Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C(Cl)(Cl)Cl.[NH2:12][C:13]1[C:14]([S:22][CH3:23])=[N:15][C:16]([CH3:21])=[CH:17][C:18]=1[S:19][CH3:20].[Br:24][CH2:25][C:26](Br)=[O:27]>O>[Br:24][CH2:25][C:26]([NH:12][C:13]1[C:14]([S:22][CH3:23])=[N:15][C:16]([CH3:21])=[CH:17][C:18]=1[S:19][CH3:20])=[O:27]
Reactant: CSc1cc(C)nc(SC)c1N
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
Triethylamine (274 mg, 2.71 mmol) was added to a chloroform (10 ml) solution of 3-amino-2,4-bis(methylthio)-6-methylpyridine (492 mg, 2.46 mmol), and bromoacetyl bromide (521 mg, 2.58 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and then extracted with methylene chloride. The organic layer was washed with 1N hydrochloric acid, water, an aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous solution of sodium chloride in this order, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 25 g, eluent—hexane:acetone=7:1→5:1→3:1) to obtain 100 mg (yield 13%) of 2-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide as a colorless crystal (melting point: 171 to 172° C.).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(#N)C.[N-:11]=[N+:12]=[N-:13].[Na+]>O>[N:11]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:12]=[N-:13]
Reactant: CCOC(=O)CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN=[N+]=[N-]
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of 490 g. (4 moles) of ethyl chloroacetate in 1500 ml. of acetonitrile were added 260 g. (4 moles) of sodium azide, and the mixture was heated at the reflux temperature for 20 hours. After heating, the reaction mixture was poured into 1 liter of water with stirring for 1/2 hour. The organic phase was separated from the aqueous phase and evaporated in vacuo to dryness. The yellow residual oil was dissolved in 1200 ml. of diethyl ether and the solution was dried over magnesium sulfate. Evaporation of the diethyl ether in vacuo gave 391 g. (76% yield) of ethyl azidoacetate.
Reaction SMILES: [F:1][C:2]1([F:40])[CH2:7][CH2:6][CH:5]([C:8]([NH:10][CH2:11][C:12]([CH3:39])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13][CH2:14][N:15]2[C@H:20]3[CH2:21][CH2:22][C@@H:16]2[CH2:17][CH:18]([N:23]2[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]2[CH3:32])[CH2:19]3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].I[CH3:44].O>CN(C=O)C>[F:40][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]([N:10]([CH3:44])[CH2:11][C:12]([CH3:39])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13][CH2:14][N:15]2[C@H:20]3[CH2:21][CH2:22][C@@H:16]2[CH2:17][CH:18]([N:23]2[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]2[CH3:32])[CH2:19]3)=[O:9])[CH2:4][CH2:3]1
Reactant: CI
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CNC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CN(C)C(=O)C1CCC(F)(F)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
To a solution of the title compound from example 21 (100 mg, 0.18 mmol) in dry DMF (1.5 mL) was added sodium hydride (9 mg, 0.22 mmol) as a 60% suspension in mineral oil and the solution stirred under a nitrogen atmosphere at room temperature for 30 min. Iodomethane (0.06 mL, 0.9 mmol) was added and the reaction stirred at room temperature for 2 h. Water was added and the reaction partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-5% methanol/CH2Cl2 followed by purification by HPLC eluting with 5-70% water/acetonitrile/0.1% TFA to afford the title compound (9 mg, 7%) which was isolated as the trifluoroacetate salt.
