Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:8][C:9]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)c1cccc(C=O)c1OCc1ccccc1
Product: CC(C)(C)c1cccc(C(O)c2ccccc2)c1OCc1ccccc1
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of 2-(benzyloxy)-3-tert-butylbenzaldehyde (5.4 g, 20 mmol) was stirred under nitrogen on an ice bath and 1M phenyl magnesium bromide (30 mL, 1.5 equiv) was added at such a rate that temperature did not exceed 7° C. Stirring was continued at room temperature for 2 hr. The reaction mixture was cooled on an ice bath and quenched with saturated ammonium chloride (50 mL). The resulting mixture was partitioned between water (25 mL) and 1:1 ethyl acetate/heptane (150 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate and the solvent was removed in a rotary evaporator. The crude product (7.3 g) was purified by chromatography on silica (75 g) with heptane (0.5 L) and 2.5% ethyl acetate in heptane (2 L) to produce 13 (5.4 g, 78%) as a pale yellow oil.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 42 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide-hydrochloride and ethyl chloroformate. Yield: 42% of theory, C28H29N7O5 (543.6) Rf value: 0.20 (silica gel; dichloromethane/ethanol=19:1) EKA mass spectrum: (M+H)+ =544
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([CH3:9])[N:3]=1.[N:10]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([CH3:34])=[CH:29][C:28]=1[S:35](Cl)(=[O:37])=[O:36]>>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([CH3:34])=[CH:29][C:28]=1[S:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:25][C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)(=[O:18])=[O:17])=[CH:24][CH:23]=2)=[C:4]([CH3:9])[N:3]=1)(=[O:37])=[O:36]
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCCCC1
Reactant: Cc1nc(N)ccc1Br
Product: Cc1cc(S(=O)(=O)Nc2ccc(Sc3ccc(S(=O)(=O)N4CCCCC4)cc3)c(C)n2)c(Cl)cc1Cl

Procedure:
2,4-Dichloro-5-methyl-N-{6-methyl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-benzenesulfonamide was prepared from 2-amino-5-bromo-6-methylpyridine and 4-(N-piperidinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2,4-dichloro-5-methylphenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 9.58 (1 H, br s, NH), 8.09 (1 H, s, A-ring CH ortho to 2×Cl), 7.67 & 6.97 (2×1 H, 2×d, 2×J 11 Hz, pyridyl CH's), 7.62 & 7.12 (2×2 H, 2×d, 2×J 10 Hz, Ar CH's of C-ring), 7.51 (1 H, s, A-ring CH ortho to SO2NH), 3.01-2.93 (4H, m, CH2NCH2), 2.50 & 2.41 (2×3H, 2×s, 2×CH3), 1.70-1.60 (4 H, m, CH2CH2CH2CH2CH2), 1.47-1.38 (2 H, m, CH2CH2CH2CH2CH2). Hplc (Luna 2, Gradient 5): rt=6.72 minutes. LC/MS rt=7.34 minutes, 586/588 (MH+).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si](C=[N+]=[N-])(C)(C)[CH3:10].[ClH:16].O1CCOCC1>C1COCC1>[Cl:16][CH2:10][C:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:7]
Reactant: Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(Cl)C1CCCC1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(CCl)C1CCCC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Cyclopentanecarbonyl chloride (5.0 g, 0.038 mol) was dissolved in THF (100 mL) and cooled to 0° C. The solution was treated with a 2M solution of TMS-Diazomethane in hexanes (56.56 mL, 0.113 mol) over 10 min. The resulting yellow solution was allowed to stand at room temperature for 12 hours. The solution was then concentrated and the residue was dissolved in THF (100 mL) and treated slowly with a 4N HCl in Dioxane solution (28.28 mL, 0.113 mol). The result was allowed to stir at 24° C. for 2 hours. The solution was concentrated to an oil which was chromatographed on silica gel eluting with 5% EtOAc in Hexanes to give the intermediate depicted below (4.9 g, 88%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:48])=O>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([Cl:48])=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Solvent: Cc1ccccc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Temperature: 25 °C

Procedure:
A solution of the product from Example 43C (224 mg, 0.443 mmol) in thionyl chloride (2 mL) was refluxed for 1 hour. The mixture was cooled to room temperature, toluene (5 mL) was added and the mixture concentrated under vacuum to provide the title product as a solid.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([F:26])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[CH:37]=O.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([F:26])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:37][C:29]3[N:28]([CH3:27])[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: Cn1c(C=O)nc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ccccc4n3C)C(=O)O2)cc1F

