Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1([C:12](OC)=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C(OCC)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COCCCC1(C(=O)OC)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COCCCC1(CO)CCCCC1
Temperature: 0 °C

Procedure:
A solution of EXAMPLE 97A (2.14 g) in diethyl ether (10 mL) was added dropwise to a suspension of LiAlH4 (0.380 g) in diethyl ether (20 mL). Once the addition was finished, the mixture was refluxed for 90 minutes, and then cooled to 0° C. NaOH (2N, aqueous, 50 mL) was then added slowly. The mixture was extracted with ethyl acetate (300 mL) and washed with brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].Br[CH2:15][CH2:16][CH2:17][Cl:18]>>[Cl:18][CH2:17][CH2:16][CH2:15][C:2]([CH3:4])([CH3:3])[C:1]#[N:5]
Reactant: ClCCCBr
Reactant: CC(C)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)(C#N)CCCCl
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a solution of isobutyronitrile (13.8 g, 0.2 mol; Aldrich) in hexanes (200 mL) was added a 2M solution of lithium diisopropylamide (100 mL, 0.2 mol; Aldrich), and the mixture stirred for 2 hrs under nitrogen. This mixture was added to a solution of 1-bromo-3-chloropropane (34.6 g, 0.22 mol; Aldrich) and stirred for 1 h. The reaction was quenched by careful addition of water, and the hexane layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (SiO2, 20–50% CH2Cl2 in Hexanes) to provide 10 g (68.7 mmol, Yield=34%) of the title compound as an amber oil: 1H NMR (CDCl3, 500 MHz) δ ppm: 1.35 (6H, s, gem-Me), 1.67 (2H, m, CH2), 1.95 (2H, m, CH2), 3.57 (2H, t, J=6.5 Hz, Cl-CH2); 13C NMR (CDCl3, 125.8 Hz) δ ppm 26.73, 28.50, 32.08, 38.47, 44.58, 124.72.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13]Br)=[O:6])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1>CC(C)=O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:29][C:26]1[CH:27]=[CH:28][C:23]([S:22][CH3:21])=[CH:24][CH:25]=1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CBr
Reactant: CSc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CSc1ccc(SC[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
trans-2-Bromomethyl-cyclohexanecarboxylic acid cyanomethyl-amide (258 mg) and cesium carbonate (329 mg) were weighed into a 15 mL vial fitted with a stir bar and a vent cap. Acetone (3 mL) and 4-(methylsulfanyl)thiophenol (162 mg) were added. The reaction mixture was stirred at 50° C. overnight and then diluted with hot acetone (7 mL) and filtered through Celite™. The Celite™ was washed with hot acetone. The filtrate and wash were combined and the solvent was removed on a rotary evaporator. Chromatography of the crude product on a silica gel (using 9:1 dichloromethane: acetone as the eluent) provided the title compound as a white solid. 1H NMR (DMSO-d6): δ=8.63 (1H, t), 7.24 (2H, d), 7.18 (2H, d), 4.13 (2H, d), 2.97 (1H, dd), 2.58 (1H, m), 2.96 (3H, s), 2.1 (2H, m), 1.7 (4H, m), 1.2 (4H, m) MS [ESI, (M−H)−] m/z=332.8 amu
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Br)[N:14]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[N:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[N:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:12]=[N:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: O=[N+]([O-])c1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NCCNc2cnc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)n2)nc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-5-bromo-2-nitropyrazine (20 mg, 0.057 mmol) in DMF (1 ml), 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile (10.0 mg, 0.06 mmol) and diisopropylethyl amine (40 μl, 0.228 mmol) were added. The reaction mixture was stirred for 12 hours at 80° C. The crude mixture was concentrated in vacuo and subjected to column chromatography (5% methanol in methylene chloride) to afford the title compound as bright yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[N:19][C:20]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH3:34])[CH:28]=2)=[C:21]([CH:25]=1)[C:22](O)=[O:23].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:16][C:17]1[CH:18]=[N:19][C:20]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH3:34])[CH:28]=2)=[C:21]([CH:25]=1)[C:22]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[OH:8])=[O:23]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: N[C@H]1CCCC[C@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@@H]2CCCC[C@@H]2O)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 58 %

