Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.[CH3:39][C:40]1[O:44][C:43]([CH2:45][NH2:46])=[N:42][N:41]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:31])[F:30])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:46][CH2:45][C:43]1[O:44][C:40]([CH3:39])=[N:41][N:42]=1)=[O:4]
Reactant: Cc1nnc(CN)o1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nnc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)o1
Reaction time: 8 h
Yield: 33.3 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 35 mg, 0.081 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.054 mL, 0.487 mmol), (5-methyl-1,3,4-oxadiazol-2-yl)methanamine (16.52 mg, 0.146 mmol), and BOP (64.6 mg, 0.146 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.5 min) to give single enantiomer 2-hydroxy-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (15.1 mg, 0.027 mmol, 33.7% yield): LCMS=527.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.13-8.24 (2 H, m), 7.66-7.78 (4 H, m), 7.54-7.66 (3 H, m), 5.21 (1 H, s), 4.63 (2 H, d, J=3.30 Hz), 2.49 (3 H, s). HPLC Peak RT=9.2 min (Analytical Method C).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[H-].[Na+].Cl.[CH:11]1([CH:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=2)[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>COCCOC>[CH:11]1([CH:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[O:24])=[CH:21][CH:20]=2)[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(Nc1ccc(C(=O)Cl)cc1)C1CCCC1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(C(C)=O)C(=O)c1ccc(NC(C)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 28.4 g. of 2,4-pentanedione and 20 ml. of 1,2-dimethoxyethane is added to a suspension of 13.6 g. of sodium hydride in 220 ml. of 1,2-dimethoxyethane under argon. A solution of 28.7 g. of 4-(1-cyclopentylethylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is stirred at room temperature for 12 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue is then chromatographed over silica gel to yield 3-[4'-(1-cyclopentylethylamino)benzoyl]-2,4-pentanedione.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31](Br)=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:37][O:38][CH2:39][Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH2:37][O:38][CH3:39])=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCC[Sn](CCCC)(CCCC)COC
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COCc1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3OC)c3ccc4c(c3)OCO4)cn(C)c2c1
Reaction time: 8 h
Yield: 11.6 %

Procedure:
To a solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole (from Example 85, 300 mg, 0.53 mmol) in 1,4-dioxane (1.5 ml) under a nitrogen atmosphere was added methoxymethyltributylstannane (220 mg, 0.66 mmol), followed by tetrakis(triphenylphosphine)palladium(O) (35 mg). The mixture was heated to reflux for 16 hours, and then cooled. An additional portion of tetrakis(triphenylphosphine)palladium(O) (30 mg) was added, and reflux was continued for a further 8 hours. The solvent was removed in vacuo, and the residue was flash chromatographed using a gradient elution of a mixture of 1% methanol and 99% dichloromethane, through to 5% methanol and 95% dichloromethane, to give the title compound (33 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12].[O-]CC.[Na+].[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27]Br>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH2:27][CH2:26][C:25]([O:24][CH3:23])=[O:29])[C:7]=1[CH2:13][CH3:14]
Reactant: CCc1n[nH]c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)CCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1nn(CCC(=O)OC)c(CC)c1Cc1cc(Cl)cc(Cl)c1

Procedure:
A solution of the pyrazole of Example 11 (198 mg, 0.70 mmol) in ethanol (1 ml) was treated with sodium ethoxide (21% w/v, in EtOH) (261 μL, 0.81 mmol) and then methyl-3-bromopropionate (153 μL, 1.40 mmol) and heated at 70° C. in a sealed Reacti-vial (Trade Mark) for 18 hours. Over a period of 3 days more sodium ethoxide (2.65 eq) and methyl-3-bromopropionate (6.0 eq) were added and the reaction was maintained under the same conditions. After cooling, the solution was concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (5:1, by volume) to afford two products.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH2:10][OH:11].Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[N:10][OH:11])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(=NO)CC1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 4,4-dimethylcyclohexanone (D294) (9.2 g, 73 mmol, 1 equiv) in EtOH (50 ml) and H2O (50 ml) were added NH2OH.HCl (6.6 g, 94.5 mmol, 1.3 equiv) and Na2CO3 (10.06 g, 94.5 mmol, 1.3 equiv) and the resulting cloudy solution was refluxed for 2 h then cooled to room temperature. Most of EtOH was removed in vacuo and the aqueous phase was extracted twice with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give 4,4-dimethylcyclohexanone oxime (D296) (10 g, 97%) as a colourless solid which was used in the next step without purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1

