Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: NCc1ccncc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCc2ccncc2)cc1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
4-geranyloxybenzoic acid(2.47 g) was dissolved in chloroform(50 ml) and triethylamine(2.49 ml), and then diphenylphosphinic chloride(1.72 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(aminomethyl)pyridine(0.97 g) added thereto, was stirred for 4 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 3.10 g of the aimed compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([OH:10])[N:5]=[C:4]([CH3:11])[CH:3]=1.[CH3:12][O-:13].[Na+]>CO>[OH:10][C:6]1[N:5]=[C:4]([CH3:11])[CH:3]=[C:2]([O:13][CH3:12])[C:7]=1[C:8]#[N:9]
Reactant: C[O-]
Reactant: Cc1cc(Cl)c(C#N)c(O)n1
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)nc(O)c1C#N
Temperature: 100 °C
Reaction time: 16 h
Yield: 21.3 %

Procedure:
To a pressure vessel was added 4-chloro-2-hydroxy-6-methylnicotinonitrile (337 mg, 2.0 mmol), sodium methoxide (530 mg, 10.0 mmol), methanol (15 mL), and a magnetic stirrer. The pressure vessel was sealed, and was stirred at 100° C. for 16 hours before the solvent was removed by rotary evaporation. To the residue was added water (10 mL) and ethyl acetate (50 mL). The organic layer was separated and concentrated in vacuo to provide crude product which was purified by column chromatography (silica gel, dichloromethane/methanol=40:1) to afford 2-hydroxy-4-methoxy-6-methylnicotinonitrile (70 mg, 21%) as a brown solid.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(OCC)(=O)C.O>[OH-].[Na+]>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc2nnn(O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)On2nnc3ccc([N+](=O)[O-])cc32)cc1
Yield: 56.1 %

Procedure:
In 1 N aqueous sodium hydroxide (45 ml) is dissolved 1-hydroxy-6-nitro-1,2,3-benzotriazole (7.2 g). To the solution is gradually added p-toluenesulfonyl chloride (7.7 g) with stirring under ice-cooling and further are added thereto ethyl acetate (100 ml) and water (50 ml) and the mixture is stirred for 1 hour. The ethyl acetate layer is separated, dried over magnesium sulfate-charcoal, and concentrated until it becomes about 30 ml. n-Hexane (about 50 ml) is added thereto and the mixture is allowed to stand. The precipitated crystals are separated and dried to give faint yellow needles of 1-(p-toluenesulfonyl-oxy)-6-nitro-1,2,3-benzotriazole (7.5 g), melting point: 142°-144° C. The product is recrystallized from ethyl acetate-n-hexane to give a pure product, melting point: 144° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([S:17](Cl)(=[O:19])=[O:18])=[CH:10][CH:9]=1.Cl.[NH2:22][C@H:23]([C@H:26]1[O:30][C:29](=[O:31])[C@H:28]([CH2:32][CH3:33])[CH2:27]1)[CH2:24][OH:25].O1CCCC1>O>[CH2:32]([C@H:28]1[C:29](=[O:31])[O:30][C@H:26]([C@@H:23]([NH:22][S:17]([C:11]2[CH:10]=[CH:9][CH:8]=[CH:13][C:12]=2[N+:14]([O-:16])=[O:15])(=[O:19])=[O:18])[CH2:24][OH:25])[CH2:27]1)[CH3:33]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 2 h
Yield: 59 %

