Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]1[NH:9][C:7](=[O:8])[CH2:6][CH2:5]1)C.S(=O)(=O)(O)O.C(O)(=O)C.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1CCCCC1.C(OCC)(=O)C>[OH:25][C:19]1[CH:24]=[CH:23][C:22]([CH:4]2[NH:9][C:7](=[O:8])[CH2:6][CH2:5]2)=[CH:21][CH:20]=1
Reactant: CCOC1CCC(=O)N1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc(O)cc2)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 26.3 %

Procedure:
12.9 g of γ-ethoxy-γ-butyrolactam, 10 ml of concentrated sulphuric acid and 90 ml of glacial acetic acid were charged initially at 0° C. and admixed a little at a time with a total of 18.8 g of phenol. After thawing, the mixture was stirred at room temperature for 2 days. For work-up, the mixture was poured onto ice and extracted three times with ethyl acetate, and the combined extracts were washed once with water and once with saturated aqueous sodium chloride solution, dried and evaporated. After some time, γ-2-hydroxyphenyl-γ-butyrolactam (XI-2b) of melting point 220° C. (6.4 g, 36% of theory) crystallized from the aqueous phase. The residue obtained on evaporation was stirred with 1:1 mixture of cyclohexane/ethyl acetate and afforded on filtration with suction 4.65 g of γ-4-hydroxyphenyl-γ-butyrolactam (XI-2a) of melting point 183° C. The filtrate was evaporated. Recrystallization from dichloromethane/hexane gave a further 3.35 g (total 45% of theory) of γ-4-hydroxyphenyl-γ-butyrolactam.
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[C:17]([C:19]2[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=2[F:26])([OH:18])[CH2:16][CH:15]2[CH2:27][CH:12]1[CH2:13][CH2:14]2)[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[C:17]([C:19]2[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=2[F:26])([OH:18])[CH2:16][CH:15]2[CH2:27][CH:12]1[CH2:13][CH2:14]2)[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1C2CCC(C2)CC1(O)c1cc(O)ccc1F
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Add H2O (175.1 mg, 9.73 mmol) and TMSCl (1.057 g, 9.73 mmol) to a solution of 2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol (2.38 g, 8.11 mmol) in 2-butanone (60 mL). Stir the reaction mixture at ambient temperature for 3 hours. After removal solvent by evaporation, wash the residue with EtOAc to give 2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol hydrochloride as white solid (2.23 g, Yield: 83.5%). 1H NMR (400 MHz, D2O) δ 6.89-6.93 (m, 2H), 6.66-6.70 (m, 1H), 3.10-3.14 (m, 1H), 2.59-2.65 (m, 4H), 2.42-2.44 (d, J=8.0, 1H), 2.36-2.41 (d, J=20.0, 3H), 2.30-2.33 (d, J=12.0, 2H), 2.18 (s, 1H), 1.89-1.95 (m, 1H), 1.74-1.78 (m, 1H), 1.51-1.67 (m, 4H), 1.47-1.50 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:18])[C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:19])[CH3:4].N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(Cl)Cl>>[C:26]([O:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:18])[C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:19])[CH3:4])(=[O:28])[CH3:27]
Reactant: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(1-hydroxypropan-2-yl)-6-methyl-5-nitroisoquinolin-1(2H)-one (100.0 mg, 0.0003813 mol), pyridine (0.062 mL, 0.00076 mol), acetic anhydride (0.0432 mL, 0.000458 mol) and methylene chloride (5 mL, 0.08 mol) was stirred at room temperature overnight. The reaction went to completion and the solvent was removed under reduced pressure, and the resulting product was dried in vacuum (yellow oil) and was used in the next reaction without any purification. MS m/z=305.4 (M+H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]=[CH:43][O:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]=[CH:43][O:42][N:41]=5)=[O:54])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ncon4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ncon4)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1,2,4-oxadiazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.60 g) in dichloromethane (15 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.35 g) in dichloromethane (5 ml) at −78° C., and the mixture was stirred at −78° C. for 1 hour. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→4:1), and was further recrystalized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1,2,4-oxadiazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 129) (534.9 mg) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([F:11])=[CH:10][C:2]=1[Br:1]
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)c(F)cc1Br
Temperature: 80 °C
Yield: 28 %

