Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[Na+].[N+:16](CC)([O-])=O>C(O)(=O)C>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:16]
Reactant: O=Cc1ccc(O)cc1O
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(O)cc1O
Yield: 58.4 %

Procedure:
A mixture of 2,4-dihydroxybenzaldehyde (5.0 g, 36.4 mmol), sodium acetate (5.94 g, 72.4 mmol), nitroethane (5.44 g, 72.4 mmol) and glacial acetic acid (10 ml) was refluxed for 6 hours. After cooling, the mixture was poured onto ice (100 g) and extracted with ethyl acetate (4×50 ml). The combined organic layers were washed with saturated NaHCO3 until the pH of the aqueous layer remained at 8, dried (Na2SO4) and the solvent removed in vacuo. Flash chromatography (SiO2, cyclohexane:ethyl acetate=1:1) afforded 2,4-dihydroxybenzonitrile (2.87 g, 59%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 6.33 (d, 1H, J=8.6 Hz), 6.43 (s, 1H), 7.37 (d, 1H, J=8.6 Hz), 10.35 (s, 1H), 10.78 (s, 1H). IB (KBr) 2200 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[O:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:18]1[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1
Reactant: COc1cccc(C=O)c1
Reactant: C1CC2(CCN1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cccc(CN2CCC3(CC2)OCCO3)c1
Reaction time: 19 h
Yield: 94.7 %

Procedure:
A mixture of 3-methoxybenzaldehyde (10.0 g, 73.4 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (10.5 g, 73.4 mmol), sodium triacetoxyborohydride (20.2 g, 95.3 mmol), and acetic acid (4.2 mL), in methylene chloride (400 mL), was stirred at ambient temperature. After 19 h, a 2 N aqueous sodium carbonate solution (220 mL) was added portionwise. After stirring for 15 min, the aqueous layer was separated and extracted with methylene chloride (100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to provide 8-(3-methoxybenzyl)-1,4-dioxa-8-azaspiro[4.5]decane (18.3 g, 95%) as a yellow oil: 1H NMR (CDCl3, 500 MHz) δ 7.25-7.19 (m, 1H), 6.91-6.89 (m, 2H), 6.80-6.77 (m, 1H), 3.94 (s, 4H), 3.80 (s, 3H), 3.50 (s, 2H), 2.53-2.49 (m, 4H), 1.76-1.72 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:19][C:13]1[CH:12]=[C:11]([N:5]2[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: Cc1cc(F)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1C#N
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a solution of 4-(trifluoromethyl)-1H-pyrazole (1.0 g, 7.0 mmol) and 4-fluoro-2-methylbenzonitrile (1.16 g, 8.50 mmol) in acetonitrile (8 mL) was slowly added potassium carbonate (1.96 g, 14.2 mmol) at room temperature. The reaction was heated to 80° C. and stirred overnight. The reaction was cooled to room temperature and poured into water. The layers were separated and the aqueous was extracted with ethyl acetate (3×15 mL). The combined organics were washed with water, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (710 mg, 40%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.26 (s, 1H), 7.94 (s, 1H), 7.72-7.74 (m, 2H), 7.61-7.64 (m, 1H), 2.64 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S-:20].[Na+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:20][CH3:19])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 71.4 %

Procedure:
Amine preparation: A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.015 g), sodium thiomethoxide (635 mg) was heated to 80° C. in DMF (10 mL). After 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified by flash chromatography to give 4-methylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (600 mg). To a solution of 4-methylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (600 mg) in chloroform (15 mL) was added mCPBA (1.46 g). After stirring for 2 days, the reaction mixture was diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo to yield 4-methanesulfonyl-piperidine-1-carboxylic acid tent-butyl ester (505 mg) as a white solid. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][NH:5]2.CC1(C)C(C)(C)OB([C:24]2[CH:44]=[CH:43][C:27]([C:28]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[O:29])=[CH:26][CH:25]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:24]3[CH:44]=[CH:43][C:27]([C:28]([N:30]4[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:34][CH2:35]4)=[O:29])=[CH:26][CH:25]=3)=[CH:11][CH:10]=2)[NH:5][CH2:6][C@@H:7]1[CH3:15])(=[O:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc2NC[C@@H]1C
Temperature: 80 °C
Yield: 82.7 %

