Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH:9]1(/[CH:14]=[C:15](\I)/[C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1(/[CH:14]=[C:15](\[C:2]2[CH:7]=[N:6][C:5]([F:8])=[CH:4][CH:3]=2)/[C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)/C(I)=C/C1CCCC1
Reactant: Fc1ccc(Br)cn1
Product: COC(=O)/C(=C/C1CCCC1)c1ccc(F)nc1

Procedure:
Reaction of 5-bromo-2-fluoropyridine (1.50 g, 8.5 mmol) with (Z)-methyl 3-cyclopentyl-2-iodoacrylate (2.60 g, 9.3 mmol), according to the cross-coupling conditions described above in Step 2 of Preparation 9, gave (E)-methyl 3-cyclopentyl-2-(6-fluoropyridin-3-yl)acrylate: m/z (ES+)=250.1 [M+H]+. Step 2: A solution of this α,β-unsaturated ester (1.50 g, 6.0 mmol) in EtOAc was treated with a suspension of Pd (10% on C, 300 mg, 0.3 mmol) in EtOH (0.5 mL). The reaction was stirred under a H2 atmosphere for 4 d and then filtered through Celite. The solvents were removed under reduced pressure, then the residue was purified by column chromatography to give methyl 3-cyclopentyl-2-(6-fluoropyridin-3-yl)propionate: m/z (ES+)=252.2 [M+H]+. Step 3: A solution of this ester (1.48 g, 5.9 mmol) and LiOH.H2O (0.49 g, 11.8 mmol) in THF-H2O (5:1, 24 mL) was stirred at 20° C. for 18 h. The THF was removed in vacuo, then the remainder was partitioned between saturated aqueous Na2CO3 (150 mL) and Et2O (75 mL). The pH of the aqueous layer was adjusted to 3 with 2M HCl. The remainder was extracted with EtOAc (100 mL+75 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated to give the title compound: m/z (ES+)=238.1 [M+H]+.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C1C(=O)N(Br)C(=[O:14])C1.C([O-])(O)=O.[Na+]>O>[CH3:8][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ccccc1
Yield: 95.9 %

