Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-])=[CH:8][C:7]=2[N:17]=1.C1(S(Cl)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CO.O>[CH3:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:2])[C:7]=2[N:17]=1
Reactant: [NH4+]
Reactant: Cc1nc2c[n+]([O-])c3cccnc3c2n1CC(C)C
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2c(N)nc3cccnc3c2n1CC(C)C
Temperature: 10 °C

Procedure:
Under a nitrogen atmosphere, aqueous ammonium hydroxide (four equivalents) was quickly added with continuous stirring to a suspension of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-5-oxide in methanol (6 mL/g) while maintaining the reaction temperature at 20° C. to 24° C. Methanol was used to rinse the addition vessel and added to the reaction. The reaction was stirred until all material was dissolved. With continuous stirring, benzenesulfonyl chloride (2 equivalents) was added over a period of 15 to 45 minutes while maintaining the reaction temperature at 20° C. to 30° C. Methanol was used to rinse the addition vessel and added to the reaction. The reaction was stirred for 45 to 75 minutes at 20° C. to 24° C. Aqueous sodium hydroxide (3 equivalents of 10% w/w) was added to the reaction mixture over a period of 15 to 45 minutes while maintaining the reaction temperature between 20° C. and 25° C. Water (10 L), used to rinse the addition vessel, was added to the reaction mixture. The resulting mixture was cooled to 10° C. and stirred for 2 to 24 hours. A precipitate was present and was isolated by filtration and washed with deionized water until the filtrate was pH 7. The solid was dried at 50° C. under vacuum to provide 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as an off-white solid.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[CH:7]=2)([CH3:3])[CH3:2].Cl[CH2:18][C:19]1[O:20][CH:21]=[CH:22][N:23]=1>>[CH:1]([C:4]1[N:5]([CH2:18][C:19]2[O:20][CH:21]=[CH:22][N:23]=2)[C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[CH:7]=2)([CH3:3])[CH3:2]
Reactant: ClCc1ncco1
Reactant: COc1ccc2c(C=O)c(C(C)C)[nH]c2c1
Product: COc1ccc2c(C=O)c(C(C)C)n(Cc3ncco3)c2c1

Procedure:
2-Isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137, 0.54 g, 2.49 mmol) and 2-(chloromethyl)oxazole (0.58 g, 4.4 mmol) were reacted as described in General Procedure J to give the title compound as an oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:15][CH2:16][CH:17](O)[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[Cl:3][CH:17]([CH2:16][O:15][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCOCC(O)Cn1ccnc1
Product: CCCCCCCCCCOCC(Cl)Cn1ccnc1

