Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20]>O1CCCC1>[CH3:16][O:17][CH:18]([CH3:22])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: COC(C)C(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: C1CCOC1
Product: COC(C)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 56.2 %

Procedure:
5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 3.6 g (29.4 millimoles) of 2-methoxypropionyl chloride in 150 ml of absolute tetrahydrofuran were refluxed for 2 hours, while stirring. The mixture was evaporated down, the residue was stirred with water and the product was filtered off under suction, washed with water, dried, and recrystallized from propanol. 4.0 g (56%) of 6-[p-(2-methoxypropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained as colorless crystals. Mp.: 193°-194° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH2:24][CH3:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH2:24]([C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1)[CH3:25]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Product: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-ethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.89) (0.30 g, 0.739 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.179 g, 0.813 mmol) according to the general procedure VI. Obtained as a white solid (0.050 g, 16%). MS (ISP) 420.1 [(M+H)+]; mp 74° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N+:3]=1[O-].[C:11]([O:14]C(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:14][CH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1)(=[O:13])[CH3:12]
Reactant: COc1cc[n+]([O-])c(C)c1
Reactant: CC(=O)OC(C)=O
Product: COc1ccnc(COC(C)=O)c1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
To 2-methyl-4-methoxypyridine-N-oxide (23 g, 0.165 mole) in a 1 liter wide necked flask fitted with a large condenser was added ice-cool acetic anhydride (35 ml, 0.37 mole) with stirring. The mixture was allowed to warm to room temperature whereupon a vigorous exothermic reaction occurred. The dark mixture was stirred for 1 hour before evaporating the excess acetic anhydride and distilling the residue to give the title compound (23.26 g, 78%), b.p. 125° C. at 0.1 mm mercury.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[CH:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50]Br)=[CH:45][CH:44]=1>CN(C=O)C.CC(OC)(C)C>[CH2:33]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[N:11]([CH2:50][CH2:49][C:46]2[CH:47]=[CH:48][CH:43]=[CH:44][CH:45]=2)[CH:12]=1)=[O:7])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)c1cn(CCc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.4 %

Procedure:
To a stirred solution of 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (200 mg, 0.4 mmol) in dry DMF (5 mL) was added K2CO3 (168 mg, 1.22 mmol) and 2-phenethyl bromide (90 mg, 0.48 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 48 h. The reaction mixture was then cooled to 0° C., diluted with MTBE and quenched with water. The layers were separated and the aqueous layer was extracted with MTBE (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a crude oil. The crude material was purified by flash chromatography (gradient from 10% to 50% EtOAc/hexanes) to provide the title compound (175 mg, 72%). 1H NMR (CDCl3) 8.65 (d, J=2.0 Hz, 1H), 8.06 (dd, J=8.0, 2.0 Hz, 1H), 7.53 (s, 1H), 7.36-7.34 (m, 3H), 7.25-7.17 (m, 5H), 6.90 (d, J=8.0 Hz, 1H), 6.81-6.79 (m, 2H), 5.14 (s, 2H), 3.99 (s, 3H), 3.97-3.95 (m, 2H), 3.67 (t, J=7.2 Hz, 2H), 3.50 (br s, 2H), 2.76 (t, J=7.2 Hz, 2H), 1.70-1.60 (m, 4H), 1.40-1.20 (m, 4H), 0.98-0.84 (m, 6H); MS(ESI+) m/z 596.2 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=O)(=O)C.[C:17]([NH:19][C:20]([NH2:22])=[NH:21])#[N:18].[ClH:23]>O1CCOCC1>[ClH:23].[NH:19]([C:17]1[O:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[N:18]=1)[C:20]([NH2:22])=[NH:21]
Reactant: CC(=O)OCC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: N#CNC(=N)N
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1nc(-c2ccc([N+](=O)[O-])cc2)co1
Reaction time: 72 h

Procedure:
A solution of 90 gm of 4-nitro-phenacyl acetate and 33.9 gm of 1-cyano-guanidine in 200 ml of dioxane and 20 ml of 5N hydrochloric acid was stirred for 2 days at room temperature. A first crop of the product was filtered off; the solution, after the addition of another 40 ml of 5N hydrochloric acid, was stirred for 3 days and furnished a second crop of the product. The total yield of the title compound was 46 gm, m.p. >285° C.
Reaction SMILES: C([Si](CC)(CC)[O:4][C:5]1([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1)C.Cl.C(O)C>O>[OH:4][C:5]1([C:12]([F:13])([F:14])[F:15])[CH:6]=[CH:7][C:8](=[O:11])[CH:9]=[CH:10]1
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)C=CC(=O)C=C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1C=CC(O)(C(F)(F)F)C=C1
Yield: 90 %