Procedure:
Methyl phenyl sulphide (20 g, 161.03 mmol) was added to a mixture of methanol (100 ml) and water (20 mL). NBS (34.39 g, 1.2 eq) was added in portions maintaining the temperature between 0° and 5° C. The mixture was stirred at the same temperature until the reaction was complete. Thereafter, the reaction mixture was quenched by the addition of Na2SO3 (10%, 60 ml). The pH of the resulting reaction mixture was adjusted to a value between 7 and 8 with saturated NaHCO3 solution. The mixture was concentrated under vacuum at a temperature between 20° C. and 25° C. The residue was extracted with dichloromethane (2×125 mL). The combined organic layer was washed with water (2×125 mL) and concentrated to 1/3 of the volume. Heptane (20 mL) was added and then removed by distillation to give 21.64 g (95.9%) of the desired product as colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([O:6][CH2:21][CH:20]=[CH2:19])=[O:5]
Reactant: C=CCBr
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of 2,4,6-trimethylbenzoic acid (10 g, 61 mmol) in DMF (100 mL) were sequentially added potassium carbonate (17 g, 122 mmol) and allyl bromide (11 g, 91.5 mmol). The mixture was stirred at rt overnight before it was poured into water (˜1 L). The resulted precipitate was filtered and washed with water, then dried in vacuo to give allyl 2,4,6-trimethylbenzoate as a solid (10.2 g, 82%) which was nitrated and then reduced as shown for Example 14 (procedure B and C) to give allyl 3-amino-2,4,6-trimethylbenzoate.
Reaction SMILES: C[Mg]Br.O1CCC[CH2:5]1.CCOC([C@H:14]1[CH2:18][CH2:17][C@@H:16]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[N:15]1C(OC(C)(C)C)=O)=O.[Cl-].[NH4+].C([O:40][CH2:41][CH3:42])(=O)C>>[F:25][C:23]1[CH:24]=[C:19]([C@H:16]2[NH:15][C@@H:14]([C:41]([OH:40])([CH3:42])[CH3:5])[CH2:18][CH2:17]2)[CH:20]=[C:21]([F:27])[C:22]=1[F:26]
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1C(=O)OC(C)(C)C
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere and under ice-cooling, methyl magnesium bromide (20.7 mL, 0.97M tetrahydrofuran solution) was added dropwise into a tetrahydrofuran (50 mL) solution of (2R,5S)-5-(3,4,5-trifluorophenyl)pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-ethyl ester (2.5 g). After stirring for 2 hours at the same temperature, ammonium chloride aqueous solution and ethyl acetate were added, and the organic layer was partitioned. The organic layer was washed with brine and was dried with magnesium sulfate, and the solvent was removed under a vacuum. Ethyl acetate (7 mL) and 4 N hydrochloric acid/ethyl acetate (20 mL) were added to the residue, and stirring was continued for 1 hour at room temperature. The solvent was removed under a vacuum, and ethyl acetate and sodium bicarbonate aqueous solution were added, and the organic layer was partitioned. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum, and the residue was purified by silica gel column chromatography (heptane/ethyl acetate→ethyl acetate), and the title compound (745 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(O[C:9](=[O:11])[CH3:10])(=O)C.[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:9](=[O:11])[CH3:10])=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(c1ccccc1)N1CCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a stifling suspension of AlCl3 (144 g, 1.08 mol) in CH2Cl2 (1070 mL) was added acetic anhydride (54 mL). The mixture was stirred for 15 minutes. A solution of 1-benzenesulfonyl-2,3-dihydro-1H-indole (46.9 g, 0.18 mol) in CH2Cl2 (1070 mL) was added dropwise. The mixture was stirred for 5 h and quenched by the slow addition of crushed ice. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated under vacuum to yield 1-(1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-ethanone (42.6 g, 79%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=2)[CH2:11][N:12]2[C:16]3=[N:17][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)=[CH:19][N:20]=[C:15]3[N:14]=[N:13]2)=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:31]1.C([O-])(=O)C.[K+].O>C1COCC1.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:10]4[CH:9]=[C:8]([C:5]5[N:4]=[CH:3][C:2]([OH:31])=[CH:7][N:6]=5)[CH:29]=[CH:28][CH:27]=4)[N:13]=[N:14][C:15]3=[N:20][CH:19]=2)[CH:22]=[N:23]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cn1cc(-c2cnc3nnn(Cc4cccc(-c5ncc(Br)cn5)c4)c3n2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3nnn(Cc4cccc(-c5ncc(O)cn5)c4)c3n2)cn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
800 mg (1.66 mmol) of 1-[3-(5-bromopyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazolo[4,5-b]pyrazine is suspended in 10 ml of THF and 1 ml of DMF, and 515 mg (1.99 mmol) of bis(pinacolato)diboron and 488 mg (4.97 mmol) of potassium acetate are added. The reaction mixture is evacuated and flushed with argon a number of times. 16.3 mg (0.023 mmol) of bis(triphenylphosphine)palladium(II) chloride is added, and the mixture is again evacuated and flushed with argon. The reaction mixture is stirred at 80° C. for 24 h. When the reaction of the starting material is complete, 255 mg (1.656 mmol) of sodium perborate trihydrate and 2 ml of water are added to the reaction mixture, which is then stirred at room temperature for 24 h. The reaction mixture is filtered off with suction and washed with ethyl acetate. The filtrate is subsequently adjusted to pH 12 using NaOH solution and extracted with ethyl acetate. The aqueous phase is neutralised using hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are then dried over sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:16]=1)=[O:9]
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: COc1ccc(N)cc1C(F)(F)F
Product: COc1ccc(NC(=O)c2cc(C)ccc2O)cc1C(F)(F)F
Yield: 65.1 %

