Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[OH:1][C:2]1[C:11]([N+:21]([O-:23])=[O:22])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:13])([F:14])[F:15])[CH:3]=1
Reactant: COC(=O)c1ccc(O)cc1C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(O)cc1C(F)(F)F
Temperature: 65 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
Methyl 4-hydroxy-2-(trifluoromethyl)benzoate (32.0 g) was dissolved in acetic acid (180 ml), and thereto was added conc. sulfuric acid (0.45 ml), and the mixture was heated to 65° C. Then, thereto was slowly added a 70% solution of conc. nitric acid (12.4 g) in acetic acid (60 ml) dropwise, and the mixture was stirred at 65° C. for one hour. The reaction mixture was cooled to room temperature, and poured into ice-water (500 ml), and the mixture was extracted twice with toluene (800 ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (15.0 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:12]2[NH:13][C:14]3[CH:20]=[C:19]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[O:21]([C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:9]3[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[NH:7][C:8]=3[CH3:28])[NH:13][C:14]=2[CH:20]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1[nH]c(C)c(-c2nc3ccc(Oc4ccccc4)cc3[nH]2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)O)c(C)c1-c1nc2ccc(Oc3ccccc3)cc2[nH]1
Temperature: 80 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
The 4-(5-phenoxybenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxylic acid ethyl ester (1.88 g, 5.0 mmol) obtained in Example 68 was dissolved in ethanol (10 ml) and tetrahydrofuran (5 ml). To this solution was added a 4 N sodium hydroxide aqueous solution (6 ml, 24 mmol), and the mixture was stirred at 80° C. for 6 hours. The reaction mixture was cooled to 0° C., and neutralized with a 1 N hydrochloric acid solution. The precipitate was collected by filtration, and washed with water and dried at reduced pressure to afford 4-(5-phenoxybenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxylic acid (1.70 g, 98%) as a light yellow solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:9][C:8]=1[F:22].[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH:26]=[O:27]>C(OCC)C>[C:16]([O:15][C:13]([NH:12][CH2:11][C:10]1[CH:20]=[CH:21][C:7]([CH:26]([OH:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH3:23])=[C:8]([F:22])[CH:9]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)c(F)c1
Reactant: CC(C)(C)CC=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)CC(O)c1ccc(CNC(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
Add butyllithium (7.3 mL, 11.7 mmol) to a solution of 4-bromo-N-(tert-butoxycarbonyl)-3-fluoro-benzylamine (1.55 g, 5.1 mmol) in diethyl ether (54 mL) at −78° C. under nitrogen and stir for 30 min. Add 3,3-dimethylbutyraldehyde (562 mg, 0.7 mL, 5.6 mmol), stir for 30 min at −78° C. and then warm to room temperature. Add water and extract twice the aqueous phase with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (85:15) to obtain the desired intermediate as a yellow oil (394 mg, 24%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[S:6][C:5]2[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.C(N=[C:21]=[O:22])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[CH3:1][C:2]1([CH3:15])[S:6][C:5]2[C:7]([S:11]([N:14]=[C:21]=[O:22])(=[O:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1
Reactant: CCCCN=C=O
Reactant: CC1(C)Cc2cccc(S(N)(=O)=O)c2S1
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: CC1(C)Cc2cccc(S(=O)(=O)N=C=O)c2S1

