Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.O.Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[OH-].[Na+]>C(OCC)(=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:3]1
Reactant: OC1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCCC(O)C1

Procedure:
To a 1-liter 3-necked round bottom flask, equipped with mechanical stirrer and two addition funnels, is added 30 g (0.2966 mole) of 3-hydroxypiperidine and 300 ml of water. The resulting solution is stirred and is cooled to ~0° C. with ice-salt bath. At this point the benzyl chloroformate (51 ml, 0.356 mole) is added dropwise from one funnel and the 2N NaOH (178 ml) from the other funnel (at a slightly faster rate) during which time the temp. is maintained at ~0° C. After addition is complete, the mixture is stirred in the cold for 2 hr, then overnight at ambient temp. After this time an oily residue separates from the reaction solution. Ethyl acetate is added (250 ml) to the reaction and is stirred for 1/2 hr. The phases are separated and the aqueous phase is extracted once more with EtOAc (250 ml). All organic phases are combined, washed with 1×150 ml saturated NaHCO3, 1×150 ml H2O, 1×150 ml 10% HCl, 1×150 ml H2O and dried overMgSO4. The mixture is filtered and concentrated on a roto-evap under reduced pressure, to yield a viscous oil, which is stored under vacuum to remove any residual solvents as, 3-Hydroxy-1-piperidinecarboxylic Acid, Phenylmethyl Ester, a clear oil.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C(=O)C(Cl)=C(Cl)[C:15](=[O:16])C=1C#N)#N.CO>C(O)(=O)C.C1(C)C=CC=CC=1>[C:1]([O:16][CH3:15])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C=Cc1ccccc1
Yield: 98 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), MeOH (15 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of acetic acid (5 drops) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with MeOH (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Methyl cinnamate is isolated in 98% yield whose NMR values are found matching with reported values as in example 1.
Reaction SMILES: [CH:1]1([C:10]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH3:12])[CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.[Li][Li].C1(C(C2C3C(=CC=CC=3)C=C2)(C)C)C2C(=CC=CC=2)C=C1.[Si:50](Cl)([CH3:53])([CH3:52])[CH3:51]>CCOCC.CCCCC>[CH3:51][Si:50]([CH3:53])([CH3:52])[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([C:10]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([Si:50]([CH3:53])([CH3:52])[CH3:51])=[CH:2]2)([CH3:11])[CH3:12])[CH:14]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C1C=Cc2ccccc21)C1C=Cc2ccccc21
Agent: [Li]
Agent: [Li]CCCC
Agent: [Li][Li]
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(C1C=C([Si](C)(C)C)c2ccccc21)C1C=C([Si](C)(C)C)c2ccccc21

Procedure:
5.45 g (20 mmol) of 2,2-bis(indenyl)propane prepared according to the procedure of example 1 was dissolved in 100 ml of ether. The solution thus obtained was taken to −20° C., and 22 ml of a 2.0 M solution of n-butyl-lithium in pentane was added, thus giving a suspension of dilithium-2,2-bis(indenyl)propane. 8.77 g (30.85 mmol) of dilithium 2,2-bis(indenyl)propane was dissolved in 100 ml of ether, and 10 ml of Me3SiCl (excess) was added at a temperature of −40° C. The resulting mixture was allowed to return to room temperature. The organic phase was then separated off, the solvent removed and the product dried in vacuo. 1H-NMR
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10]Cl.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>CC#N.ClCCl.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][C:14]1[NH:13][CH:17]=[CH:16][N:15]=1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: O=C(Cc1ncc[nH]1)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A stirred solution of 1-(2,4-dichlorophenyl)-2-chloroethan-1-one (0.95 M) and imidazole (2.68 M) in CH3CN (500 ml) were heated for 14-16 hours at 75° C. The product was stripped of solvent under reduced pressure. The residue was diluted with dichloromethane (1 L) and water (400 ml), and the mixture was stirred for 30 min. After filtering off a solid impurity, the aqueous layer was removed and discarded. The organic layer was washed sequentially with water (300 ml), sat. aq. NaHCO3 (300 ml), water (300 ml), brine (200 ml), dried with Na2SO4, filtered, and concentrated under reduced pressure. The reddish black oil was dried overnight in, vacuo giving 1-(2,4-dichlorophenyl)-2-imidazolylethan-1-one in 90% yield.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>[N+](C1C=CC=CC=1)([O-])=O>[C:9]1([C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:17])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc2ccccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)CCC(=O)c1cccc2ccccc12

