Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@@H:24]1OC(=N)C(Cl)(Cl)Cl)(=[O:21])[CH3:20].C(=O)([O-])O.[Na+]>ClCCl>[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@H:24]1[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8]1[CH:17]=[CH:18][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][CH:7]=1)(=[O:21])[CH3:20]
Reactant: C=CCOc1ccc(Cc2ccccc2O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOc1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of 2-(4-allyloxybenzyl)phenol (0.20 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.45 g) in dichloromethane (8.5 mL) was added boron trifluoride-diethyl ether complex (0.12 g), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give 2-(4-allyloxybenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.44 g).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=O)=[N:9][NH:10][CH:11]=1)=[O:5].C(Cl)CCl.[CH:24]1[CH:25]=[CH:26][C:27]2[N:32](O)N=N[C:28]=2[CH:29]=1.[CH3:34][CH2:35][O:36][C:37](C)=[O:38]>CN(C=O)C>[CH2:35]([O:36][C:37]([CH:24]1[CH2:29][CH2:28][CH:27]([NH:32][C:12]([C:8]2[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:2]=3[F:1])=[CH:11][NH:10][N:9]=2)=[O:14])[CH2:26][CH2:25]1)=[O:38])[CH3:34]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(NC(=O)c2n[nH]cc2NC(=O)c2c(F)cccc2F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the ethyl ester (103 mg, 0.60 mmol), 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (134 mg, 0.50 mmol), EDC (115 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) in DMF (5 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic portion was dried (MgSO4) and reduced in vacuo to give 4-{[4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carbonyl]-amino}-cyclohexanecarboxylic acid ethyl ester (112 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=2[F:31])[C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO.[NH2:34][OH:35]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=[N:34][OH:35])[NH2:30])=[CH:25][C:24]=2[F:31])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CN([C@H](CCC(F)(F)F)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Reactant: NO
Solvent: CO
Solvent: O
Product: NC(=O)[C@@H](CCC(F)(F)F)N(Cc1ccc(C(N)=NO)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 47.5 °C
Yield: 96 %

Procedure:
(2R)-2-[[(4-Chlorophenyl)sulfonyl][(4-cyano-2-fluorophenyl)methyl]amino]-5,5,5-trifluoropentanamide (399 g) and methanol (1.6 L) were charged to a reactor followed by hydroxylamine (50% solution in water, 93 mL, 1.8 eq). The mixture was heated to 45-50° C. until complete reaction by HPLC (<0.15 relative AP starting material). Water (0.5 L) was charged slowly, keeping the batch temperature between 30-50° C. The batch was allowed to stand until crystallization started and then water (2.7 L) was charged. The batch was cooled to 15-20° C. and filtered. The cake was washed with 2:1 MeOH:water (2 L) and then dried under vacuum at 50° C. to give the title compound as white solid (415 g, 96% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.43-1.64 (m, 1 H) 1.77-1.93 (m, 1 H) 1.93-2.17 (m, 2 H) 4.41 (dd, J=8.48, 6.03 Hz, 1 H) 4.60 (d,J=17.14 Hz, 1 H) 4.94 (d, J=16.77 Hz, 1 H) 5.81-5.98 (m, 2 H) 7.19-7.27 (m, 1 H) 7.37-7.47 (m, 2 H) 7.52 (d, J=4.14 Hz, 2 H) 7.64 (d, J=8.67,Hz, 2 H) 7.85 (d, J=8.85 Hz, 2 H) 9.71-9.83 (m, 1 H). IR (KBr): 3491, 3379, 1680, 1651, 1592, 1433, 1343.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].O.O.[Sn](Cl)(Cl)(Cl)Cl.CO.[N+](=[CH2:32])=[N-]>COCCOC>[I:1][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[O:11][CH3:32].[I:1][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([O:13][CH3:32])[C@H:10]1[OH:11]
Reactant: C=[N+]=[N-]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: COCCOC
Solvent: O
Solvent: CO
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(I)nc21
Product: CO[C@H]1[C@@H](O)[C@H](n2cnc3c(N)nc(I)nc32)O[C@@H]1CO

