Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[S:31])[NH:10]2)=[C:5]([CH3:32])[CH:4]=1)#[N:2].IC.[C:35](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]([S:31][CH3:35])=[N:10]2)=[C:5]([CH3:32])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(SC)=NC1c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-(4-cyano-2-methylphenyl)-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 21; 100 mg, 0.22 mmol), 1-iodomethane (34.0 mg, 0.24 mmol) and potassium carbonate (34.1 mg, 0.25 mmol) are dissolved in 3 ml acetone and stirred at room temperature overnight. The solvent is removed in vacuo and the crude product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[N:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:7][C:5]1[CH:6]=[C:2]([C:11]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)[S:3][CH:4]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1csc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Brc1csc(-c2ccncc2)c1
Yield: 51.5 %

Procedure:
2,4-Dibromothiophene (2.97 g, 12.28 mmol), pyridine-4-boronic acid (1.50 g, 12.28 mmol), potassium carbonate (5.52 g, 39.91 mmol) and tetrakis(triphenylphosphine)palladium (0) (426 mg, 0.38 mmol) were refluxed in ethanol/1,2-dimethoxyethane (1:4 v/v; 100 mL) at 100° C. for 7 hours. The solution was allowed to cool, and then filtered and evaporated. The residue was purified by flash chromatography using a gradient of ethyl acetate in hexane to give a yellow solid as the sub-title compound (1.52 g), m/z 240, 242 (MH+).
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH2:35]1[O:45][C:38]2([CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]2)[O:37][CH2:36]1>C1COCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[C:41]2[CH2:42][CH2:43][C:38]3([O:45][CH2:35][CH2:36][O:37]3)[CH2:39][CH2:40]2)=[CH:7][CH:8]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc(C=C2CCC3(CC2)OCCO3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a stirring solution of 4-fluorophenylmethyl triphenylphosphonium chloride (39 g, 96 mmol, Lancaster) in 500 mL of dry THF at −78° C. was added 1 M potassium t-butoxide in THF (106 mL, 106 mmol, Aldrich). The reaction was stirred for 30 min and then warmed to 0° C. The reaction was stirred for 30 min and then 1,4-cyclohexanedione mono-ethylene ketal (15.0 g, 96 mmol, Aldrich) was added. After 30 min, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was heated to reflux for 4 h and then cooled to room temperature. The reaction was quenched with saturated ammonium chloride (500 mL) and ethyl acetate (500 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, and conc in vacuo to a white solid. The solid was purified by flash chromatography (SiO2, 19:1 hexanes:ethyl acetate) to yield 18.9 g of a colorless oil. MS (ESI) 251 (M+H).
Reaction SMILES: [N:1]1[C:2]([C:12](OCC)=[O:13])=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][S:6](=[O:11])(=[O:10])[C:5]=12.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl>[N:1]1[C:2]([CH:12]=[O:13])=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][S:6](=[O:10])(=[O:11])[C:5]=12
Reactant: CCOC(=O)c1cn2c(n1)S(=O)(=O)CCC2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1cn2c(n1)S(=O)(=O)CCC2
Temperature: -70 °C

