Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH2:11])=[O:5].S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1)=[O:5]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a solution of (1R,2S)-2-amino-cyclopentanecarboxylic acid methyl ester hydrochloride (prepared as described in Example 11a, 104 mg, 0.58 mmol) in tetrahydrofuran (6 mL) at 25° C. was added magnesium sulfate (200 mg), triethylamine (0.085 mL, 0.61 mmol), and 4-fluorobenzaldehyde (0.13 mL, 1.19 mmol) sequentially. The reaction was stirred at 25° C. for 16 h. The mixture was passed through a short pad of Celite and the filtrate was concentrated and dried in vacuo. The residue was re-dissolved in methanol (10 mL) at 25° C. To this solution was added slowly sodium borohydride (45 mg, 1.19 mmol). The mixture was stirred at 25° C. for 1 h. It was then poured into a saturated sodium bicarbonate aqueous solution (10 mL) and the mixture was extracted into ethyl acetate (20 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a clear oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0-15% ethyl acetate in hexanes) afforded the desired product, (1R,2S)-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester (116 mg, 0.46 mmol, 79%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.55-1.73 (2H, m), 1.83-1.93 (3H, m), 1.99-2.08 (1H, m), 2.97 (1H, dd, J1=14.4 Hz, J2=8.0 Hz), 3.31 (1H, dd, J1=14.4 Hz, J2=7.2 Hz), 3.70 (3H, s), 3.77 (2H, dd, J1=19.6 Hz, J2=12.0 Hz), 4.67 (1H, s), 6.96-7.06 (2H, m), 7.26-7.35 (2H, m). LC-MS (ESI) calcd for C14H18FNO2 251.30, found 252.1 [M+H+].
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:3]=1.[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:4]2[N:3]=[C:2]([N:23]3[C:22]([CH3:21])=[CH:26][C:25]([CH3:27])=[N:24]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH2:11][CH3:12])=[CH:15][CH:16]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Product: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(-n3nc(C)cc3C)nc21

Procedure:
Was prepared according to Example 6 from (2-chloro-9-ethyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine and 3,5-dimethylpyrazole.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=1.[S:20]1[C:24](B(O)O)=[CH:23][C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[S:20]1[C:24]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[CH:9]=3)[N:4]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[N:3]=2)=[CH:23][C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: NC(=O)c1ccc2c(c1)c(-c1cc3ccccc3s1)nn2C1CCCCO1
Yield: 25.5 %

Procedure:
A mixture of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (425 mg, 1.31 mmol), benzo[b]thiophene-2-boronic acid (348 mg, 1.95 mmol, 1.49 equiv.), [1,1′-bis(diphenylphosphino)-ferrocene}dichloropalladium (II) complex with dichloromethane (107 mg, 0.131 mmol, 0.10 equiv.), potassium phosphate (K3PO4, 1.38 g, 6.50 mmol, 4.96 equiv.) and 6.5 mL of DME were refluxed for 18 h and concentrated. Purification by silica gel chromatography using 0-5% MeOH in EtOAc as eluent afforded the title compound (126 mg, 26% yield): ES-MS (m/z) 378 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:18][CH2:19][CH3:20])[N:6]2[CH2:13][C:14](=[NH:17])[NH:15][OH:16].[Cl:21][C:22]1[CH:27]=[C:26]([C:28](Cl)=O)[CH:25]=[C:24]([Cl:31])[N:23]=1>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:18][CH2:19][CH3:20])[N:6]2[CH2:13][C:14]1[N:17]=[C:28]([C:26]2[CH:25]=[C:24]([Cl:31])[N:23]=[C:22]([Cl:21])[CH:27]=2)[O:16][N:15]=1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Solvent: C1CCOC1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(Cl)nc(Cl)c2)n1
Temperature: 120 °C

