Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH3:16][C:17]1[CH:18]=[C:19]([O:24][CH2:25][CH:26]=[CH2:27])[CH:20]=[C:21]([CH3:23])[CH:22]=1>>[CH2:25]([O:24][C:19]1[CH:20]=[C:21]([CH3:23])[C:22]([CH:9]=[O:10])=[C:17]([CH3:16])[CH:18]=1)[CH:26]=[CH2:27]
Reactant: C=CCOc1cc(C)cc(C)c1
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCOc1cc(C)c(C=O)c(C)c1
Temperature: 70 °C
Reaction time: 0.42 h
Yield: 51 %

Procedure:
N-methyl formanilide, 20.5 ml (166 mmole), was chilled to 13°, where it began to solidify. Phosphorus oxychloride, 14.4 ml (155 mmole), was added with stirring, under nitrogen. After 25 minutes, the temperature was 45°. 3,5-Dimethylallyloxy benzene, 16.2 g (100 mmole), prepared as describe above, was added with stirring and heated in a 70° C. oil bath. The reaction exothermed to 93° C. and was stirred under nitrogen for 30 minutes. The bath was removed and when the temperature reached 35°, the product was dissolved in chloroform. Ice was added, the layers were separated and washed once with water, twice with sodium bicarbonate, once with water and once with brine. The product was chromatographed down 500 ml of silica, eluting with chloroform to give 9.67 g (51%) of subtitled product which was used without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]3[N:14]([C:7]=2[CH:6]=[CH:5][N:4]=1)[CH2:13][CH2:12][CH:11]3[CH:15](C(OC)=O)[C:16]([O:18][CH3:19])=[O:17].CS(C)=O.[Na+].[Cl-]>O>[CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]3[N:14]([C:7]=2[CH:6]=[CH:5][N:4]=1)[CH2:13][CH2:12][CH:11]3[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(C(=O)OC)C1CCn2c1cc1c(SC)nccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CC1CCn2c1cc1c(SC)nccc12
Reaction time: 18 h

Procedure:
To a mixture of dimethyl 2-[1-(methylthio)-7,8-dihydro-6H-pyrido[3,4-b]-pyrrolizin-8-yl]malonate (0.59 g, 2.17 mmol) and DMSO (4mL) was added NaCl (0.45 g) in H2O (0.45 mL). After a period of 18 h at 150° C., the reaction mixture was partitioned between ETOAc and H2O. The organic phase was separated, dried over Na2SO4 and evaporated. The title compound was then purified by flash chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([O:15]CC)=O)=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[NH4+:19]>C(OCC)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([NH2:19])=[O:15])=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc(N)cc1
Agent: [OH-]
Solvent: CCOCC
Product: NC(=O)c1c[nH]cc1-c1ccc(N)cc1
Temperature: 80 °C

Procedure:
A suspension of 0.07 g (0.304 mmol) of ethyl 4-(4-aminophenyl)-1H-pyrrole-3-carboxylate in 10 cm3 of a 22% aqueous ammonium hydroxide solution is heated in an autoclave at a temperature in the region of 80° C. for 84 hours. After stopping the heating and then returning to ambient temperature and pressure, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give an orange solid which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (98/1/1 by volume)]. After concentrating the fractions under reduced pressure, a residue is obtained which is stirred in 10 cm3 of diethyl ether and then filtered and dried under reduced pressure (2.7 kPa) to give 0.02 g of 4-(4-aminophenyl)-1H-pyrrole-3-carboxamide, in the form of a brown solid: EI: m/z=201 (M+) base peak, m/z=185 (M−NH2+), m/z=157 (M-CONH2+).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:15][N:16]1[C:24]2[CH:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33]=O)=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[N:21]=[C:20]([C:39]#[N:40])[C:19]=2[N:18]=[N:17]1.[CH3:41][NH2:42]>C1COCC1.C(OCC)(=O)C>[CH3:15][N:16]1[C:24]2[CH:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][NH:42][CH3:41])=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[N:21]=[C:20]([C:39]#[N:40])[C:19]=2[N:18]=[N:17]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(CCC=O)c(C(F)(F)F)c3)cc21
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNCCCc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaB(OAc)3H (640 mg) was added in portions to the solution of methyl-6-(4-(3-oxopropyl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile, methylamine (1.5 ml, 2M in methanol) in THF (5 ml). The mixture was stirred at rt for 3 hours, then diluted with ethyl acetate (100 ml), washed with sodium carbonate (100 ml), brine (100 ml), dried over sodium sulphate, solvent removed. The crude product was used for next step without further purification (260 mg). MS m/z 375 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24]([OH:26])=O.Cl.[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH2:35][NH:34][CH2:33][CH2:32]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24]([N:34]1[CH2:33][CH2:32][C:31]2[C:36](=[CH:37][CH:38]=[C:29]([F:28])[CH:30]=2)[CH2:35]1)=[O:26]
Reactant: COc1cc(-c2nc(C(=O)O)c3cc(F)ccc3n2)cc(OC)c1OC
Reactant: Fc1ccc2c(c1)CCNC2
Agent: Cl
Product: COc1cc(-c2nc(C(=O)N3CCc4cc(F)ccc4C3)c3cc(F)ccc3n2)cc(OC)c1OC
Yield: 54.3 %