Procedure:
To a solution of 2-bromo-4,5-difluoro-benzoic acid (5 g, 21.10 mmol) in methanol (100 mL) was added concentrated sulfuric acid (0.21 mL, 2.11 mmol) at 0° C. The reaction mixture was then heated at 80° C. for 4 hours. After cooling to room temperature, the mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then brine, dried over sodium sulfate, filtered, and concentrated to afford the crude product 2-bromo-4,5-difluoro-benzoic acid methyl ester (1.48 g, 28%) as a clear oil, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[O:15][CH3:16])[N:3]=1.CI.[C:19](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:14]=[CH:13][C:11]([NH:12][CH3:19])=[CH:10][C:9]=2[O:15][CH3:16])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(N)ccc1-n1nc(C)cc1C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CNc1ccc(-n2nc(C)cc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 22.9 %

Procedure:
200 mg of 4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-methoxyaniline was dissolved in 6 ml of dimethylformamide, and 160 μl of methyl iodide and 636 mg of potassium carbonate were added and stirred at room temperature for 2.5 hours. To the reaction mixture, 50 ml of water was added and extracted with 50 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using preparative thin-layer silica gel column chromatography (hexane:ethyl acetate=1:3) to yield 48.7 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=O.Cl.[CH3:14][NH:15][C:16](=NC)[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]1[N:15]([CH3:14])[C:16]([CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])=[N:7][N:6]=1
Reactant: NNC(=O)c1ccc(Cl)cc1Cl
Reactant: C=CCCCC(=NC)NC
Agent: Cl
Product: C=CCCCc1nnc(-c2ccc(Cl)cc2Cl)n1C

