Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6](C(OC(C)(C)C)=O)[CH:5]=1)#[N:2].[H-].[Na+].[F:24][C:25]1[C:30]([CH:31]=O)=[CH:29][CH:28]=[CH:27][N:26]=1.C(OCC)C>C1COCC1>[F:24][C:25]1[C:30](/[CH:31]=[C:3](/[C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[NH:6][CH:5]=2)\[C:1]#[N:2])=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: O=Cc1cccnc1F
Reactant: COc1ccc2c(c1)c(CC#N)cn2C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3cccnc3F)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-5-methoxy-1H-indol-1-carboxylate (719 mg, 2.51 mmol, 1.0 eq.) in anhydrous THF (30 mL) was added, under an argon atmosphere, NaH (106 mg, 80%, 3.52 mmol, 1.4 eq.). The mixture was stirred at room temperature for 2 hours, and then cooled to 0° C. before the addition of 2-fluoro-pyridine-3-carbaldehyde (440 mg, 3.52 mmol, 1.4 eq.) in anhydrous THF (6 mL). The reaction apparatus was protected from light and the mixture was stirred at 0° C. for 24 hours, at room temperature for 24 hours too and then, quenched with a saturated aqueous ammonium chloride solution. The mixture was stirred again at room temperature for 24 hours and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 98/2) to afford, after trituration with diethyl ether, the compound (48) as a yellow powder (220 mg, 30%). IR νmax (cm−1): 2219 (νCN), 3228 (νN—H); 1H NMR (DMSO, 300 MHz): δ (ppm): 3.81 (3H, s, 5′-methoxy), 6.91 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.1 Hz, H6′), 7.42 (1H, d, J7′-6′=8.9 Hz, H7′), 7.43 (1H, d, J4′-6′=2.4 Hz, H4′), 7.53 (1H, m, H5″), 7.64 (1H, s, H3), 7.84 (1H, s, H2′), 8.29 (1H, d, J6″-5″=4.5 Hz, H6″), 8.49 (1H, m, H4″), 11.73 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz): δ (ppm): 55.5 (5′-methoxy), 101.5 (C4′), 109.8 (C2), 110.0 (C3′), 112.5 (C6′), 113.3 (C7′), 117.3 (C1), 118.0 (1C, d, 2JC—F=28 Hz, C3″), 122.3 (1C, d, 4JC—F=4 Hz, C5″), 123.9 (C3a′), 125.8 (C3), 128.1 (C2′), 132.2 (C7a′), 139.4 (1C, d, 3JC—F=3 Hz, C4″), 147.5 (1C, d, 3JC—F=15 Hz, C6″), 154.7 (C5′), 159.7 (1C, d, 1JC—F=270 Hz, C2″); ESI: 294.1 ([M+H]+), 316.1 ([M+Na]+), 348.1 ([M+Na+MeOH]+); HRESI-MS: m/z 316.0861 (calcd for C17H12N3OFNa+, 316.0862).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20](=[O:34])[C:21]([CH3:33])([CH3:32])[O:22][C:23]=4[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[CH:15][CH:14]=3)[N:10]=2)[N:7]=1.C(NCC)C.[H][H]>CO.[OH-].[Pd+2].[OH-]>[N:10]1[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20](=[O:34])[C:21]([CH3:32])([CH3:33])[O:22][C:23]=3[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[CH:17][CH:18]=2)=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:7]2
Reactant: COc1ccc(C2=C(c3ccc(OCc4cn5nc(Cl)ccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCNCC
Solvent: CO
Product: COc1ccc(C2=C(c3ccc(OCc4cn5ncccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Palladium hydroxide (36 mg) was added to a solution of 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (180 mg, 0.37 mmol) and diethyl amine (28 mg, 0.37) in methanol (25 ml) at RT under an atmosphere of nitrogen. The nitrogen atmosphere was exchanged for hydrogen and was stirred at RT for 2 h (the reaction was monitored by TLC). The compound was filtered through a bed of Celite® bed washing with methanol. The filtrate was concentrated under reduced pressure to afford 4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (160 mg, 96.7%,) as a white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.45 (s, 1H), 8.4 (s, 1H) 8.15 (d, 1H), 7.55 (d, 2H), 7.25 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.25 (s, 2H) 3.8 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=442.3. HPLC: (97.4%, Condition-A).
Reaction SMILES: [C:1]([C:5]([N:7]=[C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH:11]=[C:10]([CH3:23])[S:9]1)=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1>C1COCC1>[C:1]([C:5]([N:7]=[C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH:11]=[C:10]([CH3:23])[S:9]1)=[S:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(C)(C)C)s1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=S)C(C)(C)C)s1
Yield: 57.3 %

