Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:5]=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C([Sn](CCCC)(CCCC)[C:25]1[O:29][C:28]([Si](C(C)C)(C(C)C)C(C)C)=[N:27][CH:26]=1)CCC>C1(C)C(C)=CC=CC=1.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>[O:29]1[C:25]([C:2]2[N:7]=[C:6]([NH:8][C:9]([CH:11]3[CH2:13][CH2:12]3)=[O:10])[CH:5]=[N:4][C:3]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:26][N:27]=[CH:28]1
Reactant: O=C(Nc1cnc(-c2ccncc2)c(Cl)n1)C1CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C(C)C)(C(C)C)C(C)C)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: O=C(Nc1cnc(-c2ccncc2)c(-c2cnco2)n1)C1CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
A mixture of N-(6-chloro-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide (100 mg, 0.36 mmol) and 5-(tributylstannyl)-2-(triisopropylsilyl)-1,3-oxazole (397 mg, 0.73 mmol) in xylene (3 mL) was degassed with argon. The catalyst Pd(PPh3)4 (25 mg, 0.022 mmol, 6 mol %) was added and degassing was repeated. The mixture was heated to 90° C. in a sealed tube and stirred overnight. The mixture was cooled and ethyl acetate and HCl 2N were added. The aqueous layer was washed with ethyl acetate and then neutralized with 6N NaOH. The cloudy solution was extracted with CH2Cl2. The organic layer was dried and concentrated. The residue was purified by flash silica gel chromatography (dichloromethane/methanol 95:5) to give the title compound (36 mg, 35%) as a white solid.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)(OCC)=O)C.CN(C=O)C.[H-].[Na+].[O:32]1[CH2:37][CH2:36][N:35]([C:38]2[C:39]3[N:40]([CH:44]=[C:45]([CH:47]=O)[N:46]=3)[CH:41]=[CH:42][N:43]=2)[CH2:34][CH2:33]1.CC(O)=O.Cl>C1COCC1>[O:32]1[CH2:33][CH2:34][N:35]([C:38]2[C:39]3[N:40]([CH:44]=[C:45](/[CH:47]=[CH:9]/[C:10]4[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[N:11]=4)[N:46]=3)[CH:41]=[CH:42][N:43]=2)[CH2:36][CH2:37]1
Reactant: CCOC(=O)c1cc(CP(=O)(OCC)OCC)nc2ccccc12
Reactant: O=Cc1cn2ccnc(N3CCOCC3)c2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)c1cc(/C=C/c2cn3ccnc(N4CCOCC4)c3n2)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of compound 45a (124 mg, 0.353 mmol) in DMF (3.5 mmol) was treated with 60% NaH (42.3 mg, 1.05 mmol) at 0° C. The resulting mixture was stirred at rt for 15 min, cooled to 0° C. and treated with compound 45b (90.2 mmol, 0.388 mmol) in THF (2 mL). The resulting mixture was stirred for 30 min, cooled in a dry ice/acetone bath and treated with HOAc (0.060 mL, 1.05 mmol). The reaction mixture was then allowed to warm to rt and the pH was adjusted to about 5 with concentrated HCl. The precipitate formed was collected by filtration and dried under reduced pressure to obtain (E)-2-(2-(8-morpholinoimidazo[1,2-a]pyrazin-2-yl)vinyl)quinoline-4-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[C:14]2[C:15]3[C:7]([CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.C>O1CCCC1.C(O)(=O)C.C(Cl)Cl.[Pd]>[NH2:1][C:4]1[C:14]2[C:15]3[C:7]([CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c3c(cccc13)CC2
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1ccc2c3c(cccc13)CC2
Reaction time: 2 h

Procedure:
40 gms (Aldrich lot #CY 02301 HX, containing 15% of the 3-nitro isomer) of 5-nitroacenaphthene was dissolved in a mixture of tetrahydrofuran (150 ml) and acetic acid (25 ml.). To this solution was added 1.0 of 10% Pd/C and the mixture hydrogenated (40 psi) at room temperature. After 2 hours, the mixture was filtered through a bed of celite and the filtrate concentrated in vacuo to give a mixture of a solid which darkened (to purple) considerably on exposure to air. This material was redissolved in methylene chloride and decolorized with activated charcoal and then the product recrystallized from a mixture of cyclohexane:ethyl acetate (3:1) to give 8.3 g of clean material--only the major 5-amino isomer being present by TLC. This material was used as is directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[I-].[K+].CC(C)=O>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)ccc1OCc1ccccc1
