Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C@H:8]([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:26]C=2C=1.N[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C@H:37]([OH:39])[CH3:38].CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[OH:39][C@H:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:31]=1)[CH2:38][NH:26][C:9]([C@@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:15])=[O:11]
Reactant: C[C@@H](O)c1ccccc1N
Reactant: C=CC[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C=CC[C@@H](CC(=O)OC(C)(C)C)C(=O)NC[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a solution of (S)-2-(2-tert-butoxy-2-oxoethyl)pent-4-enoic acid (0.947 g, 4.42 mmol) (described by Stanton, B. Z. et al. Nat. Chem. Biol. 2009, 5, 154-156) in DMF (31.6 mL) cooled in an ice/water bath was added EDC (1.27 g, 6.63 mmol) and HOBt (0.896 g, 6.63 mmol) and the resulting solution was stirred 30 min. (R)-2-amino-phenylethanol (0.667 g, 4.86 mmol), iPr2NEt (2.31 mL, 13.3 mmol) and DMAP (0.108 g, 0.884 mmol) were subsequently added and the reaction mixture was slowly warmed to rt and stirred for 16 h at which point LC-MS analysis indicated complete consumption of starting material. The reaction mixture was diluted with saturated NH4Cl and EtOAc and the layers separated. The aqueous was extracted 2× with EtOAc and the combined organic extracts were washed with 1 N HCl and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified using silica gel chromatography (MeOH/CH2Cl2 gradient) to yield 1.25 g of desired product as a light yellow oil in 85% yield. LRMS (M+Na)+: 356.2.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([C:8]#[C:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:6][C:5]1=[O:17])[CH3:3].FC(F)(F)C(O)=[O:21].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(Cl)Cl.C(OCC)(=O)C.O>[OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([CH2:8][C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:21])[NH:6][C:5]1=[O:17])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1C#CSc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N[C@@H]1CC(=O)Sc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
To a solution of 718 mg of (3S, 4S)-3-[(R)-1-hydroxyethyl]-4-[(phenylthio)ethynyl]-2-azetidinone in 8 ml of anhydrous methylene chloride was added, under an atmosphere of nitrogen gas, 1.1 ml of trifluoroacetic acid, with stirring and ice-cooling. The mixture was then stirred for 30 minutes under ice-cooling and for a further 1.5 hours at room temperature. The reaction mixture was then poured into a mixture of 2.44 g of sodium bicarbonate, 15 ml of water and 30 ml of ethyl acetate. The mixture was saturated with sodium chloride and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The organic layer and the ethyl acetate extracts were combined, and the combined solution was washed successively with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure and the residue was subjected to column chromatography through silica gel, eluted with a 1:3 by volume mixture of cyclohexane and ethyl acetate, to give 281 mg (yield 36.5%) of the title thioester compound, which was recrystallized from a mixture of ethyl acetate and hexane to give crystals melting at 121.5-123.5° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[O:10][C:9](=[O:18])[CH:8]=1)(=O)=O.[Br:21]N1C(=O)CCC1=O.C1(C)C=CC=CC=1.C1C[O:39][CH2:38][CH2:37]1.O>>[Br:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([C:38](=[O:39])[CH2:37][Br:21])=[CH:8][C:9](=[O:18])[O:10]2)=[CH:15][CH:14]=1
Reactant: C1CCOC1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2ccc(Br)cc2o1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CBr)c1cc(=O)oc2cc(Br)ccc12
Temperature: 25 °C

Procedure:
To a solution of 7-bromo-2-oxo-2H-chromen-4-yl trifluoromethanesulfonate (2.71 g, 9.35 mmol) in THF-water (40 mL, 10/1 mixture), N-bromosuccinimide (1.83 g, 10.3 mmol) was added. The reaction was then stirred at room temperature. After 5 hours stirring, toluene was added and the crude mixture was evaporated under reduced pressure. The crude residue obtained was purified by column chromatography (EtOAc/hexanes, 25:75) to afford the title compound. 1H NMR (400 MHz, acetone-d6 7.80 (d, 1H), 7.72-7.62 (m, 1H), 7.60 (d, 1H), 7.13 (s, 1H), 4.92 (s, 2H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([N:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[CH:28]=[N:27]4)[N:24]=3)[N:19](COCC[Si](C)(C)C)[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:4][CH2:5][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([N:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[CH:28]=[N:27]4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:7][CH2:8]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(-n3ncc4cc(Cl)ccc43)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: N#CC1CCN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-n4ncc5cc(Cl)ccc54)nc23)C2CC2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.7 %

