition was completed, the icebath was removed and the light brown solution was allowed to stir at room temperature for 3.5 h. The solution was then diluted with water and extracted 3 times with EtOAc. The combined organic layers were washed with a mixture of brine and saturated NaHCO3 solution, dried over Na2SO4 and evaporated. The remaining yellow oil was purified by silica gel chromatography (heptane/EtOAc 70:30-45:55) to obtain the title compound as yellow oil (1.29 g, 9 mmol, 90%). MS (EI): 200.3 (M+OAc)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH:8]=[C:9]([C:15]([O:17]CC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[O:17]=[C:15]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][N:1]=2)[NH:7][CH:8]=[C:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=CNc1cccnc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cccnc2c1=O
Temperature: 246.5 °C
Yield: 50.2 %

Procedure:
To a hot (248° C., mantle and thermometer were used) and colorless solution of diphenyl ether (100 mL) was added dropwise a light brown solution of diethyl 2-((pyridin-3-ylamino)methylene)malonate (24) (3 g, 11.4 mmol) in diphenyl ether (4 mL, heated to dissolve) at 248° C. for 10 min. During the addition, the reaction mixture turned to a brown solution and then to a dark brown solution. The resulting brown reaction mixture was refluxed (inside temperature was 245 to 248° C.) for 1 h. Then, the heating was stopped and it was allowed to cool to approx. 80° C. at which time some solids started to precipitate and then the mantle was removed. The resulting suspension was poured into approx. 300 mL of hexanes and the brown solids were collected by filtration and washed with hexanes. 1H NMR and LCMS analysis of this solid indicated the presence of two regioisomers in a ratio of approx. 4:1. Then, the two peaks were separated by HPLC method and the desired ethyl 4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (25) (1.25 g, 50% yield) was isolated as a brown solid.