Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=1.Cl.[CH3:17][O:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=3)=[CH:4][N:3]=2)[CH2:21][CH2:20]1
Reactant: OCc1cccc(-c2cnc(Cl)nc2)c1
Reactant: COC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC1CCN(c2ncc(-c3cccc(CO)c3)cn2)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
[3-(2-Chloropyrimidin-5-yl)phenyl]methanol (200 mg) was mixed with DMF (4 ml), and 4-methoxypiperidine hydrochloride (180 mg) and potassium carbonate (500 mg) were added thereto, followed by stirring at 70° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {3-[2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl]phenyl}methanol (249 mg).
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([OH:12])[O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1.CCN(CC)CC>CS(C)=O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:20][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]([OH:12])[O:7][C:8]3=[O:11])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: C=Cc1ccc(OC)cc1
Reactant: O=C1OC(O)c2ccc(I)cc21
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C=Cc2ccc3c(c2)C(=O)OC3O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.38 g (5 mmol) of 6-iodo-3-hydroxyisobenzofuranone, 0.74 g (5.5 mmol) of p-methoxystyrene, 0.83 ml (5.5 mmol) Et3N, 0.01 g of Pd (OAc)2 and 1 ml of DMSO was prepared in a 10 ml flask. The flask was surmounted with a reflux condenser and the solution was heated to 95° (oil bath) with stirring under N2 for 1 hour. The dark solution was allowed to cool to RT and poured onto 75 ml of ice/H2O with stirring. After standing overnight, the solid which had formed was collected, washed well with cold H2O and air dried. It was then heated with 50 ml of 95% EtOH, charcoaled and filtered. The reddish filtrate was cooled in ice and deposited 100 mg of reddish-brown solid which was found to be impurity and was discarded. The filtrate was evaporated at reduced pressure and the residual orange-yellow solid was triturated with 25 ml of Et2O and filtered to afford 860 mg (60.9%) of the desired coupling product as a yellow solid; homogeneous by TLC--used as is for the next reaction.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6](O)[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=2)=[CH:15][CH:14]=1)[CH2:2][CH3:3].CN(C)C=O.S(Cl)([Cl:39])=O>>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([Cl:39])[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=2)=[CH:15][CH:14]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)nc(O)c1Cc1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCc1nc(C)nc(Cl)c1Cc1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.5 g of 6-n-propyl-2-methyl-4-hydroxy-5-{[2'-(4,4-dimethyl-2-oxazolinyl)-4-biphenylyl]methyl}pyrimidine, prepared in Example 184, are dissolved in 3 ml of thionyl chloride. 0.1 ml of dimethylformamide is added and the mixture is stirred for 1 hour at room temperature. The thionyl chloride is evaporated off under vacuum without heating, and the residue is washed with ether, then alkalinised with ammonium hydroxide solution and washed with water. The ether phase is evaporated under vacuum to give 0.6 g of 6-n-propyl-2-methyl-4-chloro-5-{[2'-(4,4-dimethyl-2-oxazolinyl)-4-biphenylyl]methyl}pyrimidine in the form of an oil, which is used without further purification for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH3:17]>>[CH2:16]([N:18]([CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:15])[CH3:17]
Reactant: CCNCc1ccncc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: CCN(Cc1ccncc1)C(=O)c1cnoc1-c1ccc(C)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 4-(ethylaminomethyl)-pyridine (8.2 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (7.8 mg). HRMS calcd for C19H19N3O2: 321.1477, found 321.1485.
Reaction SMILES: [N:1]1([CH2:6][C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=S)[C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25](OCC)(=[O:28])[NH:26][NH2:27]>>[N:1]1([CH2:6][C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]3[C:25](=[O:28])[NH:26][N:27]=[C:12]3[C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CN1CCCC1)N1c2ccccc2NC(=S)c2cccnc21
Reactant: CCOC(=O)NN
Product: O=C(CN1CCCC1)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
In the manner given in Example 13, 6,11-dihydro-11-(pyrrolidinoacetyl)-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione is heated to about 200° C. with ethyl carbazate to give 2,9-dihydro-9-(pyrrolidinoacetyl)-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:28][CH2:27][C:10]2[C:11]3[C:16]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:26][C:9]=2[CH2:8]1)=[O:6].[NH:29]1[CH2:32][CH2:31][CH2:30]1>CN(C=O)C.C(OC)(C)(C)C>[N:29]1([CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]2[CH2:28][CH2:27][C:10]3[C:11]4[C:16]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=5)=[N:15][CH:14]=[N:13][C:12]=4[S:26][C:9]=3[CH2:8]2)=[O:6])[CH2:32][CH2:31][CH2:30]1
Reactant: O=C(/C=C/CCl)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Reactant: C1CNC1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: O=C(/C=C/CN1CCC1)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Temperature: 50 °C
Yield: 13.1 %

