Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
Into a 250-mL round-bottom flask, was placed a mixture of Pt2O (200 mg) and methanol (50 mL). The mixture was purged with nitrogen, then hydrogen was introduced and the mixture was stirred for 15 min. A solution of tert-butyl 4-(4-chlorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (compound 42.2, 6.00 g, 20.4 mmol) in methanol (50 mL) was added and the resulting mixture was stirred under hydrogen overnight at room temperature. After purging with nitrogen, the solids were filtered off and the resulting solution was concentrated under vacuum to yield the title compound as a light green oil (5.30 g, 88%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](/[CH:11]=[N:12]/[S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:19]([Mg]Cl)[CH3:20]>C1COCC1>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:19][CH3:20])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)S(=O)/N=C/C1CCC2(CC1)OCCO2
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCC(NS(=O)C(C)(C)C)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (E)-N-(1,4-dioxaspiro[4.5]decan-8-ylmethylene)-2-methylpropane-2-sulfinamide (as prepared in of Example 11 Step A, 3.66 g, 13.4 mmol) in dry THF (100 mL) was placed under an argon atmosphere and treated with ethylmagnesium chloride dropwise. After stirring at ambient temperature for 2 hours, the reaction mixture was cooled to −10° C. and cautiously quenched by the addition of saturated ammonium chloride solution. After dilution with water and ether extraction, the organic layer was concentrated in vacuo. Purification of the residue by flash chrom (silica gel, ethyl acetate) afforded the titled compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[O:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.[OH-].[K+:25]>>[K+:25].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[O:9][CH:10]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([O-:13])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)C(CC(C)C)OC(c1ccc(Br)cc1)c1nccs1
Agent: [K+]
Agent: [OH-]
Product: CC(C)CC(OC(c1ccc(Br)cc1)c1nccs1)C(=O)[O-]

Procedure:
Using the same protocol as described in example 17, step 5, methyl 2-[(4-bromophenyl)(1,3-thiazol-2-yl)methoxy]-4-methylpentanoate from step 2 (441 mg, 1.11 mmol) was hydrolysed with potassium hydroxide. The solid residue obtained was used as such in the next step.
Reaction SMILES: [NH2:1]C1C(Cl)=C(Cl)N=C(C(O)=O)C=1Cl.[Cl:14][C:15]([Cl:27])([Cl:26])[C:16]1[C:21]([Cl:22])=[C:20](Cl)[C:19]([Cl:24])=[C:18]([Cl:25])[N:17]=1.N>>[NH2:1][C:20]1[C:19]([Cl:24])=[C:18]([Cl:25])[N:17]=[C:16]([C:15]([Cl:27])([Cl:26])[Cl:14])[C:21]=1[Cl:22]
Reactant: Nc1c(Cl)c(Cl)nc(C(=O)O)c1Cl
Reactant: Clc1nc(C(Cl)(Cl)Cl)c(Cl)c(Cl)c1Cl
Agent: N
Product: Nc1c(Cl)c(Cl)nc(C(Cl)(Cl)Cl)c1Cl

Procedure:
It is known that 4-amino-3,5,6-trichloropicolinic acid is prepared by a two-step method where heptachloro-2-picoline is aminated with anhydrous liquid ammonia to form 4-amino-hexachloro-2-picoline, an intermediate product that is isolated, and which is in turn hydrolyzed with sulfuric acid to form 4-amino-3,5,6-trichloropicolinic acid. See, for example, Russian Pat. No. 445,662.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:5](=[N:15][N:16]([CH3:18])[N:17]=2)[NH:6][C:7]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:8]=2[N:9]=1.CS(C)=O.[CH3:23][N:24]1[CH2:29][CH2:28]N[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[F:14][C:11]1[CH:12]=[CH:13][C:7]2[NH:6][C:5]3=[N:15][N:16]([CH3:18])[N:17]=[C:4]3[C:3]([N:2]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)=[N:9][C:8]=2[CH:10]=1
Reactant: Cn1nc2c(n1)C(N)=Nc1cc(F)ccc1N2
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CN1CCN(C2=Nc3cc(F)ccc3Nc3nn(C)nc32)CC1
Temperature: 125 °C

