Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:19][C:20]1[CH:21]=[C:22]([C:26]2([CH2:32][CH2:33][N:34]3[CH:39]4[CH2:40][CH2:41][CH:35]3[CH2:36][CH:37]([N:42]3[C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=5[N:44]=[C:43]3[CH3:51])[CH2:38]4)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ClC1C(C(N2CCC(C3C=CC=C(F)C=3)(CCN3C4CCC3CC(N3C5C=CC=CC=5N=C3C)C4)CC2)=O)=C(Cl)C=CC=1S(NC)(=O)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:29]1[CH2:28][CH2:27][C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=2)([CH2:32][CH2:33][N:34]2[CH:35]3[CH2:41][CH2:40][CH:39]2[CH2:38][CH:37]([N:42]2[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=[C:43]2[CH3:51])[CH2:36]3)[CH2:31][CH2:30]1)=[O:6]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)c2cc(S(=O)(=O)NC(C)(C)C)ccc2Cl)CC1
Yield: 35 %

Procedure:
Prepared from a mixture of 2-chloro-5-{[(1,1-dimethylethyl)amino]sulfonyl}benzoic acid 2b, 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (100 mg, 0.16 mmol, 1 equiv), DIEA (117 μL, 0.66 mmol, 4 equiv) and HATU (62 mg, 0.16 mmol, 1 equiv) following the general procedure for 2,4-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N-methylbenzenesulfonamide example 880. The crude product was purified by column chromatography on silica gel eluting with 10% 2M NH3 in methanol in ethyl acetate to afford 4-chloro-N-(1,1-dimethylethyl)-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]benzenesulfonamide as a white solid (40.3 mg, 35% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)#[N:26].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Cl>C1(C)C=CC=CC=1.[Cl-].[Na+].O.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]1[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[CH:28][CH:29]=1)=[CH:8]2)=[O:4]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ncc2c(cc(-c3ccc(C#N)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 100 °C
Yield: 47.2 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.206 mmol), 4-cyanophenylboronic acid (45 mg, 0.308 mmol), K3PO4 (87 mg, 0.411 mmol), H2O (7.4 mg, 0.411 mmol), SPhos (5.1 mg, 0.0123 mmol) and Pd(OAc)2 (4.2 mg, 0.00617 mmol) in toluene (3 mL) was heated at 100° C. under nitrogen atmosphere for 16 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (20 mL) were added. 1 M HCl was added with stirring until pH was about 3, and the organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 40 mg of the title compound. MS: (+) m/z 412.26 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH3:27])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:24](=[O:25])[CH:23]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[CH:16]=[CH:15][N:14]=[CH:13]3)[CH3:27])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(tert-butyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 347 (M+H)+; MS (ESI−) m/z 345 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.56 (d, J 7.1, 3H), 4.22 (d, J 6.1, 2H), 4.57 (q, J 7.1, 1H), 7.10 (d, J 8.5, 2H), 7.29 (d, J 8.5, 2H), 7.98 (t, J 7.5, 1H), 8.13 (d, J 7.1, 1H), 8.34 (d, J 7.8, 1H), 8.56 (d, J 6.8, 1H), 8.69 (m, 2H), 9.78 (s, 1H); Anal. Calcd for C23H26N2O+1.1 HCl: C, 71.46; H, 7.07; N, 7.25. Found: C, 71.13; H, 7.17; N, 7.02.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1F.C([O-])(O)=O.[Na+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:17][C:24]2[CH:23]=[CH:22][C:21]([N+:26]([O-:28])=[O:27])=[CH:20][C:19]=2[F:18])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Oc1cc2cn(C3CCCCO3)nc2cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cc3cn(C4CCCCO4)nc3cc2Br)c(F)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of 6-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-5-ol (1.475 kg, 4.96 mol) in DMF (5.3 L) is added 3,4-difluoronitrobenzene (1.18 kg, 7.45 mol) and NaHCO3 (625.5 g, 7.45 mol) at RT. The reaction mixture is heated at 70° C. for 10 hours and then cooled to less than 20° C. Deionized (DI) water (7.9 L) is slowly added to the solution and the resulting slurry is stirred at 15° C. for one hour. The solid is collected by vacuum filtration, and the solid cake is washed with water (8 L). It is then air dried under vacuum on filter and is triturated with methyl MTBE (18.6 L) at reflux conditions for two hours. The slurry is then cooled to RT and the solid is collected by vacuum filtration. The solid cake is washed with MTBE (4 L×2) and dried in a vacuum oven at 35° C. to give the desired product (1.405 kg, 64.9% yield). MS (m/z): 436.0 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:44])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:43]=[CH:42][C:14]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]3[N:29]=[C:28]([N:30]4[C:34]([C:35]([F:38])([F:37])[F:36])=[C:33]([C:39]([OH:41])=[O:40])[CH:32]=[N:31]4)[CH:27]=[CH:26][CH:25]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH-:45].[Li+].Cl.[O:48]1CCOCC1>C(#N)C>[C:34]([OH:48])([C:35]([F:38])([F:37])[F:36])=[O:45].[CH3:44][N:2]([CH3:1])[C:3]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]3[N:29]=[C:28]([N:30]4[C:34]([C:35]([F:38])([F:37])[F:36])=[C:33]([C:39]([OH:41])=[O:40])[CH:32]=[N:31]4)[CH:27]=[CH:26][CH:25]=3)=[CH:42][CH:43]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: C1COCCO1
Reactant: [OH-]
Agent: Cc1ccc(OCc2ccc(C3CCN(C(=O)N(C)C)CC3)cc2)c(-c2cccc(-n3ncc(C(=O)O)c3C(F)(F)F)n2)c1
Agent: Cl
Agent: [Li+]
Solvent: CC#N
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the title compound from Example 12 Step F (48 mg, 0.071 mmol) in DCM (1 mL) were added DIEA (124 μL, 0.708 mmol) and dimethylcarbamyl chloride (20 μL, 0.213 mmol), and the resulting mixture was allowed to stir at room temperature. After 1.5 h, the reaction mixture was quenched by addition of sat aq NaHCO3 and the aqueous phase was extracted with DCM. The organic phase was separated and concentrated in vacuo to provide the crude urea, which was used without further purification: LCMS m/z 635.8 [M+H]+. To a solution of the urea in dioxane (2 mL) was added lithium hydroxide (1 mL, 2N aqueous, 2 mmol), and the mixture was stirred at 50° C. After 1 h, the reaction mixture was rendered acidic by addition of HCl (2N aqueous), then was diluted with acetonitrile and purified by reverse phase HPLC (40 to 100% acetonitrile/water, both 0.1% v/v TFA) to provide the title compound: LCMS m/z 607.8 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 8.31 (s, 1H), 8.15 (d, J=7.0 Hz, 1H), 8.11 (t, J=8.0 Hz, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.24-7.22 (m, 1H), 7.17 (d, J=8.5 Hz, 1H), 5.17 (s, 2H), 3.65-3.63 (m, 2H), 2.79-2.77 (m, 2H), 2.75 (s, 6H), 2.69-2.64 (m, 1H), 2.28 (s, 3H), 1.75-1.72 (m, 2H), 1.61-1.52 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](I)=[C:9]([O:14][CH3:15])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[C:18]([O:22][C:23](=[O:27])[C:24](C)=[CH2:25])([CH3:21])([CH3:20])[CH3:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:18]([O:22][C:23](=[O:27])/[CH:24]=[CH:25]/[C:10]1[C:11](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=2[NH:7][C:8](=[O:16])[C:9]=1[O:14][CH3:15])([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: C=C(C)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1c(/C=C/C(=O)OC(C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 104 °C