Procedure:
Ethyl 6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine-2-carboxylate-8,8-dioxide (200 mg, 0.82 mmol) was dissolved in dry dichloromethane (minimum volume) under argon and cooled to -70° C. Diisobutylaluminium hydride (1.5M in toluene, 1 ml, 1.5 mmol) was added at <-70° C. and the mixture stirred at -70° C. until thin layer chromatography and infra-red spectroscopy showed little or no starting material remaining. Water (5 ml) was added carefully, cooling removed and the mixture stirred at ambient temperature for 1 h. Celite was added to the mixture and the resulting mixture filtered through a Celite pad. The Celite pad was washed with dichloromethane and water and the filtrate and washings combined and evaporated to dryness under reduced pressure. The residue was re-evaporated with ethanol (2×), triturated under diethyl ether and the product collected by filtration, washed with diethyl ether and dried in air (274 mg, 30%) (Found: M+ 200.0256. C7H8N2O3S requires M 200.0253); nmax (Nujol) 1678, 1316, 1161 and 1191 cm-1 ; dH [250 MHz; (CD3)2SO] 2.50-2.57 (2H, m), 3.81-3.85 (2H, m), 4.31 (2H, t, J 6Hz), 8.27 (1H, s), 9.80 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[OH:10]OS([O-])=O.[K+].[OH-:16].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([S:8]([CH3:9])(=[O:10])=[O:16])=[N:6][CH:7]=1
Reactant: CSc1ncc(Br)cn1
Reactant: [OH-]
Reactant: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ncc(Br)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 5-bromo-2-methylsulfanylpyrimidine (10.0 g, 48.8 mmol) in methanol (195 mL) were added a solution of Oxone® (94.6 g, 154 mmol, 3.16 eq) in water (500 mL and aq. 4 N sodium hydroxide (40 mL, 160 mmol, 3.28 eq.) portionwise and in an alternating addition mode to maintain pH between 2 and 3 at a temperature of 0° C. After complete addition, the mixture was allowed to stir for 2 h at room temperature. Water (500 mL) was added, and the mixture was extracted with ethyl acetate (2×500 mL). The aqueous layer was adjusted to pH 7 by addition of aq. sodium hydroxide, and was again extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated to give 9.23 g (80% yield) of the desired sulfone which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.C([Li])CCC.CON(C)[C:25](=[O:29])[CH2:26][CH2:27][CH3:28].O>C1COCC1.CCCCCC>[C:9]1([C:7]2[O:8][C:4]3[CH:3]=[C:2]([C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH:16]=[CH:15][C:5]=3[N:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCC(=O)N(C)OC
Reactant: Brc1ccc2nc(-c3ccccc3)oc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
10.00 g (36.48 mmol) 6-bromo-2-phenyl-benzoxazole are dissolved in 180 ml THF and cooled to −70° C., and 35.00 ml (56.00 mmol) n-butyl lithium 1.6M in hexane are added dropwise. This solution cooled to −70° C. is added dropwise after 20 min to an equally cold −70° C. solution of 2.5 g (19.1 mmol) N-methoxy-N-methyl-butyramide and 20 ml THF. After 20 min further stirring the mixture is mixed with water and allowed to come up to RT. The reaction mixture is extracted with water and DCM, the org. phase is dried on magnesium sulphate and the solv. is eliminated by rotary evaporation i.V. The residue is separated through silica gel (eluant cyclohexane/EA).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([SH:12])=[C:9](O)[CH:10]=1)[CH:2]=[CH2:3].[C:13](=[O:16])([O-])[O-].[K+].[K+].[CH3:19]I>CC(C)=O>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([S:12][CH3:19])=[C:9]([O:16][CH3:13])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(S)c(O)c1
Reactant: CI
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(SC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(Allyloxy)-2-sulfanylphenol (37.84 g, 0.21 mol) and potassium carbonate (43 g, 0.31 mol) in acetone (450 ml) was cooled to 5° C. and treated with methyl iodide (32.32 ml, 0.52 mol) dropwise and stirred for 1 h at RT. After removal of the solvent in vacuo, the residue was partioned between diethyl ether (300 ml) and water (400 ml). The aqueous phase was separated and extracted with further diethyl ether (2×150 ml) and the combined organics were dried over MgSO4 and evaporated to a clear oil (26 g, 0.12 mol).
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH:9]1[NH:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C(#N)C.ClCCl>[CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH:9]1[N:30]1[CH2:33][C:32]([CH3:36])([CH3:35])[CH2:31]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(NCC(C)(C)CCl)C3)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(N2CC(C)(C)C2)C3)c1
Reaction time: 2 h

Procedure:
Dissolved N-(2-(3-benzyl-2-(3-chloro-2,2-dimethylpropylamino)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (17.7 mg, 0.033 mmol in dry acetonitrile (2.000 ml) and added sodium bicarbonate (5.60 mg, 0.067 mmol). Microwave at 70° C. for 2 h. Evaporated solvents and re-dissolved in dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered and evaporated to obtain the crude product as clear white oil, that was purified by column chromatography on 1.5×2.5 cm SiO2 using 5% methanol in dichloromethane to afford N-(2-(3-benzyl-2-(3,3-dimethylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide as a white solid. m=1.7 mg (10%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]([NH2:36])([CH3:35])[CH2:28][CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1.C(O)(=O)C(O)=O>C(O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]([OH:25])[CH2:20][NH:36][C:27]([CH3:35])([CH3:26])[CH2:28][CH2:29][N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N)CCn1cncn1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: COC(=O)c1cc(C(O)CNC(C)(C)CCn2cncn2)ccc1OCc1ccccc1

