Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Na+].[CH2:3]1[O:13][C:6]2([CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)[O:5][CH2:4]1.[CH3:14]I.[Cl-].[NH4+]>C1COCC1>[CH2:3]1[CH2:4][O:5][C:6]2([CH2:7][CH2:8][C:9](=[O:12])[CH:10]([CH3:14])[CH2:11]2)[O:13]1
Reactant: CI
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH2-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1CC2(CCC1=O)OCCO2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
According to the process described in Tetrahedron, 47, 1991, 3259, a solution of sodium amide (18.5 g) in THF (100 ml) was added to a solution of 1,4-cyclohexanedione monoethylene ketal (18.5 g) in THF (100 ml) under a nitrogen atmosphere while keeping the temperature of the solution at 10-20° C. After stirring at 20° C. for 30 minutes, methyl iodide (41.3 g) was added and the stirring was continued at room temperature for 1 hour. The reaction solution was mixed with a saturated aqueous solution of ammonium chloride (100 ml) and extracted with diethyl ether. The diethyl ether layer was washed with water, dried (MgSO4), and then evaporated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel and an oily mixture (mixture ratio of 1:1, 15.1 g) of 4,4-ethylenedioxy-2-methyl-1-cyclohexanone and 4,4-ethylenedioxy-2,2-dimethyl-1-cyclohexanone was obtained from the eluates with ethyl acetate-hexane (4:1). To a solution of this mixture (2.0 g) in ethanol (20 ml) was added sodium borohydride (440 mg) under ice cooling. After stirring at room temperature for 2 hours, acetic acid (0.2 ml) was added, and the mixture was evaporated under reduced pressure to remove the solvent. To the residue was added ethyl acetate and the resulting solution was washed with water, dried (MgSO4), and then evaporated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel to obtain 4-hydoxy-3-methyl-1-cyclohexanone ethylene ketal (140 mg, 1H NMR (CDCl3) δ: 1.02 (3H, d, J=6.6 Hz), 1.20-2.00 (8H, m), 3.15-3.30 (1H, m), 3.94 (4H, br s)) and 4-hydoxy-3,3-dimethyl-1-cyclohexanone ethylene ketal (470 mg, 1H NMR (CDCl3) δ: 1.00 (3H, s), 1.01 (3H,s), 1.35-1.90 (7H, m), 3.38-3.46 (1H, m), 3.90-4.00 (4H, m)) from the eluates with ethyl acetate-hexane (6:1) as oily substances, respectively.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][C:6]12[O:10][CH2:9]1.[OH2:12]>>[CH:6]1([CH2:9][OH:10])[CH2:7][CH:8]=[C:3]([C:2]([OH:12])([CH3:11])[CH3:1])[CH2:4][CH2:5]1
Reactant: O
Reactant: CC1(C)C2CCC3(CO3)C1C2
Product: CC(C)(O)C1=CCC(CO)CC1

Procedure:
A process of claim 1 wherein beta-pinene oxide is reacted with water in the presence of an acidic exchange resin catalyst to produce p-menthene-7,8-diol; reacting said diol with acetic anhydride in the presence of pyridine as a catalyst to produce 7-acetoxy-p-menth-1-en-8-ol; dehydrating said 7-acetoxy-p-menth-1-en-8-ol to produce perillyl acetate and saponifying said perillyl acetate to perillyl alcohol.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:25])=[C:15]([NH:17]C(=O)OC(C)(C)C)[CH:16]=3)[N:7]=2)[CH2:3]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O>[F:26][C:2]1([F:1])[CH2:3][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:25])=[C:15]([CH:16]=3)[NH2:17])[N:7]=2)[CH2:5]1
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.8 %

