Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)=[N:4][C:5](Cl)=[C:6]([Cl:8])[CH:7]=1.[CH2:21]([OH:24])[C:22]#[CH:23]>C(N(CC)CC)C>[F:1][C:2]1[C:3]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)=[N:4][C:5]([C:23]#[C:22][CH2:21][OH:24])=[C:6]([Cl:8])[CH:7]=1
Reactant: C#CCO
Reactant: Cn1nc(-c2nc(Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Solvent: CCN(CC)CC
Product: Cn1nc(-c2nc(C#CCO)c(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 67 °C
Reaction time: 8 h

Procedure:
2.0 of 3-(3-fluoro-5,6-dichloro-2-pyridyl)-4-chloro-5difluoromethoxy-1-methyl-[1H]-pyrazole (Example H21) are initially introduced into 15 ml of triethylamine, and 0.37 ml of propargyl alcohol is added. The mixture is then evacuated and gassed with argon 3 times under a partial water pump vacuum. Thereafter, 0.03 g of copper(I) iodide and 0.12 g of bis-triphenylphosphine-palladium dichloride (PdCl2(PPH3)2) are added and the mixture is stirred overnight at 67° C. under argon. The following day, after cooling to 22° C., 0.20 ml of propargyl alcohol, 0.03 g of copper(l) iodide and 0.12 g of PdCl2(PPH3)2 are added. The mixture is then stirred at 67° C. for 6 hours. After cooling to 22° C., ethyl acetate is added and the mixture is washed successively with dilute hydrochloric acid, water and brine. After drying over sodium sulfate, filtration and concentration in vacuo, the residue is purified over a silica gel flash column (eluting agent: n-hexane/ethyl acetate 1/1). 0.97 g of the desired title compound is obtained as a yellow oil which gradually crystallizes; melting point 92-94° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17]>CN(C=O)C>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:1]2[CH2:6][CH2:5][CH2:4][NH:3][C:2]2=[O:7])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=C1NCCCN1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCCN1Cc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (4 g, 0.04 mol) in abs. DMF (50 mL) there were added potassium carbonate (5.5 g, approximately 0.04 mol), potassium iodide (3.3 g, 0.02 mol), and 4-nitrobenzyl bromide (8.6 g, 0.04 mol) at RT. The reaction mixture was stirred at 100° C. over a period of 2 h. Following cooling of the reaction mixture, it was added to ice water (500 mL). The precipitated solid matter was filtered off in vacuo and washed with a little acetyl (4×10 mL). The desired product 1-(4-nitrobenzyl)tetrahydropyrimidin-2-one (H) was obtained as yellow solid matter (3.5 g, 40% of theory) having a melting point of 150-162° C.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[N:12]1[CH:11]=[CH:10][CH:9]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]=1[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: OB(O)c1ccncc1
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: COCCOC
Solvent: O
Product: CCOC(=O)c1cccnc1-c1ccncc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A mixture of ethyl 2-chloronicotinate (16.2 g), pyridine-4-boronic acid (12.9 g), sodium carbonate (27.8 g), tetrakis(triphenylphosphine)palladium(0) (5.04 g), water (50.0 mL) and DME (250 mL) was stirred overnight at 100° C. under a nitrogen atmosphere. The reaction mixture was diluted with water, 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. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (14.1 g).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[C:9]([C:10]#[N:11])[C:5]=2[CH:4]=[N:3][CH:2]=1.[C:12]([C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[C:22](=[O:27])[N:21]([C:28]1[C:36]3[CH2:35][O:34]B(O)[C:32]=3[CH:31]=[CH:30][CH:29]=1)[N:20]=[CH:19]2)([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1.ClC(Cl)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:12]([C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[C:22](=[O:27])[N:21]([C:28]1[C:36]([CH2:35][OH:34])=[C:32]([N:7]3[C:6]4[N:1]=[CH:2][N:3]=[CH:4][C:5]=4[C:9]([C:10]#[N:11])=[CH:8]3)[CH:31]=[CH:30][CH:29]=1)[N:20]=[CH:19]2)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc4c3COB4O)ncc2c1
Reactant: N#Cc1c[nH]c2ncncc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5cncnc54)c3CO)ncc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
In a 25 mL round-bottomed flask, 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (40.9 mg, 284 μmol, Eq: 1.00), 6-tert-butyl-8-fluoro-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)phthalazin-1(2H)-one (100 mg, 284 μmol, Eq: 1.00), copper acetate (34.8 mg) and pyridine (44.9 mg, 45.9 μl, 568 μmol, Eq: 2) were combined with dichloroethane to give a dark blue suspension. The reaction mixture was flushed with nitrogen. The reaction mixture was heated to 80° C. and stirred for 16 hr. The reaction was diluted with sat NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The mixture was separated by flash column using 30-50% EtOAc in hexanes to give the 7-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (42 mg, 31%) as a lyophilized white powder.
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[C:4]([O:13][CH2:14][CH3:15])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[CH2:14]([O:13][C:4]1[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]([CH3:12])=[C:2]([N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)[C:3]=1[CH3:16])[CH3:15]
Reactant: CCOc1c(C)c(Br)c(C)c2c1OC(C)C2
Reactant: COc1ccc(N2CCNCC2)cc1
Product: CCOc1c(C)c(N2CCN(c3ccc(OC)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 48.5 %

