Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH:14][CH:15]=[O:16])=[CH:9][CH:8]=1.[N+:17]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>C(#N)C>[N+:17]([C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:28])[NH:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][NH:14][CH:15]=[O:16])=[CH:11][CH:12]=2)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=CNNc1ccc(NC(=O)Nc2cccc([N+](=O)[O-])c2)cc1
Temperature: -5 °C

Procedure:
200 ml of acetonitrile and 200 ml of N,N-dimethylformamide were added to 60.4 g of 2-(4-aminophenyl)-1-formylhydrazine to be dissolved, followed by cooling to -5° C. 65.6 g of metanitrophenyl isocyanate dissolved in 200 ml of acetonitrile was added dropwise thereto. During this dropwise addition, the solution was cooled with stirring so that the temperature thereof would not exceed -5° C. A further 300 ml of acetonitrile was added at 0° C., and after stirring for 3 hours, formed crystals were filtered and washed with acetonitrile and then with methanol. The thus-obtained crystals were dissolved in 1 liter of N,N-dimethylformamide, the undissolved portion was filtered off, and 3 liters of methanol was added to the filtrate, followed by cooling to form crystals. The thus-formed crystals were then filtered and washed with acetonitrile and then methanol. The yield was 98.5 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:11]([C:10]1[C:9](=[O:14])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[CH:19][N:18]([CH3:20])[CH:17]=1)(=[O:13])[CH3:12]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)Cc1cccc(Br)c1
Product: CC(=O)c1cn(C)cc(-c2cccc(Br)c2)c1=O

Procedure:
To 1.5 g. of 1-(3-bromophenyl)-2,4-pentanedione was added 25 ml. of N,N-dimethylformamide dimethyl acetal. The mixture was stirred at reflux temperature for 18 hours, cooled and evaporated to a thick oil under vacuum. The oil was dissolved in 500 ml. of tetrahydrofuran, and 10 ml. of 40% aqueous methylamine was added. The mixture was stirred at ambient temperature for 4 hours, and was then evaporated under vacuum. The residue was dissolved in 800 ml. of dichloromethane, and washed with 500 ml. of water. The organic layer was dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated under vacuum. The solids were recrystallized twice from dichloromethane/diisopropyl ether. The solids were then chromatographed on a silica gel column with ethyl acetate as the eluting solvent. The yield was 0.8 g. of the desired product, m.p. 192°-194°. Nmr analysis in DMSOd6 showed peaks at δ7.25-8.40 (m, 6H, aromatic); 3.75 (s, 3H, N--CH3); 2.53 (s, 3H, COCH3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.[CH3:19][C:20]1[N:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([O:27][CH2:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:19])[N:25]=2)[N:7]=1
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Reactant: Cc1cccc(CO)n1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccc(COc2nc(N)nc(-c3ccc(C)o3)c2C#N)n1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 6-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[CH3:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(I)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1cc(I)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 90.5 %

Procedure:
A mechanically stirred mixture of 4-iodo-2-methylphenol (1.62 moles; 391 g), cesium carbonate (1.99 moles; 650 g), and 1.75 L of acetone is treated with benzyl bromide (1.70 moles; 203 mL; 291 g) over 15 m. The reaction mixture was stirred for 21 h at RT and filtered. The filter cake is washed with 1 L of acetone, and the combined filtrates are concentrated. The crude semi-solid is recrystallized from pentane to give 475 grams (90%) of the desired product as a white solid. 1H NMR (CDCl3) δ: 7.40 (m, 7H), 6.64 (d, J=8.6 Hz, 1H), 5.06 (s, 2H), 2.24 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])([C:9]#[N:10])[CH:6]([CH3:8])[CH3:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1>>[C:9]([C:5]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])([CH2:4][CH2:3][CH2:2][N:22]([CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:21])[CH:6]([CH3:8])[CH3:7])#[N:10]
Reactant: CNCCc1ccc(C(=O)OC)cc1
Reactant: COC(=O)c1cccc(C(C#N)(CCCBr)C(C)C)c1
Product: COC(=O)c1ccc(CCN(C)CCCC(C#N)(c2cccc(C(=O)OC)c2)C(C)C)cc1

