Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH2:35][C:36](O)=[O:37])=[CH:34][C:29]=2[O:28][CH2:27]1>>[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH2:35][C:36]([NH:25][C@H:22]3[CH2:21][CH2:20][C@H:19]([CH2:18][CH2:17][N:14]4[CH2:15][CH2:16][CH:11]([C:10]5[C:5]6[O:4][CH2:3][O:2][C:6]=6[CH:7]=[CH:8][CH:9]=5)[CH2:12][CH2:13]4)[CH2:24][CH2:23]3)=[O:37])=[CH:34][C:29]=2[O:28][CH2:27]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: Cl
Product: O=C(Cc1ccc2c(c1)OCO2)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (21.8 mg, 54.1%), MS (ISP) m/z=493.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 2-(benzo[d][1,3]dioxol-5-yl)acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([OH:19])=O)[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:74])[CH2:71][CH2:72][NH2:73].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:73][CH2:72][CH2:71][C:70]([O:69][CH3:68])=[O:74])=[O:19])[CH:13]=2)[CH:7]=1
Reactant: COC(=O)CCN
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (Example 75) (1.50 g, 3.36 mmol), HATU (1.41 g, 3.70 mmol) and N,N-diisopropylethylamine (1.29 g, 10 mmol) in anhydrous DMF (15 ml) was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (558 mg, 4.0 mmol). The mixture was stirred for another 10 minutes and poured into 200 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3% of methanol in chloroform to give methyl 3-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoate as off-white solid. Yield: 1.18 g, 66%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:17]3[S:13][C:14](=[O:19])[NH:15][C:16]3=[O:18])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc2ncccc2c1
Product: O=C1NC(=O)C(=Cc2ccc3ncccc3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from quinoline-6-carbaldehyde (intermediate 5) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[C:5]([O:18][CH3:19])[CH:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:5]([O:18][CH3:19])[CH:4]=1)=[O:2]
Reactant: CCOC(=O)CCCOc1ccc(C=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(C=O)ccc1OCCCC(=O)O
Yield: 58.3 %

Procedure:
4- (4-Formyl-2-methoxyphenoxy)butanoic acid, ethyl ester (240 mg, 0.90 mmol) is dissolved in 3 mL of methanol/water (3:2) and treated with 435 mg (3.15 mmol) of potassium carbonate according to the procedure described for Example 4 to give 125 mg (58%) of 4-(4-formyl-2-methoxyphenoxy)butanoic acid as a white powder: m.p. 143°-148°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 3575, 3500, 1720, 1700, 1680, 1600, 1585 cm-1 ; MS (CI (low res)) m/e 239 (M+H), 221, 207, 153.
Reaction SMILES: C(N(CC)CC)C.[N-]=[N+]=[N-].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(C(O)=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C[N:34]([CH:36]=[O:37])C>>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][C:21]([N:34]=[C:36]=[O:37])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: CN(C)C=O
Agent: [N-]=[N+]=[N-]
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N=C=O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (5.02 mL, 36.1 mmol) and diphenylhosphoryl azide (4.24 mL, 19.7 mmol) are added to a solution of 1-(tert-butoxycarbonyl)-4-phenyl-4-piperidinecarboxylic acid (5.0 g, 16.4 mmol) in dry DMF (50 mL) under nitrogen at ambient temperature. The mixture is stirred at ambient temperature for 2 h, and then heated to 60° C. for 3 h. The mixture is slightly cooled and concentrated in vacuo. Water (75 mL) is added to the remanence followed by extraction with ethyl acetate (2×75 mL). Combined organic fractions are washed with brine (3×50 mL), dried (MgSO4) and evaporated to dryness. The crude mixture is purified by silica gel chromatography eluting with ethyl acetate-heptane (1:4). This furnishes 4.8 g (98%) of the wanted 1-(tert-butoxycarbonyl)-4-isocyanato-4-phenyl-piperidine as a clear oil. LC/MS (m/z) 203.2 (M-boc+H+); tR=3.64 min. 1H NMR (CDCl3) 1.49 (s, 9H); 1.92 (bd, 2H); 2.02 (dt, 2H); 3.15 (bt, 2H); 4.17 (bs, 2H); 7.26 (dd, 1H); 7.39 (dt, 2H); 7.44 (dd, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:11]([C:13]1[N:17]=[C:16]([CH2:18][CH3:19])[O:15][N:14]=1)[OH:12])[CH2:9][CH3:10])(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:7][CH:8]([CH2:9][CH3:10])[C@@H:11]([C:13]1[N:17]=[C:16]([CH2:18][CH3:19])[O:15][N:14]=1)[OH:12]
Reactant: CCc1nc(C(O)[C@H](CC)NC(=O)OC(C)(C)C)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc([C@@H](O)C(N)CC)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of {(S)-1-[(5-ethyl-1,2,4-oxadiazol-3-yl)-hydroxy-methyl]-propyl}-carbamic acid tert-butyl ester (214 mg, 0.751 mmol) in methylene chloride (5 mL) was treated with trifluoroacetic acid (0.578 mL, 7.504 mmol) and stirred at room temperature for 3 hours. Solvent evaporated under reduced pressure to give (S)-2-amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol trifluoroacetate, a mixture of diastereoisomers, (224 mg) as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1N)=[O:5])[CH3:2].[I:17]CI.C(#N)C.N(OCCC(C)C)=O>CCCCCCC>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1[I:17])=[O:5])[CH3:2]
Reactant: ICI
Reactant: CCOC(=O)c1c(N)c(C#N)c(CC)n1C
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: CCCCCCC
Product: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Temperature: 78 °C
Yield: 57.6 %

