Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH2:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:29]>CN(C=O)C>[Cl-:1].[CH2:28]([N+:30]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:29]
Reactant: O=C(Nc1ccc(CCl)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Reactant: CCN1CCCCC1
Solvent: CN(C)C=O
Product: CC[N+]1(Cc2ccc(NC(=O)C3=Cc4cc(-c5ccccc5)ccc4CC3)cc2)CCCCC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In DMF (3 ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (140 mg), and to the mixture was added 1-ethylpiperidine (154 μl). The mixture was stirred at room temperature for 14 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 1-ethyl-1-[4-(7-phenyl-3,4-dihydronaphthalene-2-carboxamido)benzyl]piperidinium chloride (Compound 24) (125 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N:24]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:34])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:34][C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][N:29]=4)[N:24]=[CH:25][CH:26]=3)=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccnc2cccnc12
Reactant: CC1(C)OC(=O)N(c2ccc(C(=O)Cl)cc2)[C@H]1c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OC(=O)N(c2ccc(C(=O)Nc3ccnc4cccnc34)cc2)[C@H]1c1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a vessel charged with (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzoyl chloride (50 mg, 0.152 mmol) were added DCM (606 μL), 1,5-naphthyridin-4-amine (commercially available from Astatech Inc., Bristol, Pa.) (24 mg, 0.167 mmol), and DIEA (55.6 μL, 0.318 mmol) respectively. The vessel was sealed and shaken overnight at 40° C. The mixture was dried under reduced pressure and purified using a 25 g, 15 m spherical silica column (Interchim) ramping 0-100% EtOAc in heptane from 0-100% to elute product, which was lyophilized from MeOH/H2O to yield (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-N-(1,5-naphthyridin-4-yl)benzamide (64 mg, 96%) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ=10.63 (s, 1H), 9.01 (dd, J=1.6, 4.2 Hz, 1H), 8.93 (d, J=5.0 Hz, 1H), 8.54 (d, J=5.1 Hz, 1H), 8.46 (dd, J=1.6, 8.5 Hz, 1H), 8.01-7.96 (m, 2H), 7.89 (dd, J=4.3, 8.6 Hz, 1H), 7.76-7.70 (m, 2H), 7.43-7.37 (m, 2H), 7.36-7.22 (m, 3H), 5.57 (s, 1H), 1.67 (s, 3H), 0.94 (s, 3H). m/z (ESI) 439.2 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=O)=O>CN(C)C=O.O>[N:1]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Temperature: 90 °C
Yield: 95.7 %

Procedure:
Sodium azide (16.8 g, 259 mmol) was added to a solution of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate (66.9 g, 236 mmol) in N,N-dimethylformamide (400 mL). The reaction was heated at 90° C. for 1.5 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with cold water (500 mL) and then extracted with diethyl ether (4×300 mL). The combined extracts were washed with water (4×100 mL) and brine (1×200 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 52 g of tert-butyl 2-(2-azidoethoxy)ethylcarbamate.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[N+:19]([C:22]1[C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[N:23]=1)([O-:21])=[O:20].[F-].[K+]>O1CCCC1.C(P([Pd-2]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C>[N+:19]([C:22]1[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[CH:5]=[CH:6][C:7]=2[OH:8])=[CH:25][N:24]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[N:23]=1)([O-:21])=[O:20]
