Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1(C)[N:6](C)[CH2:5][C@@H:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=2)[O:3]1.[ClH:22].Cl.C(O)C1C=CC=CC=1>CCOCC>[ClH:22].[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH:4]([OH:3])[CH2:5][NH:6][CH3:2])=[O:20]
Reactant: CN1C[C@@H](c2cccc(OC(=O)C(C)(C)C)c2)OC1(C)C
Agent: Cl
Solvent: OCc1ccccc1
Solvent: CCOCC
Product: CNCC(O)c1cccc(OC(=O)C(C)(C)C)c1
Yield: 70 %

Procedure:
The filtrate obtained in the previous reaction containing (R)-2,2,3-trimethyl-5-(m-trimethylacetoxyphenyl)-1,3-oxazolidine (1.8 g, 6.2 mmole) in 60 ml of ether was treated with hydrogen chloride gas until the solution was no longer turbid. This mixture was then evaporated to dryness and the residue was dissolved in a small amount of ethanol and then diluted with hexane. The hydrolysis and crystallization took place in the solution to give 1.2 g of the final product, (R)-m-(trimethylacetoxy)-α-[methylamino)methyl]benzyl alcohol hydrochloride, 70% yield. mp 128°-130° C, αD25° = -36.7° (C2H5OH). ir (KBr): 3370, 2690, 2795, 2420, 1750, 1610, 1590, 1460, 1240 and 1110 cm-1. nmr (CD3COCD3. D2O): δ7.5-6.8 (m, 4H), 5.3 (dd, 1H, J = 5 and 10Hz), 3.8 (b, 3H), 3.4 (m, 2H), 2.9 (s, 3H) and 1.4 (s, 9H) ppm.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].[C:18]([CH:21]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:22](OCC)=[O:23])(=O)[CH3:19].P(Cl)(Cl)(Cl)=O>>[OH:10][C:9]1[CH:11]=[C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])[CH:6]=[C:7]2[C:8]=1[C:18]([CH3:19])=[C:21]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:22](=[O:23])[O:12]2
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: CCOC(=O)CCC(C(C)=O)C(=O)OCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCC(C)C(C)c1cc(O)c2c(C)c(CCC(=O)OCC)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 288 h

Procedure:
A mixture of 262 g. (1.109 mole) of 5-(3-methyl-2-octyl)resorcinol, 283 g. (1.23 mole) of diethyl α-acetylglutarate, and 170 g. (1.11 mole) of phosphorus oxychloride protected from atmospheric moisture is stirred at room temperature for 12 days. The mixture is taken up in benzene-ether and the solution is washed several times with water, aqueous sodium bicarbonate, water and dried over anhydrous magnesium sulfate. After removal of the solvent, 441 g. of an oil is obtained, which solidifies on standing.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:18](C=O)C>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:18])=[O:6]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc(I)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cccc(I)c1
Reaction time: 2 h
Yield: 99 %