Procedure:
Reaction of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 108 (54.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.92 and 3.07 (2t, 2H), 3.58 and 4.04 (2t, 2H), 3.76-3.3.77 (d, 3H), 3.86 and 3.91 (2s, 6H), 4.55 and 4.98 (2s, 2H), 6.95-7.41 (m, 3H), 7.65-7.85 (m, 3H), 7.99-8.05 (m, 1H), 8.23-8.28 (m, 1H); MS (ESI) m/z 492 ([M+H]+).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].CI.[NH4+].[Cl-]>C1COCC1>[F:13][C:14]1[C:22]([CH3:1])=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(F)ccc(C(=O)O)c1F

Procedure:
To a stirred solution of diisopropylamine (1.7 g, 16.4 mmol) in THF 2.6 M solution of n-BuLi (1.1 g, 16.4 mmol) was added at −30° C. and the mixture was stirred for an hour at the same temperature. To this mixture a solution of 2,4-difluorobenzoic acid (1.0 g, 6.3 mmol) in THF was added slowly at −78° C., followed by methyl iodide (2.2 g, 15.7 mmol) and it was stirred for another 2 h at the same temperature and allowed to attain the room temperature. The reaction mixture was treated with saturated aqueous NH4Cl solution and the aqueous layer extracted with ethylacetate (3×25 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After removal of solvent, the residue was purified over a silica gel flash column using a gradient of ethyl acetate in pet. ether to give product as a white solid. Yield: 0.77 g (70%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([N:12]([CH3:25])[C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[C:15](=[O:24])[N:16]([CH3:23])[C:17]3=[O:22])=[O:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32](Cl)(=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(#N)C>[C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([N:12]([CH3:25])[C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[C:15](=[O:24])[N:16]([CH3:23])[C:17]3=[O:22])=[O:11])=[CH:4][CH:3]=1)(=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CN1C(=O)c2cccc(N(C)C(=O)NNc3ccc(N)cc3)c2C1=O
Reactant: CCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCC(=O)Nc1ccc(NNC(=O)N(C)c2cccc3c2C(=O)N(C)C3=O)cc1
Reaction time: 2 h
Yield: 30.5 %

Procedure:
1-p-Aminophenyl-4-methyl-4-(2-methyl-1,3-dioxoisoindolin-4-yl)semicarbazide (1.5 g, 4.5 mmole) and pyridine (1 ml) were dissolved in 30 ml of acetonitrile under nitrogen and cooled to +5° C. in an ice bath. Hexanoyl chloride (0.6 g, 4.5 mmole) in 5 ml of acetonitrile was added dropwise. The mixture was stirred 11/2 hours at ice-bath temperature. The resulting solid was filtered to give 0.6 g of product, m.p. 115°-118° C. Recrystallization from acetonitrile and ethyl acetate gave 0.32 g (16% yield) of product, m.p. 147°-149° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12].N1CCCCC1>C(O)C>[C:11]([C:13]1[C:14](=[O:15])[NH:16][C:1]([CH3:2])=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2)#[N:12]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C1CCCCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(=O)c(C#N)c2c1CCCC2
Yield: 67 %

