Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:9]1([C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[O:8]=[C:2]([C:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[S:16][C:15]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)Cl
Reactant: c1ccc(-c2cc3ccccc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(-c2ccccc2)sc2ccccc12
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
Ethyl chlorooxoacetate (162 μL, 1.45 mmol) was added at 0° C. to a solution of 2-phenyl-1-benzothiophene (2a) (310 mg, 1.46 mmol) and aluminum chloride (III) (389 mg, 2.92 mmol) in dichloromethane (10 mL). After 30 minutes, the reaction mixture was quenched with a saturated aqueous solution of sodium carbonate. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the organic layer was washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired product (2b) as a pale oil (370 mg, 1.19 mmol, 70%).
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:30]=[C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:40])[N:32]1[CH2:41][CH2:42][CH2:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH:47]=O>>[CH3:29][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([CH3:2])[CH:28]=1)/[CH:6]=[CH:47]/[C:46]1[CH:45]=[C:44]([CH2:43][CH2:42][CH2:41][N:32]2[C:33](=[O:40])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]2=[O:30])[CH:51]=[CH:50][CH:49]=1
Reactant: Cc1cc(C)cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: [Br-]
Product: Cc1cc(C)cc(/C=C/c2cccc(CCCN3C(=O)c4ccccc4C3=O)c2)c1

Procedure:
3,5-Dimethylbenzyltriphenylphosphonium bromide was coupled with phthalimide 29. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave (E)-2-(3-(3-(3,5-dimethylstyryl)phenyl)propyl)isoindoline-1,3-dione as a white solid. Yield (0.3263 g, 55%): 1H NMR (400 MHz, DMSO-d6) δ 7.81-7.88 (m, 4H), 7.00-7.44 (m, 6H), 6.71-6.90 (m, 2H), 6.53 (s, 1H), 3.64 (t, J=7.2 Hz, 2H), 2.65 (t, J=7.2 Hz, 2H), 1.70-1.77 (m, 2H), 2.29 (s, 6H).
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].Cl.[Cl:27][CH2:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>COCCOC>[C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([CH2:20][CH2:21][S:22]([NH:31][CH2:30][CH2:29][CH2:28][Cl:27])(=[O:24])=[O:23])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: O=S(=O)(Cl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: NCCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: O=S(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)NCCCCl
Yield: 97.5 %

Procedure:
CF3(CF2)5(CH2)2SO2Cl (10 g), 3-chloropropyl amine hydrochloride (4.1 g), and 1,2-dimethoxyethane (20 g) solvent were added to the round bottom flask equipped with mechanical stirring under nitrogen. Solution of triethylamine (4.5 g) in 1,2-dimethoxyethane (10 g) solvent was added dropwise during 30 min at 20-30° C. at 250 rpm. Stirred for 12 h after the addition is completed. The reaction was monitored by GC to ensure the complete conversion 1. The final reaction mixture with pH of about 5 was filtered from solids through 2 mm layer of CELITE 545. The solids were washed with 1,2-dimethoxyethane (7 g) and combined filtrate was evaporated in vacuum to obtain 11.0 g of CF3(CF2)5(CH2)2SO2NH(CH2)3Cl. The product was additionally dissolved in hot toluene (8 g) and washed with 15.5 mL of 1 wt % HCl aqueous solution to remove traces of NH2(CH2)3Cl.
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[CH3:7][O:8][C:9](=[O:16])[C:10]#[C:11][C:12]([O:14][CH3:15])=[O:13]>C1C=CC=CC=1>[CH3:7][O:8][C:9]([C:10]1[CH2:5][C:4]([CH3:6])=[C:2]([CH3:3])[CH2:1][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:16]
Reactant: COC(=O)C#CC(=O)OC
Reactant: C=C(C)C(=C)C
Solvent: c1ccccc1
Product: COC(=O)C1=C(C(=O)OC)CC(C)=C(C)C1