Procedure:
A mixture of the product of part (i) (0.7 g, 2.6 mmole) and 48% hydrobromic acid (10 ml) was heated under reflux under a nitrogen atmosphere overnight. The hydrobromic acid was removed by concentration under reduced pressure, the residue dissolved in water and the solution obtained was basified with aqueous sodium bicarbonate solution. The resulting precipitate was removed by filtration and washed with methylene chloride to yield the desired product, m.p. 275°-276° (0.276 g, 41%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:20]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([Cl:20])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccccc1OCc1ccccc1
Yield: 79.07 %

Procedure:
To a suspension of 78 (3.1 g, 13.6 mmol) in dry toluene (150 ml)was added SOCl2 (12.9 g, 109.1 mmol). The mixture was reflux for 8 h and evaporated to give 83 as yellow liquid to use directly in the next step. (2.55 g, 10.3 mmol). Yield: 79.07%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](I)=[C:7]([CH:19]=1)[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])#[N:2].[C:21]([NH:24][C:25](=[CH2:30])[C:26]([O:28][CH3:29])=[O:27])(=[O:23])[CH3:22].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]([NH:24][C:25](=[CH:30][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:19][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18])[C:26]([O:28][CH3:29])=[O:27])(=[O:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1I
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(=Cc1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C)NC(C)=O

Procedure:
15.3 g (39.5 mmol) of t-butyl [2-(5-cyano-2-iodophenoxy)ethyl]carbamate, 9.05 g (63.2 mmol) of methyl 2-acetamidoacrylate, 11 ml (79 mmol) of triethylamine, 1.3 g of palladium (II) acetate and 7.30 g of tris(2-methylphenyl)phosphine were stirred in 150 ml of acetonitrile overnight. The solvent was distilled off, and the residue was treated by the silica gel chromatography (ethyl acetate/hexane) to obtain the crude product, which was washed with hexane and a mixed solvent of hexane/ethyl acetate, and then vacuum-dried to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16](CP(=O)(OCC)OCC)=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.NC1C=CC([CH2:35][CH2:36][CH2:37][CH2:38][PH:39](=[O:43])[O:40][CH2:41][CH3:42])=CC=1OC>>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:35][CH2:36][CH2:37][CH2:38][PH:39](=[O:43])[O:40][CH2:41][CH3:42])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CCO[PH](=O)CCCCc1ccc(N)c(OC)c1
Product: CCO[PH](=O)CCCCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1

Procedure:
Prepared analogously to Compound 1E replacing compound 1F with ethyl (4-amino-3-methoxybenzyl)propylphosphinate (Compound 37D, 0.971 g, 3.58 mmol). The crude material was purified on a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→95:5) as eluent to afford the title compound as 1.08 g of a white foam (67%). MS (ESI): m/z 452.10 [M+H]+. UPLC: tR=1.10 min (polar—2 min).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:14]([CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:17])[CH:15]=[CH2:16]
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)C(c1ccccc1)c1ccccc1
Yield: 85.6 %

Procedure:
Diphenylmethane (168 mg), acryloyl chloride (200 mg), and aluminium chloride (280 mg) were reacted in dichloromethane (2 mL) at from −40° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (190 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[NH:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28]([NH:30][CH3:31])[CH3:29]>>[CH2:28]([N:30]([CH3:31])[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=1)[CH3:29]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: CCNC
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2ccc(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-ethyl-N-methylamine in step E. MS (ESI/CI): predicted mass C20H24N6O2, 380.2.
Reaction SMILES: [CH3:1][N:2]([C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1[CH2:40][C:41](O)=[O:42].Cl.CN(C)CCCN=C=NCC.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1[CH2:40][C:41]([N:13]1[CH2:14][CH2:15][CH:10]([C:7]2[S:8][CH:9]=[C:5]([C:3]([N:2]([CH3:1])[C@@H:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH3:18])=[O:4])[N:6]=2)[CH2:11][CH2:12]1)=[O:42]
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCNCC2)n1
Reactant: Cc1ccc(C)c(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-N-[(1R)-1-phenylpropyl]-2-(4-piperidinyl)-4-thiazolecarboxamide (i.e. the product of Example 1, Step E) (206 mg, 0.6 mmol) was dissolved in 4 mL of dry dichloromethane. To this reaction mixture was added triethylamine (90 μL, 0.65 mmol), 2,5-dimethylbenzeneacetic acid (98 mg, 0.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (125 mg, 0.65 mmol) and a catalytic amount of 4-(dimethylamino)pyridine (˜1 mg). The mixture was shaken overnight at ambient temperature, passed through a 5 mL capacity ChemEluten™, diatomaceous filter tube, pretreated with 3 mL of 1 N aqueous hydrochloric acid solution and eluted with 2 column volumes of dichloromethane. The dichloromethane solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using acetone to give 276 mg of the title product, a compound of the present invention as a light yellow oil.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([N+]([O-])=O)[CH3:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].C([OH:20])C>>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:20])[CH3:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCO
Reactant: CCOC(=O)c1ccc(C=C(C)[N+](=O)[O-])cc1
Product: CCOC(=O)c1ccc(CC(C)=O)cc1

