Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[CH:15])(=O)=O)=CC=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CCO>[CH2:12]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:13][C:14]#[CH:15]
Reactant: C1CNCCN1
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Product: C#CCCN1CCNCC1

Procedure:
A solution of but-3-ynyl 4-methylbenzenesulfonate (2.0 mL) and piperazine (2.0 g) in EtOH (6 mL) was heated to reflux for 30 min. The mixture was concentrated, diluted with NaOH 2 M (8 mL) and extracted with Et2O (50 mL). Evaporation of the organic layer gave a 2:1 mixture of mono and bis-alkylated piperazine (450 mg) which was discarded. The aqueous layer was further extracted with DCM (100 mL) to give of 1-(but-3-ynyl)piperazine (640 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:16][S:17]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cccc(NS(C)(=O)=O)c2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
To a mixture of ethyl 7-amino-1H-indole-2-carboxylate (0.28 g) and pyridine (8 mL) was added methylsulfonyl chloride (0.13 mL) at 4° C., and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated, diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (240 mg, yield 62%) as pale-yellow crystals. melting point 157-158° C.
Reaction SMILES: C([Br:4])(=O)C.C[O:6][C:7]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O[CH:12]2[CH:9]([CH2:10][CH2:11]2)[O:8]1>>[Br:4][C@@H:12]1[CH2:11][CH2:10][C@H:9]1[O:8][C:7](=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)Br
Reactant: COC1(c2ccccc2)OC2CCC2O1
Product: O=C(O[C@@H]1CC[C@H]1Br)c1ccccc1
Yield: 101.1 %

Procedure:
16.9 g (0.189 mol) of acetyl bromide are added dropwise to 26.0 g (0.126 mol) of 3-methoxy-3-phenyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture), at 20° to 30° C. After the reaction has subsided, the mixture is heated to the reflux for 4 hours. Distillation in vacuo gives 32.5 g (99%) of trans-1-bromo-2-benzoyloxy-cyclobutane as a colourless oil of boiling point0.2 94°-97°, which solidifies in the receiver.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]=[C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][C:15]([F:34])=[C:16]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[CH2:30]([O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]=1[C:16]1[C:10]2[CH:9]=[C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:35])=[O:3])[S:12][C:11]=2[CH:13]=[CH:14][C:15]=1[F:34])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOc1c(-c2c(F)ccc3sc(C(C)=CC(=O)OCC)cc23)cc(C(C)C)cc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1c(-c2c(F)ccc3sc(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-but-2-enoic acid was isolated as a white solid. 1H-NMR (CDCl3), δ: 7.71 (dd, J=8.7, 4.4 Hz, 1H), 7.26 (t, J=16.7 Hz, 2H), 7.20 (d, J=1.8 Hz, 1H), 7.03 (d, J=1.8 Hz, 1H), 3.39 (dt, J=13.8, 6.9 Hz, 1H), 3.33 (t, J=6.3 Hz, 2H), 2.93 (dt, J=13.7, 6.8 Hz, 1H), 2.57 (s, 3H), 1.28 (m, 12H), 1.22 (m, 2H), 0.96 (m, 2H), 0.57 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=C[N:21]([C:24]([N:26]2C=[N:29][CH:28]=[CH:27]2)=O)[CH:20]=1.N1C=C(N)C=NC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:29][C:28]1[CH:20]=[N:21][CH:24]=[N:26][CH:27]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Nc1cncnc1
Solvent: C1CCOC1
Product: O=C(Nc1cncnc1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method C; 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) in THF (3 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and pyrimidin-5-amine (61.9 mg, 0.65 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane:ethyl acetate:triethylamine (4:1:0.01) to yield the title compound. 150 mg.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:41])[CH2:11][C:12](=[O:40])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:39])[C@@H:23]([NH:31]C(OC(C)(C)C)=O)[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.C(OC(NC1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=CC=2)=CC=1)=O)(C)(C)C>C(Cl)(Cl)Cl.CO>[NH2:31][C@@H:23]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]/[C:12](=[O:40])[CH2:11][C:10](=[O:41])/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:16][CH:17]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(C=CC(=O)CC(=O)C=Cc2ccc(O)cc2)cc1
Agent: CC(C)(C)OC(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1