Procedure:
Thionyl chloride (5 ml.) and 1.6 g. of 1-[3'-(n-decyloxy)-2'-hydroxypropyl]imidazole are warmed gently for a period of 2 hours and the solution is then evaporated to dryness. The residue is dissolved in dichloromethane and rendered basic with aqueous potassium carbonate solution. The organic layer is separated, dried over magnesium sulfate and evaporated to yield 1-[2'-chloro-3'-(n-decyloxy)propyl]imidazole.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[CH:7][C:8]([OH:16])=[C:9]([C:12]=1[CH:13]([CH3:15])[CH3:14])[CH:10]=[O:11])(=[O:3])[CH3:2].[H-].[Na+].[Mg].Br[CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26].Cl>O1CCCC1.O>[C:1]([O:4][C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[CH:7][C:8]([OH:16])=[C:9]([CH:10]([OH:11])[CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:12]=1[CH:13]([CH3:15])[CH3:14])(=[O:3])[CH3:2]
Reactant: CCC(Br)CC
Reactant: CC(=O)Oc1c(C(C)C)cc(O)c(C=O)c1C(C)C
Agent: Cl
Agent: [H-]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1c(O)cc(C(C)C)c(OC(C)=O)c1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon atmosphere, 0.78 g of 5-acetoxy-2-hydroxy-4,6-diisopropylbenzaldehyde was dissolved in 2 ml of anhydrous tetrahydrofuran and a solution of 0.40 g of oily sodium hydride in 1 ml of anhydrous tetrahydrofuran was added. After additional 5 ml of anhydrous tetrahydrofuran was added, the solution was stirred at room temperature for 30 minutes. Then, 5 ml of a Grignard reagent (1.48M in tetrahydrofuran) prepared from magnesium and 3-bromopentane was added dropwise to this reaction solution and the mixture was stirred at room temperature for 2 hours. Then, the mixture was combined with water and 1M hydrochloric acid and extracted with ethyl acetate. The organic layers were washed with saturated brine, then dried over anhydrous magnesium sulfate, and then concentrated. The concentrate as purified by silica gel column chromatography (in n-hexane containing 10% ethyl acetate) to give 0.51 g of 4-acetoxy-2-(2-ethyl-1-hydroxybutyl)-3,5-diisopropylphenol as a white amorphous material (yield 51%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1.S(Cl)([Cl:20])=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(OCCCCCCBr)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OCCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 452 g of 4-(6-bromohexyloxy)benzoic acid and 1000 g of thionyl chloride was stirred at room temperature for about 20 hours. The reaction mixture was concentrated in vacuo and residual thionyl chloride removed by repeated addition of toluene and concentration in vacuo. The oily product comprising 4-(6-bromohexyloxy)benzoyl chloride (450 ml) was used directly in the next reaction.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1>C1(C)C=CC=CC=1>[Cl:3][C:8]1[C:9]([CH3:11])=[CH:10][N:5]=[CH:6][C:7]=1[CH3:12]
Reactant: Cc1cncc(C)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cncc(C)c1Cl
Yield: 75 %

Procedure:
Thionyl chloride was loaded into a reaction vessel equipped with a stirrer, a condenser, a dropping funnel, and a nitrogen bubbler. The temperature was lowered to 0-5ℑ C. and 3,5-lutidine was added dropwise, keeping the temperature between 0 and 10ℑ C. When the addition was complete the reaction mixture was refluxed for 18 hours. The mixture was cooled to 65ℑ C. and toluene (4 volumes) were added. 1.5 volumes of the mixture were distilled under vacuum. The heavy brown precipitate was collected by filtration. The crude product was recrystallized from methanol (3 volumes). Filtration afforded the product, 4-Chloro-3,5-Lutidine, as a beige solid, this was washed with methanol and dried under vacuum at 40ℑ C.; yield: 75%.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C:7]2[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:34])[C@@H:15]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[C:29]([F:32])([F:31])[F:30])[C:21]3=[O:33])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:11][CH:12]=2)[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@@H:5]([C:7]1[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:34])[C@@H:15]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[C:29]([F:32])([F:30])[F:31])[C:21]2=[O:33])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:11][CH:12]=1)[CH2:4][OH:3]
Reactant: CC(C)C[C@@H](C(=O)Nc1cnc([C@H]2COC(C)(C)O2)cn1)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)Nc1cnc([C@H](O)CO)cn1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A solution of afford (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid [5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-amide (53 mg, 0.11 mmol) in tetrahydrofuran (1 mL) was treated with a 1N aqueous hydrochloric acid solution (1 mL) and stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo to remove the tetrahydrofuran and the remaining material was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo to afford (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-amide (43 mg, 88%) as a cream colored foam: [α]29D=+22.9° (c=0.14, methanol); HR-ES(+) m/e calcd for C21H23N4O4F3 [M+H]+ 453.1744, observed 453.1744; 1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 9.16 (s, 1H), 8.45 (d, J=1.07 Hz, 1H), 8.02 (dd, J=7.67, 11.29 Hz, 2H), 7.67-7.85 (m, 1H), 5.55 (d, J=4.90 Hz, 1H), 5.28 (dd, J=5.11, 10.65 Hz, 1H), 5.05 (d, J=18.33 Hz, 1H), 4.66-4.78 (m, 2H), 4.62 (q, J=4.90 Hz, 1H), 3.67 (td, J=5.30, 10.92 Hz, 1H), 3.55 (td, J=5.78, 11.24 Hz, 1H), 1.95-2.09 (m, 1H), 1.71-1.88 (m, 1H), 1.49 (br. s., 1H), 0.90-1.00 (m, 6H).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]#[N:14])[C:9]([C:15]#[N:16])=[CH:8][CH:7]=2)[CH2:2][CH3:3].[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([C:24]2[O:25][C:26]([CH2:29]Cl)=[N:27][N:28]=2)[CH:23]=1>>[Br:17][C:18]1[CH:23]=[C:22]([C:24]2[O:25][C:26]([CH2:29][N:5]3[C:6]4[C:11](=[C:10]([C:13]#[N:14])[C:9]([C:15]#[N:16])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])=[N:27][N:28]=2)[CH:21]=[N:20][CH:19]=1
Reactant: ClCc1nnc(-c2cncc(Br)c2)o1
Reactant: CCCc1cc2c(C#N)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(C#N)c(C#N)ccc2n1Cc1nnc(-c2cncc(Br)c2)o1