Procedure:
Using 5-methylsalicylic acid and 4-methoxy-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].C(Cl)Cl.[I:21]I>O>[I:21][C:12]1[CH:11]=[C:5]([CH:4]=[CH:3][C:2]=1[NH2:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(N)c(I)c1
Reaction time: 72 h

Procedure:
Part A: Ethyl 4-aminobenzoate (5.0 gr, 30.27 mmol) and sodium bicarbonate (3.81 g, 45.40 mmol, 1.5 eq.) were added to a 50:50 mixture of methylene chloride and water. The mixture was chilled to 0 degree and I2 (11.53 g, 45.40 mmol, 1.5 eq.) was added slowly. The reaction mixture was allowed to come to room temperature and was stirred for 72 hours. The layers were then separated and the aqueous layer washed with methylene chloride. All organics were combined and dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was chromatographed on silica using 30% ethyl acetate in hexanes as solvent to afford ethyl 3-iodo-4-aminobenzoate. C9H10NO2I MS 292 (M+H)+ 309 (M+NH4)+.
Reaction SMILES: [NH2:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Cl:15][CH2:16][C:17](Cl)=O.[NH:20]1[CH2:25][CH2:24][C:23]2([C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][O:26]2)[CH2:22][CH2:21]1>>[ClH:15].[CH:13]1[C:14]2[CH:2]([NH:1][CH2:16][CH2:17][N:20]3[CH2:25][CH2:24][C:23]4([C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27][O:26]4)[CH2:22][CH2:21]3)[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: NC1c2ccccc2-c2ccccc21
Reactant: O=C(Cl)CCl
Reactant: c1ccc2c(c1)COC21CCNCC1
Product: Cl
Product: c1ccc2c(c1)COC21CCN(CCNC2c3ccccc3-c3ccccc32)CC1

Procedure:
The title compound, m.p. 244° C. and MS: m/e=397.3 (M+H+), was prepared in accordance with the general method of example 1 from 9-amino-fluorene, chloroacetyl chloride, spiro[isobenzofuran-1(3H),4'-piperidine] and Hcl.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:24][C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[S:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[NH:24][C:13](=[O:14])/[C:12](/[C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=1)=[N:16]/[O:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Nc1nc2ccccc2s1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)Nc2nc3ccccc3s2)cc1Cl
Reaction time: 2 h
Yield: 56.4 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid (prepared as in Example 9, 112 mg, 0.31 mmol), 2-aminobenzothiazole (47 mg, 0.31 mmol) and N,N-diisopropylethylamine (163 μL, 0.93 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 60% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclohexyloxyimino-acetamide (86 mg, 56%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C22H22ClN3O4S2 [M+] 491.07, found 492 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.26-1.64 (m, 6H, 3×CH2), 1.75 (m, 2H, 2×CH of CH2), 2.00 (m, 2H, 2×CH of CH2), 3.32 (s, 3 H, SO2CH3), 4.36 (m, 1 H, OCH), 7.35 (brt, 1 H, Ar), 7.48 (brt, 1 H, Ar), 7.65 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.76 (d, Jm=1.5 Hz, 1 H, Ar), 7.83 (brt, 2H, Ar), 8.23 (d, Jo=8.2 Hz, 1 H, Ar), 10.24 (s, 1 H, NH).
Reaction SMILES: O[CH2:2][C:3]1[NH:8][C:7](=[O:9])[C:6]2=[CH:10][N:11]=[C:12]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:4]=1.O=S(Cl)[Cl:21]>C(Cl)Cl>[Cl:21][CH2:2][C:3]1[NH:8][C:7](=[O:9])[C:6]2=[CH:10][N:11]=[C:12]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(CO)nn2c(C3CCOCC3)ncc12
Solvent: ClCCl
Product: O=c1[nH]c(CCl)nn2c(C3CCOCC3)ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of compound 7 (400 mg, 1.6 mmol) in CH2Cl2 (50 mL) in ice-water bath was added SOCl2 (10 mL) dropwise. The resulting mixture was then stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to afford compound 8 (370 mg, 86% yield) as a white solid. LC-MS: m/z 269.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 12.50 (s, 1H), 8.02 (s, 1H), 4.57 (s, 2H), 3.95 (m, 2H), 3.48 (m, 3H), 1.88 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1>>[CH3:11][Si:10]([C:9]#[C:8][C:5]1[CH:4]=[C:3]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)[CH:2]=[CH:7][CH:6]=1)([CH3:13])[CH3:12]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C[Si](C)(C)C#Cc1ccc(Br)cc1
Product: C[Si](C)(C)C#Cc1cccc(C2(O)CCC3(CC2)OCCO3)c1