Procedure:
1.2 g of 2-iodoadenosine was suspended in 150 ml of 1 mmol tin chloride dihydrate/methanol. 50 ml of 0.4-0.5M diazomethane in 1,2-dimethoxyethane was added with stirring. After stirring for one hour at room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The resulting product was applied on ODS column and eluted with 40% (V/V) methanol in 0.1% (V/V) aqueous solution of TFA. First, 2-iodo-2'O-methyladenosine (Compound 47) was eluted, and then 2-iodo-3'-O-methyladenosine (Compound 48) was eluted. Both fractions were concentrated to dryness to give 135 mg of Compound 47 and 56 mg of Compound 48.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].S(O[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(C1C=CC(C)=CC=1)(=O)=O>[Na]>[O:26]([CH2:25][CH2:24][O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccccc2)cc1
Agent: [Na]
Product: CN1C(C)(C)CC(OCCOc2ccccc2)CC1(C)C

Procedure:
30 parts of 1,2,2,6,6,-pentamethylpiperidin-4-ol were dissolved in 250 parts of sodium added. The solution was heated overnight at reflux temperature and then cooled. 38 parts of 2-phenoxyethanol tosylate were added dropwise and the solution heated at reflux for 5 hours. On cooling the precipitate was filtered off and the filtrate evaporated in vacuo Treatment of the residue with dilute hydrochloric acid and then basification with dilute sodium hydroxide to a pH 10 was followed by extraction with ether. Evaporation afforded a pale yellow oil which was chromatographed on aluminum to give 4-(2'-phenoxyethoxy)-1,2,2,6,6-pentamethylpiperidine as a colourless oil which gave the following elemental analysis by weight:
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:6][C:7]=1[CH3:8].C(N(CC)CC)C.[Br:26]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C.O>[Br:26][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[S:6][C:7]=1[CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Temperature: 0 °C
Reaction time: 14 h
Yield: 13.5 %

Procedure:
4,5-Dimethyl-2-(4-trifluoromethyl-phenyl)-thiazole hydrochloride (2.6 g, 8.9 mmol) was suspended in ethyl acetate and ice water. Triethylamine (1.2 ml, 8.9 mmol) was added, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine/ice water 1/1 dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was dried in vacuo and dissolved in acetonitrile (30 ml) under an argon atmosphere. The solution was cooled to 0° C., N-bromosuccinimide (2.05 g, 11.5 mmol) and 2,2′-azobis(2-methylpropionitrile) (145 mg, 0.89 mmol) were added and the reaction mixture was stirred at ambient temperature for 14 h. Water was added and the formed precipitate was filtered off, washed with water and dried in vacuo to give yellow crystals. The crystals were purified by column chromatography (silica gel, n-heptane/dichloromethane) to give 385 mg (1.2 mmol, 13%) of the title compound as off-white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:10]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:9]1.[NH2:30][C:31]1[C:32]([C:39](O)=[O:40])=[N:33][C:34]([Br:38])=[C:35]([F:37])[CH:36]=1>>[NH2:30][C:31]1[C:32]([C:39]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[C@H:10]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:9]2)=[O:40])=[N:33][C:34]([Br:38])=[C:35]([F:37])[CH:36]=1
Reactant: Nc1cc(F)c(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccncc2N)C[C@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccncc2NC(=O)c2nc(Br)c(F)cc2N)C[C@H]1O[Si](C)(C)C(C)(C)C