Procedure:
The title compound was prepared in an identical manner to that described in Description 2 using 1-(4-carboethoxyphenyl)-2-nitroprop-1-ene and replacing the solvent with ethanol. γ(CDCl3) 8.62 (3H, t, J=7 Hz), 7.87 (3H, s), 6.29 (2H, s), 5.64 (2H, q, J=7 Hz), 2.76 (2H, d, J=9 Hz), 2.0 (2H, d, J=9 Hz).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].CO>O>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([OH:20])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: [Na]
Solvent: O
Solvent: CO
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 347.8 %

Procedure:
6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one (1.31 g, 4.6 mmol) and sodium borohidride (0.35 g, 9.3 mmol) were added to 50 mL methanol, and the reaction mixture was stirred at room temperature for one hour. Water (200 mL was then added to the reaction mixture, resulting in precipitation of white crystalls, which were collected by filtration and dried under N2 to give 1.2 g (4. 16 mmol, 90%) of 6-benzenesulfonyl- 1,2,3,4-tetrahydro-naphthalen- 1-ol, MS: 289 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.F[C:25]1[C:26]([C:31]#[N:32])=[N:27][CH:28]=[CH:29][CH:30]=1>CN(C=O)C>[N:1]1([C:25]2[C:26]([C:31]#[N:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: c1nnn[nH]1
Reactant: N#Cc1ncccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ncccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of tetrazole (1.0 g; 14 mmol) in DMF (150 mL) was added 40% aqueous tetrabutylammonium hydroxide (7.8 g; 12 mmol). The solvent was removed under reduced pressure. To ensure removal of all the water from the tetrabutylammonium hydroxide solution, the residue was redissolved in DMF and the solution was evaporated under reduced pressure. This procedure was repeated a total of three times. The residue was then dissolved in DMF (60 mL) and 3-fluoro-2-cyanopyridine (1.5 g; 12 mmol) was added. The reaction was stirred at ambient temperature under inert atmosphere for four days, at which time hplc analysis indicated about 65% conversion of the 3-fluoro-2-cyanopyridine to new products. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using a gradient elution of 1:4 to 100:0 EtOAc:hexanes to give 3-(tetrazol-1-yl)cyanopyridine as a white crystalline solid (TLC Rf=0.5, 1:1 EtOAc-hexanes; hplc retention time=2.04 min, method X; 1H NMR (CDCl3) δ 9.42 (s, 1H), 8.94 (dd, J=1.3, 4.6 Hz, 1H), 8.31 (dd, J=1.3, 8.4 Hz, 1H), 7.87 (dd, J=4.6, 8.4 Hz, 1H).
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C@@H:5]([CH2:14][C@H:15]2[CH2:20][CH2:19][CH2:18][O:17][CH2:16]2)[CH2:4][O:3]1>C(O)(C(F)(F)F)=O.O>[NH2:6][C@@H:5]([CH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][O:17][CH2:16]1)[CH2:4][OH:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@H]2CCCOC2)COC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N[C@H](CO)C[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 293.8 %

Procedure:
(S)-tert-butyl 2,2-dimethyl-4-(((R)-tetrahydro-2H-pyran-3-yl)methyl)oxazolidine-3-carboxylate (32 g) was dissolved in a mixture of TFA (160 mL) and water (160 mL). The mixture was stirred at room temperature for 10 min. The mixture was then concentrated in vacuo to give the crude product (50 g), which was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]C)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C12CCC(NC(=O)OCc3ccccc3)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NC12CCC(C(=O)O)(CC1)CC2)OCc1ccccc1
Yield: 91.3 %

