Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6](Cl)=[O:7].[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:7]
Reactant: CS(N)(=O)=O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(C)(=O)=O)cc1F

Procedure:
A solution of 25.2 g. of 3-fluoro-4-(hexadecylamino)-benzoyl chloride hydrochloride and 5.6 g. of methanesulfonamide in 250 ml of pyridine is stirred under reflux for 2 hours and then concentrated in vacuo. The residue is partitioned between water and diethyl ether; the aqueous layer acidified with 1 N HCl, and the organic layer separated, dried (MgSO4), and evaporated. Crystallization of the residual white solid from 60% aqueous acetic acid and then from methylene chloride-hexane affords N-[3-fluoro-4-(hexadecylamino)benzoyl]methanesulfonamide as a white solid.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C(Cl)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19]N1C=CC=CC1=S.C(S)(C)(C)C.O=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:2]1([CH2:1][CH:8]([OH:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1ccccc1=S
Reactant: O=C(Cl)C(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=O
Agent: [K+]
Solvent: CC(C)(C)S
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: OC(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
258 mg (1 mmol) of (dibenzyl)acetyl chloride in 1 ml of toluene are added at room temperature to 140 mg (1.1 mmol) of N-hydroxypyridine-2-thione and 0.1 ml of pyridine in 5 ml of toluene. The mixture is maintained with stirring for 30 minutes. The filtered solution is added dropwise during 20 minutes to 1 ml of t-butylmercaptan in 20 ml of toluene at 80° C., and a vigorous stream of oxygen is passed into this solution. The reaction is continued for 1 hour at 80° C., and the reaction mixture is then stirred for 2 hours at room temperature before being poured into 10 ml of a saturated solution of potassium carbonate. The organic phase is again washed twice with potassium carbonate (2×10 ml), then with 10 ml of water, twice with 10 ml of HCl (2N) and finally with twice 10 ml of water before being dried over sodium sulfate, filtered and evaporated to dryness. The crude product obtained is filtered on silica (100% CH2Cl2) to give 174 mg of the corresponding hydroxylated derivative. Yield 82%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH:23]([CH2:25][CH3:26])[CH3:24])[CH:16]=2)=[C:9]([Cl:27])[CH:8]=1)[CH3:2].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH:23]([CH2:25][CH3:26])[CH3:24])[CH:16]=2)=[C:9]([Cl:27])[CH:8]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)CNc1cc(Cl)c(Oc2ccc(OC)c(C(C)CC)c2)c(Cl)c1
Product: CCOC(=O)CN(C(=O)OCC)c1cc(Cl)c(Oc2ccc(OC)c(C(C)CC)c2)c(Cl)c1
Yield: 76 %

Procedure:
[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamino]-acetic acid ethyl ester (0.9 g, 2.1 mmol) was stirred with ethyl chloroformate (8 mL) at reflux temperature for 16 hrs. From the reaction mixture ethyl chloroformate was evaporated under reduced pressure and the residue was taken up in ethyl acetate, washed with H2O, brine and dried over sodium sulphate, filtered and concentrated to give {[4-(3-sec-butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}-acetic acid ethyl ester. (0.8 g, 76% yield)
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH3:13])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(O)(C)C.C(O)=O.[NH3:21]>C1(C)C=CC=CC=1>[NH2:21][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CC(=O)c1cccnc1
Reactant: N
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O=CO
Product: COC(=O)C=C(N)c1cccnc1
Temperature: 65 °C