Procedure:
Following Method 11 of Example 305, trans-(+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-3-(tert-butyldimethylsilyloxy)piperidin-4-ylcarbamate and 3-amino-6-bromo-5-fluoropicolinic acid was reacted yielding trans-(+/−)-tert-butyl 1-(3-(3-amino-6-bromo-5-fluoropicolinamido)pyridin-4-yl)-3-(tert-butyldimethylsilyloxy)piperidin-4-yl-carbamate. LCMS (m/z): 641.2 (MH+); LC Rt=4.73 min.
Reaction SMILES: [CH2:1]([Cl:4])[CH2:2][OH:3].[I-].[K+].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N:15]1[CH2:19][CH:18]([CH3:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[C:16]1=N.O.C[N:32](C)C=O>>[ClH:4].[CH3:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH3:7])[C:9]=1[N:15]1[C:19](=[NH:32])[CH:18]([CH3:20])[N:17]([C:21]2[C:22]([CH3:28])=[CH:23][CH:24]=[CH:25][C:26]=2[CH3:27])[CH:16]1[CH2:1][CH2:2][OH:3]
Reactant: OCCCl
Reactant: CN(C)C=O
Reactant: Cc1cccc(C)c1N1CC(C)N(c2c(C)cccc2C)C1=N
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(C)c1N1C(=N)C(C)N(c2c(C)cccc2C)C1CCO
Product: Cl
Reaction time: 6 h
Yield: 34.3 %

Procedure:
1.5 ml (1.8 g, 0.022 moles) of ethylene chlorohydrine and 0.35 g (0.002 moles) of potassium iodide are added to a solution of 6.14 g (0.02 moles) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine, obtained as described in Example 3, in 60 ml of dry dimethylformamide. The resulting mixture is stirred at 100° to 105° C. for 6 hours, thereafter it is poured onto 300 ml of icy water. The separated product is filtered off, washed with water and ethyl acetate, and dried. 1.6 g of 1,3-bis(2',6'-dimethylphenyl)-2-(β-hydroxyethyl)-imino-4-methyl-imidazolidine hydrochloride are obtained; m.p.: 288°-291° C. (after recrystallization from a 6:4 mixture of methanol and water).
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH3:7][CH:8]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:1][CH:2]([Cl:6])[C:3]([N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10][CH2:9][CH:8]1[CH3:7])=[O:4]
Reactant: CC1COc2ccccc2N1
Reactant: O=C(Cl)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC1COc2ccccc2N1C(=O)C(Cl)Cl
Reaction time: 0.5 h
Yield: 83 %

Procedure:
5.3 ml (55 mmoles) of dichloroacetyl chloride are added dropwise, at a temperature of 20° to 25° C. and while stirring, to a suspension of 7.5 g (50 mmoles) of 2,3-dihydro-3-methyl-1,4-benzoxazine and 5.8 g (55 mmoles) of sodium carbonate in 120 ml of benzene. The reaction mixture is then stirred at the same temperature for 30 minutes and is then taken up in a mixture of water and ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Crystallising the residue from diisopropyl ether gives 10.8 g of 4-dichloroacetyl-2,3-dihydro-3-methyl-1,4-benzoxazine, melting point 105°-107° C.
Reaction SMILES: F[C:2](F)(F)[C:3]1NC(=O)N[C:5](=[O:10])[CH:4]=1.N1[CH:18]=[CH:17][C:16](=O)NC1=O.C[Si](C)(C)CCO[CH2:26][Cl:27]>>[CH2:5]([O:10][CH2:26][Cl:27])[C:4]1[CH:3]=[CH:2][CH:18]=[CH:17][CH:16]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1cc[nH]c(=O)[nH]1
Product: ClCOCc1ccccc1

