Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][O:30][C:31]([C@@H:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=2)[CH2:34]1)=[O:32].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:29][O:30][C:31]([C@@H:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42]([O:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:41][CH:40]=2)[CH2:34]1)=[O:32]
Reactant: OCc1ccc(F)cc1
Reactant: COC(=O)[C@@H]1CC(=O)N(c2ccc(O)cc2)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4.3 mmol of 4-fluoro-benzylalcohol and 4.7 mmol of triphenylphosphine in 7 ml of tetrahydrofuran was added dropwise at 0° C. to a solution of 4.7 mmol of (R)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester [Example 2 a) or 8 a)] and 4.7 mmol of diisopropyl azodicarboxylate in 11 ml of tetrahydrofuran. The mixture was left to warm to RT and stirring was continued for 18 hours. After addition of 2 g of silica gel, the reaction mixture was evaporated under reduced pressure. The material obtained was chromatographed on silica gel using first a 2:1-mixture, then a 1:1-mixture of heptane and ethyl acetate as the eluent, yielding (R)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid; MS: m/e=344 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH2:7][CH:6]([OH:8])[C:5](=O)[C:4]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].[H-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>CN(C)P(N(C)C)(N(C)C)=O.C(Cl)(Cl)Cl.O>[OH:8][CH:6]1[CH2:7][C:3](=[O:2])[C:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:5]1
Reactant: COC1=C(CCCCCCC(=O)O)C(=O)C(O)C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 2 h