Procedure:
25.6 g of triethylamine (253 mmol) and 28.6 g of O-nitrobenzenesulfonyl chloride (129 mmol) were added to a solution of (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-ethyldihydrofuran-2-one hydrochloride obtained in the above reaction in a mixed solvent of tetrahydrofuran (350 ml) and water (35.0 ml) at 0° C., and the mixture was stirred at the same temperature for two hours. The reaction mixture was concentrated under reduced pressure and 500 ml of water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:ethyl acetate). Further, 20 ml of diisopropyl ether and 40 ml of ethyl acetate were added, and the precipitated solid was collected by filtration to obtain 17.0 g of the title compound (total yield over two steps: 59%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1([C:15]23[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:20]2([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)C(=O)OC3=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:44]([OH:47])(=O)[CH3:45]>>[C:25]1([C:22]2[C:21]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:20]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:24]3[C:45]=2[C:44](=[O:47])[N:7]2[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[N:8]=[C:23]23)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)O
Reactant: Nc1ccccc1N
Reactant: O=C1OC(=O)C2(c3ccccc3)C(c3ccccc3)=C(c3ccccc3)C=CC12c1ccccc1
Product: O=C1c2c(-c3ccccc3)c(-c3ccccc3)c(-c3ccccc3)c(-c3ccccc3)c2-c2nc3ccccc3n21

Procedure:
A 500 ml round-bottom flask equipped with a stirrer and reflux condenser is charged with 8.34 g (73.3 mmol) of o-phenylenediamine (95%), 33.0 g (66.3 mmol) of 1,2,3,4-tetraphenylphthalic anhydride, and 200 ml of glacial acetic acid. Under nitrogen atmosphere, the mixture is stirred and heated at reflux for 11 hours. The slurry is cooled and the yellow solid is isolated by filtration. The solid is washed with water and then with methanol. 35.1 g of an yellow solid is obtained (92%).
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31].C(=O)([O-])[O-].[K+].[K+].O>CC1CCCO1>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:35]2[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=2)=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(N)=O)CCOCC1
Temperature: 78 °C
Reaction time: 10 h
Yield: 67.3 %

Procedure:
To a stirred solution of (S)-tert-butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (produced in step (i), 27 g) in 2-methyltetrahydrofuran (8 rel. vol.) was added 4-cyanophenyl boronic acid (1.1 mol. eq.), potassium carbonate (2 mol. eq.), water (2 rel. vol.) and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.0065 mol. eq) at room temperature. Reaction mixture was heated to 78° C. and stirred for 10 h under nitrogen. The reaction mixture was cooled to room temperature and passed through a pad of celite. Water was added to the mixture and the layers separated. The organic layer was separated and concentrated to 5 rel. vol. under vacuum. The concentrated organic portion was stirred for 6 h at room temperature and the resulting solid filtered and washed with 2-methyltetrahydrofuran (2 rel. vol.). The solid was dried at 50° C. under vacuum to afford the sub-titled compound (17.3 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[Mn]([O-])(=O)(=O)=[O:22].[K+].[OH2:27]>>[C:15]1([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2]([C:1]([OH:22])=[O:27])=[N:3][CH:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(C(c2ccccc2)c2ccccc2)cn1
Reactant: O
Agent: [K+]
Product: O=C(O)c1ccc(C(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C

Procedure:
18 g. 2-methyl-5-(diphenylmethyl) pyridine, 1 liter of water, 9 g. of potassiumpermanganate are heated on a steam bath for about 3 hours until the reaction mixture is colorless. 9 g. of potassiumpermanganate, 200 milliliters of water are added and the reaction mixture is heated for about 5 hours until colorless. Filter and wash thoroughly with hot water (70°-90° C.), combine the filtrate and washes, cool to about 25° C., acidify with hydrochloric acid, and recover the 5-(diphenylmethyl)-picolinic acid by filtration (m.p. 189°-191° C.).
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3](=O)[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Cl.[CH:27]1([NH:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.N1CCCCC1>C(O)C>[CH:27]1([N:33]2[CH:5]([C:6]3[CH:7]=[C:8]([C:12]4[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:4][C:3]([C:2]([F:25])([F:1])[C:21]([F:24])([F:23])[F:22])=[N:34]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CSc1ccc(-c2cccc(C=CC(=O)C(F)(F)C(F)(F)F)c2)cc1
Reactant: NNC1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3C3CCCCC3)c2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 4 %

