Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH:12][C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=O)=O.[CH2:22]([CH2:24][NH2:25])[OH:23]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:25]([CH2:24][CH2:22][OH:23])[C:15](=[O:17])[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=1
Reactant: COc1ccccc1CC(=O)Nc1ccccc1C(=O)O
Reactant: NCCO
Solvent: Cc1ccccc1C
Product: COc1ccccc1Cc1nc2ccccc2c(=O)n1CCO
Temperature: 180 °C
Yield: 22 %

Procedure:
A suspension of 3.0 g (10 mmol) of methyl ester of N-(2-methoxyphenylacetyl)anthranilic acid and 1.2g (20 mmol) of monoethanolamine in xylene was heated at 180° C. for 16 hours in a sealed tube. After cooling, the precipitated crystals were collected by filtration to obtain 0.7 g (22%) of 2-(2-methoxyphenylmethyl)-3-(2-hydroxyethyl)- 4(3H)-quinazolinone (m.p.: 154°-155° C.). Subsequently, to 0.7 g (2.2 mmol) of this 3-(2-hydroxyethyl) derivative was added thionyl chloride (5 ml) and the resulting reaction mixture was stirred at room temperature for 1 hour. An excess of the thionyl chloride was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent:dichloromethane) to obtain 0.14 g (20%) of 2-(2-methoxyphenylmethyl)-3-(2-chloroethyl)-4(3H)-quinazolinone. (m.p.: 109°-111° C.).
Reaction SMILES: N1N=C(S(CC2C=CC(C(O)=O)=CC=2)=O)NC=1.[N:18]1[N:19]=[C:20]([S:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=2)(=[O:25])=[O:24])[NH:21][CH:22]=1.[Cl:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][C:38]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>>[N:18]1[N:19]=[C:20]([S:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([NH:41][C:40]3[CH:42]=[CH:43][C:37]([Cl:36])=[C:38]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=4)[CH:39]=3)=[O:33])=[CH:34][CH:35]=2)(=[O:24])=[O:25])[NH:21][CH:22]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(CS(=O)(=O)c2nnc[nH]2)cc1
Agent: O=C(O)c1ccc(CS(=O)c2nnc[nH]2)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CS(=O)(=O)c2nnc[nH]2)cc1

Procedure:
107 mg of a mixture of 4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid was coupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. The mixture was separated on reverse phase HPLC to give 4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 454.3 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].[CH2:11]([N:13](CC)[CH2:14][CH3:15])[CH3:12].Cl[CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21].N1CCCC1>O1CCCC1>[Br:7][C:5]1[S:4][C:3]([C:8]([NH2:10])=[O:9])=[C:2]([NH:1][C:20](=[O:21])[CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:13]2[CH2:14][CH2:15][CH2:12][CH2:11]2)[CH:6]=1
Reactant: CCN(CC)CC
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: NC(=O)c1sc(Br)cc1NC(=O)C(c1ccccc1)N1CCCC1
Temperature: 25 °C

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (221 mg) produced in Example 1, step D, triethylamine (0.153 mL) and tetrahydrofuran (5.0 mL) was added chloro(phenyl)acetylchloride (0.174 mL) with stirring at room temperature. The reaction mixture was stirred for 10 min, and pyrrolidine (0.42 mL) was added. The reaction mixture was stirred with heating at 70° C. for 1 hr, and the reaction system was concentrated under reduced pressure. To the residue was added 2M aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred with heating at 120° C. for 2 hr. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane). The obtained yellow solid was washed with ethyl acetate (2 mL) to give the title compound (330 mg) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH2:8]=[C:9]([CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15])[C:10]([OH:12])=[O:11]>C1(C)C=CC=CC=1.C(#N)C>[CH:1]1([CH2:4][S:5]([CH2:8][CH:9]([CH2:13][C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])[C:10]([OH:12])=[O:11])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: O=S(O)CC1CC1
Reactant: C=C(CC(=O)N1CCOCC1)C(=O)O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)CC1CC1
Temperature: 85 °C
Reaction time: 4.5 h
Yield: 40.1 %

