Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[CH:11]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:17]2[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)=[O:12].CC(=CC)C>O.C(O)(C)(C)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][N:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:13]([C:11]([OH:6])=[O:12])[C:14]=2[CH:15]=[C:16]1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: O=P([O-])(O)O
Reactant: CCOC(=O)c1cc2c(C=O)cccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cc2c(C(=O)O)cccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.3 %

Procedure:
A solution of sodium chlorite (9.70 g) and sodium dihydrogen orthophosphate (13.02 g) in water (50 ml) was added dropwise to a solution of ethyl 4-formyl-N-(3,4-dichlorobenzyl)indole-2-carboxylate (4.47 g) and 2-methylbut-2-ene (50 ml) in tert-butyl alcohol (100 ml) and the mixture stirred for 72 hours at ambient temperature, then concentrated in vacuo and the resulting precipitate was filtered and dried to give the product as an off-white solid (4.16 g. 89%); NMR δ(CD3SOCD3) 1.25 (t, 3H), 4.30 (q, 2H)) 5.85 (s, 2H), 6.85 (m, 1H), 7.35 (m, 1H), 7.40 (q, 1H), 7.50 (m, 1H), 7.80 (m, 3H); M/z (−) 390.1 (M−H+).
Reaction SMILES: O.[OH:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24]Br.O>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][O:5][C:4](=[O:6])[CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:24][C:23]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:21]([Cl:20])[CH:22]=2)=[CH:9][CH:8]=1)[OH:2]
Reactant: O=C(O)C(O)c1ccc(O)cc1
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(Cl)c(Cl)c1)C(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of hydroxy-(4-hydroxy-phenyl)-acetic acid monohydrate (10 g) in DMF (50 mL) was added K2CO3 (29.7 g) followed by 3,4-dichlorobenzyl bromide (16.1 mL). The mixture was stirred at room temperature for 3 h. The mixture was poured into water (250 mL) and extracted with EtOAc. The organic layer was washed with water 1N HCl, brine, dried over Na2SO4, and concentrated. The resulting solid was triturated with diethyl ether and filtered to provide [4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid 3,4-dichloro-benzyl ester as a white solid (9.4 g). 1H NMR (400 MHz, DMSO d6): 7.69 (d, 1H), 7.63 (d, 1H), 7.55 (d, 1H), 7.41 (m, 1H), 7.37 (d, 1H), 7.31 (m, 2H), 7.20 (m, 1H), 6.97 (m, 2H), 6.06 (d, 1H), 5.16 (d, 1H), 5.1 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12](Cl)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[C:16]([O:20][C:21](=[O:24])[NH:22][NH2:23])([CH3:19])([CH3:18])[CH3:17].[CH2:25](O)CCC>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([NH:23][NH:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:24])=[CH:11][C:10]=2[CH3:25])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: N#Cc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CCCCO
Product: Cc1cc(NNC(=O)OC(C)(C)C)nnc1-c1ccc(C#N)cc1

