Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=3[C:9]=2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28][O:29][CH2:30]Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:28][O:29][CH3:30])[C:11]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=3[C:9]=2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(Cl)cc3)c(C3CCCCC3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1c(-c2ccc(Cl)cc2)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A solution (0.20 M) of methyl 5-(4-chlorophenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in DMF was treated at 0° C. with NaH (1.5 eq., 60% dispersion in mineral oil), and the suspension was stirred at RT for 45 min then cooled again to 0° C., and treated with chloromethyl methyl ether (5 eq.). The reaction mixture was stirred at RT for 1.5 h then was cooled at 0° C. and quenched with aqueous NaHCO3 (saturated solution) and extracted with AcOEt. The combined organic phase was washed with brine and dried. Evaporation of the solvent under reduced pressure gave a residue that was purified by flash chromatography on silica gel (1:9 acetone/toluene) to afford methyl 5-(4-chlorophenyl)-6-cyclohexyl-4-(methoxymethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (100%). This compound was dissolved in THF/MeOH (2:3), and the resulting solution (0.08 M) was treated at RT with aqueous NaOH (2N solution, 5 eq.). The mixture was heated at 85° C. for 1.5 h. After cooling down, the reaction mixture was concentrated and acidified to pH 1 with aqueous HCl (1 N) and extracted with AcOEt. The combined organic phase was washed with brine and dried. Evaporation of the solvent under reduced pressure afforded the title compound (96%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[CH:12][N:11]=2.S(=O)(=O)(O)O>O.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:8](=[O:9])[CH2:3][CH2:2][CH3:7])=[CH:12][N:11]=2
Reactant: Fc1ccccc1-c1nc2cccnc2o1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCCC(=O)c1cnc2oc(-c3ccccc3F)nc2c1

Procedure:
Using the procedure described in Example 1, but replacing 2-phenyloxazolo[4,5-b]pyridine by 2-(2-fluorophenyl)oxazolo[5,4-b]pyridine (J. Med. Chem. 1978, 21, 11, 1158+) and using 8.4 ml of concentrated sulfuric acid in 16.8 ml of water and 16.8 ml of acetic acid, and after purification on a column of silica (40 to 63μ; 70-230 mesh; eluent: ethyl acetate/toluene, 1:9), the product of the title is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:17][O:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:25]([NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: ClCCl
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1
Reaction time: 0.75 h
Yield: 102.5 %

Procedure:
To a solution of t-Butyl 4-amino-3-methoxyphenylacetate (0.123 g, 0.52 mmol) in methylene chloride (2.0 mL) was added phenyl isocyanate (60 μL, 0.55 mmol). The reaction was stirred for 45 min then concentrated to afford t-butyl 3-methoxy-4-phenylureidophenylacetate (0.190 g, 100%) as a pale yellow foam: 1H NMR (CDCl3, 300 MHz, ppm) 8.00 (d,11 Hz, 1H) 7.65–6.94 (m, 7H), 6.80 (d, 9.0 Hz, 1H), 6.74 (s, 1H), 3.68 (s, 3H), 3.45 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH2:10][N:9]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CC=C(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CC=C(C)C)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperdine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine4-carboxylic