Procedure:
9.5 g of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 3.1 g of 1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamine are reacted and worked up analogously to the method described for Example 2a. The crude product is dissolved in 100 mL 95% ethanol and combined with an ethanolic solution of 1.8 g of oxalic acid. After the addition of a crystallisation aid the precipitated product is separated off and washed. Yield: 8 g (64%, bisoxalate), m.p.=220-222° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]2([CH3:21])[CH3:20].[NH2:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:26]=[CH:27][CH:28]=1>>[NH2:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][C:31]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][C:10]=2[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]3([CH3:20])[CH3:21])=[O:32])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(CCC(=O)Cl)c1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Product: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3cccc(N)c3)c([N+](=O)[O-])cc21

Procedure:
The compound is synthesized from A8 (213 mg) and freshly prepared 3-(3-amino-phenyl)-propionyl chloride (223 mg; 1.21 mmol) as described in Example 1a.
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[C:15]([C:18]([O:20]C)=[O:19])[NH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)C.[OH-].[Na+].S(=O)(=O)(O)O>O>[CH2:1]([C:13]1[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[NH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCc1c[nH]c(C(=O)O)c1
Temperature: 45 °C
Yield: 87.2 %

Procedure:
To 112.0 g (0.38 mol) of methyl 4-dodecylpyrrole-2-carboxylate prepared in Example 35 were added 1.45 liters of ethanol, 1.45 liters of water and 31.0 g (0.74 mol) of 95% sodium hydroxide, and the whole was heated under reflux for 2 hours. At 80° C., 1.45 liters of hot water was added and, at the same temperature, 6N sulfuric acid was added gradually to adjust the reaction solution to pH 2. After cooling the mixture to 45° C., precipitated crystals were filtered and washed with water. The crystals were dissolved in 4 liters of tetrahydrofuran, and the solution was washed twice with 1 liter of a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give crystals, which were then recrystallized from a mixed solvent of 600 ml of tetrahydrofurn and 600 ml of hexane to obtain 92.6 g (87% yield) of 4 -dodecylpyrrole-2-carboxylic acid as white crystals, m.p. 152°-153° C.
Reaction SMILES: C(OC([NH:8][N:9]([C:17]1[C:18]([CH3:34])=[N:19][N:20]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])=[C:23]([CH3:33])[O:22][C:21]=12)[C:10](OC(C)(C)C)=O)=O)(C)(C)C.[C:35]([CH2:38]C(=O)C)(=O)[CH3:36].[CH3:42]C(O)=O>O>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[C:24]1[N:20]2[N:19]=[C:18]([CH3:34])[C:17]([N:9]3[C:10]([CH3:42])=[CH:36][C:35]([CH3:38])=[N:8]3)=[C:21]2[O:22][C:23]=1[CH3:33]
Reactant: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(=O)O
Reactant: CC(=O)CC(C)=O
Solvent: O
Product: Cc1cc(C)n(-c2c(C)nn3c(-c4ccc(Cl)cc4Cl)c(C)oc23)n1
Temperature: 25 °C

