Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:12][CH2:13][CH3:14].[Na+].O>C(O)C>[CH2:13]([O:12][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:14]
Reactant: Nc1nnc2ccc(Cl)nn12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc2nnc(N)n2n1
Temperature: 55 °C
Reaction time: 2 h
Yield: 108.9 %

Procedure:
6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.001a, 616 mg) was dissolved in absolute ethanol (40 ml) and admixed with portions of solid sodium ethoxide (990 mg). After stirring at 55° C. for 2 h, water was added and the aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated. 709 mg of crude product of the desired compound were obtained in sufficient purity.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Br:8])[CH:3]=1.C(O[CH:14](N(C)C)[N:15]([CH3:17])[CH3:16])(C)(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Br:8])[CH:3]=1.[Br:8][C:4]1[CH:3]=[C:2](/[CH:1]=[CH:14]/[N:15]([CH3:17])[CH3:16])[CH:7]=[CH:6][N:5]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: Cc1ccnc(Br)c1
Product: CN(C)/C=C/c1ccnc(Br)c1

Procedure:
4-Methyl-2-bromopyridine (1.0 g, 5.8 mmol) and t-butoxybis(dimethylamino)methane (5 ml) were heated to 150° C. for 16 hours. 4-Methyl-2-bromopyridine was prepared as set forth in B. Adger et al., J. Chem. Soc., Perkin Trans. 1, pp. 2791-2796 (1988), which is incorporated herein by reference. The contents were evaporated and the residue dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and solvent removed in vacuo to give 1.0 g of (E)-2-(2-bromo-4-pyridinyl)-N,N-dimethylethenamine as an oil suitable for use in step 2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH2:16][CH2:17]OC(CC2CCCCC2)=O)[CH:11]=[C:12]([F:15])[C:13]=1[F:14].C([O:31][CH2:32][CH3:33])(=O)C.Cl>C1COCC1>[F:15][C:12]1[CH:11]=[C:10]([CH:16]2[CH2:17][CH2:12][CH:13]([CH2:33][CH2:32][OH:31])[CH2:8][CH2:9]2)[CH:9]=[C:8]([F:7])[C:13]=1[F:14]
Reactant: O=C(CC1CCCCC1)OCCc1cc(F)c(F)c(F)c1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCC1CCC(c2cc(F)c(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithiumaluminium hydride (2.2 g) was added to a solution of 4-(3',4',5'-trifluorophenyl)ethoxycarbonylmethylcyclohexane (17.2 g) in THF (100 ml), followed by stirring the mixture at room temperature for 2 hours, adding ethyl acetate (100 ml) little by little after completion of the reaction, further adding 2N hydrochloric acid (50 ml), washing the organic layer with water, drying over anhydrous MgSO4 and concentrating the solvent under reduced pressure, to obtain 4-(3',4',5'-trifluorophenyl)-1-(2'hydroxyethyl)cyclohexane (10.4 g).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]([CH:37]2[CH2:39][CH2:38]2)[CH:27]2C(=O)O[C:30](C)([CH3:34])[O:29][C:28]2=[O:36])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>CN(C=O)C>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]([CH:37]2[CH2:38][CH2:39]2)[CH2:27][C:28]([O:29][CH2:30][CH3:34])=[O:36])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(C(c2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C2CC2)C(=O)O1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)CC(c1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1)C1CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a solution of 5-((3-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl) (cyclopropyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (5.07 g) in DMF (40 mL) was added ethanol (20 mL), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.55 g) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=O)=[N:4][CH:5]=[CH:6][CH:7]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[S:19]1[CH:20]=[CH:21][C:17]([C:15]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:3]3[N:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:18]1
Reactant: Nc1cccnc1Nc1ccccc1C(=O)c1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: c1cnc2c(c1)N=C(c1ccsc1)c1ccccc1N2