Procedure:
A solution of 0.500 part of 2-methoxy-4-hydroxy-5-oxocyclopent-1-eneheptanoic acid dissolved in 25 parts by volume of hexamethyl phosphoramide is treated with 0.094 part of sodium hydride and stirred for 11/2 hours. Then 8.5 parts by volume of lithium aluminum hydride is added and the reaction mixture is stirred at room temperature for 1/2 hour and then heated at 70°-75° for 13/4 hours. The solution is acidified with hydrochloric acid and allowed to stand at room temperature for about 16 hours. Water and chloroform then are added to form 2 layers which are separated. The organic layer is extracted with 5% aqueous sodium carbonate. The sodium carbonate extracts are washed with chloroform and then acidified with hydrochloric acid. The acidified extracts are themselves extracted with ethyl acetate and washed with water, dried over anhydrous sodium sulfate and stripped of solvent. In that manner there is afforded 3-hydroxy-5-oxocyclopent-1-eneheptanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[S:44][CH:45]=[CH:46][N:47]=2)=[CH:38][C:37]=1[CH3:48].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:48])=[CH:38][C:39]([C:43]6[S:44][CH:45]=[CH:46][N:47]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2nccs2)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nccs6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-thiazole following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.29 min; Mass spectrum (ESI+): m/z=530 [M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([CH2:13][N:14]2[C:23](=[O:24])[C:22]3[N:21]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[C:20]([N:30]4[CH2:35][CH2:34][CH2:33][CH:32]([NH:36]C(OC(C)(C)C)=O)[CH2:31]4)=[N:19][C:18]=3[N:17]([CH3:44])[C:15]2=[O:16])=[CH:5][S:4]1(=[O:46])=[O:45].[OH-].[Na+]>C(Cl)Cl.O>[CH3:2][N:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([CH2:13][N:14]2[C:23](=[O:24])[C:22]3[N:21]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[C:20]([N:30]4[CH2:35][CH2:34][CH2:33][CH:32]([NH2:36])[CH2:31]4)=[N:19][C:18]=3[N:17]([CH3:44])[C:15]2=[O:16])=[CH:5][S:4]1(=[O:46])=[O:45]
Reactant: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC1=CS(=O)(=O)N(C)c3ccccc31)c(=O)n2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)=CCn1c(N2CCCC(N)C2)nc2c1c(=O)n(CC1=CS(=O)(=O)N(C)c3ccccc31)c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.5 ml isopropanolic hydrochloric acid (5-6 M) are added to 340 mg of 1-[(1-methyl-2,2-dioxo-1H-benzo[c][1,2]thiazin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine in 15 ml methylene chloride and the reaction mixture is stirred for three hours at ambient temperature. For working up it is diluted with water and methylene chloride and combined with 18 ml 1N sodium hydroxide solution. The aqueous phase is extracted with methylene chloride and the combined organic phases are washed with water, dried over magnesium sulphate and evaporated down. The yellowish, foamy flask residue is stirred with tert.-butyl-methylether and a little diethyl ether, the light-coloured precipitate formed is suction filtered and dried at 60° C. in the drying gun.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[CH2:24]([O:26][C:27]([CH:29]1[C:36](=[O:37])[CH2:35][CH:34]2[CH:30]1[CH2:31][C:32]1([O:41][CH2:40][CH2:39][O:38]1)[CH2:33]2)=[O:28])[CH3:25].CCC(COC(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-]>P([O-])([O-])([O-])=O>[CH2:24]([O:26][C:27]([CH:29]1[C:36](=[O:37])[CH2:35][C@H:34]2[C@@H:30]1[CH2:31][C:32]1([O:38][CH2:39][CH2:40][O:41]1)[CH2:33]2)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1C(=O)CC2CC3(CC21)OCCO3
Agent: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: CCOC(=O)C1C(=O)C[C@@H]2CC3(C[C@H]12)OCCO3
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
A solution of sucrose (15 g) in 0.lM phosphate buffer (pH7, 100 ml) was warmed to 30° C., and baker's yeast (7.0 g) was added, then shaken for 15 min at 30° C. An emulsion of (1SR,5RS)-2-ethoxycarbonyl-7,7-ethylenedioxybicyclo[3.3.0]octan-3-one (VIII) (498 mg) in 0.2% Triton X-100 (15 ml) was added and the mixture was shaken at 30° C. Sucrose (10 g) was added after 8 hours and successively sucrose (10 g) and baker's yeast (3.5 g) were added after 24 and 48 hours, then the mixture was shaken for 72 hours. Procedure similar to that of Referential Example 1 gave 109 mg of (1S,5R)-2-ethoxycarbonyl-7,7-ethylenedioxybicyclo-[3.3.0]octan-3-one (IV).
Reaction SMILES: [CH2:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:24]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[O:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccccc1/C=C/COCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Clc1ccccc1C1OC1COCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To a solution of (E)-1-(3-(benzyloxy)prop-1-enyl)-2-chlorobenzene(Preparation example 367, 4.94 g, 22 mmole) in CH2Cl2 (110 mL) was added 3-chloroperoxybenzoic acid (70˜75%, 8 g, 33 mmole) portionwise at 0° C. The mixture was stirred for 18 hr at room temperature. The TLC showed complete consumption of SM. The reaction mixture was quenched with H2O at 0° C. then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with sat′ NaHCO3, H2O, then dried over MgSO4 and evaporated under reduced pressure. The crude compound was purified by silica ge column to produce the title compound (4.3 g, 60˜80%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[NH2:13][NH2:14]>>[NH:13]([C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[NH2:14]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: NN
Solvent: O
Product: Cc1ccc(C(=O)O)c(NN)n1
Yield: 50 %

Procedure:
2-Chloro-6-methyl nicotinic acid (3.5 g, 0.02 m) was refluxed with hydrazine hydrate (5 ml) and absolute alcohol (20 ml) for 5 hours. The solid was separated, washed with alcohol and crystallised from water to yield 50% of 2-hydrazino-6-methylnicotinic acid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:10]=1[O:26][CH3:27])C1C=CC=CC=1.N.CCCCCC>Br.C(O)(=O)C.CCOCC>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][C:10]=1[O:26][CH3:27]
Reactant: COc1cc(C(=O)CCCc2ccccc2)ccc1OCc1ccccc1
Agent: Br
Agent: N
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COc1cc(C(=O)CCCc2ccccc2)ccc1O
Temperature: 0 °C