Procedure:
Tert-butyl (5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)carbamate (36) (1.2 g, 3.3 mmol) was dissolved in TFA (10 mL) and stirred at room temperature for 15 minutes. Then TFA was removed under vacuum to give the residue which was neutralized by addition of 2M Na2CO3 solution (20 mL). The solution was extracted with EtOAc and the organic phase was dried over Na2SO4. Evaporation of solvent gave 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (37) as a white solid (0.9 g, 100% yield), which was used without further purification. 1H NMR (400 MHz, d6-DMSO) δ 7.33 (d, J=1.2 Hz, 1H), 7.14 (dd, J=1.2, 7.6 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 5.37 (br, 2H), 3.84 (m, 1H), 2.98-3.24 (m, 4H), 2.12 (s, 3H). MS m/z 266.1 (M+1)+.
Reaction SMILES: [OH-].[Na+].[I:3][CH2:4][CH2:5][O:6][N:7]=[C:8]([C:14]1[N:15]=[C:16]([NH:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17][CH:18]=1)[C:9]([O:11]CC)=[O:10]>O1CCOCC1.C(O)C>[I:3][CH2:4][CH2:5][O:6][N:7]=[C:8]([C:14]1[N:15]=[C:16]([NH:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17][CH:18]=1)[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(=NOCCI)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)C(=NOCCI)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 72 h

Procedure:
5.5 ml of a 2 N sodium hydroxide solution was added dropwise under an inert atmosphere to a mixture of 6.7 g of the product of Step A in 5.5 ml of dioxane and 44 ml of absolute ethanol and after the addition of 7 ml of absolute ethanol the mixture was stirred overnight to room temperature and was vacuum filtered. The recovered product was rinsed twice with 3 ml of a 4-1 ethanol-dioxane mixture and was then empasted with ether. The product was placed in a mixture of 100 ml of water and 100 ml of chloroform and the pH was adjusted to 2 by addition of N hydrochloric acid. The decanted organic phase was washed with an aqueous saturated sodium chloride solution, was dried and evaporated to dryness under reduced pressure. The residue was dissolved in 35 ml of dichloroethane at 40° C. and crystallization was induced. The mixture stood at room temperature for 72 hours and was vacuum filtered. The recovered product was rinsed and dried to obtain 5.4 g of the syn isomer of 2-(2-iodoethoxyimino)-2-(2-tritylamino-4-thiazolyl)-acetic acid solvated with dichloroethane melting at 161° C. (= to 4.61 g of pure product).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH2:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)[NH:3]1.[CH:26](OCC)=[O:27].[O-]CC.[Na+].Cl>C(O)C>[OH:27][CH:26]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([CH2:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: O=C1Cc2ccc(Cc3cccc(NC(=O)c4cccs4)c3)cc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2cc(Cc3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Temperature: 78 °C
Yield: 52.9 %

Procedure:
Thiophene-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indol-6-ylmethyl)-phenyl]-amide (0.110 g, 0.306 mmol) and ethyl formate (0.075 mL, 0.918 mmol) were dissolved in anhydrous ethanol (0.6 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (2.85 mL, 1.53 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale brown precipitate. The suspension was filtered yielding a tan solid as the pure Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indol-6-ylmethyl)-phenyl]-amide (0.061 g, 0.162 mmol, 53%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=1)[CH3:2].N1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:8][N:7]=1)[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(N)cn1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Cc1ccc(NC(=O)OCc2ccccc2)cn1
Reaction time: 3 h

Procedure:
To a solution of ethyl(5-aminopyridin-2-yl)acetate (2.0 g) in tetrahydrofuran (30 mL) were successively added pyridine (2.7 mL) and benzyl chloroformate (1.9 mL) in an ice bath, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.6 g).
Reaction SMILES: [CH3:1][CH:2]([C:4]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:29][OH:30])=[CH:11][C:12]=1[C@@H:13]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:14][CH2:15][N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[O:5])[CH3:3].[Cl:31][C:32]1[CH:42]=[CH:41][CH:40]=[CH:39][C:33]=1[CH:34]([OH:38])[C:35]([OH:37])=[O:36]>C(OCC)(=O)C>[CH3:3][CH:2]([C:4]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:29][OH:30])=[CH:11][C:12]=1[C@@H:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:14][CH2:15][N:16]([CH:20]([CH3:21])[CH3:22])[CH:17]([CH3:18])[CH3:19])=[O:5])[CH3:1].[Cl:31][C:32]1[CH:42]=[CH:41][CH:40]=[CH:39][C:33]=1[CH:34]([OH:38])[C:35]([O-:37])=[O:36]
Reactant: O=C(O)C(O)c1ccccc1Cl
Agent: CC(C)C(=O)Oc1ccc(CO)cc1[C@H](CCN(C(C)C)C(C)C)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C([O-])C(O)c1ccccc1Cl
Reaction time: 2 h

