Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:21][C:22]1[C:23]([CH:32]2[CH2:34][O:33]2)=[CH:24][C:25]2[CH2:29][O:28][C:27](=[O:30])[C:26]=2[CH:31]=1>>[OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:34][CH:32]([OH:33])[C:23]2[C:22]([CH3:21])=[CH:31][C:26]3[C:27](=[O:30])[O:28][CH2:29][C:25]=3[CH:24]=2)[CH2:6][CH2:5]1
Reactant: Cc1cc2c(cc1C1CO1)COC2=O
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Product: Cc1cc2c(cc1C(O)CN1CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC1)COC2=O

Procedure:
5-[(1R)-1-hydroxy-2-{4-[2-hydroxy-2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl]-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 58 starting from 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one and isomer B of 6-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (65B).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH3:24])[CH:6]([N:8]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])C.Cl>C(O)C>[Cl:23][C:16]1[N:17]=[CH:18][C:19]2[NH:20][C:4](=[O:3])[CH:5]([CH3:24])[CH:6]([CH3:7])[N:8]([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[C:14]=2[N:15]=1
Reactant: CCOC(=O)C(C)C(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: Cl
Solvent: CCO
Product: CC1C(=O)Nc2cnc(Cl)nc2N(C2CCCC2)C1C
Yield: 38.2 %

Procedure:
To a solution of 1.2 g (0.0032 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2-methyl-butanoic acid ethyl ester (IV-41) in 20 mL of ethanol was added 1.82 g (0.0081 mole) of stannous chloride dihydrate and 0.5 mL of hydrochloric acid. The mixture was heated to 60 degrees for 2 hrs. The mixture was concentrated under reduced pressure. The residue was taken up in 50 mL of water and extracted with three times with 50 mL of ethyl acetate. The combined organics were dried with magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with dichloromethane-methanol (100:0-95:5) gave 0.36 g of (rac)-2-chloro-9-cyclopentyl-7,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-41) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C=O>[CH:21]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH:11]([F:12])[F:13])[CH:5]=[O:6])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCC1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OC2CCCC2)c1
Temperature: 50 °C

Procedure:
To a mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde (2.9 g,.15 mmol) and powdered potassium carbonate (3.2 g, 23 mmol) in dimethylformamide (15 mL) under an argon atmosphere was added bromocyclopentane (2.5 mL, 23 mmol) and the mixture was stirred and heated at 50° C. for 1 h and at 80°-85° C. for 1.5 h. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic extract was washed three times with water, was dried (sodium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 20-30% ether/hexanes, provided a yellow soild (3.5 g, 89%).
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].N12CCCN=C1CCCCC2.O1CCOCC1.N[C:24]([C:36]1[CH:37]=[N:38][C:39]([Cl:42])=[CH:40][CH:41]=1)([CH3:35])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([F:34])[CH:28]=1)=O>C(OCC)(=O)C>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:24]2([CH3:35])[C:25]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([F:34])[CH:28]=3)=[N:5][S:1](=[O:3])(=[O:2])[NH:4]2)=[CH:37][N:38]=1
Reactant: NS(N)(=O)=O
Reactant: CC(N)(C(=O)c1ccc(Cl)c(F)c1)c1ccc(Cl)nc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(c2ccc(Cl)nc2)NS(=O)(=O)N=C1c1ccc(Cl)c(F)c1
Temperature: 95 °C
Yield: 80 %

Procedure:
A molecular sieve 4 A (4.5 g), sulfamide (2.75 g, 28.6 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.45 g, 9.52 mmol) were added to a dioxane (60 ml) solution of the compound (2.99 g, 9.55 mmol) obtained in Step 6 above and the resulting mixture was stirred under heating at 95° C. for 18 hours. Further sulfamide (2.75 g, 28.6 mmol) was added and the resulting mixture was stirred under heating for 24 hours. The reaction mixture was concentrated under reduced pressure and then the residue obtained was diluted with ethyl acetate, washed with 10% aqueous citric acid solution and saturated brine, and then dried over anhydrous magnesium sulfate. A diisopropyl ether/ethyl acetate mixed solvent was added to the residue obtained and the resulting precipitate was collected by filtration and dried to give the title compound (2.86 g, 80%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([O:13][CH3:14])[C:3]=1[CH2:15]C1C=CC=C(C(F)(F)F)C=1.ClC1C(C[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)=C(Cl)C2C(=CC=C(I)C=2)N=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([O:13][CH3:14])[C:3]=1[CH2:15][C:39]1[CH:38]=[CH:43][CH:42]=[CH:41][C:40]=1[C:44]([F:47])([F:46])[F:45]
Reactant: FC(F)(F)c1cccc(Cc2c(Cl)nc3ccc(I)cc3c2Cl)c1
Reactant: COc1nc2ccc(I)cc2c(Cl)c1Cc1cccc(C(F)(F)F)c1
Product: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccccc1C(F)(F)F