Procedure:
To a refluxing solution of 8.6 g of 2,3-dihydro-2,2-dimethyl-7-benzo[b]thiophenesulfonamide (Example 14), 4.0 ml of n-butylisocyanate and 0.1 g of DABCO in 100 ml of xylenes was added 3.0 ml of phosgene at such a rate that the reaction temperature did not drop below 135° C. The mixture was refluxed for 1.5 hours, then the excess phosgene was purged with a stream of dry nitrogen. The mixture was cooled, filtered and concentrated in vacuo to yield the title compound as an oil. The crude yield was assumed to be near quantitative. IR (neat) 2220 cm-1 (NCO).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([NH:18][NH2:19])=[O:17])[N:13]=2)=[N:6][CH:7]=1.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[O:17][C:32]([OH:33])=[N:19][N:18]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: NNC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Oc1nnc(CCc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)o1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
To a mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanehydrazide (0.150 g, 0.345 mmol) in THF (5 mL) was added TEA (0.04814 mL, 0.3454 mmol) and cooled in an ice bath. To this mixture was added. CDI (0.0672 g, 0.414 mmol) in one portion. The mixture was allowed to warm to ambient temperature and was then heated at 50° C. overnight. The reaction was concentrated to dryness, dissolved in CH2Cl2 and washed with water, dried over Na2SO4, concentrated to a residue that was purified by preparative HPLC to give the title compound (0.045 g, 28.31% yield) was white solids. 1H NMR (d6 DMSO) δ 2.91 (s, 4H), 6.75 (s, 1H), 7.10 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.4 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.44 (t, J=7.9 Hz, 2H), 8.22 (d, J=2.1 Hz, 1H), 11.03 (br s, 1H), 12.04 (br s, 1H).
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:21](Cl)=[O:22]>COCCOC>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:21]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[O:22]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)C(C(=O)OCC)C(=O)OC(C)(C)C)cc1F

Procedure:
A solution of 28.0 g. of tert-butyl ethyl malonate in 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g of 3-fluoro-4-(hexadecylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue is then recrystallized from ether to yield tert-butyl ethyl 3-fluoro-4-(hexadecylamino)benzoylmalonate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:31]([F:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([O:44][CH3:45])[CH:38]=1>>[F:32][C:31]1[C:26]([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[CH2:19][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[S:15]([CH3:18])(=[O:17])=[O:16])=[N:27][C:28]([NH:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([O:44][CH3:45])[CH:38]=2)=[N:29][CH:30]=1
Reactant: COc1cc(CCN)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3nc(Cl)ncc3F)c2)S(C)(=O)=O)CC1
Product: COc1cc(CCNc2ncc(F)c(-c3cccc(CN(C4CCNCC4)S(C)(=O)=O)c3)n2)ccc1O

Procedure:
Intermediate 77 was coupled with 4-(2-amino-ethyl)-2-methoxy-phenol following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 530. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.25 (d, 1H), 8.14 (s, 1H), 7.97 (d, 1H), 7.48 (m, 2H), 6.82 (s, 1H), 6.69 (s, 2H), 4.54 (s, 2H), 3.91 (m, 1H), 3.80 (s, 3H) 3.60 (t, 2H), 3.32 (m, 2H), 3.03 (s, 3H), 2.94 (m, 2H), 2.81 (t, 2H), 1.87 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1.[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:37][N:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1.O>CN(C)C=O>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:26][C:27]5[CH:28]=[CH:29][C:30]([C:33](=[O:37])[CH2:34][C:35]#[N:36])=[CH:31][CH:32]=5)[C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: BrCc1ccc(-c2ccno2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(C(=O)CC#N)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a solution of 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.35 g, 1.20 mmol) in anhydrous N,N-dimethylformamide (20 mL) at 0° C. was added slowly sodium hydride (60% w/w dispersion in mineral oil, 0.072 g, 1.50 mmol). The solution was stirred at ambient temperature for 30 min, 5-(4-(bromomethyl)phenyl)isoxazole (Sasaki et al., Biorg. Med. Chem. Lett. (1998) δ:2241-2246) (0.24 g, 1.00 mmol) was added and the mixture was stirred for 16 h at ambient temperature. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (3×100 mL), dried over magnesium sulftate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 15% to 50% gradient of ethyl acetate in hexanes to afford 3-{4-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]phenyl}-3-oxopropanenitrile (0.33 g, 61%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.96-7.92 (m, 2H), 7.63-7.60 (m, 2H), 7.50-7.46 (m, 1H), 7.23-7.13 (m, 2H), 7.04 6.97 (m, 2H), 6.71-6.67 (m, 1H), 5.43-4.76 (m, 4H), 4.06 (s, 2H), 2.46 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1([CH3:22])[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:23].[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31].C(N(CC)CC)C.Cl>C1COCC1>[Cl:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([C:14]2([CH3:22])[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:7]3=[O:23])=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: Cc1ccc(N=C=O)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cc1Cl
Reaction time: 2 h
Yield: 56.9 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.50 g, 1.50 mmol) and 3-chloro-4-methyl-phenyl isocyanate (0.25 g, 1.50 mmol) in THF (25 mL), was added triethylamine (0.42 mL, 3.00 mmol) at room temperature under nitrogen. After 2 h, 2% aq. HCl (75 mL) was added. The product was extracted with EtOAc (75 mL) and the organic layer was separated and washed with water (2×75 mL), dried (MgSO4) and concentrated in vacuo to give 1-(3-chloro-4-methyl-phenyl)-3-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.40 g, 58% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.37 min (98.73%); mp: 232-234° C.; 1H NMR (DMSO-d6) δ 1.89 (s, 3H), 1.98-2.13 (m, 1H), 2.23 (s, 3H), 2.52-2.79 (m, 3H), 4.44 (d, J=6.0 Hz, 2H), 6.89 (t, J=5.9 Hz, 1H), 7.08-7.21 (m, 2H), 7.64 (d, J=1.9 Hz, 1H), 7.72-7.88 (m, 3H), 8.82 (s, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 18.74, 21.02, 28.58, 29.11, 442.65, 58.76, 116.53, 117.74, 121.37, 123.13, 127.53, 129.49, 131.02, 131.37, 132.97, 133.21, 139.49, 148.47, 155.10, 167.77, 167.93, 172.13, 172.21; LCMS: MH=469/471; Anal Calcd for C23H21ClN4O5: C, 58.91; H, 4.51; N, 11.95. Found: C, 58.63; H, 4.40; N, 11.82.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([N:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:27](Cl)=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1C=CC=CC=1>[CH2:8]([N:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:27]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CN1CCNCC1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)N1CCN(C)CC1
Reaction time: 3 h