Procedure:
Reaction of 1r with 2b produced 3am. MS found M+H=451. The oxalate salt of 3am was recrystallized from methanol/ether; mp 108-112° C.
Reaction SMILES: C(OC([C:8]1([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:14][CH2:13][C:12]([CH3:15])=[CH:11][CH:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:23])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:23]=[C:9]1[CH:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[C:12]([CH3:15])[CH2:13][CH2:14][CH:8]1[CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CC1(C(=O)OC(C)(C)C)CCC(C)=CC(Cc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC1CCC(C)=CC(Cc2ccccc2)C1=O
Reaction time: 0.75 h

Procedure:
To a stirred solution of the above di-ester (22) (1.35 g) in CH2Cl2 (20 mL) was added trifluoroacetic acid (80 mL). After stirring for 45 min the reaction was evaporated to dryness and re-evaporated twice with fresh toluene to remove any residual TFA. The oil which remained was then taken up in toluene (100 mL) and refluxed under Ar for 1 h. The product (23) was obtained after evaporation and purification by flash chromatography on silica gel eluted with 10% ethyl acetate in n-hexane (0.85 g, 85%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13](=[O:25])[C@H:14]([CH2:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19])[NH2:15].[Cl:26][C:27]1[CH:35]=[C:34]([C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=2)=[O:37])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[C:34]([C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=2)=[O:37])[CH:33]=[CH:32][C:28]=1[C:29]([NH:15][C@H:14]([C:13]([O:12][CH3:11])=[O:25])[CH2:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19])=[O:30]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)[C@@H](N)CNC(=O)c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 70.2 %

Procedure:
Diisopropylethylamine (7.00 g, 64.2 mmol) was added to a solution of 3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester hydrochloride (Example 301; 7.00 g, 26.4 mmol), 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]-carbonyl]benzoic acid (Example 26; 7.00 g, 22.9 mmol), and HBTU (13.00 g, 34.3 mmol) in DMF (75 mL). The solution was allowed to stir at room temperature for 4 days, and it was then concentrated to remove most of the DMF. Ethyl acetate (200 mL) was added, followed by water (200 mL) and 1 M HCl (100 mL). The layers were separated; the ethyl acetate layer was evaporated, and the residue was chromatographed (50-100% ethyl acetate/hexanes) to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (8.30 g, 70%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].[N:19]1([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:22]1[CH2:23][CH2:24][N:19]([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:20][CH2:21]1)=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: N#Cc1cnc(N2CCNCC2)s1
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C#N)s2)CC1
Yield: 61 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example A8) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 61%). MS (m/e): 449.4 (M+H+, 100%).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].C(N(CC)CC)C.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>C(O)C>[N+:13]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.1 %

Procedure:
Ethyl 4-fluoro-3-nitrobenzoate (160 g, 0.752 mol) prepared in the Step 1-1-1 was suspended in ethanol (500 ml). Triethylamine (91.4 g, 0.903 mol) was added to the suspension, and under an ice cooling, piperidine (76.9 g, 0.903 mol) was slowly added thereto. After the mixture was stirred at a room temperature for 2 hours, a saturated sodium bicarbonate solution was added to the mixture, and the resulting mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and a saturated saline solution in order, and then dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 to 3:1) to give the title compound (222 g, quantitative) as a poppy-red oily substance.
Reaction SMILES: C(O[C:4]([CH2:6][N:7]1[C:14]2[N:10]([N:11]=[CH:12][CH:13]=2)[CH:9]=[CH:8]1)=[O:5])C.[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:15][N:16]([CH3:17])[C:4]([CH2:6][N:7]1[C:14]2[N:10]([N:11]=[CH:12][CH:13]=2)[CH:9]=[CH:8]1)=[O:5]
Reactant: CNC
Reactant: CCOC(=O)Cn1ccn2nccc12
Solvent: CCO
Product: CN(C)C(=O)Cn1ccn2nccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-ethoxycarbonylmethyl-1H-imidazo-[1,2-b]pyrazole (7.0 g) in ethanol (35 ml) was added 50% dimethylamine aqueous solution (17 ml). The mixture was stirred at room temperature for 5 hours. The reaction mixture was evaporated in vacuo. The resultant crude powder was subjected to column chromatography on silica gel using a mixture of ethyl acetate and methanol as an eluent. Fractions containing the object compound were combined and evaporated in vacuo. The resultant precipitate was collected and washed with diisopropyl ether to give 1-(N,N-dimethylcarbamoylmethyl)-1H-imidazo[1,2-b]-pyrazole (1.6 g).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([S:15](Cl)(=[O:17])=[O:16])[CH:6]=1)(=[O:3])[CH3:2].[CH:19]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][NH:21][CH2:20]2.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([S:15]([N:21]2[CH2:22][CH:23]3[CH2:26][CH2:27][CH:19]([CH2:25][CH2:24]3)[CH2:20]2)(=[O:17])=[O:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(S(=O)(=O)Cl)cc2ccccc12
Reactant: C1CC2CCC1CNC2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(S(=O)(=O)N2CC3CCC(CC3)C2)cc2ccccc12
Yield: 63.1 %