Procedure:
In a similar manner to the procedures described in Reference Example 3, reactions were carried out using 6-trifluoromethylpyrimidine-2,4-dione, instead of pyrimidine-2,4-dione, and using 2-(trimethylsilyl)ethoxymethyl chloride, instead of benzyloxymethyl chloride, to give the title compound (yield 48%) as a colorless oil. 1H-Nuclear magnetic resonance spectrum (270 MHz, CDCl3) δ ppm: 8.84 (1H, br.s), 6.24 (1H, d, J=2 Hz), 5.32 (2H, s), 3.73-3.68 (2H, m), 0.97-0.90 (2H, m), 0.01 (9H, s).
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:8]1[N:9]=[C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:16]=3[CH:17]=2)[S:11][CH:12]=1)([CH3:7])([CH3:6])[CH3:5].Cl>O1CCCC1>[C:4]([C:8]1[N:9]=[C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([CH:22]([OH:23])[CH3:1])=[CH:18][C:16]=3[CH:17]=2)[S:11][CH:12]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C=O)ccc3o2)n1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)c1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl magnesium bromide (1M) in tetrahydrofuran (12.6 ml) was added dropwise over 30 minutes to a solution of 4-tert-butyl-2-(5-formylbenzofuran-2-yl)thiazole (3.0 g) in tetrahydrofuran (30 ml) under ice-cooling. After being stirred at same temperature for 15 minutes, the reaction mixture was poured into ice-water. The mixture was neutralized with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing the object compounds were combined and concentrated under recused pressure to give 4-tert-butyl-2-[5-(1-hydroxyethyl) benzofuran-2-yl]thiazole (2.04 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[CH3:24]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)c(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(Cl)c(Br)c1
Yield: 78 %

Procedure:
A mixture of 3-[5-(3-bromo-4-chlorophenyl)-4-isoxazolyl]propionic acid (2.74 g), conc. sulfuric acid (0.2 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(3-bromo-4-chlorophenyl)-4-isoxazolyl]propionate (2.22 g, yield 78%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 54–55° C.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8]2)=[CH:4][C:3]=1[F:17].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:17][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH2:6][N:7]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8]1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(C#C[Si](C)(C)C)c(F)c2)C1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate (25.00 g, 82.7 mmol), copper (1) iodide (3.14 g, 16.5 mmol), (trimethylsilyl)acetylene (81.9 mL, 579 mmol), bis(triphenylphosphine)palladium(ii) chloride (5.81 g, 8.27 mmol), and Hunig's base (115 mL, 662 mmol) was added in a sealable tube along with 100 mL THF. The reaction is sealed and heated to 80° C. under vigorous stirring for 24 h. The mixture was cooled to room temperature, filtered and evaporated. The resulting oil was purified using Biotage (75 L, 0-50% EtOAc/hexanes) affording methyl 1-(3-fluoro-4-(2-(trimethylsilyl)ethynyl)benzyl)azetidine-3-carboxylate as a transparent brown oil. MS (ESI) m/z: Calculated: 319.1; Observed: 320.1 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([CH2:15][C:16](=[O:18])[CH3:17])(=O)[CH3:13].[CH2:19]([O:21][C:22](=[O:27])[CH2:23][C:24](=[NH:26])[NH2:25])[CH3:20]>C(O)C>[CH2:19]([O:21][C:22]([C:23]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:15]([C:16](=[O:18])[CH3:17])=[C:12]([CH3:13])[NH:25][C:24]=1[NH2:26])=[O:27])[CH3:20]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(C)=O
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(C)=C(C(C)=O)C1c1cccc([N+](=O)[O-])c1
Yield: 48 %

Procedure:
Upon boiling a solution of 7.6 g of 3-nitrobenzaldehyde, 5.0 g of acetylacetone and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours, 2-amino-5-acetyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 217°C (ethanol) is obtained.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])C1C=CC=CC=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26].[OH-:27].[Na+].Cl>[Pd].CO>[OH:27][C:14]1[C:9](=[O:8])[CH:10]=[CH:16][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH:12]=[CH:13][C:14](=[O:15])[C:9]([OH:8])=[C:10]2[CH3:16])[C:13]=1[CH3:12]
Reactant: [OH-]
Reactant: NCCCCCCCCN
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1c(O)c(=O)ccn1CCCCCCCCn1ccc(=O)c(O)c1C