Reactant: CC1(C)OB(c2cn(C3CCCCO3)nc2[N+](=O)[O-])OC1(C)C
Reactant: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1I
Agent: CC(C)(C)[PH]([Pd-2][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(-c2cccc(C(F)(F)F)c2)ccc1O
Temperature: 65 °C
Yield: 60.3 %

Procedure:
A mixture of 3-iodo-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 2, 0.5 g, 1.3 mmol), 3-nitro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.42 g, 1.3 mmol), potassium fluoride (0.39 g, 0.65 mmol) in tetrahydrofuran (10 mL) was degassed. Bis-(tri-t-Butylphosphino)palladium (0) (35 mg, 0.068 mmol) was added and the reaction heated at 65° C. for 4 hours. After cooling the solvent was removed in vacuo and the residue was purified by silica gel chromatography (ethyl acetate:heptane 1:10) to provide the title compound (0.34 g, 61%) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]>[NH4+].[Cl-].C(Cl)Cl>[Br:1][C:2]1[C:11]([O:12][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(Br)c(O)c2n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1ccc2ccc(Br)c(O[Si](C)(C)C(C)(C)C)c2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To the product from Step A (3.0 g, 12.6 mmol) was added imidazole (1.89 g, 27.7 mmol) and CH2Cl2 (40 mL). The solution was cooled to 0° C. and then tert-butylchlorodimethylsilane (2.09 g, 13.9 mmol) was added in one portion. The reaction was gradually warmed to ambient temperature over 1 hour and then stirred overnight. The mixture was diluted with a saturated aqueous NH4Cl solution (25 mL) and CH2Cl2 (40 mL). The layers were mixed and separated and the organic layer was washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (2 to 20% CH2Cl2/hexanes) to provide 3.36 g (76%) of the desired product as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH3:18])=[O:16].CCN(C(C)C)C(C)C.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[S:29]([O:1][C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:30])=[O:28]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (2.50 g, 9.72 mmol) in DCM (50 mL) was added DIPEA (2.03 mL, 11.66 mmol) and Tf2O (1.80 mL, 10.69 mmol) at −78° C., and then it was warmed up to room temperature and stirred further for 2 h, the solution was diluted with DCM and the organic layer was washed with Sat. NaHCO3, dried and concentrated to give 1-tert-butyl 3-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate as crude product (4.4 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[O:43]1[CH2:48][CH:47]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH2:45][CH2:44]1>>[O:43]1[CH2:44][CH:45]=[C:46]([C:2]2[CH:3]=[C:4]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)[C:5]([NH:8][C:9]3[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)=[N:6][CH:7]=2)[CH2:47][CH2:48]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(Nc2ncc(C3=CCOCC3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 247 using 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Frontier Scientific), and was isolated as a yellow amorphous solid (35%). m/z (ESI, +ve ion) 392.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.76 (1H, s); 8.83 (1H, d, J=2.5 Hz); 8.54 (1H, d, J=2.7 Hz); 8.44 (1H, d, J=2.5 Hz); 8.17 (1H, dd, J=8.8, 2.7 Hz); 7.87 (1H, br. s.); 7.73 (1H, br. s.); 6.83 (1H, d, J=8.8 Hz); 6.22 (1H, br. s.); 4.24 (2H, d, J=2.5 Hz); 3.82-3.87 (5H, m); 2.47 (2H, m); 2.44 (3H, s).
