Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[K+].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])=O.[NH4+]>C(#N)C.O>[O:1]([CH2:8][CH2:9][CH2:10][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: BrCCCOc1ccccc1
Agent: O=C[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: c1ccc(OCCCN2CCCCC2)cc1
Temperature: 50 °C
Yield: 98 %

Procedure:
Mix 3-phenoxypropyl bromide (801.5 g, 3.73 mol), potassium iodide (61.8 g, 0.37 mol, 0.10 equivalents) and water (4.0 L) in a 12-L, 3-necked flask fitted with: a stirrer, thermometer in a side-arm adapter, connected to a Firestone® valve and an addition funnel fitted with a gas outlet adapter, connected to a bubbler. Add piperidine (634.6 g, 7.45 mol, 2.0 equivalents) over 1 hour, without cooling under nitrogen. The temperature at the end of the addition is 40° C. Heat the reaction mixture and maintain the temperature at 50° C. for 6 hours. Monitor the progress of the reaction by HPLC (Column=300×3.9 mm Phenomenex Bondclone 10 CN; mobile phase=65% acetonitrile:35% 0.1N ammonium formate buffer; flow=1.5 mL/minute; wavelength=215 nm; RT: 3-phenoxypropyl bromide=2.3 minutes; 37=4.4 minutes). Typically, the conversion is 94%. Cool the reaction mixture to ambient temperature over a time period of 14 hours and extract with dichloromethane (2×4.0 L). Combine the organic extracts and dry over MgSO4 (400 g). Filter off the drying agent and wash with dichloromethane (1.0 L). Concentrate the filtrate (35-40° C./50 torr) to give 800 g, 98% Yield) of 4, as an oil. HPLC analysis shows that 37 is 90% pure. Purify 4 (16.5 g portion) by distillation under vacuum and collect the title compound (10 g) as a colorless liquid at 99-105° C./0.3 mm: 1H NMR (CDCl3, 200 MHz) δ 1.38-1.5 (m, 2H), 1.5-1.64 (m, 4H), 1.9-2.1 (m, 6H), 4.0 (t, 2H), 6.85-6.95 (m. 3H), 7.22-7.3 (t, 2H). Analysis calculated for C14H21NO: C, 76.67; H, 9.65; 6.39. Found: C, 76.55; H, 9.50; N, 6.22. [M+H]+=220 m/e.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][N:20]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[ClH:21]>CO.[Pt](=O)=O>[ClH:21].[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:12][CH:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:18][CH2:19][NH:20]2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccnc(-c2ccc(S(C)(=O)=O)cc2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2ccc(S(C)(=O)=O)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
Methyl 2-(4-(methylsulfonyl)phenyl)isonicotinate (5.663 g, 19.44 mmol) was suspended in MeOH (20 mL) and hydrogen chloride (1.25 M in MeOH, 40 mL, 50.00 mmol) was added. The mixture was stirred at room temperature for 20 min and then evaporated in vacuo. The HCl salt was suspended in MeOH (100 mL) and platinum(IV) oxide (0.221 g, 0.97 mmol) added. The mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 2 h. The catalyst was filtered off and washed with MeOH. The filtrate was evaporated in vacuo yielding methyl 2-(4-(methylsulfonyl)phenyl)piperidine-4-carboxylate hydrochloride (5.84 g, 90%) as a white solid. MS m/z 298 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15](OC)=[O:16])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:19][CH3:20].CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][C:11](=[CH:14][CH2:15][OH:16])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COC(=O)C=C1CCN(c2ccc(Cl)c(OC)c2)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(N2CCC(=CCO)CC2)ccc1Cl
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 101.6 %