Procedure:
4,4,5,5,5-Pentafluoro-1-(4′-methylsulfanyl-biphenyl-3-yl)-pent-1-en-3-one (200.0 mg, 0.54 mmol) prepared in Step 3 of Preparation 4, cyclohexylhydrazine hydrochloride (98.0 mg, 0.59 mmol), and piperidine (107.0 uL, 1.08 mmol) were added to ethanol (5.0 mL). The reaction mixture was stirred at 100° C. for 18 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.ON1C2C=CC=CC=2N=N1.[NH2:29][C@H:30]([C:37]([O:39][CH3:40])=[O:38])[CH2:31][C:32]1[N:36]=[CH:35][NH:34][CH:33]=1.Cl.Cl.C(N1CCOCC1)C>CN(C)C=O>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:29][C@H:30]([C:37]([O:39][CH3:40])=[O:38])[CH2:31][C:32]1[N:36]=[CH:35][NH:34][CH:33]=1)=[O:5])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 67.4 %

Procedure:
A solution of N,N1 -dicyclohexylcarbodiimide (DCC, 13.6 g, 66 mmol) in distilled dimethylformamide (DMF, 15 ml) is added dropwise to a cold solution (0° to 5° C.) of Z-Pro-OH (15 g, 60 mmol) and 1-hydroxybenzotriazole (HOBt, 12.16 g, 120 mmol), in distilled DMF (40 ml). The mixture is stirred at 0°-5° C. for 2 hr. Thereafter, a solution of H-His-OMe.2HCl (14.56 g, 60 mmol) and N-ethylmorpholine (15.2 g, 16.89 ml, 132 mmol) in distilled DMF is added to the cold reaction mixture. The pH of the reaction mixture is adjusted to 8 and the reaction mixture stirred for 18 hr at 20°-22° C. The solid (N,N1 -dicyclohexylurea) is removed from the mixture by filtration. The filtrate is concentrated to dryness under reduced pressure. The residue is subjected to chromatography on silica gel (2400 g) using chloroform-methanolpyridine (89:10:1) as the eluant. The pure fractions are pooled and evaporated under reduced pressure to give 16.2 g of the title compound; NMR (CDCl3) δ 3.70 (s, 3H), 5.12 (s, 2H), 7.25 (s, 5H); amino acid analysis: His (1.00), Pro (0.97).
Reaction SMILES: [OH-:1].[Na+:2].[C:3](=[O:6])([OH:5])[O-:4]>>[OH2:4].[OH2:1].[OH2:4].[OH2:4].[OH2:4].[OH2:4].[OH2:4].[OH2:4].[OH2:4].[OH2:4].[C:3](=[O:4])([O-:6])[O-:5].[Na+:2].[Na+:2]
Reactant: [OH-]
Reactant: O=C([O-])O
Agent: [Na+]
Product: O
Product: O=C([O-])[O-]