Procedure:
Synthesized as described for Examples 32A-32B using 2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with 2,6-dichloro-4-pyridinecarbonyl chloride (0.021 g, 0.1 mmol) and TEA (0.012 g, 0.12 mmol) and heated at 120° C. for 1 h in the microwave: 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 2 H), 7.96 (s, 1 H), 7.76 (d, J=8.5 Hz, 1 H), 7.58 (d, J=8.7 Hz, 1 H), 5.87 (s, 2H), 2.91 (t, 2 H), 1.67-1.54 (m, 2 H), 0.92 (t, 3 H); MS (ES) m/z 447 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:31])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([OH:26])=O)=[O:5])[CH3:2].[CH:32]([NH:35][CH:36]([CH3:38])[CH3:37])([CH3:34])[CH3:33]>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:31])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([N:35]([CH:36]([CH3:38])[CH3:37])[CH:32]([CH3:34])[CH3:33])=[O:26])=[O:5])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(C(C)C)C(C)C

Procedure:
Starting materials: 19-ethoxycarbonyl-2,6,10,14,18-pentamethyl-2,6,10,14,18-nonadecapentaenoic acid and diisopropylamine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](=[N:34][NH2:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)C(C)C.C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:35][N:34]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2CCCN(Cc3ccccc3)C2)cc1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CO
Solvent: ClCCl
Product: c1ccc(CN2CCCC(c3ccc(NN=C(c4ccccc4)c4ccccc4)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
A mixture of (F1), benzophenone hydrazone (1.8 eq.), ground NaOH (1.4 eq.), Pd(AcO)2 (0.05 eq.) and XPhos (0.1 eq.) in degassed iBuOH (0.18 M) was stirred under argon at RT for 20 min and then was heated at 80° C. for 3 h. After cooling down, evaporation of the solvent gave a residue that was dissolved in DCM and washed with sat. aq. NH4Cl (2×) and sat. aq. NaHCO3 (2×) and dried (Na2SO4). Evaporation of the solvent gave a crude that was purified by flash chromatography column on silica (EtOAc/Petroleum ether 2:98 to 1:4) yielding (90%) the title compound as a yellow foam. 1H NMR (300 MHz, DMSO-d6, 300K) δ 8.68 (1H, s), 7.67-7.49 (3H, m), 7.46-7.39 (2H, m), 7.37-7.25 (10H, m), 7.13 (2H, d, J=8.3 Hz), 7.04 (2H, d, J=8.3 Hz), 3.47 (2H, s), 2.92-2.75 (2H, m), 2.70-2.56 (1H, m), 2.06-1.86 (2H, m), 1.83-1.50 (3H, m), 1.48-1.32 (1H, m). MS (ES+) C31H31N3 required: 445, found: 446 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([CH:19]2[CH2:21][CH2:20]2)=[CH:4][N:3]=1.[CH3:22][N:23]1[C:27]([NH2:28])=[CH:26][C:25]([CH3:29])=[N:24]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:19]1([C:5]2[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]([NH:13][CH3:14])=[O:12])=[CH:7][C:2]([NH:28][C:27]3[N:23]([CH3:22])[N:24]=[C:25]([CH3:29])[CH:26]=3)=[N:3][CH:4]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(N)n(C)n1
Reactant: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1cc(Nc2cc(C)nn2C)ncc1C1CC1
Reaction time: 0.67 h
Yield: 17 %

Procedure:
To a 10 mL microwave tube were added 2-(2-chloro-5-cyclopropyl-pyridin-4-ylamino)-N-methyl-benzamide (0.075 g, 0.25 mmol, 1 eq), 2,5-dimethyl-2H-pyrazol-3-ylamine (0.030 g, 0.27 mmol, 1.1 eq), Cs2CO3 (0.23 g, 0.70 mmol, 2.8 eq) and 1,4-dioxane (4 mL) and resulting mixture was degassed with N2 for 30 minutes. To this was added Pd2(dba)3 (0.008 g, 0.007 mmol, 0.03 eq) and xanthphos (0.009 g, 0.014 mmol, 0.06 eq) and reaction mixture was degassed again with N2 for another 15 minutes. The resulting reaction mixture was irradiated in a CEM microwave at 110° C. and 150 W for 40 min. The progress of reaction was monitored by LCMS. After completion of reaction, Cs2CO3 was removed by filtration and the filtrate was concentrated under reduced pressure to give a crude product. The crude compound was purified by column chromatography over neutral alumina using 0.1% MeOH-DCM as the eluant. Solid compound so obtained was washed with diethyl ether and pentane to give the title compound as a yellowish solid (16 mg, 17%). 1H-NMR (400 MHz, DMSO-d6): δ 0.52-0.59 (m, 2H), 0.89-0.99 (m, 2H), 1.52-1.62 (m, 1H), 2.05 (s, 3H), 2.76-2.77 (d, 3H, J=4.44 Hz), 3.52 (s, 3H), 5.96 (s, 1H), 6.69 (s, 1H), 7.01-7.05 (t, 1H, J=7.48 Hz), 7.42-7.45 (m, 1H), 7.51-7.60 (m, 1H) 7.64-7.66 (d, 1H, J=7.32 Hz), 7.72 (s, 1H), 8.37 (s, 1H), 8.55-8.65 (brs, 1H), 9.96 (s, 1H). LC-MS [M+H]+=377.2.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[CH2:16]([N:19]=[C:20]=[O:21])[CH2:17][CH3:18]>C1C=CC=CC=1>[CH2:16]([NH:19][C:20]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[O:21])[CH2:17][CH3:18]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CCCN=C=O
Solvent: c1ccccc1
Product: CCCNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Yield: 79.6 %