Procedure:
A mixture of 1-methylpiperazine (5 ml.), N,N-dioctadecylcarbamylchloride (5.0 g.) and benzene (50 ml.) is refluxed and stirred for three hours. The white precipitate of 1-methylpiperazine hydrochloride is removed by filtration and the filtrate concentrated in vacuo to a yellow oil (4.5 g.). The oil is then charged on a silica gel pad and eluted with benzene in 50 ml. fractions. Fractions 10-15 are combined, a large volume of methanol added and the white crystalline material which separates filtered and dried, m.p. 46°-47° C. (1.45 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Fc1cc(N2CCNCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To 60 ml of n-butanol were added 5.0 g of 3-fluoro-5-(trifluoromethyl)aniline and 5.0 g of bis(2-chloroethyl)amine hydrochloride, and the mixture was heated under reflux for 47 hours. To the reaction mixture was added 3.85 g of potassium carbonate, followed by heating under reflux for 24 hours. After cooling to room temperature, the solvent was removed by evaporation. The residue was dissolved in an 1N sodium hydroxide aqueous solution and extracted with chloroform-methanol (19:1 by volume). The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed by evaporation, and the residue was subjected to silica gel column chromatography using a 9:1 (by volume) mixed solvent of chloroform and methanol as a developing solvent. The fraction containing the desired compound was concentrated to yield 2.1 g of the title compound.
Reaction SMILES: [O:1]1[C:5]([C:6](OCC)=[O:7])=[CH:4][C:3]2[CH:11]=[CH:12][C:13]3[C:18]([C:2]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3.[BH4-].[Li+].C1COCC1.Cl>O>[O:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH:11]=[CH:12][C:13]3[C:18]([C:2]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CCOC(=O)c1cc2ccc3ccccc3c2o1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2ccc3ccccc3c2o1
Yield: 85 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet line with bubbler was added ethyl naphtho(1,2-b]furan-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc., 6.85 g, 28.5 mmol), lithium borohydride (Aldrich, 0.62 g, 28.5 mmol) and dry THF (400 mL). The mixture was stirred at reflux for 6 h and then poured into H2O (1 L). The reaction mixture was acidified with 1N HCl and the resulting white solid was filtered, washed with additional H2O (500 mL) then dissolved in CH2CL2 (500 mL), dried (Na2SO4), filtered, concentrated to 200 mL and diluted to 500 mL with hexane. The resulting material was filtered, washed with hexane (100 mL), and placed in a vacuum oven overnight (80°) to give a total of 4.8 g (69.7%) of naphtho[1,2-b]furan-2-methanol, mp 105.5°-107°, (C,H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=[O:9].O.NN>[Rh].O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][OH:9]
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Rh]
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: ONc1ccccc1F
Reaction time: 0.33 h

