Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].BrC(Br)C.Br[C:7]1[CH:8]=[C:9]([CH3:20])[C:10]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])=[C:11]([CH3:13])[CH:12]=1.[B:21]([O:26]C)([O:24]C)[O:22]C.Cl>C1COCC1>[CH2:18]([O:17][CH2:16][CH2:15][O:14][C:10]1[C:9]([CH3:20])=[CH:8][C:7]([O:22][B:21]([OH:26])[OH:24])=[CH:12][C:11]=1[CH3:13])[CH3:19]
Reactant: CCOCCOc1c(C)cc(Br)cc1C
Reactant: COB(OC)OC
Agent: CC(Br)Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOCCOc1c(C)cc(OB(O)O)cc1C
Temperature: 55 °C

Procedure:
A suspension of magnesium (2.36 g) in THF (100 ml) was stirred under a nitrogen atmosphere, and thereto was added dibromoethane (a catalytic amount) and was subsequently added dropwise a solution of 5-bromo-2-(2-ethoxyethoxy)-1,3-dimethylbenzene (24.1 g) in anhydrous THF (100 ml). The resulting mixture was heated at 55° C. for 2.5 hours and was then cooled to −78° C., and thereto was added dropwise trimethyl borate (19.8 ml). The reaction mixture was brought back to the room temperature and was stirred overnight. The reaction mixture was mixed with 1 N hydrochloric acid, was concentrated and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 4-(2-ethoxyethoxy)-3,5-dimethylphenylboric acid (8.4 g) as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][CH2:7][C:8]2[N:13]=[C:12]([NH:14]C(=O)C(C)(C)C)[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:1]1([CH2:4][CH2:5][O:6][CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)Nc1cccc(COCCC2CC2)n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(COCCC2CC2)n1