Procedure:
To a solution of cyclopropylmethylsulphinic acid (1.8 g, 15 mmol) in anhydrous toluene (45 mL) and anhydrous acetonitrile (9 mL) was added 2-Methylene4-morpholin-4-yl-4-oxo-butyric acid (2.98 g, 15 mmol). The resulting solution was warmed to 85° C. and stirred at this temperature for 4.5 h. The heterogeneous reaction mixture is then allowed to cool to room temperature then concentrated under reduced pressure. The residue is then purified by flash chromatography eluting with 7% methanol in dichloromethane to give 2-Cyclopropylmethanesulfonylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (1.92 g) as viscous oil which was re crystallized from hot ethyl acetate to give a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[F:17][C:18]1[CH:27]=[C:26]([CH:28]=O)[C:21]2[O:22][CH2:23][O:24][CH2:25][C:20]=2[CH:19]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([N:1]=[CH:28][C:26]3[C:21]4[O:22][CH2:23][O:24][CH2:25][C:20]=4[CH:19]=[C:18]([F:17])[CH:27]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1cc(F)cc2c1OCOC2
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1cc(F)cc2c1OCOC2
Yield: 60 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (100 mg) was then suspended in EtOH (4 mL) and 6-fluoro-4H-1,3-benzodioxine-8-carbaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain A29 as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (103 mg, 60% yield).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:14])[CH:20]=3)[C:10]=2[O:9]1
Reactant: CNCC1Cc2cccc(Br)c2O1
Reactant: Cc1cccc(B(O)O)c1
Product: CNCC1Cc2cccc(-c3cccc(C)c3)c2O1

Procedure:
The title compound was prepared (0.059 g, 26%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 3-methylphenylboronic acid (0.169 g, 1.24 mmol). mp 157-159° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:5]2[CH2:6][N:7]([CH2:10][CH2:11][C:12]#[N:13])[CH2:8][CH2:9][N:4]2[N:3]=1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1>>[Br:22][C:20]1[CH:21]=[C:16]([NH:1][C:2]2[CH:14]=[C:5]3[CH2:6][N:7]([CH2:10][CH2:11][C:12]#[N:13])[CH2:8][CH2:9][N:4]3[N:3]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: N#CCCN1CCn2nc(N)cc2C1
Product: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(CCC#N)C3)c1=O
Yield: 63.1 %

Procedure:
Following the procedure of Example 309c, and starting with 338b (120 mg, 0.63 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (169 mg, 0.63 mmol) afforded 338c as a yellow solid (150 mg, 63%). MS-ESI: [M+H]+ 377.2
Reaction SMILES: [CH2:1]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](O)=[O:16])=[CH:14][C:9]=2[N:8]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]1=[O:23])[CH2:2][CH:3]([CH3:5])[CH3:4].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:34]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47]([O:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53])=[O:48])[CH2:35][CH:36]([CH3:38])[CH3:37]>C(Cl)Cl.CN(C)C=O>[CH2:1]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([C:43]3[CH:44]=[CH:45][C:40]([O:39][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[C:41]([CH2:46][C:47]([O:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53])=[O:48])[CH:42]=3)=[O:16])=[CH:14][C:9]=2[N:8]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]1=[O:23])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCn1c(=O)n(CCC(C)C)c2cc(C(=O)O)ccc21
Reactant: CC(C)CCOC(=O)Cc1ccccc1OCCC(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CCOC(=O)Cc1cc(C(=O)c2ccc3c(c2)n(CCC(C)C)c(=O)n3CCC(C)C)ccc1OCCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 0.17 g of 1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid in 9 ml of methylene chloride are added 60 μl of oxalyl chloride and 20 μl of N,N-dimethylformamide successively. The mixture thus obtained is stirred at ambient temperature for 2 hours. Then, 0.42 g of aluminum chloride and 0.38 g of isopentyl 2-(2-isopentyloxyphenyl)acetate are successively added at ambient temperature, and the mixture thus obtained is stirred at the same temperature as above for 30 minutes. The reaction mixture is added to a mixture of methylene chloride and ice water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 0.29 g of isopentyl 2-[5-[(1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)carbonyl]-2-(isopentyloxy)phenyl]acetate as a light yellow oily product.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([O:17]C)[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.Br>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([OH:17])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(O)c2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To 1.5 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methoxy-4-oxo-3-quinolinecarboxylic acid was added 25 ml of hydrogen bromide in acetic acid (32%). The mixture was stirred at room temperature for 16 hours and concentrated to dryness. The residue was triturated with water:ethanol and filtered to give 1.15 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]>C(O)C.[Ni]>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Ni]
Solvent: CCO
Product: Cl
Product: Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 159.7 %

