Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:12][CH:11]([C:13]([OH:15])=O)[N:10]([CH3:16])[C:9]2=[O:17])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:49][C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:51]=1[CH2:57][NH2:58]>ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:12][CH:11]([C:13]([NH:58][CH2:57][C:51]3[CH:52]=[CH:53][C:54]([Cl:56])=[CH:55][C:50]=3[Cl:49])=[O:15])[N:10]([CH3:16])[C:9]2=[O:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN1C(=O)N(c2cccnc2Cl)CC1C(=O)O
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)N(c2cccnc2Cl)CC1C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a solution of 1-(2-chloro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (179 mg, 0.484 mmol) and N-ethylmorpholine (0.368 ml, 2.91 mmol) in dichloromethane (5 ml) was added 1-hydroxybenzotriazole hydrate (111 mg, 0.726 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (139 mg, 0.726 mmol) and the mixture was stirred for 10 minutes at room temperature. 1-(2,4-Dichlorophenyl)methanamine (128 mg, 0.726 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, water and brine and separated by hydrophobic frit and the solution was reduced under vacuum. The residue was purified by SP4 automated silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give 1-(2-chloro-3-pyridinyl)-N-[(2,4-dichlorophenyl)methyl]-3-methyl-2-oxo-4-imidazolidinecarboxamide (60 mg, 27.6% yield). LC/MS [M+H]+=413, retention time=2.21 minutes
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][CH:4]=[N:3]1.[Na].[N+:9]([CH:12]([CH:15]=O)[CH:13]=O)([O-:11])=[O:10]>C(O)(=O)C>[CH3:1][N:2]1[C:6]2=[N:7][CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:15]=[C:5]2[CH:4]=[N:3]1
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: Cn1nccc1N
Agent: [Na]
Solvent: CC(=O)O
Product: Cn1ncc2cc([N+](=O)[O-])cnc21
Temperature: 108 °C
Reaction time: 16 h
Yield: 18.7 %

Procedure:
To a solution of 1-methyl-1H-pyrazol-5-amine (291 mg, 3.00 mmol) in acetic acid (3 mL) is added nitromalonaldehyde sodium salt (474 mg, 3.00 mmol) and reaction mixture is heated to 108° C. for 1 h. The reaction mixture is allowed to cool to room temperature and is stirred for 16 h. The solvent is evaporated under reduced pressure and the residue is purified by flash column chromatography using a gradient of 0-100% ethyl acetate in heptane to afford the title compound as a solid (100 mg, 19%).
Reaction SMILES: [BH4-].[Na+].Cl[S:4]([C:7]1[C:8]([F:17])=[CH:9][C:10]([F:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13])(=[O:6])=[O:5].C1C[O:21]CC1>>[F:16][C:10]1[CH:9]=[C:8]([F:17])[C:7]([S:4]([OH:21])(=[O:6])=[O:5])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: C1CCOC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Product: O=C(O)c1cc(S(=O)(=O)O)c(F)cc1F
Reaction time: 1 h
Yield: 100 %

Procedure:
Sodium borohydride (0.59 g, 15.6 mmol, 8 equiv) was added portionwise to a solution of 5-(chlorosulfonyl)-2,4-difluorobenzoic acid 885-6a (0.5 g, 1.9 mmol, 1 equiv) in 10 mL THF at 0° C. The reaction was stirred at this temperature for 1 h and then concentrated down and the residue acidified to pH 2 with 5N HCl. The precipitate was removed by filtration and the liquid concentrated down to provide 2,4-difluoro-5-sulfobenzoic acid 885-6b as a white solid (433 mg, 100% yield)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:15])[CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[CH3:15][C@@H:8]([NH2:7])[CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: C[C@H](Cn1cccn1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)Cn1cccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
((R)-1-Methyl-2-pyrazol-1-yl-ethyl)-carbamic acid tert-butyl ester (49 mg, 0.22 mmol) was dissolved in dichloromethane (2.4 ml) and cooled in an ice bath. Trifluoroacetic acid (1.2 ml) was slowly added and the reaction was stirred at room temperature for 2 h then evaporated and dried under high vacuum to afford (R)-1-methyl-2-pyrazol-1-yl-ethylamine trifluoroacetate which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([NH2:20])=O)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1N.C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:9])[C:12]3[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:17])[N:21]3[CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[N:20]=[C:18]23)=[CH:4][CH:3]=1
Reactant: NC(=O)C1(c2ccc(F)cc2)OC(=O)c2ccccc21
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(O)(c2ccc(F)cc2)C2=NC3CCCCC3N12
Yield: 41.8 %