Procedure:
The title compound was prepared by coupling 6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione from Step 1 of Example B(14), to 1-Methyl-1H-benzoimidazole-2-carbaldehyde using the AlCl3/reduction procedure described for Example B(13).
Reaction SMILES: CC(C)=O.[O:5]([C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([SH:15])[S:14][C:10]=2[CH:9]=1)[CH2:6][CH3:7].[Br:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](O)=[O:21].C(OC(=O)C)(=O)C>C(O)(=O)C>[Br-:18].[CH2:6]([O:5][C:8]1[CH:17]=[CH:16][C:11]2[N+:12]3[C:20]([OH:21])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[S:15][C:13]=3[S:14][C:10]=2[CH:9]=1)[CH3:7]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: CCOc1ccc2nc(S)sc2c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CCOc1ccc2c(c1)sc1sc(-c3ccccc3)c(O)[n+]12
Product: [Br-]
Reaction time: 8 h
Yield: 36 %

Procedure:
A 2.5 l. acetone solution of 50.0 g. (0.237 moles) 6-ethoxyl-2-mercaptobenzothiazole and 51.0 g. (0.237 moles) α-bromophenylacetic acid containing 100 ml. glacial acetic acid and 100 ml. acetic anhydride is heated in an open flask until the solution is reduced to 2 l. The solution is allowed to stand at room temperature overnight. The precipitated solid is collected, washed with acetone and ether, and dried in an oven. The product, weighing 34.7 g. (36% yield), does not melt below 270° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:17](C(OC(C)(C)C)=O)[NH:18][C:19](OC(C)(C)C)=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](O)(=O)C>>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:19]([CH3:33])=[N:18][N:17]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(ccn2Cc2ccccc2)n1
Product: Cc1nnc2ccc3c(ccn3Cc3ccccc3)n12
Yield: 65 %

Procedure:
di-tert-Butyl 1-(1-benzyl-1H-pyrrolo[3,2-b]pyridin-5-yl)hydrazine-1,2-dicarboxylate (31 mg, 0.071 mmol, from Step 2) in acetic acid (4.0 mL) was heated in the microwave to 180° C. for 5 minutes. The solvent was removed in vacuo and the mixture was reconstituted in MeOH and purified using preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) and the eluent was frozen and lyophilized to afford a white powder (12 mg, 65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[N:18][OH:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:20]([Li])CCC.C1(=O)[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.S(=O)(=O)(O)O>O.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:26]([CH:27]([CH3:20])[C:28]([OH:30])=[O:29])[O:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(Cc2ccccc2)=NO)cc1F
Reactant: O=C1CCC(=O)O1
Reactant: [Li]CCCC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2noc(C(C)C(=O)O)c2-c2ccccc2)cc1F
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A dry, 250 mL 3-neck round-bottom flask, equipped with a thermometer, magnetic stirring bar, reflux condenser and rubber septum was charged with 1-(3-fluoro-4-methoxyphenyl)-2-phenyl-ethan-1-one oxime from Step 2 (2.00 g, 7.71 mmol) and anhydrous THF (80 mL) under a nitrogen blanket. The solution was cooled to -20° C., and n-butyllithium (1.6 N, 12.0 mL) was added, via syringe, over 20 minutes, keeping the reaction temperature <-10° C. The deep red suspension was stirred at -20° C. for 1 hour, warmed to room temperature, and stirred at room temperature for 1 hour. Succinic anhydride (926 mg, 9.26 mmol) was added in one portion, and the yellow reaction was stirred for 16 hours without temperature control. Sulfuric acid (conc., 2.1 mL) was added, and the reaction was warmed to reflux. After 2 hours, the brown mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ether (2×100 mL). The ethereal solution was extracted with dilute sodium hydroxide (2×100 mL), and the combined basic extracts were acidified to pH <2 with hydrochloric acid (conc.). The acidic system was extracted with ether (2×100 mL). This ethereal solution was evaporated under reduced pressure to a residue. The residue was applied to a column of silica gel (200 cc) and eluted (10% methanol in dichloromethane) to yield, upon concentration of the appropriate fractions, a crude solid. The solid was recrystallized from hot ethanol and 0.1 N HCl to yield, upon filtration and drying, [3-(3-fluoro-4-methoxyphenyl)-4-phenylisoxazol-5-yl]propanoic acid as ivory colored crystals (367 mg, 14%): mp 129-131° C. (dec). Mass Spectrum: MH+=342. 1H NMR (CDCl3 /300 MHz) δ 7.39 (m, 3H), 7.22-7.12 (m, 4H), 6.87 (t, J=8.46 Hz, 1H), 3.88 (s, 3H), 3.09 (t, J=8.05 Hz, 2H), 2.80 (t, J=8.05 Hz, 2H). 19F NMR(CDCl3 /282.2 MHz): -135.466 (m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.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>[NH2:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)=[CH:30][N:29]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: Nc1ncc(B(O)O)cn1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnc(N)nc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), (2-aminopyrimidin-5-yl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (45% yield). LCMS: 433.20 (M+1)+; HPLC: 98.75% (@ 254 nm) (Rt; 5.252); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 9.09 (s, 2H), 8.84 (t, 1H), 8.33 (s, 1H), 8.07 (s, 1H), 7.15 (s, 2H), 5.89 (s, 1H), 5.32-5.28 (m, 1H), 4.40 (d, 2H, J=4.0 Hz), 2.22 (s, 3H), 2.12 (s, 3H), 1.51 (d, 6H, J=6.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[F:16][C:17]([F:27])([F:26])C1C=C(C=CC=1)C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:17]([F:27])([F:26])[F:16])[CH:7]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1cccc(C(F)(F)F)c1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 3-trifluoromethylbenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:7]1[C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[C:4]([F:13])[C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: ClCCCI
Reactant: O=C1COc2c(F)cc(F)cc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2c(F)cc(F)cc2N1CCCCl
Yield: 39.1 %