Procedure:
Alternatively the title compound may be prepared by the following procedure. Charge the 3-amino-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester prepared in preparation 37, diiodomethane, and acetonitrile to a 22 L round-bottom flask equipped with an addition funnel, thermocouple, overhead stirrer, and condenser. Dilute isoamyl nitrite with heptane and charge the resulting solution to the addition funnel. Warm the reaction mixture to 78° C. Add 0.65 L of the isoamyl nitrite solution over 1.75 hours, at which point vigorous evolution of nitrogen is observed. Suspend the addition of the isoamyl nitrite solution for about 20 minutes to allow the off-gassing to subside. Add the remainder of the isoamyl nitrite solution over 15 minutes. Stir the reaction mixture at reflux for an additional 2 hours, then cool to room temperature. Remove the solvent under reduced pressure and dilute the resulting concentrate with a mixture of 0.2 L pentane and 0.2 L methylene chloride. Pour the resulting mixture onto a 4 kg column of silica gel that is pre-wetted with cyclohexane. Elute the column with 5′ gallons of cyclohexane, and discard the eluent. Next, elute the column with 6 gallons of a 1:1 mixture of cyclohexane:methylene chloride, followed by 5 gallons of 3:2 cyclohexane:methylene chloride. Combine these fractions and remove the solvent under reduced pressure. Suspend the resulting solid in 0.5 L of heptane and stir for 45 minutes. Collect the product by filtration, rinse with heptane, and vacuum-dry at 40° C. to afford the title compound (432.8 g) in 57.6% yield. Mass spectrum (m/e): 333.0 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.Br[C:26]1[S:27][C:28]([CH3:31])=[N:29][N:30]=1.P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O.O>[CH3:31][C:28]1[S:27][C:26]([N:16]2[CH2:15][CH2:14][CH:13]([C:10]3[CH:11]=[CH:12][C:7]([N:6]4[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]4=[O:1])=[CH:8][C:9]=3[F:19])[CH2:18][CH2:17]2)=[N:30][N:29]=1
Reactant: Cc1nnc(Br)s1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(c4nnc(C)s4)CC3)c(F)c2)C(=O)O1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 550 mg), 2-bromo-5-methyl-1,3,4-thiadiazole (EXAMPLE 87, Step 1, 323 mg) and potassium hydrogenphosphate (571 mg) in dimethyl sulfoxide (16 mL) is stirred under N2 at 100° C. for 2 hrs, cooled to ambient temperature, diluted with water (20 mL) and extracted with methylene chloride (3×20 mL). The combined organic phase is washed with water (20 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product which is then chromatographed on silica gel (230-400 mesh, 45 g), eluting with a gradient of methanol/methylene chloride (2/98-3/97). Pooling and concentration of those fractions with an Rf =0.44 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 193-195° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]([O:26][CH3:27])=[O:25])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[NH:8]C=O.Cl>CO>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]([O:26][CH3:27])=[O:25])=[O:18])=[CH:15][CH:16]=2)=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)C1CCCC1C(=O)c1ccc(-c2ccc(NC=O)c(F)c2)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCCC1C(=O)c1ccc(-c2ccc(N)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of methyl 2-{[3′-fluoro-4′-(formylamino)-1,1′-biphenyl-4-yl]-carbonyl}cyclopentanecarboxylate (4.24 g, 11.48 mmol) in methanol (34 mL) was added conc. HCl (11.4 mL), and the resulting solution was stirred at rt for 2 h. Solvent was then removed, the residual mixture was dissolved in water, and the acidity of the mixture was adjusted to pH ˜7 by slow addition of saturated aqueous sodium bicarbonate solution. The mixture was then extracted with dichloromethane and washed with saturated