Procedure:
A solution of 7.0 g of 4'-(benzyloxy)-3'-methoxy-4-phenylbutyrophenone in 40 ml of 33 percent hydrobromic acid in glacial acetic acid is stirred at room temperature for 5 hours and subsequently poured into 500 ml of ice-water. The solution is adjusted to pH 6.0 by the addition of conc. ammonia and extracted three times with 250 ml of ethyl acetate each time. The organic phase is washed three times with 50 ml of water each time, dried over sodium sulfate and evaporated. The oil obtained is dissolved in 20 ml of ether, whereupon the solution is treated with hexane until it becomes turbid and is left to crystallize out. There is obtained colorless 4'-hydroxy-3'-methoxy-4-phenylbutyrophenone of m.p. 91°-92°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:15]=1[CH2:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:13][C:14]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:15]=1[CH2:16][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCCCCCCNCc1ccc(F)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(O)cc1
Reaction time: 8 h
Yield: 88.1 %

Procedure:
3-(4-Hydroxyphenyl)propionic acid (108 mg, 0.650 mmol) was dissolved in DMF. N-(2,4-difluorobenzyl)-N-heptylamine (164.7 mg, 0.682 mmol) was added. The mixture was cooled in an ice-bath. TBTU (219 mg, 0.682 mmol) was added and followed by DIPEA (0.238 ml, 1.365 mmol). The mixture was stirred overnight and the temperature was allowed up to room temperature. Ethyl acetate and sodium hydrogencarbonate aqueous solution (sat.) were added and then the two phases were separated. The water phase was extracted with ethyl acetate. The organic phases were combined and dried with magnesium sulphate and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/15 ml) using DCM and then MeOH/DCM (1:99) as eluant gave 223 mg desired product, yield 88%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:24]=3)=[CH:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([O:5]C(C)(C)C)=[O:4].[C:37]([C:41]1[CH:49]=[CH:48][C:44]([C:45]([OH:47])=O)=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:37]([C:41]1[CH:42]=[CH:43][C:44]([C:45]([NH:1][C@@H:2]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:24]=4)=[CH:19][N:18]=3)=[CH:15][CH:16]=2)[C:3]([OH:5])=[O:4])=[O:47])=[CH:48][CH:49]=1)([CH3:38])([CH3:39])[CH3:40]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)OC(C)(C)C)cc3)nc2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)O)cc3)nc2)cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
A stirred solution of (S)-tert-butyl 2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate INT-9 (1.34 g, 2.74 mmol) and 4-(tert-butyl)benzoic acid (0.54 g, 3.01 mmol) in DMF (5 mL) and N-ethyl-N-isopropylpropan-2-amine (1.01 ml, 5.47 mmol) was treated with HATU (1.09 g, 2.87 mmol). After stirring for 1 h, the mixture was treated with water (60 mL) and iso-hexanes (20 mL) and stirred for 1 h. The product was collected by filtration, washed with water (3×10 mL) then iso-hexanes (10 mL) and dried in the vacuum oven. The ester was taken up in DCM (5 mL) and treated with TFA (5 mL). After 2 h, the mixture was treated with toluene (5 mL) and evaporated. The residue was taken up in DMSO (6 mL) then treated with water (20 mL) and stirred for 1 h. The product was collected by filtration, washed with water (3×15 mL) then acetonitrile (2×5 mL), and dried in the vacuum oven to give 1.40 g (85%) of (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid Compound 85 as a white solid. LCMS-ESI (m/z) calculated for C37H43N3O4; 593.3. found: 594.0 [M+H]+, tR=11.18 min (Method 9) and 97% e.e. (Chiral Method). 1H NMR (400 MHz, DMSO-d6) δ 12.79 (br, s, 1H), 9.16 (s, 2H), 8.66 (d, J=8.2 Hz, 1H), 8.45-8.27 (m, 2H), 7.89-7.69 (m, 4H), 7.57-7.38 (m, 4H), 7.18-7.02 (m, 2H), 4.77-4.62 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.30-3.24 (m, 1H), 3.22-3.12 (m, 1H), 1.80-1.68 (m, 2H), 1.48-1.20 (m, 17H), 0.96-0.82 (m, 3H).
Reaction SMILES: CCO.[C:4]([C:9]1[S:10][C:11]([C:16]([O:18]CC)=[O:17])=[C:12]([OH:15])[C:13]=1[OH:14])([O:6]CC)=[O:5].[OH-].[Na+]>O>[C:16]([C:11]1[S:10][C:9]([C:4]([OH:6])=[O:5])=[C:13]([OH:14])[C:12]=1[OH:15])([OH:18])=[O:17]
Reactant: CCOC(=O)c1sc(C(=O)OCC)c(O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1sc(C(=O)O)c(O)c1O