Procedure:
The title compound was synthesized using the same procedure employed for Example 281, but with (1E,6E)-1-(4-hydroxyphenyl-7-[4-((S)-2-tert-butoxycarbonylamino-3-phenylpropionylamino)phenyl]hepta-1,6-diene-3,5-dione (30 mg, 54 μmol, synthesized in Example 269) as the starting material instead of (1E,6E)-1-[4-(tert-butoxycarbonylamino)phenyl]-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel chromatography (chloroform/methanol=97/3 to 85/15). The product was obtained as a solid (7.4 mg, 30%) having the following characteristics.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[C:5](=[O:12])[N:4]([C@H:13]2[C@H:17]([OH:18])[C@H:16]([OH:19])[C@H:15]([CH2:20][OH:21])[O:14]2)[CH:3]=1.[NH3:22]>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:22])=[O:9])[C:5](=[O:12])[N:4]([C@H:13]2[C@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([CH2:20][OH:21])[O:14]2)[CH:3]=1
Reactant: N
Reactant: COC(=O)c1nc(Cl)cn([C@@H]2O[C@@H](CO)[C@@H](O)[C@H]2O)c1=O
Solvent: CO
Product: NC(=O)c1nc(Cl)cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1=O
Temperature: 0 °C

Procedure:
In 4 mL of methanol was dissolved 0.26 g of methyl 6-chloro-4-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate. While cooling the solution with ice, gaseous ammonia was introduced until saturation. The reaction mixture was stirred at an ice-cooled temperature for one hour and then the solvent was removed under reduced pressure. By purifying the residue thus obtained by column chromatography [eluent: chloroform:methanol=7:1], 0.06 g of 6-chloro-4-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-oxo-3,4-dihydro-2-pyrazinecarboxamide was obtained as a light yellow-colored solid product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].ClC(OC(Cl)C)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:29])[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.3 %

Procedure:
To a solution of rac-[(3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (3.50 g, 8.04 mmol) in toluene (50 mL) was added under an atmosphere of nitrogen N,N-diisopropyl ethyl amine (1.86 mL, 10.9 mmol). The flask was cooled with a water bath and 1-chloroethyl chloroformate (1.14 mL, 10.5 mmol) was added during 2 min. After stirring for 2 h at ambient temperature the solution stood over night at 5° C. The reaction mixture was concentrated in vacuo. After the addition of methanol (50 mL) it was stirred for 4 h at ambient temperature. Concentration afforded the title compound (2.95 g, 99%) as a light brown oil. MS m/e: 345.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[O:19][C:20]([F:23])([F:22])[F:21].[C:24]([O:28][CH3:29])(=[O:27])[NH:25][NH2:26].O.C([O-])([O-])=O.[K+].[K+]>O=P(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:29][O:28][C:24]([NH:25][N:26]=[C:14]([NH:13][C:10]1[CH:11]=[N:12][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([CH3:1])=[C:3]([O:19][C:20]([F:23])([F:22])[F:21])[CH:4]=2)=[CH:8][CH:9]=1)[CH3:15])=[O:27]
Reactant: COC(=O)NN
Reactant: CC(=O)Nc1ccc(Oc2ccc(C)c(OC(F)(F)F)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)NN=C(C)Nc1ccc(Oc2ccc(C)c(OC(F)(F)F)c2)nc1
Temperature: 60 °C
Yield: 59.1 %

Procedure:
To a solution of N-{6-[4-methyl-3-(trifluoromethoxy)phenoxy]pyridin-3-yl}acetamide (Intermediate 32, 500 mg, 1.53 mmol) in 2.2 mL of POCl3, methyl carbazate (152 mg) was added. The resulting mixture was heated at 60° C. for 7 hrs and overnight at room temperature. After additional heating for 5 hrs, further methyl carbazate (30 mg, 0.2 equiv) was added. The mixture was cooled to 0° C. and water was cautiously added, followed by a saturated solution of K2CO3 and then solid K2CO3 until pH=8 was reached. Ethyl acetate (50 mL) was then added and phases were separated. The aqueous phase was then back-extracted with ethyl acetate (2×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated to give 520 mg of crude as orange foam which was purified by silica flash-chromatography, eluant cyclohexane/ethyl acetate, gradient from 50/50 to 20/80 v/v giving the title compound (360 mg) as white foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=O)[CH3:11])([O-:3])=[O:2].O.[NH2:14][NH2:15].O>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[N:14][NH2:15])[CH3:11])([O-:3])=[O:2]
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(=NN)c1ccccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 120 h
Yield: 46.9 %

