Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].C(OC=C)(=O)C.[C:19]([O:34][CH2:35][CH2:36][CH2:37]C)(=[O:33])[C:20]1[C:21](=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:22]([O:24][CH2:25][CH2:26][CH2:27]C)=[O:23]>O>[C:22]([O:24][CH2:25][CH:26]=[CH2:27])(=[O:23])[C:21]1[C:20](=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:19]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33]
Reactant: CCCCOC(=O)c1ccccc1C(=O)OCCCC
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: C=COC(C)=O
Solvent: O
Product: C=CCOC(=O)c1ccccc1C(=O)OCC=C
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
0.2 g of defoamer and 12 g of Fixapret COC were added to and mixed with a solution of 47 g of polyvinyl alcohol in 600 g of water. The mixture was heated to about 80° C. About 90% of a catalyst solution of 1.3 g of ammonium persulfate in 6 g of water were then added and the mixture was homogenized for about 5 minutes. A mixture of 460 g of vinyl acetate and 10 g of dibutyl phthalate was then added over a period of about 3.5 to 4 hours so that the temperature stayed between 82 and 88° C. After the monomer mixture had been added, the remaining catalyst solution was added and the reaction mixture was stirred for about 1 hour at a temperature of about 90° C. The solids content was then adjusted to about 55%. After the dispersion had cooled to a temperature of about 35 to about 40° C., 15 g of dibutyl phthalate were added. The product thus obtained had a pH of 4.2 and a viscosity (5/2120) of 44,000 cps.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[CH2:27])[C:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])([OH:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH2:35][NH:36][C:37]([NH2:39])=[S:38].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CN(C)C=O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:11]([OH:18])([C:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:35][NH:36][C:37]([NH2:39])=[S:38])=[O:2])=[CH:9][CH:8]=1)=[CH2:27])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: NNC(N)=S
Reactant: C=C(c1ccc(C(=O)OC)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C(c1ccc(C(=O)NNC(N)=S)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A sample of the product from part (i) (370 mg, 1 mmol) was suspended in dichloromethane (15 ml), and was treated with dimethylformamide (1 drop) and oxalyl chloride (0.1 ml, 1.1 mmol). The solution was stirred at room temperature for1 hour and was evaporated under reduced pressure. The residue. was dissolved in dichloromethane (15 ml) and treated with thiosemicarbazide (0.1 g, 1 mmol) and sodium carbonate (0.1 g, 1 mmol). The mixture was stirred at room temperature for 24 hours then filtered. The filtrate was absorbed onto silica and chromatographed by gradient elution with ethyl acetate/methanol (97:3, 95:5, 94:6). Fractions containing the desired product were combined and evaporated under reduced pressure. The crude product was triturated with ether to give 4-{2-[2,4-difluorophenyl]-2-hydroxy-1-[1,2,4-triazol-1-yl]-3-buten-3-yl}benzoylthiosemicarbazide (0.21 g, 47%) as a colourless solid which was characterised by 1H-N.M.R. spectroscopy (300 MHz, DMSO). δ=4.83 (Abq, 2H), 5.32 (s,1H), 5.58 (s,1H), 6.57 (s,1H), 6.77 (m,1H), 6.98 (m,1H), 7.11 (m, 1H), 7.30 (d,2H), 7.58 (brs, 1H), 7.60 (s,1H), 7.62 (d,2H), 7.78 (brs, 1H), 8.19 (s, 1H), 9.22 (brs, 1H), 10.22 (brs,1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=O.[ClH:16].[NH2:17][OH:18]>N1C=CC=CC=1>[ClH:16].[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[N:17][OH:18]
Reactant: NO
Reactant: Nc1ccncc1C(=O)C1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ccncc1C(=NO)C1CCCCC1
Yield: 78.3 %

Procedure:
A solution of (4-amino-3-pyridinyl)cyclohexylmethanone (5 g) and hydroxylamine hydrochloride (10 g) in 70 ml pyridine was stirred at 80° C. for three hours and thereafter concentrated. The residue was stirred with water, basified with sodium carbonate and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride solution. The dried (anhy. MgSO4) organic layer was concentrated to 9 g waxy solid. This solid was triturated with acetonitrile to yield 4.9 g solid, m.p. 155°-158° C. Three grams were converted to the hydrochloride salt in methanol/ether to yield 2.8 g solid, m.p. 226°-228° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[F:14][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:18]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2ccc(F)c(-c3cccnc3)c2)OC1(C)C
Reactant: CC(C)(F)c1ccn2c(Br)cnc2n1
Product: CC(C)(F)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2n1

Procedure:
3-Bromo-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine was coupled with 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine as described in Example 65 to afford 7-(1-fluoro-1-methylethyl)-3-[4-fluoro-3-(pyridin-3-yl)phenyl]imidazo[1,2-α]pyrimidine as a white solid after crystallisation from ethyl acetate/isohexane: δH (360 MHz, CDCl3) 1.74 (6H, d, J 22), 7.26 (1H, dd, J 7 and 2), 7.53-7.60 (2H, m), 7.80 (1H, ddd, J 8, 5 and 2), 7.94 (1H, dd, J 8 and 2), 8.05 (1H, s), 8.10 (1H, ddd, J 8, 4 and 2), 8.65 (1H, dd, J 5 and 1.5), 8.89 (1H, s), 9.13 (1H, d, J 7); m/z (ES+) 351 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][C@H:14]1[O:19][C@@H:18]([CH3:20])[CH2:17][N:16]([CH2:21][C:22]2[O:26][C:25]([C:27]3[CH:35]=[C:34]([C:36]4[CH:37]=[C:38]([NH2:44])[C:39]([O:42][CH3:43])=[N:40][CH:41]=4)[CH:33]=[C:32]4[C:28]=3[CH:29]=[N:30][N:31]4[S:45]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)(=[O:47])=[O:46])=[N:24][N:23]=2)[CH2:15]1.O>N1C=CC=CC=1>[CH3:13][C@H:14]1[O:19][C@@H:18]([CH3:20])[CH2:17][N:16]([CH2:21][C:22]2[O:26][C:25]([C:27]3[CH:35]=[C:34]([C:36]4[CH:37]=[C:38]([NH:44][S:9]([C:3]5[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=5[F:1])(=[O:11])=[O:10])[C:39]([O:42][CH3:43])=[N:40][CH:41]=4)[CH:33]=[C:32]4[C:28]=3[CH:29]=[N:30][N:31]4[S:45]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)(=[O:46])=[O:47])=[N:24][N:23]=2)[CH2:15]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1N
Solvent: c1ccncc1
Solvent: O
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
2,4-Difluorobenzenesulfonyl chloride (0.048 mL, 0.354 mmol) was added dropwise to a solution of 5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinamine (185 mg, 0.321 mmol) in pyridine (1 ml). The mixture was stirred at room temperature for 2 h. 2,4-Difluorobenzenesulfonyl chloride (0.048 mL, 0.354 mmol) was added dropwise and the mixture continued stirring at room temperature for 1 h. Water (10 ml) was added and the resultant brown precipitate collected by filtration and dried in the vacuum oven for 72 h to give the title compound as a brown solid (194 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9](O)([C@H:16]([N:18]([CH2:31][CH2:32][OH:33])[C:19](=[O:30])[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[C@@H:16]([CH3:17])[N:18]([C:19](=[O:30])[C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=2)[CH2:31][CH2:32][O:33]1
Reactant: C[C@@H](N(CCO)C(=O)c1ccc(C(F)(F)F)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H]1N(C(=O)c2ccc(C(F)(F)F)cc2)CCO[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Yield: 45 %

Procedure:
A solution containing (2R*,3R*)-2-[2,4-difluorophenyl]-3-[N-(2-hydroxyethyl)-N-[4-(trifluoromethyl)benzoyl]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (500 mg, 1.03 mmol, obtained in example 3) in THF was treated with diethylazadicarboxylate (262 mg, 1.5 eq) and triphenylphosphine (393 mg, 1.5 eq) at room temperature for 24 h. The volatiles were removed in vacuo and the orange oily residue was purified by flash chromatography to afford the title compound as a colorless wax (209 mg, 45 % yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16](B4OC(C)(C)CC(C)(C)O4)[CH:15]=[C:14]([NH2:29])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:31]1[CH:36]=[CH:35][N:34]=[C:33]2[NH:37][CH:38]=[CH:39][C:32]=12.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]5[NH:37][CH:38]=[CH:39][C:32]=45)[CH:15]=[C:14]([NH2:29])[C:13]=3[CH:12]=[N:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)CC(C)(C)OB(c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)O1