Procedure:
The title compound was prepared following the procedure described for the preparation of Intermediate 7: step c, substituting 2,4-dichloro-6-iodo-3-(3-(trifluoromethyl)benzyl)quinoline (Intermediate 7: step b) with 2,4-dichloro-6-iodo-3-(2-(trifluoromethyl)benzyl)quinoline (Intermediate 8: step b).
Reaction SMILES: [CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=2)[CH2:15][C@H:14]1[C:26]([O:28][CH3:29])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:30][C:31]([F:37])([F:36])[CH:32]([OH:35])[CH:33]=[CH2:34].C(N(CCCC(OCC)=O)CCOC1C=CC(/C=C/C(O)C(F)(F)F)=CC=1)CCCCCCCCCCC>>[CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:34][CH2:33][C:32](=[O:35])[C:31]([F:37])([F:36])[F:30])=[CH:21][CH:20]=2)[CH2:15][C@H:14]1[C:26]([O:28][CH3:29])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=CC(O)C(F)(F)F
Reactant: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(I)cc2)C[C@H]1C(=O)OC
Agent: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(/C=C/C(O)C(F)(F)F)cc1
Product: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(CCC(=O)C(F)(F)F)cc2)C[C@H]1C(=O)OC
Yield: 8.5 %

Procedure:
(2S, 4S)-1-N-Dodecyl-4-(4-iodophenoxy)pyrrolidine-2-carboxylic acid, methyl ester (800 mg, 1.55 mmol) and 4,4,4-trifluorobut-1-en-3-ol (complex with 1 tetrahydrofuran, 620 mg, 3.1 mmol) were reacted by the general procedure as described in the preparation of 4-[N-dodecyl-N-2-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-en-1-yl]phenoxy]ethylamino]butanoic acid, ethyl ester and afforded the title compound (575 mg, 72%) as a colorless oil [[a]D=−28.7° (c 0.8, CHCl3)] and (2S, 4S)-1-N-dodecyl-4-[4-(3-oxo-4,4,4-trifluorobut-1-yl)phenoxy]pyrrolidine-2-carboxylic acid, methyl ester (68 mg, 9%) as a pale yellow oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]C(=O)C)=[CH:7][C:6]=1[O:15]C(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>CO.S(=O)(=O)(O)O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:15]
Reactant: CC(=O)Oc1ccc(OC(C)=O)c(OC(C)=O)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOCC
Solvent: CO
Product: Oc1ccc(O)c(O)c1
Temperature: 25 °C

Procedure:
Eighty grams of the crude 1,2,4-triacetoxybenzene were dissolved in 200 ml of methanol containing 6 g of concentrated sulfuric acid. The reaction mixture was boiled under reflux for one hour. Then the solution was cooled to room temperature and neutralized with an equivalent amount of fine powdered sodium carbonate. Thereafter 800 ml of ethylether was added whereupon sodium sulfate precipitated out, which was removed by filtration. Reaction by-products and contaminants being responsible for a dark red coloration may be removed employing solid silica gel. After evaporation of the supernatant under reduced pressure, a dark red oil is obtained which crystallized upon standing at 40° C. in the form of a slight reddish solid mass which is pure enough for the next step. This product is 1,2,4-trihydroxybenzene.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[I:12].[C:13](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[I:12][C:3]1[C:4]2[O:8][CH2:7][C:6](=[O:9])[C:5]=2[CH:10]=[CH:11][C:2]=1[O:1][CH3:13]
Reactant: O=C1COc2c1ccc(O)c2I
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1I)OCC2=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 49.8 %

Procedure:
A solution of 6-hydroxy-7-iodobenzofuran-3(2H)-one (2.58 g, 9.35 mmol) in DMF (37 mL) was added with potassium carbonate (1.55 g, 11.2 mmol) and methyl iodide (0.697 mL, 11.2 mmol), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was added with water (400 mL), and the precipitated solid was collected by filtration to obtain 7-iodo-6-methoxybenzofuran-3(2H)-one (1.35 g, 49%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:17]([CH:14]2[CH2:16][CH2:15]2)=[O:18])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)C1CC1
Reactant: NCc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Yield: 50 %