Procedure:
This material was prepared in analogy to example 86 step B] from N-[6-(2-cyclopropyl-ethoxymethyl)-pyridin-2-yl]-2,2-dimethyl-propionamide (0.51 g) and 3M aqueous NaOH (3.7 mL) as a light yellow oil (0.39 g) that was used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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.O>[C:9]1([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccnc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
2,4-dichloropyridine (10 g, 67.57 mmol), phenylboronic acid (9.0 g, 74.32 mmol), and potassium carbonate (28 g, 202.70 mmol), 300 mL dimethoxyethane and 30 mL of water was placed in a 1 L round-bottom flask. Nitrogen was bubbled directly into the mixture for 30 min. Tetrakis(triphenylphosphine)palladium(0) (780 mg, 0.675 mmol) was added and nitrogen was bubbled into the reaction mixture for a another 15 min. The reaction mixture was then heated to reflux under nitrogen for 16 h. The reaction was then allowed to cool to room temperature and diluted with ethyl acetate and water. The organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with a saturated brine solution. The organic layer was then dried over magnesium sulfate, filtered, and the solvent was removed under vacuum to give an off-white solid as crude. The crude was purified by column chromatography using silica gel as the stationary phase and 2% ethyl acetate in hexanes as the mobile phase. 8.0 g of desired product was obtained after purification (54% yield). 11.5 g of desired product was obtained after purification (89.77% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl-].[NH4+:17].Cl>N1CCCC1>[OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([N:17]1[CH2:4][CH2:3][CH2:2][CH2:11]1)=[O:6]
Reactant: C=CCc1c(O)ccc(C(=O)OC)c1O
Reactant: [NH4+]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCNC1
Product: C=CCc1c(O)ccc(C(=O)N2CCCC2)c1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Methyl 2,4-dihydroxy-3-(2-propenyl)benzoate (3.0 g) and a few crystals of ammonium chloride were added to 20 ml of pyrrolidine. The reaction mixture was heated to 50° C. and stirred overnight. The reaction mixture was neutralized with 10% hydrochloric acid and extracted with ethyl acetate. Concentration under vacuum to remove solvent gave the product as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][NH:13][C:22](=[O:23])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: COc1cc(CCN)cc(OC)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(CCNC(=O)Cc2ccc(F)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-(3,5-dimethoxy-phenyl)-ethylamine (1.01 g, 5.57 mmol) in anhydrous DMF (50 mL) is added 4-fluorophenyl acetic acid (860 mg, 5.57 mmol), PyBOP (3.17 g) and N-ethyldiisopropylamine (2.2 mL, 12.8 mmol). The mixture is stirred at rt for 14 h. Water (60 mL) is added, and the mixture is extracted with EtOAc (4×60 mL). The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography (EtOAc/Hex, 7:3) to afford the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:15]=1>[OH-].[Na+].O1CCOCC1>[CH3:6][C:2]([NH:1][S:19]([C:17]1[S:18][C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=2)=[CH:15][CH:16]=1)(=[O:20])=[O:21])([CH3:7])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(N)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(NS(=O)(=O)c1ccc(-c2ccccn2)s1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
To a solution of 2-amino-2-methylpropionic acid (2.0 grams, 19.4 mmole) in 1 N aqueous sodium hydroxide solution (45 mL) and dioxane (45 mL) was added 5-pyridin-2-ylthiophene-2-sulfonyl chloride (8.41 grams, 32.4 mmole). The resulting mixture was stirred at room temperature for 16 hours. Additional 1 N aqueous sodium hydroxide solution (45 mL) was added to the reaction mixture which was then extracted with diethyl ether. The organic extracts were discarded. The aqueous layer was acidified with 1 N hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate fractions were washed with brine, dried over magnesium sulfate and concentrated to afford 2-methyl-2-(5pyridin-2-ylthiophene-2-sulfonylamino)propionic acid as a white solid (2.18 grams, 34%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:40]([O:47][CH2:48][C@@H:49]([NH:66][CH3:67])[C:50]([N:52]([CH3:65])[C@@H:53]([C:61](=[O:64])[NH:62][CH3:63])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:66]([C@@H:49]([C:50](=[O:51])[N:52]([CH3:65])[C@@H:53]([C:61](=[O:64])[NH:62][CH3:63])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:48][O:47][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:67])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.7 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.12 g; 0.49 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.07 g; 0.49 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.1 g; 0.51 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-3-Benzyloxy-N-methyl-2-(methyl-amino)-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-propionamide (0.17 g; 0.44 mmol) and diisopropylethylamine (0.084 mL; 0.49 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was extracted with an aqueous solution of sodium hydrogen carbonate (saturated; 30 mL) and an aqueous solution of sodium hydrogen sulfate (10%; 30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2.5×30 cm) using methylene chloride/ethyl acetate (1:1) as eluent to afford 0.275 g of ((3E)-4-(N-((1R)-2-benzyloxy-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[O-]S(C(F)(F)[F:19])(=O)=O.ClC1C=[N+](F)C=C(Cl)C=1.C(OCC)(=O)C>ClCC(Cl)(Cl)Cl>[F:19][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[O:9][CH3:10]
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: ClCC(Cl)(Cl)Cl
Agent: F[n+]1cc(Cl)cc(Cl)c1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c([N+](=O)[O-])cc1F
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in tetrachloroethane (10 mL) is added 3,5-dichloro-1-fluoro-pyridinium triflate (85%, 5.07 g) and the mixture is heated to 120° C. for 5 hours. Additional 3,5-dichloro-1-fluoro-pyridinium triflate (85%, 0.25 g) is added and heating is continued for 1 hour. The solution is then cooled to room temperature and passed over a column of silica gel (hexanes followed by 30% ethyl acetate in hexanes is used as the eluant). Product containing fractions are combined, evaporated under reduced pressure, and the residue is crystallized from hexanes to provide the desired product as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[CH2:15][OH:16])=[C:4](F)[CH:3]=1.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=[CH:10][N:11]=[C:12]([CH3:14])[CH:13]=3)[CH2:15][O:16][C:4]=2[CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2F)c(CO)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2c(cn1)COc1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
To a stirred solution of (4-(4-chloro-2-fluorophenyl)-6-methylpyridin-3-yl)methanol (0.25 g, 0.993 mmol) in tetrahydrofuran (25 mL) at 0° C. was added NaH (0.06 g, 1.49 mmol) portionwise. The solution was then stirred for 16 h at RT. The reaction mixture was quenched with water (100 mL). The precipitate was collected by filtration and air dried to afford 8-chloro-2-methyl-5H-chromeno[3,4-c]pyridine (0.2 g, 0.863 mmol, 69% yield) as a white solid. LCMS (ESI) m/e 232.0 [(M+H)+, calcd for C13H11ClNO 232.0]; LC/MS retention time (Method D): tR=2.06 min; 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.65 (d, J=4.40 Hz, 1H), 7.37 (s, 1H), 7.07-7.03 (m, 2H), 5.14 (s, 2H), 2.61 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.N1C=CC=CC=1.O>CS(C)=O>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:1])[CH:3]=[O:4]
Reactant: CC(C)(CO)c1ccccc1
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 0.1 %

Procedure:
To a solution of 2-methyl-2-phenyl-propan-1-ol (13.3 g, 87.0 mmol) in DMSO (150 mL) was added triethylamine (24.7 mL, 178.0 mmo) at rt, followed by pyridine sulfuric oxide (28.6 g, 180.0 mmol). The mixture was stirred for 2.5 h at rt. Water was added and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product 2-methyl-2-phenyl-propionaldehyde (12.0 mg, 91.6%), which was used to the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][O:27][C:26]1=[O:30]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][O:27][C:26]2=[O:30])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCN1CCCl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1OCCN1CCN1CCN(Cc2ccccc2)CC1