Procedure:
A mixture of 200 mg (0.68 mmol) of 4-triethylsiloxy-4-trifluoromethyl-2,5-cyclohexadien-1-one and 1 mL of a solution of 1 part 37% hydrochloric acid in 9 parts absolute ethanol was heated at reflux overnight and poured into 10 mL of water. The resulting aqueous mixture was extracted with three 10 mL portions of dichloromethane. Combination, drying (MgSO4), and concentration of the organic layers afforded a residue which was purified by PTLC (one 2 mm silica gel plate eluted with 1% methanol--99% dichloromethane) to give 109 mg (89% yield) of 4-hydroxy-4-trifluoromethyl-2,5-cyclohexadien-1-one. An analytical sample was obtained by crystallization from dichloromethane-hexane: mp 84-86° C.; 1H NMR (CDCl3) δ 3.40 (broad s, 1H), 6.40 (d, 2H, J=10 Hz), 6.89 (d, 2H, J=10 Hz); 13C NMR (CDCl3) 70.2 (q, JCF =30 Hz), 125. 0 (q, JCF =286H), 132.2 (d), 142. 7 (d), 184.5 (s) ppm; 19F NMR (CDCl3) relative to CFCl3) -79.6 ppm (s); IR (KBr) 3374, 3105, 3022, 2919, 1693, 1671, 1632, 1620, 1396, 1249, 1235, 1195, 1174, 1089, 1078, 1003, 988, 980, 973, 863, 698 cm-1; mass spectrum (70 eV) m/z (relative intensity) 178 (5, M30), 109 (100), 81 (34), 53 (36). Anal. Calcd. for C7H5F3O2:C, 47.20; H, 2.83. Found: C, 47.42; H, 2.80.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+]>C1COCC1.O>[C:16]([NH:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:19])=[O:3])(=[O:18])[CH3:17]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(NC(C)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc(OC(C)(C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.2 %

Procedure:
2-(3-Acetylamino-phenoxy)-2-methyl-propionic acid ethyl ester (0.6 g, 2.2 mmol) was dissolved in THF (20 ml) and a solution of lithium hydroxide (0.33 g, 7.9 mmol) in water (5.8 ml) was added. The reaction mixture was allowed to stir at RT for 24 h. The solvent was removed under reduced pressure and the aqueous layer was extracted with EtOAc (10 ml). Aqueous layer was basified (pH˜5) with 1 N HCl at 0° C., extracted in EtOAc (2×50 ml) dried over Na2SO4 and concentrated under reduced pressure to afford the acid (0.45 g, 85%). 1H NMR (400 MHz, CDCl3): 1.61 (s, 6H), 2.11 (d, J=6.4 Hz, 3H), 4.65 (brs, 3H), 6.68 (d, J=8.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.29 (s, 1H), 7.60 (s, 1H); MS (EI) m/z: 238.1 (M+1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])(=[O:4])=[O:3].[CH:20]1([NH2:23])[CH2:22][CH2:21]1>N1C=CC=CC=1>[CH:20]1([NH:23][S:2]([C:5]2[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=2)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])(=[O:4])=[O:3])[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.00 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate, 1.2 mL of cyclopropylamine, and 20 mL of pyridine was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and to the residue was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with 1.0 M hydrochloric acid and saturated brine in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.12 g of 2-(trimethylsilyl)ethyl 3-(cyclopropylsulfamoyl)benzoate as a pale yellow oily substance. EI: 341
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:32])[CH2:18][CH2:17][CH:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([CH:16]1[CH2:15][CH2:14][C:13]([F:32])([F:12])[CH2:18][CH2:17]1)[C:22]1[CH:27]=[N:26][C:25]([C:28]([F:29])([F:30])[F:31])=[N:24][CH:23]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=482.1, tR (minutes, Method G)=2.76. [α]D20=+24.29 (c=0.70 mg/mL,CHCl3)
Reaction SMILES: [C:1]1([CH2:11][CH:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][C:13]2=[S:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.ClCCl>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][S:21][CH:13]1[CH:12]([CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14]1
Reactant: COC(=O)CCCBr
Reactant: S=C1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC(=O)CCCSC1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 75 mg (0.26 mmol) of 3-naphthalen-1-ylmethyl-imidazo[1,2-a]pyridine-2-thione and 70 mg (0.39 mmol) of methyl 4-bromobutyrate and 72 mg (0.52 mmol) of potassium carbonate in 3 mL of 50% acetone in dichloromethane is stirred at room temperature for 18 h. The mixture is concentrated in vacuo and the residue is purified by flash chromatography on silica gel eluting with 50˜75% ethyl acetate in hexanes to give the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[NH:21][C:20](=[O:22])[O:19][N:18]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[NH:21][C:20](=[O:22])[O:19][N:18]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2ccc3c(c2)c(-c2ccc(F)cc2)nn3C2CCCCO2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=c1[nH]c(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)no1
Yield: 19.1 %