Procedure:
The title compound was prepared by following the procedure as described in step-2 of Intermediate-30 by using (4-chloro-3-nitrophenyl)methanamine hydrochloride (0.700 g, 3.14 mmol), cyclopropylcarbonyl chloride (0.490 g, 4.71 mmol), DIPEA (3.0 mL) and THF (15 mL) to afford 0.400 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (d, J=6.0 Hz, 2H), 1.55-1.61 (m, 1H), 4.33 (d, J=6.0 Hz), 7.55 (d, J=7.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 8.68 (br s, 1H); MS (m/z): 255.09 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:14][C:9]=2[S:8][CH:7]=1)C.CO.C1COCC1.O.[OH-].[Li+]>O>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:13]1[CH:12]=[CH:11][C:10]2[C:6]([CH2:5][C:4]([OH:25])=[O:3])=[CH:7][S:8][C:9]=2[CH:14]=1
Reactant: CCOC(=O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a mixture of ethyl(6-((2,4-dichlorobenzyl)oxy)-1-benzothiophen-3-yl)acetate (200 mg), MeOH (2.0 mL), THF (dry) (3.0 mL) and water (1.0 mL) was added lithium hydroxide hydrate (63.7 mg). The mixture was stirred at room temperature for 1 h. After the mixture was concentrated, the residue was neutralized with 1M HCl, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residual solid was crystallized from EtOAc-hexane to give the title compound (177.7 mg).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl>CS(C)=O>[CH:5]1[C:6]2[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[O:7][C:1]=2[CH:2]=[CH:3][CH:4]=1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc2c(c1)oc1ccccc12
Temperature: 120 °C
Reaction time: 5 h

Procedure:
The phenol 10 is dissolved in DMSO under nitrogen, a 60% sodium hydride/mineral oil suspension is added, and the mixture is warmed to 120° C. After 5 hours at this temperature, the cooled batch is added to dil. HCl solution. The aqueous phase is extracted with MTB ether. The organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](OCC)=[O:13].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:12][OH:13]
Reactant: CCOC(=O)c1[nH]c2c(C)cccc2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(CO)[nH]c2c(C)cccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
A solution of ethyl 3,7-dimethyl-1H-indole-2-carboxylate (1.84 g, 8.4 mmol) in THF (20 mL) was added to an ice-cooled solution of 1.0 M LAH in THF (17.8 mL 17.8 mmol) and stirred overnight. The reaction was quenched with ethyl acetate (5 mL) and 15% aqueous sodium hydroxide (5 mL), filtered through celite and evaporated in vacuo. The crude reaction was chromatographed over silica gel eluting with methanol/dichloromethane (1%) to afford the title compound (440 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.06 (t, J=7.2 Hz, 1H), 6.99 (d, J=7.1 Hz, 1H), 4.82 (s, 2H), 4.11 (q, J=7.1 Hz, 2H), 2.45 (s, 3H), 2.28 (s, 3H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:24]CC)(=[O:23])/[CH:20]=[CH:21]/[CH3:22].CC(C)([O-])C.[K+].[OH-].[Na+].Cl>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:22][CH:21]=[CH:20][C:19]([OH:24])=[O:23])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: C/C=C/C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(C=CC=CC(=O)O)ccc1OCc1ccccc1
Temperature: 0 °C

