Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11](=[O:25])[CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Mg]I.[Cl-].[NH4+]>CCOCC>[CH2:1]([N:8]([CH2:10][C:11]([CH3:26])([OH:25])[CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]I
Reactant: CN(CC(=O)C(c1ccccc1)c1ccccc1)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(Cc1ccccc1)CC(C)(O)C(c1ccccc1)c1ccccc1

Procedure:
3-(N-Benzyl-N-methylamino)-1,1-diphenyl-propan-2-one (10g) in dry ether (250 ml.) was added to a solution of methyl magnesium iodide (from 2.4g. magnesium and 14 2g methyl iodide) in dry ether (250 ml.) and the mixture heated at reflux for 2 hours. Saturated ammonium chloride solution was added; isolation through ether in the usual manner gave 3-(N-benzyl,N-methylamino)-2-methyl-1,1-diphenyl-propan-2-ol, purified by chromatography on alumina using progressively graded mixtures of light petroleum and ether as eluant and isolated as the hydrochloride (6 8g , 65%), m.p. 121° - 124° (from ethanol-ether).
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].C(O)(=O)C.[CH:11](=O)[C:12]([CH3:14])=[O:13]>O>[CH:2]([NH:5][N:6]=[CH:11][C:12](=[O:13])[CH3:14])([CH3:4])[CH3:3]
Reactant: CC(C)NN
Reactant: CC(=O)C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C=NNC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of isopropylhydrazine hydrochloride (2.0 g, 18 mmol) in water (100 mL) was added acetic acid (1.7 mL) followed by the dropwise addition of pyruvaldehyde (2.6 g, 14.5 mmol) in water. The solution was stirred at room temperature overnight. The aqueous layer was extracted with CH2Cl2 (4×) and the combined organic extracts were washed with sat. aq. NaHCO3. The organic extract was dried over Na2SO4, filtered and concentrated to afford 2-oxopropanal isopropylhydrazone (1.3 g, 56%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([C:7]1[CH:12]=[C:11]([SH:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])[CH3:5].C([O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br)C.O>CC(C)=O>[CH3:6][C:4]([C:7]1[CH:12]=[C:11]([S:13][CH2:25][CH2:24][CH2:23][C:22]([OH:27])=[O:21])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:3])[CH3:5]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(SCCCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 1.5 h

Procedure:
Potassium hydroxide flakes (2.52 g, 0.045 mole) were added to a clear solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (3.57 g, 0.015 mole) and ethyl-4-bromobutyrate (3.23 g, 0.0165 mole) in acetone (10 ml). Water (20 ml) was added and the solution stirred for 1.5 hours, the solvent removed on a rotary evaporator and water (50 ml) added and extracted with ethyl ether (3×75 ml). The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ethyl ether (2×50 ml), washed with water (50 ml), dried over sodium sulfate, filtered and the solvents removed, leaving an oil, which was purified by chromatography on silica, recrystallized from ethyl ether/Skellysolve B, filtered and the product dried in vacuo at room temperature for 12 hours, m.p. ca. 112°-113.5° C.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])[C:14]([CH3:29])=[C:13]([CH3:30])[N:12]=1.CCOC(C)=O>C(COC)OC>[CH3:30][C:13]1[C:14]([CH3:29])=[C:15]([NH:20][CH2:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)NC(C)(C)CNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(=O)NC(C)(C)CNc1c(C)c(C)nc(Oc2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
A 250mL-round bottom flask was charged with NaH (60% oil dispersion, 534 mg, 13.3 mmol) under N2. The NaH was washed with three portions of hexanes and dried under a stream of N2. Dimethoxyethane (10 mL) was then added to the flask followed by phenol (1.25 g, 13.3 mmol). After stirring for 10 min, a solution of N-{2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]-1,1-dimethylethyl}acetamide (2.80 g, 8.89 mmol) in 15 mL of dimethoxyethane was added to the reaction mixture, dropwise, via cannula. The reaction mixture was then heated to reflux for 24 h. The cooled solution was then treated with 100 mL of EtOAc and washed successively with H2O, 1% Na2CO3 solution (2×), H2O and brine. The organic portion was dried with Na2SO4 and concentrated to give a brown oil. Column chromatography (SiO2, 50% EtOAc/hexanes) gave N-{2-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]-1,1-dimethylethyl}acetamide (2.40 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([CH3:24])[CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])=[C:16]([CH3:24])[CH:15]=1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Br)cc2C)n1