Procedure:
A solution of 5.0 ml (34 mmol) 2-chloro-5-nitrobenzotrifluoride in 100 ml ethanol was hydrogenated at atm. pressure by using Raney-Ni (1 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo. The residue was dissolved in ethanol and the solution was acidified with concentrated hydrochloric acid. The precipitate was filtered off to give 6.3 g (81%) of 4-chloro-3-trifluoromethylaniline, hydrochloride. M.p.>200° C.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9][S:10][CH3:11])(=O)=O.[S:20]([O-:23])([O-:22])=[O:21].[Na+:24].[Na+]>CCO.O>[C:16]([O:15][C:13]([NH:12][C@@H:7]([CH2:8][CH2:9][S:10][CH3:11])[CH2:6][S:20]([O-:23])(=[O:22])=[O:21])=[O:14])([CH3:17])([CH3:18])[CH3:19].[Na+:24]
Reactant: O=S([O-])[O-]
Reactant: CSCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSCC[C@@H](CS(=O)(=O)[O-])NC(=O)OC(C)(C)C
Yield: 33.3 %

Procedure:
(S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butyl methanesulfonate (1.1 g, 3.51 mmol, 1.0 eq) was dissolved in EtOH (10 mL) and water (8.0 mL). Sodium sulfite (2.21 g, 5.0 eq) was added. The mixture was heated to reflux for 16 hours, and concentrated. The residue was purified by reversed phase column (Diaion HP-20) using distilled water (200 ml) first, then 10% CH3CN in water and finally 20% CH3CN in water to give sodium (S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butane-1-sulfonate (376 mg, 37%). 1H NMR (DMSO-d6, 300 MHz) d 6.75 (d, 1H, NH), 3.50 (br s, 1H, BocNHCH), 2.3-2.5 (m, 4H, SCH2 and OSCH2, overlapped with DMSO solvent peak), 2.0 (s, 3H, SCH3), 1.8 (m, 1H, NHCHCH2CH2S), 1.6 (m, 1H, NHCHCH2CH2S), 1.35 (s, 9H, OC(CH3)3). LC-MS: 2.03 min; MS (ESI−) m/z 298 (M-Na)+, 198 (M-Na-Boc)+.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][OH:14])=[CH:5][CH:4]=1
Reactant: NO
Reactant: CN(C)c1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(C=NO)cc1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A solution of 4-(dimethylamino)benzaldehyde (5.0 g), hydroxylamine hydrochloride (2.3 g), and sodium acetate (2.7 g) in ethanol (61 mL)/water (11 mL) is heated at reflux temperature for 1 hour. The mixture is cooled to ambient temperature and partitioned between diethyl ether and water. The aqueous layer is back-extracted with diethyl ether and the combined organic extracts are washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.6 g pure white solid as the product. MS: m/z 165 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]4[CH2:24][CH2:23][N:22](CC5C=CC=CC=5)[CH2:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(Cl)Cl.CO>C(O)(=O)C.[Pd]>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]4[CH2:24][CH2:23][NH:22][CH2:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[O:14])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ncnc2c1CCN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ncnc2c1CCNC2
Yield: 14.9 %