Procedure:
A mixture of 5.0 g. of 6-(p-cyanophenyl)-3-chloropyridazine, 8.71 g. of t-butylcarbazate and 100 ml. of butanol are heated at reflux for 3 hours. The solvent is removed on a rotating evaporator. Water is added, the resulting product is recovered by filtration, washed with water, recrystallized from methanol and dried yielding a product having a m.p. 169°-171° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][O:22][C:23]2[CH:32]=[C:31]3[C:26]([C:27]([NH:33][C:34]4[C:39]([Cl:40])=[CH:38][N:37]=[C:36]5[O:41][CH2:42][O:43][C:35]=45)=[N:28][CH:29]=[N:30]3)=[CH:25][C:24]=2[O:44][CH3:45])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:40][C:39]1[C:34]([NH:33][C:27]2[C:26]3[C:31](=[CH:32][C:23]([O:22][CH2:21][CH:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)=[C:24]([O:44][CH3:45])[CH:25]=3)[N:30]=[CH:29][N:28]=2)=[C:35]2[O:43][CH2:42][O:41][C:36]2=[N:37][CH:38]=1
Reactant: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of 7-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-methoxyquinazoline (0.253 g) in methylene chloride (10 ml) and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated. Toluene was added to the residue and the mixture was evaporated. The residue was purified by column chromatography on silica (Isolute SCX column) using a 7M methanolic ammonia solution as eluent. There was thus obtained the title compound as a solid (0.187 g); NMR Spectrum: (DMSOd6) 1.25 (m, 2H), 1.75 (d, 2H), 1.93 (m, 1H), 2.54 (m, 2H), 3.0 (d, 2H), 3.93 (s, 3H), 3.98 (d, 2H), 6.17 (s, 2H), 7.15 (s, 1H), 7.76 (s, 1H), 7.78 (s, 1H), 8.23 (s, 1H); Mass Spectrum: M+H+ 444 and 446.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:19][C:18](=O)[NH:17][CH2:16][C@H:15]2[CH2:21]CC(O)=O)=[CH:10][CH:9]=1.[O:26]1CCCC1>>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]2[CH2:21][OH:26])=[CH:12][CH:13]=1
Reactant: O=C(O)CC[C@@H]1CNC(=O)C[C@H]1c1ccc(F)cc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1CNCCC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Lithium aluminum hydride (1.0 molar solution in tetrahydrofuran, 0.75 ml, 0.75 mmol) was added gradually to a solution of trans-4-(4-fluorophenyl)-3-carboxyethylpiperidin-6-one (0.25 g, 0.836 mmol) in tetrahydrofuran (3 ml) keeping the temperature below 25° C. The reaction mixture was stirred for 1 hour at 25° C.; then quenched with 1 drop of water, followed by 2 drops 15% sodium hydroxide solution, and finally with 5 drops of water. Extraction with dichloromethane (35 ml) followed by exaporation of the dichloromethane phase gave 0.21 g of the title compound. Yield 76%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:37]=[CH:36][C:28]2[N:29]=[C:30](S(C)(=O)=O)[O:31][C:27]=2[CH:26]=1.[OH-].[Na+].Cl>ClC(Cl)C.CO>[CH3:21][C:16]([CH3:22])([CH2:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:30]3[O:31][C:27]4[CH:26]=[C:25]([CH3:24])[CH:37]=[CH:36][C:28]=4[N:29]=3)=[CH:7][CH:6]=2)=[CH:13][CH:12]=1)=[O:23])[C:17]([OH:19])=[O:18]
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Cc1ccc2nc(S(C)(=O)=O)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CO
Product: Cc1ccc2nc(Nc3ccc(-c4ccc(C(=O)CC(C)(C)C(=O)O)cc4)cc3)oc2c1
Temperature: 85 °C
Yield: 31.7 %

Procedure:
To a solution of methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (74 mg, 0.24 mmol) in dichloroethane (3 mL), 6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (50 mg, 0.24 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was redissolved in DMF (5 mL). A solution of 1 N aqueous NaOH (0.72 mL, 0.72 mmol) was added, and the mixture was heated at 65° C. overnight. A solution of 1 N aqueous HCl (0.24 mL, 0.24 mmol) and methanol (5 mL) were added to the reaction mixture and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 2,2-dimethyl 4-{4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}4-oxobutanoic acid as a white solid (32.6 mg, 32.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.00–7.50 (m, 8 H), 7.30 (d, 2 H), 7.05 (d, 1 H), 3.30 (s, 2 H), 2.50 (s, 3 H), 1.10 (s, 6 H); LC-MS ret. time 3.53 min (method 2), m/z 429.17 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17]I.O>CN(C)C=O>[CH3:17][O:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.98 g, 74.5 mmol) was added to a solution of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (5.0 g, 24.8 mmol) in dimethylformamide (30 mL) and the mixture was stirred for 5 minutes. Methyl iodide (4.64 mL, 74.5 mmol) was added and the mixture was stirred for 30 minutes. Water (50 mL) was added and the mixture was extracted with diethyl ether (2×50 mL). The combined organic fractions were washed with water (4×50 mL) and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (5.3 g, 99%). m/z (ES+) 216 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:27][SH:28].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([S:28][CH2:27][C:26]([O:30][CH2:31][CH3:32])=[O:29])=[N:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CS
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(Cl)nc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)-4-[(6-chloropyridin-3-yl)carbonyl]piperazine obtained in Example 18 (590 mg), ethyl thioglycolate (361 mg), potassium carbonate (691 mg), and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 2 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 50:50-0:100 hexane/ethyl acetate) to provide the title compound (430 mg, 59%) as a solid.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:19])[C:14](=[CH:17][CH:18]=2)[C:15]#N)=[CH:7][CH:6]=1)(=O)C.[OH2:20].[OH-:21].[K+]>Cl>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:19])[C:14](=[CH:17][CH:18]=2)[C:15]([OH:21])=[O:20])=[CH:7][CH:6]=1
Reactant: [OH-]
Reactant: O
Reactant: CC(=O)Nc1ccc(-c2ccc(C#N)c(=O)[nH]2)cc1
Agent: Cl
Agent: [K+]
Product: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1

