Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:14]Br>>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: Cc1ccc(C(=O)C(C)(C)C)cc1
Product: CC(C)(C)C(=O)c1ccc(CBr)cc1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
To a flask equipped with stirrer, thermometer, condenser, addition funnel and heating mantle, there is added 44.0 grams (0.25 mole) of p-pivaloyl toluene at a temperature of 150°C. There is then added dropwise, while maintaining the temperature at 150°C., 40 grams (0.25 mole) of liquid bromine over a period of 10 to 15 minutes. The mixture is then stirred for an additional 10 minutes again while maintaining the temperature at about 140° to 150°C. The resulting brown liquid is cooled and degassed with nitrogen to obtain α-bromo-4-pivaloyl toluene in liquid form, b.p. 124° to 132°C. at 0.3 mm.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]C)=[CH:5][C:4]=1/[CH:15]=[C:16](\[CH3:20])/[C:17]([OH:19])=[O:18].[N+]([O-])(O)=O>C(OCC)(=O)C.CC(O)=O>[C:3]1(=[O:2])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH:5]=[C:4]1/[CH:15]=[C:16](\[CH3:20])/[C:17]([OH:19])=[O:18]
Reactant: COc1cc(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: C/C(=C\C1=CC(=O)c2ccccc2C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
Following modified procedures of Shinkawa et al. and Flader et al.16,22 the acid 29a (0.114 g, 0.419 mmol) was dissolved in ethyl acetate (10 mL) at room temperature, then HNO3 (1.0 mL) and AcOH (3 drops) were added at room temperature. The reaction was stirred at room temperature for 4 hours before being diluted with ethyl acetate and washed with brine. The organic layer was dried over MgSO4, filtered, and condensed. The yellow oil was then purified by either flash column chromatography (2:3 Et2O:hexanes 0.5% AcOH) or recrystallization from Et2O/hexanes to afford 30a (0.059 g, 0.24 mmol, 58%) as a yellow solid.
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[CH2:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[CH2:15][CH3:16]>CC(C)=O.ClCCl>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[N:17]([CH2:14][CH2:15][CH3:16])[C:11]([NH2:12])=[S:10]
Reactant: CCCNc1ccc(Cl)cc1Cl
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: CCCN(C(N)=S)c1ccc(Cl)cc1Cl
Reaction time: 0.25 h
Yield: 82 %

Procedure:
5.1 ml of benzoyl chloride are added under argon and at 0° C. to 3.4 g of ammonium thiocyanate in 80 ml of anhydrous acetone and the reaction mixture is stirred for 15 minutes. 7.48 g of N-propyl-2,4-dichloroaniline (Compound 5-1) in 60 ml of anhydrous acetone are added and the reaction mixture is stirred for 2 hours at room temperature. It is evaporated to dryness, the residue obtained is taken up in dichloromethane, washed with water and dried. 13.5 g of the expected product are obtained in the form of an oil; yield=82%.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21](O)[CH2:22][CH2:23][OH:24].[PH2](O)=O>>[C:1]([O:20][CH2:3][CH2:2][CH2:1][O:19][C:23](=[O:24])[CH2:22][CH2:21][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)O
Reactant: OCCCO
Agent: O=[PH2]O
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)CCCC/C=C\C/C=C\C/C=C\CCCCC
Temperature: 160 °C
Reaction time: 6 h

Procedure:
z,z,z-6,9,12-Octadecatrienoic acid (available from Sigma Chemicals) (0.180 mol, 50.0 g), propane-1,3-diol (0.086 mol, 6.5 g) and hypophosphorous acid (0.2 g) was heated with stirring to 160° C. under nitrogen. After 6 h, TLC (80:18:2 petroleum ether-ethyl ether-acetic acid) indicated that the reaction had gone to completion (Rf:0.56). The mixture was cooled down to room temperature and petroleum ether (700 mL) was added. The resulting solution was washed with saturated sodium bicarbonate (3×70 mL) and saturated sodium chloride (3×70 mL). It was then dried over anhydrous sodium sulphate and concentrated to dryness. Residual mono-ester and fatty acid were removed by distillation in vacuo (180° C., 10−2 mbar). The resulting oil was dissolved in petroleum ether to make up a 33% solution and was passed down a silica column. Hexane was finally removed to yield 1,3-di-(z,z,z-6,9,12-octadecatrienoyloxy)propane as a colourless oil.