Procedure:
10-Amino-7-fluoro-2-methyl-2,4-dihydro-1,2,3-triazolo[4,5-b][1,5]benzodiazepine hydrochloride (2.68 g) was added to a mixture of dry dimethyl sulphoxide (10 ml), toluene (10 ml) and dry N-methyl piperazine (3.3 ml), which had been degassed with nitrogen for 20 minutes. The stirred solution was then heated at 125° C. (oil-bath) under nitrogen for five hours, cooled to room temperature, and distilled water (33.3 ml) added, keeping the temperature below 25° C. After stirring at 5° C. for half an hour, the suspension obtained was filtered off and dried at 70° C. under reduced pressure to leave a yellow crystalline solid, which was recrystallised from ethyl acetate/n hexane, melting point 195°-197° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10](=[O:25])[C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:14]=[C:13]([F:24])[CH:12]=2)=[CH:6][C:3]=1[C:4]#[N:5].[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O.[BH4-].[Na+]>CO.[Ni](Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:20])[F:21])[CH:14]=[C:13]([F:24])[CH:12]=2)[OH:25])=[CH:6][C:3]=1[CH2:4][NH:5][C:27](=[O:26])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N#Cc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cc(C(O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-fluoro-5-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzoyl)benzonitrile (1.30 g, 3.62 mmol), BOC2O (1.68 mL, 7.24 mmol) and Nickel (II) chloride (0.47 g, 3.62 mmol) in MeOH at 0° C. was added sodium borohydride (0.96 g, 25.3 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 6 h. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was diluted with EtOAc and the solution was washed with sat. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to yield tert-butyl 2-fluoro-5-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(hydroxy)methyl)benzylcarbamate as a clear, colorless oil (1.43 g, 85% yield). This product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (m, 1H), 7.22 (m, 1H), 7.03 (m, 3H),), 6.87 (d, J=8.84 Hz, 1H), 5.90 (m, 2H), 4.98 (br. s., 1H), 4.31 (d, J=5.05 Hz, 2H).
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:13])[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][NH:4]1.[CH3:14]N(C)C=O>>[CH3:14][N:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[N:9][CH:8]=2)[C:3]1=[O:13]
Reactant: O=c1[nH]ccc2cnccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cn1ccc2cnccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in mineral oil, 328 mg, 8.2 mmol) was added portionwise to a suspension of 2H-[2,6]naphthyridin-1-one (1 g, 2.05 mmol) (see reference J. Het. Chem. 1981, 18(7), 1349) in anhydrous N,N-dimethylformamide (25 ml) under a nitrogen atmosphere and the mixture was stirred at room temperature for 1 hour. lodomethane (510 μl, 8.2 mmol) was added and the mixture was stirred for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (20 ml). The aqueous phase was extracted with dichloromethane (2×30 ml) and the combined organic layers were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane (gradient from 2:98 to 5:95) to give the title compound (750 mg).
Reaction SMILES: O[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:20])=O>CCOCC>[Cl:20][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1noc2ccccc12
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Clc1noc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Hydroxy benzisoxazole 11 (1.03 gr, 6.25 mmol), triethylarnine (632 mg, 6.25 mmol) and phosphorousoxychloride (1.92 gr, 12.5 mmol) were heated in a sealed tube at 150° C. for 18 h. After this time the reaction was cooled to room temperature and diluted with ether and carefully quenched with excess ice/water. The resulting mixture was stirred for 15 min then the organic layer was washed with water (2×), brine (1×), dried with magnesium sulfate, filtered and evaporated to afford 12 as a white solid after column chromatography (hexanes/ethyl acetate, 97:3); 1H-NMR (CDCl3, 500 MHz) δ 7.65-7.63 9 m, 2H), 7.42 (dd, 1H).
Reaction SMILES: [C:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([OH:16])[CH:9]=1)C(O)=O)#[N:2].N1C2C(=CC=CC=2)C=CC=1.C(=O)=O>>[OH:16][C:10]1[CH:9]=[C:8]([CH2:7][CH2:3][C:1]#[N:2])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(CC(C#N)C(=O)O)cc1O
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Product: COc1ccc(CCC#N)cc1O
Temperature: 165 °C
Reaction time: 0.75 h
Yield: 70 %