Procedure:
The tide compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-bromo-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (48.2 mg) with purity >90%. MS (pos) m/z 419.2, 421.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].Cl[CH2:18][C:19](=[O:21])[CH3:20]>O>[CH2:18]([O:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[C:19]([CH3:20])=[O:21]
Reactant: CC(=O)CCl
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)COc1ccc(Cl)cc1C(=O)O

Procedure:
To a solution of 5.16 g. (0.3 mole) of 5-chlorosalicylic acid in 60 ml. of ethanol and 40 ml. of water containing 1.2 g. (0.03 mole) of sodium hydroxide is added 2.8 g. (0.03 mole) of chloroacetone and the solution heated to reflux for 5 hours. The resulting solution is cooled in an ice bath and the precipitated product filtered, dried and recrystallized from ether, 800 mg., m.p. 90°-91° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:32])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:31])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:33][NH:34][CH3:35]>CS(C)=O>[CH3:33][N:34]([CH3:35])[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:32])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:31])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Solvent: CS(C)=O
Product: CN(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
Through a solution of 18 g (0.041 mole) of 4'-fluoro-4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]butyrophenone in 150 ml of dimethylsulfoxide (DMSO) was vigorously bubbled dimethylamine for 6 hours at 100°C. Most of the DMSO was removed at reduced pressure and a temperature of 120°C. The remaining mixture was poured into water and sodium carbonate to which was added a small amount of methanol. The resulting solid was filtered and dissolved in warm methanol and isopropyl alcohol, treated with charcoal filtered, and cooled. The solid which formed upon cooling was filtered off and recrystallized from acetone-heptane to give the desired product, M.P. 148°-150°C.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH2:12][C@@H:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][S:2]([N:5]([CH2:12][C@@H:13]1[N:18]([C:27]2[N:28]=[CH:29][C:30]([C:33]([OH:42])([C:34]([F:35])([F:36])[F:37])[C:38]([F:40])([F:41])[F:39])=[CH:31][N:32]=2)[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CN(c2ccccc2)S(C)(=O)=O)C1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)[C@@H](CN(c2ccccc2)S(C)(=O)=O)C1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
A 20-mL vial was charged with tert-butyl (3R)-3-(((methylsulfonyl)(phenyl)amino)methyl)-1-piperazinecarboxylate (0.425 g, 1.15 mmol, step 4), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.411 g, 1.47 mmol, Intermediate D), DIPEA (0.602 mL, 3.45 mmol) and 1,4-dioxane (5 mL). The vial was sealed and the reaction mixture was heated at 100° C. for 20 h. The reaction mixture was allowed to cool to room temperature and partitioned between water (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (2×30 mL). The combined organic phases were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 0 to 50% EtOAc in hexanes) to afford tert-butyl (3R)-3-(((methylsulfonyl)(phenyl)amino)methyl)-4-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (0.464 g) as a light-brown solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1C=CC=CC=1>[CH2:12]1[CH2:13][O:10][C:9]2[C:2](=[C:3]([CH:6]=[CH:7][CH:8]=2)[CH:4]=[O:5])[O:1]1
Reactant: O=Cc1cccc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=Cc1cccc2c1OCCO2
Temperature: 135 °C
Yield: 49 %