Procedure:
A solution of methyl 2-(1-(4-chloro-3-methoxyphenyl)piperidin-4-ylidene)acetate (275 mg, 0.930 mmol) in anhydrous THF (3 mL) was cooled to −78° C. and then treated with DIBAL-H (3.72 mL of a 1.0 M solution in toluene, 3.72 mmol). The reaction was stirred at −78° C. for 2.5 h and then quenched with EtOAc. After it warmed to 0° C., the mixture was treated with saturated potassium sodium tartrate solution and stirred vigorously for 20 min. The resulting mixture was extracted with EtOAc. The extract was dried (Na2SO4) and concentrated to give a yellow oil, which was purified by flash chromatography (4 g silica gel cartridge and gradient elution with EtOAc/hexanes) to give 2-(1-(4-chloro-3-methoxyphenyl)piperidin-4-ylidene)ethanol (253 mg, 0.945 mmol, 102% yield) as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ ppm 7.18 (1 H, d, J=8.79 Hz), 6.48 (1 H, d, J=16.92 Hz), 6.43 (1 H, s), 5.50 (1 H, t, J=7.03 Hz), 4.18 (2 H, d, J=7.03 Hz), 3.87 (3 H, s), 3.22 (4 H, dt, J=9.50, 5.68 Hz), 2.39-2.48 (2 H, m), 2.32-2.39 (2 H, m).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:11]=1.[CH3:21][O:22][C:23]1[C:26](=O)[C:25](=[O:28])[C:24]=1[O:29]C>CO>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:26]2[C:25](=[O:28])[C:24](=[O:29])[C:23]=2[O:22][CH3:21])[N:11]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Solvent: CO
Product: COc1c(NCCCCCc2csc(NC(N)=NCC(F)(F)F)n2)c(=O)c1=O
Yield: 40.6 %

Procedure:
To 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(5-aminopentyl)thiazole (0.4 g.) in methanol (1.5 ml.) was added 1,2-dimethoxycyclobutene-3,4-dione (0.2 g.). After 2.5 hours at room temperature the mixture was evaporated to dryness, and the residue purified by preparative thin layer chromatography using methanol/chloroform 1:9 v/v as developing solvent. The appropriate band was isolated to give 1-[5-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)pentylamino]-2-methoxycyclobutene-3,4-dione (0.22 g.) which was dissolved in propargylamine (1 g.) and the mixture allowed to stand at room temperature overnight. The mixture was then evaporated to dryness, and the residue purified by preparative thin layer chromatography using chloroform/methanol/aqueous ammonia 90:10:1 v/v/v as developing solvent. The product from this purification was treated in methanol/acetone with excess maleic acid and the resulting salt precipitated by the addition of diethyl ether to give 1-[5-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)pentylamino]-2-propargylaminocyclobutene-3,4-dione hydrogen maleate. The n.m.r. spectrum in d 6 dimethylsulphoxide using tetramethylsilane as internal standard (δ=0) included the following resonances (δ):1.5 (multiplet, 6H); 3.3 (singlet, 1H); 3.5 (multiplet, 2H); 4.1 (quartet, 2H); 4.8 (quartet, 2H); 6.6 (singlet, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:13][C:14]1[C:15]([C:20](O)=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[SH:12][C:3]1[C:2]([NH:1][C:20]([C:15]2[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:21])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][N:4]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: Nc1cc(C(F)(F)F)cnc1S
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)cnc1S)c1ncccc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.2 %

Procedure:
A mixture of 3-amino-5-trifluoromethylpyridin-2-thiol (0.45 g), 3-chloropyridin-2-carboxylic acid (0.39 g), WSC (0.67 g), HOBt (31 mg) and pyridine (4 ml) was stirred at room temperature for 12 hours. To the reaction mixture was added water, and the mixture was filtered to collect a solid. The resulting solid was washed with water, followed by n-hexane, and dried to give 3-chloropyridin-2-carboxylic acid (2-mercapto-5-trifluoromethylpyridin-3-yl)-amide (0.45 g), which is hereinafter referred to as “intermediate compound (M20-11)”.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:20](OC)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=1.FC1C=C(F)C=CC=1C1C=[C:34](COS(C)(=O)=O)[C:35](=O)[N:36]([CH2:38][CH:39](C)C)N=1.C(NCC)C>>[CH2:35]([N:36]([CH2:20][C:11]1[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:10]=1)[CH2:38][CH3:39])[CH3:34]
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Reactant: COC(=O)c1cc(-c2ccc(F)cc2F)nn(CC(C)C)c1=O
Solvent: CCNCC
Product: CCN(CC)Cc1cc(-c2ccc(F)cc2F)nn(CC(C)C)c1=O