Reaction SMILES: Br[CH:2]([C:14]([C:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[S:19][CH:20]=1)=[O:15])[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].C(#N)C.C[O-].[Na+].[C:31]([OH:39])(=[S:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)(=O)C>[C:31]([S:38][CH:2]([C:14]([C:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[S:19][CH:20]=1)=[O:15])[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])(=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(c1csc2ccccc12)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Reactant: OC(=S)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C(SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1csc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
As for Example 21, 1-[3-bromo-3-(benzo[b]thien-3-ylcarbonyl)propionyl]-L-proline (0.01 mole) in 25 ml. of acetonitrile is added to a mixture of 0.01 mole of sodium methoxide and 0.015 mole of thiobenzoic acid in 25 ml. of acetonitrile. The mixture is stirred at room temperature for 16 hours, one ml. of acetic acid is added and the solvent is evaporated in vacuo. The residue is partitioned between dichloromethane and water containing acetic acid. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is removed in vacuo to give the product of the Example as a yellow glass.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:24]=[CH:23][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.[C:25]([O-:28])([O-])=O.[K+].[K+].N#N>C1(C)C=CC=CC=1.CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[CH:24]=[CH:23][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:28][C:25]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: N#N
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Oc2cccc(Br)c2)cc1)c1ccc(Oc2cccc(Br)c2)cc1
Temperature: 160 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
A reaction mixture was prepared with 3.8 g (22 mmol) of m-bromophenol, 2.18 g (10 mmol) of 4,4'-difluorobenzophenone, 10 ml of dimethylacetamide (DMAc), 15 ml of toluene and 4.55 g of K2CO3, and reacted at 130° C. for 1 hour while N2 gas was passed into the mixture. Subsequently, the reaction temperature was raised to 160° C. to remove toluene and water in the reaction vessel as an azeotropic mixture, and the reaction was continued for 2 hours to obtain 5.25 g of 4,4'-bis(3-bromophenoxy) benzophenone. The yield was approximately 100%.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[C:12]([Cu])#[N:13]>C(#N)CC.CCOC(C)=O>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:12]#[N:13])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CCC#N
Product: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 86.6 %

Procedure:
To a stirred solution of 2,5-dibromo-3-nitro-pyridine (25 g, 88.68 mmol) in propionitrile (100 ml) was added CuCN (8.7 g, 97.55 mmol) and the mixture was heated to 90° C. for 17 h. Then it was allowed to cool to room temperature, diluted with EtOAc, washed twice with brine, dried with Na2SO4 and concentrated. The remaining residue was purified by chromatography (silica gel; DCM/MeOH 95:5-85:15) to obtain the title compound as yellow solid (17.5 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH:30]=[CH2:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[N+](=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N-]>C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C@@H:30]3[CH2:31][C@H:34]3[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:9][N:10]([C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:4]=2[CH:3]=1.[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C@H:30]3[CH2:31][C@H:34]3[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:9][N:10]([C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:4]=2[CH:3]=1
Reactant: C=Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@H]1c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Product: CCOC(=O)[C@@H]1C[C@H]1c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 100 °C
Yield: 31 %
Yield: 64 %

Procedure:
A mixture of 6-chloro-1-trityl-3-vinyl-1H-pyrazolo[4,3-c]pyridine (100 mg, 0.237 mmol, derived from 3a and vinylboronic acid pinacol ester as described in Scheme 1, Step 3) in toluene (2 ml) under nitrogen was treated with ethyl diazoacetate (0.074 ml, 0.711 mmol) and heated at 100° C. overnight to give a yellow solution. The reaction was cooled to room temperature and then diluted with aqueous sodium hydrogen carbonate and dichloromethane. The organic layer was concentrated and purified by column chromatography on silica gel (24 g, eluting with 0-20% EtOAc/hexanes) to give two products: trans-ethyl 2-(6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxylate (77 mg, 64% yield) and cis-ethyl 2-(6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxylate (37 mg, 31% yield). MS ESI calc'd. for C31H26ClIN3O2[M+1]+ 508, found 508.