Procedure:
12.04 g of 2,3-dihydroxybenzaldehyde was dissolved in 120 ml of dry DMF. To this solution, 9.0 ml of 1.2-dibromoethane, 12.1 g of anhydrous potassium carbonate and 1.1 g of cupric oxide were added. The reaction solution was refluxed under heating for three hours on a hot water bath at 135° C. The reaction solution was diluted with 700 ml of benzene and then washed with 500 ml of water. The aqueous layer was separated and extracted with benzene (500 ml×2 times). The extracted organic layers were combined to the previously separated organic layer, the combined organic layer was dried over anhydrous magnesium sulfate. The inorganic salt was removed by filtration, and the reaction solution was concentrated under reduced pressure to obtain a brown syrup. This syrup was purified by silica gel column chromatography (n-hexane/acetone=5/1). The eluted solution was concentrated under reduced pressure, and the residue was recrystallized from n-hexane/acetone to obtain 7.0 g of the above identified compound as white crystals (melting point: 63°-64° C.) (yield: 49%). The mother solution was concentrated and dried to obtain 3.2 g of the above identified compound as crude syrup (yield: 22%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[F:10][C:11]([F:22])([F:21])[C:12]([N:14]=[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][NH:16]1)=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][C:12](=[O:13])[C:11]([F:21])([F:22])[F:10])=[CH:4][CH:5]=1
Reactant: O=C(N=c1cccc[nH]1)C(F)(F)F
Reactant: Fc1ccc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(N=c1ccccn1Cc1ccc(F)nc1)C(F)(F)F

Procedure:
57 mg (0.30 mmol) of the 5-bromomethyl-2-fluoropyridine obtained by the aforementioned method was dissolved in 10 ml of anhydrous acetonitrile, 57 mg (0.30 mmol) of 2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetoamide synthesized by the method described in (1) of Synthetic Example P1 and 69 mg (0.50 mmol) of potassium carbonate were added thereto in sequence, and the resulting mixture was heated and refluxed for 6 hours. After the reaction was completed, the reaction solution was returned to room temperature to filter insoluble materials, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→3:1) to obtain the subject material. Amount obtained 21 mg (yield 23%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][CH:19]=O)=[CH:15][C:14]=1[C:23]([F:26])([F:25])[F:24]>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:19]([CH2:18][O:17][C:16]3[CH:21]=[CH:22][C:13]([F:12])=[C:14]([C:23]([F:26])([F:24])[F:25])[CH:15]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: O=CCOc1ccc(F)c(C(F)(F)F)c1
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2COc1ccc(F)c(C(F)(F)F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (1.540 mmol) and (4-fluoro-3-trifluoromethyl-phenoxy)-acetaldehyde (0.342 g; 1.540 mmol) afforded 3-ethyl-8-(4-fluoro-3-trifluoromethyl-phenoxymethyl)-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. Subsequent protection of the secondary amine, and purification by FC (DCM/MeOH=60/1) allowed the isolation of the pure product 3-ethyl-8-(4-fluoro-3-trifluoromethyl-phenoxymethyl)-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (0.412 g; 47%). LC-MS: tR=0.93 min.; [M+H]+=570.37 g/mol.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)O1.Br[C:33]1[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[C:35]([F:43])[CH:34]=1>>[F:43][C:35]1[CH:34]=[C:33]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)[CH:38]=[CH:37][C:36]=1[S:39]([CH3:42])(=[O:41])=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Reactant: CS(=O)(=O)c1ccc(Br)cc1F
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(S(C)(=O)=O)c(F)c4)ccc3o2)CC1
Yield: 27.5 %

Procedure:
Following the General Procedure-1, the titled compound (30 mg) was prepared from Intermediate 8 (100 mg, 0.23 mmol) and 4-bromo-2-fluoro-1-(methylsulfonyl)benzene (70 mg, 0.37 mmol) as an off-white solid. M.P.: 174.3-177.5° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.03 (t, J 7.9, 1H), 7.88 (d, J 1.6, 1H), 7.61-7.51 (m, 3H), 7.46 (dd, J 1.6, 11.1, 1H), 4.15 (d, J 11.2, 2H), 3.26 (s, 3H), 3.20-3.11 (m, 1H), 3.00 (t, J 12.2, 2H), 2.20-2.12 (m, 2H), 1.98-1.84 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[SH:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.CCCCCC>CN(C=O)C>[N+:24]([C:23]1[C:18]([S:17][CH2:2][CH2:3][S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:19][CH:20]=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: ClCCSc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1SCCSc1ccccc1
Temperature: 60 °C
Yield: 66 %