Procedure:
744 g of 1-benzyl-piperazine are treated, together with 590 g of powdered potassium carbonate, 10 g of potassium iodide and 5 litres of toluene, with 450 g of 3-(2-chloroethyl)-2-oxazolidinone and the mixture is heated to reflux for 21 hours. The mixture is cooled, filtered and concentrated under reduced pressure. The residue is distilled under reduced pressure. There is obtained 3-[2-(4-benzyl-1-piperazinyl)-ethyl]-2-oxazolidinone which boils at 225°-235° C under a pressure of 2-2.5 mm. The compound is recrystallised from ethyl acetate; melting point 82°-84° C. The dihydrochloride of melting point 243°-245° C is obtained by treatment with an excess of hydrochloric acid in ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C1N2CCN(CC2)C1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1([CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: ClCc1ccccn1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: C1CN2CCN1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccccn2)CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (10.34 g, 38.2 mmol) in DMF (40 mL) at about 0° C. was added picolyl chloride hydrochloride (5.7 g, 34.7 mmol), potassium carbonate (14.4 g, 104.1 mmol) and potassium iodide (5.76 g, 34.7 mmol). After stirring at about 0° C. for about 2 hours, the ice bath was removed and DABCO (973 mg, 8.68 mmol) was added. The reaction mixture was stirred for about 30 min. and poured into a mixture of water and IPE. The organic layer was separated and washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo. The crude residue was crystallized from hexanes to give a white solid (8.19 g, yield 65%). 1H-NMR (CDCl3) δ1.17 (t, 3H), 1.48 (s, 9H), 1.55 (s, 2H), 2.61 (m, 1H), 2.71 (m, 1H), 3.31-3.50 (m, 3H), 4.11 (d, 2H), 4.49 (d, 1H), 7.06 (br s, 1H), 7.17(d, 1H), 7.54 (m, 1H), 8.40 (s, 1H).
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH:20]([CH2:29][CH2:30][CH3:31])[C:21]([NH:23][NH:24][C:25](=[S:28])[NH:26][CH3:27])=O)(=[O:18])=[O:17])=[CH:12][CH:11]=1>CO>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH:20]([C:21]2[N:26]([CH3:27])[C:25]([SH:28])=[N:24][N:23]=2)[CH2:29][CH2:30][CH3:31])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)NNC(=S)NC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)c1nnc(S)n1C
Reaction time: 0.5 h

Procedure:
An aqueous solution (8.5 ml) of sodium hydroxide (1 mol/liter) was added, at room temperature, to a mixed solution in methanol (9.5 ml) and dioxane (19 ml) of the 2-(2-{[(4-chlorophenyl)sulfonyl]amino}pentanoyl)-N-methylhydrazine carbothioamide (2.157 g) obtained in Example 1-(3). The mixture was stirred for 30 minutes, and then stirred for 30 minutes at 85° C. The solvent was distilled off from the reaction mixture, and an aqueous solution (20 ml) of hydrochloric acid (0.5 mol/liter) was added to the residue. The mixture was extracted with ethyl acetate (100 ml), and washed with a saturated aqueous solution (100 ml) of sodium chloride.
Reaction SMILES: [ClH:1].C1C2=C3C(C4C2=CC=CC=4)=CC=CC3=C(CNC(C)(CO)CO)C=1.[CH:26]1[C:40]2=[C:41]3[C:33]([C:34]4[C:35]([CH:42]=O)=[CH:36][CH:37]=[CH:38][C:39]=42)=[CH:32][CH:31]=[CH:30][C:29]3=[CH:28][CH:27]=1.[NH2:44][C:45]([CH3:50])([CH2:48][OH:49])[CH2:46][OH:47]>>[ClH:1].[CH:26]1[C:40]2=[C:41]3[C:33]([C:34]4[C:39]2=[CH:38][CH:37]=[CH:36][C:35]=4[CH2:42][NH:44][C:45]([CH3:50])([CH2:48][OH:49])[CH2:46][OH:47])=[CH:32][CH:31]=[CH:30][C:29]3=[CH:28][CH:27]=1
Reactant: CC(N)(CO)CO
Reactant: O=Cc1cccc2c1-c1cccc3cccc-2c13
Agent: CC(CO)(CO)NCc1ccc2c3c(cccc13)-c1ccccc1-2
Agent: Cl
Product: CC(CO)(CO)NCc1cccc2c1-c1cccc3cccc-2c13