Procedure:
EtOH (30 mL) was added to 2,5-dicarbethoxy-3,4-dihydroxythiophene (1 g). A solution of NaOH (4.0 g) in H2O (20 mL) was added and refluxed under N for 20 h. Upon cooling to ambient temperature the EtOH was removed by distillation and the residue was redissolved in H2O then acidified with 15% HClaq when a white ppt was obtained This product was collected by filtration and washed with cold H2O then crystallized from dilute MeOH to give colorless needles.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH2:9])[NH:7][N:8]=1)([CH3:3])[CH3:2].[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15](OCC)=[O:16])[CH3:11]>C(O)(=O)C>[CH2:10]([O:12][C:13]([C:14]1[C:15](=[O:16])[N:7]2[N:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[C:6]2[NH:9][CH:20]=1)=[O:24])[CH3:11]
Reactant: CC(C)c1cc(N)[nH]n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2cc(C(C)C)nn2c1=O
Temperature: 120 °C
Yield: 64.2 %

Procedure:
To a solution of 5-isopropyl-2H-pyrazol-3-ylamine (2.5 g, 20 mmol, 1 eq) in acetic acid (20 mL) was added 2-ethoxymethylene-malonic acid diethyl ester (4.4 mL, 22 mmol, 1.1 eq). The mixture was heated at 120° C. for 3 h in a sealed tube. After cooling, the precipitate was filtered and washed with ethanol to afford the expected compound as beige powder (3.2 g, 65% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C#N)[C:9](=[O:20])[CH2:10][C:11]([CH3:19])([CH3:18])[CH2:12][C:13]([O:15]CC)=O)=[CH:4][CH:3]=1.O.S(=O)(=O)(O)O.C(OC(C)C)(C)C>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9](=[O:20])[CH2:10][C:11]([CH3:18])([CH3:19])[CH2:12][C:13]2=[O:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)(C)CC(=O)C(C#N)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Product: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)cc1
Temperature: 25 °C
Yield: 56.9 %

Procedure:
A 3 liter flask was equipped with a mechanical stirrer, reflux condenser, addition funnel, N2 inlet, and thermometer. The flask was charged with 156.77 g (0.52 mol) of ethyl 6-(4'-methylphenyl)-6-cyano-5-keto-3,3-dimethylhexanoate dissolved in 370 ml of glacial acetic acid, followed by 132 ml of water, and finally 132 ml of conventrated sulfuric acid was added. The reaction mixture was refluxed for 48 hours, cooled to room temperature and 600 ml of water and 300 ml of isopropyl ether added. This two-phase system was refluxed for 1 hour, cooled in an ice bath, and filtered. The precipitate was washed thoroughly with water and isopropyl ether, then dried overnight in a vacuum oven to give 68.09 g (57% yield) of the desired product as a pale yellow powder; m.p. 199.5°-201.5° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][C:25](O)=[O:26])=[CH:22][N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1.O1CCCC1.B.O1CCCC1.Cl>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][CH2:25][OH:26])=[CH:22][N:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2CCO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a mixture of {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}acetic acid (0.52 g) and tetrahydrofuran (10 mL) was added borane-tetrahydrofuran (1.02 M tetrahydrofuran solution, 2.0 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (5 mL) and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethanol as colorless crystals (0.31 g, yield 62%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 123-124° C.
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[O:16]1[CH2:27][CH:17]1[CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH:24]1[O:26][CH2:25]1>CO>[CH2:1]([N:5]([CH2:25][CH:24]([OH:26])[CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH:17]([OH:16])[CH2:27][N:5]([CH:6]1[CH2:7][C:8]([CH3:15])([CH3:14])[NH:9][C:10]([CH3:12])([CH3:13])[CH2:11]1)[CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]1[CH2:7][C:8]([CH3:14])([CH3:15])[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: C(COCC1CO1)OCC1CO1
Solvent: CO
Product: CCCCN(CC(O)COCCOCC(O)CN(CCCC)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 5 h