Procedure:
cis-2-Amino-cyclohexane-1-ol (85 mg, 0.56 mmol) and triethylamine (225 μl, 1.61 mmol) were dissolved in dimethylformamide (225 μl) and a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (150 mg, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg, 0.59 mmol) and 1-hydroxybenzotriazole (80 mg, 0.59 mmol) in dimethylformamide (5 ml) was added. The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between 0.5N HCl (10 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic phases were washed with brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (70:30, by volume). The product was triturated with pentane (3 ml) to give 5-fluoro-N-[cis-2-hydroxy-cyclohexyl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (118 mg) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22]([OH:24])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30](=[O:39])[NH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:39])[NH:31][C@H:32]1[CH2:33][CH2:34][C@H:35]([NH:38][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:14]=3[NH:21][CH:20]=2)=[O:24])[CH2:36][CH2:37]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A77) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[N:21]([C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:20][CH2:19]2
Reactant: Clc1cc(Br)cc2c1NCC2
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Product: CCC(CC)n1cc(Cl)nc(N2CCc3cc(Br)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 156–157° C.; 1H NMR (300 MHz, CDCl3): δ 7.25 (d, J=1.8 Hz, 1 H), 7.19 (d, J=2.9 Hz, 1 H), 6.71 (s, 1 H), 4.75–4.69 (m, 1 H), 4.27 (t, J=7.9 Hz, 2 H), 3.07 (t, J=8.1 Hz, 2 H), 1.78–1.51 (m, 4 H), 0.81 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C17H19N3OBrCl2 (M+H)+: 430.0089; Found m/z 430.0106.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=O.S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[CH2:4][Cl:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Product: Fc1cc(CCl)c(Cl)nc1Cl
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
2,6-Dichloro-5-fluoronicotinic acid (2) (14 g) was dissolved in thionyl chloride (70 mL). The mixture was heated at 85° C. with stirring for 2.5 h and the thionyl chloride was removed under reduced pressure, yielding a yellowish oil, 2,6-dichloro-5-fluoronicotinyl chloride (3). Monoethyl malonate (27 g) and 6 mg of biquinoline was dissolved in 560 mL of dry THF and cooled to −30° C. A solution of 2.5 M of n-butyllithium in hexane was added until a pink color remained at −5° C. (160 mL). The suspension was then cooled to −50° C. The acid chloride obtained as described above, dissolved in 50 mL THF was then added to the suspension dropwise with stirring. The dry ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction was acidified with 400 mL of 1N HCl and was extracted with ether. It was washed with aqueous sodium bicarbonate solution and water. The ether solution was dried, evaporated to dryness and washed with hexane to give 27 g of (4). m.p=63-66° C.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:37])([CH3:36])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([O:28]CC2C=CC=CC=2)[CH:27]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH:22]([CH3:24])[CH3:23])[N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3]>C1COCC1>[CH3:1][C:2]([Si:5]([CH3:37])([CH3:36])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([OH:28])[CH:27]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH:22]([CH3:24])[CH3:23])[N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3]
Reactant: CC(C)n1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Solvent: C1CCOC1
Product: CC(C)n1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.7 %

Procedure:
A solution of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]-5-[(phenylmethyl)oxy]benzamide (1.97 g, 3.77 mmol) and THF (70 mL) was evacuated and purged with Argon (×3). Palladium on carbon (10% w/w, 400 mg) was added and reaction mixture was evacuated and finally purged with hydrogen gas. Reaction mixture was left to stir at ambient temperature under hydrogen for 16 hours. The palladium on carbon was filtered off and concentrated in vacuo to give the product as a colourless oil (1.58 g, 97%).