Procedure:
In a round-bottomed flask, 2-(5-chloro-indazol-1-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (51 mg, 0.08 mmol) was dissolved in dichloromethane (0.5 ml) and trifluoroacetic acid (0.25 ml, 3.24 mmol) was added. The yellow reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was dissolved in dichloromethane (0.5 ml) and ethylenediamine (0.33 ml, 4.89 mmol) was added. The reaction was stirred at room temperature for 1.5 h then quenched with water and extracted with EtOAc (2×30 ml). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with EtOAc/hexanes (gradient 0-100% EtOAc) followed by trituration with EtOAc/hexanes (1:1) to provide 22 mg (52%) of 2-(5-chloro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a yellow solid. MS: (M+H)+=503; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 13.01 (br. s., 1H), 9.10 (s, 1H), 8.94 (dd, J=8.9, 5.1 Hz, 1H), 8.54 (d, J=0.8 Hz, 1H), 8.51 (d, J=6.8 Hz, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.07 (d, J=1.9 Hz, 1H), 7.56 (t, J=6.6 Hz, 1H), 4.92-5.02 (m, 1H), 3.70-4.06 (m, 2H), 3.09-3.68 (m, 3H), 1.50-2.08 (m, 4H), 1.20-1.39 (m, 1H), 0.31-0.61 (m, 4H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9](B(O)O)[CH:8]=1.Br[C:17]1[CH:26]=[CH:25][C:20]([CH:21]=[CH:22][CH:23]=[O:24])=[CH:19][CH:18]=1>CO.C1(C)C=CC=CC=1.ClCCl.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:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:17]2[CH:26]=[CH:25][C:20](/[CH:21]=[CH:22]/[CH:23]=[O:24])=[CH:19][CH:18]=2)[CH:8]=1
Reactant: OB(O)c1cccnc1
Reactant: O=CC=Cc1ccc(Br)cc1
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: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C/C=C/c1ccc(-c2cccnc2)cc1

Procedure:
2M aq. Na2CO3 (1 mL) and a solution of 3-pyridinylboronic acid (148 mg, 1.20 mmol) in methanol (1 mL) were added to a solution of 4-bromocinnamaldehyde (211 mg, 1.00 mmol, prepared as described in Tetrahedron 1998, 54, 10761) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.030 mmol) in toluene (2 mL) and the mixture was heated to reflux for 36 h. The cooled reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 1:1 hexane/ethyl acetate) yielded the title compound. MS 210 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:52](=[O:53])[N:6]2[C:7]([C:39]([O:41]CC3C=CC([N+]([O-])=O)=CC=3)=[O:40])=[C:8]([S:11][C@@H:12]3[CH2:16][N:15](C(OCC4C=CC([N+]([O-])=O)=CC=4)=O)[C@H:14]([C:30](=[O:38])[NH:31][CH2:32][CH2:33][N+:34]([CH3:37])([CH3:36])[CH3:35])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[F:54][S:55]([O:58]C)(=[O:57])=[O:56]>C(Cl)Cl>[F:54][S:55]([O-:58])(=[O:57])=[O:56].[OH:1][C@@H:2]([C@H:4]1[C:52](=[O:53])[N:6]2[C:7]([C:39]([OH:41])=[O:40])=[C:8]([S:11][C@@H:12]3[CH2:16][NH:15][C@H:14]([C:30](=[O:38])[NH:31][CH2:32][CH2:33][N+:34]([CH3:37])([CH3:35])[CH3:36])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)NCC[N+](C)(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: COS(=O)(=O)F
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)NCC[N+](C)(C)C)C3)[C@H](C)[C@H]12
Product: O=S(=O)([O-])F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
90 mg of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(2-trimethylammonioethylcarbamoyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate [prepared as described in step (2) above] were dissolved in 2 ml of anhydrous methylene chloride, and the solution was placed on an ice bath. Whilst the solution was still on the ice bath, 20 μl of methyl fluorosulfonate were added, and the resulting mixture was stirred for 30 minutes at room temperature. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting crude product was dissolved in 5 ml of a 1:1 by volume mixture of tetrahydrofuran and water. Hydrogen was passed through the resulting solution for 2 hours at room temperature in the presence of 90 mg of a 10% w/w palladium-on-carbon catalyst. At the end of this time, the catalyst was removed by filtration. The filtrate was condensed by evaporation under reduced pressure, and 5 ml of water were added to the residue. The soluble fraction was subjected to column chromatography through a Sephadex G-10 (Pharmacia, 40-120 μm) column, eluted with water. Those fractions containing the title compound were collected and lyophilized to give 53 mg of the title compound.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12](I)[CH:11]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[NH2:14][C:13]1[CH:15]=[CH:16][C:10]([Br:9])=[CH:11][C:12]=1/[C:3](/[CH3:4])=[CH:2]\[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C/C=C/C(=O)OCC
Reactant: Nc1ccc(Br)cc1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C(/C)c1cc(Br)ccc1N
Yield: 40 %