Procedure:
The title compound was prepared in analogy to Preparation 11 in 0.16 g yield starting from 2,4-dichlorobenzohydrazide (0.62 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.48 g). MS (m/z): 296 [MH]+.
Reaction SMILES: C[C:2]([N:4](C)C)=O.Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:27]3[N:31]([CH3:32])[C:30]([CH3:33])=[N:29][CH:28]=3)([C:20]3[N:24]([CH3:25])[C:23]([CH3:26])=[N:22][CH:21]=3)[OH:19])[CH:16]=2)[N:11]=[C:10]([O:34][CH3:35])[C:9]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Zn]>[CH3:32][N:31]1[C:27]([C:18]([C:20]2[N:24]([CH3:25])[C:23]([CH3:26])=[N:22][CH:21]=2)([OH:19])[C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[C:10]([O:34][CH3:35])[C:9]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:44])([F:46])[F:45])=[CH:41][CH:42]=2)=[C:8]3[C:2]#[N:4])=[CH:28][N:29]=[C:30]1[CH3:33]
Reactant: CC(=O)N(C)C
Reactant: COc1nc2ccc(C(O)(c3cnc(C)n3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: COc1nc2ccc(C(O)(c3cnc(C)n3C)c3cnc(C)n3C)cc2c(C#N)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
DMA (1.22 mL) was added to a mixture of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)bis(1,2-dimethyl-1H-imidazol-5-yl)methanol (70.6 mg, 0.124 mmol, Intermediate 76), zinc cyanide (27.5 mg, 0.234 mmol), Pd2(dba)3 (18.5 mg, 0.0202 mmol), zinc nanopowder (2.5 mg, 0.0382 mmol) and X-Phos (12.9 mg, 0.0262 mmol). The mixture was stirred at 120° C. under argon for 4 hours. After cooling to room temperature, the reaction was diluted with EtOAc (2 mL), filtered through Celite®, and the filter cake washed with EtOAc (2×1 mL). The combined filtrates were washed with 0.75 M aqueous EDTA tetrasodium salt (2×1 mL), water (1×2 mL), and 5 M aqueous NaCl (1×2 mL). The organic layer was diluted with DCM/MeOH, dried (Na2SO4), filtered, and concentrated, and the residue was dry load flash chromatographed with a DCM to 10% MeOH/DCM gradient to provide the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=1.81 Hz, 1H), 7.76 (d, J=9.09 Hz, 1H), 7.55 (d, J=8.59 Hz, 2H), 7.49 (d, J=8.08 Hz, 2H), 7.41 (dd, J=2.06 Hz, 9.04 Hz, 1H), 6.16 (s, 2H), 4.39 (s, 2H), 4.10 (s, 3H), 3.42 (s, 6H), 2.27 (s, 6H); MS m/e 561.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:4]([C:19]([O:21]C2C=CC=CC=2)=[O:20])[CH:3]=1.[OH-].[Na+]>CO>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([OH:1])=[CH:3][C:4]=2[C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Oc1ccccc1)c1cc(O)c2ccccc2c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(O)c2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
The product of Step 3 of Example 1, 4-hydroxy-1-(4-fluorophenyl)-2-phenoxycarbonyl naphthalene (10 grm), a 10 weight percent aqueous sodium hydroxide solution (50 mL) and methanol (50 mL) were added to a reaction flask and heated to reflux for 3 hours and then cooled to room temperature. The reaction mixture was poured onto an aqueous solution of 4N hydrochloric acid/ice mixture (approximately 400 mL). A white precipitate formed and was collected by vacuum filtration, washed with water and was air-dried. Recrystallization from ethanol (95 weight percent) gave 1-(4-fluorophenyl)-4-hydroxy-2-naphthoic acid (7 grams).
Reaction SMILES: C(#N)C.[C:4]1([CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][OH:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O:20]O)(C)(C)C.C(O)(=O)C(C(C(O)=O)O)O>C1(C)C=CC=CC=1.CCCCCCCCCC.O>[O:20]1[C@@H:12]([CH2:11][CH2:10][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@@H:13]1[CH2:14][OH:15]
Reactant: OCC=CCCc1ccccc1
Reactant: CC(C)(C)OO
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: OC[C@@H]1O[C@H]1CCc1ccccc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
A solution of L-(+)-diethyl tartrate (766 mg, 3.70 mmol) in 1HPLC system: Zorbax SB-C18 25 cm column, 90:10/ACN:water eluent, 220 nm, 1.0 mL/min. The reaction was considered complete when less than or equal to 3% area 21 remained. 2Silica gel was used as the drying agent because it also removed some baseline impurities. methylene chloride (25 ml) over activated 4 Å powdered molecular sieves (3.0 g) was cooled to -20° C. and Ti(O-i-Pr)4 (0.917 ml, 3.08 mmol) was added. After the mixture was stirred for 10 min, a solution of 15 (5.00 g, 30.8 mmol) in toluene (5.0 ml) was added maintaining the temperature below -18° C. The reaction was stirred at -20° C. for 35 min and tert-butyl hydroperoxide in decane (14.54 ml, 77.05 mmol, 5.3 M, stored over pellet 3 Å molecular sieves for 30 min prior to use) was added over 20 min, maintaining the temperature below -18° C. The reaction was allowed to stir at -20° C. until HPLC analysis3 showed >98% conversion (2.5 h). The reaction was allowed to warm to -5° C. and was poured into a mixture comprised of FeSO4 7H2O (13.2 g), tartaric acid (4.0 g), and 40 ml of water at 2° C. After stirring for 20 min the brown mixture was filtered through celite, washing with toluene. The filtrate layers were sparated and the aqueous was washed with toluene (2×20 ml). The combined organics were poured into a mixture containing NaCl (2.5 g), NaOH (15 g), and 40 ml of water at 0° C. After stirring for 1 h, the layers were separated and the aqueous layer was extracted with toluene (2×20 ml). The combined organics were dried (MgSO4), filtered, and concentrated in vacuo to give a yellow oil. Chromatography (165 g of flash SiO2) eluting with ethyl acetate:hexanes (2:1) provided 4.46 g (81%) of 16 as a colorless oil. 3 HPLC conditions: Chromsil C-18 column (1×25 cm), isocratic elution (50% acetonitrile/50% water both with 0.5% TFA), 1 ml/min flow rate for 20 min with UV detection ata 206 nm.
Reaction SMILES: [Mg].Br[CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5].BrCCCCC.[CH3:14][C:15]([CH3:27])([CH3:26])[C:16]([NH:18][C:19]1[N:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=1)=[O:17].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+].II>C(OCC)C.O1CCCC1.C(OCC)(=O)C>[CH2:4]([CH:3]([C:24]1[CH:23]=[C:22]([CH3:25])[N:21]=[N:20][C:19]=1[NH:18][C:16](=[O:17])[C:15]([CH3:26])([CH3:14])[CH3:27])[CH2:6][CH3:7])[CH3:5]
Reactant: Cc1ccc(NC(=O)C(C)(C)C)nn1
Reactant: CCC(Br)CC
Agent: II
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nnc1NC(=O)C(C)(C)C
Yield: 41454.5 %