Procedure:
Following the procedure of Example 20, [2-[(3-amino-2-pyridinyl)amino]phenyl](3-thienyl)methanone is heated with para toluene sulfonic acid catalyst in organic solvent while removing water in a Dean-Stark trap to give the title compound.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=O)[C@@H:2]1[CH2:3][CH:4]=[CH:5][CH2:6]2.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1.C(O)CCC.[ClH:34]>C(O)(C)C>[ClH:34].[N:24]1[CH:25]=[CH:26][CH:27]=[N:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:10](=[O:11])[CH:1]3[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]3[C:7]2=[O:9])[CH2:18][CH2:19]1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCCCO
Product: O=C1C2CC=CCC2C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture of cis-4-cyclohexene-1,2-dicarboxylic anhydride (633 mg; 4.25 mmol), 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (1 g; 4.25 mmol) and n-butanol (10 ml) was heated under reflux for 6 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography to give an oily substance. The oily substance was treated with a mixture of 3% hydrogen chloride in isopropanol, and the precipitate was recrystallized from isopropanol to give N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]-4-cyclohexene-1,2-dicarboximide hydrochloride. M.P., 177°-179° C.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:18]=2)=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:18]=2)=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(O)cc(-c3cccc(F)c3)c2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(F)c(NCc2cc(O)cc(-c3cccc(F)c3)c2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
To a solution of ethyl 2-[2,4-difluoro-3-[[3-(3-fluorophenyl)-5-hydroxy-phenyl]methylamino]phenoxy]acetate (II(b)) (200 mg, 0.46 mmol, 1.0 eq) in THF (10 mL) was added NaOH (1M, 6 mL, 6 mmol, 13.0 eq) at 0° C. The reaction mixture was allowed to warm room temperature and was stirred for 3 h. The THF was removed in vacuo and the remaining solution diluted with water and adjusted to pH 4-6 by addition of diluted HCl. The precipitate that formed was collected by filtration and dried in vacuo to give the title compound (I(p)) as a solid (170 mg, 91%).
Reaction SMILES: Cl([O-])=O.[Na+].C(O)(=[O:7])C.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(OCC)(=O)C>[O:7]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 131.1 %

Procedure:
To a 1000 mL four-necked flask equipped with a mechanical stirrer, a dropping funnel and a thermometer, 496.8 g (1.37 mole) of 25% sodium chlorite aqueous solution, and then 26 mL (0.46 mole) acetic acid were slowly added. The pH in the reaction system was pH 4.4. Furthermore, 100 g (0.62 mole) of diethyl malonate was slowly added under room temperature, and then the mixture was stirred under room temperature for 3 hours, and then 490 mL ethyl acetate was added to the reaction system to separate the liquids. The organic layer was separated, and ethyl acetate was distilled off under reduced pressure. Toluene was added thereto to perform azeotropic dehydration and the toluene was distilled off under reduced pressure, to give 105 g of diethyl ketomalonate as an oily substance (97 yield rate).
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:4][Si:3]([CH2:2][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)([CH3:6])[CH3:5]
Reactant: C[Si](C)(C)CCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)COc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
Chloromethyltrimethylsilane (110.5 g, 0.9 mol) is added dropwise over 30 minutes to a mixture of para-hydroxybenzaldehyde (110 g, 0.82 mol) and potassium carbonate (124.5 g, 0.9 mol) in 1 L of dry DMF maintained at 80° C., and while sparging with nitrogen. The mixture is left at 90° C. for 4 hours. The reaction mixture is filtered and the solvent is removed from the filtrate by distillation under vacuum. The final traces of DMF are removed via a stage at 60° C. under a vacuum of 2 mmHg. 142.4 g (yield: 84%) of 4-trimethylsilanylmethoxybenzaldehyde are obtained in the form of an orange-yellow oil, which is used without further purification in the next step.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH2:21][C@H:22]([O:24][CH2:25][C@H:26]([O:31][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[CH:40][C:33]=12)[C:27](OC)=[O:28])[CH3:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Si:13]([O:20][CH2:21][C@H:22]([O:24][CH2:25][C@H:26]([O:31][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[CH:40][C:33]=12)[C:27]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:28])[CH3:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@H](CO[C@H](C)CO[Si](C)(C)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Reactant: Nc1ccc(Cl)cn1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.5 %

Procedure:
Trimethylaluminium (2M in Hexanes) (0.551 mL, 1.10 mmol) was added to 5-chloropyridin-2-amine (135 mg, 1.05 mmol) in toluene (5 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-methyl 3-((R)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AN2) (500 mg, 0.96 mmol) in toluene (5 mL) was added and the reaction was allowed to warm to room temperature and then heated to 100° C. for 5 hours in the microwave reactor. The reaction was allowed to cool to room temperature before adding EtOAc (50 mL) and 20% sodium potassium tartrate solution (30 mL), which was stirred vigorously for 16 hours. The phases were separated and the organic layer was washed with sat. brine (15 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane afford the product (460 mg, 78%). 1H NMR (400 MHz, DMSO) 6-0.01 (d, 6H), 0.80 (s, 9H), 1.08 (d, 3H), 3.47-3.63 (m, 2H), 3.67-3.76 (m, 1H), 4.07-4.19 (m, 2H), 5.89-5.96 (m, 1H), 7.75-7.80 (m, 1H), 7.89-7.94 (m, 1H), 8.02-8.07 (m, 1H), 8.33-8.37 (m, 1H), 8.41-8.43 (m, 1H), 8.58 (s, 1H), 8.63 (s, 1H), 8.67-8.72 (m, 1H), 11.18 (s, 1H); m/z (ES+), (M+H)+=618.44; HPLC tR=3.53 min
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]=[C:12]3[N:7]([CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15])[C:6]=2[N:5]=[C:4]([Cl:17])[N:3]=1.[CH3:18][C:19]1([CH3:25])[O:24][CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)CC)C>>[Cl:17][C:4]1[N:3]=[C:2]([N:21]2[CH2:22][CH2:23][O:24][C:19]([CH3:25])([CH3:18])[CH2:20]2)[C:14]2[N:13]=[C:12]3[N:7]([C:6]=2[N:5]=1)[CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15]
Reactant: CC1(C)OCCn2c1nc1c(Cl)nc(Cl)nc12
Reactant: CC1(C)CNCCO1
Solvent: CCN(CC)CC
Product: CC1(C)CN(c2nc(Cl)nc3c2nc2n3CCOC2(C)C)CCO1
Temperature: 140 °C
Yield: 85.4 %