Procedure:
6,8-Difluoro-4H-benzo[1,4]oxazin-3-one (0.80 g, 4.3 mmol), Cs2CO3 (2.12 g, 6.5 mmol), and 1-chloro-3-iodopropane (0.98 g, 4.8 mmol) were mixed according to GP2. Purified by column chromatography (SiO2; heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound (0.44 g, 39%). Rf=0.65 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) d 6.66-6.59 (m, 2H), 4.64 (s, 2H), 4.09-4.03 (m, 2H), 3.62 (t, J=6.0 Hz, 2H), 2.23-2.10 (m, 2H); 13C NMR (CDCl3) d 164.2, 157.5 (dd, J=242.5 Hz, J=12.7 Hz), 151.7 (dd, J=248.5 Hz, J=14.4 Hz), 131.0 (dd, J=12.1 Hz, J=4.8 Hz), 130.4 (dd, J=15.0 Hz, J=3.2 Hz), 99.7 (dd, J=26.9 Hz, J=22.4 Hz), 98.2 (dd, J=28.4 Hz, J=3.4 Hz), 67.8, 42.2, 39.7, 30.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:12]([CH3:16])[C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CN(Cc2ccccc2)CC(C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a −78° C. solution of 1-benzyl-3-methyl-piperidin-4-one (4.06 g, 20 mmol) in anhydrous THF (20 mL) was added lithium hexamethyldisilazide (21 mL, 21 mmol of a 1.0 M solution THF). After being stirred at −78° C. for 30 min, a solution of iodomethane (1.31 mL, 21 mmol) in THF (5 mL) was added into the reaction mixture. The resultant solution was stirred at 25° C. for 2 h and quenched with water. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. The crude material was purified by flash column chromatography (hexane/EtOAc) to provide 1.37 g (31.5% yield) of 1-benzyl-3,5-dimethyl-piperidin-4-one.
Reaction SMILES: C[Li].[CH3:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1.CN(C)P(N(C)C)(N(C)C)=O.[C:22]([C:27]#N)(=[O:26])[O:23][CH2:24][CH3:25]>CCOCC.[Cu]I.O>[OH:10][C:6]1[CH2:7][CH2:8][CH2:9][C:4]([CH3:5])([CH3:3])[C:27]=1[C:22]([O:23][CH2:24][CH3:25])=[O:26]
Reactant: CC1=CC(=O)CCC1
Reactant: CCOC(=O)C#N
Agent: [Cu]I
Agent: [Li]C
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CCOC(=O)C1=C(O)CCCC1(C)C
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Into a 500 mL flame dried round-bottomed flask was added copper(I) iodide (18 g) in ether (200 mL) to give a suspension. After cooling to −5° C., methyllithium (120 mL, 1.6M in ether) was added dropwise. After stirring at −5° C. for 1 hour, 3-methylcyclohex-2-enone (5.15 mL) in 15 ml ether was added dropwise, and the mixture was stirred at −5° C. for 1 hour. After cooling to 78° C., hexamethylphosphoramide (60 mL) was added dropwise. Ethyl carbonocyanidate (23.74 mL) was added. After stirring at −78° C. for 20 minutes, the mixture was warmed up to room temperature, and stirred for 1 hour. The mixture was poured into cold water, and the layers were separated. The aqueous layer was extracted with ether (3×20 mL). The combined organic layers were washed with saturated aqueous NH4Cl (3×20 mL), dried over Na2SO4, filtered, and dried under vacuum. The crude product was added to a silica gel column and purified by eluting with 0-10% ethyl acetate in hexane.
Reaction SMILES: [C:1](O)(=O)[C:2]([OH:4])=[O:3].[CH2:7]([C:10]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33]C=3)=[C:27](C(OC(C)(C)C)=O)[CH:26]=2)[C:13]2[CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][CH2:16][CH2:17][C:12]=2[N:11]=1)[CH2:8][CH3:9].[C:44](Cl)(=[O:47])[CH2:45][CH3:46]>>[CH2:7]([C:10]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:1]=3[C:2]([O:4][C:25]([CH3:30])([CH3:26])[CH3:24])=[O:3])=[CH:27][CH:26]=2)[C:13]2[CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:15]([C:44](=[O:47])[CH2:45][CH3:46])[CH2:16][CH2:17][C:12]=2[N:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3)c(C(=O)OC(C)(C)C)c1)C(C(=O)OCC)NCC2
Reactant: CCC(=O)Cl
Reactant: O=C(O)C(=O)O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)N(C(=O)CC)CC2
Yield: 174 %