Procedure:
Using the reductive amination procedure outlined in 1D, 7-fluoranthenecarbaldehyde (1B) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-((7-fluoranthenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride mp 204°-206° (dec), (CH3OH/Et2O), (C, H, Cl, N).
Reaction SMILES: [CH2:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([C:17](=[O:19])[CH3:18])=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][CH3:3].[C:20](OCC)(=[O:22])[CH3:21].CC(C)([O-])C.[K+].Cl>O>[CH2:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([C:17](=[O:19])[CH2:18][C:20](=[O:22])[CH3:21])=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][CH3:3]
Reactant: CCCn1c2ccccc2c2cc(C(C)=O)ccc21
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCn1c2ccccc2c2cc(C(=O)CC(C)=O)ccc21
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A 200 ml four-necked flask equipped with a stirrer, a nitrogen inlet tube, a reflex condenser, and a thermometer was charged with 25.13 g of 1-(9-propyl-9H-carbazol-3-yl)ethanone, 88.11 g of ethyl acetate, and 16.83 g of potassium t-butoxide, and the mixture was refluxed in a nitrogen atmosphere for 5 hours. After cooling to room temperature, 50 ml of ion exchanged water and 50 ml of 6N hydrochloric acid were successively added, followed by stirring. The organic phase was separated and mixed with 200 ml of ethyl acetate, and the mixture was washed with a sodium chloride aqueous solution until neutral. The upper layer was dried with magnesium sulfate, and the solvent was removed by evaporation. The solid thus precipitated was dissolved in 10 ml of ethyl acetate under reflux, and n-hexane was added thereto. The precipitate thus formed was collected by filtration and dried under reduced pressure to give 23.15 g (79%) of yellow crystals, which had a melting point of 97° C. and was identified by various analyses to be β-diketone compound No. 1 having a carbazolyl group.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>>[C:1]([C:4]1[O:5][C:6]2[C:12]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:11][CH:10]=[C:9]([S:18]([Cl:17])(=[O:20])=[O:19])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CCC(C)c1cccc2cc(C(C)=O)oc12
Reactant: O=S(=O)(O)Cl
Product: CCC(C)c1ccc(S(=O)(=O)Cl)c2cc(C(C)=O)oc12
Yield: 67 %

Procedure:
There was reacted 1 g (4.6 mmole) of 2-acetyl-7-sec-butylbenzofuran with chlorosulfonic acid as in Example 1, yielding 0.97 g of 2-acetyl-4-chlorosulfonyl-7-sec-butylbenzofuran (yield: 67%, MS (m/z): 314 (M+), 285 and 186). The obtained chlorosulfonyl compound was reacted with glycine ethyl ester hyrochloride as in Example 1 to give an ester compound (yield: 82%, MS (m/z): 381 (M+), 352, 308 and 279), which was then hydrolyzed to give 2-acetyl-4-(N-carboxymethylsulfamoyl)-7-sec-butylbenzofuran (light yellow plates, yield: 73%). The physical constants are shown in Table 4.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[N:3]1.[Li]CCCC.CN([CH:21]=[O:22])C.[Cl-].[NH4+]>C1COCC1>[CH3:1][N:2]1[C:6]([CH:21]=[O:22])=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[N:3]1
Reactant: Cn1cc(-c2ccccc2)nn1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccccc2)c1C=O
Temperature: -75 °C
Reaction time: 0.67 h
Yield: 67.3 %

Procedure:
To a solution of 1-methyl-4-phenyl-1H-[1,2,3]triazole (165 mg, 1.04 mmol) in THF (5.2 mL) was added n-BuLi (1.6 M in hexane, 777 μL, 1.24 mmol) dropwise at −75° C. under Argon. The resulted orange solution was stirred at −75° C. for 40 min, then DMF (104 μL, 1.35 mmol) was added dropwise at −75° C. and the reaction mixture was allowed to warm up to room temperature over 1 h. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (131 mg, 68%) as a white solid. MS: m/e=187.0 [M]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=O.[NH2:10][C@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][C@H:11]([NH:10][C:4](=[O:6])[C@@H:3]2[CH2:7][CH2:8][CH2:9][N:2]2[CH3:1])[CH2:12]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCC[C@H]1C(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a suspension of 1-methyl-L-proline (600 mg) and (3S)-3-amino-1-(tert-butoxycarbonyl)pyrrolidine (758 mg) in anhydrous DMF (10 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (856 mg) and 1-hydroxybenzotriazole (550 mg) were added. The mixture was stirred overnight at room temperature. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with an aqueous solution of sodium carbonate, 15% saline and saturated saline, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate, 5% methanol/ethyl acetate, 10% methanol/ethyl acetate), whereby 1.11 g of (3S)-1-(tert-butoxycarbonyl)-3-(1-methyl-L-prolylamino)pyrrolidine were obtained.