Reactant: Brc1ccnc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(-c2ccnc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 80 °C
Yield: 48.8 %

Procedure:
1-(Phenylsulfonyl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-1H-indazol-4-amine (2 g, 4.84 mmol), 4-bromo-1H-pyrrolo[2,3-b]pyridine (0.953 g, 4.84 mmol), Pd(dppf)Cl2 (0.708 g, 0.968 mmol) and Tripotassium phosphate (3.08 g, 14.52 mmol) were divided between 2× microwave vials and dissolved in 1,4-dioxane (24 ml) and water (8.00 ml); 12 ml dioxane and 4 ml water in each vial. The mixtures were heated in the microwave at 80° C. for 20 min. Solvent was removed in vacuo and the residue was partitioned between DCM (100 ml) and water (100 ml). The organic layer was collected using a hydrophobic frit and the solvent removed in vacuo. DCM was added to dissolve the crude residue but a suspension resulted. The yellow solid was filtered off and dried in a vacuum oven for 30 mins to afford the title compound (919 mg). The filtrate was concentrated in vacuo and dissolved in DCM, then applied to the top of a 50 g silica SPE cartridge. This was eluted with 0-100% EtOAc/DCM over 60 mins on the FlashMaster II. The product-containing fractions were combined to give a further portion of the title compound as a yellow solid (220 mg).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:23])[C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[C:15](O)=[O:16])=[CH:6][CH:5]=1.[Cl-].[NH4+].O.[N:29]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:23])[C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[C:15]([NH2:29])=[O:16])=[CH:6][CH:5]=1
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(C(=O)O)cc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
N-(4-Trifluoromethoxyphenyl)-4-methoxyisophthalamic acid (48 mg) obtained in step F, 11 mg of ammonium chloride, 25 mg of benzotriazol-1-ol monohydrate, and 31 mg of (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride were dissolved in 2 mL of N,N-dimethylformamide, and 70 μL of N,N-diisopropylethylamine was added. This solution was stirred overnight at room temperature, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (5 g of silica gel, 2 g of aminopropyl-modified silica gel) using a 100:1 mixture of dichloromethane and methanol as an elution solvent, thereby obtaining 45 mg (96%) of 3-N-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamide.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[C:9]([CH3:21])=[N:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:12][C:3]=12.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:10]=[C:9]([CH3:21])[C:4]3=[C:5]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:6]=[N:7][C:2]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:3]3[CH:12]=2)=[CH:14][CH:15]=1
Reactant: C1COCCN1
Reactant: COc1ccc(-c2cc3c(Cl)nnc(Cl)c3c(C)n2)cc1
Product: COc1ccc(-c2cc3c(N4CCOCC4)nnc(N4CCOCC4)c3c(C)n2)cc1
Temperature: 130 °C

Procedure:
1.0 part by weight of 1,4-dichloro-7-(p-methoxyphenyl)-5-methylpyrido[3,4-d]pyridazine is added to 10 parts by volume of morpholine, and the resulting mixture is heated at 130°C for 3 hours. The excess amount of morpholine is removed by evaporating under reduced pressure, and water is added to the residue. The crude crystals are collected by filtration and recrystallized from ethanol to obtain 7-(p-methoxyphenyl)-5-methyl-1,4-dimorpholinopyrido[3,4-d]pyridazine as gray prisms melting at 206° to 209°C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([CH:20]=[O:21])=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].C[Si]([C:28]#[N:29])(C)C>C(Cl)Cl.[Zn+2].[I-].[I-]>[NH2:29][CH2:28][CH:20]([C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:22][CH3:23])[OH:21]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C=O