Procedure:
A mixture of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.200 g, 0.743 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate (0.340 g, 0.817 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.052 g, 0.074 mmol), and sodium bicarbonate (1 M in water, 1.5 mL, 1.5 mmol) in 1,4-dioxane (3.7 mL) was heated at 80° C. for 16 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (gradient elution with 0-100% ethyl acetate-hexane) to afford (S)-tert-butyl 4-(4-(1-acetyl-2-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)benzoyl)piperazine-1-carboxylate (0.294 g, 83%) as an off-white solid. MS (ESI, pos. ion) m/z 479.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)cc1F
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-bromo-2-fluoro benzyl bromide (1.5 g, 5.6 mmol) in DMF (50 mL) was added sodium cyanide (0.8 g, 17 mmol). The reaction mixture was stirred at 90° C. for 1 h, cooled to rt and quenched with brine (50 mL). After extraction with EtOAc (3×100 mL), the organic layers were combined, washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexanes:EtOAc 5:1) to afford 4-bromo-2-fluoro benzyl cyanide as yellow solid. MS (ESI) 307 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12](O)=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH2:15][C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[CH:20][C:21]=1[NH2:22]>>[CH3:23][C:18]1[CH:19]=[CH:20][C:21]2[N:22]=[C:12]([C:11]3[C:2](=[O:1])[NH:3][C:4]4[C:9]([CH:10]=3)=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:15][C:16]=2[CH:17]=1
Reactant: O=C(O)c1cc2ccccc2[nH]c1=O
Reactant: Cc1ccc(N)c(N)c1
Product: Cc1ccc2nc(-c3cc4ccccc4[nH]c3=O)[nH]c2c1
Temperature: 200 °C

Procedure:
A suspension of 2-oxo-1,2-dihydro-quinoline-3-carboxylic acid 1-1 (500 mg, 2.64 mmol, 1 equiv) and 3,4-diaminotoluene (646 mg, 5.29 mmol, 2.00 equiv) in polyphosphoric acid (10 mL) was heated under argon at 200° C. for 2 h. The hot reaction mixture was poured over ice (200 g), and the resulting mixture was allowed to stand until all polyphosphoric acid had dissolved. The precipitate was filtered, washed with water (200 mL), and air dried. The olive-colored solid was partitioned between aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL). The organic layer was dried over sodium sulfate and concentrated to give 1-3 as a yellow solid. 1H NMR (300 MHz, CDCl3) major hydrogen-bonded rotational isomer: δ 15.20 (br s, 1H), 14.30 (br s, 1H), 9.18 (s, 1H), 7.77 (br d, 1H, J=7.6 Hz), 7.61 (br d, 1H, J=7.5 Hz), 7.60 (br t, 1H, J=7.5 Hz), 7.37 (br s, 1H), 7.36 (br d, 1H, J=7.5 Hz), 7.32 (br t, 1H, J=7.6), 7.14 (br d, 1H, J=8.2 Hz), 2.52 (s, 3H); HRMS (electrospray FT/ICR) calcd for C17H14N3O [M+H]+ 276.1131, found 276.1132; TLC (40% EtOAc in hexane) Rf=0.10.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]#[N:18])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:19][O-:20].[Na+]>CO>[CH3:19][O:20][C:17]([N:14]1[CH2:13][CH2:12][CH:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][N:7]=2)[CH2:16][CH2:15]1)=[NH:18]
Reactant: C[O-]
Reactant: N#CN1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a stirred mixture of cyanogen bromide (1.8 g, 0.017 mol), sodium bicarbonate (2.80 g) and dimethyl sulfoxide (DMSO) (40 ml) was added dropwise 6-chloro-3-(4-piperidinyl)-1H-indazole (4.0 g, 0.017 mol) of Example 52 dissolved in DMSO (50 ml). The reaction was stirred at ambient temperature for 1 hour and poured into water. The resulting solid was collected, dried and weighed 4.0 g. Recrystallization from toluene-hexane afforded 3.1 g (70%) of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carbonitrile, m.p. 180°-188° C. To a stirred mixture of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carbonitrile (3.0 g., 0.015 mol) in methanol (30 ml) was added a solution of 25% sodium methoxide in methanol (2.5 ml). The reaction was warmed on a steam bath to effect solution and then stirred at ambient temperature for 16 hours. Most of the methanol was removed in vacuo and the residue was diluted with water. An initial oil solidified and 3.5 g of a solid was collected. This was recrystallized from methanol-water to yield 2.9 g (66%) of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carboximidic acid methyl ester, mp 173°-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[C:21]([CH3:26])=[CH:22]N(C)C)=[CH:16][CH:15]=3.C(O)(=O)C(O)=O.[CH2:39]([NH:41][NH2:42])[CH3:40]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:41]([CH2:39][CH3:40])[N:42]=[CH:22][C:21]=1[CH3:26])=[CH:16][CH:15]=3
Reactant: CC(=CN(C)C)C(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: CCNN
Agent: O=C(O)C(=O)O
Product: CCn1ncc(C)c1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in Example 37 above, using 3-(2,4-dichlorophenyl)-6-(3-dimethylamino-2-methylacryloyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one from preparation 1.13 above and ethylhydrazine oxalate.
Reaction SMILES: [CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH3:24])[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:24])[C:34]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([C:26]([F:36])([F:37])[F:25])=[CH:32][CH:31]=3)=[O:35])[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)cc1)OCC
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Nc3ccc(C(F)(F)F)cc3)c2)cc1)OCC
Temperature: 50 °C
Yield: 97.6 %