acid ethyl ester (6.2 g, 16 mmol) dissolved in ethanol (15 mL), 10 N sodium hydroxide (10 mL) and tetrahydrfuran (75 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.2 g (21%). brown solid mp 196-197° C., MS: 367.9 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[N:40]([CH:41]=3)[CH:39]=[CH:38][S:37]4)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[N:40]([CH:41]=3)[CH:39]=[CH:38][S:37]4)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn4ccsc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn4ccsc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[N+]=[N-])=[CH:3][CH:2]=1.[CH3:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH3:18]>>[CH2:13]([CH:14]1[CH:15]([CH2:16][CH2:17][CH3:18])[N:7]1[C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)[CH2:12][CH3:11]
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Reactant: CCC/C=C/CCC
Product: CCCC1C(CCC)N1c1ccc(C)cc1

Procedure:
p-Tolyl azide (0.113 g, 0.852 mmol), trans-4-octene (3.705 g, 33.0 mmol), and [(Me,EtTCPh)Fe(NCCH3)2](PF6)2 (0.0118 g, 0.0085 mmol) were used in the General Catalytic Reaction described above yielding 0.055 g, 30%. 1H NMR (CDCl3, 499.74 MHz): δ 7.02 (d, J=7.5 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 2.28 (s, 3H), 2.03 (t, J=5.5 Hz, 2H), 1.62 (m, 2H), 1.53 (m, 4H), 1.10 (m, 2H), 0.96 (t, J=7.0 Hz, 6H) 13C NMR (CDCl3, 125.66 MHz): δ 148.10, 130.91, 129.36, 120.95, 44.99, 33.29, 21.11, 20.80, 14.18. GC/MS (m/z): 217.2. DART HR MS (m/z): [M+H]+218.1901 (found). C5H24N, 218.1909 (calcd).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:36]1[C:37]([O:47][CH3:48])=[C:38]([O:45][CH3:46])[CH:39]=[C:40]([C:42](=[O:44])[CH3:43])[CH:41]=1)#[N:35]>O1CCCC1>[Br:1][CH2:43][C:42]([C:40]1[CH:39]=[C:38]([O:45][CH3:46])[C:37]([O:47][CH3:48])=[C:36]([CH:41]=1)[C:34]#[N:35])=[O:44]
Reactant: [Br-]
Reactant: COc1cc(C(C)=O)cc(C#N)c1OC
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)CBr)cc(C#N)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.48 g or phenyltrimethylammonium bromide dibromide dissolved in 30 ml of tetrahydrofuran are added dropwise at room temperature within 45 minutes to 1.9 g of 5'-cyano-3',4'-dimethoxyacetophenone dissolved in 30 ml of tetrahydrofuran, whereupon the mixture is stirred for 30 minutes. Thereupon, the reaction mixture is poured into 120 ml or ice-water and extracted three times with 70 ml of methylene chloride. The combined methylene chloride phases are washed with 2N sulfuric acid, dried over sodium sulfate and evaporated. The residue is chromatographed on 20 g of silica gel with methylene chloride. After recrystallization from methylene chloride/hexane there is obtained 5-(bromoacetyl)-2,3-dimethoxybenzonitrile of m.p. 138°-141°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]([NH2:24])=[O:23])[S:21][C:14]=12>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:13]1[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]([NH2:24])=[O:23])[S:21][C:14]=13)=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: NC(=O)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(N)=O)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid amide by a procedure analogous to Example 1C. MS: 323 (MH+); HPLC Rf: 3.65 min; HPLC purity: 98%.