Procedure:
3-Iodobenzoic acid (2.00 g, 8.06 mmol) was dissolved in THF (20 mL) then oxalyl chloride (1.4 mL, 16 mmol) and DMF (0.05 mL) were added and the resulting mixture stirred for 2 hours. The volatiles were evaporated under reduced pressure and the residue was dissolved in THF (20 mL) and concentrated aqueous ammonia (10 mL). After 60 minutes water (200 mL) was added and after a further 30 minutes the resulting precipitate was collected by filtration and air dried to give the title compound (I142) (1.97 g, 99% yield) as a white powder; 1H NMR (400 MHz, d4MeOH) δ 8.23 (t, J=1.8 Hz, 1H), 7.90 (ddd, J=7.9, 1.7, 1.0 Hz, 1H), 7.86 (ddd, J=7.8, 1.7, 1.0 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H). LCMS Method C: rt 5.29 min, m/z 248.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[OH:13][CH2:12][CH2:11][NH:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(NCCO)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
A mixture of 4-fluorobenzonitrile (6.06 g), 2-aminoethanol (3.71 g), potassium carbonate (8.29 g) and dimethylsulfoxide (50 mL) was stirred at 100° C. overnight. To the reaction solution was added water (200 mL), and extracted with ethyl acetate (200 mL×4). The ethyl acetate layer was washed with saturated brine (100 mL), and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (eluted with ethyl acetate:hexane=30:70, then 50:50, then 80:20, then ethyl acetate) to give 4-[(2-hydroxyethyl)amino]benzonitrile as yellow solid (5.89 g).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[C:16](\[CH2:22][CH2:23][OH:24])/[C:17]([O:19]CC)=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.[OH-].[Na+]>C(O)C.O>[NH2:5][S:6]([C:9]1[CH:10]=[CH:11][C:12](/[C:15](=[C:16]2/[C:17](=[O:19])[O:24][CH2:23][CH2:22]/2)/[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[CH:13][CH:14]=1)(=[O:8])=[O:7]
Reactant: CCOC(=O)/C(CCO)=C(\c1ccc(F)cc1)c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(/C(=C2\CCOC2=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
Ethyl (E)-3-(4-t-butylaminosulfonylphenyl)-3-(4-fluorophenyl)-2-(2-hydroxyethyl)-2-propenoate (10 g), prepared in Example 59, is dissolved in 20 ml of ethanol, and a solution of 2 g of sodium hydroxide in 10 ml of water is added. The mixture is refluxed for 2 h. After evaporation to dryness, the residue is taken up with water, acidified with 1N hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and then evaporated under vacuum. The residue is added in portions to 500 ml of concentrated sulphuric acid. The mixture is stirred for 15 minutes at room temperature and then poured into iced water and the crystals formed are filtered off, washed with diethyl ether and then taken up with 100 ml of warm acetone. 50 ml of diethyl ether are added to the solution obtained and the crystals formed are filtered off and dried to give 6 g of (E)-3-[1-(4-aminosulphonylphenyl)-1-(4-fluorophenyl)methylidene]dihydrofuran-2-one in the form of crystals melting at 202° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.CNC1CCCCC1NC>CCOC(C)=O.O.C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: COC(=O)c1ccc2c(F)c[nH]c2c1
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(F)cn(-c3ccc(F)cc3)c2c1
Temperature: 95 °C

Procedure:
Compound 69a (0.264 mmol, 51 mg), Cut (0.0264 mmol, 5 mg) and K3PO4 (0.66 mmol, 40 mg) were combined in a sealed reaction tube and the vial was back-flushed with N2. 4-fluoro-iodobenzene 69b (0.264 mmol, 0.0394 mL) and N,N′-dimethylcyclohexane-1,2-diamine (0.0792 mmol, 0.0125 mL) were added via sringe, followed by toluene. The reaction mixture was heated at 95° C. for 6 h. The reaction was diluted with EtOAc and water. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to give compound 69c.
Reaction SMILES: CC1N=C(N2C(=O)NN=C2)SC=1C(OCC)=O.[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1>>[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][N:28]([CH2:38][C:37]3[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=3)[C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19]
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: Fc1ccc(CBr)cc1
Agent: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Product: CC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Yield: 98 %