Procedure:
A mixture of 1-(4-fluorophenyl)-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamide (5 g) (Step 1 of Example 2), trans 1,2-diaminocyclohexane (8.3 g), and toluene (75 mL) was heated at reflux for 66 h in a flask equipped with a water separator. The mixture was evaporated to dryness and the residual gum was extracted with hexane. The residue was chromatographed over silica gel and eluted with 10% methanol in methylene. Crystallization from ethyl acetate afforded the title compound (2.7 g) as a white solid m.p. 203-205° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][CH2:16][CH:17]([N:19]([CH3:21])[CH3:20])[CH3:18].C(N(CC)CC)C>ClCCCl>[CH3:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH3:7])[C:9]=1[N:15]([CH2:16][CH:17]([N:19]([CH3:21])[CH3:20])[CH3:18])[C:2]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CCOC(=O)Cl
Reactant: Cc1cccc(C)c1NCC(C)N(C)C
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N(CC(C)N(C)C)c1c(C)cccc1C
Reaction time: 6 h
Yield: 67.4 %

Procedure:
0.78 ml (0.88 g, 8 mmoles) of ethyl chloroformate are added to a mixture of 1.0 g (4.85 mmoles) of 1-(2,6-dimethylphenyl-amino)-2-dimethylamino-propane, prepared as described in Example 8, 0.60 ml (0.51 g, 5 mmoles) of triethylamine and 20 ml of 1,2-dichloroethane, and the reaction mixture is boiled for 6 hours. The mixture is washed thrice with 10 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The oily residue is subjected to column chromatography on 20 g of silica gel, applying ethyl acetate as eluant. 0.91 g (67.4%) of 1-[N-(2,6-dimethylphenyl)-N-ethoxycarbonyl-amino]-2-dimethylamino-propane are obtained as a light yellow, oily substance. The hydrochloride of this base melts at 165°-167° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].[NH:6]([C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[C:7]([NH2:9])=[NH:8]>CCCCCC>[ClH:3].[NH:6]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:5])=[O:15])=[CH:12][CH:11]=1)[C:7]([NH2:9])=[NH:8]
Reactant: O=S(Cl)Cl
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCCCCC
Product: N=C(N)Nc1ccc(C(=O)Cl)cc1