Yield: 98 %

Procedure:
The mixture of 31.62 g (190 mmol) 1-(4-hydroxy-3-methoxy-phenyl)-ethanone, 16.36 g (118 mmol) potassium carbonate, 0.5 g potassium iodide, 400 ml acetone and 33.15 g (190 mmol) ml benzyl bromide were refluxed for 2 days. The solvent was evaporated, the residue was taken up in 400 ml of water. The precipitate was filtered, washed with 100 ml of sodium carbonate saturated aqueous solution and 2×100 ml of water, then dried on air to give 47.8 g of product [A]. Yield 98%.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:13]=[C:12]([CH2:14][N:15]3[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)[O:11][N:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[CH:13]=[C:12]([CH2:14][N:15]3[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)[O:11][N:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cc(Cn3cc([N+](=O)[O-])cn3)on2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2cc(Cn3cc(N)cn3)on2)OCCO1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 3-(2-methyl-[1,3]dioxolan-2-yl)-5-(4-nitro-pyrazol-1-ylmethyl)-isoxazole (150 mg, 0.54 mmol), iron powder (91 mg, 1.61 mmol) and NH4Cl (145 mg, 2.68 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 85° C. for 20 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by water (20 mL). The aq. layer was extracted with CH2Cl2 (2×20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a deep orange oil. LC-MS-conditions 02: tR=0.49 min; [M+H]+=251.34.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH:7]=[CH:6]2.Cl.CCOCC.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[N:21]1([CH2:20][CH2:19][O:18][C:17]2[CH:27]=[CH:28][C:14]([O:13][C:9]3[C:8]([C:29]4[CH:34]=[CH:33][C:32]([S:35]([C:38]([F:39])([F:40])[F:41])(=[O:36])=[O:37])=[CH:31][CH:30]=4)=[CH:7][CH:6]=[C:5]4[C:10]=3[CH:11]=[CH:12][C:3]([OH:2])=[CH:4]4)=[CH:15][CH:16]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(=O)(=O)C(F)(F)F)cc3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOCC
Product: O=S(=O)(c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 81.6 %

Procedure:
Dissolve the compound of Example 19 (250 mg, 0.42 mmol) in dichloromethane (5 mL). Add 2M HCl in ether (0.42 mL, 0.84 mmol) and stir for 1 minute. Remove the solvent in vacuo and place on a high vacuum pump for 10 minutes. Dissolve the foam in dry dichloromethane (5 mL), cool to 0° C. and add BBr3 (0.20 mL, 2.1 mmol), dropwise. After 25 minutes, slowly pour into saturated aqueous sodium bicarbonate (10 mL) and extract with dichloromethane (2×10 mL). Dry the combined organic layers with sodium sulfate and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol (3 to 5%) in dichloromethane with 0.2% ammonium hydroxide to yield 196 mg of the title compound (81%): mass spectrum (ion spray) m/z=572.3 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[CH:26][CH:25]=5)[N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:10][C:9]=2[F:46])=[O:6])[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[CH:26][CH:25]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:10][C:9]=2[F:46])=[O:6])[CH2:2][CH2:3]1
Reactant: CCN(CC)CCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)NC5CC5)c(F)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)NC5CC5)c(F)c4)ncnc3[nH]2)cc1
Yield: 48.1 %

Procedure:
After dissolving 65 mg of N-cyclopropyl-N′-(4-(6-(4-(2-diethylaminoethoxy)-phenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-fluorophenyl)urea in 2 ml of tetrahydrofuran, there was added dropwise 0.5 ml of tetrabutylammonium fluoride (1M tetrahydrofuran solution) and the mixture was refluxed for 3 hours. After returning it to room temperature, water was added, the mixture was stirred, and the precipitated crystals were filtered out, washed with water and ether-hexane (1:1) and dried under reduced pressure to obtain 25 mg of the title compound.