Procedure:
Following the procedure as described in Preparation 16, making variations as required to replace ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one to react with 4-fluorobenzyl bromide, the title compound was obtained as a yellow solid in 98% yield: 1H NMR (300 MHz, CDCl3) δ 7.32-7.22 (m, 2H), 7.07-6.97 (m, 2H), 4.45 (s, 2H), 4.10-4.04 (m, 2H), 3.48-3.37 (m, 2H), 2.67 (s, 3H), 2.38 (s, 3H); MS (ES+) m/z 334.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]([Cu])#[N:11]>CN1C(=O)CCC1>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:10]#[N:11])=[CH:3][C:4]=1[F:9]
Reactant: N#C[Cu]
Reactant: Nc1ccc(Br)cc1F
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N)c(F)c1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
50 g (0.26 mol) of 4-bromo-2-fluoroaniline and 30 g (0.34 mol) of CuCN were dissolved in 130 cm3 of NMP and the solution was refluxed with a mantle heater for 2 hours. The reaction solution was cooled to room temperature. 42 cm3 of EDA was added to the cooled solution and the solution was poured into 300 cm3 of ice water. The resulting mixture was extracted with chloroform and washed with an aqueous EDA solution and water. The chloroform was distilled off the washed mixture. The distillation residue was dissolved in ether and washed with water to remove the NMP. The residue was distilled in a vacuum (b.p. 165° C./23 mmHg) to yield 28 g (0.21 mol) of 4-amino-3-fluorobenzonitrile. It was necessary to perform the distillation under an elevated degree of vacuum since the product was extremely sublimable and the crystals adhered to the output of the distillation tube and clogged the tube.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][O:21][C:20]1=[O:24]>>[N+:1]([C:4]1[N:5]([CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][O:21][C:20]2=[O:24])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: O=C1OCCN1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1OCCN1CCCn1ccnc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
A mixture of 6 9 of 2-nitroimidazole (53 mmol) and 7.32 g of K2CO3 was heated at 60° C. for 0.5 hours. Then 8.6 g (53 mmol) of 3-(3-chloropropyl)-2-oxazolidinone (Ann. Pharm. Franc., 13, 565 (1955)) was added and stirring continued for 18 hours at 60° C. The mixture was then cooled and concentrated. The residue was partitioned between CHCl3 and water, the organic layer was dried and concentrated to give 10.4 g of a solid which was recrystallized from ethanol to provide 5.4 g (42%) of the desired product, 3-[3-(2-nitro-1H-imidazol-1-yl)propyl]-2-oxazolidinone; mp 89°-91° C.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccc(Nc2nccc(O)n2)cc1
Product: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-[(4-hydroxy-2-pyrimidinyl)amino]-benzonitrile (0.12 mol) in POCl3 (90 ml) was stirred and refluxed under Argon for 20 minutes. The reaction mixture was slowly poured onto 750 ml ice/water, and the solid was separated by filtration. The solid was suspended in 500 ml water, and the pH of the suspension was adjusted to neutral by adding a 20% NaOH solution. The solid was again separated by filtration, suspended in 200 ml 2-propanone, and 1 L methylene chloride was added. The mixture was heated till all solid had dissolved. After cooling to room temperature, the aqueous layer was separated, and the organic layer was dried over magnesium sulfate. During removal of the drying agent by filtration, a solid formed in the filtrate. Further cooling of the filtrate in the freezer, followed by filtration, yielded 21.38 g of 4-[(4-chloro-2-pyrimidinyl)amino]-benzonitrile (intermediate 2).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:17][C:16]1[CH:18]=[CH:19][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(F)cc1

Procedure:
Prepared according to Step D1 in General Procedure D using 2,4-difluoronitro-benzene (2.068 mL, 18.86 mmol) and 4-fluoroaniline (1.811 mL, 18.86 mmol) to give 5-fluoro-N-(4-fluorophenyl)-2-nitroaniline as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.56 (1H, s), 8.24 (1H, dd, J=9.5, 6.2 Hz), 7.36-7.44 (2H, m), 7.25-7.33 (2H, m), 6.67-6.74 (1H, m), 6.64 (1H, dd, J=11.8, 2.6 Hz); LC-MS (ESI) m/z 251.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([OH:3])=O.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:30]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCOCC1>[CH2:30]([N:37]1[CH2:42][CH2:41][N:40]([C:1]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3)=[O:3])[CH2:39][CH2:38]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1CCc2cc(C(=O)O)ccc2N1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C1CCc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
1.0 Gram of 6-carboxy-3,4-dihydrocarbostyril, 1.3 g of DCC and 1.1 g of benzylpiperazine were suspended in 10 ml of dioxane and the suspension was stirred at 70° C. for 5 hours. After the reaction was completed, the solvent was removed by distillation and ether was added to the residue and crystals formed were removed by filtration. After the mother liquor was concentrated, the residue was dissolved in chloroform and the chloroform solution was washed with water and a saturated sodium chloride aqueous solution then dried with anhydrous sodium sulfate and the solvent was removed by distillation. Recrystallized from ethanol to obtain 330 mg of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C@H:7]2[NH:14]C(=O)OC(C)(C)C.CO.Cl>CC(OC)(C)C.O>[Cl:1][C:2]1[C:3]([F:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C@H:7]2[NH2:14]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(C)(C)Oc2c1ccc(F)c2Cl
Agent: Cl
Solvent: O
Solvent: COC(C)(C)C
Solvent: CO
Product: CC1(C)C[C@@H](N)c2ccc(F)c(Cl)c2O1
Reaction time: 2 h
Yield: 92.6 %