Procedure:
The title compound was prepared in the manner described in Example 44 using the 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (2.18 g) and tert-butylmethacrylate (17.1 g) in toluene (70 mL) with tris (dibenzylideneacetone)dipalladium (O) (0.10 g) and tri-orthotolylphosphine (0.13 g). The mixture was treated with triethylamine (0.84 mL, 0.61 g) and heated at 104° C. for 3.7 hours. The mixture was concentrated to a dark solid which was dissolved in chloroform and chromatographed on a silica gel column (5.5 cm diameter×18 cm long) using 25% ethyl acetate in hexane. Concentration of the main fraction gave a white solid (0.77 g). A portion (0.21 g) of the solid was dissolved in hot ethyl acetate (7 mL). The solution was diluted with hexane (5 mL) and the crystals formed at room temperature. The solid was filtered off, washed with ethyl acetate, washed with hexane, and air-dried to give white crystals (0.11 g); mp=189.1°-199.8° C.; 1H NMR(CDCl3) 7.27 (s,1) for olefin proton; MS: m/z=322 (base peak), 378 (M+1). Analysis for C19H20ClNO5 : Calculated: C, 60.40; H, 5.34; N, 3.71; Found: C, 60.18; H, 5.43; N, 3.72.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1.[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH:24]=[O:25].[Cl-].[NH4+]>C(OCC)(=O)C.CCCCCC.O1CCCC1>[Cl:13][C:14]1[CH:19]=[C:18]([CH:24]([C:23]2[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:22]=2[F:21])[OH:25])[C:17]([Cl:20])=[CH:16][N:15]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Clc1ccc(Cl)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: OC(c1cc(F)ccc1F)c1cc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
To a tetrahydrofuran solution (14 ml) of diisopropylamine (1.4 ml, 10 mmol) was added n-butyl lithium (6.3 ml, a 1.59M hexane solution) at −78° C. After stirring for 10 minutes, 2,5-dichloropyridine (1.48 g, 10 mmol) was added to the reaction mixture. Thirty minutes later, 2,5-difluorobenzaldehyde (1.09 ml, 10 mmol) was added and the temperature of the resulting mixture was raised gradually to 0° C. Stirring was conducted for further 10 minutes. After addition of an aqueous solution of ammonium chloride, the resulting mixture was diluted with ethyl acetate (80 ml). The organic layer was separated, washed with brine and then dried. After filtration, the precipitate obtained by concentrating the filtrate under reduced pressure was triturated with ethanol to give the title compound (1.93 g, 67%).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]([Br:16])[C:14]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[O:13][N:12]=2)=[CH:7][C:6]=1[CH3:29])C.O.[OH-].[Li+].CO>O>[Br:16][CH:15]1[C:14]([C:21]2[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=2)([C:17]([F:18])([F:19])[F:20])[O:13][N:12]=[C:11]1[C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[C:6]([CH3:29])[CH:7]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2Br)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 60 h
Yield: 87.9 %

