Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11](C(O)=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C1C2C(=CC=CC=2)C=CC=1O.[OH-].[Na+:27]>>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[O-:1].[Na+:27]
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: Oc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Product: [O-]c1ccc2ccccc2c1

Procedure:
2-hydroxy-3-naphthoic acid can be prepared by reacting 2-naphthol with sodium hydroxide to give sodium 2-naphtholate, reacting the sodium 2-naphtolate with carbon dioxide under an increased pressure, and separating the product by means of acid crystallization. The product may optionally be purified.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:29][CH3:30])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23](C(=O)C)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1.CC#N>Cl>[CH3:1][C:2]1[N:3]=[C:4]([NH:29][CH3:30])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[N:8]=1
Reactant: CNc1nc(C)c(-c2ccnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)n2)s1
Agent: Cl
Solvent: CC#N
Product: CNc1nc(C)c(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)s1

Procedure:
By hydrolysis of 1-(4-{4-[4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone in 2 M aq HCl. Yellow solid. Anal. RP-HPLC: tR=8.8 min (10-70% MeCN, purity>95%). 1H-NMR (DMSO-d6) δ: 2.45 (3, 3H, CH3), 2.83 (t, 4H, J=5.9 Hz, CH2), 2.85 (d, 3H, J=4.9 Hz, CH2), 2.95 (t, 4H, J=4.9 Hz, CH2), 6.81 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 6.85 (d, 2H, J=9.3 Hz, Ph-H), 7.58 (d, 2H, J=8.8 Hz, Ph-H), 7.99 (m, 1H, NH), 8.26 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.14 (brs, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:20]([O-:22])=[O:21])[CH:6]=[CH:7][C:8]=2B2OC(C)(C)C(C)(C)O2)[C:3]1=[O:23].FC(F)(F)S(O[C:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH:31]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].ClCCl.O1CCOCC1.O>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:20]([O-:22])=[O:21])[CH:6]=[CH:7][C:8]=2[C:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH:31]=2)[C:3]1=[O:23]
Reactant: CN1Cc2c(B3OC(C)(C)C(C)(C)O3)ccc([N+](=O)[O-])c2C1=O
Reactant: CCOC(=O)C1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)C1CC=C(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Yield: 63.4 %

Procedure:
A mixture of 2-methyl-7-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (1.50 g, 4.72 mmol), ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}cyclohex-3-ene-1-carboxylate (1.57 g, 5.19 mmol), potassium carbonate (1.95 g, 14.1 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.385 g, 0.472 mmol) in 1,4-dioxane (12.0 mL, 154 mmol) and H2O (3.00 mL, 166 mmol) was evacuated and refilled with Ar(g)((3×) and irradiated in the microwave at 100° C. for 30 min. The crude mixture was concentrated in vacuo to a solid and purified by CombiFlash®Rf 4X Organic Purification System [120 g RediSep® Normal-phase GOLD Silica Flash Column, dried loaded, elution gradient: 0→40% EtOAc in DCM] to afford 1.03 g (63% yield) of the desired product. 1H NMR (400 MHz, Chloroform-d) δ ppm 7.71 (d, J=8.08 Hz, 1 H), 7.45 (d, 1 H), 5.93-5.99 (m, 1 H), 4.20 (q, J=7.07 Hz, 2 H), 2.65-2.75 (m, 1 H), 2.49-2.56 (m, 2 H), 2.36-2.49 (m, 2 H), 2.16-2.24 (m, 1 H), 1.87-2.00 (m, 1 H), 1.54 (br. s., 3 H), 1.31 (t, J=7.20 Hz, 3 H). MS (ES+): m/z 346.15/347.15 (100/15) [MH+]. HPLC: tR=1.43 min (UPLC TOF, polar—3 min).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>C1C=CC=CC=1>[CH3:8][C:2]1[CH:1]=[C:6]([CH:5]=[CH:4][CH:3]=1)[O:7][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1cccc(OCC(=O)c2ccccc2)c1

Procedure:
Using an alternative condensation, equimolar amounts of m-cresol and alpha-bromoacetophenone are refluxed in benzene in the presence of potassium carbonate with azeotropic removal of water to provide alpha-(3-methylphenoxy)acetophenone.
Reaction SMILES: [Na].C(O)C.Cl.[CH2:6]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[NH:12])[CH3:7].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>C(O)(=O)C>[O:20]=[C:21]1[NH:13][C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][CH2:6][CH3:7])=[N:12][CH:28]=[C:22]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOc1ccccc1C(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2OCC)[nH]c1=O
Temperature: 0 °C

