Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[C:18]([C:21]1[CH:26]=[C:25]([C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: O=C(O)c1cccnc1Oc1ccc(Cl)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: CC(=O)c1cccc(-c2ccc(Oc3ncccc3C(=O)O)cc2)c1
Yield: 91.5 %

Procedure:
The general procedure described in Example 3 was used with 2-(4-chloro-phenoxy)-nicotinic acid (250 mg, 1.00 mmol), 3-acetylphenylboronic acid (246 mg, 1.50 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol, 1 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (10.0 mg, 0.020 mmol, 2 mol %), K2CO3 (414 mg, 3.00 mmol), water (2.0 mL), 12 h, 80° C. The product was isolated as a white solid (305 mg, 92%). Mp=188° C. 1H NMR (400 MHz, d 6-DMSO) δ: 8.27 (m, 2H), 8.20 (s, 1H), 7.93 (d, 2H, J=7.6 Hz), 7.77 (d, 2H, J=8.8 Hz), 7.61 (t, 1H, J=7.6 Hz), 7.23 (m, 3H), 2.66 (s, 3H). 13C NMR (125 MHz, d6-DMSO) δ: 198.0, 166.0, 160.7, 153.9, 150.3, 141.5, 140.0, 137.5, 135.6, 131.3, 129.4, 128.2, 126.9, 126.4, 121.9, 119.1, 117.2, 26.9. IR (neat, cm−1): 3000-4000 (br), 1674, 1651, 1585, 1418, 1231, 896, 770. Anal. Calcd for C20H15NO4: C, 72.06; H, 4.54. Found: C, 71.68; H, 4.41.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].[NH2-].[Na+].N.Cl.[NH2:13][CH2:14][CH2:15][CH2:16]Cl>O>[NH2:13][CH2:14][CH2:15][CH2:16][CH2:8][C:2]1[C:3]([CH3:7])=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: NCCCCl
Reactant: Cc1cccnc1C
Agent: Cl
Agent: N
Agent: [NH2-]
Solvent: O
Product: Cc1cccnc1CCCCN
Reaction time: 8 h
Yield: 62.3 %

Procedure:
2,3-Lutidine (321 g) was added with stirring to a solution of sodamide (351 g) in liquid ammonia (3 l). 1-Amino-3-chloropropane hydrochloride (429 g) was added to this mixture over 8 minutes with stirring. Any liquid ammonia lost through evaporation was replaced. After 2 hours the reaction was quenched by the addition of ammonium chloride (120 g) and the reaction mixture was left to stand overnight to allow substantially complete escape of ammonia through evaporation. The residue so obtained was diluted with water (2 l) and extracted with dichloromethane. The extracts were dried (Na2SO4), the dichloromethane removed by evaporation and the residue distilled in vacuo to give 2-(4-aminobutyl)-3-methylpyridine (306.6 g).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:8][N:7]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:15][CH:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][OH:4])=[N:7][CH:8]=1)[CH3:14]
Reactant: CC(=O)OCc1ccc(OC(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)Oc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
[5-(1-Methylethoxy)pyridin-2-yl]methyl acetate (209 mg) was dissolved in methanol (2.0 mL), added potassium carbonate (276 mg, 2.0 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo, added water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and [5-(1-methylethoxy)pyridin-2-yl]methanol (137 mg (yield 83%)) was obtained as a yellow oil.