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C(O)CN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 0.679 g of 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde in 1.5 mL of CH2Cl2 was added ca. 5 mg of ZnI2, then 0.23 g of trimethylsilyl cyanide. The mixture was stirred at room temperature for 3 h, and then partitioned between 15 mL of water and 10 mL of Et2O. The aqueous phase was extracted with 2×10 mL of Et2O. The combined organics were dried over Na2SO4 and concentrated. The residue was dissolved in 15 mL of Et2O and cooled to 0° C. A 1-M solution of LiAlH4 in Et2O (4.2 mL) was added dropwise via addition funnel. The cooling bath was removed once the addition was complete, and the mixture was stirred overnight at room temperature, then recooled to 0° C. and quenched by dropwise addition of 0.15 mL of water, 0.15 mL of 15% aqueous NaOH, and 0.4 mL of water. The cooling bath was removed once the addition was complete, and the mixture was stirred 30 min at room temperature, filtered (washing the solids liberally with Et2O), and concentrated to provide the title compound, which was used without further purification. Mass spectrum (ESI) 354.2 (M+1). Some 1H NMR signals are doubled because of atropoisomerism. 1H NMR (500 MHz, CDCl3): δ 7.88 (s, 1H), 7.55 (app t, J=7.5 Hz, 1H), 7.22-7.28 (m, 2H), 6.99, 6.95 (d, J=2.5 Hz, 1H), 6.92, 6.90 (sm 1H), 4.52 (m, 1H), 3.70 (s, 3H), 2.90 (septet, J=7 Hz, 1H), 2.81 (m, 1H), 2.60-2.70 (m, 2H), 1.23-1.28 (m, 6H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:21]=[CH:20][CH:19]=[C:18](I)[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])=[O:8]>CO>[Cl:4][C:5]1[N:21]=[CH:20][CH:19]=[C:18]([O:2][CH3:1])[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])=[O:8]
Reactant: O=C(Nc1ccc(F)cc1F)c1c(I)ccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(Cl)c1C(=O)Nc1ccc(F)cc1F
Temperature: 60 °C
Yield: 27.3 %

Procedure:
To a solution of sodium methoxide (0.023 g, 0.43 mmol) in anhydrous methanol (3 mL) was added 2-chloro-N-(2,4-difluorophenyl)-4-iodonicotinamide (0.17 g, 0.43 mmol). The mixture was heated at 60° C. for 12 hours then allowed to cool to ambient temperature. Concentration of the reaction mixture resulted in a residue that was triturated with methanol and water. Isolation by vacuum filtration afforded the desired compound (0.035 g) as an off-white solid. The filtrate was concentrated in vacuo to a residue that was purified by flash column chromatography (SiO2, eluting with 25-100% EtOAc in hexane) to afford an additional amount desired compound (0.049 g, overall yield 65%) that was spectroscopically consistant with the initially isolated material. 1H NMR (DMSO-d6) δ 10.48 (s, 1H), 8.38 (d, 1H, J=5.8 Hz), 7.85-7.96 (m, 1H), 7.33-7.40 (m, 1H), 7.27 (d, 1H, J=5.8 Hz), 7.05-7.20 (m, 1H), 3.92 (s, 3H); MS(ESI+) m/z 299 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([CH:27]=[C:28]([CH2:30][CH2:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:29]=3)[C:17]([C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1.[CH3:42][S:43]([NH:46][C:47](=O)[O:48]CC)(=[O:45])=[O:44].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[O:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]3[N:16]([CH:27]=[C:28]([CH2:30][CH2:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:29]=3)[C:17]([C:20]3[CH:26]=[CH:25][C:23]([NH:24][C:47]([NH:46][S:43]([CH3:42])(=[O:45])=[O:44])=[O:48])=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[CH2:12][CH2:13]1
Reactant: Nc1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1