Procedure:
A mixture of 1 g (3 mmol) of ethyl (Z)-2-ethoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate (prepared according to Example 43b) and 0.8 mL (6 mmol) of 4-trifluoromethylphenyl isocyanate is placed in a sealed tube and heated at 50° C. for 15 hours. The reaction medium is cooled and the residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 1.5 g (95%) of ethyl (Z)-2-ethoxy-3-{3′-[1-methyl-3-(4-trifluoromethylphenyl)ureido]biphenyl-4-yl}acrylate are obtained in the form of a white foam.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[C:18]([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: CC(C)(C)CI
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Cl)n(CC(C)(C)C)c1=O
Reaction time: 48 h

Procedure:
6-Chloro-3-methyl uracil (10.0 g) and potassium carbonate (10.34 g) in DMF (70 ml) under nitrogen were treated with neopentyl iodide (9.9 ml) and stirred for 48 h. Neopentyl iodide (7.4 ml) was added and the reaction was stirred under reflux for a further 37 h. The reaction was poured into water (700 ml) and extracted with ethyl acetate. The combined organics were dried and concentrated in vacuo to afford the subtitle compound an orange oil, 8.1 g.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[N:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH2:24]([N:31]1[CH2:35][CH:34]2[CH2:36][NH:37][CH2:38][CH:33]2[CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>C(O)CCCC>[CH2:24]([N:31]1[CH2:35][CH:34]2[CH2:36][N:37]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:18]5[CH:23]=[CH:22][N:21]=[N:20][CH:19]=5)=[C:9]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[N:10]=4)[N:7]=3)[CH2:38][CH:33]2[CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Fc1ccc(-c2nc3ccc(Cl)nn3c2-c2ccnnc2)cc1
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Agent: Cl
Solvent: CCCCCO
Product: Fc1ccc(-c2nc3ccc(N4CC5CN(Cc6ccccc6)CC5C4)nn3c2-c2ccnnc2)cc1
Temperature: 150 °C
Yield: 87.2 %