Procedure:
0.5 g of a commercial rhodium catalyst (5% on charcoal) was added to a stirred mixture of 25 g of 2-fluoronitrobenzene and 250 ml of tetrahydrofuran at room temperature. Then 16.5 g of hydrazine hydrate was added, drop-by-drop, to the stirred mixture, maintained at 15°-20° C. After 20 minutes, another 0.5 g of the rhodium catalyst was added, then another 2 g of hydrazine hydrate was added. The mixture was stirred at 15°-20° C. for 2 hours, then filtered through Celite. The filtrate was extracted with ether, the extract was washed with water, and dried (MgSO4) and the solvent was evaporated. The residue was triturated with ether and hexane, and kept cold until filtered. The filter cake was washed with cold hexane and air-dried to give N-(2-fluorophenyl)hydroxylamine (1B) as a colorless solid, mp: 70°-71° C. It is moderately unstable at room temperature.
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:6]([C:16]([O:18]C)=[O:17])=[C:7]([N:9]3[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]3[CH3:15])[N:8]=2)[CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+]>C1COCC1>[CH:1]1([C:4]2[N:5]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:6]([C:16]([OH:18])=[O:17])=[C:7]([N:9]3[C:10]([CH3:15])=[CH:11][CH:12]=[C:13]3[CH3:14])[N:8]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1c(-n2c(C)ccc2C)nc(C2CC2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1nc(C2CC2)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 2-cyclopropyl-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylate (Example 42, 1.91 g) in anhydrous THF was added potassium trimethylsilanolate (1.57 g) and the mixture stirred at ambient temperature for 20 hours. The solvent was removed under reduced pressure and the residue taken-up in water (25 mL). The aqueous solution was filtered and extracted with ethyl acetate. The aqueous layer was acidified to pH 4.5 with 1N HCl and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated to give the title compound 2-cyclopropyl-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylic acid. MS (CI, CH4 +NH3) 480 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:33]([O:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCC(N)CC2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC(NC(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 4-(4-aminopiperidin-1-yl)-benzoic acid ethyl ester (15.7 g, 63.2 mmol) obtained in Example 7(1) was dissolved in THF (200 ml), and a 2M sodium carbonate aqueous solution (63 ml) was added thereto. Subsequently, benzyloxycarbonyl chloride (11.7 ml, 82.2 mmol) was added thereto, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solid obtained by evaporation under reduced pressure was collected by filtration and dried under reduced pressure, thereby obtaining 4-(4-benzyloxycarbonylaminopiperidin-1-yl)-benzoic acid ethyl ester (18.0 g, 74%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.B([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[CH3:22])(O)O>>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[CH3:22])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(C(=O)O)ccc1B(O)O
Reactant: Cc1cc(Br)ccc1N
Product: Cc1cc(-c2ccc(C(=O)O)cc2C)ccc1N

Procedure:
The title compound was prepared from 4-bromo-2-methylaniline and 4-borono-3-methylbenzoic acid (D29) using a similar procedure to Description 1 as a brown solid (41%). This was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:40])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([C:20]([F:23])([F:21])[F:22])=[CH:10][C:9]2[NH:24][C:25](=[O:40])[CH2:26][C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N:34]4[CH:38]=[CH:37][CH:36]=[N:35]4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cccn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cccn3)c1)=N2

Procedure:
The title compound was prepared from {5-(isobutyl-methyl-amino)-2-[3-oxo-3-(3-pyrazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M119) (0.49 g, 0.85 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (324 mg, 83%).