Reactant: CCOC(=O)NS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)Nc1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of compound 59a (100 mg, 0.147 mmol) and ethyl methylsulfonylcarbamate (148 mg, 0.888 mmol) and DIEA (0.191 mL, 1.11 mmol) in DMF (2 mL) was stirred at 100° C. for 2 h. The reaction mixture was allowed to cool to rt and diluted with DCM. The reaction mixture was concentrated and the residue obtained was purified by flash column chromatography on silica gel (0-20% MeOH/EtOAc), recrystallized with EtOAc/heptanes and purified by prep-TLC (1:5:5 MeOH/DCM/EtOAc) to give the title compound 40. 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.22-3.30 (m, 2H), 3.33 (s, 3H), 3.37-3.47 (m, 2H), 3.69-3.87 (m, 4H), 4.03-4.21 (m, 4H), 7.16 (s, 1H), 7.31 (s, 1H), 7.28 (s, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.43-7.60 (m, 3H), 7.67-7.76 (m, 1H), 7.82 (d, J=7.6 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 8.15 (d, J=8.3 Hz, 1H), 8.81 (br. s., 1H). Mass Spectrum LCMS, ESI (pos.) Calcd. for C29H29N7O4S: 572.2 [M+H]. found 572.5.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][Mg]Br.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2(/[CH:25]=[N:26]/[S@@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18].[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOCC>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2([CH:25]([NH:26][S@@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[CH2:8][CH2:7][CH:2]3[O:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Br[Mg]CCC1OCCCO1
Reactant: CC(C)(C)[S@@](=O)/N=C/C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)[S@@](=O)NC(CCC1OCCCO1)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
A flame dried flask under N2 was charged with anhydrous Et2O (5 mL) and (1,3-Dioxan-2-ylethyl)-magnesium bromide (0.5M in THF, 5.6 mL, 2.8 mmol) and cooled to −78° C. (R,E)-N-((1-(3,4-dichlorophenyl)cyclohexyl)methylene)-2-methylpropane-2-sulfinamide (460 mg, 1.28 mmol) in anhydrous Et2O (3 mL) was added dropwise and the solution was stirred at −78° C. for 1 h, then allowed to warm to RT overnight. After 20 h sat'd aqueous Na2SO4 solution (4 mL) was added and the suspension was filtered, dried (Na2SO4), filtered and concentrated. Purification on the Biotage with a 25M column and an ethyl acetate/hexane (0.1% DEA) gradient (0→100% EtOAc over 3 CV, hold at 100% EtOAc for 5 CV) gave the pure title compound (300 mg, 49%) as a clear oil. HPLC Rt=2.62 min; 1H NMR (400 MHz, CDCl3) 7.45-7.43 (m, 2H), 7.24-7.22 (d, J=8.43 Hz, 1H), 4.44-4.42 (m, 1H), 4.11-4.04 (m, 2H), 3.75-3.67 (m, 2H), 3.11-3.01 (m, 2H), 2.64 (d, J=12.8 Hz, 1H), 2.27 (d, J=13.9 Hz, 1H), 2.04-1.99 (m, 1H), 1.88-1.44 (m, 8H), 1.33-1.19 (m, 12H), 0.93-0.80 (m, 1H); 13C NMR (100 MHz, CDCl3) 141.8, 132.7, 130.8, 130.4, 130.2, 128.4, 101.7, 66.8, 66.3, 57.1, 46.2, 34.3, 32.5, 26.1, 25.7 (d), 23.1, 22.2, 21.8; LC-MS 10.5 min, (M+1)+476 @10.6 min.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[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.[F:73][C:74]([F:79])([F:78])[C:75]([O-:77])=[O:76].[CH3:80][N+:81]1[C:82]([SH:91])=[N:83][C:84]2[C:89]=1[CH:88]=[CH:87][N:86]([CH3:90])[CH:85]=2>>[F:73][C:74]([F:79])([F:78])[C:75]([O-:77])=[O:76].[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:91][C:82]4[N+:81]([CH3:80])=[C:89]5[CH:88]=[CH:87][N:86]([CH3:90])[CH:85]=[C:84]5[N:83]=4)[CH2:35][S:36][C@H:31]23)=[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
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: Cn1ccc2[n+](C)c(S)nc-2c1
Agent: O=C([O-])C(F)(F)F
Product: COc1ccc(COC(=O)C2=C(CSc3nc4cn(C)ccc-4[n+]3C)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 87.2 %

Procedure:
Using 306 mg of p-methoxybenzyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-{(S)-1-diphenylmethoxycarbonylethoxyimino}acetamido]-3-chloromethyl-3-cephem-4-carboxylate and 153 mg of 1,5-dimethyl-2-mercaptoimidazolo[4,5-c]pyridinium trifluoroacetate in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 2-mercapto-4-methylthiazolo[5,4-b]pyridinium trifluoroacetate, respectively, the reaction and purification were carried out in the same manner as in Example 15(a) to obtain 334 mg of the title compound in a yield of 88%.