Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:38][O:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:10]([NH:12][C@@H:13]2[C:36](=[O:37])[N:15]3[C:16]([C:33]([O-:35])=[O:34])=[C:17]([CH2:20][N+:21]([CH3:32])([CH3:31])[CH2:22][C:23]4[NH:24][CH:25]=[C:26]([OH:30])[C:27](=[O:29])[CH:28]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO.O>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:38][O:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:10]([NH:12][C@@H:13]2[C:36](=[O:37])[N:15]3[C:16]([C:33]([O-:35])=[O:34])=[C:17]([CH2:20][N+:21]([CH3:32])([CH3:31])[CH2:22][C:23]4[NH:24][CH:25]=[C:26]([OH:30])[C:27](=[O:29])[CH:28]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+](C)(C)Cc3cc(=O)c(O)c[nH]3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+](C)(C)Cc3cc(=O)c(O)c[nH]3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
To a suspension of 7β-[2-(2-formamidothiazol-4-yl)- 2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate (syn isomer) (0.70 g) in methanol (35 ml) was added conc. hydrochloric acid (0.53 ml). After being stirred at ambient temperature, the reaction mixture was diluted with water (50 ml) and methanol was evaporated under reduced pressure. The resulting aqueous solution was adjusted to pH 1.0 and subjected to column chromatography on Diaion HP-20 (50 ml). The column was washed with water and the elution was carried out with 40% aqueous isopropanol. The fractions containing the object compound was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl} ammonio]methyl-3-cephem-4-carboxyl ate (syn isomer) (0.53 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:15])[CH:13]=[CH2:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)Cl
Reactant: Cc1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: C=CC(=O)c1ccc2c(C)cccc2c1
Yield: 86.2 %

Procedure:
1-methylnaphthalene (142 mg), acryloyl chloride (100 mg), and aluminium chloride (150 mg) were reacted in carbon disulfide (0.5 mL) at from −20° C. to room temperature for 1 hour. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (169 mg) in a viscous liquid form.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:24])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[N:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br.O>C1COCC1>[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40][N:2]([CH3:1])[C:3](=[O:24])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[N:6][CH:5]=1
Reactant: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of 2.5 g (7.7 mmol) N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide in 51 ml THF at 4° C. was added dropwise over 30 min 10.2 ml (10.2 mmol) potassium bis(trimethylsilyl) amide (1M in THF). The reaction mixture was stirred for 30 min and subsequently treated at 4° C. dropwise over 30 min with 1.46 ml (7.7 mmol) 3,5-bis-trifluoromethyl-benzylbromide. The reaction mixture was stirred for 1.5 h at 4° C., treated with 31 ml water and extracted. The aqueous phase was separated and adjusted to pH 12 with 2N NaOH and subsequently extracted with 30 ml ethyl acetate. The aqueous phase was separated, the combined organic phases were dried over Na2SO4, the solvent was removed under reduced pressure and the residue purified by chromatography over silica gel (CH2Cl2:MeOH=99:1) to yield 3.6 g (84.1%) product as a beige foam.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Ca+2].[OH-]>O>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=[CH:11][C:12](=[O:13])[CH3:14]
Reactant: CC(C)=O
Reactant: Cc1cccc(C)c1C=O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)cccc1C
Yield: 90 %

Procedure:
13,4 g (0,1 mol) of 2,6-dimethylbenzaldehyde, 100 ml of acetone, 100 ml of water and 2 g of calcium hydroxide are mixed together and refluxed for about 20-25 h with agitation. The precipitate is filtered off from the cold reaction mixture. 1 l of ice water is added to the filtrate with agitation. The product is crystallized at a yield of about 90%. M.p. of the recrystallized product: 34°-35° C.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:20])[CH2:4][N:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].C(Cl)(Cl)Cl>O>[CH2:6]([N:5]([CH2:4][CH:3]1[CH2:2][O:20]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC(CCl)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)CC2CO2)cc1
Yield: 76 %