Procedure:
To a solution of 2′-nitroacetophenone (8.26 g, 50.00 mmol) in ethanol (50 ml) was added hydrazine monohydrate (4.85 ml, 100 mmol) and the reaction mixture was heated at 70° C. for 5 h. The reaction mixture was cooled to room temperature and water (100 ml) was added. After 5 d, the reaction mixture was concentrated in vacuo to ca. 100 ml and diethyl ether (100 ml) was added. The layers were separated and the aqueous layer was extracted with diethyl ether (100 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford ca. 8.0 g of a crude yellow oil. This was purified by chromatography in two batches using a Biotage Flash 40M™ cartridge packed with silica gel (90 g) eluting with dichloromethane: diethyl ether (19:1) to afford the title compound as viscous yellow oil (4.20 g, 45%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](Cl)[CH:20]=[CH:21][CH3:22].[I-].[Li+].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH3:11][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:19]/[CH:20]=[CH:21]/[CH3:22])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: CC=CCCl
Reactant: CC(C(=O)OCc1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C=C/CC(C)(C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
A solution of 2-phenyl-propionic acid benzyl ester (2.0 g, 8.32 mmol), crotyl chloride (1.02 mL, 9.99 mmol), and lithium iodide (1 g) in tetrahydrofuran (15 mL) at 0° C. was treated dropwise with the lithium hexamethyldisilazide (9.99 mL, IM in tetrahydrofuran, 9.99 mmol). The reaction was allowed to warm to 25° C. and stirred for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.43 g, 99%). 1H NMR (300 MHz, CDCl3): δ ppm 1.55 (m, 6 H) 2.68 (m, 2 H) 5.10 (m, 2 H) 5.21 (m, 1 H) 5.45 (m, 1 H) 7.26 (m, 10 H). MS (ESI+) m/z 312 (M+NH4)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]([CH2:13][SH:14])[CH2:11][CH:10]([CH2:15][SH:16])[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1>CCOCC.C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]([CH2:13][S:14][CH:23]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:11][CH:10]([CH2:15][S:16][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(CS)CC(CS)N1Cc1ccccc1
Reactant: C1=COCCC1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C1C(CSC2CCCCO2)CC(CSC2CCCCO2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-benzyl-2,4-bis(mercaptomethyl)-4-butanelactam (compound No.15-2, 134 mg) in dry ether (2 ml), dihydropyran (110 mg) dissolved in dry ether (2 ml) is added under nitrogen atmosphere and then boron trifluoride diethyl ether complex (15 mg) dissolved in dry ether (1 ml) is added to the mixture. The mixture is stirred overnight at room temperature. The mixture is diluted with a mixture of benzene and ethyl acetate and washed with 10% aqueous sodium bicarbonate solution, water and saturated sodium chloride solution. The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue is purified by silica gel column chromatography to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]=O)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[S:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]=[C:34]3[S:30][C:31](=[O:36])[NH:32][C:33]3=[O:35])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: O=C1CSC(=O)N1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C=O)cn2)cc1Cl
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C=C3SC(=O)NC3=O)cn2)cc1Cl
Temperature: 25 °C
Yield: 74.8 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl-pyrazin-2-yl)-propionamide (prepared as in Example 18, 44 mg, 0.1 mmol), 2,4-thiazolidinedione (18 mg, 0.15 mmol), piperidine (2 μL, 0.02 mmol), and benzoic acid (1.2 mg, 0.01 mmol) in anhydrous ethanol (5 mL) was heated under reflux overnight. The reaction mixture was allowed to cool to 25° C. and then was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 0%–60% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-pyrazin-2-yl]-propionamide (40 mg, 75%) as a white solid: LC-MS m/e 535 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12]O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CCO)cc1OC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCCl)cc1OC

Procedure:
The reaction mixture of 2-(3,4-dimethoxyphenyl)ethanol (6.0 g, 32.8 mmol) and thionyl chloride (19 g, 164 mmol) in chloroform (20 mL) was stirred at reflux for 4 h, concentrated, and partitioned between water and ethyl acetate. The organic layer was washed with NaHCO3 and brine, dried over anhydrous sodium sulfate, and concentrated to afford 4-(2-chloroethyl)-1,2-dimethoxybenzene (K) quantitatively (6.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])(=O)C.[Na+].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=1Cl)([O-:16])=[O:15]>C(O)C>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])([O-:16])=[O:15]
Reactant: Nc1ccccc1O
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccccc1O
Temperature: 25 °C