Procedure:
Following the procedure of Example 9 (4), 6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethylamine were reacted to yield the title compound as a pale yellow oil (yield: quantitative).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[CH3:35][N:36]1[CH2:41]COC[CH2:37]1.C=O.CN>CCO>[Br:1][C:2]1[C:10]2[S:9][C:8]([N:11]3[CH2:37][N:36]([CH3:41])[CH2:35][N:13]([CH2:14][CH3:15])[C:12]3=[O:16])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1
Reactant: CN1CCOCC1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Agent: C=O
Agent: CN
Solvent: CCO
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(Br)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
Ethyl 1-[5-[7-bromo-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (3.11 g, 5.68 mmol) was suspended in EtOH (120 mL). To the stirred suspension was added, NMM (3.1 mL, 28.4 mmol), aqueous formaldehyde (4.61 mL, 56.8 mmol) and methylamine solution (14.2 mL, 28.4 mmol). The reaction mixture was then stirred at 80° C. for 16 h. The reaction mixture was cooled to rt and filtered. The precipitate was washed with EtOH, Et2O and dried to afford the desired compound (2.58 g, 75%) as an off-white solid. m/z=602.09 and 604.02 [M+H]+.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:11][O:12][C:13]1[CH:14]=[C:15](I)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCOCC.[Cu]I>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(I)c1
Reactant: O=C(O)c1ccccc1S
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cccc(Sc2ccccc2C(=O)O)c1
Yield: 39.6 %

Procedure:
First, 2-[(3-methoxyphenyl)thio]benzoic acid was prepared. A mixture of thiosalicylic acid (1.5 g, 9.7 mmol), 3-methoxyiodobenzene (4.6 g, 19.4 mmol), copper (I) iodide (0.07 g, 0.4 mmol), potassium carbonate (4.0 g, 29.2 mmol), and N,N-dimethylformamide (25 mL) was heated at reflux for 2 h and then cooled to ambient. The reaction mixture was diluted with ether, washed twice with 10% aqueous HCl, and dried (Na2SO4). The solvent is removed at reduced pressure to deposit a brown solid. The product was purified by recrystallization from heptane to provide 1.0 g (40% of theory) of 2-[(3-methoxyphenyl)thio]benzoic acid as a tan solid. 1H NMR (CDCl3): δ 3.80 (s, 3H), 6.90 (d, 1H), 7.00 (d, 1H), 7.25 (m, 5H), 8.11 (d, 1H).
Reaction SMILES: [CH2:1]1[O:20][C:4]([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C3=CC=CC=C3C2=O)([CH3:5])[O:3][CH2:2]1.C(O)C.CCOCC.[OH-].[K+]>O>[CH2:1]1[O:20][C:4]([CH2:6][CH2:7][CH2:8][NH2:9])([CH3:5])[O:3][CH2:2]1
Reactant: CC1(CCCN2C(=O)c3ccccc3C2=O)OCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CC1(CCCN)OCCO1

Procedure:
Seventy-one grams of 5-phthalimido-2-pentanone ethylene ketal (0.26 moles) were suspended into 250 ml of 95% ethanol. Then 13.0 g of NH2 ·NH2 ·H2O (0.26 moles) was added and the reaction mixture was brought to reflux. The stirred mixture was refluxed for 2 hours. Ether (400 ml) was added to the cooled suspension, which was then treated with 40 g of potassium hydroxide in 150 ml of water. The two layers were separated and the aqueous The ether was combined and dried over sodium sulfate. The solvent was then removed under pressure and the remaining liquid that contained crude product was weighed.
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[CH:24][C:10]3[O:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:14][C:13]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[B:31](OC)([O:34]C)[O:32]C.Cl>CCCCCC.C(OCC)(=O)C.O1CCCC1>[C:18]1([C:15]2[CH:16]=[C:17]([B:31]([OH:34])[OH:32])[C:12]3[O:11][C:10]4[CH:24]=[CH:25][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:8][C:9]=4[C:13]=3[CH:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COB(OC)OC
Reactant: c1ccc(-c2ccc3oc4ccc(-c5ccccc5)cc4c3c2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1cc(-c2ccccc2)cc2c1oc1ccc(-c3ccccc3)cc12
Temperature: -80 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
In a 200 mL three-neck flask was put 2.4 g (7.5 mmol) of 2,8-diphenyldibenzofuran. The air in the flask was replaced with nitrogen. To this mixture was added 40 mL of tetrahydrofuran (THF), and this solution was cooled to −80° C. Then, 5.6 mL (9.0 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dripped into this solution with a syringe. After that, this solution was stirred for 2 hours while its temperature was returned to room temperature. Then, this solution was again cooled to −80° C., and 1.7 mL (15 mmol) of trimethyl borate was added to this solution. This solution was stirred for 3 days while its temperature was returned to room temperature. After that, about 30 mL of diluted hydrochloric acid (1.0 mol/L) was added to this solution, followed by stirring for 1 hour. Then, the aqueous layer of this mixture was extracted with ethyl acetate, and the ethyl acetate solution and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate. Then, this mixture was gravity filtered. The resulting filtrate was concentrated to give an oily substance, and a mixed solvent of ethyl acetate and hexane was added to the oily substance. The mixture was irradiated with ultrasonic waves, whereby a solid was precipitated. This solid was collected by suction filtration to give 2.2 g of a white powder in 82% □ yield, which was the substance to be produced.
Reaction SMILES: [N:1]([C:4]1[C:14]([F:15])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:16])[C:5]=1[O:17][CH:18]([F:20])[F:19])=[N+]=[N-]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[NH2:1][C:4]1[C:14]([F:15])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:16])[C:5]=1[O:17][CH:18]([F:19])[F:20]
Reactant: CCOC(=O)c1cc(F)c(N=[N+]=[N-])c(OC(F)F)c1F
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(F)c(N)c(OC(F)F)c1F
Temperature: 50 °C
Reaction time: 6 h