Procedure:
The mixture of 0.90 g (2.8 mmol) of 6-chloro-2-(4-fluorophenyl)-3-(pyridazin-4-yl)-imidazo[1,2-b]pyridazine and 1.7 g (8.3 mmol) of 5-benzyloctahydropyrrolo[3,4-c]pyrrole in 15 ml of pentanol is heated in a sealed tube at 150° C. for 18 hours. The reaction medium is poured into a 1N aqueous solution of hydrochloric acid and the aqueous phase is washed with ethyl acetate. The aqueous phase is then basified using aqueous sodium hydroxide and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. The product is chromatographed on a silica gel column, elution being carried out with a mixture of aqueous ammonia, methanol and dichloromethane (0.2/2/98), to give 1.2 g of solid in the form of an amorphous white foam.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:26][C:27]([NH:19][S:16]([C:14]2[CH:13]=[CH:12][C:9]3[CH2:10][CH2:11][N:5]([C:3](=[O:4])[NH:2][CH3:1])[CH2:6][CH2:7][C:8]=3[CH:15]=2)(=[O:18])=[O:17])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CNC(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Reactant: O=C=NC1CCCCC1
Product: CNC(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1

Procedure:
By the reaction of 3-methylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-[(3-methylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea. The starting material is prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with methylisocyanate in a manner analogous to that described in Example 8.
Reaction SMILES: [CH3:1][C:2]1[O:11][C:10](=[O:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([CH:14]([CH3:16])[CH3:15])[O:5][C:4]=2[CH:3]=1.[OH-].[K+].C(OC)(C)(C)C.Cl>CO>[OH:5][C:4]1[CH:3]=[C:2]([CH3:1])[O:11][C:10](=[O:12])[C:9]=1[C:8](=[O:13])[CH:7]=[CH:6][CH:14]([CH3:15])[CH3:16]
Reactant: Cc1cc2c(c(=O)o1)C(=O)CC(C(C)C)O2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: COC(C)(C)C
Product: Cc1cc(O)c(C(=O)C=CC(C)C)c(=O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
In 10 ml of methanol, 222 mg of 2, 3-dihydro-7-methyl-2-(1-methylethyl)-4H, 5H-pyrano[4,3-b]pyran-4,5-dione were dissolved, and 200 mg of potassium hydroxide were added thereto and stirred at room temperature for 1 hour. After that, methyl t-butyl ether and 3% hydrochloric acid were added to the reaction mixture. The separated organic layer was washed with saturated brine once, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 130 mg of 4-hydroxy-6-methyl-3-(4-methyl-2-pentenoyl)-2-pyrone. 1H-NMR (CDC13, TMS) δ (ppm): 1.13 (6H, d), 2.27 (3H, s), 2.60 (1 H, m), 5.93 (1H, s), 7.23 (1H, dd), 7.58 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=O.Cl.[CH:19]([O:22][NH2:23])([CH3:21])[CH3:20]>CO>[CH3:1][O:2][C:3](=[O:17])/[C:4](/[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=[N:23]/[O:22][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)ON
Reactant: COC(=O)C(=O)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cl
Solvent: CO
Product: COC(=O)/C(=N/OC(C)C)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
(3-Chloro-4-methanesulfonyl-phenyl)-oxo-acetic acid methyl ester (prepared as in Example 1, 1.30 g, 4.70 mmol) was stirred in methanol (9.5 mL) and warmed in a 70° C. oil bath. O-Isopropyl-hydroxylamine hydrochloride (786 mg, 7.04 mmol) was added. After 7 h, the reaction mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with 0.2 M aqueous potassium bisulfate solution (50 mL), 50% aqueous sodium bicarbonate solution (50 mL) and brine (50 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes to 33% ethyl acetate/hexanes) afforded (E)-(3-chloro-4-methanesulfonyl-phenyl)-isopropoxyimino-acetic acid methyl ester as a faintly yellow oil contaminated with an unknown impurity (645 mg, <41%): LC-MS (ESI) m/e calcd for C13H16ClNO5S [M+] 333.04, found 334 [M+H+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=[O:15])[C:12]([O-:14])=[O:13])=[CH:2]1.[NH2:16][C@H:17]([C:23]([O-:25])=[O:24])[CH2:18]CC([O-])=O>>[CH:6]1[CH:5]=[C:4]2[C:3]([CH2:10][C@@:11]([OH:15])([C:12]([OH:14])=[O:13])[CH2:18][C@H:17]([NH2:16])[C:23]([OH:25])=[O:24])=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1
Reactant: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Reactant: O=C([O-])C(=O)Cc1c[nH]c2ccccc12
Product: N[C@@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O