Reaction SMILES: [CH3:1][CH:2]([OH:13])[CH2:3][N:4]([CH2:9][CH:10]([OH:12])[CH3:11])[CH2:5][CH:6]([OH:8])[CH3:7].[C:14]([C:27]1[CH:35]=[C:31]([C:32]([OH:34])=[O:33])[C:30]([OH:36])=[CH:29][CH:28]=1)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(O)(C)C>[C:14]([C:27]1[CH:35]=[C:31]([C:32]([O-:34])=[O:33])[C:30]([OH:36])=[CH:29][CH:28]=1)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:12][CH:10]([CH3:11])[CH2:9][NH+:4]([CH2:5][CH:6]([OH:8])[CH3:7])[CH2:3][CH:2]([OH:13])[CH3:1]
Reactant: CC(O)CN(CC(C)O)CC(C)O
Reactant: CCCCCCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Solvent: CC(C)O
Product: CC(O)C[NH+](CC(C)O)CC(C)O
Product: CCCCCCCCCCCC(=O)c1ccc(O)c(C(=O)[O-])c1
Yield: 94.8 %

Procedure:
Into a beaker, are added, with stirring, 11.4 g (0.06 mole) of triisopropanolamine in 100 ml of isopropanol. The reaction medium is stirred and cooled to between 5° and 10° C. 19.2 g (0.06 mole) of 5-n-dodecanoylsalicylic acid are then added. The mixture is stirred for 30 min at room temperature and then the clear mixture is filtered. The filtrate is evaporated to dryness. An oil is obtained which crystallizes at room temperature. It is filtered on sintered glass. The white powder obtained is dried under vacuum over phosphoric anhydride. 29.1 g of product are obtained, equivalent to a yield of 95%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)(=O)=O.[C:21]([C:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)#[CH:22].C(N(CC)CC)C.N>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH2:13][C:12]1[C:7]([C:22]#[C:21][C:23]2([OH:31])[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(Oc1ncccc1Cc1cccs1)C(F)(F)F
Reactant: C#CC1(O)CN2CCC1CC2
Agent: [Pd]
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1(C#Cc2ncccc2Cc2cccs2)CN2CCC1CC2
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
A mixture of 89 mg of 3-(2-thienylmethyl)-2-pyridyl trifluoromethanesulfonate, 50 mg of 3-ethynyl-3-quinuclidinol, 64 mg of tetrakis (triphenylphosphine) palladium(0), 11 mg of cuprous iodide, 105 μl of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring at 70° C. for 1.5 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, followed by extracting with ethyl acetate. Then, the organic phase was washed with brine and the solvent was removed, and the residue was subjected to NH-silica gel (Fuji silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 88 mg of the target compound.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([O:26][CH3:27])=[C:21]([Cl:28])[CH:20]=1.CN(C)C1C=CC=CC=1.C(OC1C(=CC=CC=1)C(Cl)=O)(=O)C.Cl>CC(C)=O>[Cl:25][C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([Cl:28])[C:22]=1[O:26][CH3:27])[NH:18][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[OH:4]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: COc1c(Cl)cc(N)cc1Cl
Agent: CC(=O)Oc1ccccc1C(=O)Cl
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Solvent: CN(C)c1ccccc1
Product: COc1c(Cl)cc(NC(=O)c2ccccc2O)cc1Cl
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
Acetylsalicylic acid (1.8 g.) was converted to its acid chloride by conventional method using thionyl chloride and dissolved in acetone (30 ml.). 4-Amino-2,6-dichloroanisole (2.13 g.) with N,N-dimethylaniline (1.27 ml.) was dissolved in acetone (25 ml.) to which, with stirring in the cold at 0°-10° C., the above acetone solution of acetylsalicyloyl chloride was added dropwise over 20-30 minutes. Reaction continued for 1-2 hours, then the solution was evaporated to dryness under reduced pressure, the residue being put in sodium hydroxide solution and gently agitated for 1-2 hours for cleavage of the acetyl group. After reaction was complete the solution was made acidic by the addition of 2 N hydrochloric acid and the precipitate which formed was collected by filtration and recrystallized from aqueous acetone to give needle-like crystals (2.0 g.) of 3',5'-dichloro-2-hydroxy-4'-methoxybenzanilide. Yield 64%. The melting point of the product is 226°- 228° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18]([NH2:20])=[O:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH2:22]([C:24]1[O:28][C:27]([CH2:29][CH2:30]N)=[N:26][CH:25]=1)[CH3:23].O1CCOCC1.CN(C=O)C>C(N(CC)CC)C>[CH2:22]([C:24]1[O:28][C:27]([CH2:29][CH2:30][NH:20][C:18]([NH:17][C:15]2[S:16][C:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([F:1])[CH:3]=3)=[C:13]([CH3:21])[N:14]=2)=[O:19])=[N:26][CH:25]=1)[CH3:23]