Procedure:
A suspension of 422 g (1.67 mol) of the above nitrile and 3650 mol of water containing 932 g of potassium hydroxide is heated at 105° for 40 hrs. The solution is cooled and acidified to pH 4.0 with 1360 ml of concentrated hydrochloric acid and 400 g of potassium hydroxide pellets are added with stirring. After filtration, the pH of the filtrate is adjusted to 4.5 with concentrated hydrochloric acid. The solid is filtered, suspended in 8 L of water and filtered. The solid is washed with methanol and finally ethyl acetate and dried at 60° to give 328 g of the title compound; mp>314°-316° dec.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([CH:13]2[NH:17][C:16]([CH3:19])([CH3:18])[CH2:15][O:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(N(CC)CC)C>[C:7]1([CH:13]2[N:17]([C:22](=[O:23])[CH2:21][Cl:20])[C:16]([CH3:19])([CH3:18])[CH2:15][O:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)CCl
Reactant: CC1(C)COC(c2ccccc2)N1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)COC(c2ccccc2)N1C(=O)CCl
Reaction time: 0.5 h

Procedure:
Twenty-one and three tenths (21.3) ml. of a benzene solution containing 5.3 g. of 2-phenyl-4,4-dimethyl oxazolidine was mixed with 50 ml. of benzene and 3.4 g. of chloroacetyl chloride. To this solution was added 3.1 g. of triethylamine, dropwise with stirring in an ice bath. The mixture was stirred for about 30 minutes after addition was complete and then washed with water, separated and dried over magnesium sulfate and the solvent stripped. There was obtained a yield of 6.5 g. of an oil, the title compound, ND30 =1.5364.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:36])[CH3:35])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[C:38]1([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:35])[CH3:36])[CH:28]=3)[CH2:21]2)[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CC(C)Oc1cccc(CC(=O)N2CC[C@](CCOS(C)(=O)=O)(c3cccc4ccccc34)C2)c1
Solvent: CC#N
Product: CC(C)Oc1cccc(CC(=O)N2CC[C@@](CCN3CCC(N4CCCCC4)CC3)(c3cccc4ccccc34)C2)c1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(1-naphthyl)-1-[(3-isopropoxyphenyl)acetyl)pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum an the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=2)[CH:10]=1)#[N:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:28][C:29]1[CH:30]=[C:31]([C:36]2[N:40]=[C:39]([CH:41]3[CH2:44][N:43]([C:45]([O:47][CH3:48])=[O:46])[CH2:42]3)[O:38][N:37]=2)[CH:32]=[CH:33][C:34]=1[CH3:35]>ClCCl.N1C=CC=CC=1>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([NH:28][C:29]3[CH:30]=[C:31]([C:36]4[N:40]=[C:39]([CH:41]5[CH2:44][N:43]([C:45]([O:47][CH3:48])=[O:46])[CH2:42]5)[O:38][N:37]=4)[CH:32]=[CH:33][C:34]=3[CH3:35])=[O:16])=[CH:12][N:13]=2)[CH:10]=1)#[N:2]
Reactant: N#CCCc1ccc2ncc(C(=O)O)n2c1
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(CCC#N)cn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 6-(2-cyanoethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (75) (50 mg, 0.232 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (22 uL, 0.256 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated and the crude solid was dried under vacuo. Methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (33 mg, 0.116 mmol) and anhydrous pyridine (2 mL) were added to the acid chloride. The reaction was stirred to room temperature under Argon for 20 minutes. The crude product was purified by reverse phase preparative HPLC to give methyl 3-(3-(3-(6-(2-cyanoethyl)imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F64). 1H NMR (400 MHz, d6-DMSO) δ 10.08 (s, 1H), 9.45 (s, 1H), 8.63 (s, 1H), 8.12 (d, J=1.6 Hz, 1H), 7.85 (dd, J=2.0, 5.6 Hz, 1H), 7.82 (d, J=6.8 Hz, 1H), 7.60 (dd, J=1.6, 9.2 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 4.38-4.33 (m, 2H), 4.31-4.24 (m, 1H), 4.21-4.18 (m, 2H), 3.59 (s, 3H), 3.01 (t, J=7.6 Hz, 2H), 2.91 (t, J=6.4 Hz, 2H), 2.38 (s, 3H). MS m/z 486.18 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:26])[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][N:31]([CH3:33])[CH3:32])=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CCC1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of tert-butyl(1-(4-(2-phenylacetyl)phenyl)cyclobutyl)carbamate (25.0 g, 68 mmol) in N,N-dimethylformamide dimethylacetal (150 mL) was heated to 80° C. under a nitrogen atmosphere for 18 hours. The resulting brown solution was allowed to cool to room temperature and concentrated to dryness under reduced pressure to give the desired product as a yellow/brown solid (30.6 g, quantitative yield). 1H-NMR (500 MHz, CDCl3) δ 7.14-7.48 (10H, m), 5.09 (1H, br s), 2.74 (6H, s), 2.45-2.60 (4H, m), 2.04-2.16 (1H, m), 1.80-1.90 (1H, m), 1.10-1.52 (9H, br m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[F:29][C:30]([F:41])([F:40])[C:31]1[C:36]([C:37](O)=[O:38])=[CH:35][N:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:37](=[O:38])[C:36]3[C:31]([C:30]([F:41])([F:29])[F:40])=[CH:32][CH:33]=[N:34][CH:35]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Product: CC(C)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(=O)c1cnccc1C(F)(F)F