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][CH:22]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:23]([O:25]C)=[O:24])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.CC1(C)C(C)(C)OB([C:43]2[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=2[NH2:45])O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.Cl.[Li+].[OH-]>C(O)CCC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:45][C:44]1[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=1[C:2]1[N:3]([CH2:21][C@@H:22]([C:23]([OH:25])=[O:24])[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(NC(=O)OC(C)(C)C)C(=O)OC)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCCCO
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3N)n(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-bromo-1-{2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl}-3-cyclohexyl1H-indole-6-carboxylate in nBuOH:H2O (9:1, 0.08 M) were added 1.5 eq of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, 6 eq of K3PO4, 5 mol % of dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine and 2.5 mol % of palladium acetate. The mixture was heated at 90° C. for 4 h. After cooling to RT, the mixture was acidified with HCl (IN) and extracted (twice) with EtOAc. The combined organics were washed with brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude product mixture was redissolved in THF:H2O (1:1, 0.08 M) and 2 eq LiOH added. After stirring for 1 h, ester deprotection was complete as evidenced by RP-HPLC analysis. The volatiles were removed in vacuo and the residue partitioned between EtOAc and H2O. The organics were washed with brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude residue was used directly in the next step; MS (ES+) m/z 536 (M+H)+, 558 (M+Na)+.
Reaction SMILES: CC(C)(C)CC(Cl)=O.NC1C=CC(OC)=NC=1.C(OCC)C.Cl.C[O:25][C:26]1[N:31]=[CH:30][C:29]([NH:32][C:33](=[O:39])[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:28][CH:27]=1>O1CCCC1.CO>[OH:25][C:26]1[N:31]=[CH:30][C:29]([NH:32][C:33](=[O:39])[CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:28][CH:27]=1
Reactant: COc1ccc(NC(=O)CC(C)(C)C)cn1
Agent: CC(C)(C)CC(=O)Cl
Agent: COc1ccc(N)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)CC(=O)Nc1ccc(O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
3,3-Dimethylbutyroyl chloride (4.04 g, 30.0 mmol) was added dropwise to a stirred solution of 5-amino-2-methoxypyridine (3.72 g, 30.0 mmol) in tetrahydrofuran (25 mL). After stirring for 1 hour at room temperature, diethyl ether was added and the solid material was isolated by suction. The N-(6-methoxy-pyridin-3-yl)-3,3-dimethyl-butyramide hydrochloride (4.13 g, 15.96 mmol) was heated at 180° C. for 15 minutes. After cooling to room temperature the product was dissolved in methanol. Partial evaporation of the solvent yielded the title compound (1.15 g, 35% yield) as a solid.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]3[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=3)[C:28]([OH:30])=[O:29])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]3[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=3)[C:28]([OH:30])=[O:29])=[O:21])[CH2:16][CH2:15]2)=[CH:32][CH:33]=1
Reactant: O=C(O)c1cncc(OC(=O)N2CCC(Oc3ccc(OCc4ccccc4)cc3)CC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)c1cncc(OC(=O)N2CCC(Oc3ccc(O)cc3)CC2)c1
Yield: 34.4 %

Procedure:
10% Palladium-carbon (catalytic amount) was added to a THF (10 ml) solution containing 5-[({4-[4-(benzyloxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinic acid (200 mg), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 3 hours. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to obtain 5-[({4-[4-(hydroxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinic acid (55 mg).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38][CH:39]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:83])/[C:55](/[C:58]2[N:59]=[C:60]([NH:63][C:64]([C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[S:61][CH:62]=2)=[N:56]\[OH:57])[C:19]3=[O:84])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:91][CH2:92][C:93]([O:95][C:96]1[C:104]([O:105][C:106](=[O:109])[CH2:107][Cl:108])=[CH:103][C:99]([C:100](Cl)=[O:101])=[C:98]([CH3:110])[CH:97]=1)=[O:94]>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38][CH:39]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:83])/[C:55](/[C:58]2[N:59]=[C:60]([NH:63][C:64]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)([C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[S:61][CH:62]=2)=[N:56]\[O:57][C:100](=[O:101])[C:99]2[CH:103]=[C:104]([O:105][C:106](=[O:109])[CH2:107][Cl:108])[C:96]([O:95][C:93](=[O:94])[CH2:92][Cl:91])=[CH:97][C:98]=2[CH3:110])[C:19]3=[O:84])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Reactant: Cc1cc(OC(=O)CCl)c(OC(=O)CCl)cc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(=O)c4cc(OC(=O)CCl)c(OC(=O)CCl)cc4C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of (6R, 7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (1.0 g) in dry dichloromethane (24 ml) was added potassium carbonate (0.17 g) at once, followed by dropwise addition of a solution of 4,5-bis(chloroacetoxy)-2-methylbenzoyl chloride (0.43) dry dichloromethane (16 ml) over a period of ten minutes, and the mixture was stirred at 0° C. for three hours. After filtering off the insoluble matters, the filtrate was washed twice with water, once with brine, and dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure, and the residue was crystallized with ether, giving 1.13 g of the objective compound as pale yellow crystals.