Procedure:
A solution of Pd(Amphos)2Cl2 (1.188 g, 1.678 mmol), ethyl crotonate (5.01 ml, 40.3 mmol), 4-bromo-2-iodoaniline (Spectrum Bioscience, 10.000 g, 33.6 mmol), and n,n-diisopropylethylamine (7.03 ml, 40.3 mmol) in 6 mL DMF was heated to 90° C. for 6 hours. The reaction mixture was then poured into water and was extracted with DCM. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0-100% EtOAc/heptane) gave (Z)-ethyl 3-(2-amino-5-bromophenyl)but-2-enoate (3.817 g, 13.43 mmol, 40.0% yield) with minor impurities. m/z (ESI) 286.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16](O)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.CCN(CC)CC.CS(Cl)(=O)=O.C[O-].[Na+]>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]1([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[C@H:16]([CH3:17])[O:19]1
Reactant: C[C@@H](O)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Agent: CS(=O)(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1O[C@@]1(Cn1cncn1)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a solution of (2R,3R)-2-(2,5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (53.0 g, 197 mmol) and Et3N (54.8 mL, 394 mmol) in CH2Cl2-EtOAc (1:3, 400 mL) cooled in an ice-bath was added MsCl (17.5 mL, 227 mmol) dropwise over a period of 15 min. After stirring for 30 min at 0° C., the mixture was warmed to room temperature and quenched with water (200 mL). EtOAc (200 mL) was added and the organic layer was washed with water and brine, dried over MgSO4 and evaporated under reduced pressure. The obtaining residue was dissolved in MeOH (500 mL) and cooled in an ice-bath. A solution of NaOMe (41.8 g, 28% in MeOH, 217 mmol) was added dropwise and after the completion of the addition, the mixture was stirred for 15 min at 0° C. MeOH was evaporated under reduced pressure and the resulting residue was dissolved in EtOAc (500 mL). The EtOAc solution was washed with water and brine, dried over MgSO4 and evaporated under reduced pressure. The obtaining solid was recrystalized from t-BuOMe-hexane to give pure (2R,3S)-2-(2,5-Difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)-methyl]-oxirane (43.5 g, 88%).
Reaction SMILES: C([N:4]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])C=C.ClC1C=CC=[C:44]([C:48](OO)=[O:49])[CH:43]=1.C(OCC)(=O)C.CO>C(Cl)Cl>[CH2:48]([O:49][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:44]=[CH2:43]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCN(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCON(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.4 %

Procedure:
Into a cooled solution of 5.0 g (9 mmol) of N-allyl-N,N-dioctadecylamine in 50 ml of methylene chloride at 0° C. under a nitrogen atmosphere is added dropwise with stirring a solution of 1.54 g (9 mmol) of 85% active m-chloroperbenzoic acid in 50 ml of methylene chloride. After the addition is complete (approximately 15 minutes), the resultant solution is allowed to warm to ambient temperature (about 22°-24° C.). The reaction is complete after about 5 hours when TLC analysis (silica gel, 19:1 v/v ethyl acetate:methanol)indicates the starting material has completely reacted. The reaction mixture is transferred to a separatory funnel and washed sequentially with three 50 ml portions of 10% aqueous sodium hydroxide solution and then with 100 ml of distilled water. The organic layer is dried over anhydrous sodium sulfate and heated under reflux at approximately 40° C. for two hours. The resultant solution is concentrated in vacuo and the residue is purified by flash chromatography (silica gel, 94:6 v/v hexane:ethyl acetate eluent) to give 3.3 g (64% yield) of the title compound as a white solid melting at 62°-65° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:13]>C1C=CC=CC=1.CO>[Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([C:8]([O:10][CH3:13])=[O:9])[CH:7]=1
Reactant: O=C(O)c1cnc(O)c(Cl)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1cnc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a stirred solution of 3-chloro-2-hydroxypyridine-5-carboxylic acid (1 g, 5.762 mmol) in benzene (16 mL) and MeOH (4 mL) was added dropwise TMSCHN2 (3.17 mL, 6.338 mmol) at 0° C., and the resulting mixture was stirred overnight at room temp. The reaction mixture was quenched by the addition of AcOH and the mixture was evaporated off. The residue was suspended in water and precipitate was collected. The crude solid was washed with Et2O, and dried under a reduced pressure to give 728.1 mg (67%) methyl 3-chloro-2-hydroxypyridine-5-carboxylate as a white crystalline powder. IR (KBr) 1655, 1282, 1245, 769 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ3.79 (s, 3H), 8.01 (s, 1H), 8.06 (s, 1H); MS (FAB) m/z 188 (M++1); Anal. Calcd. for C7H6ClNO3: C, 44.82; H, 3.22; Cl, 18.90; N, 7.47. Found: C, 44.74; H, 3.22; Cl, 19.00; N, 7.34.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[N:15]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:24][CH2:23][CH2:22][CH2:21][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:11])=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: NCCCN1CCCCC1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NCCCN2CCCCC2)cc1