Procedure:
A 100 ml. round bottom flask equipped with a magnetic stirrer, cold water condenser, CO2 outlet and bubbler, and a heated oil bath was charged with 14.9 g. of crude α-cyano-3-hydroxy-4-methoxydihydrocinnamic acid (above) and freshly redistilled quinoline (8 ml.). The acid underwent smooth decarboxylation at an oil bath temperature of 150°-155°C with CO2 evolution continuing 45 min. The mixture was then heated 1 hour at 165°C (oil bath) and permitted to cool to room temperature. For workup, the cooled mixture was treated with 500 ml. of 1N HCl and extracted thoroughly with several portions of ether totalling 350 ml. The ether was washed with water (1 × 100 ml.), saturated NaHCO3 (4 × 50 ml.), brine (1 × 100 ml.), and finally dried over anhydrous Na2SO4. Concentration of the ether solution gave 8.3 g. (70% yield) of β-(3-hydroxy-4-methoxyphenyl)propionitrile as a pale yellow solid. Recrystallization from ethyl acetate/hexane gave the pure compound as light yellow crystals, m.p. 82°C (62% yield of recrystallized product).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH:22]([CH3:25])[CH2:21][N:20]([CH:26]5[CH2:29][CH:28]([NH:30]C(=O)OC(C)(C)C)[CH2:27]5)[CH2:19][C:18]=4[C:17]([C:38]#[N:39])=[C:16]([Cl:40])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.O1CCOCC1>Cl>[ClH:40].[ClH:40].[ClH:40].[NH2:30][CH:28]1[CH2:27][CH:26]([N:20]2[CH2:19][C:18]3=[C:17]([C:38]#[N:39])[C:16]([Cl:40])=[CH:15][C:14]([CH:12]([N:8]4[C:4]5=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]5[C:10]([CH3:11])=[N:9]4)[CH3:13])=[C:24]3[O:23][CH:22]([CH3:25])[CH2:21]2)[CH2:29]1
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CC(NC(=O)OC(C)(C)C)C2)C3)c2ncnc(N)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CC(N)C2)C3)c2ncnc(N)c12
Reaction time: 1 h

Procedure:
Tert-butyl {3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutyl}carbamate was taken up in 4.0 M hydrogen chloride in dioxane (1 mL, 4 mmol) and was stirred for 1 h. The reaction was concentrated in vacuo to give crude 4-(3-aminocyclobutyl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile trishydrochloride as a solid. LCMS calculated for C23H28ClN8O (M+H)+: m/z=467.2; found: 467.2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.[O:14]1[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:16]=[CH:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1CCC(P(C2C(C3C=CC=CC=3)=CC=CC=2)C2CCCCC2)CC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][C:15]3[O:14][CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:16]=3)[CH:4]=2)[N:9]=1
Reactant: CCOC(=O)c1cocn1
Reactant: Cc1ccc2cc(CCl)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1coc(Cc2ccc3nc(C)ccc3c2)n1
Temperature: 100 °C

Procedure:
A mixture of 6-(Chloromethyl)-2-methylquinoline (1.09 g, 5.69 mmol), Ethyl oxazole-4-carboxylate (1.00 g, 7.11 mmol), Cesium carbonate (3.7 g, 11.37 mmol), Palladium(II)acetate (64 mg, 0.284 mmol) and (2-Biphenyl)dicyclohexyl-phosphine (199 mg, 0.569 mmol) in dioxane (28 ml) was stirred at 100° C. over night. The reaction mixture was quenched with H2O/brine and extracted with EA (3×). The combined organic layers were dried over Na2SO4, filtered and evaporated under vacuum. The crude product was purified by flash-chromatography on silica gel (29 g), gradient of cyclohexane/EA (60 ml/min.) from 100/0 (2 min.) to 70/30 (25 min.) to afford pure Ethyl 2-((2-methylquinolin-6-yl)methyl)oxazole-4-carboxylate. MS (Method V) [M+H]+=297.1
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH:4]=C[CH:2]=1.COC1C=NC2C(C=1)=CC=C1C=CC=CC=21.C([Li])CCC.CCO[C:39]([CH3:41])=[O:40]>C1COCC1>[CH3:2][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH:4]=[CH:41][CH:39]1[OH:40]
Reactant: c1ccc2c(c1)ccc1cccnc12
Reactant: CCOC(C)=O
Agent: COc1cnc2c(ccc3ccccc32)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1c2c(ccc3ccccc23)C=CC1O
Reaction time: 1 h