Reaction SMILES: [CH:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=O.O.NN.[OH-].[K+]>C(O)CO>[CH3:1][C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1
Reactant: O=CC1(c2ccccc2)CCC(=O)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CC1(c2ccccc2)CCC(=O)CC1
Reaction time: 5 h
Yield: 67 %

Procedure:
A mixture of 9.3 g. (0.038 mole) of 4-formyl-4-phenyl cyclohexanone, ethylene ketal (prepared in Example 30), 5 ml. of hydrazine hydrate and 6.4 g. of potassium hydroxide in 120 ml. of ethylene glycol is heated at reflux for about 1 hour. The solvent is then allowed to distill until the pot temperature comes to about 200°C. After about 5 hours the mixture is allowed to cool and then diluted with water and brine and evaporated to dryness. The residue is chromatographed on 750 ml. of Florisil (magnesium silicate) with elution by 1% ethyl acetate in Skellysolve B. The crystalline fractions are combined and recrystallized from a mixture of methanol and water to give 5.92 g. (67% yield) of 4-methyl-4-phenylcyclohexanone, ethylene ketal, having a melting point of 48° to 50°C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=1.CCOCC>CN(C)C=O>[CH3:1][O:19][C:13]1[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]([Br:9])=[CH:11][C:12]=1[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(Br)cc([N+](=O)[O-])c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOCC
Product: COc1c([N+](=O)[O-])cc(Br)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
Potassium carbonate (453 g) and methyl iodide (164 ml) were added to a solution of 4-bromo-2-(tert-butyl)-6-nitrophenol (600 g) in dimethylformamide (6000 ml) and the mixture was stirred at 50° C. for 4 hours. Ether (6000 ml) was added and the reaction mixture was washed 3 times with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to yield a crude product of the title compound (569 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:8](=[O:23])[NH:9][N:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1.N>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:9]2[C:8](=[O:23])[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=3)=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[CH:11]=[N:10]2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(I)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Oc2ccc(F)cc2)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, starting with 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 1-fluoro-4-iodobenzene in place of 4-bromothioanisole (yield: 60 mg, 53%). mp 83-85° C. 1H NMR (300 MHz, CDCl3) δ 3.10 (s, 3H), 6.89-7.03 (m, 4H), 7.15 (t, J=9 Hz, 2H), 7.65 (dd, J=9 Hz, 6 Hz, 2H), 7.83 (d, J=6 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.08 (s, 1H). MS (DCI/NH3) m/z 455 (M+H)+, 472 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:54])[C:28]([CH3:53])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45][CH2:46][C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:54])[C:28]=3[CH3:53])[CH:37]=[CH:38][C:39]=2[O:45][CH2:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)Nc3ccncc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 9.2 %

Procedure:
4-Aminopyridine (0.141 g, 1.500 mmol), triethylamine (0.152 g, 1.500 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.254 g, 1.500 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.2115 g, 0.500 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.023 g, 0.0460 mmol, 9%).