Procedure:
3.44 g (20.0 mmol) (2-chloroethyl)(phenyl)sulfane and 5.53 g (40.0 mmol) potassium carbonate were added to a solution of 1.56 g (10.0 mmol) 2-mercapto-3-nitropyridine in DMF (30 ml) and heated for 4 h at 60° C. Then the mixture was diluted with EE and washed with brine. The organic phase was separated off, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 9:1) of the residue yielded 1.93 g (6.6 mmol, 66%) 3-nitro-2-(2-phenylsulfanyl-ethylsulfanyl)pyridine.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH3:7][C:8]1([CH2:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=O>C(Cl)Cl>[CH2:21]([O:20][C:16](=[O:19])[CH:17]=[N:15][CH2:14][C:8]1([CH3:7])[CH:9]=[CH:10][CH:11]=[CH:12][CH2:13]1)[CH3:22]
Reactant: CCOC(=O)C=O
Reactant: CC1(CN)C=CC=CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOC(=O)C=NCC1(C)C=CC=CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 989.9 %

Procedure:
To a suspension of magnesium sulfate (150 g) and 1-methylphenylmethylamine (37.87 g, 32.9 mmol) in methylene chloride was added dropwise a solution of ethyl glyoxylate (33.55 g; 32.9 mmol) in methylene chloride, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, the filtrate was concentrated in vacuo to afford 67.5 g (quantitative) of N-[(1-methyl)phenylmethyl]imino-acetic acid ethyl ester, as an oil.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>C(O)C>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[N:16]1[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]1=[O:11]
Reactant: Nc1ccccc1F
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2ccccc2F)C1=O
Yield: 77.9 %

Procedure:
A mixture of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g; 2.94 mmol) and 2-fluoroaniline (0.851 mL; 8.82 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. The mixture was concentrated under reduced pressure and the residue was dissolved in a solution of sodium hydroxide 6N, washed with dichloromethane, acidified with a solution of hydrochloric acid 6N to pH=2, extracted with ethyl acetate dried and concentrated under reduced pressure to yield 0.511 g (78%) of a yellow solid, which was used in the next step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14])=[O:8]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([Cl:3])=[O:14])=[O:8]
Reactant: O=C(CCl)Nc1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(CCl)Nc1cccc(C(=O)Cl)c1
Yield: 80 %