Procedure:
The title compound was prepared as a white solid from (4-bromo-phenylethynyl)-trimethyl-silane (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:34]O>>[CH3:34][O:18][C:17](=[O:19])[CH2:16][C:14]1[N:15]=[C:11]([NH:10][C:8](=[O:9])[CH:7]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[S:12][CH:13]=1
Reactant: CO
Reactant: O=C(O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Agent: Cl
Product: COC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Yield: 61 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid (prepared in Example 16, 80 mg, 0.18 mmol) in methanol (10 mL) was treated with concentrated hydrochloric acid (1 mL) and then heated under reflux for 16 h. At this time, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL) and then washed with water (5 mL). The aqueous layer was further extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded {2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (50 mg, 61%) as a yellow oil: EI-HRMS m/e calcd for C26H28N2O4S (M+) 464.1770, found 464.1769.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>ClCCl.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][O:5][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C[Si](C)(C)CCO
Reactant: C=C(C)C(=O)Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCC[Si](C)(C)C
Yield: 44.7 %

Procedure:
2-Trimethylsilylethanol (Aldrich) (30 g, 0.25 mole) was placed in a round bottom flask equipped with a condenser, addition funnel, magnetic stirrer and a nitrogen inlet. 200 ml dichloromethane, pyridine (20.80 g, 0.26 mole) and 100 mg of phenothiazine were added to the flask. While stirring, methacryloyl chloride (27.18 g, 0.26 mole) in 100 ml dichloromethane was added dropwise at room temperature. A mildly exothermic reaction occurred. The mixture was stirred overnight at room temperature. Afterwards, the mixture was washed with 1×100 ml deionized water and 2×100 ml brine and dried over anhydrous magnesium sulfate. The solution was concentrated in vacuo. Fractional distillation under reduced pressure gave 20.82 grams of the desired product at 35-38° C. at 0.5 mm.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[Cl:12][CH2:13][CH2:14][CH2:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:2][N:3]([CH3:4])[S:16]([CH2:15][CH2:14][CH2:13][Cl:12])(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)CCCCl

Procedure:
To a suspension of dimethylamine hydrochloride (1.38 g) in dichloromethane (20 mL) was added triethylamine (2.52 mL) and then 3-chloropropanesulfonyl chloride (0.69 mL) and the reaction was stirred at room temperature for 16 h. The reaction was quenched with water (20 mL) and extracted into dichloromethane (2×30 mL). The combined organics were washed with 1 M aqueous hydrochloric acid solution (40 mL) then saturated aqueous sodium hydrogen carbonate solution, dried (MgSO4) and reduced in vacuo to give 3-chloro-propane-1-sulfonic acid dimethylamide as a yellow solid.
Reaction SMILES: [CH3:1][P:2]([CH3:34])(=[O:33])[O:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[CH:17]=[CH:16][C:15]=2[NH:25]C(OC(C)(C)C)=O)=[O:12])=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][P:2]([CH3:34])(=[O:33])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[CH:17]=[CH:16][C:15]=2[NH2:25])=[O:12])=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(COP(C)(C)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CP(C)(=O)OCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1