Procedure:
To a stirred and chilled (10°-15° C.) solution of 0.027 mole of 3-[3-(trifluoromethyl)phenoxy]azetidine in 100 ml of dry benzene was added dropwise 4.0 g (0.047 mole) of n-propyl isocyanate. The reaction mixture was stirred at room temperature for 30 minutes. The benzene was washed with dilute sodium bicarbonate (50 ml), water (25 ml), saturated sodium chloride (25 ml), and dried (sodium sulfate). The solution volume was reduced to 50 ml, and 30 ml of petroleum ether was added, yielding 6.5 g (81%) of product. Recrystallization from isopropyl etherisopropyl alcohol gave 6.0 g of small white needles, m.p. 115°-117° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][CH2:29][C@@H:28]([C:32]([O:34]CC)=[O:33])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:5])[CH3:4].CO>O>[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][CH2:29][C@@H:28]([C:32]([OH:34])=[O:33])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)[C@@H]1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCC[C@@H](C(=O)O)C3)ccc2n1CC1CCOCC1
Reaction time: 8 h

Procedure:
NaOH (0.5 mL, 2 M, 1.0 mmol) was added to a solution of ethyl (3R)-1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}piperidine-3-carboxylate (255 mg, 0.52 mmol) in a 1:1 mixture of MeOH:H2O (10 mL) at ambient temperature. The reaction mixture was stirred overnight and diluted with water (50 mL). The solvent was concentrated to 50 mL. The resulting solution was neutralized with HCl solution, the product was extracted with EtOAc and dried over anhydrous Na2SO4. The solvent was concentrated to provide the title compound as white solid. Yield: 236 mg (98%); MS (ESI) (M+H)+=464.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O.C(O)(C(F)(F)F)=O>>[CH:13]1([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH2:2][NH:1]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 9.4 %

Procedure:
This product was prepared using the same procedure as for intermediate 1 with tryptamine (2.8 g, 17.4 mmol), 4-formylbenzoic acid, methyl ester (2.87 g, 1.1 equiv.) and TFA (2.7 mL, 2 equiv.) to give the title compound (0.5 g, 9%) as white crystals after recrystallization from isopropanol:H2O.
Reaction SMILES: C(O[CH:5]([C:17]1[N:21]([CH2:22][C:23]2S[C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:27]=2)[C:20]([CH2:32][CH2:33][CH2:34][CH3:35])=[N:19][CH:18]=1)[CH:6]([CH2:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][CH3:10])=[O:8])(=O)C.[N:36]12CCCN=C1CCCC[CH2:37]2>C1(C)C=CC=CC=1>[CH2:32]([C:20]1[N:21]([CH2:22][C:23]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:37][N:36]=2)[C:17](/[CH:5]=[C:6](\[CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)/[C:7]([O:9][CH3:10])=[O:8])=[CH:18][N:19]=1)[CH2:33][CH2:34][CH3:35]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCCc1ncc(C(OC(C)=O)C(Cc2cccs2)C(=O)OC)n1Cc1ccc(C(=O)OC)s1
Solvent: Cc1ccccc1
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OC)n1Cc1ccc(C(=O)OC)cn1
Temperature: 80 °C