Reaction SMILES: C([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:21])=[C:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]3)[N:13]=2)[C:8](=[O:22])[C:7]([C:23]([O:25]CC)=[O:24])=[CH:6]1)(C)(C)C>Cl>[F:21][C:11]1[CH:10]=[C:9]2[C:14](=[N:13][C:12]=1[N:15]1[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]1)[NH:5][CH:6]=[C:7]([C:23]([OH:25])=[O:24])[C:8]2=[O:22]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CC[C@@H](O)C3)c(F)cc2c1=O
Agent: Cl
Product: O=C(O)c1c[nH]c2nc(N3CC[C@@H](O)C3)c(F)cc2c1=O

Procedure:
A solution of Example 58A (100 mg) in 6M HCl (6 mL) was heated at 90° C. for 28 hours then cooled and concentrated; and the concentrate was recrystallized from methanol.
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C)C=O.[CH:28](O)([CH3:30])C>>[ClH:1].[Cl:1][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[CH2:28][CH3:30])[NH:2][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1
Reactant: CC(C)O
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CN(C)C=O
Product: CCc1ccc(Nc2cc(C)nc3ccc4nc[nH]c4c23)cc1Cl

Procedure:
A 500 ml. 3-neck, r.b. flask fitted with stirrer, condenser and thermometer was charged with the filtrate from Part A, the compound of Example I, C. (44.3 g. 0.204 mole) and an additional 100 ml. dimethylformamide and the mixture was heated at reflux overnight while stirring. The near solution was chilled and the crystals were collected by filtration. The solid was washed with ether (ca. 300 ml.). Crop I was dried at 60°C to yield 46.8 g. straw colored crystals, m.p. 258°-272°C. The ether filtrate was concentrated to near dryness and chilled. Crop II was collected and dried to yield 7.2 g. tan crystals, m.p. 256°-270°C. The reaction filtrate was concentrated to about 200 ml. diluted with ether (100 ml.) and chilled. Crop III was collected and dried to yield 6.8 g. tan crystals, m.p. 120°-130°C. The crude product (Crops, I, II and III) was dissolved in isopropanol (ca. 2800 ml.) and filtered while hot. The filtrate was chilled and the crystals collected by filtration and dried at 60°C to yield 25.3 g. light yellow crystals, m.p. 283°-287° C. The filtrae was concentrated to 1400 ml. by rotary evaporator and chilled. The crystals were collected and dried to yield 8.9 g. light yellow crystals, m.p. 282°-287°C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[C:24]1([CH:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.C(Cl)Cl>[C:34]1([CH:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:31]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:11]2)=[O:32])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3)) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl)-2-methylpropanamide and diphenylacetyl chloride: ESMS m/e: 512.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[O:25][C:26]3[C:35]4[C:34](=O)[CH2:33][CH2:32][C:31]=4[CH:30]=[CH:29][C:27]=3[N:28]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[O:25][C:26]3[C:35]4[C:34](=[CH:5][C:3]#[N:4])[CH2:33][CH2:32][C:31]=4[CH:30]=[CH:29][C:27]=3[N:28]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCc2ccc3nc(CCCCc4ccccc4)oc3c21
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#CC=C1CCc2ccc3nc(CCCCc4ccccc4)oc3c21
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
To a suspension of 60% sodium hydride (19.5 mg, 0.487 mmol) in tetrahydrofuran (2 mL) was added diethyl cyanomethylphosphonate (85.4 μL, 0.528 mmol) under ice-cooling, and the mixture was stirred for 15 min. Thereto was added a solution of 2-(4-phenylbutyl)-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-one (124 mg, 0.406=mol) in tetrahydrofuran (2 mL), and the mixture was further stirred for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. 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=10/90→40/60) to give the title compound (125 mg, yield 94%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:1][CH2:2][CH2:3][C:4]2([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: OCCC1(O)CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 1-(2-hydroxyethyl)cyclohexanol (11.2 g) and pyridine (17 ml) in dichloromethane (100 ml) was added p-toluenesulphonyl chloride (19.5 g). The mixture was then stirred at room temperature under an atomosphere of nitrogen for 3 hours before being partitioned between ether (300 ml) and water. The organic layer was washed consecutively with 4N hydrochloric acid, water, 5% sodium hydrogen carbonate solution, and brine, and dried. Concentration in vacuo gave a residue which was purified by chromatography (500 g silica gel; 20% ethyl acetate in petroleum ether as eluant) to give 1-(2-p-toluenesulphonyloxyethyl)cyclohexanol [E; n=1, R1 +R2 =--(CH2)5 --] as an oil.