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.[CH2:22](N(CC)CC)C.[N:29]([CH:32]1[C:38](=[O:39])[N:37]2[CH:33]1[CH2:34][C:35](=O)[CH:36]2[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])=[N+:30]=[N-:31]>C(Cl)Cl>[N:29]([CH:32]1[C:38](=[O:39])[N:37]2[CH:33]1[CH2:34][C:35]([O:10][S:11]([C:14]1[C:15]([CH3:22])=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])=[C:36]2[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])=[N+:30]=[N-:31]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)CC12
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(N=[N+]=[N-])C2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
p-Toluenesulfonic anhydride (1 mmol) and triethylamine (1.2 mmol) are added to an ice-cold solution of benzyl 6-azido-1-azabicyclo[3.2.0]-heptan-3,7-dione-2-carboxylate (1 mmol) in anhydrous methylene chloride (10 ml). After stirring in the cold for 2 hr, the solution is washed with water, pH 3 phosphate buffer, and 5% sodium bicarbonate solution, dried over magnesium sulfate, filtered, and evaporated under vacuum to give benzyl 6-azido-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Se](=O)=[O:10]>O1CCOCC1>[Br:1][C:2]1[C:3]([CH:8]=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Se]=O
Reactant: Cc1ncccc1Br
Solvent: C1COCCO1
Product: O=Cc1ncccc1Br
Yield: 28.9 %

Procedure:
To a solution of 3-bromo-2-picoline (prepared as described by Guthikonda, R. N.; Cama, L. D.; Quesada, M.; Woods, M. F.; Salzmann, T. N.; Christensen, B. G. J. Med. Chem. 1987, 30, 871-880) (249 mg, 1.45 mmol) in dioxane (2 mL) was added selenium(IV) oxide (212 mg, 1.91 mmol) and the mixture stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (Hexanes/ether, 3:1) to afford the title compound (78 mg, 29%) as a pale yellow solid. 1H NMR (CDCl3): δ 7.38 (dd, 1H, J=9, 6 Hz), 8.05 (d, 1H, J=9 Hz), 8.76 (d, 1H, J=3 Hz), 10.25 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:14]([OH:17])(=[O:16])=[O:15])[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[C:12]=1[OH:13])=[O:2].C(=O)([O-])[O-:19].[Na+].[Na+].[K]>>[C:1]([C:3]1[CH:4]=[C:5]([S:14]([OH:17])(=[O:16])=[O:15])[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[C:12]=1[OH:13])([OH:19])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(S(=O)(=O)O)c2cccnc2c1O
Agent: [K]
Agent: [Na+]
Product: O=C(O)c1cc(S(=O)(=O)O)c2cccnc2c1O
Temperature: 52 °C
Reaction time: 0.92 h
Yield: 48.5 %

Procedure:
The 7-formyl-8-hydroxyquinoline-5-sulfonic acid (15 mmol, 3.80 g) was dissolved in sodium carbonate solution (34.5 mmol, 3.66 g in 200 mL of H2O). The solution was stirred and heated at 52° C. (oil bath). Then to the hot solution potassium permaganate (37.5 mmol, 5.94 g) was added. The temperature was increased to 68° C. The stirring and heating (60°-65° C.) was continued for 55 minutes. After that time the reaction mixture was filtered, and the solid was washed with sodium carbonate solution followed by water. The filtrate was concentrated under reduced pressure, acidified with 50% sulfuric acid (pH 3) and left for crystallization. The precipitate was filtered off, washed with a small amount of water and dried to give 1.96 g of 7-carboxy-8-hydroxyquinoline-5-sulfonic acid (48.5%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:37]([O:39]C)=[O:38])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[CH2:1]([O:8][C:9]1[C:10]([C:37]([OH:39])=[O:38])=[N:11][C:12]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:23][CH2:24]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(N2CCN(CCCCNC(=O)OC(C)(C)C)CC2)c2cccnc2c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCN1CCN(c2nc(C(=O)O)c(OCc3ccccc3)c3ncccc23)CC1
Reaction time: 4 h
Yield: 62.2 %

Procedure:
To a solution of methyl 8-(benzyloxy)-5-(4-(4-(tert-butoxycarbonylamino)butyl)-piperazin-1-yl)-1,6-naphthyridine-7-carboxylate (Example 4.1; 1.2 mmol) in a mixtire of methanol (2.5 ml) and water (2.5 ml) was added sodium hydroxide (2.5 mmol). The reaction mixture was stied at r.t. for 4 hr. The mixture was quenched with water and 2N HCl until pH=6 was reached. The mixture was extracted with AcOEt (2×). The organic layer was dried (MgSO4), and filtered to afford a solid (400 mg), that was used as such in the next step.