Procedure:
To a suspension of Example 59A (100 mg, 0.20 mmol) in DMF (2 mL) was added azetidine (23 mg, 0.40 mmol), and the mixture was heated to 50° C. for 1 h. It was then diluted with methyl tert-butyl ether, washed with water and dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified by preparative HPLC to yield 12.4 mg (13%) of the title compound.
Reaction SMILES: [Na].C(OC(=O)[CH2:6][CH2:7][N:8]([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13]CC)=O)C.CN1CCC(=O)C(C(OCC)=O)C1=O>C(O)C.CCOCC>[CH3:17][N:8]1[CH2:7][CH2:6][C:11](=[O:13])[CH2:10][C:9]1=[O:16]
Reactant: CCOC(=O)CCN(C)C(=O)CC(=O)OCC
Agent: CCOC(=O)C1C(=O)CCN(C)C1=O
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CN1CCC(=O)CC1=O
Temperature: 80 °C

Procedure:
Into a 50-mL round bottomed flask was added ethanol (4 mL) under argon, followed by sodium (0.121 g, 5.25 mmol). The mixture was stirred at room temperature for 15 min, during which a solution of ethyl 3-((3-ethoxy-3-oxopropyl)(methyl)amino)-3-oxopropanoate (1.17 g, 4.77 mmol) in ethanol (5 mL) was added. The resulting clear, colorless mixture was heated at 80° C. for 1 h, during which LC-MS indicated completion of reaction and a clean conversion to the desired ethyl 1-methyl-2,4-dioxopiperidine-3-carboxylate intermediate. Upon cooling to room temperature, the reaction was diluted with Et2O, resulting in the formation of a white precipitate (desired product). The white precipitate was collected via filtration, taken up in 5% aqueous HCl solution (8 mL), and refluxed for 1 h. The cooled mixture was extracted with CH2Cl2 (5×) and the combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% EtOAc/Hexanes to 100% EtOAc) afforded 1-methylpiperidine-2,4-dione as a viscous milky oil. [M+1]=128.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)CCC>>[CH2:1]([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(Br)cc2)CC1
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(-c3cccs3)cc2)CC1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared starting from 1-(4-Bromo-benzyl)-4-(4-methoxy-benzensulfonyl)- piperidine-4-carboxylic acid ethyl ester (3 g, 6.05 mmol) and 2-(tributylstannyl)-thiophene (6.8 g, 18.14 mmol) in the presence of tetrakis palladium (0) in boiling tolune. Yield 1.58 g (52%); brown solid; mp 130° C.; MS: 500 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5](C(O)=O)=[N:6][N:7]([C:9]2[C:22]([F:23])=[CH:21][C:12]3[O:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[O:16][C:11]=3[CH:10]=2)[CH:8]=1.C1C=CC(P([N:42]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:42][C:5]1[C:4](=[O:27])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[C:22]([F:23])=[CH:21][C:12]3[O:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[O:16][C:11]=3[CH:10]=2)[N:6]=1
Reactant: COc1cn(-c2cc3c(cc2F)OC(F)(F)C(F)(F)O3)nc(C(=O)O)c1=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cn(-c2cc3c(cc2F)OC(F)(F)C(F)(F)O3)nc(N)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-(2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1,4-dihydropyridazine-3-carboxylic acid (2.33 g, 5.91 mmol), DPPA (1.90 mL, 8.86 mmol) and Et3N (1.23 mL, 8.86 mmol) in toluene (23 mL) was heated to 100° C. for 90 min. To the mixture was added 8 M NaOH aqueous solution (7.4 mL) at 0° C. The mixture was stirred at room temperature for 2 h, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100) and on silica gel (hexane/EtOAc=80/20 to 0/100) and triturated with EtOAc/hexane to yield the title compound (1.12 g, 53% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.73 (3H, s), 6.24 (2H, s), 7.92 (1H, d, J=10.5 Hz), 7.99 (1H, d, J=6.8 Hz), 8.37 (1H, d, J=1.5 Hz).
Reaction SMILES: [CH:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]([NH:14][CH:15]=[O:16])[CH2:4]1)=[O:2].[N+:17]([O-])([O-:19])=[O:18].[Na+]>FC(F)(F)C(O)=O>[CH:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][C:11]=2[N+:17]([O-:19])=[O:18])[CH2:6][CH:5]([NH:14][CH:15]=[O:16])[CH2:4]1)=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=CNC1Cc2cc(Br)ccc2N(C=O)C1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=CNC1Cc2cc(Br)cc([N+](=O)[O-])c2N(C=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
A mixture of N-(1-formyl-6-bromo-1,2,3,4-tetrahydro-3-quinolyl)formamide (12.8 g, 5.2 retool) and sodium nitrate (12.8 g, 150 mmol) in trifluoracetic acid (100 mL) was stirred at room temperature for 18 hours. The bulk of the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The ethyl acetate was washed with sodium hydroxide and water, and the ethyl acetate was removed to give 14.2 g of N-(1-formyl-6-bromo-1,2,3,4-tetrahydro-8-nitro-3-quinolyl)formamide (compound XXVIII) as a solid. This was dissolved in ethanolic hydrogen chloride (100 mL of 4.0 N), the mixture was refluxed for 1 hour, ether (200 mL) was added, and the precipitate was filtered off, washed with ether and dried to give 12.8 g (82%) of 6-bromo-1,2,3,4-tetrahydro-8-nitro-3-quinolinamine dihydrochloride, mp >300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](I)=[C:9]([O:14][CH3:15])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[C:18]([O:22][C:23](=[O:27])[C:24](C)=[CH2:25])([CH3:21])([CH3:20])[CH3:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:18]([O:22][C:23](=[O:27])/[CH:24]=[CH:25]/[C:10]1[C:11](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=2[NH:7][C:8](=[O:16])[C:9]=1[O:14][CH3:15])([CH3:21])([CH3:20])[CH3:19]
Reactant: C=C(C)C(=O)OC(C)(C)C
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1c(/C=C/C(=O)OC(C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 104 °C