Procedure:
A mixture of naphthalene (40 g) and succinic anhydride (20 g) was added to a well stirred suspension of aluminum trichloride (55 g) in nitrobenzene (140 ml). The resulting mixture was stirred overnight at room temperature. The mixture was then poured slowly onto ice-water (600 g) and acidified with 6N-hydrochloric acid. The crude acid was filtered, washed with water until washings were neutral and recrystallized from ethanol yielding the product (m.p. 170°-172° C.).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:44]1[N:45]=[C:46]([NH:49][CH:50]=[O:51])[S:47][CH:48]=1)[C:5]([NH:7][CH:8]1[C:42](=[O:43])[N:10]2[C:11]([C:26]([O:28]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:27])=[C:12]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])[CH2:13][S:14][C@H:9]12)=[O:6].FC(F)(F)C([O-])=O.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:44]1[N:45]=[C:46]([NH:49][CH:50]=[O:51])[S:47][CH:48]=1)[C:5]([NH:7][CH:8]1[C:42](=[O:43])[N:10]2[C:11]([C:26]([OH:28])=[O:27])=[C:12]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)N3CCN(C)CC3)CS[C@H]12)c1csc(NC=O)n1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)N3CCN(C)CC3)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 4 h

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate.trifluoroacetate (syn isomer) (1.4 g ) in methylene chloride (30 ml) were added anisole (1.4 ml) and trifluoroacetic acid (1.83 ml) with stirring under ice-cooling and the stirring was continued for 4 hours at 5° C. The reaction mixture was evaporated and the residual oil was pulverized in diethyl ether, collected by filtration and then dried to give 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylic acid.trifluoroacetate (syn isomer) (1.1 g).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.Br[C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1>C1COCC1>[O:19]1[C:16]2[CH:17]=[CH:18][C:13]([C:7]3([OH:10])[CH2:6][CH2:5][C:4]4([O:3][CH2:2][CH2:1][O:11]4)[CH2:9][CH2:8]3)=[CH:14][C:15]=2[O:21][CH2:20]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Product: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Yield: 52 %

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal in dry THF was reacted with the Grignard reagent prepared from 4-bromo-1,2-methylenedioxybenzene as described in example 1 to give the product (52%, mp: 95°-96° C.). Calc'd for C15H18O2 : C, 64.74%; H, 6.52%. Found: C, 64.41%; H, 6.41%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[CH:10]([OH:11])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:27])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: OC(COCc1ccccc1)[C@@H]1CCCN1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COCc1ccccc1
Yield: 48.8 %

Procedure:
By the same procedure as in Example 26-D), (2S)-2-(2-benzyloxy-1-hydroxyethyl)pyrrolidine (297 mg) and N-(tert-butoxycarbonyl)-L-proline (318 mg) were subjected to dehydration condensation reaction to give 274 mg of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C:22]4[C:23]([C:30]5[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])=[N:24][O:25][C:26]=4[CH:27]4[CH2:29][CH2:28]4)[CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[N:7]([CH3:38])[CH:6]=1)=[O:4].[OH-].[K+]>CO.C1COCC1.O1CCOCC1>[CH:27]1([C:26]2[O:25][N:24]=[C:23]([C:30]3[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=3[Cl:36])[C:22]=2[CH2:21][O:20][CH:17]2[CH2:18][CH2:19][N:14]([C:10]3[CH:9]=[C:8]4[C:13]([C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]4[CH3:38])=[CH:12][CH:11]=3)[CH2:15][CH2:16]2)[CH2:28][CH2:29]1
Reactant: COC(=O)c1cn(C)c2cc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(C(=O)O)c2ccc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
In a 500 mL round bottom flask under nitrogen, containing a solution of 9 g (16.23 mmol) of 6-{4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-1-methyl-1H-indole-3-carboxylic acid methyl ester in 80 mL of methanol, 80 mL of THF and 30 mL dioxane, is added 2N KOH (40 mL, 81.16 mmol). The reaction mixture is stirred at 70° C. overnight. The reaction mixture is then cooled to room temperature, and the solvent removed under vacuum. The residue is diluted with 100 mL of water, and washed with MTBE. The aqueous layer is acidified (pH 5) by addition of 2N HCl, then, it is extracted with CH2Cl2 (3×150 mL). The organics are dried over MgSO4, filtered, and evaporated to yield a light green solid that is recrystallized from MeOH/CH3CN (6.05 g (70%)). MS (m/e): 540 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(#N)C.[OH-].[Li+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3046 g of methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate, 10 l of acetonitrile and 6701 ml of 2M lithium hydroxide is stirred at room temperature overnight, and then diluted with 20 l of water. Acetic acid (1 l) is added to adjust pH to 5.5 and additional water (12 l) is added. The precipitated product is collected and resuspended in 50 l of water. The suspension is stirred, the precipitate is collected, washed with water and dried at 60°/3 mm Hg (=4.00 mbar) for 48 h. The product is recrystallized twice from ethyl acetate and once from acetonitrile to yield 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoic acid, m.p. 116.5°-118°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][C:4]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH2:17]([O:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[O:22][CH2:23][CH2:24][NH2:25])[CH3:18].[H][H].[ClH:32]>[Ni].CO>[CH3:18][CH2:17][O:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[O:22][CH2:23][CH2:24][NH:25][C@@H:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:5]=1)[CH3:11].[ClH:32]
Reactant: COc1ccc(CC(C)=O)cc1S(N)(=O)=O
Reactant: CCOc1ccccc1OCCN
Reactant: [H][H]
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: CCOc1ccccc1OCCN[C@H](C)Cc1ccc(OC)c(S(N)(=O)=O)c1