Procedure:
50.7 g (0.175 mol) of 1-chloro-3-dibenzylamino-2-propanol and 9.5 g (0.24 mol) of sodium hydroxide in 5 ml of water are stirred together for one hour at 95° c. After the addition of 50 ml of chloroform and 20 ml of water, the phases are separated and the organic phase is washed with 20 ml of water, dehydrated with sodium sulphate and concentrated by evaporation. Distillation of the resulting yellow oil under vacuum yields 33.7 g (76%) of the oxirane as a colourless oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C>CN(C=O)C>[CH2:11]([O:10][C:8]([CH:5]1[CH2:4][CH2:3][CH:2]([O:1][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][CH2:6]1)=[O:9])[CH3:12]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@H]1CC[C@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.3 %

Procedure:
Treat a solution of cis/trans ethyl 4-hydroxycyclohexanecarboxylate (21.3 g, 0.124 mol) and imidazole (10.10 g, 0.148 mol) in DMF (150 mL) with t-butyl-diphenylsilyl chloride (37.39 g, 0.136 mol) and stir for 72 hours at room temperature. Dilute the reaction with diethyl ether and wash with 1N HCl and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 20% ethyl acetate in hexanes gradient on silica gel to afford 40.4 g (80%) of the titled product. Rf=0.49 and 0.29 (5/1 hexanes/ethyl acetate).
Reaction SMILES: Br[C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:4][N:5]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:6]=12.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.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>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]2[C:2]([C:27]3[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=3)=[C:6]3[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][N:5]3[N:4]=2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: N#Cc1ccc2c(Br)c(-c3ccc(F)cc3)nn2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3cc(C#N)ccc23)cc1
Yield: 6.4 %

Procedure:
To a solution of 3-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carbonitrile (0.24 g 0.76 mmol) in DMF (20 ml) was added 4-methanesulfonylphenylboronic acid (0.202 g 1.1 mmol), ground potassium phosphate (0.45 g 20 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.03 g) and the mixture heated to 90° for 6 h under nitrogen. The cooled mixture was poured into water (200 ml) and extracted with ethyl acetate (3×40 ml). The combined organic phases were washed with water (50 ml), brine (50 ml) and dried. Removal of solvent gave a solid which was purified by biotage chromatography. Elution with cyclohexane:ethyl acetate (4:1) gave the title compound as a white solid (0.019 g 6%). MH+: 392; NMR: (CDCl3) δ 3.14 (3H, s) 7.09 (2H, t) 7.30 (1H, dd) 7.50-7.56 (4H, m) 7.62 (1H, dd) 8.00 (2H, d) 8.9 (1H, s).
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)[CH3:3].Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:4]2[CH:2]([CH3:3])[N:31]([CH:29]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[C:17]([CH3:16])[CH:18]=3)[CH3:30])[C:6](=[O:8])[C:5]=2[CH:10]=[CH:11][N:12]=1
Reactant: COC(=O)c1ccnc(Cl)c1C(C)Br
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Agent: Cl
Product: Cc1cc(C(C)N2C(=O)c3ccnc(Cl)c3C2C)cnc1OCC(F)(F)F
Yield: 12 %