Procedure:
A method according to claim 26 further comprising the step of adding a sufficient amount of sodium hydroxide to reduce the remaining bicarbonate in the resulting aqueous solution to no more than about 2 weight percent prior to the step of cooling the resulting solution to form solid crystals of sodium carbonate decahydrate.
Reaction SMILES: [OH-].[K+].CS(C)=O.[C:7]([O:11][C:12]([NH:14][CH2:15][C@H:16]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([F:28])[CH:22]=1)CC(O)=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].I[CH3:30].C[CH2:32][O:33][C:34]([CH3:36])=[O:35]>>[C:7]([O:11][C:12]([N:14]([CH3:30])[CH2:15][C@H:16]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([F:28])[CH:22]=1)[CH2:36][C:34]([O:33][CH3:32])=[O:35])=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: CCOC(C)=O
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC[C@@H](CC(=O)O)c1ccc(Cl)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(=O)C[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
Powdered KOH (1525 mg, 27.19 mmol) was added to DMSO (3 mL) and the resulting mixture was stirred for 5 min at RT. To this solution was added 100 (902 mg, 2.719 mmol) followed immediately by iodomethane (1.35 mL, 21.75 mmol). The resulting mixture was stirred at RT for 5 h. The reaction mixture was diluted with EtOAc and washed sequentially with H2O, 2M HCl and brine. The organic layer was dried, filtered, and concentrated. The crude product was purified by SiO2 chromatography eluting with 10:1 DCM/EtOAc. The impure product therefrom was rechromatographed under similar conditions to afford 586 mg (59.90%) of (S)-methyl 4-(tert-butoxycarbonyl(methyl)amino)-3-(4-chloro-3-fluorophenyl)butanoate (102).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].Cl[CH2:28][C@H:29]([OH:32])[CH2:30][OH:31]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH:22]([CH3:23])[CH3:24])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[O:26][CH2:28][C@H:29]([OH:32])[CH2:30][OH:31])[CH3:2]
Reactant: OC[C@@H](O)CCl
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1OC[C@H](O)CO
Reaction time: 144 h
Yield: 16.5 %

Procedure:
To a solution of 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (200 mg, 0.569 mmol) in isopropanol (10 mL) and 3 N aq. NaOH (3 mL), (R)-3-chloro-1,2-propanediol (252 mg, 2.28 mmol) is added. The mixture is stirred at 60° C. for 24 h before another portion of (R)-3-chloro-1,2-propanediol (252 mg, 2.28 mmol) is added. Stirring is continued at 60° C. for 6 days. The mixture is diluted with EA and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with EA to give 3-{2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-(R)-propane-1,2-diol (40 mg) as a pale yellow oil; LC-MS: tR=0.84 min; [M+1]+=426.16; 1H NMR (CDCl3): δ 7.90 (s, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.70 (s, 1H), 4.20-4.14 (m, 1H), 3.95-3.85 (m, 4H), 2.80-2.74 (m, 4H), 2.70 (s, 3H), 2.42 (s, 3H), 2.24-2.16 (m, 1H), 1.34 (t, J=7.5 Hz, 3H), 1.00 (d, J=6.5 Hz, 6 H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[N:9]([CH3:17])[C:8]2=[O:18])[CH2:4]1.Cl[C:20]1[N:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.O>[F:16][C:14]1[CH:15]=[C:10]2[N:9]([CH3:17])[C:8](=[O:18])[N:7]([C@H:5]3[CH2:6][C@H:3]([NH:2][C:20]4[N:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)[CH2:4]3)[C:11]2=[N:12][CH:13]=1
Reactant: Clc1ncc2ccccc2n1
Reactant: Cn1c(=O)n([C@H]2C[C@H](N)C2)c2ncc(F)cc21
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n([C@H]2C[C@H](Nc3ncc4ccccc4n3)C2)c2ncc(F)cc21
Temperature: 120 °C
Reaction time: 3 h

Procedure:
3-(Trans-3-aminocyclobutyl)-6-fluoro-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one hydrochloride (0.105 g, 0.385 mmol), 2-chloroquinazoline (0.076 g, 0.462 mmol), and N,N-diisopropylethylamine (0.268 mL, 1.540 mmol) were mixed in DMSO (0.5 mL). The reaction mixture was warmed to 120° C. and stirred for 3 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield 6-fluoro-1-methyl-3-(trans-3-(quinazolin-2-ylamino)cyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3h)-one (0.054 g, 0.148 mmol, 38.5% yield) as a yellow solid. M+1: 365.1. 1H NMR (400 MHz, DMSO-d) δ ppm 2.42-2.50 (m, 2 H) 3.25-3.34 (m, 2 H) 3.35 (s, 3 H) 4.63-4.74 (m, 1 H) 5.25 (quin, J=8.51 Hz, 1 H) 7.22-7.27 (m, 1 H) 7.49 (d, J=8.41 Hz, 1 H) 7.64-7.73 (m, 2 H) 7.81 (dd, J=8.02, 0.78 Hz, 1 H) 7.99 (br. d, J=6.30 Hz, 1 H) 8.05 (t, J=2.25 Hz, 1 H) 9.15 (s, 1 H).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(OCC)C>[Br:1][CH:2]([CH3:6])[C:3]([O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: CC(Br)C(=O)Cl
Solvent: CCOCC
Solvent: O
Product: CC(Br)C(=O)OCc1ccccc1

