Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:15]3[S@@:14](=O)[C:13]2([CH3:32])[CH3:31])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:35]([N:38]=[C:39]=[O:40])(=[O:37])[CH3:36].[O:41]1CCOCC1>>[N+:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:15]3[S:14][C@:13]2([CH2:32][O:40][C:39](=[O:41])[NH:38][C:35](=[O:37])[CH3:36])[CH3:31])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC1(C)[C@H](C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2[S@]1=O
Reactant: CC(=O)N=C=O
Reactant: C1COCCO1
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 45 %

Procedure:
A solution of (1S,3S,5R,6R) 2,2-dimethyl-6-phenylacetamidopenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester (4.85 g, 10.0 mmol) and acetyl isocyanate (2.3 ml, 30 mmol) in dioxane (50 ml) was refluxed under nitrogen for 7 hours. The light orange solution was concentrated in vacuo to a foam which was chromatogaphed on silica gel (500 g) with methylene chloride:acetone; 9:1, v:v. Two major bands were eluted; the first was the Δ3 3-methylcepham (28%, 1.29 g) and the second was the title compound obtained in 45% yield (2.56 g) as an off-white foam: mp 83°-85°; nmr 100 MHz (CDCl3) ppm 8.24 (2, d, J=9 Hz, 1/2 aromatic AB pNB), 7.61 (2, d, J=9, 1/2 pNB AB), 7.28 (5, s, phenyl), 5.54 (2, m's C6 -C5 -H's), 5.40 (2, br s, pNB methylene), 4.91 (1, s, C3 -H), 4.27 1, d, J=12, 1/2 C2 -CHHO AB), 4.08 (1, d, J=12, 1/2 C2 -methylene AB), 3.12 ##STR73## 2.12 (3, s, acetyl), and 1.41 (3, s, C2 -CH3).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)=[O:15].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[C:36]([F:39])([F:38])[F:37]>C1COCC1.CS(C)=O>[F:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[C:36]([F:37])([F:38])[F:39])[N:18]=1)=[O:15]
Reactant: COc1ccc(CBr)c(C(F)(F)F)c1
Reactant: O=C(Nc1cc[nH]n1)c1ccccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2ccc(NC(=O)c3ccccc3F)n2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 M lithium bis(trimethylsilyl)amide (100 μl, 0.1 mmol, Aldrich) was slowly added to a solution of 2-fluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 43) (20.5 mg, 0.1 mmol) in THF (400 μl). The resulting solution was then transferred to a solution of 1-(bromomethyl)-4-(methyloxy)-2-(trifluoromethyl)benzene 24.7 mg, 0.1 mmol, JRD Fluorochemicals Ltd) in THF (200 μl) and stirred for 2 h under nitrogen at ambient temperature. The mixture was diluted with DMSO (0.6 ml) and purified by MDAP using the Sunfire C18 column (Method D) using Acetonitrile-Water with a TFA modifier. The solvent was removed under a stream of nitrogen to give the title compound (27 mg). LCMS (System 4)
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17][CH2:18]CS([O-])(=O)=O)(=[O:4])=[O:3].[I-].[K+].C(N(CC)C(C)C)(C)C.[CH3:35][O:36][C:37]1[C:38]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[N:39][CH:40]=[N:41][CH:42]=1>C(#N)C.C(Cl)Cl>[CH3:35][O:36][C:37]1[C:38]([N:43]2[CH2:48][CH2:47][N:46]([CH2:18][CH2:17][CH2:16][C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:8]=4)[NH:12][CH:11]=3)[CH2:45][CH2:44]2)=[N:39][CH:40]=[N:41][CH:42]=1
Reactant: CS(=O)(=O)NCc1ccc2[nH]cc(CCCCS(=O)(=O)[O-])c2c1
Reactant: COc1cncnc1N1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(CNS(C)(=O)=O)cc23)CC1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
To a solution of crude 3-[5-[[(methylsulfonyl)amino]methyl]-1H-indol-3-yl]propylmethanesulfonate (15.1 mmol, 1.0 equiv.) in 200 mL of anhydrous acetonitrile were added 2.51 g (15.1 mmol, 1.0 equiv.) of potassium iodide, 3.15 mL of N,N-diisopropylethylamine and 3.23 g of 1-(5-methoxy-4-pyrimidinyl)piperazine. The mixture was heated to reflux for 48 hours. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was dissolved in 250 mL of chloroform, washed with 50 mL portions of 10% aqueous potassium carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield an oil. Chromatography on silica gel using 7.5% methanol in methylene chloride containing 0.75% concentrated aqueous ammonium hydroxide gave 3.93 g (57%) of 4-(5-methoxy-4-pyrimidinyl)-1-[[5-[[(methylsulfonyl)amino]methyl]-1H-indol-3-yl]propyl]piperazine. The hydrochloride was prepared by addition of 3N ethanolic HCl to an ethanolic solution of the base. Recrystallization from ethanol followed by drying in vacuo at 65° C. gave 0.268 g (53%) of the hydrochloride ethanolate: C22H30N6O3S/2.4 HCl/0.4 C2H6O, m.p. 204°-206° C. Elemental analysis calculated C., 48.51; H, 6.21; N, 14.89; found: C., 48.59; H, 6.21; N, 14.95.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][CH2:9][C:10]1[C:11]([NH:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[C:12]2[CH:20]=[N:19][N:18]([CH2:21][CH3:22])[C:13]2=[N:14][C:15]=1[CH2:16][CH3:17])=[O:7].[Br:33][C:34]1[CH:35]=[C:36]([CH2:41][NH:42][CH3:43])[CH:37]=[CH:38][C:39]=1[F:40].CCOC(C)=O>CN(C=O)C>[Br:33][C:34]1[CH:35]=[C:36]([CH2:41][N:42]([CH2:2][C:3]2[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=2)[C:6]([NH:8][CH2:9][C:10]2[C:11]([NH:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[C:12]3[CH:20]=[N:19][N:18]([CH2:21][CH3:22])[C:13]3=[N:14][C:15]=2[CH2:16][CH3:17])=[O:7])[CH3:43])[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: CNCc1ccc(F)c(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CCl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 66 h
Yield: 93.4 %