Procedure:
For example, terephtalic acid monomethyl ester chloride is treated with an alkylamine, in this case 3-piperidinopropylamine, and triethylamine, in a suitable solvent such as dichloromethane at ambient temperature for 1-12 hours to provide the desired amide, N-(3-piperidin-1-yl-propyl)-terephthalamic acid methyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].CCN(CC)CC.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[C:12]([F:15])([F:14])[F:13])[CH2:26][CH2:25]1
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a solution of crude 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (13.33 mmol, 75% pure) in DCM (10 mL) was added Et3N (1.4 mL, 10 mmol) and 1-methylpiperazine (1.1 mL, 10 mmol). After stirring for 3 h at rt, aq. NaHCO3 was added, and the mixture was extracted with DCM. The combined organic layer was dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 10% MeOH/DCM) to provide 2.21 g of product as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:36]CCl>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([Cl:36])=[O:27])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
To a solution of (E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoic acid (9b) (0.25 g, 0.5 mmol) in dichloromethane (7 mL) oxalyl chloride (0.15 mL, 1.75 mmol) and a drop of dimethylformamide were added. The reaction mixture was stirred at ambient temperature for 1 hour, then the mixture was evaporated and the residue was dried in vacuum to give (E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10b) (0.26 g) in a form of a crude product.
Reaction SMILES: [CH:1]1(/[CH:4]=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.[CH2:18]([N:25]([CH2:31]O)[CH2:26][Si](C)(C)C)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:18]([N:25]1[CH2:31][C@@H:4]([CH:1]2[CH2:3][CH2:2]2)[C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)/C=C/C1CC1
Reactant: C[Si](C)(C)CN(CO)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C1CC1
Yield: 56 %

Procedure:
To a stirred solution of ethyl (2E)-3-cyclopropylacrylate (5.3 g, 37.9 mmol) and TFA (0.43 g, 3.79 mmol) in DCM (100 mL) was added dropwise {benzyl[(trimethylsilyl)methyl]amino}methanol (13.5 g, 56.8 mmol) at 0° C. After the addition, the mixture was refluxed overnight. TLC (petroleum ether: EtOAc 10:1) indicated most of ethyl (2E)-3-cyclopropylacrylate was consumed. The reaction mixture was quenched with sat. NaHCO3 (100 mL), brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether: EtOAc=50:1 to 30:1) to give the title compound (5.8 g, 54% yield) as a yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]([S:15]([OH:17])=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:18]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Br)[CH:23]=1)(=[O:20])[CH3:19].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:15]([CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:18](=[O:20])[CH3:19])[CH:23]=2)(=[O:17])=[O:16])=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(CBr)c1
Reactant: CC(=O)Nc1ccc(S(=O)O)c2cccnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Cc2cccc(OC(C)=O)c2)c2cccnc12
Reaction time: 0.5 h

Procedure:
8-Acetamido-5-quinolinesulfinic acid (10 g, 40 mmole), m-(bromomethyl)phenyl acetate (11 g, 44 mmole), excess sodium bicarbonate (5 g) and dry dimethylformamide (50 ml) were mixed and heated on the steam bath for 11/2 hours. The mixture was slowly poured into 800 ml stirred water and the mixture stirred another 30 min. The solid was filtered off, washed with water, and air-dried overnight. Yield 15.8 g (99 percent) of crude but relatively pure product, m.p. 179°-182° C. A sample recrystallized from toluene, melted 180°-182° C.