Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](Cl)=[C:8](Cl)[N+:9]([CH3:13])=[CH:10]2)=[CH:5][CH:4]=1.[CH3:16][Mg]Cl.O>O1CCCC1>[NH2:2][C:3]1[CH:12]=[C:11]2[CH:6]([CH2:7][CH2:8][N:9]([CH3:13])[CH:10]2[CH3:16])[CH2:5][CH:4]=1
Reactant: C[n+]1cc2cc(N)ccc2c(Cl)c1Cl
Reactant: C[Mg]Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: CC1C2=CC(N)=CCC2CCN1C
Temperature: -78 °C
Reaction time: 18 h

Procedure:
(±) 7-Amino-2-methyl-3,4-dichloroisoquinolinium iodide (0.50 g, 1.7 mmol) was suspended in anhydrous tetrahydrofuran (50 ml) and cooled to −78° C. The cooled solution was treated with methyl magnesium chloride (2.14 ml of a 3M solution in THF, 6.96 mmol), added as a single portion. The reaction was allowed to reach room temperature over 18 h before being poured into water (50 ml). The organic solvent was removed in vacuo and the organic product extracted into dichloromethane. Drying over magnesium sulfate and evaporation in vacuo fuinished the title compound as a pale yellow oil (0.3 g, 98%). For ease of handling the product was converted into a monohydrochloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CC(C)([O-])C.[Na+]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:3][CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: N#Cc1ccc(N2CCOCC2)cc1
Yield: 78.7 %

Procedure:
According to the general to procedure B, 4-chlorocyanobenzene (71 mg, 0.52 mmol) reacted with morpholine (53 mg, 0.61 mmol) using 1 mol % of catalyst and sodium tert-butoxide (58 mg, 0.60 mmol) at 45° C. for 27 h to give the title compound (77 mg, 82%) as a solid: 1H-NMR (400 MHz, CDCl3): δ 7.49 (d, 2H, J=8.0 Hz), 6.85 (d, 2H, J=8.8 Hz), 3.84 (t, 4H, J=4.8 Hz), 3.27 (t, 4H, J=4.8 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 153.36, 133.36, 119.76, 113.93, 100.69, 66.31, 47.15. GC/MS(EI): m/z 188 (M+).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8](=O)[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][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH:25](=[C:5]1/[C:4](=[O:6])[NH:3][C:2](=[O:7])[S:1]/1)\[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: O=C1CSC(=O)N1
Reactant: CCCCCCCCCCCCCCCCCC=O
Product: CCCCCCCCCCCCCCCCC/C=C1\SC(=O)NC1=O

Procedure:
TZD18 was prepared according to General Procedure A presented hereinabove using 2,4-thiazolidinedione and stearaldehyde as reactants.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C@@H:22]3[CH2:26][C@H:25]([S:27][C:28]4[C@H:29]([CH3:52])[C@@H:30]5[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]5[C:32]=4[C:33]([O:35]CC4C=CC([N+]([O-])=O)=CC=4)=[O:34])[CH2:24][N:23]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:21])[CH2:15][CH2:14]2)=[O:11])=CC=1)([O-])=O.O1CCCC1.Cl>O>[C:10]([CH2:12][N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C@@H:22]2[CH2:26][C@H:25]([S:27][C:28]3[C@H:29]([CH3:52])[C@@H:30]4[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]4[C:32]=3[C:33]([OH:35])=[O:34])[CH2:24][NH:23]2)=[O:21])[CH2:15][CH2:14]1)([OH:11])=[O:9]
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)N4CCCN(CC(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCCN(CC(=O)O)CC4)C3)[C@H](C)[C@H]12
Yield: 64.8 %

Procedure:
A solution of 0.5 g of 4-nitrobenzyl (1R, 5S, 6S)-2-[(2S, 4S)-2-[4-(4-nitrobenzyloxycarbonylmethyl)-1-homopiperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] in 15 ml of a 1:1 by volume mixture of tetrahydrofuran and water was mixed with 0.26 ml of 1N aqueous hydrochloric acid, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 90 minutes in the presence of 0.5 g of 10% w/w palladium-on-charcoal. The catalyst was then removed by filtration, and the filtrate was washed with diethyl ether. The washed aqueous solution was then concentrated by evaporation under reduced pressure, and the concentrate was purified by reverse phase column chromatography through a Lobar column (Merck, LiChroprep RP-8, size B), using 1% v/v aqueous methanol as the eluent. Those fractions containing the title compound were collected, concentrated by evaporation under reduced pressure and lyophilized, to give 170 mg of the title compound as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][NH:25][C:24]2=[O:29])=[CH:4][C:3]=1[F:30].[H-].[Na+].C1(O[C:40]#[N:41])C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10][C@H:9]2[CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:40]#[N:41])[C:24]2=[O:29])=[CH:4][C:3]=1[F:30]
Reactant: N#COc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN2CCCNC2=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN2CCCN(C#N)C2=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(4-chloro-3-fluorophenyl)-6-[(2-oxotetrahydropyrimidin-1(2H)-yl)methyl]-1,4-oxazepane-4-carboxylate (260 mg) in DMF (2.9 mL) was added sodium hydride (94.0 mg, 60% in oil) under ice-cooling, and the mixture was stirred at 0° C. for 1 hr, and at room temperature for 1 hr. Then, phenyl cyanate (210 mg) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (147 mg).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([Sn](=O)CCCC)CCC.[N:51]([Si](C)(C)C)=[N+:52]=[N-:53].C1(C)C=CC=CC=1>C(OCC)(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]5[NH:53][N:52]=[N:51][N:34]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(N3CCOCC3)CC2)c2ncnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCC(N3CCOCC3)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 23.1 %