Procedure:
To 100 ml of thionyl chloride, was added 21.6 g of 4-guanidinobenzoic acid hydrochloride. The mixture was heated with stirring under reflux for one hour. n-Hexane was added to the reaction mixture to obtain pale yellow crystals of 4-guanidinobenzoyl chloride hydrochloride. Into 200 ml of pyridine, was dissolved 28.2 g of 6-amidino-2-naphthol methanesulfonate. To the resulting solution, while being cooled in ice, was added 4-guanidinobenzoyl chloride hydrochloride which was obtained above. The mixture was stirred under cooling in ice for one hour and then at room temperature overnight. After completion of the reaction, the reaction mixture was mixed with about 300 ml of ethyl ether. The oily substance which was separated was dissolved in about 300 ml of water and the insolubles were removed by filtration. A saturated aqueous sodium hydrogencarbonate solution was added to the filtrate to precipitate pale yellow crystals. The crystals were collected by filtration and washed with water and acetone to obtain 30 g (63.7% yield) of 6-amidino-2-naphthyl 4-guanidinobenzoate carbonate. The carbonate was suspended in 100 ml of methanol. Upon addition of 17 g of methanesulfonic acid to the suspension, a clear solution was formed accompanied by effervescence. About 200 ml of ethyl ether was added to the solution to precipitate white crystals which were collected by filtration to obtain 6-amidino-2-naphthyl 4-guanidinobenzoate dimethanesulfonate.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:8]=1[O:17][CH3:18].[CH3:19]O>>[CH3:19][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([OH:6])=[C:8]([O:17][CH3:18])[CH:9]=1
Reactant: COc1cc(CC(=O)O)ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(O)c(OC)c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
Concentrated sulfuric acid (12 ml) was added to a solution of (4-hydroxy-3-methyoxy-phenyl)-acetic acid (22.5 g, 123 mmol) in methanol (450 ml) at room temperature, and the reaction was heated to 90° C. for 2.45 hours. The reaction was then cooled to room temperature and stirred for 18 hours, and the solvent was removed under reduced pressure. The residue was suspended in ice water (300 ml) and extracted with diethylether (2×300 ml). The combined organic extracts were washed with saturated sodium bicarbonate solution (2×100 ml), brine (100 ml), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of cyclohexane:ethyl acetate (80:20 changing to 70:30, 60:40 and finally 1:1, by volume) to give (4-hydroxy-3-methoxy-phenyl)-acetic acid methyl ester (23 g) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=6.82-6.85 (1H, d), 6.80 (1H, s), 6.76-6.79 (1H, d), 5.49 (1H 3.66 (3H, s), 3.53 (2H, s) ppm. LRMS (electrospray): m/z [M+Na]+ 219.
Reaction SMILES: N#N.[NH:3]([C:19]([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C@H:4]([C:16](O)=[O:17])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>O.C(OCC)(=O)C.CCCCCC.C(COC)OC>[CH:25]1[C:24]2[CH:23]([CH2:22][O:21][C:19](=[O:20])[NH:3][C@H:4]([CH2:16][OH:17])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#N
Agent: [BH4-]
Solvent: CCCCCC
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCC[C@@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
20 mL of dimethoxyethane was added to a dry 100 mL round bottom under N2. 4.54 g (10.0 mmol) of Fmoc-Orn(Boc)—OH, lxxx, was added with stirring. The suspension was cooled in an ice/water/salt bath at −15° C. To the well suspended solid was added 1.11 mL (10 mmol) of N-methylmorpholine followed by 1.36 mL (10 mmol) of isobutyl chloroformate. The reaction was stirred vigorously for 1 min then vacuum filtered. The filtrate was stirred, and a solution of 570 mg (15 mmol) of sodium borohydride in 20 mL of water was immediately added. After 20 min, 150 mL of water was added, and after an additional hour, the resulting white precipitate was filtered, washed with water and hexane, then dried in a vacuum oven at 40° C. for 36 hours to give 3.75 g (8.52 mmol, 85%); white solid; TLC Rf (60% ethyl acetate/hexane): 0.45; mp: 107–109° C.; HRMS calcd (M+ less C4H9O, C21H23N2O4) 367.1658, found 367.1664. 1H NMR (300 MHz, D2O) δ 7.74 (d, 2H, J=7.5), 7.58 (d, 2H, J=7.2), 7.38 (t, 2, J=7.3), 7.29 (t, 2H, J=7.2), 5.05 (m, 1H), 4.57 (m, 1H), 4.42 (d, 2H, J=6.6), 4.19 (t, 1H, J=6.5), 3.72–3.50 (m, 3H), 3.11 (m, 2H), 2.14 (m, 1H), 1.62–1.41 (m, 4H), 1.43 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 156.7, 156.2, 143.8, 141.2, 127.6, 127.0, 125.0, 119.9, 79.2, 66.4, 64.8, 52.8, 47.2, 40.2, 28.4, 28.2, 26.7.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:22])([CH3:21])[C:15]=2[CH:23]=1)(=O)=O.[C:27]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1)(=[O:29])[CH3:28]>>[C:27]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]3[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:21])([CH3:22])[C:15]=3[CH:23]=2)=[CH:33][CH:32]=1)(=[O:29])[CH3:28]
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCOS(C)(=O)=O)cc21
Reactant: CC(=O)Nc1ccc(S)cc1
Product: CC(=O)Nc1ccc(SCCCCOc2cc3c(cc2[N+](=O)[O-])NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 210 from 6-(4-methanesulfonyloxy-butoxy)-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[I-:19].[K+]>Cl.O>[I:19][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(N)cc(C(=O)O)c1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cc(I)cc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 55.1 %