Procedure:
The title compound was prepared in the manner described in Example 44 using the 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (2.18 g) and tert-butylmethacrylate (17.1 g) in toluene (70 mL) with tris (dibenzylideneacetone)dipalladium (O) (0.10 g) and tri-orthotolylphosphine (0.13 g). The mixture was treated with triethylamine (0.84 mL, 0.61 g) and heated at 104° C. for 3.7 hours. The mixture was concentrated to a dark solid which was dissolved in chloroform and chromatographed on a silica gel column (5.5 cm diameter×18 cm long) using 25% ethyl acetate in hexane. Concentration of the main fraction gave a white solid (0.77 g). A portion (0.21 g) of the solid was dissolved in hot ethyl acetate (7 mL). The solution was diluted with hexane (5 mL) and the crystals formed at room temperature. The solid was filtered off, washed with ethyl acetate, washed with hexane, and air-dried to give white crystals (0.11 g); mp=189.1°-199.8° C.; 1H NMR(CDCl3) 7.27 (s,1) for olefin proton; MS: m/z=322 (base peak), 378 (M+1). Analysis for C19H20ClNO5 : Calculated: C, 60.40; H, 5.34; N, 3.71; Found: C, 60.18; H, 5.43; N, 3.72.
Reaction SMILES: CN1CCCC1=O.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH:19]([CH2:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:20]([OH:22])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:47][OH:48]>C(OCC)(=O)C>[OH:48][NH:47][C:20](=[O:22])[CH:19]([CH2:18][S:15]([C:12]1[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=1)(=[O:17])=[O:16])[CH2:23][S:24]([C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)CC(CS(=O)(=O)c2ccc(C)cc2)C(=O)O)cc1
Reactant: NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)CC(CS(=O)(=O)c2ccc(C)cc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-methylpyrrolidinone (20 mL) cooled in an ice bath, is added 2-[(4-methylbenzenesulfonyl)methyl]-3-(4-methylbenzenesulfonyl)-propionoic acid (4.4 g, 11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.2 g, 22 mmol), and hydroxylamine hydrochloride (1.5 g, 22 mmol). After stirring overnight at ambient temperature, the mixture is transferred to ethyl acetate and extracted with aqueous 10% hydrochloric acid, distilled water, aqueous sodium bicarbonate, brine, and dried over anhydrous sodium sulfate. The organic phase is concentrated in vacuo and triturated from hexane to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9]N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[CH2:16][CH2:15]2>C(O)C.C(O)(=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17]1[NH:9][C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=3[C:16]=1[CH2:15]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: Cc1cc(C)cc(NN)c1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C)c2c3c([nH]c2c1)-c1ccc(F)cc1C3
Temperature: 85 °C