Reaction SMILES: [C:1]1([N:7]([CH2:14][CH2:15][CH2:16]Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[OH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CCOCC.C1(C)C=CC=CC=1>[C:1]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][CH2:16][N:29]2[CH2:28][CH2:27][CH:26]([CH:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[OH:25])[CH2:31][CH2:30]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)C1CCNCC1
Reactant: ClCCCN(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: OC(c1ccccc1)C1CCN(CCCN(c2ccccc2)c2ccccc2)CC1
Yield: 16.6 %

Procedure:
A mixture of 9.8 g. (0.040 moles) of 3-[N,N-diphenylamino]-1-chloropropane, 5.7 g. (0.030 moles) of alpha-phenyl-4-piperidine methanol (preparation described in U.S. Pat. No. 3,029,244 to Lyle, Jr. et al, issued Apr. 10, 1962), 4.2 g. (0.040 moles) of sodium carbonate and 0.5 g. of sodium iodide in 90 ml. of toluene is refluxed for about 18 hours. The reaction mixture is cooled, washed with water, and then shaken with dilute hydrochloric acid. The viscous third layer which falls to the bottom is isolated and shaken with ether and dilute caustic. The resulting ether layer is then washed with water, dried, and passed into a column of silica gel. The product is eluted with ethyl acetate and the product fractions are combined, evaporated, and triturated with isopropyl ether. The resulting crystals are isolated by filtration and recrystallized from ethanol to give 2.0 g of 1-[3-(diphenylamino)propyl]-alpha-penyl-4-piperidine methanol, mp. 129.0°-130.5° C. 1-[3-(Diphenylamino)propyl]-alpha-phenyl-4-piperidine methanol shows approximately no inhibition of 3H-haloperidol binding at 10 n moles concentration and approximately 18% inhibition of hu 3H-haloperidol binding at 100 n moles concentration in the 3H-Haloperidol Receptor Binding Assay.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[F:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[OH-].[Na+]>CN(C)C=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])=[CH:13][CH:12]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
tert-Butyl-2-bromoacetate (1.95 g, 10.0 mmol) was added to a mixture of 4-fluorophenol (1.12 g, 10.0 mmol) and NaOH (400 mg, 10.0 mmol) in N,N-dimethylformamide (15 ml) and stirred at room temperature for 17 hours. The reaction was quenched with H2O (50 ml) and extracted by ethyl acetate (50 ml×3). The combined organic phase was washed with H2O (50 ml×4) and brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 2-(4-fluorophenoxy)acetate (2.16 g, 95%) as yellow oil: LC-MS: 171 [M−55]+.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:12]([C:13]([O:15]CC)=[O:14])[CH2:11][CH2:10][N:9]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[Na+].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[C:21]([O:20][C:18]([N:9]1[CH2:10][CH2:11][C@@H:12]([C:13]([OH:15])=[O:14])[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)[C@H](c2ccccc2)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of the compound (6.3 g) obtained in step 2 in ethanol (60 mL) was added tBuONa (3.63 g), and the mixture was stirred at 90° C. for 1 hr. The reaction mixture was cooled, 8N aqueous sodium hydroxide solution (60 mL) and water (60 mL) were added, and the mixture was stirred at 85° C. for 2 hr. The reaction mixture was cooled, and citric acid (51 g) was added. Ethanol was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (200 mL). The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-IPE-hexane to give (3R*,4R*)-1-(tert-butoxycarbonyl)-3-phenylpiperidine-4-carboxylic acid (5.26 g, 91%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH:13]=[CH2:14])=[CH:8][CH:7]=1.C1(C(C2C=CC=CC=2)=[N:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])C=CC=CC=1.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1.CC([C@@H]1N=C([C]2[C](P(C3C=CC=CC=3)C3C=CC=CC=3)[CH][CH][CH]2)OC1)C.[CH]1[CH][CH][CH][CH]1.[Fe].C1CCN2C(=NCCC2)CC1>[CH2:32]([O:31][C:29]([CH:28]1[CH2:14][CH2:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[F:1])=[CH:7][CH:8]=2)=[N:27]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)c1ccc(OCc2ccccc2F)cc1