Procedure:
Compound 13 was alkylated with Mel according to a general amino group alkylation procedure as follows. The 3-methoxybenzoquinoline derivative (100 mg) 13 was suspended in 5 mL of dry THF and cooled to -5° C. (ice/NaCl). 1.1 equivalents of n-butyl lithium (1 M) was added dropwise, and the reaction was stirred for 1 hour. 3 equivalents of the Mel alkylating agent was added slowly and the reaction was allowed to stir at room temperature for 2 hours. Aqueous work-up using NH4C1 and EtOAc gave a crude alkylated 3-methoxybenzoquinoline intermediate 14. Intermediate 14 was then purified by normal phase flash chromatography employing EtOAc: hexane (1:19) as the mobile phase (1HNMR: CD3Cl d 8.1 (broad d, 1 H, J=8.1 Hz), 7.68(dd, 1 H, J=8.1, 1.8 Hz), 7.34 (m, 2 H), 6.8 (s, 1 H), 3.92 (s, 3 H), 3.21 (m, 2 H), 2.94 (s, 3 H), 2.77 (t, 2H, J=6.6 Hz), 1.92 (m, 2 H)). Subsequent methoxy group deprotection by the general boron tribromide procedure described above in Example 1 resulted in the N-methyl-hydroxybenzoquinoline derivative 15.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([N:11]1[CH2:14][C:13]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:12]1)[CH2:6][CH2:5]2.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Cl[C:51]1[N:56]=[CH:55][CH:54]=[CH:53][N:52]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[N:52]1[CH:53]=[CH:54][CH:55]=[N:56][C:51]=1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([N:11]1[CH2:14][C:13]3([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]3)[CH2:12]1)[CH2:6][CH2:5]2
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(Br)ccc31)C2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ncccn4)ccc31)C2
Temperature: 110 °C
Yield: 78.5 %

Procedure:
To an oven-dried round-bottomed flask was added tert-butyl 2-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (3-1a, 267 mg, 0.63 mmol), anhydrous dioxane (9 mL), bis(pinacolato)diboron (177 mg, 0.69 mmol) and potassium acetate (249 mg, 2.53 mmol). The resulting mixture was purged with nitrogen for 15 minutes. Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added and the reaction mixture was purged with nitrogen for an additional 15 minutes. The reaction was heated under nitrogen at 110° C. for 5 hours. After consumption of the starting material (as monitored by TLC), the reaction was cooled to room temperature and 2-chloro-pyrimidine (71.0 mg, 0.63 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol) and aqueous K2CO3 solution (2M, 2.25 mL, de-oxygenated with nitrogen for 15 minutes prior to addition) were added. The reaction was purged with nitrogen (3×) and heated under nitrogen for 20 hours at 110° C. The reaction was cooled to room temperature and was filtered through a short plug of silica gel, eluting with methanol. The solvents were removed in vacuo and the residue was partitioned between 50 mL of ethyl acetate and 50 mL of 1N NaOH solution. The layers were separated and the organic layer was washed with 50 mL of brine. The organic layer was dried (Na2SO4) and concentrated to give the crude product as a black semi-solid. The crude product was purified by column chromatography using a Combiflash ISCO purification system (Teledyne Isco Inc., Lincoln, Nebr.) system, eluting with 0-10% MeOH in CH2Cl2 to give the title compound as a black gum (208 mg, 78%). MS (ES+) 421.2 (M+H)+. 1H NMR (CDCl3) δ 1.39 (s, 9H), 1.59-1.69 (m, 4H), 1.75-1.94 (m, 1H), 2.12 (dq, 1H), 2.76-2.92 (m, 1H), 2.95-3.18 (m, 5H), 3.19-3.36 (m, 4H), 3.92 (dd, 1H), 7.09 (t, 1H), 7.33 (d, 1H), 8.18-8.26 (m, 2H), 8.71 (d, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[C:12]([CH3:24])=[N:11]2)=[CH:6][CH:5]=1.[OH-:25].[Na+]>OS(O)(=O)=O>[Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]([NH2:20])=[O:25])[C:12]([CH3:24])=[N:11]2)=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: Cc1nn(-c2ccc(CCCl)cc2)c(C)c1-c1cccc(C#N)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nn(-c2ccc(CCCl)cc2)c(C)c1-c1cccc(C(N)=O)c1
Yield: 84 %