Procedure:
To a solution of 3-(chloromethyl)-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (0.284 g, 0.623 mmol) in DMF (2.5 mL) was added [(3-bromo-4-fluorophenyl)methyl]methylamine (0.436 g, 2.0 mmol). This mixture was stirred at room temperature for 66 h. Then EtOAc (50 mL) was added and that solution washed with H2O (7.5+2×5 mL), brine (5 mL), dried over Na2SO4. The dried organic solution was filtered, concentrated and purified by CombiFlash chromatograph to afford the title compound 0.371 g (93%). LC-MS m/z 637 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[NH:15][CH2:14][CH:13]2[CH:9]1[CH2:10][C:11]1[CH:18]=[CH:17][S:16][C:12]=12.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(Cl)Cl.[Cl-].[Na+].O>[CH2:23]([O:22][C:20]([N:15]1[CH2:14][CH:13]2[CH:9]([CH2:10][C:11]3[CH:18]=[CH:17][S:16][C:12]=32)[CH2:8]1)=[O:21])[CH3:24]
Reactant: c1cc2c(s1)C1CNCC1C2
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)N1CC2Cc3ccsc3C2C1
Reaction time: 2 h

Procedure:
Triethylamine (741 mg, 7.32 mmol) was added to a solution of the product from step h) (493 mg, 2.44 mmol) in 12 mL of CH2Cl2 at ° C. followed by the addition of ethyl chloroformate (529 mg, 4.88 mmol). The reaction was allowed to come to room temperature and was stirred for two hours. The reaction mixture was diluted with brine (15 mL) and extracted with dichloromethane (3×15 mL). The combined organic extracts were dried with MgSO4 and the solvent was evaporated in vacuo give the crude product that was purified by column chromatography (SiO2) using a 0-30% ethyl acetate-hexane gradient to give the subtitle compound. MS calculated for C12H15NO2S +H: 238, observed: 238.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](Cl)=[O:13])=[CH:10][N:11]=2)[CH:2]=1.C(N(CC)CC)C.Cl.[CH3:23][O:24][NH:25][CH3:26]>C(Cl)Cl.CN(C1C=CC=CN=1)C>[CH3:23][O:24][N:25]([CH3:26])[C:12]([C:9]1[S:8][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:11][CH:10]=1)=[O:13]
Reactant: O=C(Cl)c1cnc(-c2cccnc2)s1
Reactant: CNOC
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cnc(-c2cccnc2)s1
Temperature: 0 °C
Yield: 82.1 %