Procedure:
17.30 g (157 mmol) of 99% strength 2-aminophenol and 17.15 g (209 mmol) of anhydrous sodium acetate are added to a solution of 25.0 g (121 mmol) of 98% strength 2,6-dinitrochlorobenzene in 185 ml of anhydrous ethanol under nitrogen while stirring. The reaction solution is refluxed for 2 hours and subsequently cooled to room temperature. The red-violet crystalline needles are separated off on a “black band” filter, washed with water until the washings are colorless and dried at 50° C. under reduced pressure. This gives 27.90 g (84% of theory) of shiny black needles which melt at 189-192° C. (lit.: 191° C.).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([F:39])([F:38])[C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C.O>[F:20][C:21]([F:38])([F:39])[C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][N:10]3[C:11]4[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=4[N:8]=[CH:9]3)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(C(F)(F)F)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.5 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (20 ml) were added potassium carbonate (1.66 g) and 4-[4-(trifluoromethyl)benzoyl]benzyl bromide (3.43 g) and the mixture was stirred at room temperature for 20 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was distilled off. To the residue was added 4N-hydrogen chloride/ethyl acetate and the resulting precipitate was harvested by filtration. To this precipitate was added a saturated aqueous solution of NaHCO3 and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was distilled off to provide the title compound as colorless powder (1.57 g, 36%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: CCCCCCCCC1COC(c2ccc(Br)cc2)OC1
Reactant: OB(O)c1cccc(F)c1F
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+]
Product: CCCCCCCCC1COC(c2ccc(-c3cccc(F)c3F)cc2)OC1

Procedure:
Quantities: compound from Example 14 (10.7 g, 30 mmol), compound from Example 36 (5.5 g, 35 mmol), tetrakis(triphenylphosphine)palladium(0) (1.04 mg, 0.9 mmol) and aqueous sodium carbonate (30 cm3, 2M). The experimental procedure was as described in Example 63.
Reaction SMILES: ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[CH:14]([N:17]([CH2:21][CH3:22])[CH:18]([CH3:20])C)(C)C.[CH3:23][C@H:24]1[CH2:33][NH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:34]3[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=3)[CH:30]=2)[N:25]1[C:44](=[O:46])[CH3:45].N1CCCC1>>[CH3:23][C@H:24]1[CH2:33][N:32]([C:14]([N:17]2[CH2:18][CH2:20][CH2:22][CH2:21]2)=[O:3])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:34]3[CH:35]=[CH:36][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:38][CH:39]=3)[CH:30]=2)[N:25]1[C:44](=[O:46])[CH3:45]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)N1c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2NC[C@@H]1C
Solvent: C1CCNC1
Product: CC(=O)N1c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)N2CCCC2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
4-Nitrophenyl chloroformate (0.4 M in 1,4-dioxane, 0.075 mL, 0.030 mmol) and N,N-diisopropylethylamine (0.015 mL, 0.086 mmol) were added to (S)-1-(2-methyl-6-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.2 M in 1,4-dioxane, 0.100 mL, 0.020 mmol) and the mixture stirred at 50° C. for 1 h. Pyrrolidine (0.2 M in 1,4-dioxane, 0.200 mL, 0.040 mmol) was then added and the mixture was stirred at 80° C. for 16 h. The reaction was concentrated and the crude product was purified by mass-triggered preparatory HPLC. The product-containing fractions were combined and concentrated to afford (S)-1-(2-methyl-6-(4-(methylsulfonyl)phenyl)-4-(pyrrolidine-1-carbonyl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.0038 g, 43% yield). MS (ESI, pos. ion) m/z 442
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:3].[CH:12]1[C:18]([NH2:19])=[N:17][C:15](=[O:16])[N:14]([C@@H:20]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C:21]2([F:29])[F:28])[CH:13]=1.Cl>>[F:29][C:21]1([F:28])[C@H:22]([OH:27])[C@@H:23]([CH2:25][OH:26])[O:24][C@H:20]1[N:14]1[CH:13]=[CH:12][C:18]([NH:19][C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:3])=[N:17][C:15]1=[O:16]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: CCCCCCCOC(=O)Cl
Agent: Cl
Product: CCCCCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Yield: 93 %

Procedure:
Using Method A and heptyl chloroformate, gemcitabine hydrochloride was converted to 43 (white solid, 93% yield): 1H NMR (200 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.24-8.28 (d, 1H), 7.12-7.16 (d, 1H), 6.33-6.37 (d, 1H), 6.16-6.24 (t, 1H), 5.31-5.36 (t, 1H), 4.19-4.33 (m, 1H), 4.10-4.17 (t, 2H), 3.63-3.94 (m, 3H), 1.60-1.66 (t, 2H), 1.29-1.31 (t, 8H), 0.86-0.92 (t, 3H).