Agent: [Fe]
Agent: CC(C)[C@H]1COC([C]2[CH][CH][CH][C]2P(c2ccccc2)c2ccccc2)=N1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1CCC(c2ccc(OCc3ccccc3F)cc2)=N1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
(S)-4-Isopropyl-2-[(S)-2-(diphenylphosphino)ferrocen-1-yl]oxazoline (18.8 mg, 0.039 mmol) and Cu(MeCN)4PF6 (14.5 mg, 0.039 mmol) were added to a dried, nitrogen swept reaction vessel. Anhydrous, degassed, BHT inhibited THF (5.0 mL) was then added and the mixture was stirred for 30 minutes at 20-25° C. The resulting solution was then cooled to −78° C. and a solution of 1-(4-[2-fluorobenzyloxy]phenyl)-2-propen-1-one (P4, 2.0 g, 7.80 mmol) and ethyl N-(diphenylmethylidene)glycinate (2.29 g, 8.58 mmol) in THF (15 mL total volume) was added over 1-2 minutes. After 3-5 minutes, a solution of DBU (5.9 mg, 0.039 mmol) in THF (0.5 mL total volume) was added. The solution was then stirred for 8-12 hours at −78° C. The reaction mixture was then warmed to 0-5° C. and 1 M H2SO4 (aq., 25 mL) was then added. The reaction mixture was then warmed to 20-25° C. and mixed vigorously for 2 hours. The mixture was then poured into a rapidly stirring solution of NaHCO3 (saturated, enough to bring the pH to 7.0). After 5 minutes of stirring, the mixture was extracted twice with TBME and the organic extracts were pooled, dried over Na2SO4, and concentrated to near dryness. The resulting residue was purified by flash column chromatography eluting with 0→40% acetone/hexanes (gradient). Concentration of the fractions containing the title compound gave a crystalline solid (2.23 g, 84% yield).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][C:21](=[O:25])[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cu](I)I>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:22]2[CH2:23][CH2:24][N:19]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:20][C:21]2=[O:25])=[CH:3][CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: COC(=O)c1ccc(I)cc1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2=O)cc1
Temperature: 150 °C

Procedure:
A mixture of 1 g of methyl 4-iodobenzoate, 920 mg of 4-Boc-piperazinone, 1.1 g of potassium carbonate, 32 mg of N,N′-dimethylethylenediamine and 70 mg of copper iodide in 10 mL of toluene was heated to 150° C. in a sealed microwave reactor for 3 h. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (20-80% ethyl acetate/hexane) to afford tert-butyl 4-(4-(methoxycarbonyl)phenyl)-3-oxopiperazine-1-carboxylate. 500 mg of tert-butyl 4-(4-(methoxycarbonyl)phenyl)-3-oxopiperazine-1-carboxylate was hydrolyzed via Procedure M to give 4-(4-(tert-buthoxycarbonyl)-2-oxopiperazin-1-yl)benzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(4-(tert-buthoxycarbonyl)-2-oxopiperazin-1-yl)benzoic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide and brine, dried (MgSO4) and evaporated to afford tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenyl)-3-oxopiperazine-1-carboxylate. 300 mg of crude tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenyl)-3-oxopiperazine-1-carboxylate was treated with TFA (2 mL) containing trace amounts of H2O for 1 h. The reaction mixture was evaporated and the crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopiperazin-1-yl)benzamide. MS (Q1) 407.3 (M)+.