Procedure:
Methyl nicotinoylacetate (88 g, 0.5 mol) was dissolved in toluene (200 g), isopropyl alcohol (200 g), and formic acid (98-100%, 1.22 g, 0.03 mol) and heated to 60-65° C. Gaseous ammonia (23 g, 1.35 mol) was bubbled through the solution for 15 minutes. The white suspension was stirred at 65° C. until a homogeneous solution formed. The solution was stirred for two hours at 65° C. and then concentrated (ca. 200 g) at 65° C. The residue was cooled to −5° C. with stirring and methyl 3-amino-3-(3-pyridyl)-2-propenoate crystallized as colorless needles. The process of reducing the volume to 50% followed by cooling was repeated three times with the mother liquors. Filtration, washing with toluene, and drying at 30° C. resulted in 77.74 g (88.8%) of methyl 3-amino-3-(3-pyridyl)-2-propenoate as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:23][C:24]3[C:25]([F:35])=[C:26]([CH:32]=[CH:33][CH:34]=3)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:7]([CH:20]3[CH2:22][CH2:21]3)[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][OH:19])[CH:16]=2)=[CH:4][CH:3]=1.[NH3:36].C1[CH2:41][O:40]CC1>>[C:41]([O:19][CH2:18][CH2:17][N:15]1[CH:16]=[C:12]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=3[F:11])[C:6]([S:23][C:24]3[C:25]([F:35])=[C:26]([CH:32]=[CH:33][CH:34]=3)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:7]2[CH:20]2[CH2:22][CH2:21]2)[CH:13]=[N:14]1)(=[O:40])[NH2:36]
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCO)c3)c3c(F)c(Cl)ccc23)c1F
Reactant: N
Reactant: C1CCOC1
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCOC(N)=O)c3)c3c(F)c(Cl)ccc23)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a stirred solution of compound 2 (20 mg, 0.031 mmol) in THF (3 mL) under inert atmosphere was passed ammonia gas at 0° C. for 15 min; warmed to RT and stirred for 30 min. The volatiles were removed under reduced pressure and the crude was purified by triturating with n-pentane (2×5 mL) and dried under reduced pressure to afford 3 (6 mg, 35%) as a pale brown oil. 1H NMR (500 MHz, CDCl3): δ 7.73 (s, 1H), 7.70 (s, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.11-7.08 (m, 1H), 6.95 (t, J=8.0 Hz, 1H), 6.79 (t, J=8.0 Hz, 1H), 4.65 (br s, 2H), 4.54-4.47 (m, 4H), 4.42 (q, 2H), 1.74-1.70 (m, 1H), 1.43 (t, J=7.5 Hz, 3H), 1.07-1.05 (m, 2H), 0.91-0.88 (m, 2H); LC-MS: m/z 561.7 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH:19]3[N:23]([CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:22](=[O:30])[C@H:21]([CH2:31][C:32](O)=[O:33])[S:20]3)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[NH:58]1[CH2:63][CH2:62][CH:61]([N:64]2[CH2:70][CH2:69][C:68]3[CH:71]=[CH:72][CH:73]=[CH:74][C:67]=3[NH:66][C:65]2=[O:75])[CH2:60][CH2:59]1>C(Cl)Cl>[CH3:29][C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][N:23]1[C:22](=[O:30])[C@H:21]([CH2:31][C:32](=[O:33])[N:58]2[CH2:59][CH2:60][CH:61]([N:64]3[CH2:70][CH2:69][C:68]4[CH:71]=[CH:72][CH:73]=[CH:74][C:67]=4[NH:66][C:65]3=[O:75])[CH2:62][CH2:63]2)[S:20][CH:19]1[C:16]1[S:15][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[N:18][CH:17]=1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: CC(C)(C)CCN1C(=O)[C@H](CC(=O)O)SC1c1cnc(C2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)SC1c1cnc(C2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a solution of 2-((5S)-2-(2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)thiazol-5-yl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid (360 mg, 0.7 mmol, 1 eq) in DCM (8 mL) was added HOBt (162 mg, 1.06 mmol, 1.5 eq), EDC (202 mg, 1.06 mmol, 1.5 eq), DIEA (364 mg, 2.8 mmol, 4 eq) and 3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one (207 mg, 0.84 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with DCM (10 mL) and washed with water (5 mL), brine (5 mL), dried (MgSO4) then concentrated in vacuo. The residue was purified by column chromatography over silica gel eluted with 0 to 10% MeOH in DCM to afford 390 mg of compound I-492 in 75% yield. (M+1) 739. 1H NMR (CDCl3) δ 7.19-6.91 (m, 5H), 6.75 (d, J=7.8 Hz, 1H), 5.68 (m, 1H), 4.75 (m, 1H), 4.47 (m, 1H), 4.18 (m, 1H), 3.93 (m, 1H), 3.46-2.67 (m, 11H), 2.08 (m, 6H), 1.71 (m, 6H), 1.47 (m, 9H), 0.85 (m, 9H) ppm.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:29](=[O:44])[N:30]([CH2:40][C:41]([NH2:43])=[O:42])[C:31]3[N:32]([N:37]=[CH:38][N:39]=3)[C:33]=2[CH2:34][CH2:35][CH3:36])=[CH:23][CH:22]=1)#[N:14]>C(OCC)(=O)C>[O:44]=[C:29]1[C:28]([CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:13]3[NH:3][C:4](=[O:7])[O:5][N:14]=3)=[CH:26][CH:25]=2)=[C:33]([CH2:34][CH2:35][CH3:36])[N:32]2[N:37]=[CH:38][N:39]=[C:31]2[N:30]1[CH2:40][C:41]([NH2:43])=[O:42]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(N)=O)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(N)=O)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (2.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 2-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}acetamide (0.48 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 42%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16](SC)[N:17]=[N:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[F:22])=[CH:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>C1COCC1.C(Cl)Cl.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:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)[N:17]=[N:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[F:22])=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CSc1nncc(-c2ccc(F)c(-c3ccc(F)cc3C#N)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnnc(-c3ccc(F)cc3)n2)ccc1F
Temperature: 50 °C