Procedure:
A mixture of 4′-{[4-(4-morpholin-4-ylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.08 g), dibutyltin oxide (0.0037 g), azidotrimethylsilane (0.26 g) and toluene (10 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.02 g, 23%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1)=O.[CH3:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:20]([N:19]([CH2:1][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1)[CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1sc(C=O)cc1-c1ccccc1
Reactant: CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1sc(CN(C)Cc2ccccc2)cc1-c1ccccc1
Reaction time: 18 h
Yield: 94.3 %

Procedure:
To a solution of 172 (0.706 g, 2.87 mmol) in DCE (15 mL) was added N-Methylbenzylamine (0.388 mL, 3.01 mmol) and sodium triacetoxyborohydride (0.851 g, 4.01 mmol) and stirred for 18 hours. The reaction mixture was diluted in DCM and washed with a saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude residue was purified by ISCO (40 g column, 0-30% ethyl acetate in hexanes) to yield compound 173 (951 mg, 94%) a colorless oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N+:8]([C:11]1[C:12]([NH:37][CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:19]=2[NH:29][C:30](=O)OC(C)(C)C)=[N:15][CH:16]=1)([O-:10])=[O:9]>C(Cl)Cl>[N+:8]([C:11]1[C:12]([NH:37][CH:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)=[N:13][C:14]([N:17]2[C:18]3[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:19]=3[N:29]=[CH:30]2)=[N:15][CH:16]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1Nc1ncc([N+](=O)[O-])c(NC2CCOCC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(-n2cnc3ccc(OC(F)(F)F)cc32)nc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
A freshly prepared solution of 30% TFA in DCM (25 mL) was added to the 1.0 g tert-Butyl 2-(5-nitro-4-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-ylamino)-4-(trifluoromethoxy)phenylcarbamate and the solution were stirred at room temperature for 2 hrs. The solvents were removed in vacuo to yield an orange residue that was carried on without further purification (MH+=415). This residue was dissolved in 20 mL 1:1 trimethyl orthoformate: MeOH and the resulting solution were stirred for 30 minutes at room temperature. Yellow solids were precipitated from the orange solution. Desired product (0.6 g, 70% overall yield) was obtained after filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([CH3:10])=[N:9][C:5]=2[CH:4]=1.S(Cl)([Cl:16])(=O)=O.O>C(O)(=O)C>[Cl:16][C:4]1[C:5]2[N:9]=[C:8]([CH3:10])[NH:7][C:6]=2[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc2[nH]c(C)nc2c1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2[nH]c(C)nc2c1Cl
Reaction time: 2 h

Procedure:
1.30 g (8.02 mmol) 5-methoxy-2-methyl-1H-benzo[d]imidazole and 0.70 mL (8.56 mmol) sulphuryl chloride in 30.0 mL acetic acid were stirred for 2 h. Another 0.3 mL sulphuryl chloride were added and the mixture was stirred for a further 2 h. The reaction mixture was mixed with water and evaporated down i.vac. The residue was stirred with DIPE and isopropanol, suction filtered and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][C:11]=3[CH:21]=2)[S:5][CH:6]=1.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][C:11]=3[CH:21]=2)[S:5][CH:6]=1
Reactant: COC(=O)C1=Cc2cc(-c3cc(C)cs3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1csc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.9 %