Procedure:
The crude (R)-tert-butyl 8-chloro-7-fluoro-2,2-dimethylchroman-4-ylcarbamate (4.47 g, 13.5 mmol), MeOH (36 mL), and concentrated HCl (4 mL) were heated to 50° C. After 2 hours, complete deprotection was observed by LCMS. The reaction mixture was cooled, stirred for 8 hours, and then diluted with MTBE (60 mL) and water (40 mL). The mixture was partitioned and the organic layer was extracted with water (50 mL). The aqueous layer was basified with 2N NaOH (40 mL) and extracted with dichloromethane (2×40 mL). The organic extracts were dried (Na2SO4), filtered, and concentrated to give the title compound (2.87 g, 12.50 mmol, 92%). MS (ESI+) m/z 230 (M+H)+.
Reaction SMILES: [Se](=O)=[O:2].[C:4]([O:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]=1)=[O:11])([CH2:7][CH3:8])([CH3:6])[CH3:5]>O1CCOCC1.O>[C:4]([O:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18](=[O:2])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]=1)=[O:11])([CH2:7][CH3:8])([CH3:6])[CH3:5]
Reactant: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)CC)n1
Reactant: O=[Se]=O
Agent: CCOC(=O)Cc1csc(=NC(=O)OC(C)(C)CC)[nH]1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)c1csc(NC(=O)OC(C)(C)CC)n1

Procedure:
To a solution of selenium dioxide (0.11 g.) in a mixture of dioxane (2.5 ml.) and water (0.1 ml.) was added a mixture of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (0.3 g.) and dioxane (2.5 ml.) at 110° C. with stirring. The mixture was stirred for 30 minutes at the same temperature, and selenium dioxide (0.055 g.) was further added thereto and then the mixture was stirred for 1.5 hours at the same temperature. After the reaction, the reaction liquid is separated by decantation, and the residue was washed with a small amount of dioxane. The reaction liquid and washing are combined together, and then the solvents were distilled off. The residue was dissolved in ethyl acetate. The solution was washed with water and dried and then the solvent was distilled off to give brown oil of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (0.22 g.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:27]([O:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.02 h

Procedure:
4-(Hydroxymethyl)-1-(triphenylmethyl)imidazole, as described in Example 1, Step A, (1.97 g, 5.72 mmol) and 4-(dimethylamino) pyridine (280 mg, 2.29 mmol) were stirred in CH2Cl2 (15 mL) and tert-butyldimethylsilyl chloride (905 mg, 6.01 mmol) was added. After 1 min, triethylamine (0.88 mL, 6.31 mmol) was added dropwise over 3 min. The reaction mixture was stirred for 45 min, then CH2Cl2 (150 mL) was added and the solution was washed with 0.1 N HCl (50 mL). The organic layer was dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexane—30% EtOAc, to yield the titled product as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=1>O>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=3)=[CH:8][C:7]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#Cc1cc(Br)cs1
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3csc(C#N)c3)cc21