Reaction SMILES: [ClH:1].[C:2]([N:5]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH:11]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:12]2)C)(=O)C.[OH-].[K+]>C(O)COCCO.O>[ClH:1].[ClH:1].[CH3:2][NH:5][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH:11]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:12]2
Reactant: CCCNC1CCc2c(cccc2N(C)C(C)=O)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCNC1CCc2c(cccc2NC)C1

Procedure:
0.50 g (1.92 mmol) of 5-(N-acetyl-N-methyl-amino)-2-n-propylamino-tetraline-hydrochloride (Example 4.7.8) are stirred with 12.5 g (0.22 mol) of potassium hydroxide in 40 ml of diethyleneglycol for 24 hours at 150° C. The mixture is then cooled, diluted with 400 ml of water and extracted three times with ethyl acetate (50, 15 and 15 ml). The combined extracts are washed with 20 ml of water, dried with sodium sulphate and, after the drying agent has been filtered off, concentrated by rotary evaporation, finally at 80° C. under a complete water-jet vacuum. The residue is crystallised as the hydrochloride analogously to Example 4.1.1. The title compound is obtained in a yield of 0.39 g (69.7% of theory) and with a melting point of 245° C. which does not change when recrystallised from ethanol/ether.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([O:41][C:42]1[CH:46]=[CH:45][O:44][N:43]=1)[CH2:20][O:21]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(SCC(N1C(C)=NN=N1)CO)CCCCCCCCCCCCCCC>CO.O1CCCC1>[CH2:1]([S:17][CH2:18][CH:19]([O:41][C:42]1[CH:46]=[CH:45][O:44][N:43]=1)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1ccon1
Agent: CCCCCCCCCCCCCCCCSCC(CO)n1nnnc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCSCC(CO)Oc1ccon1
Yield: 93.5 %

Procedure:
A mixture of 7.30 g (11 mM) of 1-hexadecylthio-2-(3-isoxazolyloxy)-3-triphenylmethoxypropane 5j and 433 mg (2.3 mM) of p-toluenesulfonic acid monohydrate in 150 ml of methanol-tetrahydrofuran (1:1) mixture by the same procedure as described in (81) to give 4.25 g of the titled compound Vj1 (94% yield).
Reaction SMILES: Cl.[CH3:2][Si:3]([C:6]#[C:7][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=1)([CH3:5])[CH3:4].[CH3:14][C@@:15]1([CH2:22][S:23](Cl)(=[O:25])=[O:24])[C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:14][C@:15]1([CH2:22][S:23]([N:11]2[CH2:10][CH:9]=[C:8]([C:7]#[C:6][Si:3]([CH3:4])([CH3:5])[CH3:2])[CH2:13][CH2:12]2)(=[O:25])=[O:24])[NH:16][C:17](=[O:21])[NH:18][C:19]1=[O:20]
Reactant: C[Si](C)(C)C#CC1=CCNCC1
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@]1(CS(=O)(=O)N2CC=C(C#C[Si](C)(C)C)CC2)NC(=O)NC1=O
Temperature: -10 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
4-[(Trimethylsilyl)ethynyl]-1,2,3,6-tetrahydropyridine hydrochloride (3.43 g, 15.9 mmol) was stirred in THF (100 mL) with [(4S)-4-methyl-2,5-dioxoimidazolidin -4-yl]methanesulfonyl chloride (3.39 g, 15 mmol) and cooled in an ice salt bath (temperature about −10° C.). N-Ethyldiisopropylamine (5.13 mL, 30 mmol) in THF (100 mL) was added dropwise over 2 hours and the mixture stirred a further 2 hours. The reaction mixture was washed with water, the aqueous layer extracted into EtOAc (×2), the organic phases combined, washed with 2M HCl (×2), saturated bicarbonate solution (x2), followed by brine, dried (sodium sulphate) and evaporated to give the crude product (5.06 g). This was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[F:23][S:24]([F:37])([F:36])([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29].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.[OH-].[Na+]>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([S:24]([F:37])([F:23])([F:34])([F:35])[F:36])[CH:26]=2)=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
150 mg (0.52 mmol) of the compound of Example 6A, 128 mg (0.52 mmol) of 3-(pentafluoro-λ6-sulphanyl)benzoic acid and 237 mg (0.62 mmol) of HATU were initially charged in 1.8 ml of DMF, 0.11 ml (0.62 mmol) of N,N-diisopropylethylamine were added and the reaction was stirred at RT for 1 h. The reaction was then stirred into 15 ml of 0.1 M aqueous sodium hydroxide solution. After a further 10 min of stirring at RT, the precipitate formed was filtered off, washed with water and dried. This gave 235 mg (83% of theory) of the title compound.