Procedure:
To a cooled solution of sodium (8.2 g., 0.356 g-atom) in 300 ml. ethanol was added all at onece 2-ethoxybenzamidine hydrochloride (35.7 g., 0.178 mole). A solution of diethyl ethoxymethylenemalonate (38.4g., 0.178 mole) in 80 ml. of ethanol was added to the suspension and the mixture was heated under reflux for 21/4 hours. The cooled solution was added to about 2800 ml. of ice-water and the mixture was acidified to pH 5 with glacial acetic acid. The precipitated title product was dried to give 47 g. of an off-white solid, m.p. 147°-150°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1nn(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 53.7 %

Procedure:
To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (3.1 g, 18.1 mmol) in dry acetone (2 ml) was added K2CO3 (5 g, 36.2 mmol) at 25° C. The reaction mixture was cooled to 0° C., and methyl iodide (2.2 ml, 36.3 mmol) was added. The temperature was again raised to 25° C., and then heated to 70° C. for 2 hrs. The solvent was removed in vacuo The residue was diluted with EtOA and washed with water and with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography over silica gel. Elution with 20% EtOAc/hexane) gave the undesired isomer 2-methyl-4-nitro-2H-pyrazole-3-carboxylic acid methyl ester (1 g, 30%), subsequent elution with 40% EtOAc/hexane provided the desired isomer 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.8 g, 54%).
Reaction SMILES: [P:1]([O-:43])([O-:42])([O:3][C:4](C(C)(C)C)(C(C)(C)C)[N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:32])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])=[CH:7][C:6]1=[O:33])=[O:2].C(O)(=O)C>C(#N)C.O>[P:1]([OH:43])([OH:42])([O:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:32])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])=[CH:7][C:6]1=[O:33])=[O:2]
Reactant: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(C(OP(=O)([O-])[O-])(C(C)(C)C)C(C)(C)C)c(=O)c1
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(COP(=O)(O)O)c(=O)c1
Yield: 48.4 %

Procedure:
A solution of di-tert-butyl[4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (20) (50 mg, 0.080 mmol) in acetonitrile (1 mL), H2O (1 mL), and acetic acid (1 mL) was stirred at 70° C. for 3 hours then evaporated to dryness. The material was then co-evaporated with acetonitrile (3×), triturated with acetonitrile, filtered, washed with acetonitrile and desiccated to give [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate (9) (20 mg, 49%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 2H), 10.77 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.61 (d, J=7.6 Hz, 2H), 7.27-7.19 (m, 1H), 7.11 (dd, J=10.9, 7.6 Hz, 2H), 6.98 (s, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.43 (dd, J=7.5, 2.1 Hz, 1H), 5.53 (d, J=9.7 Hz, 2H), 2.16 (s, 3H) ppm. 31P NMR (162 MHz, DMSO-d6-85% H3PO4 aq. as internal standard—0 ppm) δ−1.76 (t, J=9.6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].CN(C=O)C.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 34.4 %

Procedure:
To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (73.36 g, 0.27 mol) in DMF (734 mL) lithium carbonate (50 g, 0.676 mol) was added, followed by benzyl bromide (55.44 g, 0.324 mol). The mixture was heated to about 60° C. and stirred for about 20 hours. The reaction mixture was then cooled to room temperature and extracted with IPE, washed with water and dried over magnesium sulfate. After filtration and concentration in vacuo a solid was obtained. Recrystallization of the crude product in hexane afforded a white solid (33.6 g, yield 38.2%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH2:12])=[C:7]([Cl:13])[N:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCOCC1>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([Cl:13])=[C:8]([NH2:12])[N:9]=1
Reactant: COC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nc(N)c(C(=O)O)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl-3,5-diamino-6-chloropyrazine-2-carboxylate (8.5 g, 41.9 mmol) is dissolved in dioxane (200 mL), sodium hydroxide (1 M in water, 125 mL, 125 mmol) added and the mixture stirred overnight at room temperature. The reaction mixture is acidified to pH 5 with 4 M hydrochloric acid and concentrated to one third of the initial volume. The resulting solid is collected by filtration, washed with water and dried under vacuum at 50° C. Yield: 7.4 g
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S([O-])([O-])(=O)=O.[Mg+2]>>[NH2:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([C:10]=1[NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCCCO
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: Nc1c(Cl)nc2ccccc2c1NCCCO
Reaction time: 1 h
Yield: 111.9 %