Procedure:
Methyl 4-benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylate (64.3 g) was dissolved in ethanol (1100 mL). To this solution, a 1 mol/L aqueous solution of sodium hydroxide (1000 mL) was added and the mixture was stirred at 50° C. for 1 hour Ethanol in the mixture was evaporated under reduced pressure and the residue washed with diethylether (500 mL), followed by addition of concentrated hydrochloric acid to adjust the pH to 1. The resulting crystals were filtrated, washed with water, dried under reduced pressure to give 4-benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (56.1 g).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[C:4]=1[CH2:13][CH2:14][OH:15])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:24])C=1>ClCCl>[OH:15][CH2:14][CH2:13][C:4]1[C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=[CH:12][C:3]=1[CH:1]1[CH2:2][O:24]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1CCO)COC2=O
Solvent: ClCCl
Product: O=C1OCc2c1ccc(C1CO1)c2CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Ethenyl-4-(2-hydroxyethyl)-2-benzofuran-1(3H)-one (1.2 g, 5.9 mmol) was added to a flask containing a stir bar. To the flask was then added dichloromethane (20 mL). The flask was placed in a cool bath of 0° C.; to the flask was poured mCPBA (1.5 g, 8.8 mmol) and the resulting mixture was stirred at room temperature for overnight; LC as well as TLC (hexanes/EtOAc=1/1) indicated that reaction had gone to completion. The solution was treated with dichloromethane and washed with NaHCO3, Na2S2O3, and water, the organic layer was then dried over Na2SO4, filtered and concentrated to dryness, it was then treated with AcOH (20 mL) and stirred overnight; LC indicated formation of cyclized product. The solvent was removed and the resulting residue was absorbed onto silica gel and the title compound was isolated with the solvent system of hexanes/EtOAc (1/1).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:17].N([O-])=O.[Na+]>O1CCOCC1.O>[OH:17][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccccc1-c1cccc(N)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccccc1-c1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A solution of 3′-aminobiphenyl-2-carbonitrile (10.9 g, 56 mmol) in 1,4-dioxane (30 ml) was treated with a solution of 25% aqueous sulphuric acid (150 ml). The resulting suspension was cooled to 0° C. before being treated dropwise over 10 minutes with a solution of sodium nitrite (4.6 g, 67 mmol) in water (10 ml). After stirring at 0° C. for 30 minutes the reaction was poured into hot (70° C.) water (500 ml). On cooling to ambient temperature the product was extracted into ethyl acetate (500 ml), the organics were washed with water (300 ml), brine (300 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded 3′-hydroxybiphenyl-2-carbonitrile as a dark oil (7.1 g, 65%). 1H NMR (400 MHz, CDCl3) δH 5.40 (1H, br), 6.92 (1H, ddd, J 8, 3 and 1), 7.04 (1H, dd, J 3 and 3), 7.11 (1H, ddd, J 8, 3 and 1), 7.35 (1H, dd, J 8 and 8), 7.44 (1H, ddd, J 8, 8 and 1), 7.51 (1H, dd, J 8 and 1), 7.64 (1H, ddd, J 8, 8 and 1), 7.75 (1H, dd, J 8 and 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH:33]=[CH2:34]>C(C(C)=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:11]([O:13][CH2:34][CH:33]=[CH2:32])=[O:12])=[CH:4][CH:3]=1
Reactant: C=CCI
Reactant: O=C(O)C(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Yield: 73.3 %

Procedure:
To a 250 mL flask stirring under nitrogen was charged 3.55 g (0.010 mole) of a 4-(4-chlorophenyl)-2-phenyl-2-[(1,2,4-triazol-1-yl)methyl]butanoic acid in 40 mL of methyl ethyl ketone and 10 mL of dimethyl formamide. To the mixture was added 2.07 g (0.015 mole) of potassium carbonate and 1.85 g (0.011 mole) of allyl iodide. The reaction was stirred for 16 hours at 45° C. The reaction was quenched by adding 150 mL of ether and 25 mL of water. The organic phase was washed with 50 mL of saturated sodium bicarbonate and 20 mL of 10% sodium hydroxide, then 50 mL of water. After decolorizing with charcoal, the solvent was filtered and concentrated and gave 2.9 g (79.4% yield) of a solid, Example 137 of Table 1.