Procedure:
In a round bottom flask, 7-Benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimdine-4-carboxylic acid(adamantan-1-ylmethyl)-amide(1.15 g, 2.74 mmol) was dissolved in glacial acetic acid (10 mL) with stirring and 10% Pd/C (417 mg) was added. The suspension was stirred under an atmosphere of H2 for 16 h. By LCMS and TLC (DCM:MeOH::20:1), no starting material appeared to be present. The desired m/z was observed at 327.3 (M+H). The reaction mixture was then filtered through a pad of celite. The filtrate was concentrated. The resulting oil was re-dissolved in EtOAc (50 mL) with stirring. A 10% NaOH solution (50 mL) was added. The mixture was stirred at RT for 1 h. The layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were filtered through a Horizon Technologies DryDisk and concentrated. The crude oil was chromatographed using DCM/MeOH (0-30% gradient) as elutant affording 0.133 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].C1COCC1.[OH-].[Na+].[N+:22]([C:25]1[CH:40]=[CH:39][C:28]([C:29]([C:31]2[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>CCO>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:35][C:34]1[CH:37]=[CH:38][C:31]([C:29](=[O:30])[C:28]2[CH:39]=[CH:40][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[CH:32][CH:33]=1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc([N+](=O)[O-])cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5-dimethyl-2-mercaptoquinazolin-4-one (2.03 g, 9.74 mmol) in EtOH (30.0 ml)-THF (30.0 ml) was added 1N-aqueous sodium hydroxide solution (10.0 ml). Then, 4-(4-nitrobenzoyl)benzyl bromide (3.50 g, 10.9 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was then distilled off and the residue was dissolved in ethyl acetate and washed with saturated aqueous NaCl solution. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized from methanol to provide light-yellow needles.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:31]=1[CH2:32]Br>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:32][C:31]3[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:30]=3[F:29])[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Product: Cn1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccn(Cc3cc(F)ccc3F)c2c1=O

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 2,5-difluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.65-7.60 (m, 1H), 7.50-7.45 (m, 2H), 7.44-7.38 (m, 1H), 7.13-7.10 (m, 1H), 7.07-6.99 (m, 2H), 6.97-6.89 (m, 1H), 6.03-5.99 (m, 1H), 5.93-5.82 (m, 2H), 5.35-5.32 (m, 1H), 3.66 (s, 3H), 1.02 (s, 9H); LCMS (m/z) ES+=515 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]([SH:24])([CH3:23])[CH3:22].O>CN(C=O)C>[Br:1][C:2]1[C:3]([S:24][C:21]([CH3:23])([CH3:22])[CH3:20])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc([N+](=O)[O-])cc(Br)c1F
Reactant: CC(C)(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1c(Br)cc([N+](=O)[O-])cc1C=O
Temperature: 110 °C
Yield: 104.8 %

Procedure:
A mixture of 3-bromo-2-fluoro-5-nitro-benzaldehyde (1.0 g, 4 mmol), potassium carbonate (667 mg, 4.8 mmol) and 2-methyl-2-propanethiol (326 mg, 0.40 mL, 3.6 mmol) in dry DMF (5 mL) was heated at 110° C. in a sealed tube for 16 h. The reaction was cooled to RT, water was added, and the mixture extracted with dichloromethane (2×30 mL). The combined organic fractions were washed with water (3×15 mL), dried over sodium sulfate, filtered and concentrated to afford 1.2 g of the crude title compound, which was used without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:32])[NH:19][NH:20][C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24](S(C)(=O)=O)[N:23]=2)=[CH:13][CH:12]=1>C1COCC1.C([O-])(O)=O.[Na+]>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:32])[NH:19][NH:20][C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:23]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2[nH][nH]c(=O)c2-c2ccc(F)cc2)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH][nH]c(-c2ccnc(Oc3ccccc3)n2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of phenol (0.66 g, 7.08 mmol) in THF (5 mL) is added NaH (0.24 g, 5.91 mmol) followed by a solution of the crude 4-(4-fluorophenyl)-5-(2-methanesulfonylpyrimidin-4-yl)-1,2-dihydro-pyrazol-3-one, 5, prepared herein above (0.22 g, 0.67 mmol) in THF (2 mL). The reaction mixture is stirred for 1.5 hours at room temperature, diluted with aqueous NaHCO3 and extracted with twice with ethyl acetate. The organic layers are combined, dried over MgSO4, and concentrated in vacuo to afford the crude product which is purified over silica (100% EtOAc, followed by 10% MeOH/EtOAc) to provide the desired product as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:11](I)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[CH2:11]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCI
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCCCOc1cccc([N+](=O)[O-])c1