Reactant: Cc1nc(NC(N)=O)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: CCc1cnc(CCN)o1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3ccc(S(C)(=O)=O)c(F)c3)s2)o1

Procedure:
The title compound is prepared by the same procedure as -[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-Methyl-thiazol-2-yl]-urea (Example 177) by replacing ammonia (part 177b) with the hydrochloride salt of 2-(5-Ethyl-oxazol-2-yl)-ethylamine (details of preparation procedure follows below), by replacing dioxane with DMF and by using triethylamine as a base.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[N:31][CH:32]=2)[CH:12]=[CH:11][C:10]=1[C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=1[CH3:50]>CO>[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][C:18]=2[C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[N:31][CH:32]=2)[CH:12]=[CH:11][C:10]=1[C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=1[CH3:50]
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3C)c(Cl)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Cl)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2-c2ccc(C(=O)NCCC(=O)O)nc2)cc1Cl
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (5.6 mL, 16.7 mmol) was added to a THF (20 mL) and MeOH (10 mL) solution of ethyl 3-(5-(2-(((2,4′-dichloro-2′-methyl-[1,1′-biphenyl]-4-yl)amino)methyl)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (3.5 g, 5.6 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off, dried in vacuo, and purified via HPLC to yield the title compound.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:9]([NH2:15])=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=1.[CH3:16][C:17]1[C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[C:20]([CH3:34])[O:19][N:18]=1.O>ClCCl>[CH3:16][C:17]1[C:21]([CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([NH:15][C:9]3[C:8]([CH3:7])=[CH:13][C:12]([CH3:14])=[CH:11][N:10]=3)(=[O:32])=[O:31])=[CH:28][CH:29]=2)=[C:20]([CH3:34])[O:19][N:18]=1
Reactant: Cc1cnc(N)c(C)c1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1cnc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)c(C)c1
Temperature: 70 °C
Yield: 14.1 %

Procedure:
To a solution of pyridine (0.083 mL, 1.023 mmol) and 3,5-dimethyl-2-pyridinamine (125 mg, 1.023 mmol) in dichloromethane (1 mL) was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (309 mg, 1.023 mmol). The mixture was heated at 70° C. for 4 hours. Water (5 mL) was added and the organic phase separated and purified by flash silica (Si) chromatography (50% dichloromethane-ethyl acetate gradient) to give the title compound (56 mg) as a bright yellow solid. LCMS (2 min, formic) Rt 0.93 min, m/z (ES+) 388 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6](O)[C:7](=[CH:9][CH:10]=1)[OH:8])[CH2:2][CH3:3].[C:12]([O-])([O-])=[O:13].[K+].[K+]>CN(C=O)C.ClCCl>[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]2[O:8][O:13][CH2:12][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCCc1ccc(O)c(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1ccc2c(c1)COO2
Temperature: 117.5 °C

Procedure:
4-Propyl catechol (10.7 g; 70 mmols) was dissolved in a 90:10 (v/v) DMF/dichloromethane mixture (17 ml). The resulting solution was added very slowly to a suspension of anhydrous K2CO3 (14.1 g; 87 mmols) in a 90:10 (v/v) DMF/dichloromethane mixture (85 ml), maintained at 115-120° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C@H:11]2[NH:14][CH2:15][C:16]2[N:17]([C:21](OC(C)(C)C)=[O:22])[CH:18]=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH2:30]1COCC1>>[CH3:30][C:18]1[N:17]2[C:21](=[O:22])[N:14]([C@H:11]3[C:12]4[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:13]=4)[CH2:9][CH2:10]3)[CH2:15][C:16]2=[CH:20][CH:19]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc2c(c1)[C@H](NCc1cccn1C(=O)OC(C)(C)C)CC2
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc2n1C(=O)N([C@@H]1CCc3ccc(C(=O)O)cc31)C2
Temperature: 25 °C
Reaction time: 14 h