Procedure:
A mixture of 6.4 g of 4-butylamino-2,2,6,6-tetramethylpiperidine and 2.6 g of ethylene glycol bis(2,3-epoxypropyl)ether in 50 ml of methanol was refluxed, with stirring for 5 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure and then the residue was recrystallized from n-hexane, giving the desired compound in the form of white crystals melting at 81°-83° C. and boiling at 258°-262° C. at 0.06 mmHg.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[NH:13][CH:14]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:16]=1[C:17]([NH2:19])=[O:18].O>C(O)C>[CH:1]([NH:11][C:12]1[NH:13][CH:14]=[C:15]([C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[C:16]=1[C:17]([NH2:19])=[O:18])=[O:2]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Reactant: O=CO
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1NC=O
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A solution of 2 cm3 (52.9 mmol) of formic acid in 5 cm3 (52.9 mmol) of acetic anhydride is added, at a temperature close to 25° C., to a solution of 0.3 g (1.21 mmol) of 2-amino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in 5 cm3 of absolute ethanol. After stirring for 2 hours at this temperature, the reaction medium is poured into 100 cm3 of water. The suspension is then filtered. The solid is drained, dried to give 0.257 g of 2-formylamino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in the form of a green powder. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm), from 6.22 to 8.53 (very broad m, 2H); 6.78 (d, J=3.0 Hz, 1H); 7.64 (d, J=9.0 Hz, 2H); 8.19 (d, J=9.0 Hz, 2H); 8.32 (d, J=1.5 Hz, 1H); 10.55 (broad s, 1H); 11.6 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:15][Cl:16])[CH2:13][C:12](=O)[CH2:11][O:10]1.[CH2:17]([OH:20])[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:16][CH2:15][C:9]1([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:13][CH2:12][C:11]2([O:20][CH2:17][CH2:18][O:19]2)[O:10]1
Reactant: OCCO
Reactant: O=C1COC(CCl)(c2ccc(Cl)cc2Cl)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: ClCC1(c2ccc(Cl)cc2Cl)CCC2(OCCO2)O1

Procedure:
The furanone obtained in stage b) (4.2 g), in toluene (50 cc), is heated at reflux temperature in the presence of ethylene glycol (6.5 cc) and p-toluenesulphonic acid (0.1 g), with the separation of the water formed, until the disappearance of the starting product.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:25][C:26]#[N:27])=[N:6][C:7]([CH:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[CH:8][CH:9]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:10][C:7]1[N:6]=[C:5]([CH2:25][C:26]#[N:27])[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(CC#N)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc([N+](=O)[O-])c(CC#N)n1
Yield: 59.3 %

Procedure:
A mixture of (3-nitro-6-(dicarbo-t-butoxymethyl)-2-pyridyl)acetonitrile (6.85 g, 18.2 mmol), dioxane (150 mL), and 2M sulfuric acid (25 mL) was heated at reflux for 12 hours. The resulting solution was cooled, neutralized with sodium carbonate, and extracted with ethyl acetate (3×50 mL). These extracts were combined, dried (MgSO4), and evaporated under reduced pressure to yield an oil. This oil was passed through a silica gel filter (approximately 100 g) followed by methylene chloride. This filtrate was evaporated under reduced pressure to afford (6-methyl-3-nitro-2-pyridyl)acetonitrile (1.91 g, 10.8 mmol, 59%) as an off-white solid: mp, 70°-72° C.; IR (KBr) 2,245, 1,595, 1,580, 1,515, 1,450, 1,370, 1,340 cm-1 ; 1H NMR (CDCl3) δ 8.38 (d, J=8.4 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 4.39 (s, 2H), 2.70 (s, 3H); 13C NMR (CDCl3) δ 164.7, 145.3, 142.1, 133.8, 123.9, 115.1, 27.1, 24.7; LRMS (m/z, relative intensity) 178 (29), 177 (M+, 93), 160 (16), 132 (26), 131 (92), 105 (37), 104 (100), 92 (32), 79 (50), 78 (51), 77 (81), 63 (54); HRMS 3.98; N, 23.72; found: C, 53.90; H, 3.95; N, 23.47.