Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.[O:36]1[CH2:41][CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37]1.C([O-])([O-])=O.[Na+].[Na+].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.O>[O:36]1[CH2:37][CH:38]=[C:39]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)[CH2:40][CH2:41]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cn(-c2ccc(C3=CCOCC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (459 mg, 0.9 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (210 mg, 1.0 mmol), Pd(PPh3)4 (52 mg, 0.045 mmol), Na2CO3 (212 mg, 2.0 mmol), DME (4 mL), and H2O (1 mL) was refluxed overnight under Ar atmosphere. After cooling to room temperature, the precipitate was collected by filtration and recrystallized from THF/MeOH to give the title compound (364 mg, 91% yield) as a white solid: mp 229-231° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 2.40-2.50 (2H, m), 3.77 (3H, s), 3.82 (2H, t, J=5.5 Hz), 4.22-4.27 (2H, m), 6.43-6.48 (1H, m), 6.97 (1H, d, J=1.9 Hz), 7.02 (1H, t, J=8.7 Hz), 7.29-7.46 (6H, m), 7.52 (1H, dd, J=1.9, 12.8 Hz), 7.79 (1H, d, J=1.9 Hz), 8.48 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 445 [M+H]+. Anal. Calcd for C25H21FN4O3: C, 67.56; H, 4.76; N, 12.61. Found: C, 67.31; H, 4.58; N, 12.52.
Reaction SMILES: [O:1]1[C@H:12]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C@H:2]1[C:3]([O:5]C1C=CC=CC=1)=[O:4].[OH-].[Na+].O.O.P([O-])(O)(O)=O.[Na+]>CO>[O:1]1[C@H:12]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[C@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(Oc1ccccc1)[C@H]1O[C@@H]1C1CCCCC1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H]1O[C@@H]1C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
Into a 2,000 ml three-necked flask equipped with a dropping funnel and a stirrer, the phenyl (2S,3R)-2,3-epoxy-3-cyclohexylpropionate (54.0 g, 219 mmol) obtained in Example 2 and methanol (437 ml) were charged and cooled to 0° C. Then, a 4% sodium hydroxide aqueous solution (250 g, 250 mmol) was added thereto over a period of 1 hour, and the reaction was carried out for further 2 hours at the same temperature. After completion of the reaction, sodium dihydrogenphosphate dihydrate (3.42 g) was added, and then, the solvent was distilled off. Then, water (250 ml) was added, followed by extraction with dichloromethane (50 ml×4 times). Then, sodium dihydrogen phosphate dihydrate (116 g) was added, followed by extraction with ethyl acetate (50 ml×4 times). Then, a 10% hydrochloric acid aqueous solution (200 ml) was added, and the pH was adjusted to 3, followed by extraction with ethyl acetate (50 ml×3 times), drying and concentration, to obtain crude (2S,3R)-2,3-epoxy-3-cyclohexylpropionic acid (20.5 g). The obtained crude product was recrystallized from n-heptane/toluene=2/1 (vol/vol) to obtain the desired (2S,3R)-2,3-epoxy-3-cyclohexylpropionic acid (18.0 g, 106 mmol) (yield: 48%).
Reaction SMILES: [F:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:6]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:5]=[CH:4][CH:3]=1.I[CH2:29][CH2:30][OH:31].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:6]([N:16]([CH2:29][CH2:30][OH:31])[S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:5]=[CH:4][CH:3]=1
Reactant: OCCI
Reactant: COc1ccc(S(=O)(=O)Nc2cccc(F)c2/C=C/c2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(CCO)c2cccc(F)c2/C=C/c2ccncc2)cc1
Yield: 21.5 %

Procedure:
In tetrahydrofuran was dissolved 1.92 g of the compound obtained in Example 43, followed by addition of 1.72 g of 2-iodoethanol and 0.69 g of potassium carbonate. The mixture was refluxed overnight and after-treated to give crystals. This crystal crop was recrystallized from ethanol to provide 0.46 g of the title compound,(light yellow needles). m.p. 152-153° C.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]2[C:5]([NH:6][C:7](=[O:22])[C:8]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[CH3:23]I.[H-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:23])[C:7](=[O:22])[C:8]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1
Reactant: CI
Reactant: CCC1(CC)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC1(CC)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Temperature: 3 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 10-chloro-2-cyclopentyl-4,4-diethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 251; 2.5 g, 7.76 mmol) in DMA (50 mL) under nitrogen was added methyl iodide (0.627 mL, 10.0 mmol). The mixture was cooled on an ice/water bath to 3° C., and sodium hydride (60% mineral oil dispersion; 0.567 g, 11.8 mmol) added in one portion. The reaction mixture was stirred on the ice/water bath for 1 hour before warming to room temperature and the reaction stirred for 4 hours. The reaction mixture was evaporated to dryness to afford a black solid, which was quenched with saturated aqueous NH4Cl solution (50 mL), extracted with DCM (3×100 mL), dried and solvent removed in vacuo to yield a black solid which was purified on a silica column eluting with DCM. The obtained solid was added to a diethyl ether and sonicated and the resultant material filtered and dried to yield the title compound as an off white solid (2.1 g, 80%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 52 h
Yield: 89.5 %