Procedure:
A mixture of methyl 3-acetoxy-3-[2-n-butyl-1-{(5-carbomethoxy-2-thienyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methylpropanoate (1.99 g, 3.88 mmol) in dry toluene (150 ml) was treated with 17 ml of 1,8-diazabicyclo-[ 5.4.0]undec-7-ene (DBU) and the resulting solution was heated at 80° C. under argon for 1 hour. The solvent was evaporated, the residue triturated with diethyl ether and activated charcoal was added. After filtration, the filtrate was concentrated to give 6.29 g of an oil that was chromatographed over silica gel with hexane/ethyl acetate (1:1) to give 0.43 g (24%) of methyl (E)-3-[2-n-butyl-1-{(5-carbomethoxy-2-thienyl)methyl)-1H-imidazol-5-yl-2-(2-thienyl)methyl-2-propenoate.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+](=[CH:11][C:12]([O:14][C:15]1([CH3:24])[CH2:20][CH2:19][CH:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]1)=[O:13])=[N-]>ClCCl>[C:3]1([CH:2]2[CH2:1][CH:11]2[C:12]([O:14][C:15]2([CH3:24])[CH2:20][CH2:19][CH:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CC(C)C1CCC(C)(OC(=O)C=[N+]=[N-])CC1
Solvent: ClCCl
Product: CC(C)C1CCC(C)(OC(=O)C2CC2c2ccccc2)CC1

Procedure:
To a mixture of styrene (1.063 g, 10.2 mmol) and Rh2 (4R-BNOX)4 (0.0050 g, 0.0058 mmol) in 3.0 mL of refluxing anhydrous dichloromethane was added, by syringe at room temperature, 1-menthyl diazoacetate (0.109 g, 0.485 mmol) in 3.0 mL of dichloromethane under nitrogen &nd at an addition rate of 0.8 mL/h (syringe pump). After addition was complete, the dichloromethane solution was passed through a plug of neutral alumina, and solvent was removed under reduced pressure. The residue was analyzed by capillary gas chromatography (SPB-5 column) for diastereomeric separation and enantiomeric purity. Similar procedures were followed for the cyclopropanation of 3,3-dimethyl-1-butene, ethyl vinyl ether, and dihydropyran.
Reaction SMILES: S(=O)(=O)(O)N.[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[CH:24]=[O:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O-:26]Cl=O.[Na+]>CC(C)=O.O>[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[C:24]([OH:26])=[O:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c(OCc2ccccc2)ccc2ccccc12
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1c(OCc2ccccc2)ccc2ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sulfamic acid (17.28 g, 178 mmol) was added to a solution of 9 (21.11 g, 80.5 mmol) in acetone (420 ml) and water (210 ml) at 0° C. Over a period of 20 minutes, 80% NaClO2 (10.42 g, 92.2 mmol) was added at 0° C. The solution was stirred at 0° C. for 30 minutes and then concentrated to about 200 ml. After dilution with water (200 ml), the mixture was extracted with CH2Cl2 (1×200 ml, 2×100 ml). The organic layer was dried (MgSO4) and concentrated. Crystallization from cyclohexane/ethyl acetate (1:1) generated 19.12 g (85%) of 10 as pale yellow crystals, mp 127°-128° C. (lit. mp 128°-130° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:40][N:41]([CH3:46])[C:42](=[O:45])[CH2:43]O.O>CN(C=O)C>[CH3:40][N:41]([CH3:46])[C:42](=[O:45])[CH2:43][O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([C:10]2[NH:11][C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)=[CH:20][CH:21]=1
Reactant: CN(C)C(=O)CO
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)COC(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzoic acid (0.15 g, 0.42 mmol) [See Ex. 9 above] in DMF(10 ml) was added carbonyldiimidazole (0.34 g, 2.1 mmol). After stirring for 18 h at rt, N,N-dimethylglycolamide (0.43 g, 4.2 mmol) was added and stirring was continued for an additional 3 h at rt. The reaction mixture was poured into H2O extracted with EtOAc and evaporated. The residue was purified by flash chromatography eluting with a solvent gradient of 2% MeOH/CHCl3 to afford the title compound: CIMS (NH3,m/z): 445 (M++H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
4-benzyloxy-2(1H)-pyridone (50.0 g, 248.47 mmol) was dissolved in dimethyl sulfoxide (300 mL). Potassium carbonate (68.68 g, 496.94 mmol) was added, followed by 4-fluorobenzonitrile (31.60 g, 260.89 mmol). The reaction was stirred at 100° C. for 20 hours. After cooling to room temperature the reaction was diluted with H2O (600 mL) and the solids were collected by filtration washing with diethyl ether. The solids were then washed with hot methanol to provide a tan solid (55.6 g, 74%). 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.44-7.41 (m, 5H), 7.22 (d, J=13.3, 1H), 6.13 (dd, J=2.6, 7.7 Hz, 1H), 6.06 (d, J=2.6 Hz, 1H), 5.07 (s, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:8][O:7][CH:6]([CH3:9])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl.CO>CO>[CH3:9][CH:6]1[CH2:5][NH:4][CH2:3][CH:2]([OH:1])[CH2:8][O:7]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(O)CO1
Agent: Cl
Solvent: CO
Product: CC1CNCC(O)CO1
Temperature: 30 °C
Reaction time: 5 h
Yield: 137.2 %