Procedure:
The title compound is prepared in 12% yield (40 mg, colorless oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (262 mg, 0.94 mmol, Step-1 of Intermediate-6, racemate) and 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (200 mg, 0.85 mmol, Amine-2, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[I:17][CH2:18][C:19](Cl)=[O:20].Cl>O>[I:17][CH2:18][C:19]([NH:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1)=[O:20]
Reactant: NC(=O)c1cc(N)ccc1O
Reactant: O=C(Cl)CI
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cc(NC(=O)CI)ccc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To an ice-cooled, stirred solution of 5-Aminosalicylamide (10.0 grams, 0.073 mol), in 300 mL of water containing NaHCO3 (42.0 grams, 0.5 mol), iodoacetyl chloride (18.4 grams, 0.09 mol) is added dropwise over 15 min. After stirring at 0°-5° C. for 1 hr., the solution is acidified with cold 6N HCl. The precipitate is collected and dried in vacuo over NaOH pellets, to afford 21.3 grams (96% yield) of crude 5-(iodoacetamido)salicylamide.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:37])[N:13]2[CH:16]([C:33](=C)[CH2:34][Cl:35])[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:38]=[O+][O-]>C(Cl)Cl.CO>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:37])[N:13]2[C:16](=[C:33]([OH:38])[CH2:34][Cl:35])[C:17]([O:19][CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CCl)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C(=C(O)CCl)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a dry ice acetone cooled solution of diphenylmethyl α[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-chloro-2-propen-2-yl)acetate (160 mg) in a mixture of methylene chloride (3.2 ml) and methanol (0.3 ml) is introduced ozone until the reaction mixture shows blue color. Then excess ozone is purged with oxygen, mixed with an aqueous solution of 95% sodium hydrogen sulfite (100 mg), warmed to room temperature to decompose the ozonide. After 1.5 hours, the solution is washed with 5% sodium hydrogen carbonate and water, dried, and concentrated to remove methylene chloride. The resultant oil (132 mg) is purified over thin-layer chromatographic plate (Merck 60F-254) using a mixture of benzene and ethyl acetate (1:1) as developing solvent to give diphenylmethyl α-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]-hept-2en-6-yl]-α-(2-chloro-1-hydroxyethylidene)acetate (44 mg) as glass.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:15][CH2:16]2)[N:7]=1
Reactant: COc1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.5 %

Procedure:
To a solution of 2,4-dichloro-6-methoxypyrimidine (5.0 g, 28.0 mmol) and tert-butyl piperidin-4-ylcarbamate (5.6 g, 28.0 mmol) in DMF (50 mL) was added K2CO3 (7.74 g, 56.0 mmol) and the mixture was stirred at RT for 6 h. The reaction was quenched with water and the suspension was filtered, washed with water and dried. The crude was purified with silica gel chromatography (eluting with 20% EtOAc in petroleum ether) to give tert-butyl (1-(4-chloro-6-methoxypyrimidin-2-yl)piperidin-4-yl)carbamate 276a (6.0 g, 73% yield). MS (ESI, pos. ion) m/z: 342.8 (M+1); 1H-NMR (400 MHz, CDCl3): δ ppm 5.97 (s, 1H), 4.64 (d, 2 H, J=13.2 Hz), 4.49 (brs, 1H), 3.88 (s, 3H), 3.04 (t, 2 H, J=11.6 Hz), 2.03 (d, 2 H, J=10.4 Hz), 1.57 (s, 3H), 1.46 (s, 9H). And tert-butyl (1-(2-chloro-6-methoxypyrimidin-4-yl)piperidin-4-yl)carbamate 276b (1.0 g, 12% yield). MS (ESI, pos. ion) m/z: 343.1 (M+1); 1H-NMR (400 MHz, CDCl3): δ ppm 5.70 (s, 1H), 4.49 (brs, 1H), 4.22 (d, 2 H, J=12.4 Hz), 3.91 (s, 3H), 2.96-3.00 (m, 2H), 2.03 (d, 2 H, J=8.4 Hz), 1.45 (s, 9H), 1.3-1.39 (m, 2H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][CH2:14][O:15][CH2:16][C:17]([CH3:19])=[CH2:18].C(=O)([O-])O.[Na+].O>C(Cl)Cl>[CH3:12][O:13][CH2:14][O:15][CH2:16][C:17]1([CH3:19])[CH2:18][O:9]1
Reactant: C=C(C)COCOC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCOCC1(C)CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.3 %