Procedure:
2-Methoxy-5-(2-oxopropyl)-benzene sulfonamide (37.3 gm, 153.3 mmol), 2-(2-ethoxyphenoxy)-1-ethanamine (29.8 gm, 164.4 mmol) and methanol (250 mL) were taken into a one liter stainless steel flask and mixed well. Catalyst Raney nickel (8 gm) was added to the flask and the mixture hydrogenated at 50° C. at hydrogen pressure of 40 psi for 30 hrs. The catalyst was removed by filtration and solvent from the filtrate was distilled off completely at 50° C. under vacuum. The dark brown crude obtained was treated with methanolic hydrochloric acid (175 mL) at 0-5° C. under stirring. Tamsulosin hydrochloride formed as a solid was filtered, washed with ethyl acetate (200 mL), suspended in methanol (120 mL) and the methanol slurry filtered to obtain off white solid material. It was dried for 3 hrs at 80° C. to give racemic tamsulosin hydrochloride. Melting point 255-257° C., chemical purity of 98.8 area % (by HPLC) and R,S ratio of 51.45:48.55 (by chiral HPLC).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:19](=[O:36])[N:20]([C:27]2[O:35][C:31]3=[CH:32][CH:33]=[CH:34][C:30]3=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O>[CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:19](=[O:36])[N:20]([C:27]2[O:35][C:31]3=[CH:32][CH:33]=[CH:34][C:30]3=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][C:15]([C:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: OB(O)C1=CCCCC1
Reactant: COC(=O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(C3=CCCCC3)cc2)cc1
Temperature: 130 °C
Yield: 102.1 %

Procedure:
A mixture of 4-[2-(4-benzofuran-2yl-phenylcarbamoyl)-2-(4-bromo-phenyl)-ethyl]-benzoic acid methyl ester (0.4 g, 0.74 mmol), cyclohexen-2-ylboronic acid (0.23 g, 1.85 mmol), PdCl2(o-tolylphosphine) (75 mg, 0.096 mmol), and Na2CO3(390 mg, 3.70 mmol) in DME/EtOH/H2O (4:2:1)(17.5 mL) was heated in an oil bath at 130° C. for 2 h, cooled to rt, filtered and washed with EtOAc (20 mL). The solvent was removed under reduced pressure. The crude mixture was extracted with ethyl acetate (100 mL) and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography on silica gel, eluting with ethyl acetate:hexanes (3:2) to afford 4-[2-(4-benzofuran-2-yl-phenylcarbamoyl)-2-(4-cyclohex-1-enyl-phenyl)-ethyl]-benzoic acid methyl ester as a white solid (0.42 g). 1H NMR (300 MHz, CDCl3): δ 10.23 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.54-7.65 (m, 4H), 7.21-7.34 (m, 8H), 6.10 (bt, 1H), 4.02 (m, 1H), 3.78 (s, 3H), 3.45 (dd, J=8.7, 13.5 Hz, 1H), 3.04 (dd, J=6.6, 13.5 Hz, 1H), 2.25-2.40 (m, 2H), 2.10-2.20 (m, 2H), 1.64-1.72 (m, 2H), 1.54-1.59 (m, 2H); LC-MS m/z=556 [C37H33NO4+H]1; TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate/hexanes (2:1); R1=0.45.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH:23]([NH:26][CH2:27][CH2:28][OH:29])([CH3:25])[CH3:24]>>[OH:29][CH2:28][CH2:27][N:26]([CH:23]([CH3:25])[CH3:24])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CC(C)NCCO
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 2-(isopropylamino)ethanol (1.2 equiv) to give 209 (10.8 mg, M+1 399.1)
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCOCC1>[CH3:3][C@@H:2]([NH:1][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:4]([OH:6])=[O:5]
Reactant: C[C@@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Yield: 83.9 %