Procedure:
To a dry 3 L flask fitted with a condensor and drop funnel is added 19.2 g (0.792 moles) of activated magnesium powder. Heat gun dry the entire apparatus under vacuum, allow to cool, add enough ether to cover the magnesium. To the addition funnel is added 100 g (0.662 mmol) of 3-bromopentane in 175 ml of diethyl ether. Add ⅓ of the bromopentane solution to the magnesium and stir under nitrogen until bubbling occurs, then drip in the rest at such a rate so that the bubbling continues gently. Stir 30 minutes longer after bubbling ceases. Next, drip in 21.3 g (0.110 mmol) of 2,2-dimethyl-N-(6-methyl-pyridazine-3-yl)-propionamide dissolved in 225 ml dry tetrahydrofuran. Stir 1 h. Carefully add over 1 L of saturated sodium tartrate and stir 30 minutes. Transfer to larger flask and add 2 L of ethyl acetate and stir 1 h. Separate layers and extract aqueous several times with ethyl acetate. Combine organic layers and evaporate solvents. Take up in 600 ml of methylene chloride and add 28 g (0.110 mol) of iodine and stir 2 h. Wash the organic phase once with aqueous solution of sodium sulfite then water. Dry over sodium sulfate, filter and evaporate to red oil. Chromatograph using 6:1 hexanes:ethyl acetate to 100% ethyl acetate. Combine product fractions, evaporate, and triturate residue in ethyl acetate and filter to obtain 12.0 g (45.6 mmol, 41.4%) of the title compound as a light tan solid. 1H-NMR (DMSO-d6): δ 9.88 (s, 1H); 7.59 (s, 1H); 2.60 (s, 3H); 2.39-2.42 (m, 1H); 1.21-1.37 (m, 2H); 1.38-1.43 (m, 2H); 1.23 (s, 9H); 0.71 (t, J=7.49 Hz, 6H) ppm. MS/ES+=264.
Reaction SMILES: [ClH:1].Cl.[C:3]1([NH:9][C:10]2([C:23]([OH:25])=[O:24])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:31](O)[CH3:32]>>[ClH:1].[ClH:1].[C:3]1([NH:9][C:10]2([C:23]([O:25][CH2:31][CH3:32])=[O:24])[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO
Reactant: O=C(O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 19 parts of 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylic acid dihydrochloride, 14.4 parts of sulfuric acid and 64 parts of ethanol is stirred and refluxed for 16 hours. The solvent is decanted. The residue is dissolved in water. The aqueous solution is alkalized with ammonium hydroxide and extracted with a mixture of methylbenzene and 2,2'-oxybispropane. The combined organic layers are dried over magnesium sulfate, filtered and evaporated. The oily residue is dissolved in 200 parts of 2,2'-oxybispropane and gaseous hydrogen chloride is introduced into the solution. The precipitated hydrochloride is filtered off, washed with 2-propanol, filtered off again and dried, yielding 11.5 parts of ethyl 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate dihydrochloride; mp. 212°-214.4° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:42])[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:42])[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)N(C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNC(=O)N(C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-butylaminocarbonyl)-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH2:1]([N:3]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[F:11])[CH3:2].[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>O1CCOCC1.CO>[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N:3]([CH2:1][CH3:2])[CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:5]=1[F:11])=[O:23]
Reactant: CCN(c1cccc(N)c1F)C1CCN(C)CC1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCN(c1cccc(NC(=O)c2ccc(F)cc2Cl)c1F)C1CCN(C)CC1