Procedure:
2,3-Dimethyl-buta-1,3-diene (2.0 g, 24.3 mmol) and but-2-ynedioic acid dimethyl ester in benzene (14 mL) were heated to reflux for 16 h. The resulting mixture was cooled and evaporated in vacuo to yield a solid, which was purified via flash column chromatography (EtOAc/heptane 9:1) to yield 4,5-dimethyl-cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=O)[CH3:2].[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O1CCCC1>[CH2:1]([O:3][C:4](=[O:11])[C:5]([CH3:10])([CH3:9])[C:6]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:8])[CH3:2]
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)C(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)C(C)(C)C(=O)NCCN1CCOCC1
Temperature: 5 °C

Procedure:
19 g 2,2-Dimethyl-malonic acid monoethyl ester were weighed into a round-bottomed flask and under N2 atmosphere and room temperature, 200 ml tetrahydrofurane, 15.6 ml 4-(2-Aminoethyl)-morpholine and 32.6 ml N-Methylmorpholine were added. The reaction was stirred and cooled down to 5° C. Then, 43.8 g TBTU were added and the mixture was allowed to stir for another 1.5 hours. Finally the solvent was removed and the residue dissolved in 400 ml dichloromethane. This organic phase was washed two times with 500 ml NaHCO3 solution. The dichloromethane phase was dried then the solvent was evaporated. Purity of the product was judged by gas chromatography.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:11][CH:10]=2)([O:3][CH2:4]C)=[O:2].[Na].O.[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH2:25]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([C:1]([O:3][CH3:4])=[O:2])=[CH:7]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1cnc2ccc(C3CCCCC3)cc2c1O
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)c1cn(Cc2ccccc2)c2ccc(C3CCCCC3)cc2c1=O
Reaction time: 5 h

Procedure:
14 g of 3-carboethoxy-4-hydroxy-6-cyclohexyl-quinoline are added to a solution of 1.45 g of sodium in 150 ml of absolute methanol, whilst stirring, and the mixture is heated to the boil for 1 hour, with exclusion of water. 7.15 g of benzyl chloride are then added dropwise to the reaction mixture, which is boiled for a further 5 hours under reflux. It is then evaporated to dryness in vacuo and the residue is partitioned between 4 times 500 ml of chloroform and 500 ml of 1 N potassium hydroxide solution at 0°C. The organic phases are washed with twice 500 ml of water, dried over sodium sulphate and evaporated to dryness in vacuo. Repeated crystallisation of the evaporation residue from ethanol gives 1-benzyl-3-carbomethoxy-4-oxo-6-cyclohexyl-1,4-dihydroquinoline of melting point 211°-213°C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([N+:23]([O-])=O)=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:26][CH3:27])=[CH:10][CH:9]=1)(=[O:4])[CH2:2][CH3:3].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:26][CH3:27])=[CH:12][CH:13]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3cc([N+](=O)[O-])ccc32)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCC(=O)OCCc1ccc(-n2c(CC)nc3cc(N)ccc32)cc1
Yield: 83 %