Procedure:
The product was prepared, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 4-bromo-2-thiophenecarbonitrile according to the procedure outlined in Example 5, as a yellowish solid: mp 230-231° C. (decomposed); 1H-NMR (CDCl3) δ 8.32 (s, 1H, D2O exchangeable), 7.83 (d, 1H, J=1.5 Hz), 7.61 (d, 1H, J=1.4 Hz), 7.43 (dd, 1H, J=8.2, 1.9 Hz), 7.29 (d, 1H, J=1.8 Hz), 6.85 (d, 1H, J=8.2 Hz), 1.78 (s, 6H); MS (EI) m/z 283 ([M−H]−, 100%); Anal. Calcd. For C15H12N2O2S.0.2 H2O: C, 62.57; H, 4.34; N, 9.73. Found: C, 62.48; H, 4.31; N, 9.64.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[N+:15]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N

Procedure:
The title compound was prepared from (4-chloro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A5) (22.12 g, 85 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a red solid (13.93 g).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl.[Cl:64][CH2:65][CH:66]1[NH:69][C:68](=[O:70])[CH:67]1[NH2:71].O>C(Cl)Cl.C(N(CC)CC)C>[Cl:64][CH2:65][CH:66]1[NH:69][C:68](=[O:70])[CH:67]1[NH:71][C:27](=[O:28])[C:26]([C:24]1[N:25]=[C:21]([NH:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[S:22][CH:23]=1)=[N:30][O:31][C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NC1C(=O)NC1CCl
Reactant: O=C(O)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC1C(=O)NC1CCl)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.67 h

Procedure:
A mixture of 1.527 g of the syn isomer of sodium 2-(2-tritylamino-4-thiazolyl)-2-trityloxyimino-acetic acid, 419 mg of tosyl chloride and 15 ml of methylene chloride was stirred for 40 minutes and then a solution of 342 mg of 4-chloromethyl-3-amino-2-oxo-azetidine hydrochloride in 15 ml of methylene chloride and 0.6 ml of triethylamine was added thereto. The mixture was stirred for 2 hours and water was added thereto with stirring. The decanted aqueous phase was extracted with methylene chloride and the combined organic phases were dried, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with ether to obtain 736 mg of syn isomer of 4-chloromethyl-3-[2-(2-tritylamino-4-thiazolyl)-2-trityloxyimino-acetamido]-2-oxo-azetidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]([CH2:5][C:6](Cl)([Cl:8])[Cl:7])[CH:3]1[C:10]([O:12][CH3:13])=[O:11].N1CCCC1>CN(C)C=O>[Cl:7][C:6]([Cl:8])=[CH:5][CH:4]1[CH:3]([C:10]([O:12][CH3:13])=[O:11])[C:2]1([CH3:1])[CH3:14]
Reactant: COC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: COC(=O)C1C(C=C(Cl)Cl)C1(C)C

Procedure:
A mixture of 2.6 g (0.01 mol) of methyl 2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropane-1-carboxylate (compound Z, C/T=80/20), 1.0 ml of pyrrolidine, and 20 ml of dimethylformamide was heated at 100° for 20 hours to give, by glpc analysis, 68.5% cis and 24.0% trans (C/T=74/26) methyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate, compound C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.O.C(=O)([O-])O.[Na+].[CH2:23](O)[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH2:23][CH3:24])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(C)c(F)c1
Temperature: 0 °C
Yield: 94.4 %

Procedure:
To a solution of 3-fluoro-4-methylbenzoic acid (7.707 g, 50.00 mmol) in ethanol (35 ml) was added concentrated sulfuric acid (1.5 ml), and the mixture was heated under reflux for 6 hrs. The reaction mixture was cooled to 0° C., iced water and saturated aqueous sodium hydrogen carbonate were added, and the mixture was extracted twice with diethyl ether. The combined organic layer was washed twice with saturated aqueous sodium hydrogen carbonate and once with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give ethyl 3-fluoro-4-methylbenzoate (8.599 g, yield 94.4%) as a colorless oil.