Procedure:
Heat a mixture of N-ethyl-2-fluoro-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 27) and 2-chloro-4-fluorobenzoyl chloride (23 mg) in 1,4-dioxane (5 mL) at reflux for 1 hour. Dilute with methanol (5 mL), load on a SCX column (10 g), wash with methanol, elute the product with 2M NH3 in methanol, evaporate to give the title compound: mass spectrum (electric spray) m/z=408 (M+1). Purify further by HPLC to give the di-trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:10]=[C:6]2[C:5]([CH3:31])=[CH:4][CH:3]=1.[C:32]1([C:38]2[N:39]=[C:40]([CH:43]=O)[NH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH:11]=[CH:43][C:40]3[NH:41][CH:42]=[C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:39]=3)[N:10]=[C:6]2[C:5]([CH3:31])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: O=Cc1nc(-c2ccccc2)c[nH]1
Product: Cc1ccc(C)n2nc(C=Cc3nc(-c4ccccc4)c[nH]3)nc12

Procedure:
One example of a synthetic route for the synthesis of the PET-preursor compound of formula IIa is shown in scheme 4: The (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-triphenylphosphonium salt 1 is coupled under basic conditions with commercially available 4-phenyl-1H-imidazole-2-carbaldehyde 2 (Anichem Inc. catalog number FH10994) to form the 5,8-Dimethyl-2-[2-(4-phenyl-1H-imidazol-2-yl)-vinyl]-[1,2,4]triazolo[1,5-a]pyridine, compound 3.
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]/C(O)=O.[NH:9]([C:11]1[N:16]=[N:15][C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:13]=2[CH:12]=1)[NH2:10].[OH-].[Na+].C(Cl)(Cl)Cl>CC(C)=O.N>[C:2](=[N:10][NH:9][C:11]1[N:16]=[N:15][C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:13]=2[CH:12]=1)([CH3:3])[CH3:1]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: NNc1cc2c(nn1)CCCCCCCCCC2
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(C)=NNc1cc2c(nn1)CCCCCCCCCC2

Procedure:
1.5 g of 3-hydrazino-5,6,7,8,9,10,11,12,13,14-decahydrocyclododeca[c]pyridazine fumarate are heated in 20 cc of acetone, to which a few drops of concentrated aqueous ammonia solution have been added, on a water bath for 1 hour. The mixture is cooled with ice, and the resulting crude title compound is divided between 5 cc of concentrated aqueous caustic soda solution and 20 cc of chloroform. The chloroform phase is concentrated, whereby a yellowish foam results, from which the title compound is obtained by recrystallization from absolute ethanol. M.P. 165°-166° (decomp.).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[N:13]1([C:19]([S:21][CH3:22])=[S:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][N:16]1[CH2:17][CH2:18][N:13]([C:19]([S:21][CH3:22])=[S:20])[CH2:14][CH2:15]1
Reactant: CN(C)c1ccccc1CCl
Reactant: CSC(=S)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CSC(=S)N1CCN(Cc2ccccc2N(C)C)CC1
Yield: 42.7 %

Procedure:
In 20 ml of acetone, 2.06 g (10 mmol.) of 2-dimethylaminobenzyl chloride hydrochloride, 1.76 g (10 mmol.) of methyl piperazinecarbodithioate, and 1.06 g (10 mmol.) of sodium carbonate were stirred overnight at room temperature. Acetone was distilled off under reduced pressure. Water was added to the residue. The aqueous mixture was extracted with ether. The ether portion was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was purified by means of silica gel column and then recrystallized from ether to give 1.32g of the desired compound as a white crystalline product, m.p. 90°-91° C., yield 42.7%.