Procedure:
A mixture of 4-[4-bromo-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ethyl ester (0.71 g, 1.35 mmol) (Example 1.6), lithium hydroxide monohydrate (0.17 g, 4 mmol), methanol (25 ml) and water (5 ml) was stirred at ambient temperature for 60 hours. The mixture was concentrated and the residue dissolved in water. The solution was acidified by addition of aqueous hydrochloric acid (1N). The precipitate was isolated by filtration and dried under vacuum to afford 4-[4-bromo-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-benzoic acid (0.59 g, 88% yield) as a white powder. 1H-NMR (CDCl3, 400 MHz): 8.05-7.45 (m, 6H), 5.87 (s, 1H), 2.65 (s, 3H) ppm.
Reaction SMILES: [N:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=2[O:9][C:10]2[CH:11]=[CH:12][C:13]([N+:25]([O-])=O)=[C:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>[Pd].CO>[NH2:25][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=2[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:15][C:14]=1[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCOCC2)ccc1N
Yield: 89.6 %

Procedure:
By using 1.44 g of t-butyl N-{5-[2-(morpholin-4-yl)phenoxy]-2-nitrophenyl}-N-methylcarbamate, 0.20 g of 10% palladium on carbon and 50 ml of methanol, reaction and purification were carried out in a similar manner to Reference Example 7, whereby 1.20 g of the title compound was obtained.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[C:2][CH2:3][CH2:4][CH3:5].[N+:12]([CH:15](C(OCC)=O)[C:16]([O:18]CC)=[O:17])([O-])=[O:13]>C(OCC)(=O)C>[C:6]1([C:1]2[O:13][N:12]=[C:15]([C:16]([OH:18])=[O:17])[C:2]=2[CH2:3][CH2:4][CH3:5])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCCC#Cc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CCCc1c(C(=O)O)noc1-c1ccccc1
Temperature: 160 °C
Yield: 81.6 %

Procedure:
Pent-1-ynylbenzene (17 mL, 106 mmol) and diethyl 2-nitromalonate (30 mL, 172 mmol) were placed in a stainless steel pressure bomb and heated to 160° C. for 18 hours. Cooled in ice bath then slowly released remaining pressure. The reaction mixture was diluted with ethyl acetate and washed with 1N NaOH. The aqueous layer was back extracted once. The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was treated with 1N NaOH/EtOH at 75° C. for two hours. Diluted with water and washed with EtOAc. The aqueous layer was separated, acidified with concentrated HCl, and extracted with EtOAc. The organic layer was dried with MgSO4, filtered and concentrated to afford 20 g of 5-phenyl-4-propylisoxazole-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:30][CH2:31]OS(C)(=O)=O)[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:48]([NH:51][C:52]1([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)(=[O:50])[CH3:49].O.Cl>CN(C=O)C.C(Cl)Cl.CCOCC>[OH2:13].[ClH:1].[C:48]([NH:51][C:52]1([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:53][CH2:54][N:55]([CH2:31][CH2:30][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[C:18]([C:26]([F:28])([F:27])[F:29])[CH:17]=3)[CH2:10]2)[CH2:56][CH2:57]1)(=[O:50])[CH3:49]
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C(=O)O2)CC1
Temperature: 80 °C
Yield: 67.5 %