Procedure:
Synthesized as described in Example 4 from 2-propyl-1H-indole-4,5-dicarbonitrile and 3-bromo-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridine: 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J=1.7 Hz, 1 H), 8.95 (d, J=2.1 Hz, 1 H), 8.48 (s, 1 H), 8.16 (s, 1 H), 7.91 (d, J=8.7 Hz, 1 H), 7.57 (d, J=8.7 Hz, 1 H), 6.05 (s, 2 H), 3.07 (t, J=7.6 Hz, 2 H), 1.78-1.67 (m, 2 H), 0.96 (t, J=7.6 Hz, 3 H); MS (ES) m/z 448 (M+1).
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:4][C:3]1=2.C[Si]([C:22]#[N:23])(C)C>B(F)(F)F.Cl>[C:22]([C:2]1[C:3]2[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:8]=2[CH2:9][CH2:10][CH:11]=1)#[N:23]
Reactant: C[Si](C)(C)C#N
Reactant: COC(=O)COc1ccc2c(c1)CCCC2=O
Agent: Cl
Agent: FB(F)F
Product: COC(=O)COc1ccc2c(c1)CCC=C2C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 to 3 drops of BF3 -etherate solution are added to 0.1 mol of methyl 5-oxo-5,6,7,8-tetrahydro-naphth-2-yl-oxyacetate and 0.15 mol of trimethylsilyl cyanide, and the mixture is stirred at room temperature for 30 minutes and then at 50° C. for 1 hour. 250 ml of a saturated methanolic hydrogen chloride solution are added to this solution at room temperature and the mixture is stirred for 1 hour. Some of the product precipitates out and is filtered off. A further batch is obtained by evaporating the motor liquor, taking up the residue in CH2Cl2, extracting the mixture twice by shaking with 0.5N NaOH, drying the extract over Na2SO4 and evaporating it and recrystallizing the residue from a little methanol or diisopropyl ether.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[OH-].[Na+:21]>C(#N)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([O-:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[Na+:21]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.6 %

Procedure:
A slurry of amorphous ibandronic acid (5 g) in acetonitrile (50 ml) was stirred at room temperature. Solid sodium hydroxide (0.63 g) was added, and the reaction mixture was stirred at room temperature for an additional 72 hours. The precipitate was isolated by vacuum filtration and dried in a vacuum oven at 50° C. for 20 hours to obtain 5.0 g of amorphous ibandronate sodium.
Reaction SMILES: [F:1][C:2]([F:29])([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3=[N:15][S:16](=[O:20])(=[O:19])[CH2:17][CH2:18][N:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>C1COCC1.CO.[Pt](=O)=O>[F:29][C:2]([F:1])([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=1)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3=[N:15][S:16](=[O:19])(=[O:20])[CH2:17][CH2:18][N:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: Cc1cc(C(F)(F)c2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)ccc1F
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)c2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.1 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-{4-[difluoro(4-fluoro-3-methylphenyl)methyl]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (148 mg) in THF (dry) (50 mL) and MeOH (50 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (46.5 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[CH2:10][CH2:11][C:12]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)O>C(O)=O>[CH3:1][O:2][C:3](=[O:28])[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[CH2:10][CH:11]=[C:12]([C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1
Reactant: COC(=O)C1CCCCN1CCC(O)(c1ccc(F)cc1)c1ccc(Cl)cc1
Solvent: O=CO
Product: COC(=O)C1CCCCN1CC=C(c1ccc(F)cc1)c1ccc(Cl)cc1
Yield: 54 %