Procedure:
By using 5-bromo-7-ethoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran (570 mg, 2.0 mmol) synthesized in Reference example 84 and 1-(4-methoxyphenyl)piperazine (768 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 21 to synthesize the title compound 385 mg (yield 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.N1C=CC=CC=1.P(Br)(Br)[Br:26]>C1(C)C=CC=CC=1>[Br:26][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(Br)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
Bis(4-methoxyphenyl)methanol (2.0 g, 8.2 mmol) was dissolved in toluene (60 mL) and pyridine (661 μL, 8.2 mmol)) was added. The solution was cooled to 0° C. PBr3 (768 μL, 8.2 mmol) was added dropwise over 15 min. The reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was washed with K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to give the crude product 4,4′-(bromomethylene)bis(methoxybenzene) (780 mg, 31%), as a colourless oil. This was used in the next reaction step without further purification. Sodium ethoxide (133 mg, 1.96 mmol) was added to DMF (5 mL) at 0° C., and the suspension was stirred for 10 min. 7-hydroxy-4-methylcoumarin (345 mg, 1.96 mmol) was slowly added and resulting mixture was stirred at this temp for 0.5 h. To this mixture 4,4′-(bromomethylene)bis(methoxybenzene (500 mg, 1.63 mmol) was added portionwise. Resulting reaction mixture was stirred at room temperature for 16 h. DMF was evaporated off in-vacuo and the residue was taken up in EtOAc, and washed with brine, water and 1M NaOH (2×30 mL). The organic layer was dried (MgSO4) and product was purified by flash chromatography, eluting with hexane:EtOAc (2:1) to give 49 (100 mg, 15%) as a white solid. Mpt=142-145° C. m/z=403 (M+H). H1 NMR (500 MHz, acetone-d6): δ=7.60 (1H, d, ArH), 7.45 (4H, d, ArH), 7.04 (1H, d, ArH), 6.94 (5H, d, ArH), 6.56 (1H, s ArH), 6.10 (1H, s, qCH), 3.78 (6H, s, 2×CH3O), 2.39 (3H, s, CH3). 13C NMR (500 MHz, acetone-d6, DEPT 135): δ=206.3 (qC), 134.1 (2×qC), 129.3 (2×CH), 129.2 (2×CH), 129.0, (2×CH), 126.9 (Ar CH), 114.4 (Ar CH), 114.7 (Ar CH), 115.1 (Ar CH), 112.5 (Ar CH), 104.0 (Ar CH), 81.7 (CH), 55.6 (2×CH3), 18.2 (CH3).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:33][CH:30]1[CH2:32][CH2:31]1)=[O:6]
Reactant: NC1CC1
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: Nc1c(Br)cccc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a heterogenous mixture of 2-amino-3-bromobenzoic acid (Sigma-Aldrich; 8.00 g, 37.0 mmol) in EtOAc (80 mL) at 0° C. was added 1-propanephosphonic acid cyclic anhydride (T3P) (Alfa-Aesar; 50 wt. % solution in EtOAc, 24.00 mL, 40.7 mmol) followed by cyclopropylamine (2.57 mL, 37.0 mmol). The ice bath was removed and the reaction was stirred at RT for 1 h. Saturated NaHCO3 (aq.) was added and the mixture was stirred for 5 minutes. The layers were separated and the organic layer was washed with saturated NaHCO3 (aq.) and brine. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to afford 2-amino-3-bromo-N-cyclopropylbenzamide (723a; 6.00 g, 23.52 mmol, 64% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.50 (dd, J=7.82, 1.37 Hz, 1H), 7.20 (dd, J=7.92, 1.27 Hz, 1H), 6.50 (t, J=7.82 Hz, 1H), 6.13 (br. s., 2H), 2.85 (tq, J=7.02, 3.54 Hz, 1H), 0.83-0.91 (m, 2H), 0.57-0.64 (m, 2H). m/z (ES, +ve) 255.1, 257.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][NH:11][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]([CH:27](O)[O:28]C)([F:26])([F:25])[F:24]>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:27]([OH:28])[C:23]([F:26])([F:25])[F:24])=[CH:12][NH:11][C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Reactant: COC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1OCc1ccccc1
Temperature: 120 °C
Yield: 37.8 %