Procedure:
3-Benzyloxy-2-methyl-4-pyrone (0.066 moles) and 1,8-diaminooctane (0.022 moles) are mixed in 2:1 v/v aqueous methanol (300 ml), solid sodium hydroxide (2 g) is added, and the mixture is heated on a steam bath for 5 hours. The mixture is allowed to cool and an aliquot is taken, acidified to pH 2 with concentrated hydrochloric acid and the solvent removed on the rotary evaporator to give a solid residue. This residue is checked for completion of the reaction through its n.m.r. spectrum, the presence of protons exchangeable at ca δ=8.3 (d6DMSO) showing that the reaction is not complete. If this is the case, refluxing is continued until the solid obtained from an aliquot shows no such protons. On complete reaction being found to have occurred, the mixture is cooled and acidified to pH 2 with concentrated hydrochloric acid, any precipitate formed at this stage being dissolved by the addition of methanol to the mixture. Palladium/carbon catalyst is then added and the solution is hydrogenated at room temperature and atmospheric pressure in order to effect debenzylation. The catalyst is removed by filtration and the solvent by rotary evaporation, the resulting solid then being recrystallised from water to give the title compound(1) in 40% yield as a white solid of m.p. 297°-300° dec; γmax (nujol) 1340 and 1620 cm-1 ; δ(d6DMSO/D2O), 1.5 (m, 12H), 2.5 (s, 6H), 4.3 (m, 4H), 7.1 (d, 2H) and 8.1 (d, 2H); m/e 360.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([OH:11])=[O:10])[NH:7][N:8]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[C:17](=O)([O-])[O-].[K+].[K+]>CO>[CH3:17][O:10][C:9]([C:6]1[NH:7][N:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:11]
Reactant: O=C(O)c1cc([N+](=O)[O-])n[nH]1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-nitro-2H-pyrazole-3-carboxylic acid (524, 10.0 g, 0.0637 mol) in methanol (100.0 mL) was added concentrated sulfuric acid (1.00 mL, 0.0180 mol). The reaction was stirred at room temperature overnight. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (525, 1.5 g, 13.8%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[S:16][C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]=2[OH:17])[CH:9]=1.IC>CN(C)C=O.O>[Cl:7][C:8]1[S:16][C:15]2[C:14](=[O:17])[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:11]([CH3:1])[C:10]=2[CH:9]=1
Reactant: CCOC(=O)c1cnc2cc(Cl)sc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cn(C)c2cc(Cl)sc2c1=O
Reaction time: 18 h

Procedure:
Potassium carbonate (0.56 g) was added to a stirred solution of ethyl 2-chloro-7-hydroxythieno[3,2-b]pyridine-6-carboxylate (1.1 g) in dry dimethylformamide (100 ml) at ambient temperature. After 5 minutes iodomethane (0.3 ml) was added to the mixture and stirring was continued for 18 hours. The mixture was stirred at 60° for 2 hours and then evaporated to dryness to give a residue which was dissolved in water (80 ml). The aqueous solution was extracted with dichloromethane (3×150 ml) and the combined extracts dried over anhydrous sodium sulphate and evaporated to give the novel compound ethyl 2-chloro-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate, m.p. 168°-171°.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=2)[N:8]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>CO>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=2)[N:8]([S:19]([CH3:22])(=[O:20])=[O:21])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(S(C)(=O)=O)c2ccc(C(=O)OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CCN(S(C)(=O)=O)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.8 %

Procedure:
To a stirred solution of methyl 4-butyl-1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (144 mg) in methanol (1.3 mL) was added 1 M potassium hydroxide (13 mL). The mixture was stirred at room temperature for 48 h and concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified to pH 4 with 1 N hydrochloric acid and extracted with chloroform (4×100 mL). The combined organic extracts were dried (sodium sulfate), filtered, and concentrated under reduced pressure to give 99 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.43, 7.39, 7.24, 3.77, 3.39, 3.32, 1.56, 1.33, 0.90.