Procedure:
2-Acetylcyclohexanone (5 g) and cyanoacetamide (3 g) were added to 25 ml of ethanol and a small amount of piperidine was also added. The mixture was heated under reflux for 2 hours. After cooling, deposited crystals were filtered out and washed with ethanol. There was obtained 4.5 g of 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-3-oxoisoquinoline.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=2)=[CH:2]1.S(=O)(=O)(O)O.[CH2:20](O)[CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=[N:9]1
Reactant: O=C(O)Cn1nnnc1-c1ccsc1
Reactant: OCCO
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1ccsc1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 50 %

Procedure:
To a solution of 1 g (4.7 mM) of [5-(3-thienyl)tetrazol-1-yl] acetic acid in 5 ml of ethylene glycol was added 0.5 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and the precipitated crystal was filtered off, washed with water and recrystrallized from ethyl alcohol, to give 620 mg (yield 50%) of [5-(3-thienyl)tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:25](C4CCCCO4)[N:26]=[CH:27][C:10]=13)[CH2:2]2.Cl>O1CCOCC1>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=3)[N:12]=[C:11]3[NH:25][N:26]=[CH:27][C:10]=13)[CH2:2]2
Reactant: CC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCCCO4)c3n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cn[nH]c3n2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (21 mmol) is taken up as a suspension in dry ethyl acetate (50 mL). Following the addition of 4-toluenesulfonic acid monohydrate (25 mg), the mixture is heated to 60° C. and 3,4-dihydro-2H-pyran (2.5 mL) is added in drops. The reaction mixture is maintained at 60° C. for 18 hours and is then concentrated under reduced pressure. The residue is purified by flash silica gel chromatography. Following concentration of fractions, 6-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine is obtained. 6-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (3.1 mmol) is coupled to 4-acetamidophenylboronic acid (0.83 g, 4.6 mmol) with tetrakis(triphenylphosphine) palladium (0) (2.5 mol %), 2 M aqueous sodium carbonate solution, and ethylene glycol dimethyl ether (DME) and under microwave irradiation (175 C, 10 min). Following an aqueous workup and flash chromatography, N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide is obtained. N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide (1.2 mmol) is taken up in dioxane (5 mL), treated with 4 M hydrogen chloride in dioxane (5 mL), and allowed to stir at room temperature for 3 days. The slurry is concentrated and purified by reverse phase preparative high performance liquid chromatography, employing a Phenomenex Prodigy 250 mm×21.2 mm 5 μm column and a 5% acetonitrile/95% water/0.1% trifluoroacetic acid to 100% acetonitrile gradient over 40 minutes. After concentration, N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide is provided.
Reaction SMILES: O[CH2:2][C:3]1[C:7]([CH3:8])=[N:6][O:5][N:4]=1.Cl.[NH2:10][CH2:11][CH2:12][SH:13]>Br>[CH3:8][C:7]1[C:3]([CH2:2][S:13][CH2:12][CH2:11][NH2:10])=[N:4][O:5][N:6]=1
Reactant: NCCS
Reactant: Cc1nonc1CO
Agent: Br
Agent: Cl
Product: Cc1nonc1CSCCN
Reaction time: 40 h

Procedure:
A solution of 3-hydroxymethyl-4-methylfurazan (2.49 g; 21.8 mmoles) [prepared in Step A] and 2-aminoethanethiol hydrochloride (2.48 g; 21.8 mmoles) in 60 ml of 48% aqueous hydrobromic acid was stirred and heated at reflux temperature for 23 hours and then at ambient temperature for 40 hours. The excess hydrobromic acid was removed under reduced pressure, and the oil residue was dissolved in isopropyl alcohol, filtered though Celite and the product was crystallized from the filtrate. Recrystallization from isopropyl alcohol yielded the title compound as the hydrobromide salt, mp 142°-143°.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:27]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:40][C:41]([F:44])([CH3:43])[CH3:42])(=O)=O>CN(C=O)C>[F:20][C:14]1[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:27]3)[C:18]=2[CH:17]=[C:16]([O:19][CH2:40][C:41]([F:44])([CH3:43])[CH3:42])[CH:15]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1c(F)cc(O)cc12
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(F)COc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Reaction time: 0.17 h