Procedure:
To an ice-cold, stirred solution of commercially available 3-amino-5-(methoxycarbonyl)benzoic acid (5.19 g, 26.59 mmol) in 2 N hydrochloric acid (156 mL) was added a solution of sodium nitrite (1.84 g, 26.67 mmol) in water (10.8 mL). This mixture was then added dropwise to an ice-cold, stirred solution of potassium iodide (8.84 g, 53.25 mmol) in water (26.2 mL). After stirring for 35 min, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium thiosulfate, and saturated sodium chloride, dried (sodium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (silica, 50:50:2 hexanes/ethyl acetate/acetic acid) afforded the title compound (4.48 g, 55% yield) as an off-white solid. ESI-MS (m/z): 305 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([C@H:13]([CH:15]3[CH2:17][CH2:16]3)[OH:14])[O:11]C(C)(C)[N:9]2C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.Cl.[OH-].[Na+]>CO.CCOCC>[NH2:9][C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C@@H:12]([OH:11])[C@H:13]([CH:15]1[CH2:17][CH2:16]1)[OH:14]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)C2CC2)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 3 h
Yield: 66.1 %

Procedure:
1.42 g (3.86 mmol) of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-cyclopropylhydroxymethyl]-2,2-dimethyl-3-oxazolidinecarboxylate dissolved in 15 ml of methanol and 10 ml of water are treated with 4 ml of 7.5N hydrochloric acid and stirred at 50° for 3 hours. The reaction solution is cooled to 3° in an ice bath, treated dropwise with 4 ml of 7.5N sodium hydroxide solution and stirred for 1 hour. The suspension obtained is evaporated under reduced pressure, the water is removed azeotropically twice with 10 ml of toluene and the residue is stirred three times with 10 ml of a 95:5 mixture of methylene chloride and methanol. The insoluble residue is filtered off and the filtrate is evaporated under reduced pressure. The crude product obtained (1.14 g) is suspended in 15 ml of ether and then filtered. There is obtained 0.58 g of (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol as a colourless crystals, m.p. 141°-142°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:12][C@H:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][C@H:9]2[C:24](OC)=[O:25])[CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:12][C@H:11]([NH:13][S:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)(=[O:15])=[O:16])[CH2:10][C@H:9]2[CH:24]=[O:25])[CH:2]=1
Reactant: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1Cc1cccnc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1Cc1cccnc1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 112.2 %

Procedure:
In an atmosphere of nitrogen, (2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-(4chlorophenylsulfonylamino)pyrrolidine (10 g, 0.0244 mol) was dissolved in methylene chloride (200 ml) and the solution was cooled to -50°~-55° C. Then, 1M diisobutylaluminum hydride in toluene (73.2 ml, 0.0732 mol) was added thereto dropwise at -50° C. and the mixture was stirred for 30 minutes. Then, 20% sodium potassium tartrate solution was added thereto at 25° C. for precipitation of insolubles. The insolubles were separated by filtration and washed with methylene chloride. The mother liquor and the washings were combined and, after phase separation, the methylene chloride layer was taken. The methylene chloride layer was concentrated to dryness to provide (2S,4R)-1-(3-pyridylmethyl)-2-formyl-4-(4-chlorophenylsulfonylamino)-pyrrolidine (10.4 g) as an oil.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:14][C:15]1[N:16]=[C:17]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:18]=[N:19][CH:20]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A mixture of 5 g of tert-butyl 1-piperazinecarboxylate, 4 g of 2,6-dichloropyrazine and 9.5 ml de DIPEA in 40 ml of n-butanol is heated at reflux for 3 hours. It is concentrated under vacuum, the residue is taken up in 100 ml of EtOH, the system is left to stand overnight and the crystalline product formed is isolated with suction. This gives 4.7 g of the expected product, m.p.=108° C.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([OH:10])[CH:4]=1)#[N:2].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[S:20]>C(O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Br:11])=[S:20])=[C:5]([OH:10])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N)c(O)c1
Reactant: S=C=Nc1ccccc1Br
Solvent: CCO
Product: N#Cc1ccc(NC(=S)Nc2ccccc2Br)c(O)c1
Reaction time: 24 h
Yield: 76.6 %

Procedure:
To a solution of 4-cyano-2-hydroxyl aniline (1.0 g, 7.5 mmol) in ethanol (20 mL) was added 2-bromophenylisothiocyanate (1.0 mL, 7.5 mmol). After 24 h, the reaction mixture was concentrated under reduced pressure to give 2.0 g (77%) of N-(4-cyano-2-hydroxyphenyl)-N′-(2-bromophenyl) thiourea as a yellow solid which required no further purification. 1H NMR (400 MHz, DMSO) δ 10.8 (s, 1H), 10.1 (s, 1H), 9.6 (s, 1H), 8.7 (d, 1H), 7.7 (d, 1H), 7.6 (d, 1H), 7.4 (t, 1H), 7.25 (d, 1H and d, 2H); MS(EI) m/e 229 (100), 348 (75 (M+)), 462 (30), 695 (10).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1(O)[C:10]2[CH:11]=[C:12]([NH:17][C:18](=[O:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=2[O:8][C:7]1([CH3:26])[CH3:25]>C(OCC)(=O)C.CCCCCC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:10]2[CH:11]=[C:12]([NH:17][C:18](=[O:24])[CH2:19][C:20]([CH3:22])([CH3:21])[CH3:23])[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=2[O:8][C:7]1([CH3:26])[CH3:25]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1ccco1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccco1
Yield: 67 %