Procedure:
4-Acetoxy-2-naphthalenesulfonyl chloride (861 mg, 3.02 mmol) and 3-azabicyclo[3.2.2]nonane (379 mg, 3.02 mmol) were combined in CHCl3 (20 ml) and pyridine (20 ml) and the mixture was stirred at room temperature for 15 hr. At this time the solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc and 1N aq HCl. The EtOAc was then washed with saturated aq NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography using 1% acetone in CHCl3 to provide the pure product as a white foam (712 mg, 63% yield): 1H NMR (CDCl3) δ 1.52-1.84 (8H, m, 4×CH2), 2.02-2.13 (2H, br s, 2×CH), 2.46 (3H, s, CH3CO), 3.31 (4H, d, J=4.2 Hz, 2×CH2), 7.56-7.71 (3H, m, ArH), 7.92-8.02 (2H, m, ArH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[NH2:14]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCOCC2)cc1F
Reaction time: 2.5 h
Yield: 96.7 %

Procedure:
2-Fluoro-4-morpholinonitrobenzene (1.80 g) was dissolved in methanol (100 mL) and 10% Pd/C (94 mg) was added. The mixture was placed in a hydrogenator (45 psi) for 2.5 h. The reaction mixture was filtered through celite and washed with methanol. The filtrate was concentrated to give 1.51 g solid. 1H NMR (CDCl3) δ 6.76–6.54 (m, 3H), 3.84 (t, 4H), 3.45 (bs, 2H), 3.02 (t, 4H) ppm. ESI mass spectrum z (rel. intensity) 197.1 (M+H, 100).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[CH:23]4)=[CH:18][C:17]=3[N+:27]([O-])=O)[CH:12]=[CH:13][CH:14]=2)=[CH:5][N:4]=1.[H][H]>[Pd].C(O)C>[CH3:1][N:2]([CH3:30])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[CH:23]4)=[CH:18][C:17]=3[NH2:27])[CH:12]=[CH:13][CH:14]=2)=[CH:5][N:4]=1
Reactant: CN(C)c1ncc(-c2cccc(Nc3ccc(-n4cccc4)cc3[N+](=O)[O-])c2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1ncc(-c2cccc(Nc3ccc(-n4cccc4)cc3N)c2)cn1

Procedure:
To a suspension of 3f (0.2g, 0.5mmol) in abs. ethanol is added palladium catalyst (5% Pd on activated carbon) and the mixture is hydrogenated at ambient pressure until the hydrogen uptake has ceased. The mixture is filtered through celite and the filtrate is concentrated under reduced pressure. This crude product is used directly for the next step. See Example 11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4([O:37][CH3:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:26]=3)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:39]C1C=C(C2(OC)CCOCC2)C=C(O)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:23][O:24][C:25]3[CH:26]=[C:27]([C:31]4([O:37][CH3:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:28]=[C:29]([F:39])[CH:30]=3)[O:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Reactant: COC1(c2cccc(OCc3nc(-c4ccc(F)cc4)c(-c4ccc(S(C)(=O)=O)cc4)o3)c2)CCOCC1
Product: COC1(c2cc(F)cc(OCc3nc(-c4ccc(F)cc4)c(-c4ccc(S(C)(=O)=O)cc4)o3)c2)CCOCC1