Procedure:
A vial was charged with (S)-2-amino-4′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (61.0 mg, 0.167 mmol), cesium carbonate (82 mg, 0.251 mmol), and DMF (670 μL). The resulting mixture was stirred vigorously for 10 min, then the vial was placed in large ice-bath for 10 min. 2-fluoro-2-methylpropyl trifluoromethanesulfonate (33.3 μL, 0.201 mmol) was added dropwise and the ice-bath was removed after 5 minutes. The mixture was stirred at for 6 hours, then the mixture was diluted with water (10 mL) and extracted with EtOAc (3×5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 12 g Redi-Sep column, eluting with 5-60% gradient of DCM/MeOH/NH4OH (90:10:1) in DCM to give (S)-4′-fluoro-2′-(2-fluoro-2-methylpropoxy)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off-white solid. Found MS: MH+=439.
Reaction SMILES: N1(N[C:8]([C:10]2[CH:40]=[CH:39][C:13]3[N:14]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:15]([C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:21]=[N:20]5)=[N:16][C:12]=3[CH:11]=2)=[O:9])CCOCC1.[NH2:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[CH:48]=[C:47]([C:52]([OH:54])=[O:53])[CH:46]=[CH:45]2>>[CH:33]1([N:14]2[C:13]3[CH:39]=[CH:40][C:10]([C:8]([NH:41][C:42]4[CH:43]=[C:44]5[C:49](=[CH:50][CH:51]=4)[CH:48]=[C:47]([C:52]([OH:54])=[O:53])[CH:46]=[CH:45]5)=[O:9])=[CH:11][C:12]=3[N:16]=[C:15]2[C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=[N:20]3)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(NN1CCOCC1)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Reactant: Nc1ccc2cc(C(=O)O)ccc2c1
Product: O=C(O)c1ccc2cc(NC(=O)c3ccc4c(c3)nc(-c3ccc5nc(-c6ccccc6)cnc5c3)n4C3CCCCC3)ccc2c1
Yield: 53 %

Procedure:
The general procedure described for Compound 574 was used with 6-amino-naphthalene-2-carboxylic acid (18.7 mg), producing 15 mg of the title compound (53% yield). MS: 618.30 (M+H+) HPLC Procedure A, retention time=16.24 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[I:12](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(O)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([I:12])[CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(N)c(I)c1
Temperature: 55 °C

Procedure:
To a solution of 4-amino-benzoic acid methyl ester (1 g) in 10 mL of acetic acid and 10 mL of CH2Cl2 was added benzyltrimethylammonium dichloroiodate (2.763 g) at ambient temperature. The reaction mixture was heated at 55° C. for 1.5 h. The reaction mixture was concentrated to give the crude 4-amino-3-iodo-benzoic acid methyl ester: MS (m/z) 278.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][C@H:18]2[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][C@@H:17]12>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:16]2[CH2:20][CH2:19][C@H:18]3[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][C@@H:17]23)[CH:12]=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cncc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCN[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CCN(c3cncc(OCc4ccccc4)c3)[C@@H]2C1

Procedure:
3-(Benzyloxy)-5-bromopyridine and (3aS,6aS)-tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (prepared as described in WO2001081347) were processed as described in Example 53B to provide the title compound. MS (ESI) m/z 396 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.[CH:19]1N=C[N:21](C(N2C=NC=C2)=O)[CH:20]=1.C(N)C.CO>>[CH2:20]([NH:21][C:14]([C:7]1([CH3:17])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:8]1)=[O:16])[CH3:19]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Solvent: CO
Product: CCNC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 356 mg CDI (2.20 mmol) and 1.1 mL of a 2.0 solution of ethylamine in methanol (2.2 mmol) produced 334 mg of as N-ethyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](O)=[O:28])=[CH:21][CH:20]=1>O>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4](=[O:18])[C:3]=1[C:27](=[O:28])[CH2:26][CH2:25][C:22]1[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Reactant: O=C(O)CCc1ccncc1
Solvent: O
Product: O=C(CCc1ccncc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Temperature: 150 °C
Yield: 51 %