Procedure:
To a solution of 3,5-dimethylphenylhydrazine (2.54 g, 14.7 mmol) and 5-fluoro-1-indanone (2.21 g, 14.7 mmol) in ethanol (24 mL) was added glacial acetic acid (3 drops). The solution was stirred at reflux (85° C.) for 15 minutes and cooled to room temperature. Ethanol was removed in vacuo and the resulting orange solid was dissolved in isopropanol (24 mL). Sulfuric acid (36N, 1.65 mL) was added via syringe and the mixture was stirred at reflux (90° C.) for 17 hours and subsequently cooled to room temperature. The solution was basified to pH 10 via addition of aqueous sodium hydroxide (2% by mass) resulting in the formation of a precipitate. The solid was collected by vacuum filtration to yield 47b in 76% crude yield (2.80 g, 11.2 mmol). Crude product was brought on to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.32-7.35 (dd, 1H, J=8.2, 5.2 Hz), 0.24-7.26 (m, 1H), 7.01-7.05 (m, 2H), 6.79 (s, 1H), 3.83 (s, 2H), 2.60 (s, 3H), 2.44 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 160.7 (d, J=361.5), 150.0 (d, J=12.0 Hz), 140.9, 140.6, 131.8, 131.2, 128.9, 122.6, 122.3, 121.6 (d, J=4.5 Hz), 117.2 (d, J=13.5 Hz), 113.4 (d, J=25.5 Hz), 113.1 (d, J=25.5 Hz), 109.6, 31.7 (d, J=3.0 Hz), 21.8, 19.3; 19F NMR (CD3CD, 376 MHz): δ −117.9 (m).
Reaction SMILES: [C:1]1([N:7]=[C:8]=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([NH:13][NH2:14])(=O)[CH3:11].[N+]([O-])(O)=O.[OH-].[NH4+]>C(O)C>[CH3:11][C:10]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[N:14][N:13]=1
Reactant: S=C=Nc1ccccc1
Reactant: CC(=O)NN
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: Cc1nncn1-c1ccccc1
Temperature: 25 °C

Procedure:
2.5 mol of phenyl isothiocyanate (Formula XXI of Chart B) is added to 0.5 mol of acethydrazide (Formula IV of Chart B) in 500 ml of absolute ethanol and refluxed for one hour, cooled and filtered. This is then dissolved in a solution of 28.0 gm sodium hydroxide in 400 ml of water and the mixture is refluxed for two hours. The reaction mixture is cooled in an ice bath and treated with 100 ml of concentrated hydrochloric acid. The resulting solid is filtered and recrystallized. 66.7 mmol of the solid is added to 53 ml of 20% nitric acid and heated on a steam bath. When the vigorous exothermic reaction is complete, an additional 53 ml of 20% nitric acid is added, and an additional 66.7 mmol of previous solid. Portions of the solid are reacted with nitric acid until all of the previous solid is reacted. After the final addition the reaction mixture is heated twenty minutes on a steam bath, cooled to ambient temperature and poured into cold 15% aqueous ammonium hydroxide solution. The subtitled product is extracted with chloroform, dried and concentrated to yield 3-methyl-4-phenyl-4H-1,2,4-triazole, (Formula XXIV, Chart B) mp 109°-111° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH3:12].[C:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=2[CH2:4][CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]2[CH3:12])=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: CN1CCCCC1CCc1ccccc1N
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)Nc2ccccc2CCC2CCCCN2C)cc1

Procedure:
Reaction of 2-(o-aminophenethyl)-1-methylpiperidine with p-acetoxybenzoyl chloride in pyridine according to Example 1 provides 4-acetoxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide. Analytically pure product is obtained by crystallization from isopropyl ether, m.p. 88°-108° C. (corr.). The broad melting point of the analytically pure material is due to polymorphism.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=1.Br[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[C:32]=1[CH3:38].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[C:32]=2[CH3:38])=[CH:10][CH:11]=1
Reactant: Cc1nccc(Br)c1C
Reactant: COC(=O)[C@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
Suzuki coupling.: To a mixture of (S)-2-tert-butoxycarbonylamino-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid methyl ester (8.22 g) in 140 mL toluene and 40 mL water was added 4-bromo-2,3-dimethyl-pyridine (6.77 g), Na2CO3 (7.5 g), and Pd(PPh3)4. The mixture was purged with nitrogen and stirred under nitrogen at 80° C. for 18 h. The mixture was then cooled to rt and poured into water-EtOAc. The organic layer was washed with water and saturated brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexanes-EtOAc) to provide (S)-2-tert-butoxycarbonylamino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (4.5 g). LCMS (m/z) 386.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[N:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[F:9]
Reactant: OB(O)c1ccncc1
Reactant: Fc1cc(I)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cc(-c2ccncc2)ccc1Br
Temperature: 25 °C
Yield: 21.9 %

Procedure:
1-Bromo-2-fluoro-4-iodobenzene (300 mg, 0.997 mmol), 4-pyridineboronic acid (147 mg, 1.196 mmol), Na2CO3(211 mg, 1.994 mmol) and tetrakis(triphenylphosphine)palladium (230 mg, 0.199 mmol) in 3.3 mL of 1:1 Dioxane/water were heated to 100° C. for 20 h. The reaction was slowly warmed to room temperature, diluted with water and extracted with EtOAc. The organic phase was separated, dried (Na2SO4) and evaporated to dryness, giving an oil. This material was chromatographed on silica gel, eluting with 0-10% ethyl acetate in hexanes to give 4-(4-bromo-3-fluorophenyl)pyridine (55 mg) as an off-white solid.