Reaction SMILES: NC1C=CC(Cl)=C(C2C=CC(C(OC)=O)=CN=2)C=1.CS(CC1C=CC(C(O)=O)=CC=1)(=O)=O.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:53])[C:42]2[CH:47]=[CH:46][C:45]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:44][CH:43]=2)=[CH:36][C:35]=1[C:54]1[CH:63]=[CH:62][C:57]([C:58](OC)=[O:59])=[CH:56][N:55]=1.[BH4-].[Na+]>CCO>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:53])[C:42]2[CH:47]=[CH:46][C:45]([CH2:48][S:49]([CH3:52])(=[O:50])=[O:51])=[CH:44][CH:43]=2)=[CH:36][C:35]=1[C:54]1[CH:63]=[CH:62][C:57]([CH2:58][OH:59])=[CH:56][N:55]=1
Reactant: COC(=O)c1ccc(-c2cc(NC(=O)c3ccc(CS(C)(=O)=O)cc3)ccc2Cl)nc1
Agent: COC(=O)c1ccc(-c2cc(N)ccc2Cl)nc1
Agent: CS(=O)(=O)Cc1ccc(C(=O)O)cc1
Agent: [BH4-]
Solvent: CCO
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccc(CO)cn3)c2)cc1

Procedure:
75 mL of (5-methylpyridin-2-yl)zinc(II) bromide was reacted with 4 g of 1-chloro-2-iodo-4-nitrobenzene via Procedure B. To 935 mg of 2-(2-chloro-5-nitrophenyl)-5-methylpyridine in 5 mL of Sulfuric Acid was slowly added 2.25 g of Chromium (III) Oxide and the reaction was stirred for several hours at room temperature until complete. Icewater was added to dilute the reaction and the aqueous layer was extracted 3 times with Ethyl Acetate. The organic layers were combined, dried over Magnesium Sulfate, filtered and concentrated to give 6-(2-chloro-5-nitrophenyl)nicotinic acid. 704 mg of 6-(2-chloro-5-nitrophenyl)nicotinic acid was esterified with 3.1 mL of 4N HCl in Dioxane in 20 mL of MeOH. The reaction was concentrated and subjected to basic workup, dried over Magnesium Sulfate, filtered and concentrated to give methyl 6-(2-chloro-5-nitrophenyl)nicotinate. 681 mg of methyl 6-(2-chloro-5-nitrophenyl)nicotinate was treated with 2.1 g of Tin (II) Chloride and 1 mL of HCl in 25 mL of EtOH. Upon completion, EtOH was concentrated and the reaction was extracted with Ethyl Acetate and water with TEA to decrease emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 6-(5-amino-2-chlorophenyl)nicotinate. 296 mg of methyl 6-(5-amino-2-chlorophenyl)nicotinate was coupled to 266 mg of 4-(methylsulfonylmethyl)benzoic acid via Procedure G. To 518 mg of methyl 6-(2-chloro-5-(4-(methylsulfonylmethyl)benzamido)phenyl)nicotinate at 0° C. in 20 mL of EtOH was slowly added 640 mg of Sodium Borohydride. The reaction was subsquently refluxed for 1 hour until complete, quenched with water and extracted with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate, filtered, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(5-(hydroxymethyl)pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 431.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21](=[O:28])[C:22]#[C:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21](=[O:28])/[CH:22]=[CH:23]\[CH2:24][N:25]([CH3:26])[CH3:27])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CN(C)C/C=C\C(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Reaction time: 8 h
Yield: 36 %

Procedure:
A mixture of 0.05 g (0.118 mmol) N-[4[(3-chloro-4-fluorophenyl)amino]-3-cyano-6-quinolinyl]-4-dimethylamino-2-butynamide and 6 mg of Lindlar catalyst in 10 mL of methanol was hydrogenated at room temperature overnight. The mixture was filtered through a pad of Celite. After the solvent was removed, the residue was purified by thin-layer chromatography eluted with 30% methanol in ethyl acetate. The product was dried to give 0.018 g (36%) pale yellow solid; HRMS m/z 423.1270 (M+.).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([C@H:34]([CH3:38])[CH2:35][C:36]#[N:37])[CH2:30][CH2:29]2)=[CH:23][CH:22]=1)[CH3:19].CCN(CC)CC>C(Cl)Cl.CN(C=O)C.C1COCC1>[C:36]([CH2:35][C@H:34]([N:31]1[CH2:30][CH2:29][CH:28]([N:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:18][CH3:19])=[CH:22][CH:23]=2)[C:9](=[O:11])[C:8]2[C:3]([CH3:2])=[CH:4][CH:5]=[N:6][CH:7]=2)[CH2:33][CH2:32]1)[CH3:38])#[N:37]
Reactant: CCOc1ccc(NC2CCN([C@H](C)CC#N)CC2)cc1
Reactant: Cc1ccncc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc(N(C(=O)c2cnccc2C)C2CCN([C@H](C)CC#N)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methyl-nicotinic acid hydrochloride (0.83 g, 4.8 mmol) was suspended in CH2Cl2 (25 mL) with DMF (6 drops). Oxalyl chloride (2.5 mL, 28.8 mmol) was added and the mixture stirred at room temperature for 2 h. The homogenous solution was then concentrated and dried in vacuo. To the solid was added THF (12.5 mL) and a solution of (R)-3-[4-(4-ethoxy-phenylamino)-piperidin-1-yl]-butyronitrile (0.69 g, 2.4 mmol) in THF (12.5 mL). The mixture was treated with Et3N (1.0 mL, 7.2 mmol) and heated to reflux, stirring for 16 h. The reaction was cooled to room temperature, concentrated under reduced pressure, diluted with CH2Cl2 (100 mL) and washed with brine solution (100 mL). The aqueous phase was back-extracted with CH2Cl2 (100 mL) and the combined organic phases rewashed with brine (200 mL). The organic phase was dried (Na2SO4), filtered and concentrated and the crude material purified by flash column chromatography on silica gel (10:1 Et2O/MeOH to afford N-[(R)-1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-N-(4-ethoxy-phenyl)-4-methyl-nicotinamide contaminated with nicotinyl chloride by-product (24%).