Procedure:
A suspension of 2-(3-pyridyl)thiazole-5-carbonyl chloride (4.6 g, 19.5 mmol) prepared according to WO 2009/149858) in methylene chloride (100 ml) was cooled to 0° C. and treated with triethyl amine (6.03 g, 58.4 mmol), dimethylamino pyridine (12 mg, 0.097 mmol) and then N-methoxymethanamine hydrochloride (2.9 g, 29.2 mmol). The mixture was allowed to warm up to ambient temperature and monitored by TLC and LC/MS. After completion, the reaction mixture was diluted with methylene chloride, washed with water, dried over magnesium sulfate, and the solvent removed by concentration in vacuo, to give 3.99 g (82%) of N-methoxy-N-methyl-2-(3-pyridyl)thiazole-5-carboxamide as a pale solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][C:4]=1[CH3:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1.C(OC(=O)C)C>[CH3:32][C:4]1[CH:5]=[C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:11])[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:34]([CH3:33])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)c(C)c2)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)c(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a stirred solution of 2-(4-(aminomethyl)-3-methylphenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (83 mg, 0.19 mmol) in pyridine was added methanesulfonyl chloride (0.02 mL, 0.24 mmol) The reaction mixture was stirred for overnight at room temperature. The mixture was diluted with ethylacetate and washed with 1N HCl and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(3-Methyl-4-(methylsulfonamidomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 97) (60 mg) was obtained as 61% yield.
Reaction SMILES: O=C(CCC=C(C)CCC=C(C)CCC=C(C)C)CC(OC)=O.[O:24]=[C:25]([CH2:33][CH2:34][CH:35]=[C:36]([CH3:48])[CH2:37][CH2:38][CH:39]=[C:40]([CH3:47])[CH2:41][CH2:42][CH:43]=[C:44]([CH3:46])[CH3:45])[CH2:26][P:27](=[O:32])([O:30]C)[O:28]C>>[OH:24][CH:25]([CH2:33][CH2:34][CH:35]=[C:36]([CH3:48])[CH2:37][CH2:38][CH:39]=[C:40]([CH3:47])[CH2:41][CH2:42][CH:43]=[C:44]([CH3:46])[CH3:45])[CH2:26][P:27](=[O:28])([OH:32])[OH:30]
Reactant: COP(=O)(CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C)OC
Agent: COC(=O)CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(O)CP(=O)(O)O

Procedure:
This compound was prepared similarly by the method described in Step 2 of Example 1 except that methyl 3-oxo-7,11,15-trimethylhexadeca-6,10,14-trienoate was replaced by dimethyl [2-oxo-6,10,14-trimethyl-pentadeca-5,9,13-trienyl]phosphonate and the product from this reaction was used in the hydrolysis step similarly to the method used in Step 2 in Example 2 to give, after lyophilization, title compound as a nearly colorless gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:34]1[CH2:39][CH2:38][CH:37](N2CCC(C(O)=O)CC2)[CH2:36][CH2:35]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([CH:37]4[CH2:38][CH2:39][O:34][CH2:35][CH2:36]4)[CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C2CCOCC2)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(C3CCOCC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(tetrahydro-pyran-4-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(tetrahydro-pyran-4-yl)-piperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 578.2 [M]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8]C=1.C(Cl)Cl.[C:15]12([C:31](Cl)=[O:32])[CH2:24][C:19]3([C:25](Cl)=[O:26])[CH2:20][CH:21]([CH2:23][C:17]([C:28](Cl)=[O:29])([CH2:18]3)[CH2:16]1)[CH2:22]2>C1(C)C=CC=CC=1>[N:1]1([C:31]([C:15]23[CH2:24][C:19]4([C:25]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:26])[CH2:20][CH:21]([CH2:23][C:17]([C:28]([N:6]5[CH2:8][CH2:9][CH2:10][CH2:11]5)=[O:29])([CH2:18]4)[CH2:16]2)[CH2:22]3)=[O:32])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C12CC3CC(C(=O)Cl)(C1)CC(C(=O)Cl)(C3)C2
Reactant: C1CCNC1
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(N1CCCC1)C12CC3CC(C(=O)N4CCCC4)(C1)CC(C(=O)N1CCCC1)(C3)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
In a 500-ml flask equipped with a stirrer, a thermometer and a dropping funnel were placed 34.5 g (485 mmol) of pyrrolidine, 38.4 g (485 mmol) of pyridine and 140 ml of methylene chloride. To the stirred mixture under ice-cooling in a nitrogen atmosphere, 31.4 g (97 mmol) of 1,3,5-adamantanetricarbonyl trichloride in 190 ml of toluene was added dropwise over 1 hour. This was warmed to room temperature, was stirred for further 1 hour and was washed with water, 1 N aqueous hydrochloric acid, and 10% aqueous sodium carbonate solution, and the solvent was removed under reduced pressure, to yield 37.2 g (87 mmol) of 1,3,5-tris(1-pyrrolidinylcarbonyl)adamantane in a yield of 90%.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.Cl.[NH2:17][CH2:18][C:19]([NH2:21])=[O:20].[OH-].[K+]>C(O)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:17][CH2:18][C:19]([NH2:21])=[O:20]
Reactant: CN(C)CCCOc1ccccc1C=O
Reactant: NCC(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCCOc1ccccc1C=NCC(N)=O
Yield: 93.9 %