Reaction SMILES: [NH2:1][CH:2]([CH:8]([F:10])[F:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>ClCCl>[CH2:15]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH:2]([NH2:1])[CH:8]([F:10])[F:9])[CH3:16]
Reactant: NC(CCC(=O)O)C(F)F
Reactant: CCO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCC(N)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2 mmole of 4-amino-4-difluoromethylbutyric acid in 15 ml of dichloromethane is treated with 2 mmole of thionyl chloride at 25° C. for one hour after which 20 ml of ethanol is added. The solution is stirred at 25° C. for one hour, washed with water, dried and concentrated to afford 4-amino-4-difluoromethylbutyric acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].Cl>O1CCOCC1.CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][NH2:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(-c2cccc(NCCNC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cccc(NCCN)c2)c1
Reaction time: 16 h
Yield: 22 %

Procedure:
To methyl-3′-[(2-[[(tert-butoxy)carbonyl]amino]ethyl)amino]-[1,1′-biphenyl]-3-carboxylate (730 mg) was added 4 N HCl in dioxane (20 mL) and the mixture was stirred under nitrogen for 16 h. The white mixture was diluted with ether, and the dihydrochloride salt of the title compound was collected as a white solid (566 mg) by suction filtration. A portion of this material (128 mg) was partitioned between saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the title compound (117 mg) as a colorless oil. Electrospray MS (positive ion): (M+H) 272
Reaction SMILES: Cl.O1CCOCC1.[Si]([O:25][CH2:26][C@@H:27]1[C@@H:31]([CH2:32][O:33][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:30][CH2:29][C@H:28]1[N:51]1[CH:59]=[N:58][C:57]2[C:52]1=[N:53][CH:54]=[N:55][C:56]=2[NH2:60])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CO>[OH:25][CH2:26][C@@H:27]1[C@@H:31]([CH2:32][OH:33])[CH2:30][CH2:29][C@H:28]1[N:51]1[CH:59]=[N:58][C:57]2[C:52]1=[N:53][CH:54]=[N:55][C:56]=2[NH2:60]
Reactant: CC(C)(C)[Si](OC[C@H]1CC[C@@H](n2cnc3c(N)ncnc32)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncnc2c1ncn2[C@@H]1CC[C@H](CO)[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
4N-Hydrochloric acid/dioxane (0.17 ml, 0.68 mmole) was added to a solution of 9-[(1R,2R,3S)-2,3-bis-(t-butyldiphenylsilyloxymethyl)-1-cyclopentyl]-adenine (129 mg, 0.17 mmole) in methanol (1 ml). After stirring the mixture at room temperature overnight, solvent was distilled off from the reaction mixture under reduced pressure, after which water was added to the residue, ether-soluble material was removed therefrom, the residual solution was neutralized with 0.1N solution of sodium hydroxide, and solvent was distilled off therefrom. The residue was purified by Diaion HP-20 column chromatography (methanol concentration gradient) to obtain 9-[(1R,2R,3S)-2,3-bis(hydroxymethyl)-1-cyclopentyl]-adenine (43 mg, Yield 94%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20].C(OCC)(=O)C>COC(C)C(O)=O>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNc1ccc(C(=O)O)cc1
Agent: COC(C)C(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of methoxypropionic acid is heated to 100° C. The mixture is maintained and stirred at this temperature for 1 hour. After completion of the reaction, the mixture is cooled and 5 ml of ethyl acetate are added. The resulting mixture is stirred for 10 minutes, then it is filtered and the crystals are washed with ethyl acetate. After drying, 0.66 g of raw deferasirox is obtained, i.e. 60% of the theory, with an HPLC content of 99.3% and a melting temperature of 259 to 263° C.