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 4-trifluoromethyl-nicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 570. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.4 (s, 1H)) 9.0 (d, 1H) 8.4 (s, 1H) 8.3 (d, 1H) 8.1 (s, 1H) 7.9 (d, 1H) 7.7 (d, 1H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 6.9 (d, 1H) 5.7 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H) 1.2 (d, 6H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[CH:34]2)=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][CH:35]=[CH:34]4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc5[nH]ccc5c4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-formylindole to the procedure of step 1, Example 66. MS (ESI) m/z 508.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([CH3:17])[N:11]=1.O>O1CCCC1>[Cl:9][C:10]1[N:15]=[C:14]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: Oc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2ccc(F)cc2)nc(Cl)n1
Temperature: 20 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
4-Fluorophenol (103 mg, 0.92 mmol) and potassium-tert-butylate (113 mg, 1.0 mmol) were dissolved in 7 mL of tetrahydrofurane. 2,4-dichloro-6-methylpyrimidine (150 mg, 0.92 mmol) was added and the mixture stirred at 20° C. overnight. Water was added and the mixture extracted with diethyl ether. Chromatography of the crude reaction product on silica gel using a heptane/ethyl acetate as an eluent gave the title compound (150 mg, 68%) as a slightly yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.50-7.40 (m, 2H), 7.28 (t, 1H), 7.14 (d, 2H), 6.57 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10](C)[CH3:11])[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C(C1C=CC=C(C(C)C)C=1CC(Cl)=O)(C)C.C(Cl)(=O)CCCCCCCCC>>[C:14]([C:16]1[C:17]([CH:30]([CH3:31])[CH3:32])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)(=[O:15])[CH2:13][CH2:5][CH2:4][CH2:9][CH2:8][CH2:7][CH2:6][CH2:10][CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)Cl
Agent: CCCCCCCCCC(=O)Cl
Product: CCCCCCCCCC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetyl chloride was replaced with decanoyl chloride, mp 92°-94° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C.[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:32]Br>C(#N)C>[F:27][C:28]([F:41])([F:42])[C:29]1[CH:30]=[C:31]([CH2:32][NH:1][C@H:2]2[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@H:3]2[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COC(=O)[C@H]1CC[C@H](N)[C@@H]1c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccc(F)cc1
Yield: 71.7 %

Procedure:
A solution of 20 mg of amine from Example 63, 0.050 mL of DIPEA and 30 mg of 3,5-bis(trifluoromethyl)benzyl bromide in 1 mL of acetonitrile was stirred for 20 h in a sealed vial and evaporated. The residue was purified on a 1 mm preparative silica gel plate eluted with 20% ethyl acetate in hexanes to obtain 28 mg of title compound as an oil. Mass spec (NH3 /CI): 464 (M+1).
Reaction SMILES: [C:1]([C:9]1C([N+]([O-])=O)=CC(C(OCC)=O)=CC=1O)(=O)[C:2]1C=CC=C[CH:3]=1.C(I)C.[OH:27][C:28]1[CH:29]=[C:30]([CH:36]=[C:37]([N+:48]([O-:50])=[O:49])[C:38]=1[C:39](=[O:47])[C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)[C:31]([O:33]CC)=[O:32].C(I)CCC.C(O)C>>[CH2:9]([O:27][C:28]1[CH:29]=[C:30]([CH:36]=[C:37]([N+:48]([O-:50])=[O:49])[C:38]=1[C:39](=[O:47])[C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)[C:31]([OH:33])=[O:32])[CH2:1][CH2:2][CH3:3]
Reactant: CCOC(=O)c1cc(O)c(C(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Reactant: CCOC(=O)c1cc(O)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Solvent: CCCCI
Solvent: CCO
Solvent: CCI
Product: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccc(C)cc1

Procedure:
By replacing in Example 6, step B, ethyl 4-benzoyl3-hydroxy-5-nitrobenzoate and ethyl iodide with equimolar amounts of ethyl 3-hydroxy-4-(4'-methylbenzoyl)-5-nitrobenzoate and n-butyl iodide respectively and following the procedure described, 3-n-butoxy-4-(4'-methylbenzoyl)5-nitrobenzoic acid crystallizing with 0.5mole of ethanol is obtained with a melting point of 162.5°-163° C.