Procedure:
Using N-(3-(2-furyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 252, the title compound was synthesized in the same manner as in Example 271. Yield: 67%. Melting point: 126-127° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]2[CH2:17][O:18][C:19]2[C:24]([F:25])=[CH:23][C:22]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:21][C:20]=2[F:31])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:36]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]2[CH2:17][O:18][C:19]2[C:20]([F:31])=[CH:21][C:22]([CH2:26][CH2:27][C:28]([O:30][CH3:36])=[O:29])=[CH:23][C:24]=2[F:25])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccc(Cl)cc2)c(F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccc(Cl)cc2)c(F)c1
Reaction time: 3 h

Procedure:
To a solution of the product prepared in Example 1 (1.10 g, 2.39 mmol, 1 eq) in methanol (20 mL) at room temperature was added thionyl chloride (0.027 mL, 0.36 mmol, 0.15 eq). After stirring the resulting mixture for 3 hrs, the solution was concentrated. Purification of the mixture by chromatography (40 g) eluting with 2 to 10% ethyl acetate//heptane yielded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>O>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1cc([N+](=O)[O-])c(F)cc1Cl
Yield: 157.5 %

Procedure:
To a mixture of 2-chloro-4-fluoro-5-nitrophenol (9.6 g) and potassium carbonate (3.8 g) in acetontrile (50 ml), there was added methyl iodide (14 g), and the resultant mixture was heated under reflux for 3 hours. After being allowed to cool to room temperature (ca. 20° C.), water was added thereto, and the resulting mixture was extracted with ether. The ether extract was washed with water, dried and concentrated. The residue was recrystallized from ethanol to give 8.9 g of 4-chloro-2-fluoro-5-methoxynitrobenzene. M.P., 67.5°-69.8° C.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:4](=[O:7])[CH:5]=[CH2:6])[CH3:3].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[S:19])[S-:18])=[N:14][CH:15]=1.C([NH+](CC)CC)C>C(#N)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[S:18])[S:19][CH2:6][CH2:5][C:4](=[O:7])[C:2]([CH3:8])([CH3:3])[CH3:1])=[N:14][CH:15]=1
Reactant: S=C([S-])Nc1ccc(Cl)cn1
Reactant: C=CC(=O)C(C)(C)C
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: CC(C)(C)C(=O)CCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 3 h
Yield: 82.6 %

Procedure:
A solution of 2,2-dimethylpent-4-en-3-one (30.0 g) in anhydrous acetonitrile (60 cc) is added, at a maximum of 5° C., to a suspension of triethylammonium 5-chloropyrid-2-yldithiocarbamate (82.0 g) in anhydrous acetonitrile (400 cc). The reaction is allowed to proceed for 3 hours at between 5° and 20° C. The crystals which have appeared are filtered off and the filtrate is evaporated under reduced pressure (20 mm Hg) at 45° C. The resulting residue and the crystals which have been separated beforehand are dissolved in methylene chloride (750 cc). The organic solution is washed 4 times with distilled water (600 cc in total), dried over sodium sulphate and evaporated. The resulting product (98.0 g) is dissolved in chloroform (400 cc). The solution is chromatographed on a column of diameter 6.8 cm, containing silica (0.063-0.2 mm, 800 g). Elution is carried out first with chloroform (2.6 liters), this eluate being discarded, and then with chloroform (7.2 liters), this eluate being collected and evaporated to dryness. The resulting product (85.0 g) is purified by recrystallisation from acetonitrile (350 cc). 4,4-Dimethyl-3-oxopentyl 5-chloropyrid-2-yldithiocarbamate (70.0 g) (structure determined by I.R. spectroscopy in petroleum jelly), which melts at 111° C., is obtained.