Procedure:
Fesoterodine base (5 g) and ethyl acetate (20 ml) were added to a four-neck two liter round bottom flask. Further, 2-chloro-mandelic acid (2.3 g) was added at 25° C. to 35° C. The reaction mass was stirred for 2 hours at 25° C. to 35° C. The reaction mass was cooled to 0° C. to 5° C. The product was filtered and washed with chilled ethyl acetate (2×2.5 ml). The wet cake was dried at 60° C. to 65° C. for 8 to 10 to afford solid fesoterodine 2-chloro-mandelate (Purity by HPLC: 99.8%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[C:21]([OH:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].[CH:25]1(O)[CH2:30][CH2:29][CH2:28][CH:27]=[CH:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C1COCC1>[Br:13][C:14]1[C:21]([O:22][CH:30]2[CH2:29][CH2:28][CH2:27][CH:26]=[CH:25]2)=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: COc1ccc(C=O)c(Br)c1O
Reactant: OC1C=CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C=O)c(Br)c1OC1C=CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl azodicarboxylate (2.7 ml) was dropwise added to a mixture of 2-bromo-3-hydroxy-4-methoxy-benzaldehyde (4.0 g), THF (80 ml), 2-cyclohexen-1-ol (1.2 ml), and triphenylphosphine (4.5 g) under ice-cooling, followed by stirring at room temperature for 2 hours. The mixture was poured into water followed by extraction with ether. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and with a saturated saline, and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (hexane:ethyl acetate=10:1 and 5:1) to give Compound IIn-a (1.8 g, 47%) as a pale-yellow oily substance.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+].O>CC(O)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccccc1Nc1ccccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 43.4 %

Procedure:
1-Fluoro-2-nitro-benzene (0.53 mL, 5.0 mmol), 2-Amino-benzoic acid (750 mg, 5.5 mmol) and Na2CO3 (420 mg, 4.0 mmol) are added together in reaction flask and the mixture is heated at 130° C. for 60 hrs. After it is cooled down to room temperature, 50 mL of water is added and HOAc is used to adjust the pH to slightly acidic. Then the mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, washed with water (3×50 mL), dried (Na2SO4) and concentrated to give crude product. Purifiction by flash column chromatography affords 560 mg (43%) of 2-(2-Nitro-phenylamino)-benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[C@H:12]2[CH2:17][C@@H:9]1[C@H:10]([OH:18])[CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25]#[N:26].CN(C)CCCN=C=NCC>CN(C)C=O>[C:25]([C@@H:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:14]([C@@H:13]1[C@H:12]2[CH2:17][C@H:9]([C@H:10]([OH:18])[CH2:11]2)[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])#[N:26]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)O
Reactant: N#C[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.8 %

Procedure:
To a solution of (1R,3S,4S,6R)-2-(tert-butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid obtained in Example 5-6 (90 mg) in N,N-dimethylformamide (1.6 mL), was added (2S)-2-pyrrolidinecarbonitrile hydrochloride (55.7 mg) 1-hydroxy-7-azabenzotriazole (57.2 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (65 mg). The mixture was then stirred at room temperature for 6 hrs. The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate to give the target compound (85.4 mg) as a solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCCCC)=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:26][CH:25]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 74.5 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.242 g, 1.22 mmol) was reacted with 2-azidoethanamine (0.105 g, 1.22 mmol) and triethylamine (0.246 g, 2.43 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-butylbenzamide (0.224 g, 75%). 1H NMR (300 MHz, CDCl3) δ 7.73 (d, 2H), δ 7.39 (t, 1H), δ 7.17 (d, 2H), δ 3.55 (q, 2H), δ 3.45 (t, 2H), δ 2.60 (t, 2H), δ 1.56 (m, 2H), δ 1.30 (m, 2H), δ 0.90 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.5, 147.2, 131.7, 128.8, 127.4, 50.9, 39.7, 35.7, 33.5, 22.5, 14.1 ppm; HRMS (ESI) calcd for C13H18N4O (M+) 246.1481. Found 246.1476.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:22][C:23]1[C:28]([Br:29])=[CH:27][C:26]([CH2:30][CH2:31]Cl)=[CH:25][C:24]=1[Br:33]>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:16])[CH2:31][CH2:30][C:26]3[CH:27]=[C:28]([Br:29])[C:23]([NH2:22])=[C:24]([Br:33])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Reactant: Nc1c(Br)cc(CCCl)cc1Br
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Br)c(N)c(Br)c1)CC2