Procedure:
A solution of 3-{1-[4-(2-chloroethyl)phenyl]-3,5-dimethyl-1H-pyrazol-4-yl}benzonitrile (step 2, 2.62 mmol) in conc. H2SO4 was heated at 80° C. for 5 h. It was neutralized by 5 M NaOH aq. and extracted with dichloromethane. Organic phase was dried over Na2SO4 and the solvent was removed under reduced pressure to afford 780 mg (84%) of the title compound as yellow solids: MS (ESI) m/z 354 [M+H]+, 1H-NMR (CDCl3) δ 7.80-7.36 (8H, m), 3.75 (2H, t, J=7.2 Hz), 3.14 (2H, t, J=7.2 Hz), 2.33 (3H, s), 2.31 (3H, s).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:34]=3)=[CH:29][CH:28]=2)=[O:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:26][C:25]([C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:34]=2)=[CH:31][CH:32]=1)([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[CH3:43]
Reactant: C[Mg]Br
Reactant: CC(=O)Nc1cccc(-c2ccc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(-c2ccc(C(C)(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-[4′-[(1-trityl-1H-imidazol-4-yl)carbonyl][1,1′-biphenyl]-3-yl]acetamide (800 mg) in THF (14 ml) was added dropwise a solution (1.0 M; 4.38 ml) of methylmagnesium bromide in THF at 0° C., and the mixture was stirred at 0° C. for 20 min. Saturated ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate-methanol-hexane to give the title compound (823 mg) as colorless powder crystals.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:37](=[O:49])[NH:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:11][C:12]1[CH:36]=[CH:35][C:15]([O:16][CH:17]([C:21]2[N:22]=[N:23][N:24](C(C)(C3C=CC=CC=3)C)[N:25]=2)[C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[K])=O>CCO.[Pd]>[C:1]([NH:9][C@H:10]([C:37](=[O:49])[NH:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:11][C:12]1[CH:36]=[CH:35][C:15]([O:16][CH:17]([C:21]2[N:22]=[N:23][NH:24][N:25]=2)[C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccccc1)n1nnc(C(Oc2ccc(C[C@H](NC(=O)c3ccccc3)C(=O)NCCCCc3ccccc3)cc2)C(=O)O)n1
Agent: [Pd]
Agent: O=CO[K]
Solvent: CCO
Product: O=C(N[C@@H](Cc1ccc(OC(C(=O)O)c2nn[nH]n2)cc1)C(=O)NCCCCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10% Pd/C (40 mg) is added to a stirred slurry of {4-[(2S)-2-benzoylamino-2-(4-phenyl-butylcarbamoyl)--ethyl]-phenoxy}-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5- yl]-acetic acid of Step D (0.045 g, 0.068 mmol) and HCO2K (0.034 g, 0.409 mmol) in EtOH (2 mL). The reaction mixture is heated to reflux under N2. After 5 h, the reaction mixture is cooled to RT and filtered to remove Pd/C. The filtrate is diluted with EtOAc, water and 10% HCl and the layers separated. The organic layer is washed with 10% HCl and brine, dried (MgSO4) and concentrated under reduced pressure to provide {4-[(2S)-2-benzoylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-phenoxy}-(2H-tetrazol-5-yl )-acetic acid (compound 18); 1H NMR (400 MHz, acetone-d6) δ7.82 (m, 3H), 7.45 (m, 4H), 7.19 (m, 7H), 6.99 (d, 2H), 6.36 (s, 1H), 4.81 (m, 1H), 3.21 (m, 3H), 3.05 (m, 1H) 2.58 (t, 2H), 1.59 (m, 2H), 1.48 (m, 2H); MS (ES+) m/z 543 (M+1); MS (ES−) m/z 541 (M−1).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:19]2[C:14](=[C:15]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:29])[CH:11]=1.CS(C)=O>C1COCC1>[CH2:2]([CH:3]([O:6][C:10]1[C:19]2[C:14](=[C:15]([C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])[CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:29])[CH:11]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: Cc1cc(C)c(-c2cccc3c(Cl)cc(C)nc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCC(CC)Oc1cc(C)nc2c(-c3c(C)cc(C)cc3C)cccc12
Temperature: 12 °C

Procedure:
To a solution of 3-pentanol (5.8 ml, 52.7 mmol) in dry THF (5 ml) was added sodium hydride (NaH) portionwise over a period of 10 min. A solution of 4-chloro-2-methyl-8-(2,4,6-trimethyl-phenyl)-quinoline (4.0006 g, 13.52 mmol) in dry THF (10 ml) was added. After stirring at room temperature as for 10 min, 15 ml of dry DMSO was added. The resulting mixture was heated in a 12° C. oil bath for 1.5 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried, filtered, and concentrated to give the title compound as 5.002 g of a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[CH:9][CH:8]=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(c1ccc(OCCCCBr)cc1)c1c(-c2ccccc2)oc2ccccc12
Reactant: CN
Product: CNCCCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
Reaction of 3-[4-(4-bromobutoxy)-benzoyl]-2-phenylbenzofuran with methylamine according to the procedure described in Example 4 gives 3-[4-(4-methylaminobutoxy)benzoyl]-2-phenylbenzofuran.