Reaction SMILES: [C:1]1([C:7]([CH2:18][C:19]([CH3:21])=[CH2:20])([C:13](OCC)=O)[C:8]([O:10]CC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CCO.O>[CH3:13][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH2:18][C:19]([CH3:21])=[CH2:20])[C:8]([OH:10])=[O:9]
Reactant: C=C(C)CC(C(=O)OCC)(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C(C)CC(C)(C(=O)O)c1ccccc1
Reaction time: 24 h

Procedure:
A solution of diethyl 2-phenyl-2-(2-methyl-2-propenyl)malonate (1.63 g, 5.6 mmole) in 20 mL of EtOH and 5 mL of H2O was treated with NaOH (2 g), and refluxed for 3 hours. The reaction was cooled, diluted with H2O, and washed with Et2O. The aqueous layer was acidified and extracted with CH2Cl2. The extracts were dried and evaporated. The residue was dissolved in 5 mL of dimethylacetamide and heated to 125° for 1 hour. The reaction was cooled, diluted with H2O, acified, and extracted with Et2O. The extracts were washed with H2O, dried, and the solvent removed. The residue was dissolved in 10 mL of MEOH, a drop of concentrated H2SO4 was added, and stirred for 24 hours. The reaction was diluted with H2O, and extracted with Et2O. The extracts were washed with H2O, aqueous NaHCO3, dried and the solvent removed, and gave the titled compound, 953 mg (83%). MS (ESI) 205 (MH+)
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1)C>O1CCCC1.O>[O:4]=[CH:5][CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1
Reactant: CCOC(COc1ccc(CC2SC(=O)NC2=O)cc1)OCC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=CCOc1ccc(CC2SC(=O)NC2=O)cc1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
20 ml of 6N aqueous hydrochloric acid were added to a solution of 10.07 g of 5-[4-(2,2-diethoxyethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Preparation 46) in 80 ml of tetrahydrofuran, and the resulting mixture was allowed to stand overnight at room temperature. At the end of this time, the reaction reduced pressure. The residue was diluted with water, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 5.92 g of the title compound having Rf=0.37 (on silica gel thin layer chromatography using a 1:2 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [F:1][CH:2]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:11]3[C:6](=[CH:7][C:8]([F:16])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[C:3]1=[O:17].[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O>C(O)(=O)C>[F:1][CH:2]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:11]3[C:6](=[CH:7][C:8]([F:16])=[CH:9][C:10]=3[N+:18]([O-:20])=[O:19])[CH2:5][C:4]=2[C:3]1=[O:17]
Reactant: CC1=CC(F)C(=O)C2=C1c1ccc(F)cc1C2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1=CC(F)C(=O)C2=C1c1c(cc(F)cc1[N+](=O)[O-])C2

Procedure:
Treatment of 2,7-difluor-4-methyl-9H-fluorenone in acetic acid with a mixture of nitric acid and sulfuric acid gave 2,7-difluoro-4-methyl-5-nitro-9H-fluorenone as the major product. 5-Amino-2,7-difluoro-4-methyl-9H-fluorenone was obtained by reduction using tin(II)chloride in a mixture of ethanol and aqueous hydrochloric acid. Thermal decomposition in hot xylene of the diazonium tetrafluoroborate, formed with sodium nitrite in aqueous fluorboric acid, provided 2,4,7-tri-fluoro-5-methyl-9H-fluorenone. Treatment of the ketone with potassium cyanide and ammonium carbonate in ethanol at 120° C. for 18 hours provided the title compound.
Reaction SMILES: COC[S:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[CH:7][CH:6]=1>C1COCC1.CCO.[N+]([O-])([O-])=O.[Ag+]>[SH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: COCSc1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(S)cc1
Temperature: 40 °C
Reaction time: 21 h

Procedure:
A solution of 2-(4-methoxymethylsulfanylphenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 77, 1.29 g, 3.28 mmol) in THF (50 mL) was added to a stirred solution of AgNO3 (0.59 g, 3.28 mmol) in EtOH (85 mL) at 40° C. The mixture was protected from light and stirred at 40° C. for 21 h. The solvents were evaporated off under reduced pressure, then the remaining solid was triturated with i-PrOH (60 mL), THF (60 mL), and Et2O (60 mL). After air-drying, the solid was stirred vigorously with CH2Cl2 (200 mL) and 6M HCl (82 mL) for 4 h under Ar. The layers were separated, then the aqueous phase was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were filtered through Celite, washed with brine (100 mL) and dried (MgSO4). Filtration and solvent evaporation furnished 2-(4-mercaptophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide: m/z (ES+)=349.2 [M+H]+. NEt3 (0.14 mL, 1006 μmol) and a solution of 4-iodomethyltetrahydropyran (151 mg, 668 μmol) in anhydrous DMF (3 mL) were added to a stirred solution of this benzenethiol (197 mg, 565 μmol) in anhydrous DMF (7 mL) at 0° C. The mixture was warmed to 20° C., before being stirred for 16 h. The solvents were evaporated off under reduced pressure, then the residue was partitioned between CH2Cl2 (25 mL) and 2% aqueous citric acid (10 mL). The aqueous layer was extracted with CH2Cl2 (10 mL), then the combined organic layers were washed with H2O (10 mL), saturated aqueous Na2CO3 (10 mL), H2O (10 mL), and brine (10 mL). After drying (MgSO4), filtration and solvent evaporation gave a residue that was subjected to flash chromatography (IH-EtOAc, 3:1 to 0:1) to furnish the title compound: RTA=3.61 min; m/z (ES+)=447.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26](F)[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1>>[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26]([NH:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5])[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(CN)CO
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(NCC(C)(C)CO)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials 3-amino-2,2-dimethylpropan-1-ol was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(3-hydroxy-2,2-dimethylpropyl)amino]-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 0.88 (s, 6H), 2.29 (s, 3H), 2.83 (m, 1H), 3.06 (d, 2H), 3.20 (s, 2H), 6.78 (m, 2H), 7.19 (s, 1H), 7.28 (d, 1H), 7.57 (d, 1H), 7.89 (s, 1H), 7.98 (d, 1H), 8.38 (d, 1H), 9.89 (s, 1M); Mass Spectrum: M+Na+ 463.
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:9][CH2:10]O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:9][CH2:10][Br:2]
Reactant: OCCc1ccc(Cl)c(Cl)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CCBr)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Phosphorus tribromide (2.17 g) was added, dropwise, to a solution of 3,4-dichlorophenethyl alcohol (4.26 g) in carbon tetrachloride (30 ml). The mixture was stirred at room temperature for 10 minutes then heated under reflux for 2 hours. 5% Aqueous sodium carbonate (10 ml) was added dropwise and the mixture was extracted with dichloromethane (3×70 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a yellow oil which was purified by column chromatography on silica eluting with dichloromethane containing hexane (30% down to 0%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil, yield, 1.8 g.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].FC(F)(F)C(O)=O>ClCCl>[CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(c2)N(S(C)(=O)=O)CCO3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCOc2ccc(CN3CCNCC3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.2 %

Procedure:
tert-Butyl 4-(4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)piperazine-1-carboxylate (2.5 g, 6.1 mmol) was dissolved in dichloromethane (50 mL) and treated with trifluoroacetic acid (182 mmol). The resulting mixture was stirred at ambient temperature for 3 h then evaporated to dryness under reduced pressure. The residue was extracted with hot ethanol and the combined extracts evaporated to dryness under reduced pressure. Chromatography on SiO2, eluting with 0.880 ammonia/methanol/dichloromethane (1:9:90), gave the title compound (1.2 g, 63%) as an off-white solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]1([NH:13][C:14]2[C:23]3[C:18](=[CH:19][N:20]=[CH:21][CH:22]=3)[C:17]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:16]=3[N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C)C=O.O>[C:7]1([NH:13][C:14]2[C:23]3[C:18](=[CH:19][N:20]=[CH:21][CH:22]=3)[C:17]3[CH:24]=[CH:25][C:26]([C:28]4[NH:29][N:3]=[N:2][N:1]=4)=[CH:27][C:16]=3[N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)nc(Nc1ccccc1)c1ccncc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Nc2nc3cc(-c4nnn[nH]4)ccc3c3cnccc23)cc1