Procedure:
A mixture of 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b,9-tetraaza-fluorene (100 mg, 0.366 mmol), 2,2-dimethyl-morpholine (84 mg, 0.732 mmol) and triethylamine (77 μL, 0.55 mmol) in IMS (2 mL) was heated at 140° C. for 20 mins in a microwave reactor, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 10% ethyl acetate in cyclohexane) affording 3-Chloro-1-(2,2-dimethyl-morpholin-4-yl)-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b,9-tetraaza-fluorene as a white solid (110 mg, 85%). LCMS (method A): RT=3.51 min, [M+H]+=352.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[NH:9][C@H:8]([C:10]([NH:12][C@H:13]([C:23](=[O:31])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][S:19]C(=O)C)=[O:11])[CH2:7][CH2:6][CH2:5]1.O>CCO>[SH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]([NH:12][C:10]([C@@H:8]1[CH2:7][CH2:6][CH2:5][C:4](=[O:3])[NH:9]1)=[O:11])[C:23](=[O:31])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)SCCCCC[C@H](NC(=O)[C@@H]1CCCC(=O)N1)C(=O)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CCC[C@@H](C(=O)N[C@@H](CCCCCS)C(=O)Nc2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2N solution of NaOH (7.0 mmol) was added to a solution of thioacetic acid S—{(S)-6-[((S)-6-oxo-piperidine-2-carbonyl)-amino]-6-phenylcarbamoyl-hexyl}ester (0.95 mmol) in EtOH (13 ml). The reaction mixture was stirred at RT overnight and then poured into water and extracted with AcOEt, washed with water, brine and finally dried over Na2SO4. Removal of the solvent under reduced pressure led to the desired adduct, which was purified through HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([SH:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].Cl.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: ClCc1ccccn1
Reactant: O=[N+]([O-])c1ccc(S)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1ccc(SCc2ccccn2)nc1
Yield: 65.3 %

Procedure:
5-nitro-2-pyridinethiol (6.0 g) was dissolved in an aqueous solution of methanol (150 ml), and to this solution was added sodium hydroxide (4.6 g) and then, 2-(chloromethyl)pyridine hydrochloride (7.6 g), and the mixture was stirred for 15 minutes at room temperature. The solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 5-nitro-2-[(2-pyridinylmethyl)sulfanyl]pyridine (6.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15]([C:17]1([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)[CH2:21][CH2:20][N:19]([C:10](=[O:11])[NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)Nc2ccc(OC)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 71 using 4-methoxy phenyl isocyanate and 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 65) to afford the racemate as a yellow liquid (78, mg, 88%)
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[O:20][CH:4]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[C:3]([OH:29])=[O:2]
Reactant: COC(=O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of (2,4-difluoro-phenoxy)-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (0.35 g, 0.82 mmol) in THF (3 ml), was added lithium hydroxide monohydrate (0.035 g, 2.05 mmol) in 1 ml water and stirred overnight at room temperature. Solvent was removed under reduced pressure, residue obtained was taken into water (5 ml), extracted with diethyl ether (10 ml×2). Aqueous layer was acidified with 1 N HCl solution, and extracted with ethyl acetate (10 ml×3), washed with water and brine (20 ml, each) dried over anhydrous sodium sulfate, filtered and solvent was concentrated to provide (2,4-difluoro-phenoxy)-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid (0.28 gm).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C(C)C)=[CH:6][C:5]([N:12]2[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][F:21])[C:14]([CH3:22])=[N:13]2)=[C:4]([F:23])[CH:3]=1>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:12]2[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][F:21])[C:14]([CH3:22])=[N:13]2)=[C:4]([F:23])[CH:3]=1
Reactant: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1CCCF
Agent: O=S(=O)(O)O
Product: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1CCCF
Temperature: 0 °C
Yield: 82.3 %