Procedure:
To a solution containing 260 g of 4-benzyloxy-3-methoxybenzaldehyde and 200 ml of ethyl crotonate in 1200 ml of N-methylpyrrolidone was gradually added while stirring and cooling at 0° C. 149.6 g of potassium tert.-butoxide. The solution was stirred for 0.5 h after which 200 ml of 10 N NaOH-solution was added and stirred for 0.5 h more at 0° C. The reaction mixture was added to a mixture of hydrochloric acid and ice. The semisolid product was separated and used without purification to the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:33])[NH:20][C:21]4[CH:27]=[C:26]([N:28]5[CH:32]=[CH:31][CH:30]=[CH:29]5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[S:9][CH:10]=1)=O)C.COCCO[AlH2-]OCCOC.[Na+].C1(C)C=CC=CC=1>C1COCC1>[OH:3][CH2:4][C:6]1[N:7]=[C:8]([C:11]2[CH:12]=[C:13]([C:17]3[CH2:18][C:19](=[O:33])[NH:20][C:21]4[CH:27]=[C:26]([N:28]5[CH:29]=[CH:30][CH:31]=[CH:32]5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:14]=[CH:15][CH:16]=2)[S:9][CH:10]=1
Reactant: CCOC(=O)c1csc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(-c3nc(CO)cs3)c2)=Nc2ccc(-n3cccc3)cc2N1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
To a stirred suspension of 2-[3-(4-oxo-7-pyrrol-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-phenyl]-thiazole-4-carboxylic acid ethyl ester (Example 19) (0.34 g, 0.75 mmol) in THF (35 mL) was added at −20° C. over 40 min in 3 portions a 3.5 M solution of sodium dihydrido-bis(2-methoxyethoxy)aluminate in toluene (0.94 mL, 3.3 mmol). Stirring was continued at −20° C. for 20 min. and the reaction mixture was then poured into ice-cold 10% aqueous acetic acid. The product was extracted with EtOAc and the organic layer was washed successively with H2O, sat. Na2CO3-solution and brine, dried over Na2SO4 and evaporated in vacuum. The residue was triturated with methanol to give the title compound (0.28 g) as light-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[CH3:15][C:16]([CH3:22])=[CH:17][C:18](OC)=[O:19]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:16]([CH3:22])([CH3:15])[CH2:17][C:18](=[O:19])[O:9]2)=[CH:7][CH:8]=1
Reactant: COC(=O)C=C(C)C
Reactant: COc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)OC(=O)CC2(C)C
Temperature: 130 °C
Yield: 39 %

Procedure:
A mixture of 3-methoxy-phenol (12 g, 96.5 mmol) and conc. sulfuric acid (0.5 ml) was heated at 130° C. with stirring, and methyl 3,3-dimethylacrylate (5.8 g, 51 mmol) was added. The mixture was stirred at 13° C. for 3 hours. After being cooled to ambient temperature, the organic layer was dissolved in ethyl acetate. The organic layer washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane= 1/9 to furnish 4.1 g (39% yield) of the title compound as a brown solid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]2[C:10]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)([CH2:11]2)[C:9]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>C(O)C.[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]23[CH2:11][CH:12]2[C:13](=[O:14])[N:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:9]3=[O:24])=[CH:20][CH:19]=1
Reactant: CCCCCCCN1C(=O)C2CC2(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCN1C(=O)C2CC2(c2ccc(N)cc2)C1=O

Procedure:
Following the procedure of Example3, a solution of 5 g of 3-n-heptyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione in 100 ml of ethanol is hydrogenated in the presence of 0.3 g of 5% palladium on carbon and worked up, affording the title compound which melts at 78°-79° C. after recrystallisation from ether/petroleum ether.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=2)=[CH:6][N:7]=1)[CH3:2].[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C1(C)C=CC=CC=1>[CH2:24]([NH:26][C:27]([NH:17][C:15]1[N:16]=[C:12]2[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=[C:8]([C:5]3[S:4][C:3]([CH2:1][CH3:2])=[N:7][CH:6]=3)[N:13]2[N:14]=1)=[O:28])[CH3:25]
Reactant: CCN=C=O
Reactant: CCc1ncc(-c2cc(-c3cccnc3)cc3nc(N)nn23)s1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cnc(CC)s3)n2n1
Temperature: 125 °C

Procedure:
A suspension of the product of Step 1 (75 mg, 0.23 mmol), ethylisocyanate (92 μL, 1.17 mmol), and dibutyltin diacetate (2 drops) in dry toluene (5 mL) was heated at 125° C. in a microwave reactor for 1 h. After being cooled at room temperature, the precipitated solid was filtered, and washed with chloroform to give the title compound as a solid. MS m/z 394 (M+H+).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:13]=[O:14]>>[O-:13][OH:14].[CH:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=O
Agent: c1ccc(C2CCCCC2)cc1
Product: [O-]O