Procedure:
Fifteen grams of 2-(3-dimethylaminopropoxy)benzal-dehyde and 8.1 g of glycinamide, hydrochloride are reacted in 300 ml of ethanol in the presence of 4.8 g of 85% potassium hydroxide as described in Example 1 to give 20 g of a crude semi-solid product. The crude product is triturated with 100 ml of isopropyl ether and cooled to yield 17.9 g of solid; melting point 71-73° C (sintering at 60° C).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:18]=[CH:17][N:16]=1>CN(C=O)C>[F:30][C:27]([F:28])([F:29])[C:24]1[CH:23]=[CH:22][C:21]([C:19]2[CH:20]=[CH:15][N:16]=[C:17]([O:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)[CH:18]=2)=[CH:26][CH:25]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2ccnc(Oc3ccc4cccnc4c3)c2)cc1
Temperature: 155 °C
Reaction time: 0.17 h

Procedure:
To an oven-dried, 50-mL, round-bottomed flask were added 7-hydroxyquinoline (Aldrich) (87 mg, 0.6 mmol) and DMF (1 mL). The solution was place under nitrogen, and NaH (24 mg, 0.6 mmol) was added in one portion. After stirring for 10 min, 2-chloro-4-(4-trifluoromethylphenyl) pyridine (Example 410 (c), 129 mg, 0.5 mmol) was added. The reaction mixture was heated in a 155° C. oil bath for 72 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, concentrated in vacuo. The crude material was purified on a Biotage 40 S column (3:1 hexanes:EtOAc) to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 367 (M+1). Mp: 156.5-158.5° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][NH2:5].C(N(CC)C(C)C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.FC1C=C(OC)C=C(F)C=1CN1[C:42]2[N:43]=[CH:44][CH:45]=[CH:46][C:41]=2[S:40](=[O:48])(=[O:47])[N:39]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[C:51]([O:57][CH3:58])[CH:50]=2)[C:38]1=[O:59]>CN(C=O)C>[Cl:10][C:8]1[CH:9]=[C:2]([F:1])[C:3]([CH2:4][N:5]2[C:42]3[N:43]=[CH:44][CH:45]=[CH:46][C:41]=3[S:40](=[O:48])(=[O:47])[N:39]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[C:51]([O:57][CH3:58])[CH:50]=3)[C:38]2=[O:59])=[C:6]([F:11])[CH:7]=1
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Reactant: NCc1c(F)cc(Cl)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)N(Cc3c(F)cc(Cl)cc3F)c3ncccc3S2(=O)=O)cc1OC

Procedure:
The title compound (38 mg, 0.08 mmol) was prepared in two steps from (IntC1) (208 mg, 0.63 mmol), 2,6-difluoro-4-chlorobenzylamine (135 mg, 0.76 mmol) and N,N-diisopropylethylamine (113 uL, 0.63 mmol); followed by 1,1′-carbonyldiimidazole (166 mg, 1.0 mmol) in DMF (8.5 mL) using the methods of (95).
Reaction SMILES: [Cl-:1].[NH3+:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[NH+:11][CH:12]=[CH:13][CH:14]=1)=O.[Cl-].[C:16]1([C:22]2[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(C)C>[ClH:1].[ClH:1].[C:16]1([C:22]2[O:26][C:25]([CH:27]=[C:6]3[CH2:5][CH2:4][CH2:3][N:2]=[C:7]3[C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [Cl-]
Reactant: O=Cc1ccc(-c2ccccc2)o1
Reactant: [NH3+]CCCCC(=O)c1ccc[nH+]c1
Solvent: CC(C)O
Product: C(=C1CCCN=C1c1cccnc1)c1ccc(-c2ccccc2)o1
Product: Cl
Temperature: 85 °C
Reaction time: 6 h
Yield: 181.8 %