Procedure:
The method of Part B of Example 1 was used to hydrogenate 3-[(2-chloro-3-nitroquinolin-4-yl)amino]propan-1-ol (10.0 g, 35.5 mmol) with the modifications that the reaction was stopped after one hour, and magnesium sulfate was added to the mixture before filtration. 3-[(3-Amino-2-chloroquinolin-4-yl)amino]propan-1-ol (10 g) was isolated as an amber oil and was combined with material made in separate experiments.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:15])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:26](=S)=[S:27]>C1COCC1>[Br:15][C:12]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]2[C:13]=1[O:14][C:26](=[S:27])[CH:2]=[C:1]2[OH:3]
Reactant: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Reactant: S=C=S
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c2oc(=S)cc(O)c2c1
Temperature: -2.5 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
To a suspension of methyl 3-acetyl-5-bromo-4-hydroxybenzoate (75 g, 258 mmol) in THF (350 mL) at −50° C. under nitrogen was added sodium bis(trimethylsilyl)amide (1M in THF) (904 mL, 903.58 mmol) over a 15 min period. The dark solution was allowed to warm to −5-0° C. and stirred for 1 h. Carbon disulfide (24.8 mL, 413 mmol) was added in one portion to the solution at −20° C. The mixture was allowed to warm to RT and stirred for 24 hrs. The reaction mixture was cooled to −50° C., quenched slowly with a 15% aq. sol. H2SO4 (750 mL) (need to trap the H2S formed). The reaction was extracted 3 times with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. This residue was triturated with DCM (500 mL), collected by filtration, washed with ether and dried under vacuum to give methyl 8-bromo-4-hydroxy-2-thioxo-2H-chromene-6-carboxylate (33.5 g, 41%) as an yellow solid. The filtrate was evaporated and the resulting dark gum was triturated with ethyl acetate (300 mL) to give a solid which was collected by filtration washed with ether and dried under vacuum to give a second batch of methyl 8-bromo-4-hydroxy-2-thioxo-2H-chromene-6-carboxylate (17.5 g, 22%) as a orange solid. Mass Spectrum: [M−H]− 314 for both batches.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(O)ncn1
Product: CC(C)(C)c1cc(Cl)ncn1
Yield: 78 %

Procedure:
Next, 4.7 g of 4-hydroxy-6-tert-butylpyrimidine obtained in Step 1 and 14 mL of phosphoryl chloride were put in a 50 mL three-neck flask, and the mixture was heated and refluxed for 1.5 hours. After the reflux, phosphoryl chloride was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane, and washed with water and then a saturated aqueous solution of sodium hydrogen carbonate. Anhydrate magnesium sulfate was added to the obtained organic layer for drying. This mixture was subjected to gravity filtration, and the filtrate was condensed to give a solid. This solid was purified by silica gel column chromatography. As a developing solvent, a mixed solvent of hexane and ethyl acetate in a ratio of 10:1 (v/v) was used. The obtained fraction was condensed to give 4-chloro-6-tert-butylpyrimidine (white solid, yield of 78%). A synthetic scheme of Step 2 is shown in (b-2) below.
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].S(OC)(OC)=O>CN(C)C=O>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH3:14])[CH:1]=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: [K+]
Solvent: COS(=O)OC
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OC)c1OC
Temperature: 100 °C
Yield: 56.6 %

Procedure:
In a three-neck flask (capicity 100 ml) equipped with a mechanical stirrer and reflux condenser, 20 ml of dimethylformamide, 10.0 g (0.054 mol) of syringaldehyde and 5.00 g (0.036 mol) of anhydrous potassium carbonate were placed and the mixture was heated under a nitrogen atmosphere to 100° C. To this mixture was added 8.00 ml (0.094 mol) of dimethyl sulfite. The mixture was maintained at about 100° C. for eight hours and then cooled to 25° C. and quenched with 500 ml water. The mixture was extracted with 100 ml of methylene chloride. The extracts were washed with water and concentrated in vacuo to give 4.0 g of 3, 4, 5-trimethoxybenzaldehyde.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[Cl:42]Cl>ClCCl>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:42])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Reactant: ClCl
Solvent: ClCCl
Solvent: O
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 88 %

Procedure:
A 2.0 g quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 10 ml of dichloromethane and to the solution was added 5 to ml of water. The mixture was cooled in an ice bath with stirring while thereto was added dropwise over 30 minutes about 10 ml of methylene chloride having dissolved therein 6.9 mmol of chlorine gas. After the addition, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layer thus separated and the dichloromethane layer were washed successively with aqueous solutions each of NaHCO3, Na2S2O3 and NaCl and dried over anhydrous magnesium sulfate. The solvent was distilled off at reduced pressure. The resulting residue was separated and purified by silica gel column chromatography, giving 1.87 g of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 88% yield.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].[OH-].[Na+].[O-2].[Ba+2].[H-].[Na+].CN(C)[CH:18]=[O:19]>[Ag]=O.O1CCCC1.CS(C)=O.CCOCC.C(N(CC)CC)C>[C:1]1([O:19][CH2:18][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CN(C)C=O
Agent: O=[Ag]
Agent: [Ba+2]
Agent: [H-]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: c1ccc(COc2ccccc2)cc1