Procedure:
A solution of 0.70 g (0.002 mole) of 1-[4-chloro-2-fluoro-5-(1-methylethoxy)phenyl]-4-(3-fluoropropyl)-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one (prepared in Example 1) in 10 mL of concentrated sulfuric acid was stirred for 30 minutes at ambient temperature. The reaction mixture was poured into ice-water and the mixture was extracted with diethyl ether. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 0.5 g of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-(3-fluoropropyl)-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, which was used immediately in the next step of this reaction sequence.
Reaction SMILES: [C:1]([C:3]1[C:12]([N+:13]([O-])=O)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:16])[CH:4]=1)#[N:2]>C(O)(=O)C.[Fe]>[NH2:13][C:12]1[C:3]([C:1]#[N:2])=[CH:4][C:5]([F:16])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C#N)cc1F
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of methyl 4-cyano-2-fluoro-5-nitrobenzoate (785 mg, 3.5 mmol) in acetic acid (15 mL) was added iron powder (1.17 g, 21.0 mmol). The mixture was stirred vigorously at room temperature for 2 h. Insoluble solids were then removed by filtration through celite. Water was added to the filtrate and the aqueous mixture was extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (30% ethyl acetate in hexanes) to provide methyl 5-amino-4-cyano-2-fluorobenzoate (463 mg, 2.38 mmol, 68% yield). 1H NMR (400 MHz, CDCl3): 7.30 (d, 1H), 7.19 (d, 1H), 4.41 (br s, 2H), 3.94 (s, 3H); MS (EI) for C9H7FN2O2: 193 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=[CH:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:26][CH2:25]2)=[O:23])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=[CH:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][O:32][CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:28][CH2:29]2)=[O:23])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[OH:9]
Reactant: COCCOCOc1c(OC)cc(C=CC=CC(=O)N2CCN(CCOC(c3ccccc3)c3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: COc1cc(C=CC=CC(=O)N2CCN(CCOC(c3ccccc3)c3ccccc3)CC2)cc(OC)c1O

Procedure:
To a solution of 413 mg (0.670 mmol) of of the amide compound in methanol (10 ml) was added 148 mg (0.778 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 1 hour. A saturated aqueous solution of sodium chloride was added to the reaction mixture, which was adjusted to a pH value of 10 by the addition of an aqueous solution of sodium carbonate, and then extracted with ethyl acetate. The organic layer was washed with water and concentrated by evaporation under reduced pressure. The residue was subjected to Sephadex column chromatography, eluted with methanol, to give 194 mg (0.367 mmol) of N-[5-(3,5-dimethoxy-4-hydroxyphenyl)-2,4-pentadienoyl)-N'-(2-benzhydroxyethyl)piperazine. Spectrophotometric data of the product support the structure shown below. ##STR111##
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:39]([CH3:41])[CH3:40])=[C:6]([CH:38]=1)[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[N:24]=[C:23]([C:25]([NH:27][CH2:28][CH2:29][NH:30]C(=O)OC(C)(C)C)=[O:26])[CH:22]=[CH:21][N:20]=2)[CH2:11][CH2:10]1.FC(F)(F)C(O)=O>ClCCl>[NH2:30][CH2:29][CH2:28][NH:27][C:25]([C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:18][CH2:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][CH:9]([CH2:8][O:7][C:6]3[CH:38]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[CH:39]([CH3:41])[CH3:40])[CH2:10][CH2:11]2)[N:24]=1)=[O:26]
Reactant: Cc1ccc(C(C)C)c(OCC2CCN(CCCNc3nccc(C(=O)NCCNC(=O)OC(C)(C)C)n3)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(C)C)c(OCC2CCN(CCCNc3nccc(C(=O)NCCN)n3)CC2)c1

Procedure:
2.8 g (4.92 mmol) of 1,1-dimethylethyl 2-[[[2-[[3-[4-[[5-methyl-2-(1-methylethyl)phenoxy]methyl]piperidin-1-yl]propyl]amino]pyrimidin-4-yl]carbonyl]amino]ethylcarbamate in solution in 20 ml of dichloromethane are introduced into a 0.25 l round-bottomed flask, 20 ml of trifluoroacetic acid are then added and the mixture is heated at reflux for 5 h.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](N)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: C[C@H](N)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.5 %

Procedure:
(S)-1-(3-nitrophenyl)-1-aminoethane (approx. 80% pure, 75.2 mg) was dissolved in THF (2 mL) and 10% Pd/C (13.8 mg) was added. The system was fitted with a balloon of hydrogen and purged 3×, the mixture left stirring 16 h at room temperature. Filtered the solution through Celite®, washing thoroughly with methanol, and the solvent removed in vacuo. The residue was eluted on silica gel (3-6%(2M NH3 in MeOH)/CH2Cl2) to yield 23.7 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 7.13 (t, J=7.7 Hz, 1H); 6.74 (m, 1H); 6.71 (m, 1H); 6.58 (m, 1H); 4.03 (q, J=6.7 Hz, 1H); 3.68 (br s, 2H); 1.37 (d, J=6.7 Hz, 3H).