Procedure:
The invention also relates to a hydrogenation and oxidation process in which a feed comprising cyclohexenylbenzene is contacted with hydrogen in the presence of a hydrogenation catalyst under hydrogenation conditions to form cyclohexylbenzene. The cyclohexylbenzene is then reacted with oxygen (e.g., air) in the presence of an oxidation catalyst under oxidation conditions to form cyclohexylbenzene hydroperoxide.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([CH3:6])=O.[CH2:9]([NH2:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>O>[CH3:6][CH:4]1[N:19]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1](=[O:8])[CH2:2][CH2:3]1
Reactant: CC(=O)CCC(=O)O
Reactant: CCCCCCCCCCN
Solvent: O
Product: CCCCCCCCCCN1C(=O)CCC1C
Temperature: 150 °C

Procedure:
The feedstock used in examples 78 through 86 was 25% of the ammonium salt of levulinic acid, 25% decylamine, and 41% water, by weight. The temperature and pressure of the reactions were maintained at 150° C. and 6.9 MPa. Water was used as the solvent medium for the reactions. The results are set forth in the following table.
Reaction SMILES: [CH3:1][P:2]([CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([NH:15][C:16]2[CH:17]=[C:18]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:19]=[CH:20][C:21]=2[NH:22]C(=O)OC(C)(C)C)=[O:14])=[CH:11][CH:10]=1)([CH3:4])=[O:3].CCN(C(C)C)C(C)C.Cl[C:48]([O:50][CH3:51])=[O:49]>C(Cl)Cl.C(O)(C(F)(F)F)=O.ClCCCl>[NH2:22][C:21]1[CH:20]=[CH:19][C:18]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:17][C:16]=1[NH:15][C:13]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:7]([CH2:6][CH2:5][P:2]([CH3:1])([CH3:4])=[O:3])[C:48](=[O:49])[O:50][CH3:51])=[CH:37][CH:36]=1)=[O:14]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CNCCP(C)(C)=O)cc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(CCP(C)(C)=O)Cc1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3-{[4-({[2-(dimethylphosphoryl)ethyl]amino}methyl)benzoyl]amino}biphenyl-4-yl)carbamate (295 mg, 0.566 mmol) in CH2Cl2 (10 mL) were added DIEA (198 μl, 1.13 mmol) and methyl chloroformate (70 mg, 0.735 mmol). After stirring for 30 min at room temperature, the reaction was diluted with CH2Cl2 and washed with saturated NaHCO3. The aqueous layer was extracted with additional CH2Cl2. The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/CH2Cl2) afforded a colorless solid. This solid was taken up in CH2Cl2 (5 mL) and TFA (1 mL). After stirring at room temperature for 1 h, the solution was diluted with 1,2-DCE and concentrated. The residue was diluted with EtOAc, washed with saturated NaHCO3 and brine, dried (MgSO4), and evaporated to afford the title compound as a pale yellow solid. NMR (DMSO-d6, 600 MHz) δ 9.70 (bs, 1H), 7.96 (d, J=8.1 Hz, 2H), 7.54-7.50 (m, 2H), 7.50-7.48 (m, 1H), 7.37-7.32 (m, 4H), 7.29 (dd, J=8.2, 2.1 Hz, 1H), 7.20 (t, J=7.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 5.07 (bs, 2H), 4.52 (s, 2H), 3.69-3.57 (m, 3H), 3.45-3.34 (m, 2H), 1.99-1.87 (m, 2H), 1.34 (d, J=12.9 Hz, 6H). MS: cal'd 480 (MH+), exp 480 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([CH3:26])[CH:17]=2)[CH:3]=1.[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Sn](CCCC)(CCCC)CCCC)[N:42]=2)[CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[N:42]=[C:43]([C:6]3[CH:5]=[C:4]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[C:18]([CH3:26])[CH:17]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:44]=[CH:45][CH:46]=2)[CH:36]=1)(=[O:33])=[O:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)cc(OS(=O)(=O)C(F)(F)F)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)n1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1

Procedure:
A stirred mixture of trifluoro-methanesulfonic acid 6-methyl-4-(3-methyl-4-trifluoromethyl-phenyl)-pyridin-2-yl ester (Example A.64) (0.250 g, 0.626 mmol), N-tert-butyl-3-(6-tributylstannanyl-pyridin-2-yl)-benzenesulfonamide (Example F.6) (0.363 g, 0.626 mmol), tetrakis(triphenyl-phosphine)palladium (0.036 g, 5 mol %) in toluene (5 mL) was heated under reflux conditions for 18 h. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the title compound after trituration with diethyl ether as a white solid (300 mg, 88%). MS (ISP) 539.8 [(M+H)+]; mp 150° C. (dec.).