sodium chloride solution, dried over sodium sulfate, and the solvent was removed in vacuo. The crude mixture was then triturated with ethyl acetate/hexane to afford methyl 2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylate (3.5 g, 89%, 80% ee). LC-MS ret. time 3.00 min, m/z 370.0 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 1.52-1.84 (m, 4H), 1.97-2.02 (m, 1H), 2.14-2.18 (m, 1H), 3.24-3.33 (m, 1H), 3.56 (s, 3H), 4.08 (q, 1H), 5.47 (br s, 2H), 6.84 (t, 1H), 7.34 (dd, 1H), 7.48 (dd, 1H), 7.78 (d, 2H), 7.99 (d, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:21][OH:22])[C:10]=1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[CH2:29][CH2:28][CH:27]([CH2:30][O:31][C:32]2[CH:33]=[C:34](O)[CH:35]=[CH:36][CH:37]=2)[CH2:26][CH2:25]1.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:21][O:22][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH2:30][CH:27]3[CH2:26][CH2:25][O:24][CH2:29][CH2:28]3)[CH:37]=2)[C:10]=1[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc2c(OCc3ccccc3)c(C)c(CO)nc12
Reactant: Oc1cccc(OCC2CCOCC2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc2c(OCc3ccccc3)c(C)c(COc3cccc(OCC4CCOCC4)c3)nc12
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of [4-(benzyloxy)-8-methoxy-3-methylquinolin-2-yl]methanol (250 mg) in THF (10 mL) were added 3-(tetrahydro-2H-pyran-4-ylmethoxy)phenol (185 mg) and 1,1-(azodicarbonyl)dipiperidine (245 mg), followed by dropwise addition of tributylphosphine (0.24 mL) at room temperature and stirring. After 1 hour, tributyl phosphine (0.24 mL) was added thereto, followed by stirring for 12 hours. Ethyl acetate was added to the reaction mixture, and then insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography twice (eluent for the first round: hexane/ethyl acetate=80/20˜67/33˜60/40, eluent for the second round: chloroform˜chloroform/methanol=95/5), and also by thin layer silica gel chromatography (developer: chloroform/methanol=95/5) to obtain 4-(benzyloxy)-8-methoxy-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (340 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Li]CCCC.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O1CCOCC1>[CH2:17]([N:24]1[CH2:25][CH:26]=[C:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH2:28][CH2:29]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
4-Iodobenzo trifluoride (2.97 g, 10.92 mmol) in THF (50 mL) was added dropwise over 0.5 h to a solution of n-BuLi (7.5 ml, 1.6 M, 12 mmol) in THF (50 mL) at −78° C. The reaction mixture was stirred an additional 0.5 h upon which N-benzyl-4-piperidone (2.13 g, 11.69 mmol) in THF (10 mL) was added over 10 minutes. Stirring was continued for 0.5 h at −78° C., followed by room temperature overnight. The reaction was quenched with saturated ammonium chloride and the organic layer was separated. The aqueous layer was extracted with THF and the combined organic layers were dried (MgSO4), filtered and concentrated to afford a brown oil. The crude product was then dissolved in conc. HCl (30 mL) and 1,4-dioxane (6 mL) and stirred at 100° C. overnight. The reaction was poured into saturated sodium bicarbonate and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The product was purified by silica gel flash column chromatography (20% ethyl acetate in hexanes) to afford 1-benzyl-4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (981 mg, 28%). 1H NMR (400 MHz, CDCl3) δ 7.61 (d, 2H), 7.52 (d, 2H), 7.40 (m, 5H), 6.21 (m, 1H), 3.70 (s, 2H), 3.25 (q, 2H), 2.78 (t, 2H), 2.62 (m, 2H); LCMS: 318.4 (M+1)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[Cl:10][C:11]1[C:12]([O:9][CH2:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: C[C@H]1CC[C@H](CO)CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OC[C@H]2CC[C@H](C)CC2)cc1F
Temperature: 70 °C