Reaction SMILES: C(OC([N:8]1[C:12]([CH2:13][CH:14]([C:28]([S:30][CH2:31][CH:32]([NH:37][C:38](=[O:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[O:29])[NH:15][C:16](=[O:27])[CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)=[CH:11][N:10]=[CH:9]1)=O)(C)(C)C.[ClH:41]>O1CCOCC1>[ClH:41].[ClH:41].[C:38]([NH:37][C@@H:32]([CH2:31][S:30][C:28](=[O:29])[C@@H:14]([NH:15][C:16](=[O:27])[CH2:17][CH2:18][NH2:19])[CH2:13][C:12]1[NH:8][CH:9]=[N:10][CH:11]=1)[C:33]([O:35][CH3:36])=[O:34])(=[O:40])[CH3:39]
Reactant: COC(=O)C(CSC(=O)C(Cc1cncn1C(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)NC(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](CSC(=O)[C@H](Cc1cnc[nH]1)NC(=O)CCN)NC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-[2-(2-Acetylamino-2-methoxycarbonyl-ethylsulfanylcarbonyl)-2-(3-tert-butoxycarbonylamino-propionylamino)-ethyl]-imidazole-1-carboxylic acid tert-butyl ester (46a, 0.1028 g, 0.175 mmol) in dry dioxane (2 mL) was added dropwise to 4N HCl in dioxane (5.0 mL, 114 mmol) and the mixture was stirred about 2 hours at room temperature. The reaction mixture was concentrated to dryness and residual volatiles removed in high vacuum. The product was obtained as a white solid. MS: (M+1)+=386.1. 1H NMR (DMSO-d6) δ 9.15 (bm, 1H), 9.11 (s, 1H), 8.48 (bs, 1H), 8.00 (bm, 3H), 7.44 (bs, 1H), 4.69 (bm, 1H), 4.37 (bm, 1H), 3.64-3.56 (bm, 5H), 3.4-3.1 (bm, number of protons obscured by water peak and residual dioxane), 2.93 (bs, 2H), 2.58 (bm, 2H), 1.85, (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:31]=[CH:30][C:25]([C:26](NC)=O)=[CH:24][CH:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:53][C:54]([CH3:58])([CH3:57])[CH2:55][OH:56]>C(Cl)Cl.O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:22]2[CH:23]=[CH:24][C:25]([C:26]3[O:56][CH2:55][C:54]([CH3:58])([CH3:57])[N:53]=3)=[CH:30][CH:31]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: CNC(=O)c1ccc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(C2(c3ccc(C4=NC(C)(C)CO4)cc3)CCN(Cc3ccccc3)CC2)c1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-N-methyl-benzamide (1.01 g, 2.44 mmol), in CH2Cl2 (24 mL) was added pyridine (0.30 mL, 3.71 mmol). The reaction was cooled to −50° C. and triflic anhydride (0.45, 2.67 mmo) was added dropwise over 1 minutes. The reaction was stirred at −50° C. for 1.5 hours and at room temperature for 0.5 hours. The mixture was cooled to −50° C. and 2-amino-2-methyl propanol (0.36 mL, 3.77 mmol) was added. The reaction was allowed to warm to room temperature and stirred at room temperature for 16 hours. To the mixture was added water (5 mL) and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined extracts were dried (MgSO4) and concentrated. Purification by flash chromatography with hexanes/EtOAc (1:1) afforded 0.75 g (68% yield) of 1-Benzyl-4-[4-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-4-(3-methoxy-phenyl)-piperidine. 1HNMR (400 MHz, CDCl3) δ; 7.83 (d, 2H), 7.38-7.21 (comp, 7H), 7.18 (t, 1H), 6.81-6.75 (comp, 2H), 6.63 (d, 1H), 4.08 (s, 2H), 3.78 (s, 3H), 3.41 (s, 2H), 2.79-2.40 (comp, 8H), 1.38 (s, 3H); MS (M+1) 454.2.