Procedure:
2-Bromopropionyl chloride (213.4 g) was added dropwise to benzyl alcohol (145.8 g) with stirring under a stream of nitrogen, keeping the temperature of the reaction mixture below 30° C. by cooling with cold water. When all the acid chloride has been added, the mixture was stirred for another two hours at ambient temperature. The reaction mixture was then diluted with diethyl ether (200 ml) and washed with water until free of acid. The ethereal solution was dried and evaporated and the residue distilled to give benzyl 2-bromopropionate, b.p. 82°-85°/0.5 Torr.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.CS(C)=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:22]3[CH:23]=[CH:24][N:25]=[C:21]3[CH3:20])[O:3][C:4]=2[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=1
Reactant: Cc1ncc[nH]1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (805.4 g), 2-methylimidazole (1101.7 g) and dimethyl sulfoxide (2416 mL) was stirred at 110° C. for 8 h and water was added to the obtained mixture. The mixture was extracted with ethyl acetate and the extract was washed with 5% brine. The solvent was evaporated and the residue was dissolved in ethyl acetate (1611 mL) with heating. n-Heptane (4832 mL) was added at 30° C. The precipitated crystals were collected by filtration and washed with ethyl acetate-n-heptane (1:3) to give the title compound (716.6 g, yield: 77.2%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[C:26]#[N:27]>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[CH:23]=[N:24][C:25]([C:26]#[N:27])=[C:21]3[N:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1[nH]cnc1N
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Yield: 35.1 %

Procedure:
Reaction of 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg, 1.0 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (125 mg, 35%). MS (ISP) 357.0 [(M+H)+]; mp 202° C.
Reaction SMILES: C(O[C:4](=[O:28])[CH2:5][C:6]([CH:8]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10][CH2:9]1)=O)C.[NH2:29][C:30]1[CH:34]=[CH:33][NH:32][N:31]=1>ClCCl>[OH:28][C:4]1[N:31]2[N:32]=[CH:33][CH:34]=[C:30]2[N:29]=[C:6]([CH:8]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH:11]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:10][CH2:9]2)[CH:5]=1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)C1CCC(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(c2cc(O)n3nccc3n2)CN1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
Di-tert-butyl 5-(3-ethoxy-3-oxopropanoyl)piperidine-1,2-dicarboxylate (18.79 mmol, 7.5 g) and 3-amino-1H-pyrazole (15.0 mmol, 1.25 g) were mixed and heated neat at 100° C. for 16 hours. The resulting residue is dissolved in dichloromethane (100 mL) and concentrated in vacuo to remove water formed during cyclization. LC-MS: 419 [M+H]. This solid is taken forward without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.Br[CH2:39][C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[C:42]([O:50][CH2:51][CH2:52][CH2:53][O:54][CH3:55])[CH:41]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:3][CH:2]2[O:1][CH2:39][C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[C:42]([O:50][CH2:51][CH2:52][CH2:53][O:54][CH3:55])[CH:41]=2)=[CH:9][CH:10]=1
Reactant: COCCCOc1cc(CBr)ccc1C(=O)OC
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)OC

Procedure:
Analogously to Method D, 3.25 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]-phenyl}piperidine-1-carboxylate (Example 10f) and 4.05 g of methyl 4-bromomethyl-2(3-methoxypropoxy)benzoate are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.30 (1:2 toluene-EtOAc); Rt=6.00.