Procedure:
In THF (10 ml) was dissolved methyl 7-(4-methyl-2-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (420 mg), and to the mixture was added 1N sodium hydroxide (8.4 ml). The mixture was stirred at room temperature for 15 hours. Under reduced pressure, the organic solvent was removed, and to the residue was added ethyl acetate. The mixture was extracted with water, and to the aqueous layer was added 6N hydrochloric acid to make the solution pH 4-5, which was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed to give 7-(4-methyl-2-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (320 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH2:21][CH3:22])=[CH:10][C:9]=2[CH3:23])=[O:4].[CH2:25]([NH:27][CH3:28])[CH3:26]>>[CH2:21]([C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:23])[CH:10]=1)[N:7]=[C:6]([N:27]([CH2:25][CH3:26])[CH3:28])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:22]
Reactant: CCc1cc(C)c2nc(Cl)c(C(=O)OC)c(-c3ccccc3)c2c1
Reactant: CCNC
Product: CCc1cc(C)c2nc(N(C)CC)c(C(=O)O)c(-c3ccccc3)c2c1

Procedure:
The title compound was prepared in analogy to example 54 step F from 2-chloro-6-ethyl-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 54 step E) and ethyl-methyl-amine. Light brown solid. MS (ESI): 349.3 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[N:7]([C:10]2[S:11][C:12]([C:16]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:6]=[N:5]1.[H-].[Na+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1>O1CCCC1.C(OCC)(=O)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][CH2:2][CH2:3][N:4]2[C:8](=[O:9])[N:7]([C:10]3[S:11][C:12]([C:16]([NH:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[O:17])=[C:13]([CH3:15])[N:14]=3)[CH:6]=[N:5]2)=[CH:31][CH:32]=1
Reactant: Cc1nc(-n2cnn(CCO)c2=O)sc1C(=O)NCc1cccnc1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-n2cnn(CCOCc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To the solution of 2-(1-(2-hydroxyethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.11 g, 0.31 mmol) in anhydrous tetrahydrofuran was added sodium hydride (60% in mineral oil, 0.015 g, 0.35 mmol) at 0° C. The reaction mixture was stirred for 30 minutes, followed by the addition of 1-(bromomethyl)-4-fluorobenzene (0.04 mL, 0.31 mmol). The resulting mixture was stirred at ambient temperature for 17 hours, diluted with ethyl acetate and washed with water and brine. The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate to afford the title compound as a white solid in 46% yield (0.06 g): mp 235-236° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 9.14 (br s, 1H), 9.11-9.06 (m, 1H), 8.95 (t, J=5.5 Hz, 1H), 8.73 (s, 1H), 8.56-8.48 (m, 1H), 8.15-8.08 (m, 1H), 7.65-7.56 (m, 2H), 7.32-7.22 (m, 2H), 5.81 (s, 2H), 4.57 (d, J=5.5 Hz, 2H), 3.79 (t, J=5.4 Hz, 2H), 3.64 (t, J=5.4 Hz, 2H), 2.54 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.0, 161.4, 152.6, 152.1, 150.6, 145.1, 143.8, 14-3.7, 141.1, 131.9, 131.9, 131.0, 128.7, 121.9, 116.6, 62.9, 58.6, 48.3, 40.7, 17.5; MS (ES+) m/z 469.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:5])[CH3:2].[NH2:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=O>>[Cl:32][C:30]1[CH:31]=[C:23]2[C:24]([C:25](=[O:27])[N:19]([S:16]([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15][CH:14]=3)(=[O:17])=[O:18])[C:20](=[O:21])[NH:22]2)=[CH:28][CH:29]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: CCOC(=O)CCCOc1ccc(S(=O)(=O)N=C=O)cc1
Product: CCOC(=O)CCCOc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1
Yield: 26.9 %

Procedure:
763 mg (2.44 mmol) of 4-(3-ethyloxycarbonylpropyloxy)benzenesulfonylisocyanate and 418 mg (2.44 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 306 mg of the above-identified compound (yield 27.0%). Properties: colorless crystal, Melting point: 167°-169° C., PMR (δppm, DMSO-d6):1.18 (3H,s), 1.98-2.03 (1H,m), 2.46 (2H,t), 4.04-4.14 (4H,m), 7.12 (1H,s), 7.16 (2H,d), 7.21 (1H,d), 7.85 (1H,d), 8.09 (2H,d), 11.58 (1H,s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[S:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH3:13]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH2:13])=[S:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N
Reactant: O=[N+]([O-])c1cccc(N=C=S)c1
Solvent: CO
Product: NC(=S)Nc1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To 7.20 g (40 mmol) of 3-nitrophenylisothiocyanate in 25 mL of methanol was added 28.5 mL (200 mmol) of 7 N ammonia in methanol. After 30 min., the slurry was concentrated to give 7.9 g (100%) of the title compound as a yellow-orange powder that did not require further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:16]([C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][N:22]1[CH:23]=[C:19]([N+:16]([O-:18])=[O:17])[N:20]=[CH:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCn1cnc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 32 %