Procedure:
To a solution of 3-[3-(4-fluorophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazol-5-yl]-1,2,4-oxadiazolin-5-one (88 mg, 0.23 mmol) in dioxane (4.0 mL) was added 6 N HCl (4.0 mL) at ambient temperature. After stirring for 16 h an additional amount of dioxane (1.0 mL) was added and the reaction mixture was gently heated in a 60° C. oil bath for 4 h after which an additional amount of 6 N HCl (1.0 mL) and several drops of methanol were added and after an additional 4 h of heating the reaction was stopped by slowly pouring into vigorously stirred aqueous 6 N NaOH (6.0 mL). The solution was adjusted to pH=8 with the addition of 4 N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give a pale orange solid which was purified by flash chromatography on silica gel eluting with 10% methanol in dichloromethane to give a pale yellow solid which was dissolved in a minimum amount of methanol and precipitated with ethyl ether and hexanes to afford the desired product as a pale powder (13 mg, 19% yield) 1H NMR (DMSO-d6): δ 13.6 (s, 1H), 13.0 (br s, 1H), 8.5 (s, 1H), 8.1–8.0 (m, 2H), 7.8 (q, 2H), 7.3 (t, 2H); ES-MS (m/z) 297 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8](=[N:27][OH:28])[C:9]2[C:10](F)=[C:11]([F:25])[C:12]([N:17]3[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]3)=[C:13]([CH2:15][OH:16])[CH:14]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:8]2[C:9]3[CH:14]=[C:13]([CH2:15][OH:16])[C:12]([N:17]4[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]4)=[C:11]([F:25])[C:10]=3[O:28][N:27]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C[C@@H]1CN(c2c(CO)cc(C(=NO)c3nccnc3Cl)c(F)c2F)C[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2c(CO)cc3c(-c4nccnc4Cl)noc3c2F)C[C@H](C)O1
Yield: 88.1 %

Procedure:
{5-[(3-chloropyrazin-2-yl)(hydroxyimino)methyl]-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3,4-difluorophenyl}methanol (Intermediate 198, 106 mg, 0.26 mmol) in MeCN (4 mL) was treated with K2CO3 (53.2 mg, 0.39 mmol) at 120° C. for 1 hr. The mixture was diluted with EtOAc and washed with water and brine. The EtOAc solution was dried over anhydrous sodium sulfate, filtered and concentrated to afford 90 mg of product.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.CCN(CC)CC.[Cl:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:17][CH2:18][CH2:19][CH2:20][C:21]([NH:8][CH:5]1[CH2:6][CH2:7][C:2]([F:9])([F:1])[CH2:3][CH2:4]1)=[O:22]
Reactant: O=C(Cl)CCCCl
Reactant: NC1CCC(F)(F)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCl)NC1CCC(F)(F)CC1
Reaction time: 4 h
Yield: 78.4 %