Procedure:
To a stirred solution of 2-[4-(2-ethyl-5-nitro-1H-benzimidazol-1-yl)phenyl]ethyl propionate (step 3, 1.12 g, 3.0 mmol) in ethanol/water (v/v, 2:1, 15 mL) was added ammonium chloride (80 mg, 1.5 mmol) and iron powder (840 mg, 15 mmol) at room temperature. The mixture was heated at reflux temperature for 4 h and filtered through a pad of Celite. The filtrate was concentrated, and the residue was dissolved in dichloromethane (200 mL), then dried (MgSO4). Removal of solvent gave 0.84 g (83%) of the title compound as a yellow oil: 1H-NMR (CDCl3) δ 7.41 (2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.6 Hz), 7.10 (1H, d, J=1.8 Hz), 6.89 (1H, d, J=8.4 Hz), 6.63 (1H, dd, J=2.2, 8.4 Hz), 4.37 (2H, t, J=7.0 Hz), 3.05 82H, t, J=7.1 Hz), 2.79 (2H, q, J=7.5 Hz), 2.35 (2H, q, J=7.5 Hz), 1.33 (3H, t, J=7.50 Hz), 1.14 (3H, t, J=7.7 Hz).
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C.[N:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:44]([OH:46])=O)[CH:42]=2)[CH:37]=[CH:36][CH:35]=1.[CH3:47][O:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][C:51]=1[Cl:57]>O1CCCC1>[CH3:47][O:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:44]([C:41]2[CH:42]=[C:43]3[C:38]([CH:37]=[CH:36][CH:35]=[N:34]3)=[CH:39][CH:40]=2)=[O:46])=[CH:52][C:51]=1[Cl:57]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: O=C(O)c1ccc2cccnc2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2ccc3cccnc3c2)cc1Cl
Temperature: 25 °C
Yield: 35 %

Procedure:
Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (6.03 g, 12.9 mmol, 1.1 equiv.) and diisopropyl ethyl amine (3.19 g, 12.9 mmol, 1.1 equiv.) were added to a solution of quinoline-7-carboxylic acid (2.03 g, 11.75 mmol) in tetrahydrofuran (100 ml) and the resultant mixture stirred for 10 minutes. 4-Amino-2-chlorobenzoic acid methyl ester (2.40 g, 12.9 mmol, 1.1 equiv.) in tetrahydrofuran (20 ml) was added and the mixture refluxed for 16 hours. Additional Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.10 g, 2.36 mmol, 0.2 equiv.) and diisopropyl ethyl amine (0.61 g, 4.7 mmol, 0.4 equiv.) were added and the mixture refluxed for a further 16 hours. The mixture was evaporated then dissolved in isopropanol (100 ml). Water (5 ml) and 60% aqueous perchloric acid (0.5 ml) were added and the mixture was refluxed for 24 hours. The mixture was filtered while hot then left to cool to room temperature whereupon a crystalline solid was formed. The solid was filtered and washed with cold isopropanol (20 ml) and dichloromethane (20 ml) to give 2-chloro-4-[(quinoline-7-carbonyl)-amino]-benzoic acid methyl ester, 1.42 g (35% yield), as a tan solid. LC @215 nm; Rt 1.11: 100%, m/z (ES+): 341 (M+H+.); δH (400 MHz; d6-DMSO) 10.96 (1H, br.s), 9.05 (1H, m), 8.73 (1H, s), 8.49 (1H, d), 8.18-8.10 (3H, m), 7.94 (2H, s), 7.68 (1H, dd), 3.86 (3H, s).
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CO.C(OC(C)C)(C)C>>[C:1]([O:9][CH2:10][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCCCCCO
Reactant: COC(=O)c1ccccc1
Solvent: CC(C)OC(C)C
Product: NCCCCCCCCOC(=O)c1ccccc1
Yield: 90 %

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (3.0 mmol), 8-aminooctan-1-ol (3.6 mmol), Zn4(OCOCF3)6O (1.25 mol % in terms of mole number) and diisopropyl ether (5.0 ml) was heated to reflux for 20 hours, and as a result, 8-aminooctyl benzoate was obtained at a yield of 90%. The yield of 8-benzoylaminooctyl benzoate was 7%.
Reaction SMILES: N1C=CN=C1[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:22][C:15]3[NH:16][C:17](=[S:21])[NH:18][C:19](=[O:20])[C:14]=3[CH2:13][C:12]=2[CH:23]=1)=[O:7].[NH2:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1.O.Cl>CN(C)C=O>[NH:26]1[C:25]([NH:24][C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:22][C:15]4[NH:16][C:17](=[S:21])[NH:18][C:19](=[O:20])[C:14]=4[CH2:13][C:12]=3[CH:23]=2)=[O:7])=[N:29][N:28]=[N:27]1
Reactant: O=C(c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2)c1ncc[nH]1
Reactant: Nc1nnn[nH]1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2