Procedure:
m-Chloroperbenzoic acid (22.7 g, 92 mmol) was gradually added to a solution of 3-methoxymethoxy-2-methyl-1-propene (9.7 g, 84 mmol) prepared in Reference Example 176 in methylene chloride (200 ml) while cooling in an ice-bath and the mixture was stirred at room temperature for 6 hours. Sodium hydrogencarbonate (14.1 g, 168 mmol), water and methylene chloride were added to the reaction mixture, which was stirred for a while. The organic layer was separated, washed with sodium hydrogencarbonate aqueous solution, sodium thiosulfate aqueous solution and then sodium hydrogencarbonate aqueous solution, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 2-methoxymethoxymethyl-2-methyloxirane (6.8 g, yield 62%) as a green-colored oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][CH2:14][N:15]1[C:19](=[O:20])[CH2:18][S:17][C:16]1=[O:21].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:13]([CH2:14][N:15]1[C:19](=[O:20])[CH2:18][S:17][C:16]1=[O:21])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH3:6])=[O:4]
Reactant: Cc1ccccc1NCN1C(=O)CSC1=O
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccccc1N(CN1C(=O)CSC1=O)C(=O)CCl
Reaction time: 3 h

Procedure:
A solution of 4.5 g of chloroacetyl chloride in 10 ml of toluene was added dropwise to a suspension of 7.8 g of N-(2-methylphenylaminomethyl)-2,4-thiazolidinedione and 3 g of pyridine in 80 ml of toluene at -5° C with stirring and kept on an ice bath for 3 hrs. The resulting precipitate was filtered and washed with water to give 2-chloro-N-(2,4-dioxothiazolidin-3-ylmethyl)-N-(2-methylphenyl)acetamide, mp 133°-136° C. The toluene filtrate was extracted with two 50 ml portions of 5% hydrochloric acid, 50 ml of water, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated on a rotary evaporator to give the product which was crystallized from benzene-ether, mp 134°-137° C. The total yield was 6.0 g [M+ = 312 (molecular ion by mass spec.)].
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:15]=O)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:23].[O:24]([NH2:26])[CH3:25]>C(O)C>[ClH:23].[CH3:25][O:24]/[N:26]=[CH:15]/[C:11]1[CH:12]=[N:13][CH:14]=[C:9]([C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=1
Reactant: O=Cc1cncc(C#Cc2ccccc2)c1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CO/N=C/c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
Dissolve 5-phenylethynylpyridine-3-carbaldehyde (0.20 g, 0.97 mmol), (prepared essentially as described in EXAMPLE 5), in ethanol (2.0 mL) and sequentially add potassium carbonate (0.67 g, 4.8 mmol) and methoxylamine hydrochloride (0.64 g, 5.6 mmol). Heat at reflux overnight, cool to room temperature and filter. Concentrate and purify by silica gel chromatography, eluting with a linear gradient of 90:10 to 50:50 hexanes:ethyl acetate to obtain the free base of the title compound as a colorless oil as well as a minor amount of EXAMPLE 86.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[N:2]1.[C:11](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:11]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[N:2]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1c[nH]nn1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Yield: 88.8 %