Procedure:
A mixture of methanesulfonic acid 2-tert-butoxycarbonylamino-ethyl ester (compound 39.1; 2.04 g, 8.53 mmol, prepared according to the procedure of Hey, M. P. et. al J. Med. Chem 37, 1994, 381), 4-nitroimidazole (876 mg, 7.75 mmol), K2CO3 (1.18 g, 8.53 mmol), in DMF is stirred at 110° C. for 2 hours. After cooling to room temperature, the mixture is diluted with EtOAc and washed with water. The aqueous layer was extracted three times with EtOAc and the combined organic phases were dried (Na2SO4) and concentrated. The crude residue was purified by flash column chromatography (SiO2, 45 to 100% EtOAc in hexanes) to yield 634 mg (32%) of [2-(4-nitro-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (compound 39.2) as a solid, ES (+) MS m/e=257 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([S:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[C:14]#[N:15].Cl.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[CH2:43][NH:42][CH2:41][CH2:40]2>>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([C:13]([S:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:42]2[CH2:41][CH2:40][C:39]3[C:44](=[CH:45][C:46]([O:47][CH3:48])=[C:37]([O:36][CH3:35])[CH:38]=3)[CH2:43]2)[C:14]#[N:15])[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1ccc(C(C#N)(CCCCCCCCCCCBr)Sc2ccc(C)cc2)cc1OC
Agent: Cl
Product: COc1ccc(C(C#N)(CCCCCCCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 57.9 %

Procedure:
The procedure of Example 3 is repeated using 3.14 g of α-(11-bromoundecyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 2.03 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 2.2 g of the desired product as a light yellow oil. MS(Hi res): m/z Calcd for C39H52N2O4S 644.3648 Found 645.3730(M+H). Calcd for C39H52N2O4S 1/2H2O: C=71.63, H=8.17, N=4.29, S=4.90 Found C=71.31, H=8.19, N=4.10, S=4.71
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]=[N+]=[N-])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN=[N+]=[N-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)COc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.2 %

Procedure:
To a mixed liquid of 5.16 g of t-butyl[3-(azidomethyl)phenoxy]acetate and 50 ml of THF were added 6.17 g of triphenylphosphine and 1.04 ml of water, followed by stirring at room temperature for 4 days. The solvent was evaporated and diisopropyl ether was added thereto. The precipitated solid was separated by filtration and the solvent was evaporated again. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol-saturated aqueous ammonia) to obtain 4.10 g of t-butyl[3-(aminomethyl)phenoxy]acetate as a pale yellow oily substance.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]([CH3:16])=[CH:14][C:10]2[N:11]=[CH:12][S:13][C:9]=2[C:8]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)(=O)=O.[CH2:26](C([Sn])=C(CCCC)CCCC)[CH2:27]CC.[Li+].[Cl-].C(OCC)(=O)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:8]2[C:9]3[S:13][CH:12]=[N:11][C:10]=3[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:26]=[CH2:27])=[CH:18][CH:19]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1c(C)cc2ncsc2c1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl trifluoromethanesulfonate (5F) from above reaction was dissolved in DMF (3 ml). Tributylvinyltin (130 uL), PdCl2(PPh3)2 (27 mg, 0.039 mmol) and LiCl (49 mg, 1.17 mmol) were added. The reaction mixture was stirred at 120° C. in microwave for 30 min. The reaction mixture was diluted by ethyl acetate, washed with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated and purified by silica gel column (0-50% ethyl acetate/hexanes). LCMS-ESI+: calc'd for C16H20ClNS: 286.0 (M+H+). Found: 286.1 (M+H+).
Reaction SMILES: [C:1]1([CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.[C:11]1(=[O:18])[O:17][C:15](=[O:16])[CH:14]=[C:12]1[CH3:13]>CC(C)=O>[C:1]1([CH2:9][NH:10][C:15](=[O:16])/[CH:14]=[C:12](/[CH3:13])\[C:11]([OH:18])=[O:17])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:15](=[O:16])/[CH:14]=[C:12](/[CH3:13])\[C:11]([OH:17])=[O:18])[CH:2]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: NCc1cccc(CN)c1
Solvent: CC(C)=O
Product: C/C(=C/C(=O)NCc1cccc(CNC(=O)/C=C(/C)C(=O)O)c1)C(=O)O
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A 2.5-liter glass resin kettle was charged with 136.2 g (1.0 mole) of m-xylylenediamine and 2000 ml of reagent acetone and flushed with nitrogen. The kettle was fitted with a dropping funnel, reflux condenser, mechanical stirrer and thermocouple. The addition funnel was charged with 246 g (2.2 moles) of citraconic anhydride which was slowly added over a 21/2-hour period, with stirring and refluxing the acetone. The reaction mixture was allowed to cool to room temperature with stirring. Suction filtering and acetone wash of the solid product (air-drying) gives a 246 g of a tan powder, melting at 148°-150° C. The structure was confirmed by NMR analysis.