Procedure:
4-(4-Fluorophenyl)-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy)methyl]-5-(4-(methylsulfonyl)phenyl)oxazole was prepared in a similar fashion from the reaction of the mesylate (Example 2, Step 4) and 4-(3-fluoro-5-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran: 1H-NMR (CDCl3, 300 MHz) δ 1.84-2.02 (m, 4H), 2.98 (s, 3H), 3.08 (s, 3H), 3.81 (m, 4H), 5.23 (s, 2H), 6.76 (m, 2H), 6.92 (s, 1H), 7.13 (m, 2H), 7.60 (m, 2H), 7.79 (d, 2H, J=8.5 Hz) and 7.93 (d, 2H, J=8.5 Hz). 19F-NMR (CDCl3, 280 MHz ) δ -110.8 and -111.7. Anal. Calc'd. for C29H27NO6F2 : C, 62.69; H, 4.90; N, 2.52. Found: C, 62.53; H, 4.96; N, 2.51.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[CH:9][CH:8]=1)[C:3]([CH3:6])([OH:5])[CH3:4].[Cl:18][C:19]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:18][C:19]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][CH:2]([C:7]1[CH:8]=[CH:9][C:10]([S:13][CH2:14][CH:15]2[CH2:16][CH2:17]2)=[CH:11][CH:12]=1)[C:3]([OH:5])([CH3:6])[CH3:4])=[O:22]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: CC(C)(O)C(N)c1ccc(SCC2CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(O)C(NC(=O)c1cccc(C(F)(F)F)c1Cl)c1ccc(SCC2CC2)cc1
Reaction time: 16 h
Yield: 69.2 %

Procedure:
1-Amino-1-(4-[(cyclopropylmethyl)thio]phenyl)-2-methylpropan-2-ol (150 mg) and 2-chloro-3-(trifluoromethyl)benzoyl chloride (300 mg) in dichloromethane (2 mL) were treated with saturated sodium bicarbonate solution (2 mL) and stirred vigorously for 16 h. The organic phase was dried (MgSO4), concentrated and the residue purified by chromatography on silica (eluting with iso-hexane on a gradient of ethyl acetate) to give the title compound as a foam (189 mg). 1H NMR (500 MHz, CDCl3): δ 7.76 (1H, d, J=7.8 Hz), 7.64 (1H, d, J=7.6 Hz), 7.41 (1H, t, J=7.8 Hz), 7.34 (2H, d, J=8.2 Hz), 7.28 (2H, d, J=8.2 Hz), 7.05 (1H, br d, J=8.5 Hz), 4.98 (1H, d, J=8.5 Hz), 2.87 (2H, d, J=7.0 Hz), 1.45 (3H, s), 1.10 (3H, s), 1.09-1.04 (1H, m), 0.59 (2H, q, J=5:1 Hz), 0.26 (2H, q, J=5.1 Hz); m/z 457, 459.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:13]([OH:14])=[C:12]([CH:15]([OH:17])[CH3:16])[C:11]([CH:18]=[CH2:19])=[CH:10][N:9]=1>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH3:7][C:8]1[C:13]([OH:14])=[C:12]([C:15](=[O:17])[CH3:16])[C:11]([CH:18]=[CH2:19])=[CH:10][N:9]=1
Reactant: C=Cc1cnc(C)c(O)c1C(C)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=Cc1cnc(C)c(O)c1C(C)=O
Reaction time: 0.33 h