Procedure:
A solution of 2-[(t-butylcarbonyl)imino]-3-[3-(trifluoromethyl)phenyl]-5-methylthiazoline (1 g) and 2,4bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4disulfide (2 g) in THF (10 ml) was refluxed for 2 days. After cooling and removal of the solvent under reduced pressure, the concentrated residue was added pottasium hydrogencarbonate. The obtained crystallines were recrystallized to give 0.6 g of 2-[t-butyl(thiocarbonyl)]imino-3-[3-(trifluoromethyl)phenyl]-5-methylthiazoline (Compound No. 3).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH:25]=[C:24](B(O)O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH:23]=[C:24]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:6][N:7]=2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Brc1ccc(-c2ncccn2)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B(O)O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3ncccn3)cn2)CC1

Procedure:
Refluxed mixture of 2-(6-Bromo-pyridin-3-yl)-pyrimidine (1Q) (200 mg, 0.85 mmol), N-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid, pinacol ester (290 mg, 0.93 mmol); Cesium Carbonate (500 mg, 1.538 mmol); PdCl2dppf (30 mg) in dioxane/H2O (10 ml v/v 4/1) for 4 hours. Cooled reaction, then evaporated solvent. Extracted with EtOAc (200 ml) washed with H2O (50 ml), dried over MgSO4, filtered and solvent evaporated yielding a solid which chromatographed on silica gel eluting with 30% v/v acetone/hexanes yielding 2Q as a white solid (110 mg, 38%) ESMS (MH, 339).
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].N[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[C@H:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[C:10]([O:12][CH3:13])=[O:11].N1C=CC=CC=1.[FH:29]>>[C:20]([NH:19][C@@H:17]([C:16]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[F:29])[CH3:18])(=[O:22])[CH3:21]
Reactant: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(N)c1
Reactant: F
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium nitrate (640 mg) was added to a solution of methyl (R)-3-amino-4-(1-acetamidoethyl)benzoate (2 g) in hydrogen fluoride-pyridine (20 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to give 690 mg of methyl (R)-4-(1-acetamidoethyl)-3-fluorobenzoate.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][CH2:25][CH:26]2[O:28][CH2:27]2)=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S(=O)(=O)(O)[OH:32].COCCOC>O>[CH2:1]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][CH2:25][CH:26]([OH:28])[CH2:27][OH:32])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC2CO2)cc1
Solvent: O
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A mixture of 100 mg of 2,3-epoxypropyl 4-(n-hexadecylamino)benzoate, 0.2 ml of 1N sulfuric acid, and 1.0 ml of 1,2-dimethoxyethane is heated under reflux for one hour, diluted with water, and filtered to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate as a white solid, mp 112° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C@@H:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][C:6]=2[CH:22]=1.[N:23]1[C:32]2[NH:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:26]=[CH:25][C:24]=1[CH2:33][CH2:34]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:23]1[C:32]2[NH:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:26]=[CH:25][C:24]=1[CH2:33][CH2:34][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C@@H:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][C:6]=2[CH:22]=1
Reactant: CCOC(=O)C[C@@H]1Cc2ccc(O)cc2Cc2ccccc21
Reactant: OCCc1ccc2c(n1)NCCC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1Cc2ccc(OCCc3ccc4c(n3)NCCC4)cc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.7 %