Procedure:
The compound obtained in Example 62 (1.0 g) is treated in the same manner as in Example 64 with using propionyl chloride (0.23 g) instead of acetic anhydride to give ethyl 2-n-propyl-5-propionyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-4-carboxylate (0.82 g) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>C(Cl)Cl>[C:18]([Si:15]([O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])([CH3:17])[CH3:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cccc(F)c1O
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(F)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-fluoro-6-methylphenol (176 mg, 1.40 mmol) in DCM (6.3 mL), cooled to 0° Celsius, were added imidazole (142 mg, 2.09 mmol) followed by tert-butyldimethylsilyl chloride (231 mg, 1.54 mmol). The flask was warmed to rt and stirred for 2 hours The reaction mixture was then poured in to water (50 mL) and extracted with DCM (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to dryness to provide the title compound that was used without further purification. 1H NMR (500 MHz, CDCl3) δ 6.91-6.85 (m, 2H), 6.80-6.73 (m, 1H), 2.24 (t, J=0.7, 3H), 1.02 (s, 9H), 0.20 (d, J=2.5, 6H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.CN([CH:25]=[O:26])C>C1COCC1>[Br:13][C:14]1[C:15]([CH:25]=[O:26])=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1
Reactant: COc1ccc(Br)cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc(C=O)c(Br)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine in THF (0.1M) at 0° C. was added n-BuLi (1.1 eq.). The solution was stirred for 30 min and then was cannulated in a solution of commercially available 5-bromo-2-methoxypyridine in THF (0.1M) at −78° C. The resulting solution was stirred at −78° C. for 30 min then DMF (1.5 eq.) was added. Final reaction mixture was allowed to warm to 0° C. before it was quenched with saturated aqueous NH4Cl and then extracted with EtOAc. The organic extract was washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 50% in 30 min) afforded the desired compound as a white solid.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][CH:41]=[CH2:42]>>[CH2:40]([NH:39][C:32](=[O:34])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[S:27]([CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:29])=[O:28])[CH:41]=[CH2:42]
Reactant: C=CCN
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: C=CCNC(=O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 66.7 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropene (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 38 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]+.