Procedure:
N′-[3-(2,4-Dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazol-7-yl]-N′-tert-butoxy carbonyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate JA) (50 mg, 0.098 mmol), acetylacetone (0.514 ml, 4.99 mmol) and AcOH (5 ml) are stirred at 85° C. for 54 hours. The reaction is allowed to cool to RT and added to water (50 ml). The product is extracted into EtOAc (2×50 ml) and the combined organics are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by ISCO combiflash chromatography, eluting with 0 to 100% (iso-hexane/EtOAc) on a 12 g SiO2-column. The resulting gum is crystallised by dissolving in hot EtOAc, adding iso-hexane and scratching and allowing to cool at 0° C. over night. The title compound 3-(2,4-dichloro-phenyl)-7-(3,5-dimethyl-pyrazol-1-yl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole is isolated as a yellow solid; MS: m/z 375.12 [M+H]+; 1H NMR (400.13 MHz (CDCl3) δ 7.60 (2H, m), 7.44 (1H, d), 6.01 (1H, s), 2.38 (3H, s), 2.33 (3H, s), 2.27 (3H, s), 2.22 (3H, s)
Reaction SMILES: [CH3:1][C:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:3](O)=[O:4].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[O:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[O:49][NH2:50]>C(Cl)Cl.O>[CH3:1][C:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[C:3]([NH:50][O:49][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][O:43]1)=[O:4]
Reactant: NOC1CCCCO1
Reactant: CC(CCc1ccc(Oc2ccccc2)cc1)(C(=O)O)S(C)(=O)=O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(CCc1ccc(Oc2ccccc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoic acid (285 mg, 0.818 mmol) in methylene chloride (8.18 mL) at ambient temperature was added 1,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (220 mg, 1.1 mmol), 1-hydroxy benzotriazole monohydrate (230 mg, 1.5 mmol), triethylamine (0.2 mL, 1.4 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (140 mg, 1.2 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and water. The phases were separated and the aqueous layer extracted with methylene chloride two times. The organic extracts were combined and dried over magnesium sulfate, filtered and concentrated in vacuo to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing the desired product were combined and concentrated in vacuo to afford 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as a solid. 247.2 mg
Reaction SMILES: [CH3:1][CH:2]([C:19]([OH:21])=[O:20])[C:3]1[CH:4]=[CH:5][C:6]2[S:18][C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:10](=[O:11])[CH2:9][C:7]=2[CH:8]=1.NC1C=CC(C(C)C(O)=[O:31])=CC=1CC(O)=O.C1(S)C=CC=CC=1>>[C:10]([CH2:9][C:7]1[CH:8]=[C:3]([CH:2]([CH3:1])[C:19]([OH:21])=[O:20])[CH:4]=[CH:5][C:6]=1[S:18][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:11])=[O:31]
Reactant: CC(C(=O)O)c1ccc2c(c1)CC(=O)c1ccccc1S2
Reactant: CC(C(=O)O)c1ccc(N)c(CC(=O)O)c1
Agent: Sc1ccccc1
Product: CC(C(=O)O)c1ccc(Sc2ccccc2)c(CC(=O)O)c1