Procedure:
Following procedure A, 4-fluoronitrobenzene (500 mg, 3.54 mmol, 1.00 eq) and 4-tert-butylphenol (671 mg, 4.46 mmol, 1.26 eq) were dissolved in DMF (6.0 mL). Anhydrous K2CO3 (857 mg, 6.20 mmol, 1.75 eq) was added and the reaction mixture was stirred at room temperature for 52 h. After extraction with EtOAc, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100) to afford the title compound as pale yellow solid (860 mg, 3.17 mmol, 89% yield). Rf=0.72 (EtOAc/PE 1:9). HRMS (ESI) calcd. for C16H18NO3+ [M+H]+ 272.1281. found: 272.1272. 1H NMR (400 MHz, CDCl3) δ 8.24-8.16 (m, 2H, aromatic H), 7.49-7.39 (m, 2H, aromatic H), 7.06-6.97 (m, 4H, aromatic H), 1.35 (s, 9H, C(CH3)3). 13C NMR (101 MHz, CDCl3) δ 163.82, 152.29, 148.59, 142.54, 127.27, 126.03, 120.15, 116.98, 34.67, 31.58.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1C=O>>[C:1]1([S:7](/[CH:10]=[CH:11]/[C:20]2[CH:19]=[CH:16][C:15]([Cl:14])=[CH:22][C:21]=2[Cl:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1Cl)c1ccccc1
Yield: 60 %

Procedure:
A solution of phenyl sulfonylacetic acid (0.01 mol) and 2,4-dichlorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 60-65% yield.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:28])[CH:12]([NH:13][C:14](=[O:27])[C:15](=[N:24][O:25][CH3:26])[C:16]3[NH:17][C:18](=[N:21]C=O)[S:19][CH:20]=3)[C@H:4]2[S:3]1.[ClH:29].C(OCC)C>CO>[ClH:29].[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:28])[CH:12]([NH:13][C:14](=[O:27])[C:15](=[N:24][O:25][CH3:26])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(=NC=O)[nH]1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-methyl-b 7-[2-methoxyimino-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (9.0 g.) in methanol (90 ml.) was added concentrated hydrochloric acid (2.12 ml.) with stirring at room temperature, and the mixture was stirred for 7 hours at the same temperature. To the reaction mixture was gradually added diethyl ether till crystals started to precipitate. The mixture was allowed to stand for 30 minutes, and the precipitated crystals were collected by filtration, washed with diethyl ether and then dried to give white crystals of 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer), (7.9 g.) The remaining filtrate was concentrated till the total volume became half. To the concentrated filtrate was gradully added diethyl ether till crystals started to precipitate, and the mixture was allowed to stand for 1 hour. The precipitated crystals were collected by filtration, washed with diethyl ether and then dried to give further the same object compound (0.5 g.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]1[O:27][CH2:26]1>CCOC(C)=O>[N+:9]([C:5]1[CH:4]=[N:3][C:2]2[NH:1][CH:25]([CH2:26][OH:27])[CH2:24][O:8][C:7]=2[CH:6]=1)([O-:11])=[O:10]
Reactant: Nc1ncc([N+](=O)[O-])cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2c(c1)OCC(CO)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
Into a 75 mL sealed tube were combined 2-amino-3-hydroxy-5-nitropyridine (0.138 g, 0.000890 mol), N,N-dimethylformamide (4.1 mL) and potassium carbonate (0.39 g, 0.0028 mol). The mixture was allowed to stir at room temperature for 10 minutes then 1-bromo-2,3-epoxypropane (0.12 g, 0.00089 mol) was added in one portion. The flask was sealed, then heated to 110° C. and stirred overnight. After allowing to cool, the mixture was concentrated under vacuum to give a crude solid which was dissolved in EtOAc (75 mL), washed with water and brine, then dried (Na2SO4), filtered and concentrated under vacuum to leave a crude residue. The residue was purified by column chromatography on silica gel using MeOH/CH2Cl2 (0-10% gradient) as eluent to give a solid (0.092 g, 46%). LC-MS 1.92 min. M/Z=212.0 (M+1). 1H NMR (d6-DMSO) δ 8.8 (d, 1 H), 7.8 (d, 1 H), 5.1 (t, 1H),4.2 (m, 1 H), 4.0 (m, 1H), 3.62 (m, 1H), 3.45 (m, 1H), 3.21 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[NH:18][N:17]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[C:29]([Cl:31])[N:28]=[CH:27]4)=[C:22]([O:32][CH3:33])[CH:21]=3)[N:15]=2)[CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[CH:4][CH:3]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][N:18]3[N:17]=[C:16]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH:30]=[C:29]([Cl:31])[N:28]=[CH:27]5)=[C:22]([O:32][CH3:33])[CH:21]=4)[N:15]=[C:14]23)=[CH:4][CH:3]=1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(Br)cc3)n2)ccc1-n1cnc(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2ccc(Br)cc2)ccc1-n1cnc(Cl)c1
Yield: 20.4 %