Procedure:
To a solution of ethyl (S)-10,11 -dihydro-3-hydroxy-5H-dibenzo[a,d]cycloheptene-10-acetate (200 mg, 0.67 mmole), 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1 -ethanol (241 mg, 1.35 mmole), and PPh3 (354 mg, 1.35 mmole) in dry THF (5 mL) was added diisopropyl azodicarboxylate (0.27 mL, 1.35 mmole) at 0° C. The mixture was allowed to warm to RT as the bath warmed. After 18 hr, the mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel (1:4.5 hexanes/Et2O) to give the title compound (94 mg, 31%) as a clear oil: MS (ES) m/e 457 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][CH:4]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:33][NH:34][O:35][CH3:36]>O1CCCC1>[CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:34]([O:35][CH3:36])[CH3:33])=[O:11])=[CH:5][CH:4]=1
Reactant: CNOC
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CON(C)C(=O)Cc1ccc(N(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To a 0° C. mixture of 4-(dimethylamino)phenylacetic acid (4.91 g, 27.40 mmol) in tetrahydrofuran (150 ml), were added 2-chloro-4,6-dimethoxy-1,3,5-triazine (5.05 g, 28.76 mmol) and 4-methylmorpholine (9.6 ml, 87.32 mmol). The reaction mixture was stirred for 1 hour at 0° C. N,O-dimethylhydroxylamine hydrochloride (5.35 g, 54.84 mmol) was added and stirred for 18 hours at room temperature. The reaction was quenched with saturated ammonium chloride solution, and extracted with methylene chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (0 to 40% ethyl acetate in hexanes) to give 2.76 g (45%) of 2-(4-dimethylamino-phenyl)-N-methoxy-N-methyl-acetamide. 1H NMR (250 MHz, CDCl3) δ 7.15 (d, J=8.7 Hz, 2H), 6.67 (s, J=8.7 Hz, 2H), 3.65 (s, 2H), 3.58 (s, 3H), 3.16 (s, 3H), 2.89 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].S(Cl)([Cl:18])(=O)=O.C(=O)(O)[O-].[Na+].[Na+].[Cl-]>CC#N.CCOC(C)=O>[NH2:1][C:2]1[C:7]([Cl:18])=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1nc(Cl)cc(N)c1OC
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Cl)c(Cl)c(N)c1OC
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
Methyl 4-amino-6-chloro-3-methoxypicolinate (260 mg, 1.2 mmol) was dissolved in dry CH3CN (7 mL), treated with sulfuryl chloride (120 μL, 1.5 mmol) and stirred for 30 min The solution was stirred with satd aq sodium bicarbonate (NaHCO3; 10 mL) for 20 min and then mixed with EtOAc (20 mL) and satd aq NaCl (10 mL). The aqueous phase was extracted with EtOAc (15 mL), and the combined organic phases were washed with satd aq NaCl (10 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (240 mg, 80%): mp 119-121° C.; 1H NMR (400 MHz, CDCl3) δ 5.04 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H); EIMS m/z 250.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:23])=[C:10]([C:12]2[NH:21][C:20](=O)[C:19]3[C:14](=[N:15][CH:16]=[CH:17][N:18]=3)[N:13]=2)[CH:11]=1>C(Cl)(Cl)Cl.CN(C=O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:23])=[C:10]([C:12]2[N:21]=[C:20]([Cl:3])[C:19]3[C:14](=[N:15][CH:16]=[CH:17][N:18]=3)[N:13]=2)[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Fc1ccc(Br)cc1-c1nc(Cl)c2nccnc2n1
Yield: 99.3 %

Procedure:
Thionyl chloride (371 mg, 3.11 mmol) was added to the stirred suspension of 2-(5-bromo-2-fluorophenyl)pteridin-4-one 104 (200 mg, 0.623 mmol) in chloroform (5 mL) and dry DMF (100 μL). The reaction mixture was refluxed under nitrogen for 1 h (starting material gone by HPLC). The solvent was removed in vacuo. Then the residue was triturated in Et2O and filtered off to give 210 mg of the title product 106 as a yellow solid (LCMS analysis).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:13]([NH2:14])=[C:12]([Cl:21])[CH:11]=1.O>C(#N)C>[Br:9][C:10]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:13]([NH:14][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:12]([Cl:21])[CH:11]=1
Reactant: Nc1c(Cl)cc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)CC(=O)Cl
Solvent: O
Solvent: CC#N
Product: CC(C)(C)CC(=O)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,3-Dimethylbutanoyl chloride (1.08 g, 8.0 mmol) was added to a solution of 4-bromo-2-chloro-6-(trifluoromethyl)aniline (2.0 g, 7.3 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography in dichloromethane afforded the title compound as a powder (1.22 g, 65% over the two steps).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[NH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:46]([O:45][C:43](=[O:44])[NH:42][CH2:41][CH2:40][NH:39][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 5-(4′-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole made as described in Preparation 1 (20.9 g, 40 mmol), N-(2-aminoethyl)(t-butoxy) carboxamide (15 g, 90 mmol), and potassium carbonate (15.5 g, 110 mmol) in THF (75 mL) was stirred for 48 hours at room temperature. The mixture was concentrated and extracted with 1M aqueous KOH (20 mL) and EtOAc (2×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Silica gel chromatography (EtOAc:hexanes) gave intermediate (7a) as a white solid (12.7 g).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:22])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:22])[NH:11][C:12]([C:15]1[CH:16]=[C:17]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:18]=[CH:19][CH:20]=1)([CH3:14])[CH3:13])[CH2:2]2
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cccc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cccc(-c2ccc(F)cc2)c1
Yield: 59.8 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromophenyl)propan-2-yl]carbamate (600 mg, 1.63 mmol), 4-fluorophenyl boronic acid (457 mg, 3.27 mmol) and palladium (II) acetate gave the title compound as a white solid (373 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.52 (dd, J=5.4, 8.4 Hz, 2H), 7.42-7.38 (m, 3H), 7.12 (m, 2H), 5.18 (s, 1H), 4.62 (s, 1H), 2.66 (m, 6H), 1.72 (s, 6H), 2.01-0.83 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 125.0, 124.0, 123.8, 116.0, 116.0, 71.3, 55.9, 55.5, 47.6, 46.7, 29.6, 25.6, 24.8, 19.8 ppm. Purity: 98.0% UPLCMS (210 nm); retention time 0.95 min; (M+1) 382.9. Anal. Calcd. for C23H27FN2O2.0.37 (CHCl3): C, 65.86; H, 6.47; N, 6.57. Found: C, 65.85; H, 6.69; N, 6.49.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:11]=2[CH:29]=1.[CH:30]1([C:36]2[CH:41]=[CH:40][C:39]([SH:42])=[CH:38][CH:37]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([C:36]2[CH:37]=[CH:38][C:39]([S:42][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[CH:9][C:10]4[NH:15][C:14](=[O:16])[O:13][C:12]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)([CH:17]5[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]5)[C:11]=4[CH:29]=3)=[CH:40][CH:41]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: O=C1Nc2ccc(OCCCCCl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Reactant: Sc1ccc(C2CCCCC2)cc1
Product: O=C1Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc2C(C2CCCCC2)(C2CCCCC2)O1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dicyclohexyl-4H-3,1-benzoxazin-2-one and 4-cyclohexyl-thiophenol.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=O)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9](/[CH:13]=[CH:24]/[C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[O:25])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CON=C1CCc2cc(C=O)ccc21
Product: CON=C1CCc2cc(/C=C/C(=O)c3ccc(OC)cc3)ccc21
Yield: 91 %