Procedure:
This compound was prepared analogous to Example 12 from N-[-3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 2-(4-amino-3,5-dibromophenyl)-ethyl chloride.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[O:7][CH:6]([CH3:23])[CH2:5]2.N([O-])=O.[Na+].O[PH2]=O>OS(O)(=O)=O>[CH3:23][CH:6]1[CH2:5][C:4]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[CH:2][CH:3]=2)[CH:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[O:7]1
Reactant: COc1cc2c(cc1N)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=[PH2]O
Product: COc1ccc2c(c1)C(c1ccc([N+](=O)[O-])cc1)OC(C)C2
Yield: 85.6 %

Procedure:
Solution of 15 (100 mg, 0.32 mmol) in 5 ml of 4N H2SO4 was treated with NaNO2 (29.6 mg, 1.16 eq) at 0° C. for 15 min, followed by adding H3PO2 (50%, 0.25 ml) at such temperature. After refluxing for 5 hours, the solution was extracted with ethyl acetate three times. The combined organic phases were dried over Na2SO4. Removal of the solvent afforded the crude product. Purification of the crude product by using silica gel column gave the desired product 16 (82 mg, 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[OH:12])([O-])=O.[CH2:13](OC(OCC)OCC)C>[Pd].C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:11][O:10][C:6]1[C:5]2[O:12][CH:13]=[N:1][C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: COc1cccc2ncoc12
Reaction time: 1.25 h
Yield: 85.2 %

Procedure:
A mixture of 2-nitro-6-methoxyphenol (2.62 g, 15.5 mmol) (EP 333176) and 10% Palladium on carbon (130 mg) in ethanol (50.0 ml) was stirred under an atmosphere of H2 for 75 min. The mixture was filtered through Celite® then immediately treated with p-toluenesulphonic acid (32.0 mg) and triethylorthoformate (6.45 ml, 38.8 mmol) then heated under reflux under an atmosphere of N2. After 20 h p-toluenesulphonic acid (30.0 mg) and triethylorthoformate (6.45 ml, 38.8 mmol) were added. After a total of 44 h heating, the reaction was allowed to cool and reduced in vacuo. The resulting residue was purified by flash chromatography (25:75 ethyl acetate/hexane) to give 1.97 g (85%) of the title compound as a yellow solid: m.p. 28°-31° C.; IR (film) 1629, 1497, 1434, 1285, 1097; 1H NMR (CDCl3) δ 8.09 (1H, s), 7.40 (1H, d, J=8.0), 7.28 (1H, t, J=8.0), 6.89 (1H, d, J=8.0), 4.02 (3H, s); 13C NMR (CDCl3) δ 152.84, 145.82, 142.50, 139.99, 125.75, 113.42, 108.80, 56.97. Anal. Calcd. for C8H7 N1O2.0.1H2O: C, 63.65; H, 4.81; N, 9.29. Found: C, 63.43, H, 4.88, N, 9.05. M.S. (+FAB); 150 (M+ +1).
Reaction SMILES: N[C:2]1[C:7](Cl)=[CH:6][N:5]=[C:4]2[O:9][CH2:10][O:11][C:3]=12.[CH2:12]1[O:20]C2C(=NC=CC=2)[O:13]1.C(=O)=O>>[CH2:10]1[O:11][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[C:12]([OH:20])=[O:13])[O:9]1
Reactant: c1cnc2c(c1)OCO2
Reactant: Nc1c(Cl)cnc2c1OCO2
Agent: O=C=O
Product: O=C(O)c1ccnc2c1OCO2
Yield: 80 %