Procedure:
A solution of 0.035 g (0.086 mmol) N-[3-(4-chlorophenyl)-3-(4 fluorophenyl)-3-hydroxypropyl]pipecolic acid methyl ester (Compound B30) in 1 ml 99% formic acid was heated under reflux for 0.5 hours. The mixture was concentrated under vacuum the residue dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and brine, and the solvent evaporated. The residue was purified by preparative silica gel TLC with 5% diethyl ether in dichlorometane to give 0.018 g (yield 54%) N-[3-(4-chlorophenyl)-3-(4-fluorophenyl)prop-2-enyl]pipecolic acid methyl ester (Compound B20)
Reaction SMILES: [CH2:1]([C@@H:10]1[O:12][C@H:11]1[C:13]([OH:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:16]([S:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=2)=[CH:27][N:26]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C@@H:10]1[O:12][C@H:11]1[C:13]([O:15][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[CH:27]=[N:26][C:25]([S:24][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:30][CH:29]=2)=[CH:36][CH:35]=1)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC[C@@H]1O[C@H]1C(=O)O
Reactant: CCCCCCCCSc1ncc(-c2ccc(O)cc2)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCC[C@@H]1O[C@H]1C(=O)Oc1ccc(-c2cnc(SCCCCCCCC)nc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 413 mg (2.0 mmol) of dicyclohexyldicarbodiimide in 10 ml of dry CH2Cl2 is added while stirring at room temperature to 429 mg (2 mmol) of (2R,3S)-3-nonyloxirane-2-carboxylic acid, 633 mg (2 mmol) of 4-(2-n-octylthiopyrimidin-5-yl) phenol and also 20 mg of 4-dimethylaminopyridine. After stirring for 4 hours at room temperature, the reaction solution is evaporated down in vacuo. After chromatographic purification and recrystallization from n-hexane, 120 mg (12%) of colorless crystals are obtained. The substance exhibits the liquid-crystal phase sequence: X 73 SA 93.5 I.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH:5]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[CH2:6]1.S(Cl)([Cl:14])=O.C1COCC1.ClCCl>ClC(Cl)C>[Cl:14][CH2:2][CH2:3][NH:4][CH:5]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[CH2:6]1
Reactant: O=S1(=O)CCC(NCCO)C1
Reactant: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=S1(=O)CCC(NCCCl)C1
Temperature: 78 °C
Yield: 80.2 %