Procedure:
3.47 g of ethyl 1,2,3-triazole-4-carboxylate and 7.55 g of trityl chloride were dissolved in 100 ml of chloroform and 3.77 ml of triethylamine was added dropwise thereto under stirring and cooling in an ice-bath. The resulting mixture was stirred for 30 minutes at room temperature. Chloroform was distilled off and the residue was dissolved in ethyl acetate and the mixture was washed with an aqueous solution of sodium chloride and then dried with sodium sulfate. Ethyl acetate was distilled off and the residue was purified by silica gel column chromatography with benzene and chloroform eluent to give 8.37 g of ethyl N-trityl-1,2,3-triazole-4-carboxylate with mp 201°-203° C.
Reaction SMILES: [CH2:1]([C:3]([C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:18]([CH3:30])[CH:17]=1)([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:9]=2[CH:10]=1)[CH2:4][CH3:5])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33].CCN(CC)CC>C(Cl)Cl>[CH3:26][C:23]([CH3:25])([CH3:24])[C:22](=[O:27])[CH2:21][O:20][C:19]1[CH:28]=[CH:29][C:16]([C:3]([C:6]2[O:7][C:8]3[CH:14]=[CH:13][C:12]([O:15][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:11][C:9]=3[CH:10]=2)([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:17][C:18]=1[CH3:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(O)ccc2o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(OS(C)(=O)=O)ccc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
A solution of 1-{4-[1-ethyl-1-(5-hydroxy-benzofuran-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (236 mg, 0.579 mmol) in CH2Cl2 (10 mL) was treated with methanesulfonic chloride (99 mg, 0.868 mmol) and Et3N (0.40 mL). The mixture was stirred at 0° C. for 30 min, and the reaction is quenched with MeOH (1.0 mL). The mixture is purified with EtOAc/Hexanes (25%) to obtain the title compound (260 mg, 92%). MS (ES) m/e: 504.2 (M+18).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])=[CH:13][CH:12]=1.Cl[C:25]([O:27][CH3:28])=[O:26]>C(Cl)Cl>[O:23]=[C:18]1[CH2:19][O:20][CH2:21][CH2:22][N:17]1[C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:25](=[O:26])[O:27][CH3:28])=[CH:16][CH:15]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
N,N-Diisopropylethylamine (27.2 mL, 156.08 mmol) was added over 3 min to a stirred suspension of 4-(4-aminophenyl)-3-morpholinone (2, 25 g, 130.07 mmol) in CH2Cl2 (750 mL). The reaction mixture was stirred at room temperature for 15 min and methyl chloroformate (11.6 mL, 149.58 mmol) was added drop-wise over 10 min. The resulting thick suspension was stirred for another 1 h and filtered through a Buchner funnel. The solid was washed with CH2Cl2 (2×75 mL) and dried under vacuum to obtain methyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (5b, 30.92 g, 95%) as a crystalline solid.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[ClH:14].[CH2:15](O)[CH3:16]>>[ClH:14].[CH2:15]([O:12][C:11](=[O:13])[C@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)[NH2:1])[CH3:16]
Reactant: CCO
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
L-Tyrosine (1.00 kg, 5.52 tool) is suspended in 2B anhydrous ethanol (5.0 L). Anhydrous hydrogen chloride is introduced into this suspension initially at ambient temperature for 2.5 hours at which time the temperature rises to 56° C. The resulting clear solution is refluxed for 5 hours with continued introduction of a slow stream of hydrogen chloride. The solution is allowed to cool overnight and completion of precipitation of product is induced by the addition of t-butyl methyl ether (12.0 L). The crystals are collected by filtration and the filtrate is washed with more t-butyl methyl ether (2×500 mL). The solid is first air-dried and then vacuum-dried for 36 hours (40° C., 3 Torr) to yield L-tyrosine ethyl ester monohydrochloride, m.p. 165°-166° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1O)[C:20]([O:22][CH3:23])=[O:21]>N1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5.5 ml of trifluoromethanesulphonic anhydride (33 mmol) are slowly added dropwise to a solution of 5.49 g methyl 3-chloro-4-hydroxy-benzoate (29.4 mmol) in 15 ml of pyridine at 0° C. After the reaction mixture has been stirred at 0° C. for 5 minutes and at room temperature for 4 hours, it is partitioned between water and ether. The organic phase is washed in succession with water, dilute hydrochloric acid, water and saturated sodium chloride. solution, dried over sodium sulphate and concentrated and the residue is chromatographed over silica gel using methylene chloride to give 8.93 g of a pale yellow thinly mobile oil [95.2% of theory, Rf 0.63 (hexane:ethyl acetate=3:1)].