Procedure:
In 210 ml of ethanol and 70 ml of ethyl acetate was dissolved 13.8 g of ethyl 4-azido-2,5-difluoro-3-difluoromethoxybenzoate, and 1.38 g of 5% palladium-carbon was added to the solution, after which the resulting mixture was stirred at 50° C. for six hours under a hydrogen stream. The reaction mixture was filtered, and the filtrate obtained was concentrated under reduced pressure, to obtain 12.3 g of colorless, crystalline ethyl 4-amino-2,5-difluoro-3-difluoromethoxybenzoate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:33])[CH2:23][C:24]([C:26]1[S:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[S:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=3)[CH2:23][C:22](=[O:33])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1ccc(C#N)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C2=Nc3ccc(-c4ccccc4F)cc3NC(=O)C2)s1

Procedure:
Prepared from {3-[3-(5-cyano-thiophen-2-yl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K69) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (263 mg).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:11][CH2:10][O:9][C:8]2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[NH4+:14]>C(O)C>[CH:1]1([CH:7]2[CH2:11][CH2:10][NH:14][C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1OCCC1C1CCCCC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: O=C1NCCC1C1CCCCC1
Yield: 94 %

Procedure:
Heat a mixture of 3-cyclohexyl-dihydro-furan-2-one (32.2 g), ammonium hydroxide (700 mL) and ethanol (700 mL) at 230° C. in a sealed steel bottle for 18 hours. Cool the reaction and remove the solvent in vacuo. Partition the residue with ethyl acetate (500 mL) and HCl (1N, 300 mL). Dry the organic over sodium sulfate. After filtration and concentration, recrystallize with 1:3 ethyl acetate:hexane to afford 30 grams (94%) of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: [Pd]
Solvent: CO
Product: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](CCCc1ccccc1)C(=O)NOC1CCCCO1
Yield: 92.6 %

Procedure:
A solution of 1.0 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 20 ml of methanol was hydrogenated in the presence of 0.100 g of 5% palladium-on-carbon for 0.5 hours. The catalyst was removed by filtration and the solvent was evaporated to give 0.93 g of 2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenylbutyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9].[OH-].[Na+].[CH3:22]O>>[NH2:6][C@H:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:8]([O:10][CH3:22])=[O:9]
Reactant: COc1ccc(C[C@@H](N)C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)[C@H](N)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
20 ml of sulphuric acid are added, dropwise, over a period of 30 minutes, to a solution containing 13 g (66.6 mmol) of (R)-2-amino-3-(4-methoxyphenyl)propionic acid in 150 ml of methanol. After stirring for 24 hours at ambient temperature, the reaction medium is basified to pH 8-9 by introducing 10N sodium hydroxide and a saturated solution of sodium hydrogen carbonate, followed by extraction with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated. 12.8 g in the form of a pale yellow oil are obtained with a yield of 92%.
Reaction SMILES: [CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([OH:20])=[CH:15][CH:16]=2)[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>CN(C)C=O>[CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH3:21])=[CH:15][CH:16]=2)[S:9]1(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCOCCBr
Reactant: O=C1c2ccc(O)cc2S(=O)(=O)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: COCCOCCOc1ccc2c(c1)S(=O)(=O)N(Cc1ccccc1)C2=O
Temperature: 0 °C
Yield: 78 %