Temperature: 120 °C
Yield: 49.1 %

Procedure:
Sodium azide (65 mg, 1 mmol) and ammonium chloride (53 mg, 1 mmol) were added to a crude mixture of the 5-(phenylamino)benzo[c][2,6]naphthyridine-8-carbonitrile (25 mg, 0.084 mmol) in dimethylformamide (0.2 mL). The mixture was heated for 18 h at 120° C. at which time LCMS analysis indicated the absence of any starting material. The mixture was diluted with water and purified by preparative HPLC to give N-phenyl-8-(1H-tetrazol-5-yl)benzo[c][2,6]naphthyridin-5-amine (14 mg). LCMS (ESI) 340.3 (M+1)+. 1HNMR (400 MHz, CD3OD) 10.11 (1H, s), 8.96 (1H, d, 5.9 Hz), 8.85 (1H, d, 8.2 Hz), 8.53 (1H, d, 5.5 Hz), 8.47 (1H,$), 8.16 (1H, d, 8.6 Hz), 7.88 (1H, s), 7.86 (1H, d, 0.8 Hz), 7.57-7.51 (3H, m), 7.36-7.31 (2H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)#[CH:2].Br[C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15].C(N(CC)CC)C>ClCCl>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:24]2[CH:25]=[CH:11][CH:12]=[C:13]([C:14](=[O:15])[C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:23]=2)=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: O=C(c1ccc(F)cc1)c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1cccc(C#Cc2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Into a 500 mL, 3-neck, round-bottom flask equipped with a magnetic stirrer, a thermocouple, and a condenser were placed 24.00 g (200.0 mMol) of 1-ethynyl-4-fluorobenzene (see examples A1 or A2), 55.82 g (200.0 mMol) of 3-bromo-4′-fluorobenzophenone (Rieke Metals, Inc.), 3.0 g of tetrakis(triphenylphosphine)palladium[0], and 300 mL of de-aerated triethylamine. The reaction mixture was heated to 80° C. with stirring under argon for 3 hr and then cooled to ambient; stirring was continued overnight (approximately 16 hr). The reaction mixture was filtered to remove a white precipitate of triethylamine hydrobromide. The triethylamine solvent was evaporated and the solids obtained dissolved in dichloromethane. The resulting solution was washed with water (2×100 mL), 2% HCl (2×100 mL), brine, and then dried over sodium sulfate. After removal of the solvent, the product was purified by silica gel column chromatography using hexanes as the elutant. After removal of the solvent, white crystals with a melting point of 127-128° C. were obtained in a yield of 85%.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]2[CH:14]=1)[CH2:2][C:3]#[CH:4].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][F:23])[N:17]=1>>[Cl:13][C:12]1[C:7]2[N:8]([CH:14]=[C:5]([CH2:1][CH2:2][C:3]#[C:4][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][F:23])[N:17]=3)[N:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C#CCCc1cn2cccc(Cl)c2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCc2cn3cccc(Cl)c3n2)n1
Yield: 54.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-8-chloro-imidazo[1,2-a]pyridine (500 mg, 2.44 mmol, Example 255(B)); and 2-bromo-6-(fluoromethyl)pyridine (487 mg, 2.57 mmol, Example 190(E)). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 420 mg (1.34 mmol, 55%) of 8-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine as a slightly yellow solid (M.P.=73-74.5° C.).
Reaction SMILES: [NH2:1][CH:2]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>C1COCC1>[C:26]([NH:1][CH:2]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:28])[CH3:27]
Reactant: CCOC(=O)C(N)c1ccc(C(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(C)=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(1-amino-2-ethoxy-2-oxoethyl)benzoic acid, as described in Example 1, Step B, (0.94 g, 2.79 mmol) and DIPEA (1.509 mL, 8.64 mmol) were suspended in THF (4 mL) and acetic anhydride (0.289 mL, 3.07 mmol) was added. The mixture was stirred at room temperature overnight. 2N HCl was added and the products extracted into EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by prep-HPLC to give the desired product as a white powder. 1H NMR (DMSO-d6, 600 MHz) δ 13.00 (br s, 1H), 8.77 (d, J=7.2 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 5.45 (d, J=7.2 Hz, 1H), 4.07 (m, 2H), 1.88 (s, 3H), 1.09 (t, J=7.2 Hz, 3H). MS: cal'd 266 (MH+), exp 266 (MH+).