Procedure:
To a solution of 4,4-difluoro-cyclohexylamine (295 mg) and Et3N (0.91 mL) in 22 mL of CH2Cl2, add 4-chloro-butyryl chloride (0.42 g). Allow the resulting mixture to stand at room temp for 4 hr. Remove the organic solvent under vacuum. Dissolve the residue in Et2O. Wash the organic layer with 1N HCl, then brine, and then H2O, and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford 0.41 g of the title compound: mass spectrum (m/z): 240 (M+1).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:21][CH:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1>>[N:24]12[CH2:29][CH2:28][CH:27]([CH2:26][CH2:25]1)[CH:22]([NH:21][C:16]([C:15]1[C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=[CH:13][CH:14]=1)=[O:18])[CH2:23]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1cccc2nc(-c3ccccc3)oc12
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1cccc2nc(-c3ccccc3)oc12
Yield: 57 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenylbenzoxazole-7-carboxamide was prepared from 2-phenylbenzoxazole-7-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 7. This compound was obtained in 57% yield as a white solid: mp 179-180° C.; 1H NMR (300 MHz, CDCl3) δ 8.21 (dd, J=7.5, 2.1 Hz, 2H), 8.10 (dd, J=7.8, 1.2 Hz, 1H), 7.92 (dd, J=7.8, 1.2 Hz, 1H), 7.61-7.54 (m, 3H), 7.51-7.46 (m, 2H), 4.38-4.33 (m, 1H), 3.63-3.54 (m, 1H), 3.13-3.05 (m, 2H), 2.23 (q, J=3.0 Hz, 1H), 2.00-1.90 (m, 1H), 1.84-1.73 (m, 2H), 1.71-1.64 (m, 1H); MS (ESI) m/z 348[M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:18]([O:34][CH3:35])=[C:19]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[C:25]([F:32])[CH:24]=3)[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>[Fe].CO.O>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([NH:21][C:19]2[CH:20]=[C:15]([C:14]3[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:16]=[C:17]([C:36]([CH3:38])([CH3:39])[CH3:37])[C:18]=2[O:34][CH3:35])=[O:33])=[CH:24][C:25]=1[F:32]
Reactant: COc1c(NC(=O)c2ccc([N+](=O)[O-])c(F)c2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1c(NC(=O)c2ccc(N)c(F)c2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Temperature: 105 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
step 2—To a suspension of 316 (595 mg, 1.12 mmol) in a 1:1 mixture of MeOH/H2O (4 mL each) at RT was added NH4Cl (601 mg, 11.2 mmol) and iron powder (314 mg, 5.62 mmol). The reaction mixture was warmed to 105° C. and stirred overnight. The reaction was cooled to RT and filtered via Büchner funnel and the filtrate was rinsed with DCM. The filtrate was diluted with H2O and extracted with DCM. The extracts were washed with H2O and brine. The combined aqueous phases were back-extracted with DCM. The combined organic extracts were combined, dried (MgSO4), filtered, and concentrated. The crude residue was purified by SiO2 chromatography, eluting with an EtOAc/hexane gradient (0% to 40% EtOAc) to afford 405 mg (72%) of 4-amino-N-[5-(2-benzyloxy-pyridin-3-yl)-3-tert-butyl-2-methoxy-phenyl]-3-fluoro-benzamide (318) as a foamy, yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14](C(O)=O)[NH:15]2)=[CH:11][C:10]=1[F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN1CCCC1=O.[Cu]>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][C:10]=1[F:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc2cc(F)c(OCc3ccccc3)cc2[nH]1
Agent: [Cu]
Solvent: CN1CCCC1=O
Product: Fc1cc2cc[nH]c2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A mixture of compound 4-2 (2.58 g, 9.07 mmol) and copper (2.97 g, 45.1 mmol) in 80 mL of 1-methylpyrrolidin-2-one was heated at reflux overnight under nitrogen. After cooling to room temperature, the mixture was filtered through Celite and washed with EtOAc. The filtrate was partitioned between water and EtOAc (2×150 mL). The combined organic phase was washed with water and brine, and then dried over anhydrous Na2SO4. The black residue was purified by column chromatography (hexanes/EtOAc 2% to 12%) to give compound 4-3 (1.31 g, 60%) as a white solid. 1H NMR (CDCl3, 300 MHz) □ 5.16 (s, 2H), 6.94-6.98 (m, 1H), 6.96 (d, 1H, J=7.1), 7.10-7.14 (m, 1H), 7.29-7.42 (m, 4H), 7.44-7.50 (m, 2H), 8.01 (bs, 1H). APCI [M−1]: 240.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:10]([CH2:18][CH3:19])=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=1.[Li+].[OH-].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:10]([CH2:18][CH3:19])=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1CC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(C(=O)O)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Part A: Ethyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylate was obtained according to WO03040107. To a magnetically stirred solution of ethyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylate (5.80 g, 0.0149 mol) in tetrahydrofuran (40 ml) was added a solution of LiOH (0.715 g) in water (40 ml). The resulting mixture was heated at 70° C. for 16 hours. The resulting mixture was allowed to attain room temperature and subsequently treated with concentrated hydrochloric acid (3.5 ml). The tetrahydrofuran was evaporated in vacuo and the resulting mixture was stirred overnight. The formed precipitate was collected by filtration and washed with petrolaum ether (40-60) to give 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylic acid (4.52 gram, 84% yield). 1H-NMR (400 MHz, CDCl3): δ 1.09 (t, J=7, 3H), 2.90 (q, J=7, 2H), 3.70 (br s, 1H), 7.12 (dt, J=8 and 2, 2H), 7.22-7.28 (m, 1H), 7.29-7.38 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)([CH3:23])[CH3:22]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([CH:21]([CH3:23])[CH3:22])[CH:29]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(C(C)C)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-isopropyl-phenylboronic acid (53 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.