Procedure:
A mixture of 2-benzyl-6-hydroxysaccharin (0.86 g), 2-bromoethyl 2-methoxyethyl ether (d=1.347, 0.45 mL), potassium carbonate (1.24 g), methyl ethyl ketone (50 mL) and dimethylformamide (2 mL) was heated under reflux for five hours, then poured into ice-water (500 mL). The resulting solid was collected, washed with water and dried affording 2-benzyl-6-[2-(2-methoxyethoxy)ethoxy]saccharin (0.92 g, 78% yield, mp 86°-88° C.).
Reaction SMILES: Br[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:11][CH3:12].[CH2:13]([O:15][CH:16]([O:19]CC)[CH:17]=[CH2:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][CH2:18][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:11][CH3:12])[CH3:14]
Reactant: CCc1cc(C#N)cc(C)c1Br
Reactant: C=CC(OCC)OCC
Product: CCOC(=O)CCc1c(C)cc(C#N)cc1CC

Procedure:
The title compound is prepared from 4-bromo-3-ethyl-5-methyl-benzonitrile and commercially available acrolein diethyl acetal following literature procedures (G. Battistuzzi, S. Cacchi, G. Fabrizi, R. Bernini, Synlett 8 (2003) 1133-1136); LC-MS: tR=0.91 min; 1H NMR (CDCl3): δ 1.2 (m, 6H), 2.38 (s, 3H), 2.44 (m, 2H), 2.70 (q, J 7.5 Hz, 2H), 3.03 (m, 2H), 4.18 (q, J 7.3 Hz, 2H), 7.30 (s, 1H), 7.34 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:6]([NH:19][C:20]2[C:21]3[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[N:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=1.[OH-].[Na+].Cl>O1CCCC1>[CH:30]([C:27]1[CH:28]=[CH:29][C:21]2[C:20]([NH:19][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=3[S:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:3]([OH:33])=[O:2])=[N:25][CH:24]=[N:23][C:22]=2[N:26]=1)([CH3:32])[CH3:31]
Reactant: COC(=O)c1ccc(Sc2ccc(OC)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Sc2ccc(C(=O)O)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Temperature: 50 °C

Procedure:
To the product from Example 136C (1.56 g, 3.4 mmol) in tetrahydrofuran (20 mL) was added 1N aqueous sodium hydroxide (10 mL, 10 mmol) and the reaction mixture heated at 50° C. for 3 hours. After cooling the reaction mixture to room temperature, the pH was adjusted to 6.5 with 1N aqueous hydrochloric acid and the resulting precipitate was removed by vacuum filtration. The product was dried under high vacuum overnight to provide the title compound as an off white solid (643 mg, 42%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10](=[O:14])[CH:11]=[CH:12][CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.C(O)(=[O:17])C>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:3]([C:10](=[O:14])[CH:11]=[CH:12][CH3:13])[C:4]([CH3:8])([CH3:9])[CH2:5][C:6](=[O:17])[CH:7]=1
Reactant: CC=CC(=O)C1C(C)=CCCC1(C)C
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC=CC(=O)C1C(C)=CC(=O)CC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 ml of acetic anhydride were first added to a solution kept at 10° of 3.5 g of Na2Cr2O7 .2H2O in 10 ml of acetic acid and the obtained mixture was stirred for one hour. A solution of 2.1 g of 2,6,6-trimethyl-1-(but-2-enoyl)-cyclohex-2-ene [prepared according to the method described in Helv. Chim. Acta 53, 541 (1970)], in 10 ml of acetic anhydride was then added to the above mixture. After having been stirred overnight at room temperature, the reaction mixture was then poured onto crushed ice and extracted with ether. After the usual treatments of washing, drying and evaporation, there was obtained 2.0 g of crude material containing 80 % of the desired keto compound.