Procedure:
[4-({[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl dimethylphosphinate (1.1 g, 2.198 mmol) was taken up in DCM (20 mL)/TFA (8 mL). After 2 hours at room temperature the solvent was removed in vacuo. Saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated in EtOAc to give [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl dimethylphosphinate as a beige solid. 1H-NMR (600 mHz, DMSO-d6) δ 9.72 (s, 1H), 7.98 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.44 (d, J=1.8 Hz, 1H), 7.32 (dd, J=4.8 and 1.2 Hz, 1H), 7.27 (dd, J=8.4 and 2.4 Hz, 1H), 7.21 (dd, J=3.6 and 1.2 Hz, 1H), 7.01 (dd, J=4.8 and 3.6 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 5.13 (s, 2H), 5.01 (d, J=8.4 Hz, 2H), 1.45 (d, J=14.4 Hz, 6H). MS: cal'd 401 (MH+), exp 401 (MH+).
Reaction SMILES: [F:1][C:2]([F:13])([C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8])[C:3]([OH:5])=[O:4].[CH3:14]S(O)(=O)=O>CO>[F:1][C:2]([F:13])([C:6]([F:11])([F:12])[C:7]([F:8])([F:9])[F:10])[C:3]([O:5][CH3:14])=[O:4]
Reactant: CS(=O)(=O)O
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CO
Product: COC(=O)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Perfluorobutyric acid (55 g, 0.26 m) in 25 ml of methanol containing 0.1 g of methane sulfonic acid was refluxed for 16 hours. The product was washed with a sodium carbonate solution and dried over magnesium carbonate. IR analysis showed the following major absorption bands: 2970, 1785, 1310, 1225, 1145, 1085 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)=[CH:5][C:4]=1[O:15][CH2:16][CH:17]([OH:31])[CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)=[CH:5][C:4]=1[O:15][CH2:16][CH:17]([O:31][C:32](=[O:34])[CH3:33])[CH2:18][N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:23][CH2:24]1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OCC(O)CN1CCN(c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C2CNC(=O)C2)cc1OCC(CN1CCN(c2ccccc2)CC1)OC(C)=O
Yield: 86 %

Procedure:
7.5 mmol of 4-{4-methoxy- 3-[3-(4-phenylpiperazin-1-yl)-2-hydroxypropoxy]phenyl}-2-pyrrolidone is dissolved in 50 ml. of dry pyridine. After adding 15 mmol of acetic anhydride, the mixture is heated for 3 hours under reflux. After cooling, the reaction mixture is concentrated under vacuum. The residue is chromatographed over silica gel (acetone/dichloromethane 1:1) and recrystallized from isopropanol, thus obtaining in an 86% yield 4-{4-methoxy-3-[3-(4-phenylpiperazin-1-yl)-2-acetoxypropoxy]phenyl}-2-pyrrolidone, m.p. 128°-133°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[O:17])[N:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)(C)N
Reactant: CC(C)(C)OC(=O)NCc1nc(C(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)NC(=O)c1csc(CNC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a round bottom flask with 50 mL methylene chloride was added 2-((tert-butoxycarbonylamino)methyl)thiazole-4-carboxylic acid (2.0 g, 7.74 mmole) and methyl 2-amino-2-methylpropanoate hydrochloride salt (1.25 g, 8.13 mmole). To the mixture, triethylamine (5.4 mL, 38.7 mmole) was then added, followed by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (2.97 g, 15.5 mmole) and hydroxybenzotriazole (2.09 g, 15.5 mmole). The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with methylene chloride. The mixture was then washed with water and the aqueous layer was extracted with methylene chloride. The combined organic layer was then dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 1:1 EtOAc/hexane to provide the desired product (2.40 g, 87% yield).