Procedure:
The title compound (7.75 g, 91%) was prepared from the product of Example 1 Step 2 and 1-(4-methoxy-phenyl)ethanone using the method of Example 2 Step 1; MS(ES+) m/e 322 [M+H]+.
Reaction SMILES: CS(O[N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@@H:13]2[CH2:17][C@H:16]([S:18][C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][N:14]2[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)=[O:39])[CH2:8][CH2:7]1)(=O)=O.[N-:51]=[N+:52]=[N-:53].[Na+]>CN(C)C=O>[N:51]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@@H:13]2[CH2:17][C@H:16]([S:18][C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][N:14]2[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)=[O:39])[CH2:8][CH2:7]1)=[N+:52]=[N-:53]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)ON1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NN1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 61.9 %

Procedure:
A solution of (2S,4S)-2-[(4-methanesulfonyloxypiperizin-1-yl)methyl]-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (4.38 g) and sodium azide (1.19 g) in N,N-dimethylformamide (40 ml) was stirred at 90°-100° C. for 2 hours. The reaction mixture was poured into ice-water (300 ml) and extracted 3 times with saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of dichloromethane and acetone (10:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-[(4-azidopiperizin-1-yl)methyl]-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (2.51 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]3[CH:18]=[CH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:21][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]3[CH:18]=[CH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:21][C:10]=3[N:9]=2)=[CH:4][CH:3]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)cc1)n2C1CCCC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(NC(=O)c3ccccc3)cc1)n2C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
Ethyl 1-cyclopentyl-2-(4-aminophenyl)benzimidazole-5-carboxylate (300 mg) obtained in Example 22 was dissolved in pyridine (3 ml) and chloroform (3 ml), and benzoyl chloride (127 mg) was added. The mixture was stirred for 30 min at room temperature. The reaction mixture was concentrated under reduced pressure and water was added to the residue to allow crystallization. The crystals were collected by filtration to give the title compound (403 mg, yield 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:6][C:5]=1[OH:21].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:6][C:5]=1[O:21][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCOc1ccc(O)c(C(=O)OC)c1
Product: CCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Yield: 81 %

Procedure:
The reaction of 5-(decyloxy)-2-hydroxybenzoic acid methyl ester with benzyl bromide under conditions described in Example 59 gave 5-(decyloxy)-2-(phenylmethoxy)benzoic acid methyl ester (81% yield, mp 32°-34°).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[C:8]([Cl:21])[C:7]=1[CH2:22][CH3:23])(=[O:4])[CH2:2][CH3:3].[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>>[C:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[CH:16][CH:15]=2)=[C:8]([Cl:21])[C:7]=1[CH2:22][CH3:23])(=[O:4])[CH2:2][CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CCC(=O)Oc1cc(Cl)c(Oc2ccc(N)cc2)c(Cl)c1CC
Product: CCC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)C(C)C)cc2)c(Cl)c1CC
Yield: 83.5 %

Procedure:
Ethyl(3,5-dichloro-4-[4-aminophenoxy]phenyl) propionate (80 mg) was coupled with isobutyryl chloride (30 mg), using the method described in Example 1(h). After recrystallization (ethyl acetate/petrolium ether), 80 mg of ethyl(3,5-dichloro-4-[4-isobutyr-amidophenoxy]phenyl) propionate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 50 mg of 3,5-dichloro-4-(4-isobutyramidophenoxy)-phenylpropionic acid, m/z 382.