Procedure:
To a mixture of 4,2′-difluoro-5′-(3-methylsulfanyl-[1,2,4]triazin-5-yl)biphenyl-2-carbonitrile (0.11 g, 0.32 mmol), cuprous 3-methylsalicylate (0.153 g, 0.711 mmol) and 4-fluorobenzeneboronic acid (0.1 g, 0.711 mmol) in dry THF (8 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.037 g, 0.032 mmol) and the mixture heated at 50° C. for 5 h. The reaction was allowed to cool to ambient temperature, diluted with DCM (20 ml) and filtered through a glass fibre filter. The dark brown solution was evaporated to give a brown solid. The crude product was chromatographed on silica (eluted with 3% MeOH in DCM) to give the product as a yellow solid. Recrystallisation from DCM/MeOH gave the title compound as a pale yellow solid (52 mg): δH (400 MHz, CDCl3) 7.24 (2H, m), 7.44-7.49 (2H, m), 7.55-7.62 (2H, m), 8.36-8.39 (2H, m), 8.64-8.69 (2H, m), 9.62 (1H, s); m/z (ES+) 389 (M++H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.CCOC(C)=O>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: Oc1cccc(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(Cl)c3)c2cc1OC
Temperature: 25 °C

Procedure:
THF (5 ml) and NaH (60% disp in oil, approx. 28 mg) is added to a dry flask maintained under inert atmosphere at room temperature. 3-Chlorophenol (0.09 g) is added as a soln. in THF (1 mL) and stirring is continued until the solution became clear. 4-Chloro-6,7-dimethoxyquinazoline is added all at once (as the solid) and stirring was maintained overnight at RT. The solution is partitioned between CH2Cl2 and 5% NaOH. The organic layer is washed with brine, dried (Na2SO4) and concentrated. Flash column chromatography (40% EtOAc/Hex) provided the pure compound. An analytical sample is obtained by recrystallization from EtOAc/Hex to provide 4-(3-chlorophenoxy)-6,7-dimethoxyquinazoline (0.05 g), white needles, m.p. 152-153° C.
Reaction SMILES: [CH2:1]([CH:6]1[CH:10]([C:11]#N)[CH2:9][CH2:8][C:7]1=[O:13])[CH2:2][CH:3]([CH3:5])[CH3:4].[OH2:14].[CH2:15]([OH:17])[CH3:16]>>[CH2:1]([CH:6]1[C:7](=[O:13])[CH2:8][CH2:9][CH:10]1[C:11]([O:17][CH2:15][CH3:16])=[O:14])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CCO
Reactant: O
Reactant: CC(C)CCC1C(=O)CCC1C#N
Product: CCOC(=O)C1CCC(=O)C1CCC(C)C
Yield: 58 %