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[CH3:14][O:15][C:16]1[CH:24]=[C:23]([NH2:25])[C:22]([Cl:26])=[CH:21][C:17]=1[C:18]([OH:20])=O.[CH:27]1([CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH:36]([CH3:41])[CH2:35]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[CH:27]1([CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([NH:40][C:18](=[O:20])[C:17]3[CH:21]=[C:22]([Cl:26])[C:23]([NH2:25])=[CH:24][C:16]=3[O:15][CH3:14])[CH:36]([CH3:41])[CH2:35]2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC1CN(CC2CCCCC2)CCC1N
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
Triethylamine (2.78 ml; 0.02 moles) and ethyl chloroformate (1.9 ml; 0.02 moles) were added successively to a stirred suspension of 2-methoxy-4-amino-5-chlorobenzoic acid (4.0 g; 0.02 moles) in anhydrous tetrahydrofuran (150 ml) whilst maintaining the temperature between -5° and -10° C. After stirring at this temperature for half an hour, a solution of 1-cyclohexylmethyl-3-methyl-4-aminopiperidine (4.2 g; 0.02 moles) in anhydrous tetrahydrofuran (25 ml) was added and, after stirring for 1 hour at -5° to -10° C., the temperature was allowed overnight to reach room temperature. The solvent of the mixture was removed in vacuo, the residue poured into water, extracted with chloroform and the organic layers washed with water. The chloroformic solution was dried (Na2SO4) and the solvent removed in vacuo to give N-(1-cyclohexylmethyl-3-methylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide (3.5 g), m.p. 173°-176° C.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[S:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[O:3]=[CH:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[S:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(-c2cccc(OCC(OCC)OCC)c2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(-c2cccc(OCC=O)c2)s1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Ethyl 5-(3-{[2,2-bis(ethyloxy)ethyl]oxy}phenyl)-2-thiophenecarboxylate (Intermediate KK-2-3) (1.41 g, 3.87 mmol) was dissolved in 20 ml of chloroform and cooled to 0° C. 5 ml of 50% aqueous trifluoroacetic acid solution was added. The mixture was stirred for 15 h at room temperature and 6 h at 65° C., cooled, diluted with chloroform and neutralized with saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (10 to 50% ethyl acetate in hexanes) to afford the title compound as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:54])[NH:22][CH:23]([C:27]([N:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34]1[NH:35][C:36]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)=[CH:37][N:38]=1)=[O:28])[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].COCCOC>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>[CH3:19][O:20][C:21](=[O:54])[NH:22][CH:23]([C:27]([N:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34]1[NH:35][C:36]([C:39]2[CH:40]=[CH:41][C:42]([C:14]3[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18])=[CH:12][CH:13]=3)=[CH:43][CH:44]=2)=[CH:37][N:38]=1)=[O:28])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(Br)cc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(C(=O)CNC(=O)OC(C)(C)C)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
A mixture of [2-(4-Bromo-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (1 g, 3.2 mmol), [2-methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (1.57 g, 3.2 mmol), tetrakis(triphenylphosphine)palladium(0) (183 mg, 0.15 mmol), potassium carbonate (878 mg, 6.5 mmol), 1,2-dimethoxyethane (25 mL) and water (2.5 mL) was stirred at 80° C. for 16 hours. The mixture was cooled and all volatiles were removed under reduced pressure. The resulting residue was taken up in dichloromethane (100 mL) and washed with water (25 mL) and saturated sodium chloride (25 mL). The organic phase was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide [1-(2-{5-[4′-(2-tert-butoxycarbonylamino-acetyl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (869 mg, 1.4 mmol, 44%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:46][O:47][C:48]1[C:49]2[N:62]=[C:61]([NH2:63])[S:60][C:50]=2[C:51]([N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)=[N:52][CH:53]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:63][C:61]2[S:60][C:50]3[C:51]([N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)=[N:52][CH:53]=[C:48]([O:47][CH3:46])[C:49]=3[N:62]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: COCCOc1ccc(C(=O)O)cc1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCCOc1ccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)cc1

Procedure:
From 4-(2-methoxy-ethoxy)-benzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 445 (M+H+, 100).