Procedure:
Preparation-I of the invention for preparing Zaltoprofen is characterized in that 2-(4-amino-3-carboxymethylphenyl)propionic acid or its salt is diazotized and then reacted with thiophenol to give 2-(3-carboxymethyl-4-phenylthiophenyl)propionic acid or its salt, and the resulting product is then subjected to cyclization reaction. Preparation-I is illustrated in the following reaction scheme I: ##STR7## 1) Preparation of 2-(3-carboxymethyl-4-phenylthiophenyl)propionic acid or its salt
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:15][C:14]=3[C:24](O)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1C=O.[CH2:35]([O:42][C:43](=[O:52])[C:44]1[CH:49]=[C:48]([NH2:50])[CH:47]=[CH:46][C:45]=1[CH3:51])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43](=[O:52])[C:44]1[CH:49]=[C:48]([NH:50][C:24]([C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[O:25])[CH:47]=[CH:46][C:45]=1[CH3:51])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1ccc(N)cc1C(=O)OCc1ccccc1
Reactant: O=C(O)c1nc(-c2ccccn2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Agent: O=Cc1ccccn1
Product: Cc1ccc(NC(=O)c2nc(-c3ccccn3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)cc1C(=O)OCc1ccccc1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-pyridine-2-yl-1H-imidazole-4-carboxylic acid (prepared according to the procedure of Example 70, steps a and b, with the modification that pyridine-2-carboxaldehyde was used instead of 2-dimethylamino-benzaldehyde in step a) was reacted with 5-amino-2-methyl-benzoic acid benzyl ester according to the procedure of Example 177, step a to afford 5-{[5-(2-adamantan-1-yl-ethyl)-2-pyridine-2-yl-1H-imidazole-4-carbonyl]-amino}-2-methyl-benzoic acid benzyl ester. The benzyl group was removed following the procedure of Example 1, step e, to afford the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) 13.18 (1H, br s), 9.71 (1H, br s), 8.66 (1H, d), 8.32 (1H, s), 8.25 (1H, d), 7.96 (1H, td), 7.86 (1H, dd), 7.44 (1H, m), 7.24 (1H, d), 2.98 (2H, m), 2.48 (3H, s),1.94 (3H, br s), 1.63 (6H, m), 1.53 (6H, m), 1.42 (2H, m). The product was converted to the L-tartaric acid salt and lyophilised from water/dioxan. Found: C, 59.07; H, 6.40; N, 8.28%. C33H38N4O8.2.0 mols H2O requires: C, 59.10; H, 6.31; N, 8.35%.
Reaction SMILES: N1[C:8]([Cl:9])=NC(Cl)=NC=1Cl.C(Cl)Cl.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20]CO)=[CH:18][CH:17]=1)([O-:15])=[O:14]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[Cl:9][CH2:8][CH2:20][C:19]1[CH:23]=[CH:24][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of cyanuric chloride (1.83 g) in DMF (2 mL) was stirred at RT for 1 h. To the resulting white suspension was added DCM (25 mL) followed by 4-nitrophenethyl alcohol (1.59 g). The reaction mixture was stirred at RT for 4 h and diluted with 1M Na2CO3. The phases were separated, the org. layer was washed with 1M HCl and brine and evaporated in vacuo to afford 1.4 g of orange slurry. 1H-NMR (CDCl3): 8.22 (m, 2H); 7.43 (m, 2H); 3.79 (t, 2H, 7.0 Hz); 3.20 (t, 2H, 6.8 Hz).
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][S:25][C:26]3[S:27][CH:28]=[N:29][N:30]=3)[C@H:8]2[S:7]1.C(OCC)(=O)C>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][S:25][C:26]3[S:27][CH:28]=[N:29][N:30]=3)[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CSc3nncs3)[C@H]2S1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)CSc3nncs3)[C@H]2S1
Yield: 43.6 %

Procedure:
Acetic acid (8 ml) and zinc powder (6 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)-acetamido]-3-cephem-4-carboxylate (4.65 g) in anhydrous dimethylformamide (30 ml), and the mixture was stirred for 1 hour at the same temperature. After the reaction, ethyl acetate (150 ml) was added to the reaction mixture. The insoluble material was filtered off, and the filtrate was washed with 5% hydrochloride acid saturated with sodium chloride, and then extracted with a sodium bicarbonate aqueous solution. The extract was acidified with 10% hydrochloric acid and extracted with ethyl acetate, after which the ethyl acetate layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from a mixture of ethyl acetate and benzene to give 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)-acetamido]-3-cephem-4-carboxylic acid (1.5 g), mp 197° to 199° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])[CH:8]=[C:7]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=2)=[O:22])[CH:6]=1)(=O)C.C[O-].[Na+].Cl>C1COCC1.CO>[N+:30]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21](=[O:22])[C:7]2[CH:6]=[C:5]([OH:4])[CH:10]=[C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]#[N:20])[CH:8]=2)=[N:25][CH:26]=1)([O-:32])=[O:31]
Reactant: CC(=O)Oc1cc(OCc2ccccc2C#N)cc(C(=O)Nc2ccc([N+](=O)[O-])cn2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccccc1COc1cc(O)cc(C(=O)Nc2ccc([N+](=O)[O-])cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
A suspension of 3-{[(5-nitropyridin-2-yl)amino]carbonyl}-5-[(2-cyanobenzyl)oxy]phenyl acetate (5710 mg) in THF (35 ml) was treated with 25% NaOMe in methanol (6 ml). Stirred at ambient temperature for 30 minutes. Acidified with 2 m hydrochloric acid (25 ml), then extracted with ethyl acetate (100 ml). The extract was washed with water (50 ml), brine (50 ml), dried over MgSO4. Volatile material was removed by evaporation to give a solid. This was washed with hot methanol to give the title compound (4358 mg) as a solid, LCMS rt=2.38 min (90.5%). ES+391.45 (M+H)+.