Procedure:
By repeating the procedure described in Example 16 but starting from 10 g 2-iso-pentyl-3-cyanocyclopentanone and 1 ml of water in 100 ml of absolute ethanol, there is obtained 7.3 g (58%) of ethyl 2-isopentyl-3-oxocyclopentanecarboxylate boiling at 84°C/0.25 mm, nD20 1.4530.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH:19][NH2:20]>CN1C(=O)CCC1>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:2]2=[N:9][CH:8]=[CH:7][C:6]([I:10])=[C:3]2[CH:4]=[N:20]1
Reactant: O=Cc1c(I)ccnc1F
Reactant: NNc1ccc(F)cc1F
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncc3c(I)ccnc32)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.7 %

Procedure:
To a dry 16×100 mm Chem-Glass reaction tube under N2 was added 2-fluoro-4-iodonicotinaldehyde (5 g, 19.92 mmol), (2,4-difluorophenyl)hydrazine (3.01 g, 20.92 mmol) and anhydrous NMP (35 mL). The reaction mixture was flushed with argon, securely capped, stirred for 20 min at room temp, and then placed in a 180° C. oil bath for 4 h. The reaction mixture was then allowed to stir at room temperature for 72 h. The reaction mixture was diluted with EtOAc (1200 mL) and the organic layer was extracted with water (6×350 mL), brine (1×100 mL), dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by Biotage Silica gel chromatography on a 300 g Thompson Single Step™ silica cartridge using a linear gradient from 100% hexanes to 100% dichloromethane over 10 column volumes to give 4.53 g (44.6%) of Intermediate 13A, as a light yellow solid that contained 28% of the uncyclized hydrazone intermediate ((E)-3-(2-(2,4-difluorophenyl)hydrazono)methyl)-2-fluoro-4-iodopyridine). 1H NMR (500 MHz, CCl3D) δ ppm 8.21 (1 H, d, J=4.58 Hz), 8.14 (1 H, s), 7.59-7.71 (2 H, m), 7.10 (2 H, td, J=7.55, 3.81 Hz). LC/MS (Condition A): T=3.7 min, (M+H)+ 357.90.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:19]([O-])([OH:21])=[O:20]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CCCCC(=O)Nc1ccc(Cl)cc1C(=O)OC
Solvent: CC(=O)OC(C)=O
Product: CCCCC(=O)Nc1c(C(=O)OC)cc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a solution of methyl 5-chloro-2-valerylaminobenzoate (13.4 g) in acetic anhydride (10 ml) was added dropwise, while stirring under ice-cooling, fuming nitric acid. The mixture was stirred for one hour at room temperature, then there was added ice water. The mixture was allowed to stand to give crystals. Recrystallization from isopropyl ether afforded pale yellow crystals (9.5 g, 61%), m.p. 84-85° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].C(O[C:11](=[O:13])[CH3:12])(=O)C.N1C=CC=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[C:15]([CH3:16])=[CH:12][C:11](=[O:13])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)NC
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Product: Cc1cc(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of N,N′-dimethylurea (commercial) (72.1 g, 819 mmol) and DMAP (100 g, 819 mmol) in pyridine (300 mL) under N2 was added dropwise with stirring acetic anhydride (255 mL, 2701 mmol). On complete addition the reaction mixture was allowed to stir at RT for 3 hours. After this time, the volatiles were removed under reduced pressure to afford a viscous orange pyridine solution, which was seeded with product. The mixture was stored at 0-4° C. for 7 days. The resulting crystalline solid was then filtered under reduced pressure, washed with diethyl ether and dried to afford the title compound as colourless crystals. The mother liquors were further purified by chromatography on silica eluting with 30-50% EtOAc in iso-hexane. The resulting solid was diluted with diethyl ether (500 mL) and was stored at 0-4° C. overnight. The resulting crystals were filtered off and washed with iso-hexane, then dried to afford the title compound as colourless crystals and combined. The title product was obtained as white crystals.
Reaction SMILES: N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)[Cl:8].C1(CC([NH:22][CH:23]2[C:47](=[O:48])[N:25]3[C:26]([C:31]([O:33][CH:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[S:32])=[C:27]([CH3:30])[CH2:28][S:29][C@H:24]23)=O)C=CC=CC=1.CO>C(Cl)Cl>[ClH:8].[NH2:22][CH:23]1[C:47](=[O:48])[N:25]2[C:26]([C:31]([O:33][CH:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[S:32])=[C:27]([CH3:30])[CH2:28][S:29][C@H:24]12
Reactant: CC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: CC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Product: Cl
Yield: 64 %