Procedure:
To a solution of trans-(4-methylcyclohexyl)methanol (3.00 g, 23.4 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (6.43 g, 25.90 mmol) in anhydrous dimethylsulfoxide (40 mL) was added cesium carbonate (16.11 g, 49.44 mmol). The mixture was heated at 70° C. for 96 hours, and then cooled to ambient temperature; diluted with water (300 mL) and extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 10% ethyl acetate in hexanes gradient) to give the title compound (6.48 g 78%): 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J=7.7 Hz, 1H), 6.61 (d, J=12.3 Hz, 1H), 3.82 (d, J=6.2 Hz, 2H), 1.91-1.73 (m, 8H), 1.56 (s, 9H), 1.17-0.96 (m, 5H).
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].Br[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.Cl.N>O1CCCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:9]2[NH:13][CH:12]=[CH:11][N:10]=2)[OH:8])=[CH:17][CH:18]=1
Reactant: O=C(c1ccccc1)c1ncc[nH]1
Reactant: Clc1ccc(Br)cc1
Agent: Cl
Agent: N
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccc(Cl)cc1)c1ncc[nH]1

Procedure:
A solution of 17.2 g. of 2-benzoylimidazole (A. Sonn and P. Greif, Ber. 66 (1933), 1900) in 100 ml. of anhydrous tetrahydrofuran was added drop-wise to a Grignard reagent prepared from 5.8 g. of magnesium and 45.9 g. of 1-bromo-4-chlorobenzene in 150 ml. of anhydrous tetrahydrofuran. The reaction mixture was boiled under reflux for half an hour, cooled and poured onto a mixture of ice and hydrochloric acid. The solution was neutralized with concentrated ammonia solution and extracted with tetrahydrofuran. The organic solvents layer was dried and concentrated; the residue was crystallised from isopropyl alcohol. Melting point of the product was 162°-165° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=[N:7][OH:8])[NH2:6].Cl.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[N:17]1[CH:18]=[CH:19][C:14]([C:13]2[O:8][N:7]=[C:5]([C:4]3[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][CH:9]=3)[N:6]=2)=[CH:15][CH:16]=1
Reactant: ClCc1ccncc1
Reactant: NC(=NO)c1cccc(O)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc(-c2noc(-c3ccncc3)n2)c1