Reaction SMILES: [PH2:1](=[O:3])[O-:2].[NH4+].C[Si](C)(C)N[Si](C)(C)C.[CH2:14](Br)[CH:15]=[CH2:16].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([O:29][CH3:30])[CH:21]=1>C(Cl)Cl>[CH3:30][O:29][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[N+:26]([O-:28])=[O:27])[CH2:19][CH:14]=[CH:15][CH2:16][PH:1](=[O:2])[OH:3]
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Reactant: O=[PH2][O-]
Reactant: C=CCBr
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [NH4+]
Solvent: ClCCl
Product: COc1cc(CC=CC[PH](=O)O)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of ammonium phosphinate (1.00 g, 12.0 mmol) and Hexamethyldisilazane (1.94 g, 12.0 mmol) was heated to 110° C. under N2 for approximately 1.5 hours. The reaction mixture was cooled to 0° C., charged with anhydrous DCM (10 mL) followed by Allyl bromide (1.46 g, 12.0 mmol) and allowed to stir at RT for 16 hours. The reaction mixture was then cooled to 0° C. and charged with more hexamethyldisilazane (1.94 g, 12.0 mmol). The reaction mixture was stirred at 0° C. for 2 hours then treated with 4-(bromomethyl)-2-methoxy-1-nitrobenzene (3.00 g, 12.2 mmol). The reaction mixture was allowed to stir for 16 hours at rt after which it was filtered. The filtrate was quenched with 1N HCl (10 mL) and extracted with DCM (20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to a yellow oil. The material was dissolved in DCM and extracted with aq. NaHCO3. The aqueous layer was cooled to 0° C. and then acidified with 6 M HCl. The aqueous layer was saturated with solid NaCl then extracted with DCM. The organic layer was concentrated under reduced pressure to a yellow oil (1.29 g, 39%). This material was used in successive reactions without any further purification. 1H NMR (CDCl3, 400 MHz): δ=9.81 (br. s., 1H), 7.81 (d, J=8.3 Hz, 1H), 7.01 (s, 1H), 6.89 (td, J=1.8, 8.3 Hz, 1H), 5.79-5.67 (m, 1H), 5.29-5.18 (m, 2H), 3.96 (s, 3H), 3.10 (d, J=15.9 Hz, 2H), 2.53-2.44 (m, 2H). MS (ESI): m/z 270.37 [M−H]+. UPLC: tR=0.76 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19]>ClCCl.C(N(CC)CC)C>[CH3:1][S:2]([O:6][CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])(=[O:4])=[O:3]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.7 %

Procedure:
After methanesulfonyl chloride (12.7 g) was added to a solution of N-(2-hydroxyethyl)phthalimide (19.1 g) in anhydrous dichloromethane (200 ml), triethylamine (20 ml) was added dropwise to the mixture in an ice bath. The mixture was stirred at ambient temperature for 4 hours. At the end of this time the reaction mixture was concentrated under reduced pressure. The residual solid was washed with ethyl acetate and water and then recrystallized from ethyl acetate to afford the desired compound (18.2 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([NH2:22])=[N:3]1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([N:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:3]1
Reactant: O=Cc1ccccc1
Reactant: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Solvent: c1ccccc1
Product: CN(C)Cc1cccc(OCCCNc2nc(N=Cc3ccccc3)nn2C)c1
Yield: 94.4 %

Procedure:
A mixture of 1-methyl-N5 -[3-[3-[(dimethylamino)methyl]phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (6.08 g) and benzaldehyde (2.4 g) in dry benzene was heated under reflux during 12 hr in a Dean & Stark apparatus. The solvent was removed and the residue purified by column chromatography on silica using methanol to give the title compound as a yellow oil (7.4 g). TLC silica; methanol:ammonia (80:1) Rf 0.43. NMR (CDCl3) 0.85 s (1H); 2.05 m (2H); 2.5-3.0 m (4H); 3.0-3.3 m (3H); 5.35 t (1H); 5.88 t (2H); 6.39 q (2H); 6.42 s (3H); 6.62 s (2H); 7.77 s (6H); 7.83 m (2H).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[Li].[C:7]12[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12]C(=O)O[C:8]2=[O:9].Cl>CS(C)=O.C(OCC)C>[CH3:1][S:2]([NH:5][C:8]([C:7]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:12])=[O:9])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Agent: [Li]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1ccccc1N