Procedure:
A solution of 5-(1-(4-bromophenyl)-5-chloropentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (2.5 g, 4.54 mmol), sodium iodide (3.40 g, 22.7 mmol), and diisopropylethylamine (0.793 mL, 4.54 mmol) in acetone (10 mL) was heated in a sealed vessel at 100° C. for 12 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (50% EtOAc/chloroform) to afford 475 mg (19% yield) of the titled compound as an off-white solid. LC-MS (M+H)+ 515.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.45-7.47 (m, 3 H), 7.40 (d, J=2.1 Hz, 1 H), 7.04-7.10 (m, 3 H), 7.00 (d, J=1.5 Hz, 1 H), 6.79 (dd, J=8.5, 2.4 Hz, 1 H), 6.64 (s, 1 H), 4.15-4.27 (m, 3 H), 3.76 (s, 3 H), 2.14-2.21 (m, 1 H), 1.91-2.10 (m, 3 H), 1.80-1.91 (m, 2 H).
Reaction SMILES: Br.[CH2:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10]Br)[CH2:3][CH2:4][CH3:5].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO.O>[CH2:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Nc1ccccc1
Reactant: CCCCNc1cc(CBr)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: Br
Solvent: CO
Solvent: O
Product: CCCCNc1cc(CNc2ccccc2)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzyl bromide hydrobromide (2.5 g; prepared as described in Example 67) and aniline (10 ml) in methanol (20 ml) is refluxed for 16 hours. After cooling the mixture is diluted with water (about 80 ml); the resulting semi-solid precipitate is washed twice with water, which is decanted, and is then crystallized from aqueous ethanol. After filtration and recrystallization from ethanol, (3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)aniline is obtained with a melting point of 142°-143° C.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CS(C)=O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:11]=[CH:10][C:5]3[C:6](=[O:9])[CH2:7][O:8][C:4]=3[CH:3]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: O=C1COc2cc(F)ccc21
Solvent: CS(C)=O
Product: CN1CCN(c2ccc3c(c2)OCC3=O)CC1
Temperature: 25 °C

Procedure:
A mixture of Example 1109B (0.152 g) and 1-methylpiperazine (0.22 g) in DMSO (1 ml) was heated at 150 C for 30 min, allowed to cool to r.t. (room temperature) then partitioned between water and EtOAc. Organics were dried (Na2SO4), concentrated and purified via silica gel chromatography eluting with 5% MeOH-CH2Cl2 to give the title compound. MS ESI(+)m/e 233.0(M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>C(OC(C)C)(C)C>[CH2:16]([NH:18][C:19]([N:10]1[CH2:9][CH:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:13][CH:12]=2)[CH2:11]1)=[O:20])[CH3:17]
Reactant: CCN=C=O
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Solvent: CC(C)OC(C)C
Product: CCNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A solution of 6.5 g (0.03 mole) of crude 3-[4-(trifluoromethyl)phenoxy]azetidine in 50 ml of isopropyl ether was stirred under a blanket of nitrogen while 2.85 g (0.04 mole) of ethyl isocyanate was added dropwise. After stirring for 2 hr at ambient temperature, a solid began to precipitate, and after 4 hr, the solid was collected by filtration to yield 3.7 g of beige product, m.p. 94°-96° C. Rework of the filtrate gave only a trace of additional product. The product was recrystallized from isopropyl ether/hexane (treated with charcoal) to yield 2.61 g (30%) of product, m.p. 109°-110° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[C:20]([CH3:23])[C:19]([F:24])=[C:18]([NH2:25])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:26])(=[O:3])[CH3:2].[H-].[Na+].I[CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[C:20]([CH3:23])[C:19]([F:24])=[C:18]([NH2:25])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:26])[CH2:30][CH2:31][CH3:32])(=[O:3])[CH3:2]
Reactant: CCCI
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)c(C)c(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)c(C)c(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.6 %