Procedure:
To a suspension of pyridine phosphorus pentachloride complex prepared from pyridine (20 g) and phosphorus pentachloride (52.5 g) in methylene chloride (860 ml) was added benzhydryl 7-phenylacetamido-3-methylthio-3-cephem-4-carboxylate (67.0 g) under ice-cooling with stirring. The mixture was stirred at the same temperature for 30 minutes, and poured into methanol (650 ml) at -30° C. The mixed solution was stirred at -5° to -15° C. for 10 minutes and then evaporated under reduced pressure. To the residue were added ethyl acetate (500 ml) and cooled water (500 ml). The mixture was stirred for several minutes. The crystalline materials were collected by filtration and washed with diethyl ether to give benzhydryl 7-amino-3-methylthio-3-cephem-4-carboxylate hydrochloride (36.1 g), mp. 170° to 171° C. (dec.).
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH2:21][F:22])([CH2:19][F:20])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:6]=12.[OH:23][C:24]1[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH3:31])[N:25]=1.N1C=CC=CC=1>C(O)C>[F:18][C:12]([F:17])([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:21][F:22])([CH2:19][F:20])[C@@H:2]([OH:1])[C@H:7]([O:23][C:24]3[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH3:31])[N:25]=3)[C:6]=2[CH:8]=1)[C:13]([F:15])([F:16])[F:14]
Reactant: FCC1(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc2C2OC21
Reactant: Cn1nc(O)ccc1=O
Solvent: CCO
Solvent: c1ccncc1
Product: Cn1nc(O[C@@H]2c3cc(C(F)(F)C(F)(F)F)ccc3OC(CF)(CF)[C@H]2O)ccc1=O
Yield: 75.4 %

Procedure:
A mixture of 0.58 g of 3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran, 0.22 g of 3-hydroxy-1-methyl-1,6-dihydropyridazin-6-one, 0.16 g of pyridine and 5 ml of ethanol was refluxed for 5 hours. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.60 g of trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-4-[(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)oxy]-2H-1-benzopyran-3-ol represented by the following formula having a melting point of 189°-191° C. in Example 20.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:16])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:7]1=[O:25])[CH3:2].C([NH:30][C:31]([NH:33][CH2:34][C:35]#[CH:36])=[O:32])C.[CH3:37][CH2:38]N(CC)CC.C1(C)C=CC=CC=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:16])[CH:11]=[C:12]([C:36]#[C:35][CH2:34][N:33]([CH2:37][CH3:38])[C:31]([NH2:30])=[O:32])[CH:13]=2)[C:8]([OH:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:7]1=[O:25])[CH3:2]
Reactant: C#CCNC(=O)NCC
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(I)cc21
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(C#CCN(CC)C(N)=O)cc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To 1-(2-diethylaminoethyl)-3-hydroxy-3-(2-chlorophenyl)-4-bromo-6-iodooxindole (21.0 mg, 3.89×10−5 mol), N-ethyl-N′-propargylurea (7.36 mg, 1.5 eq.), Pd(PPh3)2Cl2 (4.10 mg, 15 mol %) and CuI (1.10 mg, 15 mol %) under a nitrogen atmosphere was added anhydrous Et3N (0.5 mL), anhydrous toluene (0.5 mL) and anhydrous THF (0.5 mL). The resulting yellow mixture was heated to 50° C. (bath temperature) and stirred at that temperature for 2 hours. The solvent was then removed in vacuo to give a yellow solid. Purification was carried out by column chromatography (silica gel, 10% MeOH in CHCl3) to yield the title compound (18.8 mg, 86%) as a light brown solid.