Procedure:
A mixture of 1.5 g of the compound obtained in step B of EXAMPLE 21, 1.5 g of 4-acetamido-4-phenylpiperidine p-toluenesulfonate and 1.6 g of K2 CO3 in 4 ml of DMF is heated at 80° C. for 3 hours. After cooling, the reaction mixture is poured into water and extracted with an AcOEt/ether mixture (50/50; v/v), the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (100/3; v/v) as the eluent. The product obtained is dissolved in DCM, a saturated solution of gaseous HCl in ether is added until the pH is 1, and the solvent is evaporated off under vacuum to give 0.66 g of the expected product after crystallization from a DCM/pentane mixture. M.p.=165°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH:32]2[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C.C(OCC)(=O)C>[CH:32]1([S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH:17]([O:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH2:33][CH2:34]1
Reactant: Oc1ccc(F)cc1F
Reactant: CCOC(=O)C(Br)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 12 h

Procedure:
To a solution of 2,4-difluorophenol in acetonitrile, was added potassium carbonate followed by bromo-(4-cyclopropanesulfonyl-phenyl)-acetic acid ethyl ester (obtained in step I) and stirred for 10-14 hours. After completion, the reaction mixture was filtered; the filtrate was concentrated to obtain a residue which was dissolved in ethyl acetate; this solution was washed with water followed by brine solution, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to provide a crude product which was purified by column chromatography to provide the compound A1-II.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH:10][CH:11]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:12][NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>CS(C)=O>[OH:10][CH:11]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:12][NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:18][CH:17]=1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(CCNCC(O)COc2ccccc2)cc1
Solvent: CS(C)=O
Product: CCOC(=O)CCCOc1ccc(CCNCC(O)COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
525 mg of ethyl 4-bromobutyrate were added to a solution of 574 mg of p-[2-[[(RS)-2-hydroxy-3-phenoxypropyl]-amino]ethyl]phenol and 300 mg of potassium t-butylate in 10 ml of dimethylsulfoxide and the mixture was stirred at room temperature under argon for 6 hours. The solvent was evaporated in vacuo and the residue was chromatographed on 75 g of silica gel. Utilizing chloroform/n-propanol/saturate ammonia (500:10:1), there were obtained 600 mg of pure, amorphous ethyl 4-[p-[2-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenoxy]butyrate, ε221 =17510.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:15][C:16]1[CH:36]=[CH:35][C:19]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[O:13][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:35][CH:36]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1

Procedure:
A mixture of methyl 4-methoxysalicylate (176 mg, 0.97 mmol), the title C compound, 4-[2-(4-bromomethyl-phenoxy)-ethyl]-5-methyl-2-phenyl-oxazole (300 mg, 0.81 mmol) and potassium carbonate (334 mg, 2.42 mmol) in DMF (10 mL) is stirred at RT overnight. The mixture is partitioned between EtOAc and water. The organic phase is washed with brine, dried over magnesium sulfate, and concentrated. The residue is chromatographed on silica gel using 15% EtOAc in hexane as the eluent to give 4-methoxy-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-benzoic acid methyl ester.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9][C:10]2[NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:24].C(=O)(O)[O-].[Na+].C(O)C>C(Cl)(Cl)Cl>[C:1]1([CH2:7][CH2:8][S:9]([C:10]2[NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:18]=2)=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(CCSc2nc3cnccc3[nH]2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=S(CCc1ccccc1)c1nc2cnccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[(2-Phenylethyl)thio]-1H-imidazo[4,5-c]pyridine (2.4 g, 0.0094 mol) was dissolved in 120 mL of chloroform with heating. The reaction solution was cooled in an ice bath to 0°-5° C. m-Chloroperoxybenzoic acid (1.91 g, 0.0094 mol) was added portionwise. The reaction mixture was then stirred at room temperature for 1 hour. 10% aqueous sodium bicarbonate was added and the organic layer was separated and dried over magnesium sulfate. After filtering, the filtrate was evaporated to half the volume in a rotary evaporator. Ether was added to the cloudy point and the reaction mixture was cooled in ice. The crystals that had formed amounted to 0.63 g. An analytical sample, m.p. 171°-174° C., was obtained by recrystallization from ethanol.