Reaction SMILES: [CH:1]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.Cl[CH2:24][C:25]1[CH:26]=[C:27]([CH:38]=[CH:39][CH:40]=1)[C:28]([NH:30][C:31]([CH3:37])([CH3:36])[C:32]([F:35])([F:34])[F:33])=[O:29].C(N(CC)CC)C.[I-].[Na+]>O1CCCC1.C(OCC)(=O)C.C(#N)C>[CH:1]1([NH:5][C:6](=[O:7])[NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([CH2:24][C:25]4[CH:26]=[C:27]([CH:38]=[CH:39][CH:40]=4)[C:28]([NH:30][C:31]([CH3:37])([CH3:36])[C:32]([F:33])([F:35])[F:34])=[O:29])[CH2:21][CH2:22]3)=[O:16])=[CH:13][CH:14]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(NC(=O)c1cccc(CCl)c1)C(F)(F)F
Reactant: O=C(Nc1ccc(C(=O)N2CCNCC2)cc1)NC1CCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)cc3)CC2)c1)C(F)(F)F
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To 1-cyclobutyl-3-(4-(piperazine-1-carbonyl)phenyl)urea (0.165 mmol, 50 mg) in tetrahydrofuran (1654 μl) was added 3-(chloromethyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide (0.182 mmol, 50.9 mg) and triethylamine (0.496 mmol, 69.1 μl, 50.2 mg). The reaction was heated to reflux and stirred for 30 minutes then acetonitrile (0.5 mL) and sodium iodide (catalytic amount) were added. After 3 hours stirring, ethyl acetate was added and the organic mixture was washed with water and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure. This material was lyophilised to give the title compound (81 mg). MS (ESI) m/z 546.5 [M+H]+
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(OCC)C>[N:15]1([CH2:2][CH2:3][C:4]2[CH:14]=[CH:13][CH:12]=[C:6]3[C:7]([NH:9][C:10](=[O:11])[C:5]=23)=[O:8])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=C1NC(=O)c2c(CCBr)cccc21
Reactant: C1COCCN1
Solvent: CCOCC
Product: O=C1NC(=O)c2c(CCN3CCOCC3)cccc21
Temperature: 25 °C
Yield: 52.1 %

Procedure:
2-Bromoethylphthalimide (508 mg; 2.0 mmoles) and morpholine (0.35 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). The mixture was allowed to stir at room temperature for 30 hours approx. The reaction was discontinued by solvent evaporation under reduced pressure. The obtained residue was purified by chromatography on silica gel (CH2Cl2 /MeOH 95:5) yielding 271 mg of pure product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[C:5]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)[CH3:2].[C:41]([O-:44])(=[O:43])[CH3:42].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(#N)C>[CH2:1]([O:3][C:4](=[O:40])[C:5]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:43][C:41](=[O:44])[CH3:42])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:40][C:4](=[O:3])[CH3:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCCCCCCCCCCBr)c(C(=O)OCC)cc1OCCCCCCCCCCBr
Reactant: CC(=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OCCCCCCCCCCOC(C)=O)c(C(=O)OCC)cc1OCCCCCCCCCCOC(C)=O

Procedure:
46.4 g (67.0 mmol) diethyl-2,5-bis-(10-bromodecoxy)terephthalate, 65.8 g (671 mmol) potassium acetate and 3.4 g (8.5 mmol) Aliquat 336® in 350 ml absolute acetonitrile are heated under N2 under reflux for 48 hours. After distilling off the solvent, the reaction mixture is taken up in 300 ml chloroform, insoluble salts are filtered off and the filtrate is washed twice with 150 ml water. The organic phase is dried over Na2SO4 and the solvent is then distilled off. 300 ml petroleum ether are added to the remaining, oily residue, the product crystallising out after 16 hours at -20° C. It is then recrystallized from ethanol.
Reaction SMILES: C([C:5]1[CH:12]=[C:11]([O:13][CH3:14])[C:8]([C:9]#[N:10])=[C:7]([CH3:15])[C:6]=1[C:16](=[O:25])[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:14][O:13][C:11]1[C:8]([C:9]#[N:10])=[C:7]([CH3:15])[C:6]([C:16](=[O:25])[CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][C:19]2=[O:24])=[CH:5][CH:12]=1
Reactant: COc1cc(C(C)(C)C)c(C(=O)CN2CCNCC2=O)c(C)c1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)CN2CCNCC2=O)c(C)c1C#N
Reaction time: 0.33 h

Procedure:
To a flask was added tert-Butyl 6-methoxy-2-methyl3-[{2-oxopiperazin-1-yl}acetyl]benzonitrile (0.060 g, 0.15 mmol) followed by addition of TFA (2 mL) and a stir bar; the resulting mixture was stirred for 20 minutes. Analysis of the reaction mixture by LC indicated that reaction had gone to completion. The solution was concentrated in vacuo and the crude was co-evaporated with dichloroethane (3×8 mL) to furnish the title product. LC/MS (IE, m/z): [M+1]+=288.