Yield: 26 %

Procedure:
A solution of (R)-tert-butyl 2-((6-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-ylamino)methyl)-1H-pyrrole-1-carboxylate (500 mg, 1.3 mmol, 1.0 eq.) in THF (5 ml) was added to a stirred suspension of NaH (104 mg, 2.6 mmol, 2.0 eq., 60% in mineral oil) in THF (15 ml) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 14 h. The reaction mixture was quenched with water (50 ml) and washed with ethyl acetate (50 ml). The aqueous layer was acidified with 2 N HCl (5 ml) and extracted with ethyl acetate (2×100 ml). The combined organic fractions were washed with brine (50 ml), dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue obtained was used for the next step without further purification. Yield: 26% (100 mg, 0.34 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].O.[S-2:13].[Na+].[Na+].CN(C)C=O.[C:21]1([CH2:27][CH2:28][CH2:29]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:13][CH2:29][CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: BrCCCc1ccccc1
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(SCCCc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
3.45 G. of 2-amino-4-chloro-1-nitrobenzene and 5.3 g. of sodium sulfide monohydrate in 30 ml. of dimethylformamide is heated at about 100° for 1 hour under nitrogen, cooled and 4.5 g. of 3-phenylpropyl bromide added, held at 20°-25° for 4 hours, then diluted with water. The product is filtered off and recrystallized from methanol to afford 2-amino-4-(3-phenylpropylthio)-1-nitrobenzene.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10].Br[CH2:26][CH2:27][CH2:28][C:29]1[CH:33]=[CH:32][NH:31][CH:30]=1>>[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:26][CH2:27][CH2:28][C:29]3[CH:33]=[CH:32][NH:31][CH:30]=3)[CH2:20][CH2:19]2)[CH:13]=1)=[O:10]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: BrCCCc1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3cc[nH]c3)CC2)c1

Procedure:
Prepared by Procedure K (KI) and Scheme E (K2CO3) using 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 3-(3-bromopropyl)-1H-pyrrole: ESMS m/e: 354.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[C:17]([CH3:18])=[N:16][N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[OH:25])=[CH:11][C:10]([CH3:26])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([C:13]2[C:14](=[O:25])[N:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:16]([CH3:27])[C:17]=2[CH3:18])=[CH:11][C:10]([CH3:26])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(Cc2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: Cc1cc(-c2c(C)n(C)n(-c3ccccc3)c2=O)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
To 2-benzyl-5,5′-dimethyl-2′-phenyl-2H,2′H-[3,4′]bipyrazolyl-3′-ol (Example 36, 0.200 g, 0.58 mmol) in DMF add cesium carbonate (0.944 g, 2.90 mmol), and then iodomethane (0.823 g, 5.8 mmol). Stir this mixture at room temperature overnight. Dilute the reaction mixture with ethyl acetate, wash with water (25 ml×5) and dry (sodium sulfate). Chromatograph on silica gel, eluting with 50-100% ethyl acetate/heptane to provide 0.045 g of the title compound.
Reaction SMILES: [CH:1]1([C:5]2[C:14]([I:15])=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH2:16][CH3:17])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:5]2[C:14]([I:15])=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH2:16][CH3:17])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1cc(C2CCC2)c(I)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1cc(C2CCC2)c(I)cc1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a round-bottom flask, was added a solution of methyl 4-cyclobutyl-2-ethyl-5-iodobenzoate (compound 181.4, 10.3 g, 30.0 mmol, 1.00 equiv) in methanol (100 mL). A solution of sodium hydroxide (3.60 g, 3.00 equiv) in water (10 mL) was added dropwise to the stirred reaction mixture. The resulting mixture was stirred for 2 h at 60° C. After cooling to ambient temperature, the volatiles were removed under reduced pressure. The pH of the remaining aqueous mixture was adjusted to ˜4 using HCl (aq., 1 M). The resulting precipitate was collected by filtration and dried to yield 9.00 g (91%) of 4-cyclobutyl-2-ethyl-5-iodobenzoic acid as a white solid.