Procedure:
In Scheme 3, the starting phenol is reacted with a benzyl halide in the presence of a base (e.g. sodium amide, triethylamine, sodium hydroxide, barium oxide, silver oxide, sodium hydride) in an inert solvent (e.g. ether, dimethylsulfoxide, dimethylformamide, tetrahydrofuran) to give a benzyl phenyl ether, which is an example of the derivative of the alkoxyiminocarboxylic acid (V).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][C:25]([OH:27])=[O:26]>ClCCl>[CH3:1][NH:2][C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][N:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=1)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:22][C@H:23]([C:28]([O-:30])=[O:29])[CH2:24][C:25]([O-:27])=[O:26]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Solvent: ClCCl
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.57 g (0.5 cmole) of ranitidine and 0.66 g (0.5 cmole) of aspartic acid was suspended in 15 ml of dichloromethane. The mixture was stirred for 3 hours at room temperature, was filtered, washed with dichloromethane and dried. Weight: 2.16 g (yield 97%). M.p. 163°-166° C. IR FIG. 4.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[CH2:12][CH2:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)C.[OH-].[K+].Cl>C1COCC1>[O:21]=[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][CH2:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:23])=[O:3])=[CH:6][CH:7]=1)=[O:22]
Reactant: CCOC(=O)c1ccc(C(=O)CCC(=O)c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)CCC(=O)c2ccccc2)cc1
Temperature: 65 °C
Yield: 99.8 %

Procedure:
4-(4-Oxo-4-phenyl-butyryl)-benzoic acid ethyl ester (3.22 g, 10.4 mmol) is dissolved in THF (100 mL) and an aqueous solution of KOH (15.6 mmol in 50 mL) is added. The reaction is stirred and heated (65° C.) for 6 h, whereupon HPLC analysis indicated the formation of a single product at the expense of the diketone. The reaction is neutralized with aqueous HCl and the THF removed in vacuo. The resulting solid is dissolved in EtOAc and the organic phase dried (Na2SO4), filtered and concentrated to afford 2.93 g (>99%) of the desired carboxylic acid (RT=0.90). LCMS confirmed the identity of the product (ES+Exact Mass: 282.09, Obs.: 283.48). This product is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:33]=[CH2:34])=[C:4]([CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:5]([O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:6]2[C:10]=1[CH2:9][O:8][C:7]2=[O:11]>C1C=CC=CC=1.C(O)C.[Rh](Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:33]([C:3]1[C:2]([CH3:1])=[C:10]2[C:6]([C:7](=[O:11])[O:8][CH2:9]2)=[C:5]([O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:4]=1[CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH3:34]
Reactant: C=Cc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Agent: Cl[Rh](Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCO
Product: CCc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2

Procedure:
A solution of methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-vinylisobenzofuran-5-yl)-4-methyl-4-hexenoate (17.7 g) and tris(triphenylphosphine) rhodium chloride (1.2 g) in benzene (180 ml) and ethanol (180 ml) was hydrogenated for 11 hours. The solvents were removed under vacuum and the residue was crystallized from ethyl acetate/tert butyl methyl ether to afford methyl (E) 6-(1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate, mp 101.3°-102.08° C.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])(=[O:6])=[O:5])([CH3:3])[CH3:2].[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[N:22]=[C:21]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(isopropylsulfonyl)aniline (B-3) (32 g, 0.16 mol) in DMF (300 mL) at 0° C., was added NaH (13 g, 0.32 mol). After stirred at 0° C. for 0.5 h, 2,4,5-trichloropyrimidine (35 g, 0.13 mol) was dropwised to the mixture at 0° C. The solution was stirred for 12 h at RT, then poured into water, extracted with EtOAc, washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (10:1 to 5:1) to give the title compound (B) as a yellow solid. MS-ESI (m/z): 346 (M+1)+.
Reaction SMILES: [N:1]([CH:4]1[CH2:22][CH2:21][N:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:6]2[CH2:5]1)=[N+]=[N-].S(OC1CCN2C3C=CC=CC=3CC3C=CC=CC=3C2C1)(C1C=CC(C)=CC=1)(=O)=O.O>CCOCC>[NH2:1][CH:4]1[CH2:22][CH2:21][N:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:6]2[CH2:5]1
Reactant: [N-]=[N+]=NC1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: Cc1ccc(S(=O)(=O)OC2CCN3c4ccccc4Cc4ccccc4C3C2)cc1
Solvent: CCOCC
Solvent: O
Product: NC1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
4 g of 2-azido-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[ c,f]-azepine (axial) is added to a suspension of 3 g of LiAlH 4 in dry ether. The mixture obtained is heated for 1 hour, and after that cooled down. Then 12 ml of water are added to the mixture dropwise, whereby an inorganic precipitate is formed. The inorganic residue is removed by filtration after which the filtrate is evaporated to dryness.