Procedure:
506 mg (1.40 mmol) of the above 2-(4-acetylamino-3-fluorophenyl)-5-amino-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one was dissolved in 30 mL of dimethylformamide under argon atmosphere, 60 mg (1.5 mmol) of sodium hydride (60% oil dispersion) and 0.28 mL (2.8 mmol) of 1-iodopropane were added thereto under ice-cooling and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to give 315 mg of 2-[4-[N-acetyl-N-(1-propyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one (yield: 56%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:3]=1.[CH3:16][C:17]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][S:9][C:4]1[N:5]=[C:6]([Cl:8])[CH:7]=[C:2]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:17]=2[CH3:16])[N:3]=1)[CH3:15]
Reactant: Cc1cccc(N)c1C
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(Nc2cccc(C)c2C)n1

Procedure:
A stirred mixture of 2.7 g of (4.6-dichloro-2-pyrimidinylthio)acetic acid, ethyl ester, 1.2 g of 2,3-dimethylaniline and 1.06 g of anhydrous sodium carbonate in 20 ml. of ethanol was heated under reflux for 4 hr. The mixture was filtered and water added to the filtrate until a precipitate appeared. The solid was recrystallized from 95% ethanol to a mp. of 88°-93°C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CS(O[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)(=O)=O>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CCOS(C)(=O)=O)cc1
Reactant: COc1ccc2c(c1)C(C(=O)Nc1ccc(C(C)C)cc1)CCC2
Product: COc1ccc(CCN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cc1
Yield: 21.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.49 g) and 1-methanesulfonyloxy-2-(4-methoxyphenyl)ethane (0.38 g) as starting materials, N-(4-isopropylphenyl)-N-[2-(4-methoxyphenyl)ethyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.15 g) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>COCCOC>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1cc2cccc(Cl)c2nc1-c1ccccc1
Temperature: 110 °C
Yield: 97.1 %

Procedure:
A mixture of 2,8-dichloroquinoline-3-carbaldehyde (2.0 g, 8.85 mmol), 2M aqueous Na2CO3 solution (8 mL), phenylboronic acid (1.5 g, 12.3 mmol) and tetrakis-(triphenylphosphine)palladium(0) (0.25 g, 0.216 mmol) in DME (30 mL) was degassed and the mixture heated at 110° C. for 4 h. The mixture was allowed to cool to room temperature, diluted with EtOAc and washed with brine. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. The resultant solid was triturated in ether, filtered, washed with small amount of ether, then light petroleum, and dried, to give the title compound (2.3 g, 97%) as an off-white solid. δH (CDCl3) 10.25 (s, 1H), 8.86 (s, 1H), 7.95-8.02 (m, 2H), 7.78-7.14 (m, 2H), 7.54-7.62 (m, 4H). LCMS (ES+) 268 (M+H)+, RT 1.98 minutes.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][O:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=O>>[CH3:30][O:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:36]
Reactant: COc1ccccc1C(=O)O
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: COc1ccccc1C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 2-methoxybenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(2-methoxybenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 498 (M-H)-.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18][OH:19])[CH2:15][O:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[F:8][C:6]1[C:5]([F:9])=[C:4]([O:19][CH2:18][CH:16]2[CH2:15][O:14][C:13]([CH3:20])([CH3:12])[O:17]2)[C:3]([F:11])=[C:2]([F:1])[N:7]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC1(C)OCC(COc2c(F)c(F)nc(F)c2F)O1
Temperature: 60 °C
Yield: 94.8 %

Procedure:
To pentafluoropyridine (2.0 g, 12 mmol) dissolved in DMSO was added 2,2-dimethyl-1,3-dioxolane-4-methanol (solketal) (1.5 mL, 12 mmol) and Cs2CO3 (3.8 g, 12 mmol). The slurry was heated in an oil bath at 60° C. for 1 day. The reaction was partitioned with water and ethyl acetate, washed with water and brine, dried (Na2SO4) and the solvent was removed to give 2,3,5,6-tetrafluoro-4-[[(2,2-dimethyl)dioxolan-4-yl]methoxy]pyridine (3.2 g).