Procedure:
3-Benzyloxy-2-methyl-1H-pyridin-4-one (1 g, 4.64 mmol) was mixed with potassium carbonate (0.2 g, 1.45 mmol) and CF3CH(OCH3)OH (4.34 g, 33.36 mmol) in sealed parallel synthesizer reactor and heated at 120° C. metal block temperature for 2 days. The mixture was cooled, and an additional amount of potassium carbonate (2 g, 14.5 mmol) and CF3CH(OCH3)OH (2 g, 15.30 mmol) was added. The mixture was again heated in a sealed tube at 120° C. for 60 hours. The mixture was cooled to room temperature and then evaporated to dryness. The residual material was purified by column chromatography (5% MeOH:dichloromethane) to give 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (0.55 g, 37.8% yield).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])C=C.F[C:13]1[CH:18]=CC=C[C:14]=1O.C(Br)C=C>CCOCC>[CH2:18]([C:10]1[C:5]([OH:4])=[C:6]([F:11])[CH:7]=[CH:8][CH:9]=1)[CH:13]=[CH2:14]
Reactant: Oc1ccccc1F
Reactant: C=CCOc1ccccc1F
Solvent: C=CCBr
Solvent: CCOCC
Product: C=CCc1cccc(F)c1O
Yield: 80 %

Procedure:
Other workers have prepared o-fluorophenyl allyl ether in a 90.5-93% yield from o-fluorophenol and allyl bromide. Thereafter using a thermal Claisen rearrangement of the ether gave 6-allyl-2-fluorophenol in an 80% yield. However, attempts to oxidize this last named compound to 3-fluorosalicylaldehyde using dichromate solutions gave no reproducible results, i.e., a 55% yield from the first experiment but less than 5% in subsequent runs.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][Br:9])[C:3](Br)=[O:4].[C:10]([O:13][CH:14]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[CH2:15][NH:16][C:17]([C:19]1[C:24]([I:25])=[C:23]([NH2:26])[C:22]([I:27])=[C:21]([C:28]([NH:30][CH2:31][CH:32]([O:38][C:39](=[O:41])[CH3:40])[CH2:33][O:34][C:35](=[O:37])[CH3:36])=[O:29])[C:20]=1[I:42])=[O:18])(=[O:12])[CH3:11]>CN(C)C(=O)C>[C:10]([O:13][CH:14]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[CH2:15][NH:16][C:17]([C:19]1[C:24]([I:25])=[C:23]([NH:26][C:3](=[O:4])[CH:2]([Br:1])[CH2:6][CH2:7][CH2:8][Br:9])[C:22]([I:27])=[C:21]([C:28]([NH:30][CH2:31][CH:32]([O:38][C:39](=[O:41])[CH3:40])[CH2:33][O:34][C:35](=[O:37])[CH3:36])=[O:29])[C:20]=1[I:42])=[O:18])(=[O:12])[CH3:11]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reactant: O=C(Br)C(Br)CCCBr
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)C(Br)CCCBr)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reaction time: 1 h
Yield: 95.5 %