Procedure:
3-(5-Pyridin-4-yl-[1,2,4]oxadiazol-3-yl)phenol was prepared using 3-hydroxybenzamidoxime (3 g, 19.7 mM) and isonicotinyl chloride hydrochloride (3.51 g, 19.6 mM) in pyridine (15 mL) using Preparation 62 to provide 3.65 g of a brown precipitate; m.p., 145-146° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.Br[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31]>[OH-].[Na+]>[C:1]([C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:29][C:30]([OH:32])=[O:31])=[O:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2cccc(O)c2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2cccc(OCC(=O)O)c2)cc1

Procedure:
To a round-bottomed flask equipped with magnetic stirring was added (2E)-3-[4-(tert-butyl)phenyl]-N-(3-hydroxyphenyl)prop-2-enamide, Example 23, (120 mg, 0.407 mmol), THF (10 mL), tert-butyl bromoacetate (60 uL, 0.407 mmol, Aldrich) and 5 N NaOH (10 mL). The reaction mixture was stirred at 25° C. overnight. The mixture was extracted with EtOAc (20 mL), the organic extract washed with water (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was treated with trifluoroacetic acid (10 mL), stirred at 25° C. for 2 h, then concentrated in vacuo. Purification by silica gel chromatography (1:2 hexane:EtOAc) provided the title product as an off-white solid. MP 166-172° C. MS (ESI, pos. ion) m/z: 354 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:14]([O:18][C:19]([CH:21]([O:23][NH2:24])[CH3:22])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([CH:21]([O:23][N:24]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:12])=[O:11])[CH3:22])=[O:20])([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(ON)C(=O)OC(C)(C)C
Reactant: O=C(O)C(=O)c1ccc(O)c(Cl)c1
Product: CC(ON=C(C(=O)O)c1ccc(O)c(Cl)c1)C(=O)OC(C)(C)C
Yield: 96.3 %

Procedure:
2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2.0 g.) and O-(1-t-butoxycarbonylethyl)hydroxylamine (3.2 g.) were reacted according to a similar manner to that of Preparation 5-7) to give 2-(1-t-butoxycarbonylethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (3.3 g.), mp 148° to 151° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:3]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].[C:27]([N:30]1[C:35]([CH3:37])([CH3:36])[CH2:34][CH:33]([OH:38])[CH2:32][C:31]1([CH3:40])[CH3:39])(=[O:29])[CH3:28]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:8][C:6]1[N:7]=[C:2]([O:38][CH:33]2[CH2:34][C:35]([CH3:36])([CH3:37])[N:30]([C:27](=[O:29])[CH3:28])[C:31]([CH3:40])([CH3:39])[CH2:32]2)[N:3]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:5]=1
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)nc(Cl)n1
Reactant: CC(=O)N1C(C)(C)CC(O)CC1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1C(C)(C)CC(Oc2nc(Cl)nc(N3C(C)(C)CCCC3(C)C)n2)CC1(C)C
Reaction time: 3.5 h

Procedure:
43.4 g of 2,4-dichloro-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 1) are dissolved in 175 ml of toluene, after which 42.1 g of pulverized KOH, 1 g of potassium carbonate and 3.4 g of tetrabutylammonium hydrogen sulfate are added. A solution of 29.9 g of 1-acetyl-2,2,6,6-tetramethyl-4-hydroxy-piperidine in 110 ml of toluene is then added dropwise, the internal temperature being maintained at 10° using an ice bath. After stirring for 3.5 hours, 100 ml of water are added. The phases are separated, and the organic phase is washed with water, dried over Na2SO4 and evaporated. After recrystallizing from hexane, the above product is produced as a white powder which melts at 114°-116° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]2[C:3](=[O:20])[N:4]([CH3:19])[C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8]2)=[O:24])=[CH:35][CH:34]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: COc1ccc(CNC(=O)C(C)C(=O)O)cc1
Product: COc1ccc(CNC(=O)C(C)C(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)cc1

Procedure:
The title compound, MS: m/e=485.4 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(4-methoxy-benzyl)-malonamic acid.