Procedure:
A mixture of 4-hydroxy-1-phenyl-1,8-naphthyridin-2 (1H)-one (2.0 g, 8.4 mmol; synthesized according to JP, A, 61-246183 (1986)), 3-(pyridin-4-yl)propionic acid (19.03 g, 126 mmol, 15 eq.) and polyphosphoric acid (about 100 ml) was heated overnight at 150° C. while stirring. The mixture was poured into water with stirring to form a solution while it was occasionally cooled. The operation including 3 times washing of the aqueous layer with chloroform, then addition of saturated aqueous sodium hydrogen carbonate followed by occasional extraction with chloroform was repeated until the aqueous layer was made pH3 to 3.5. The organic layers which were collected during neutralizing were pooled, dried over anhydrous magnesium sulfate, and then evaporated to give a residue which was purified by flash column chromatography to afford 4-hydroxy-3-[1-oxo-3-(pyridin-4-yl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (1.59 g, 51%) as crystals.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[OH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[OH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: OCc1ccc(B(O)O)cc1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccc(CO)cc3)nc2c1
Yield: 77.4 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4-(hydroxymethyl)phenylboronic acid (66.12 mg, 0.43 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) afforded 80 mg (76%) of 3-(4-(hydroxymethyl)phenyl)-2-phenylquinoxaline-6-carboxylic acid as a light yellow solid.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:21]1([C:27]2[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[C:27]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:28]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: COC(=O)C(Oc1cccc(-c2ccccc2)c1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
In a similar manner as in Example 39, 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate is reacted with 4.25 g of 3-phenylphenol in methanol to give a yellow oil, which is subjected to fractional bulb-to-bulb distillation (175°-178° C. @ 0.02 mm) to remove volatile impurities. The glassy residue is subjected to filtration through 200 g of silica gel (benzene) and concentration to yield the product as an orange foam.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](O)=[C:9]([C:14]#[N:15])[CH:10]=[N:11]2)=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:21].P(Cl)(Cl)(Cl)=O>CCCCCC>[Cl:21][C:8]1[C:7]2[C:12](=[CH:13][C:4]([O:3][CH2:1][CH3:2])=[C:5]([N+:17]([O-:19])=[O:18])[CH:6]=2)[N:11]=[CH:10][C:9]=1[C:14]#[N:15]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOc1cc2ncc(C#N)c(O)c2cc1[N+](=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CCOc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Yield: 58.2 %

Procedure:
A mixture of 3.45 g (13 mmol) of 7-Ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 5.55 g (26 mmol) of phosphorous pentachloride, and 10 ml of phosphorous oxychloride was refluxed for 3 hours. The mixture was diluted with hexane and the solid was collected. The solid was dissolved in 500 ml of ethyl acetate and washed with cold diluted sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel. The solvent was removed giving 2.1 g of beige solid: mass spectrum (electrospray, m/e) M+H 277.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[N+:15]([O-])=O.CO>ClCCl.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:5][C:4]=1[NH2:15]
Reactant: COc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(N2CCOCC2)cc1N
Yield: 87.7 %

Procedure:
4-(4-Methoxy-3-nitro-phenyl)-morpholine (6 g) is hydrogenated in dichloromethane (100 ml) and methanol (600 ml) using palladium on carbon (10%, 600 mg) for 12 hours. The catalyst is removed by filtration and the solution evaporated in vacuo. Purification by flash chromatography (silica, eluent ethyl acetate/n-hexane 1:1, then) affords the product as off-white solid (4.6 g, 88%). MS: m/e=209 (M+H+).