Procedure:
The KHG aldolases from B. subtilis, E. coli, and S. meliloti were also used with the E. coli L-aspartate aminotransferase to produce monatin enzymatically. The following reaction conditions were used: 50 mM NH4—OAc pH 8.3, 2 mM MgCl2, 200 mM pyruvate, 5 mM glutamate, 0.05 mM pyridoxal phosphate, deaerated water to achieve a final volume of 0.5 mL after the addition of the enzymes, 3 mM potassium phosphate, 20 μg/mL of recombinant B. subtilis KHG aldolase (purified), ca. 400 μg/mL of E. coli L-aspartate aminotransferase (AspC) unpurified from cell extract, and 12 mM indole-3-pyruvate. The reactions were incubated at 30° C. for 30 minutes with shaking. The amount of monatin produced using the B. subtilis enzyme was 80 ng/mL, and increased with increasing amounts of aldolase. If indole-3-pyruvate and glutamate were replaced by saturating amounts of tryptophan and 5 mM alpha-ketoglutarate, the production of monatin was increased to 360 ng/mL. Reactions were repeated with 30 μg/mL of each of the three KHG enzymes in 50 mM Tris pH 8.3, with saturating amounts of tryptophan, and were allowed to proceed for an hour in order to increase detection. The Bacillus enzyme had the highest activity as in Example 4, producing approximately 4000 ng/mL monatin. The E. coli KHG produced 3000 ng/mL monatin, and the S. meliloti enzyme produced 2300 ng/mL.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[Cl:17])[CH2:15][CH:16]=1
Reactant: Clc1ccccc1CBr
Reactant: C1=C(c2nc3ccccc3s2)CCNC1
Agent: Cl
Product: Clc1ccccc1CN1CC=C(c2nc3ccccc3s2)CC1
Yield: 44 %

Procedure:
4-(Benzothiazol-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (200 mg, 0.8 mmol) was reacted with 2-chlorobenzyl bromide (0.13 ml, 0.8 mmol) as exemplified in Example 1. The crude product was purified by flash chromatography eluting with 15% ethyl acetate in petroleum ether to give the title compound as a yellow solid (120 mg, 44%). (Found: C, 65.13; H, 4.72; N, 7.33. C19H17ClN2S. 0.5H2O requires C, 65.22; H, 5.19; N, 8.01%). δH (CDCl3), 2.84 (4H, m, CH2), 3.33 (2H, m, NCH2CH2), 3.80 (2H, s, NCH2Ar), 6.70 (1H, m, NCH2CH), 7.41 (6H, m, ArH), 7.82 (1H, d, J 7.8Hz, ArH), 7.98 (1H, d, J 8.1Hz, ArH). m/z (ES+) 341 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([N+:26]([O-])=[O:27])[CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[C:18]([NH:26][OH:27])[CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1NO
Reaction time: 3 h
Yield: 58.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide (150 mg, 0.354 mmol) in methanol (3 mL) was treated with 10% palladium on activated carbon (50 mg). The reaction mixture was stirred under a positive pressure of hydrogen gas (balloon) at 25° C. and atmospheric pressure for 3 h. The catalyst was then filtered off through a pad of celite, and the celite pad was washed well with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 20/1 methylene chloride/methanol) afforded 3-cyclopentyl-2-(3-hydroxyamino-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (85 mg, 59%) as a white solid: mp 124-126° C.; EI-HRMS m/e calcd for C18H23N3O4S2 (M+) 409.1130, found 409.1131.