Temperature: 25 °C

Procedure:
Lithium methanesulfonamidate (1.0 g, 10 mmol) and isatoic anhydride (1.63 g, 10 mmol) in dimethyl sulfoxide (5 mL) were heated at 80° C. for 30 min. The reaction was cooled down to room temperature and acidified with hydrogen chloride in diethyl ether. The ether was evaporated and water added. The precipitated oil was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (95:5). The desired material was obtained in a yield of 0.52 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl[CH2:25][CH2:26][N:27]([CH2:35][CH2:36]Cl)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:25][CH2:26][N:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:35][CH2:36]1)=[O:23])[CH3:2]
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (6 g, 16.9 mmol) and bis-(2-chloro-ethyl)-benzyl amine (6.44 g, 24 mmol). Yield 2.21 g (25%); yellow oil; MS: 513.9 (M+H)+
Reaction SMILES: C[O-].[Na+].[SH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[BH4-].[Na+].CS(O[CH2:19][CH:20]([O:41][CH3:42])[CH2:21][O: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])(=O)=O>O.C1COCC1.CO>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][S:4][CH2:19][CH:20]([O:41][CH3:42])[CH2:21][O: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]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COS(C)(=O)=O)OC
Reactant: OCCCCCCS
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOCC(CSCCCCCCO)OC
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To 14 ml of a methanol solution of sodium methoxide (1M solution) are added 2.04 g of 6-mercaptohexanol and 0.24 g of sodium borohydride, to which a THF (20 ml) solution containing 2.18 g of 2-methoxy-3-octadecyloxypropyl methanesulfonate is added dropwise under nitrogen streams with stirring. The mixture is stirred at room temperature for 20 hours and then at 40° C. for 1 hour. After the addition of water, the mixture is extracted with ethyl acetate. The extracted layer is washed with water, dried and concentrated under reduced pressures to obtain an oily product. Purification of the oily product by silica gel column chromatography gives 2.31 g of the captioned compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[C:10]=1[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2]>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[C:10]=1[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCO[Si](C)(C)C(C)(C)C)c1CCC(=O)OCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCCOc1cccc(CCCCCCO)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 4-[3-[6-(tert-butyl-dimethyl-silanyloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (0.837 mmol, 438 mg) in THF (12 mL) was added a solution of n-tetrabutyl ammonium fluoride (1.25 mmol, 1.25 mL, 1.0M) in THF at 0° C. Then, the resulting colorless solution was allowed to warm to room temperature in 2 h and the mixture was stirred for another 2 h at room temperature before being diluted with water (˜50 mL). The organic compound was extracted into ethyl acetate (2×50 mL) and the combined extracts were washed with brine solution (100 mL). The organic solution was dried over anhydrous magnesium sulfate and the filtrate was removed under vacuum after filtration of the drying agent. The crude residue was dried further under high vacuum and the desired 4-[2-(2-ethoxycarbonyl-ethyl)-3-(6-hydroxy-hexyl)-phenoxy]-butyric acid ethyl ester (342 mg, 99%) was isolated as a colorless oil: ES(+)-HRMS m/e calculated for C23H36O6 (M+Na)+ 431.2404. found 431.2404.