Procedure:
2,5-Dibromopentanoyl bromide (11 g, 34 mmol) was added dropwise to a stirred solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (23.0 g, 26.3 mmol) in N,N-dimethylacetamide (240 ml) at 0°. After the addition, the reaction mixture was stirred at 0° for 1 hour, and then at room temperature for 20 hours. The solvent was removed in vacuo at 45° and the resulting solid was dissolved in ethyl acetate (400 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (1×70 ml), water (1×70 ml) and saturated sodium chloride (1×70 ml). After drying over magnesium sulfate, the solvent was removed in vacuo to obtain a yellow residue (28 g). Purification by column chromatography over silica gel furnished pure N,N'-bis[2,3-bis(acetyloxy)propyl]-5-[(2,5-dibromo-1-oxopentyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide as an off-white crystalline compound (20.2 g, yield 69%).
Reaction SMILES: [CH2:1]([S:8][C@H:9]1[N:12]([CH2:13][C:14]([OH:16])=O)[C:11](=[O:17])[C@@H:10]1[Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:14](=[O:16])[CH2:13][N:12]2[C@H:9]([S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([Cl:18])[C:11]2=[O:17])=[CH:24][CH:25]=1
Reactant: NCCCCCCc1ccc(F)cc1
Reactant: O=C(O)CN1C(=O)[C@H](Cl)[C@H]1SCc1ccccc1
Product: O=C(CN1C(=O)[C@H](Cl)[C@H]1SCc1ccccc1)NCCCCCCc1ccc(F)cc1
Yield: 85 %

Procedure:
Treatment of (3S,4R)-(4-benzylthio-3-chloro-2-oxoazetidin-1-yl)acetic acid with 6-(4-fluorophenyl)hexylamine under the conditions described for Example 86 gave the title compound as a colourless oil, 85% yield. 1H NMR δ (CDCl3) 1.3-1.6 (8H, m, 4xCH2), 2.56 (2H, t, J=7.6 Hz, CH2Ph), 3.22 (2H, m, NHCH2), 3.51, 3.81 (each 1H, d, J=16.5 Hz, NCH2), 3.83 (2H, s, SCH2), 4.58 (1H, d, J=1.7 Hz, H4), 4.79 (1H, d, J=1.7 Hz, H3), 5.80 (1H, m, NH), 6.95 (2H, m, 4-FPh--H), (2H, m, 4-FPh--H), 7.30 (5H, m. Ph--H)
Reaction SMILES: [C:1]([C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:20][C:21]1[CH:22]=[C:23]([OH:28])[C:24](=[CH:26][CH:27]=1)O.Cl>C1C=CC=CC=1.C(OCC)C>[CH3:20][C:21]1[CH:27]=[CH:26][C:24]2[O:8][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:28][C:23]=2[CH:22]=1
Reactant: Cc1ccc(O)c(O)c1
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)C1(c2ccccc2)Oc2ccc(C)cc2O1
Temperature: 25 °C
Yield: 15.7 %

Procedure:
To a solution of ethyl benzoylformate (520 mg, 2.92 mmoL) in dry benzene 5 mL) was added PCl5 (608 mg, 1.0 equiv). After stirring at reflux for 16 h TLC analysis indicated that all the starting material appeared consumed. The solvent was removed in vacuo and the crude dichloride (Rf=0.61 6:1 hexane/ethyl acetate) was mixed with 4-methyl-catechol (724 mg 2.0 equiv) and heated to 175° C. until HCl evolution ceased (ca. 20 min). The mixture was cooled to rt and the glue-like material was dissolved in diethyl ether and washed several times with 1N NaOH and then brine. The organic was dried over anhydrous MgSO4 and concentrated in vacuo and the residue was chromatographed on a silica column eluting with hexane/ethyl acetate (20:1). Removal of the solvent afforded 130 mg (16%) of the titled compound. Rf=0.57 (6:1 hexane/ethyl acetate).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([N:3]([O:4][CH3:5])[CH3:2])=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
While under argon, a solution of N,O-dimethylhydroxylamine hydrochloride (16.9 g, 0.173 mol) and triethylamine (53 mL, 0.381 mol) in dichloromethane (240 mL) was carefully treated with 4-chlorobutyryl chloride (20 g, 0.19 mol) over 40 minutes. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The solid triethylamine hydrochloride was removed by filtration and the remaining solution was washed successively with aq 2 N HCl (×2), 1M K2CO3 and saturated aqueous sodium chloride. The organic layer was dried over MgSO4, filtered and concentrated to give 4-chloro-N-methoxy-N-methylbutanamide (21.8 g) of crude yellow oil that was used in the next step without further purification. ESI MS found for C6H12ClNO2 m/z [166.0/168.0 (M+1)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])([OH:12])[C:9]([OH:11])=O.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:33]=[CH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([OH:12])[C:9]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:33]=[CH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1)=[O:11]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C(O)(c1ccccc1Cl)c1ccccc1Cl
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(O)(c2ccccc2Cl)c2ccccc2Cl)CC1