Procedure:
3-(5-Ammoniopentanoyl)pyridinium chloride (188 mg, 0.75 mmol) was transferred to a reaction vessel and treated with isopropanol (12 mL). 5-Phenyl-2-furaldehyde (193 mg, 1.12 mmol) was added, the reaction vessel was sealed, and the reaction was heated to 85° C. with stirring for 6 hours. The reaction was then cooled to room temperature, and the precipitate was recovered by vacuum filtration, washed with isopropanol and ether then dried under vacuum giving 264 mg (91%) of an orange solid. LC-MS: RT=5.15 min, [M+H]+=315.1.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([C:14]1[N:31]([CH2:32][C@H:33]2[CH2:38][CH2:37][C@H:36]([CH3:39])[CH2:35][CH2:34]2)[C:17]2[C:18]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([Cl:30])[CH:29]=3)=[N:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=2[N:15]=1)[O:11][CH2:12][CH3:13])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:30][C:28]1[CH:29]=[C:24]([C:18]2[C:17]3[N:31]([CH2:32][C@H:33]4[CH2:34][CH2:35][C@H:36]([CH3:39])[CH2:37][CH2:38]4)[C:14]([CH:10]([O:11][CH2:12][CH3:13])[CH2:9][OH:8])=[N:15][C:16]=3[CH:21]=[C:20]([C:22]#[N:23])[N:19]=2)[CH:25]=[N:26][CH:27]=1
Reactant: CCOC(CO[Si](C)(C)C(C)(C)C)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(CO)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
2-(2-((tert-butyldimethylsilyl)oxy)-1-ethoxyethyl)-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile was dissolved in THF (3.9 mL) and cooled to 0° C. before adding TBAF (1 M in THF, 1.5 mL). After stirring at 0° C. for 25 minutes, the reaction mixture was diluted with ethyl acetate and washed with water followed by brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (DCM/0-10% MeOH) to afford 4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-hydroxyethyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C24H28ClN5O2 [M+H]+ 454. found 454.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16]C(C)=O.[OH-:24].[Na+].Cl>C(O)C.C(Cl)(=O)C.ClCCl>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH2:16][C:15](=[O:20])[O:21][C:22](=[O:24])[CH2:23]2)=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: O=C1CC(c2ccc(-c3ccccc3)cc2)CC(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of commercial 4-biphenylcarboxaldehyde (5.37 g) and ethyl acetoacetate (7.68 g) in ethanol (10 ml) piperidine (1 ml) was added with stirring at rt. The yellow solution was kept at rt overnight. The precipitate was collected by suction filtration and washed with ethanol. After drying in vacuo 10.2 g of a faint yellowish solid (the bis-adduct of acetoacetate to the aldehyde) was isolated. The finely divided solid was added in portions to 40% NaOH (120 g) with stirring. The resulting yellow slurry was stirred at reflux for 2 h. After cooling in an ice bath the mixture was acidified by portionwise addition of conc. HCl (110 ml) to give a yellowish precipitate. The solid was collected by suction filtration and washed with water. After drying in vacuo slightly impure 3-(4-biphenyl-4-yl)glutaric acid (8.1 g) was obtained. The suspension of finely divided 3-(4-biphenyl-4-yl)glutaric acid in acetyl chloride (28 ml) was heated to reflux with stirring for 2 h. After cooling to rt precipitation of the product is completed by addition of petrol ether (100 ml). The precipitate is isolated by suction filtration, washed with petrol ether, and dried at the air to give a crude (4.39 g). The crude was dissolved in dichloromethane (110 ml), filtered, and the filtrate concentrated in vacuo to afford 3-(biphenyl-4-yl)glutaric anhydride (3.37 g) as colourless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#N.[Li]CCCC.Cl.[OH-:24].[Na+]>C1(C)C=CC=CC=1>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)=[O:24]
Reactant: Fc1ccc(Br)nc1
Reactant: N#Cc1ccccc1N
Reactant: [OH-]
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)c1ccc(F)cn1
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
2-Bromo-5-fluoropyridine (10 g, 56.8 mmol) and 2-aminobenzonitrile (5.6 g, 47.4 mmol) were dissolved in 100 mL of toluene and cooled to −30° C. To the resulting solution was added nBuLi (1.6 M in hexanes, 65 mL, 104 mmol, 2.2 equv) dropwise, and the reaction mixture was warmed to 0 deg for 90 minutes. The reaction mixture was then poured into 100 mL of cooled 3N HCl and stirred for 15 minutes, then 5N NaOH was added until the reaction mixture turned basic. The reaction mixture was extracted with CH2Cl2 (3×100 ml), washed with brine (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (0% to 30% EtOAc/hexanes) gave the title compound as a solid (LC/MS found: 217.2)