Procedure:
To a warm (55°-60° C.) solution of 250 ml. of thionyl chloride and 50 ml. of chloroform and 6 drops of pyridine is added 3-(chloroacetylamino)benzoic acid (150 g., 0.702 mole) in 3 equal portions at 0.5 hr. intervals. After the addition is complete, the reaction mixture is warmed to a temperature of 55°-65° C. for 2 hrs., cooled and diluted with 500 ml. of petroleum ether (b.p. 30°-60° C.). The precipitate which forms is collected, washed with petroleum ether (b.p. 30°-60° C.) and dried under vacuum over potassium hydroxide at room temperature to afford 143 g. (80% yield) of 3-(chloroacetylamino)benzoyl chloride, m.p. 106°-108° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:18])[C@H:6]([CH2:8][S:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:7])[CH3:3].[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26])(=[O:21])[CH3:20]>CO>[CH2:2]([O:4][C:5](=[O:18])[C@H:6]([CH2:8][S:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:7][C:25](=[O:26])[CH:24]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:23][S:22][C:19](=[O:21])[CH3:20])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CSCCc1ccccc1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: CO
Product: CCOC(=O)[C@H](CSCCc1ccccc1)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React S-phenethyl-L-cysteine ethyl ester hydrochloride (2.85 g) and 3-acetylthio-2-benzylpropionic acid, (2.38 g) in a manner similar to that described in Example 1, Step 1 to give an amber oil. Chromatograph this oil on Prep 500 (2 silica gel cartridges) and elute with CH2Cl2 (4L) and then CH2Cl2 :ethyl acetate 100:2 to give Isomer A, a white solid (1.32 g), m.p. 63°-64°[α]D26 =-51.2° (MeOH); overlap Isomer A and Isomer B (0.63 g); and Isomer B, white solid (1.14 g), m.p. 84°-86°, [α]D26 =+5.3° (MeOH).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][CH:9]=[N:8][C:7]=1[NH2:11])=[O:5])[CH3:2].[N:12]([O-])=O.[Na+]>Cl>[CH2:1]([O:3][C:4]([C:6]1[S:10][CH:9]=[N:8][C:7]=1[NH:11][NH2:12])=[O:5])[CH3:2]
Reactant: O=N[O-]
Reactant: CCOC(=O)c1scnc1N
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)c1scnc1NN
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To 100 ml of a concentrated hydrochloric acid solution containing 19.3 g of 4-aminothiazole-5-carboxylic acid ethyl ester, 12 ml of an aqueous solution of 8.5 g of sodium nitrite was added dropwise at 0 to 5° C. This mixture was stirred at 0° C. for 30 minutes, and then 120 ml of a concentrated hydrochloric acid solution containing 84.9 g of stannous chloride was added dropwise thereto at 0 to 10° C. The mixture was further stirred at the same temperature for 2 hours and then stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was carefully added to 2 liters of an ethyl acetate suspension containing 500 g of potassium carbonate and 100 g of celite with stirring. Further, the filtered substance was added to this ethyl acetate suspension, and then the suspension was made basic with 150 ml of a 5 N sodium hydroxide aqueous solution. The mixture was allowed to stand, and then most of the supernatant (organic layer A: 1.5 liters) was collected. The remaining suspension was filtered through celite, and the celite was washed with 1 liter of ethyl acetate and 500 ml of water. The filtrate was separated into organic layer B and aqueous layer A. Ethyl acetate (1 liter) and anhydrous magnesium sulfate were added to the filtered substance, and the mixture was stirred and then filtered. Aqueous layer A was re-extracted with the resulting filtrate. Washing of the filtered substance and re-extraction of aqueous layer A were repeated 4 times in the same manner. Organic layer A and organic layer B were combined with the obtained organic layers, and the mixture was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (11.9 g) as a light yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][CH3:16])[CH:8]=[C:9]2[O:13][CH:12]([CH3:14])[CH2:11][C:10]=12)=[O:4].[OH-].[Na+]>O.C(O)C>[CH3:16][O:15][C:7]1[CH:8]=[C:9]2[O:13][CH:12]([CH3:14])[CH2:11][C:10]2=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1
Reactant: COC(=O)c1cc(OC)cc2c1CC(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2c(c(C(=O)O)c1)CC(C)O2

Procedure:
To a stirred mixture of 158 grams of 2,3-dihydro-6-methoxy-2-methyl-4-benzofurancarboxylic acid methyl ester and 88.5 grams of flake sodium hydroxide in 320 cc of water, ethanol is gradually added until a clear solution is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17])=[O:9]>CN(C)C=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([OH:17])=[C:10]([C:8](=[O:9])[CH2:7][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:15]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)c1cc(Cl)ccc1O
Solvent: CN(C)C=O
Product: O=C(Cn1ccnc1)c1cc(Cl)ccc1O
Temperature: 0 °C
Yield: 82.4 %

Procedure:
Imidazole (17.9 g, 0.26 mol) was added to a solution of 2-bromo-1-(5-chloro-2-hydroxyphenyl)-1-ethanone [compound (4-1)] (21.8 g, 87.7 mmol) in N,N-dimethylformamide (50 mL), and the resultant mixture was stirred for 17 hours at room temperature. The reaction mixture was added to ice-water, followed by extraction with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate. Subsequently, the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography, followed by drying under reduced pressure, to thereby yield 1-(5-chloro-2-hydroxyphenyl)-2-(1H-1-imidazolyl)-1-ethanone as colorless crystals (17.1 g, yield: 82.4%).