Procedure:
To 750 ml. of dry methylene chloride containing 47.5 ml. of dry pyridine was added with stirring and cooling 29.6 g. of chromium trioxide. The mixture was aged 20 minutes at room temperature and then treated with a solution of 10.96 g. of the product from Example 10, Step B, in 250 ml. of dry methylene chloride over 15 minutes. After one hour at room temperature, the reaction mixture was filtered and the residue was washed with 2 × 100 ml. of methylene chloride. The methylene chloride filtrates were extracted with 3 × 500 ml. of 5% (w/w) aqueous sodium hydroxide solution, dried over magnesium sulfate and evaporated to dryness. The residue was crystallized from hexane to give 2-methyl-3-hydroxy-4-acetyl-5-vinylpyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=[CH:15][C:8]=3[C:7](=[O:19])[C:6]=2[CH:20]=1.[CH3:21][N:22](C)C=O.C(Cl)(Cl)Cl.[C-]#N.[Na+]>O>[CH:16]([C:13]1[CH:14]=[CH:15][C:8]2[C:7](=[O:19])[C:6]3[CH:20]=[C:2]([C:21]#[N:22])[CH:3]=[CH:4][C:5]=3[CH2:11][O:10][C:9]=2[CH:12]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ccc2c(c1)OCc1ccc(Br)cc1C2=O
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)c1ccc2c(c1)OCc1ccc(C#N)cc1C2=O

Procedure:
Reflux a mixture of 8.39 gm. (0.0253 mole) of 9-bromo-6,11-dihydro-3-isopropyl-11-oxodibenz[b,e]oxepin, 4.83 gm. (0.0539 mole) of cuprous cyanide and 30 ml. of dimethylformamide for 8 hours with vigorous stirring. Cool the reaction mixture and shake with a mixture of 36 ml. of chloroform, 25 ml. of saturated sodium cyanide solution and 25 ml. of water until all solids have dissolved. Separate the organic layer, wash with aqueous sodium cyanide solution and water and dry over anhydrous magnesium sulfate. Remove the solvent under vacuum. Purity the resulting oil (7.01 gm.) by column chromatography on silica gel with benzene as eluant to obtain the title product [yield 2.8 gm., m.p. 101°-108° C., showing a single spot, Rf =0.18 on thin layer chromatography or silica gel with benzene as the solvent system, pmr (CDCl3 1,23(6H, d, (CH3)2CH--), 2.95 (1H,m, (CH3)2CH--), 5.20 (2H,s, CH2O)].
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:21])[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:42]1[C:46](=[O:47])[C:45]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:44]2[C:43]1=[O:52].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][CH2:9][C@@H:10]([O:21][N:42]1[C:43](=[O:52])[C:44]2=[CH:51][CH:50]=[CH:49][CH:48]=[C:45]2[C:46]1=[O:47])[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O[C@H](CCOCc1ccccc1)COCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1O[C@@H](CCOCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-1,4-dibenzyloxy-2-hydroxybutane (8 g, 28 mmol) in dry tetrahydrofuran (150 ml) was added triphenylphosphine (11 g, 42 mmol) and N-hydroxyphthalimide (6.8 g, 42 mmol). The solution was treated dropwise with diethyl azodicarboxylate (6.6 ml, 42 mmol). A dark red colouration appeared, gradually fading and the solution became warm. The solution was stirred at room temperature for 16 hours, then treated with additional triphenyl phosphine (2.25 g, 8.5 mmol) N-hydroxyphthalimide (1.35 g, 8.5 mmol) and diethyl azodicarboxylate (1.35 ml, 8.5 mmol). After stirring for an additional 24 hours at room temperature, the solvent was removed under reduced pressure and the residue dissolved in ethyl acetate-hexane 1:1 (100 ml) and refrigerated. A white solid crystallised out and was filtered off. The solution was evaporated to dryness and the residue dissolved in ethyl acetate-hexane 1:1 (50 ml) and refrigerated. After filtration, the filtrate was evaporated to dryness and the residue chromatographed on silica, eluting with ethyl acetate-hexane 1:2 to give (S)-N-(1,4-dibenzyloxybut-2-oxy)phthalimide (11 g, (91%), [α]25 -17.4° (c 0.8 in ethanol); IR: υmax
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH2:24]([O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH2:25][CH2:26][CH2:27][CH3:28]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:34][C:33]4[CH:32]=[CH:31][C:30]([O:29][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:36][CH:35]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CCCCCOc1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCCCCOc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 50.2 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-pentyloxyaniline (61.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-pentyloxyphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (37.6 mg).