Procedure:
Under ice cooling, commercially available D-alanine (6.00 g, 73.5 mmol) was dissolved in an aqueous solution (225 mL) of sodium carbonate (21.45 g, 202 mmol), and a dioxane (60 mL) solution of benzyl chloroformate (Z—Cl) (10.5 mL, 73.5 mmol) was slowly added dropwise thereto. After completion of the dropwise addition, the reaction liquid was returned to room temperature, and continuously stirred overnight. The reaction liquid was transferred to a separating funnel, and excess Z—Cl was removed by diethyl ether extraction. Citric acid was added to the aqueous layer to adjust the pH to 3, and then the mixture was extracted three times with ethyl acetate. The combined organic layer was washed once with a saturated saline solution, and the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and then the concentrated residue was recrystallized by ethyl acetate-hexane to obtain a colorless crystal Z-D-alanine (13.77 g, 91.6%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C([BH3-])#N.[Na+]>C1COCC1.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)CC1
Temperature: 60 °C
Yield: 38.1 %

Procedure:
To a solution of 1-tert-butyloxycarbonylpiperazine (2.24 g, 12.0 mmol) in THF (20 ml) were added water (0.2 ml), cyclobutanone (1.35 ml, 18.1 mmol), acetic acid (2.20 ml) and sodium cyanoborohydride (18 ml of a 1M solution in THF, 18 mmol). The mixture was stirred at 60° C. over night, concentrated, and the residue was mixed with water (50 ml) and 1N aqueous hydrochloric acid (15 ml). The solution was washed with ethyl acetate (2×30 ml), made basic by addition of potassium carbonate, extracted (2×20 ml ethyl acetate), and the combined extracts were washed with brine, dried with magnesium sulphate, and concentrated. 1.1 g (38%) of the title compound was obtained as a colourless oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:15])([F:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13]>C(#N)C.O>[N+:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([F:15])([F:14])[F:5])[C:8]=1[OH:13])([O-:4])=[O:2]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=[N+]([O-])O
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Reaction time: 0.17 h
Yield: 33.8 %

Procedure:
Acetyl nitrate obtained mixing acetyl anhydride (3.30 g, 33 mmol) with fuming nitric acid (2.05 g, 33 mmol) at 0° C. was dropped into a solution of 2-trifluoromethylphenol (4.86 mg, 30 mmol) in acetonitrile (60 ml) at 0° C. followed by stirring for 10 minutes. The reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (60 g of silica gel; developing solvent, hexane:methylene chloride=5:1) to provide 2.1 g (yield 33%) of 2-nitro-6-trifluoromethylphenol as pale yellow crystals.
Reaction SMILES: N[C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(#N)C.[BrH:15].N([O-])=O.[Na+]>O.[Cu]Br>[Br:15][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Br
Reactant: Nc1c(F)cccc1C(=O)O
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cccc(F)c1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
In a 1 L, three necked flask fitted with a dropping funnel and thermometer, were charged 2-amino-3-fluorobenzoic acid (20.0 g, 0.13 mol) and acetonitrile (160 mL). After cooling to 0° C., HBr (47%, 160 mL) was added drop wise over 10 min. To the resulting solution a solution of NaNO2 (10.0 g, 0.14 mol) in water (20.0 mL) was added drop wise over 1 h. After addition, the reaction mixture was stirred at 0° C. for 5 min, and copper(I) bromide (22.0 g, 0.15 mol) was added portionwise over 30 min. Stirring was continued at 70° C. in a an oil bath for 1 h. After cooling to 0° C., 700 mL of water was added and the precipitate was filtered, washed with cold water and dried under vacuum to give 28.23 g (100%) of the title compound as a white solid. The crude product was used in the next step without purification.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([O:12]O)(=[O:11])[CH3:10]>>[CH3:8][C:1]1[C:6]([OH:7])=[C:5]([OH:11])[CH:4]=[CH:3][CH:2]=1.[CH3:2][C:1]1[CH:10]=[C:9]([OH:12])[CH:4]=[CH:5][C:6]=1[OH:7]
Reactant: CC(=O)OO
Reactant: Cc1ccccc1O
Product: Cc1cc(O)ccc1O
Product: Cc1cccc(O)c1O

Procedure:
The procedure of Example 7 was repeated, except that 0.5 mol of ortho-cresol was used in place of para-cresol and the peracetic acid was used at a proportion of 0.05 mol and the reaction temperature was held at 50° C. Analysis of the reaction mixture by gas chromatograph showed the conversion of ortho-cresol to be 4.00 percent and the yields of 3-methyl-1,2-dihydroxybenzene and 2-methyl-1,4-dihydroxybenzene to be 35.6 mol percent and 33.9 mol percent respectively based on the consumed peracetic acid.