Procedure:
A mixture of 3-nitrophenol (57.0 g, 0.41 mol), n-hexyliodide (87.0 g, 0.41 mol), potassium carbonate (57.0 g, 0.42 mol) and ethylmethylketone (300 ml) was heated at reflux for 18 h. Water (500 ml) was added and the mixture was extracted with ethyl acetate (2×500 ml). The combined extracts were washed with 8% aqueous sodium bicarbonate (2×250 ml) and brine (250 ml) and then dried (MgSO4) and evaporated to afford a dark brown liquid. Distillation under reduced pressure gave the ether (Intermediate 66) as a mobile yellow liquid (70.3 g, 77%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH:22]4[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]4)[CH2:18]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[N:19]12[CH2:20][CH2:21][CH:22]([CH2:23][CH2:24]1)[CH:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)=[CH:15][CH:14]=1)[CH2:18]2
Reactant: O=[N+]([O-])c1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1
Yield: 73.8 %

Procedure:
The product of Example 15A (300 mg, 0.92 mmol) was treated with Pd/C (Aldrich, wt. 10%, 30 mg) in methanol (20 mL) under H2 at ambient temperature for 30 min. After the reaction was complete, the catalyst was removed through a short column of diatomaceous earth. The filtrate was concentrated under reduced pressure to provide the title compound (200 mg, yield, 74%). 1H NMR (300 MHz, CD3OD) δ 1.44-1.58 (m, 1H), 1.63-1.89 (m, 2H), 1.99-2.13 (m, 1H), 2.15-2.23 (m, 1H), 2.72-3.04 (m, 5H), 3.29-3.39 (m, 1H), 4.50-4.58 (m, 1H), 6.77 (dt, J=8.8, 2.5 Hz, 2H), 6.91 (dt, J=8.8, 2.4 Hz, 2H), 7.32 (dt, J=8.5, 2.5 Hz, 2H), 7.43 (dt, J=9.2, 2.8 Hz, 2H) ppm. MS (DCI/NH3) m/z 295 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[CH:6][CH:7]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]1=[O:16].C(N(CC)CC)C>CN(C)C(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:12]2[CH2:13][CH2:14][CH2:15][NH:9][C:10](=[O:16])[CH2:11]2)=[N:4][CH:3]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O=C1CNCCCN1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CN(c2ccc(Br)cn2)CCCN1

Procedure:
A solution of 3-bromo-6-fluoropyridine (315 mg, 1.79 mmol), 1,4-diazepan-2-one (200 mg, 1.75 mmol), and triethylamine (0.269 ml, 1.93 mmol) in N,N-dimethylacetamide (3 mL) was irradiated in a microwave reactor for twenty minutes at 220° C. The reaction mixture was diluted with ethyl acetate (35 mL) and then washed with saturated aqueous sodium bicarbonate (15 mL), water (3×10 mL), and brine (15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0.5-8.5% methanol/dichloromethane) to afford 4-(5-bromopyridin-2-yl)-1,4-diazepan-2-one. MS ESI calc'd. for C10H13BrN3O [M+H]+ 270 and 272. found 270 and 272. 1H NMR (500 MHz, DMSO-d6): δ 8.14 (d, J=2.4 Hz, 1H), 7.68 (dd, J=9.1, 2.7 Hz, 1H), 7.48 (m, 1H), 6.70 (d, J=9.1 Hz, 1H), 4.11 (s, 2H), 3.85 (s, 2H), 3.18 (m, 2H), 1.62 (m, 2H).