Procedure:
To a mixture of tert-butyl 6-hydroxy-2-methyl-1,4-oxazepane-4-carboxylate (D1, 494.00 mg, 2.14 mmol, 1.00 eq) in MeOH (5.00 mL), was added HCl/MeOH (15.00 mL) in one portion at 30° C. under N2. The mixture was stirred at 30° C. for 5 hours. TLC showed the reaction was completed. The mixture was concentrated in vacuum to afford 2-methyl-1,4-oxazepan-6-ol (385.00 mg, crude) as yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[I:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:18])[N:3]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(Cl)n1
Reactant: Ic1c[nH]cn1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared 2-chloro-6-methyl-4-(4-trifluoromethyl-phenyl)pyridine (example A.30) (1.0 g, 3.7 mmol) and commercially available 4-iodo-imidazole (0.857 g, 4.4 mmol) according to the general procedure IVa. Obtained as a yellow solid (0.98 g, 62%). MS (ISP) 430.2 [(M+H)+].
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[CH3:12][O:13][C:14]([NH:16][NH:17][C:18]1[C:26]2[O:25][CH:24]([CH3:27])[CH2:23][C:22]=2[C:21]([CH3:28])=[CH:20][CH:19]=1)=[O:15]>C(Cl)Cl>[CH3:12][O:13][C:14]([N:16]=[N:17][C:18]1[C:26]2[O:25][CH:24]([CH3:27])[CH2:23][C:22]=2[C:21]([CH3:28])=[CH:20][CH:19]=1)=[O:15]
Reactant: COC(=O)NNc1ccc(C)c2c1OC(C)C2
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)N=Nc1ccc(C)c2c1OC(C)C2
Temperature: 37 °C
Reaction time: 18 h

Procedure:
A solution of 5.3 g of 85% m-chloroperoxybenzoic acid (MCPBA) in 100 ml of methylene chloride was added slowly to a solution of 6.2 g of 1F in 100 ml of methylene chloride, at room temperature. The mixture warmed to about 37° C. It was allowed to cool to room temperature, let stand for 18 hours, washed with 10% aqueous sodium carbonate solution, then water, then the liquid phases were separated. The methylene chloride phase was dried (MgSO4) and the solvent was evaporated. The residue was crystallized from ether/hexane (1:1, v:v) to give 1, as an orange solid, m.p.: 62°-65° C.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.[CH2:19]1[O:21][CH2:20]1.[NH4+].[Cl-]>C1COCC1.CCOCC>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:19][CH2:20][OH:21])[CH:16]=[CH:15]2
Reactant: C1CO1
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2cc(CCO)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
tert-Butyllithium (5.2 mL, 8.84 mmol, 1.7 M/pentane) was added to a −78° C. solution of 2-bromo-6-methoxynaphthalene (1.0471 g, 4.42 mmol) in THF (10 mL)/ether (10 mL). After 30 minutes, a solution of ethylene oxide in THF (2 mL, 23 mmol, 0.5 g/mL) was added and the reaction was allowed to warm to room temperature. After overnight stirring, 30 mL saturated NH4Cl solution was added and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic solution was then dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (478 mg, 53%).