Procedure:
Suspend 7-(imidazolylcarbonyl)-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione (0.6 g.) in dry dimethylformamide (20 ml.). With stirring, add 5-aminotetrazole (0.61 g.) and warm the mixture to 65°-75° C. and keep at that temperature for about 3/4 hour. Allow the mixture to cool, pour into water and acidify with hydrochloric acid. Filter and wash with isopropanol and ether to yield 7-(5-tetrazolylaminocarbonyl)-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][CH2:8][CH2:9][CH2:10][OH:11]>>[Cl:7][CH2:8][CH2:9][C:10]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[O:11]
Reactant: OCCCCl
Reactant: O=C(Cl)CCCl
Product: O=C(CCCl)OCCCCl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
101.5 ml (129.6 g, 1.00 mol) of 3-chloropropionyl chloride are added dropwise over about 30 minutes, at 90° C., to 86.1 ml of 3-chloro-1-propanol (97.4 g, 1.00 mol). During the addition, spontaneous evolution of gas occurs, and the reaction temperature drops to about 70° C. When the addition is complete, the reaction mixture is again heated to 100° C. and stirred at this temperature for a further 30 minutes. After cooling, the resultant crude product is purified by distillation.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9].Cl[CH2:11][CH2:12][O:13][C:14]1[CH:18]=[C:17]([CH3:19])[N:16]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[N:15]=1.O>CN(C=O)C>[CH3:19][C:17]1[N:16]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[N:15]=[C:14]([O:13][CH2:12][CH2:11][N:3]2[CH2:8][CH2:7][O:6][CH2:5][C:4]2=[O:9])[CH:18]=1
Reactant: O=C1COCCN1
Reactant: Cc1cc(OCCCl)nn1-c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCN2CCOCC2=O)nn1-c1ccc2ccccc2c1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
To a stirred suspension of sodium hydride (65 mg 60% dispersion in mineral oil, 1.63 mmol) in DMF (3 ml), cooled to 0-5° C., a solution of morpholin-3-one (91 mg, 0.91 mmol) in DMF (3 ml) was added dropwise. The mixture was stirred at room temperature for 3 hrs. Then, a solution of 3-(2-chloroethoxy)-5-methyl-1-(naphthalen-2-yl)-1H-pyrazole (200 mg, 0.7 mmol) in DMF (4 ml) was added and the mixture was heated to 50° C. for 14 hrs. The reaction mixture was cooled, water (2 ml) added dropwise, and it was evaporated to dryness in vacuum. The resulting residue was partitioned between dichloromethane and water. The organic layer was washed with water, dried over Na2SO4, filtered and evaporated giving 223 mg of crude residue, which was purified by a silica gel column chromatography (eluent: ethyl acetate) and 4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one (192 mg, 78%) was obtained as an amorphous white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].O>O1CCCC1.O>[C:1]([O:5][C:6]([C:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C2(C(=O)OC(C)(C)C)CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(c2ccc(C(=O)O)cc2)CCCCC1
Yield: 88.2 %