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:15]=[N:16][N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[K+].O1CCC[CH2:28]1>>[CH3:28][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[N:15]=[N:16][N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:18]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: CC(C)(C)NC(=O)N1CC=C(c2cn(-c3ccccc3)nn2)CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [K+]
Product: CN(C(=O)N1CC=C(c2cn(-c3ccccc3)nn2)CC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-[1-Phenyl-1H-[1,2,3]triazol-4-yl]-1,2,3,6-tetra-hydropyridine-1-carboxylic acid tert-butylamide (15 mg) prepared in Example 74 was added to a solution of 35 mg of potassium hydride in 1 ml of tetrahydrofuran washed with hexane. After stirring at room temperature for 10 minutes, 20 μl of methyl iodide was added thereto and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution followed by extracting with chloroform. The resulting organic layer washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated saline solution, dried over sodium sulfate and the solvent was evaporated in vacuo. The resulting residue was separated and purified by a preparative thin-layer chromatography (chloroform/methanol=20/1+0.3% aqueous ammonia) to give 8.5 mg of the title compound as a white solid
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]([O:17]C)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19]>CO.C1COCC1>[C:1]([NH:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]([NH2:19])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1sccc1NC(=O)c1ccccc1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1sccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 89 %

Procedure:
To a stirred solution of 14.21 g (54.4 mmol) of crude methyl 3-(benzoylamino)-2-thiophenecarboxylate in 100 mL of methanol and 100 mL of THF was added 100 mL of concentrated aqueous ammonia. The mixture was stirred at room temperature for 5 days and an additional 100 mL of concentrated aqueous ammonia was added. After stirring for 5 more days the mixture was rotovapped to remove the bulk of the organic solvents and the residue was extracted with two 125 mL portions of ethyl acetate. The insoluble material was collected by filtration and combined with the residue from evaporating the ethyl acetate extracts to dryness to furnish 11.96 g (89%) of crude 3-(benzoylamino)-2-thiophenecarboxamide as a tan solid. 1H-NMR (d6-DMSO)δ7.55(3H,m), 7.7(1H, d), 7.95(2H,m), 8.18(1H,d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.[CH3:15][NH:16][CH3:17]>O1CCCC1>[CH3:15][N:16]([CH3:17])[C:11](=[O:12])[CH2:10][CH2:9][C:8](=[O:14])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)CCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 30.5 g (0.155 Mol) of 4-fluoro-γ-oxobenzenebutanoic acid in 470 ml tetrahydrofuran, 35.0 g (0.216 Mol) of N,N′-carbonyldiimidazole was added with stirring and at room temperature and held at room temperature for a further 2.5 hours. Then, 13.7 g (0.304 Mol) of dimethylamine was added under strong external cooling by means of an ice-ethanol mixture. After the mixture had stood at room temperature for 12 hours, the solvent was removed in vacuo, the residue was divided between dichloromethane and 10% aqueous citric acid solution, the organic phase was dried over sodium sulphate and once again evaporated down in vacuo. After purification by column chromatography (eluant:ethyl acetate) on silica gel the crude product yielded 30.22 g (87% of theory) of colourless crystals of Rf=0.31 (eluant:ethyl acetate/glacial acetic acid 99.99/0.01).