Procedure:
Using an analogous procedure to that described in the second paragraph of the portion of Example 1 that is concerned with the preparation of the starting material 4-amino-5-chloro-2,3-methylenedioxypyridine, 2,3-methylenedioxypyridine was reacted with carbon dioxide gas to give 2,3-methylenedioxypyridine-4-carboxylic acid in 80% yield; NMR Spectrum: (DMSOd6) 6.24 (s, 2H), 7.13 (d, 1H); 7.63 (d, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH:19]=[CH:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.[Pd].Cl>[NH:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1
Reactant: C1=Cc2ccccc2C(=CC2CN(Cc3ccccc3)CCO2)c2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: C(=C1c2ccccc2CCc2ccccc21)C1CNCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(4-benzylmorpholin-2-yl)methylidene-5H-dibenzo[a,d]cycloheptene (0.32 g) in acetic acid was added to 10 % palladium on charcoal (90 mg) pretreated under hydrogen in hydrochloric acid, and the resulting mixture was stirred under hydrogen at room temperature for 8 hours. After elimination of the catalyst by filtration, the filtrate was evaporated. The residue was neutralized with 10 % aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract was washed with water, dried and evaporated to afford 5-(morpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 221° - 224° C (oxalate).
Reaction SMILES: C(N(CC)CC)C.[N:8]1([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][C:36](O)=[O:37])[CH:29]=1.C(Cl)CCl>C1COCC1>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][C:36]([N:11]2[CH2:10][CH2:9][N:8]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])=[CH:21][CH:22]=3)(=[O:15])=[O:16])[CH2:13][CH2:12]2)=[O:37])[CH:29]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCCl
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)CCc3cccnc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.8 %

Procedure:
Triethylamine (0.28 ml, 2.04 mmol) was added in one portion to a stirred solution of N-[4-(piperazine-1-sulfonyl)-phenyl]-acrylamide (0.2 g, 0.68 mmol) and 3-pyridine propionic acid (0.1 g, 0.68 mmol) in THF (5 ml). The mixture was stirred at room temperature for 5 minutes before EDC (0.26 g, 1.36 mmol) was added in one portion and the resulting mixture and stirred at room temperature under a nitrogen atmosphere for 18 hours. The crude reaction mixture was concentrated under vacuum and the resulting residue dissolved in DCM (20 ml), washed with water (20 ml), dried (MgSO4), filtered and concentrated under vacuum. The crude product was purified by Prep HPLC to give the title compound (0.046 g, 15% yield) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C:5]([O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)([CH3:28])[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20]CC2C=CC=CC=2)=[CH:16][CH:15]=1)OC(=O)C(F)(F)F)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:37])[C:5]([O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)([CH3:28])[CH2:6][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccc(F)cc1)C(OC(=O)C(F)(F)F)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Reaction time: 20 h

Procedure:
3-(4-Benzyloxyphenyl)-2-(4-fluoro-phenoxy)-2-methyl-3-(2,2,2-trifluoroacetoxy)propionic acid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[C:21]([O:23]CC4C=CC(OC)=CC=4)[CH:20]=[CH:19][C:18]=3[CH3:33])=[O:16])=[C:11]([N+:34]([O-:36])=[O:35])[CH:10]=2)=[C:4]([CH3:37])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:18]=3[CH3:33])=[O:16])=[C:11]([N+:34]([O-:36])=[O:35])[CH:10]=2)=[C:4]([CH3:37])[CH:3]=1
Reactant: COc1ccc(COc2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4C)cc3[N+](=O)[O-])c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(O)ccc2C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 298 (0.57 g, 1.14 mmol) was dissolved in CH2Cl2 (10 mL) and CF3COOH (10 mL) was added. The reaction mixture was stirred at room temperature for 2 h after which the solvent was concentrated. The solid was recrystallized from CH2Cl2. This gave the title compound as a solid.