Procedure:
To a solution of methyl 4-[1-(tert-butoxycarbonyl)cyclohexyl]benzoate (1) (0.273 g, 0.86 mmol) in tetrahydrofuran (5 ml) was added 0.63 N LiOH water solution (3 ml, 1.89 mmol) and the resultant suspension was stirred at ambient temperature for 5 days. The reaction mixture was diluted with water (20 ml) and saturated NaH2PO4 (5 ml), and the obtained suspension was extracted with ethyl acetate (2×30 ml). The extract was washed with brine (15 ml), dried (Na2SO4), and the solvent was removed in vacuo. The residue was chromatographed on silica gel with toluene-ethyl acetate-acetic acid (8:2:01) as eluent to give the title compound (0.231 g, 88%) as a white solid. 1H NMR (CDCl3, HMDSO) δ: 1.07-1.91 (8H, m); 1.35 (9H, s); 2.20-2.63 (2H, m); 7.52 (2H, d, J=8.5 Hz); 8.06 (2H, d, J=8.5 Hz); 11.20 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13]O)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(NC(C)C)(C)C.CS(Cl)(=O)=O.[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:15])[CH2:13][S:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: Sc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 0° C. solution of N-(tert-butoxycarbonyl)-L-serine methyl ester (30 g, 137 mmol) and diisopropylamine (58 mL, 330 mmol) in dichloromethane (250 mL) was treated with methanesulfonyl chloride (11.65 mL, 151 mmol), stirred for 20 minutes, treated with thiophenol (15.5 mL, 151 mmol), warmed to room temperature, stirred for 30 minutes, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 310 (M−H)−.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH3:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:4][CH2:3][CH2:2][N:9]1[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]1
Reactant: OCCBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(CCO)CC1
Yield: 46.4 %

Procedure:
2-Bromoethanol (2.36 g, 19 mmol) was added dropwise to a mixture of 1-methylpiperazine (1.26 g, 13 mmol) and potassium carbonate (5.0 g, 36 mmol) in absolute ethanol (150 ml) and the mixture heated at reflux for 18 hours. The mixture was allowed to cool and the precipitates were removed by filtration and the solvent volatiles were removed by evaporation. The residue was treated with acetone/methylene chloride, the insolubles were removed by filtration and the solvent was removed from the filtrate by evaporation to give 4-(2-hydroxyethyl)-1-methylpiperazine (870 mg, 48%) as a light brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:26]([CH3:27])=[C:25](I)[N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29](=[O:31])[CH3:30]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:26]([CH3:27])=[C:25]([CH:29]([OH:31])[CH3:30])[N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(I)nnn1-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: CC=O
Product: Cc1c(C(C)O)nnn1-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-tert-butyl-N-(4-chloro-2-(4-iodo-5-methyl 1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide (synthesized according to general procedure P, 200 mg, 0.38 mmol) was placed in a 10 mL 2-neck flask and the flask was evacuated and purged with N2 three times. To the solid was added THF (1.9 mL) and the solution was lowered to −78° C. PhMgBr (0.21 mL, 1.8 M) was added to the solution and it was stirred for 15 minutes. n-BuLi (0.19 mL, 2.0 M) was subsequently added and the reaction was stirred an additional 30 minutes. Acetaldehyde (0.085 mL, 1.5 mmol) was added to the reaction and it was warmed to 0° C. The solution was subsequently quenched with 10% HCl and the aqueous layer was extracted three times with EtOac. The combined organics were dried over sodium sulfate, concentrated in vacuo, and purified by HPLC to afford 4-tert-butyl-N-(4-chloro-2-(4-(1-hydroxyethyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide as a white solid: MS (ES) M+H expected 449.1, found 449.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.CS(O[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35][CH3:36])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:34]([O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH2:35][CH3:36]
Reactant: CCCOc1ccccc1CCCOS(C)(=O)=O
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1ccccc1CCCOc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 125.5 %

Procedure:
Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 3-(2-propoxyphenyl)propyl methanesulfonate (1.06 g) and potassium carbonate (309 mg) were suspended in DMF (15 ml), and the resulting suspension was stirred at 60° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain methyl 7-[3-(2-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (832 mg) as a yellow oil.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.N1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[CH:23](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: C1CCNCC1
Solvent: CCO
Product: CCCCCCCCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 2.41 g (7.5 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 1.41 ml (7.5 mmol) of decylaldehyde in 50 ml of ethanol, 0.08 ml (0.8 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/1→1/2) to yield 2.59 g (75.1%, light yellow oily substance) of the desired product.