Procedure:
A mixture of 3-((2-hydroxyethyl)amino)tetrahydrothiophene 1,1-dioxide (260 mg, 1.451 mmol) and sulfurous dichloride (863 mg, 7.25 mmol) in dichloroethane (3 mL) was heated up at 78° C. for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to provide the black oil. To this black oil was added THF (5 mL) and dichloromethane (5 mL), grey-white solid was observed. The solid was filtered and collected to provide the desired product as a grey solid (230 mg, 80%). LCMS: m/e 198.1 (M+H)+, 0.60 min (method 6).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>CN(C=O)C>[CH3:20][O:19][C:17](=[O:18])[CH2:16][CH:15]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5]1)[CH3:21]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)CC(C)Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CC(C)N1CCN(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a mixture of 4-piperazin-1-yl-phenol (2 g, 11.2 mmol) and methyl 3-bromo-butyrate (2.03 g, 11.2 mmol) in DMF (5 mL) was added triethylamine (4.5 mL, 11.53 mmol) dropwise and the reaction mixture was stirred at ambient temperature overnight. The mixture was poured onto water and extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to dryness. The residue was purified by silica gel flash chromatography (1% methanol in CH2Cl2) to furnish the title compound (1.85 g, 59.3%); MS; m/z 279 (M+H).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].O.[C:25]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:25][O:12][C:11](=[O:13])[C@@H:2]([NH:1][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:3][C:4]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To Cbz-Asp(O-tert-Bu)-OH.H2O (5.00 g, 14.6 mmol) and K2CO3 (4.05 g, 2.0 eq) were added DMF (100 mL) and MeI (2.74 mL, 3 eq), which was then stirred for 2-3 h at room temperature. The solvent was distilled under reduced pressure. The residue was extracted with ethyl acetate (100 mL×2), washed with water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried (anhydrous Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (30% ethyl acetate/hexane) to give (S)-2-benzyloxycarbonylamino-succinic acid 4-tert-butyl ester 1-methyl ester in a stoichiometric yield. This compound was dissolved in MeOH (100 mL), c-HCl (1.1 mL, 1.0 eq) was added, and subjected to debenzyloxycarbonylation (Pd/C) for 40 min under hydrogen balloon, whereby giving 3.28 g (96%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:26])[C:19]([Cl:25])=[C:20]([Cl:24])[C:21]([OH:23])=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[CH:35]=2)[CH:30]=[CH:29]1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2([C:30]3[C:31]4[C:36](=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=4)[N:28]([CH3:27])[CH:29]=3)[O:26][C:21](=[O:23])[C:20]([Cl:24])=[C:19]2[Cl:25])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(Cl)=C(Cl)C(=O)c1cn(Cc2ccccc2)c2ccc(F)cc12
Reactant: Cn1ccc2ccc([N+](=O)[O-])cc21
Product: Cn1cc(C2(c3cn(Cc4ccccc4)c4ccc(F)cc34)OC(=O)C(Cl)=C2Cl)c2ccc([N+](=O)[O-])cc21

Procedure:
Following a procedure similar to that described above in part B of this example by using 4-(1-benzyl-5-fluoro-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid instead of 4-(1,2-dimethyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid and 1-methyl-6-nitroindole in place of 1,2-dimethylindole, there is obtained 5-(1-benzyl-5-fluoro-3-indolyl)-5-(1-methyl-6-nitro-3-indolyl)-3,4-dichloro-2(5H)-furanone (Formula V: R=C6H5CH2 ; R1 =R3 =H; R2 =CH3 ; Y=6-F; Y1 =6-NO2).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([O:14][CH3:15])[C:10]([NH:12][CH3:13])=[O:11].S(Cl)(Cl)=O.[CH:20](=[N:27]O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.O>[CH:20](=[N:27]/[O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([O:14][CH3:15])[C:10]([NH:12][CH3:13])=[O:11])\[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ON=Cc1ccccc1
Reactant: CNC(=O)C(OC)c1ccccc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: CNC(=O)C(OC)c1ccccc1CO/N=C/c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
A solution of 2-hydroxymethyl-α-methoxy-N-methyl-phenylacetamide (0.42 g, 2.0 mmol) in tetrahydrofuran (4 ml) was stirred at 0° C., and thionyl chloride (0.17 ml, 2.4 mmol) and one drop of N,N-dimethylformamide were added. The mixture was stirred at room temperature for 2 hours, and water was added. The resulting mixture was extracted with ether, washed with saturated brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude product (0.38 g) as an oil. Benzaldehyde oxime (0.37 g, 3.1 mmol) and potassium carbonate (0.55 g, 4.0 mmol) were added to a solution of the crude product in N,N-dimethylformamide (6 ml), and the mixture was stirred at room temperature for 3 days. Water was added, and the mixture was extracted with ether and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=13/7) to give the desired compound (E)-2-benzylideneaminooxymethyl-α-methoxy-N-methylphenylacetamide (0.32 g, 51%) as white crystals.