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=1>[Pt](=O)=O.CCO>[OH:1][CH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)CCC#Cc1cccc(CO)n1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)(C)OC(=O)CCCCc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a 200 mL round-bottom flask, 2.76 g of t-butyl 5-(6-hydroxymethylpyridin-2-yl)pent-4-ynoate, 50 mg of platinum dioxide and 25 mL of EtOH were added, the mixture was stirred under hydrogen atmosphere at room temperature for 8 hours. The insoluble material was removed off, and then the filtrate was concentrated to give 2.78 g of t-butyl 5-(6-hydroxymethylpyridin-2-yl)pentanoate as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]=2[N:3]=[CH:2]1.I[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O.[Cu-]=O>[C:23]1([N:1]2[C:9]3[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]=3[N:3]=[CH:2]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1c2nc[nH]c2CCN1C(=O)OC(C)(C)C
Reactant: Ic1ccccc1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1c2ncn(-c3ccccc3)c2CCN1C(=O)OC(C)(C)C
Yield: 50.2 %

Procedure:
A solution of 5-tert-butyl 4-ethyl 6,7-dihydro-1H-imidazo[4,5-c]pyridine-4,5(4H)-dicarboxylate (0.65 g, 2.20 mmol), iodobenzene (0.45 g, 2.20 mmol), copper (I) oxide (0.03 g, 0.22 mmol), 8-hydroxyquinoline (0.06 g, 0.44 mmol), and Cs2CO3 (1.40 g, 4.40 mmol) in DMSO (2 mL) was irradiated in a microwave apparatus for 1 hour at 140° C. The reaction was diluted with H2O (100 mL) and extracted with EtOAc (75 mL×3). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (0.41 g, 50%). MS (ESI): mass calculated for C20H25N3O4, 371.2. m/z found 272.2 [M+H—BOC]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[Cl:25][C:26]1[CH:45]=[CH:44][CH:43]=[CH:42][C:27]=1[CH2:28][O:29][C:30]1[C:39]([Cl:40])=[CH:38][C:33]([O:34][CH2:35][CH:36]=O)=[CH:32][C:31]=1[Cl:41]>C(Cl)Cl.[Zn]>[Cl:25][C:26]1[CH:45]=[CH:44][CH:43]=[CH:42][C:27]=1[CH2:28][O:29][C:30]1[C:39]([Cl:40])=[CH:38][C:33]([O:34][CH2:35][CH:36]=[C:20]([Br:24])[Br:21])=[CH:32][C:31]=1[Cl:41]
Reactant: BrC(Br)(Br)Br
Reactant: O=CCOc1cc(Cl)c(OCc2ccccc2Cl)c(Cl)c1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccccc1COc1c(Cl)cc(OCC=C(Br)Br)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
In a reaction vessel were placed 0.26 g of zinc dust, 1.0 g of triphenylphosphine, 1.3 g of carbon tetrabromide and 20 ml of methylene chloride, followed by stirring at room temperature. After 24 hours, a solution of 0.70 g of (4-(2-chlorobenzyloxy)-3,5-dichlorophenoxy)acetaldehyde dissolved in 5 ml of methylene chloride was added dropwise to the above solution, while stirring at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.63 g of 4-(2-chlorobenzyloxy)-3,5-dichloro-1-(3,3-dibromo-2-propenyloxy)benzene (63% yield), m.p. 83.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O.[CH:24]1([C:27]2[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[N:32]=[C:31]([C:33]3[NH:1][C:2]4=[N:7][C:6]([N:8]5[CH2:13][CH2:12][O:11][C@@H:10]([C:14]([N:16]6[CH2:20][CH2:19][CH2:18][CH2:17]6)=[O:15])[CH2:9]5)=[CH:5][CH:4]=[C:3]4[N:21]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25]1
Reactant: O=Cc1cccc(C2CC2)n1
Reactant: Nc1nc(N2CCO[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Product: O=C([C@H]1CN(c2ccc3nc(-c4cccc(C5CC5)n4)[nH]c3n2)CCO1)N1CCCC1

Procedure:
The title compound was prepared by a method analogous to the one used for Example 112, but using Intermediate 31 and 6-cyclopropylpicolinaldehyde. MS (ES+) (M+H) 418.9; LCMS retention time 2.411 (Method G).