Procedure:
Example 158 was prepared from bis(2-chlorophenyl)(hydroxy)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1 H), 7.43–7.18 (m, 11 H), 7.05 (d, 1 H, J=8.0 Hz), 5.03 (s, 1 H), 3.60–3.49 (m, 2 H), 3.03–2.91 (m, 2 H), 2.71–2.54 (m, 1 H), 2.54–2.37 (m, 3 H), 2.25 (s, 3 H), 2.08–1.91 (m, 2 H), 1.84–1.63 (m, 4 H), 1.63–1.50 (m, 2 H), 1.17 (d, 6 H, J=6.8 Hz); ESMS m/e: 596.3 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)(O)[O-].[Na+]>>[CH3:1][N:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCCCCBr
Reactant: CNc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CCCCCN(C)c1ccccc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 72.5 %

Procedure:
A mixture of N-methylaniline (25 g) and ethyl 6-bromohexanoate (50 g) was stirred at 120° C. for 24 hours. After cooling, an aqueous sodium bicarbonate was added to make the mixture alkaline. Then the resulting mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and distilled to obtain ethyl 6-(N-methylanilino)hexanoate (40.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(OCCCCC)(=O)C>O>[ClH:13].[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCOC(C)=O
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a 125 mL 3 neck flask with mechanical stirring, condenser, and a heating apparatus consisting of an RTD probe hooked via a temperature controller to a heating mantle, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g β-chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 mL amyl acetate. The mixture was heated in an oil bath under nitrogen to 115° C.-120° C. for 4 hour. HPLC indicated that the reaction was complete. The mixture was then cooled to ambient temperature and 40 mL of deionized water were added to dissolve solids. The aqueous layer was separated and discarded and the water wash was repeated. 5 mL of the organic phase was removed as an analytical standard. 25 mL 8N hydrochloric acid was added to remaining organic phase to extract the intermediate. The layers were separated and the acidified aqueous layers returned to the reaction flasks. The organic phase was discarded. The aqueous phase was heated to 95° C. until HPLC indicated complete hydrolysis of the ester (about 4 hours). The mixtures were cooled to 0° C.-5° C. for 1 hour and filtered. The filter cakes were rinsed with acetone (approx. 25 mL) and dried. Yield 12.61 g (83.6% theoretical).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:19]1[CH:24]=[C:23]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=[O:28])[CH:22]=[N:21][CH:20]=1.[F:33][C:34]([Si](C)(C)C)([F:36])[F:35].Cl>C1COCC1>[F:33][C:34]([F:36])([F:35])[CH:27]([C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[C:23]1[CH:24]=[N:19][CH:20]=[N:21][CH:22]=1)[OH:28]
Reactant: O=Cc1ccccc1-c1cncnc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccccc1-c1cncnc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
Tetrabutylammonium fluoride (TBAF, 0.1 ml of 1M in THF) was added to a solution of 2-pyrimidin-5-yl-benzaldehyde (184 mg, 1 mmol) and trifluoromethyl trimethylsilane (TMSCF3, 0.2 ml, 1.2 mmol) in 10 ml THF at 0° C. The mixture was warmed up to room temperature and stirred for 4 hours. The mixture was then treated with 3 ml of 1M HCl and stirred overnight. The product was extracted with ethyl acetate (3×20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 0.21 g of 2,2,2-trifluoro-1-(2-pyrimidin-5-yl-phenyl)-ethanol (yield: 84%), which was directly used in next step without purification.