Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[F:15].[CH3:16][C:17]1([CH3:36])[O:21][C@H:20]([CH2:22]OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:19][O:18]1.CN1CCCC1=O.N12CCCN=C1CCCCC2.C(OC(C)C)(=O)C.O>>[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:22][C@@H:20]3[CH2:19][O:18][C:17]([CH3:36])([CH3:16])[O:21]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[F:15]
Reactant: CC1(C)OC[C@@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Reactant: Cn1c(=O)c(F)c(Cl)c2c(=O)[nH]cnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)OC(C)C
Solvent: CN1CCCC1=O
Product: Cn1c(=O)c(F)c(Cl)c2c(=O)n(C[C@@H]3COC(C)(C)O3)cnc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Combine 5-chloro-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (5.00 g, 21.8 mmol), (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-4-nitrobenzenesulfonate (7.60 g, 24.0 mmol), and N-methylpyrrolidinone (25.0 mL, 259 mmol). Add 1,8-Diazabicyclo[5.4.0]undec-7-ene (3.58 mL, 24.0 mmol) to the suspension. Heat to 60° C. and stir overnight. Add isopropyl acetate (50.0 mL, 427 mmol) followed by water (50.0 mL, 2780 mmol) while maintaining the temperature above 50° C. Stir at 60° C. for 1 hour, separate the phases and transfer the aqueous phase to a flask. Add isopropyl acetate (50.0 mL, 427 mmol) to the flask and stir at 60° C. for 1 hour and then separate the layers. Combine the organic phases and concentrate under vacuum to about 25 mL to give a solid. Cool to ambient temperature and stir for no longer than 2 hours, collect the solid by filtration, dry under vacuum overnight to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.N12CCN(CC1)CC2.[CH3:16][CH:17]([N:19]=[C:20]=[O:21])[CH3:18]>CN(C)C=O>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20]([NH:19][CH:17]([CH3:18])[CH3:16])=[O:21])=[CH:3][N:4]=1
Reactant: Nc1ccnnc1
Reactant: CC(C)N=C=O
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1ccnnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.9 %

Procedure:
To a stirred solution of 2.3 grams (0.024 mole) of 4-aminopyridazine (prepared as in Example 1, Step A) and 0.5 gram (0.004 mole) of 1,4-diazabicyclo[2.2.2]octane in 20 ml of dimethylformamide is added dropwise 3.3 ml (0.033 mole) of (1-methylethyl) isocyanate. Upon completion of addition the reaction mixture is stirred at ambient temperature for two days. The reaction mixture is concentrated under reduced pressure and the solid residue dried at 60°-70° C. The solid is stirred with ethanol and collected by filtration to yield 1.9 grams of N-(4-pyridazinyl)-N'-(1-methylethyl)urea; m.p. 206°-209° C. then 266°-269° C. The nmr spectrum is cnsistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[N:14]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[NH:27][C:28](=[O:30])[CH3:29].C([O-])(=O)C.[K+].[CH:36]([NH2:38])=O.C(OC(=O)C)(=O)C>[Cu]I.C(OCCCC)(=O)C>[C:36]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[N:14]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[NH:27][C:28](=[O:30])[CH3:29])#[N:38]
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Reactant: NC=O
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CCCCOC(C)=O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
2-Bromo-4,6-dinitro-2'-acetylamino-4'-(N,N-diethylamino) azobenzene (2.4 parts), copper (I) iodide (0.95 parts), anhydrous potassium acetate (1.5 parts), formamide (1.8 parts), acetic anhydride (2.0 parts) and n-butyl acetate (44 parts) are mixed together and heated, with stirring, to 110° C. during 15 minutes. The temperature is maintained at 110° C. for 2 hours when reaction is complete. The mixture is cooled to room temperature and poured into petroleum ether (boiling range 60-80° C.) (400 parts). The precipitate is collected, washed with petroleum ether (100 parts) and dried. 2-Cyano-4,6-dinitro-2'-acetylamino-4'-(N,N-diethylamino)azobenzene is obtained in 95% yield.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21].I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:26]1([CH2:25][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[C:11]([C:20]([F:21])([F:22])[F:23])[CH:12]=2)[C:17]([OH:19])=[O:18])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: ICC1CCCC1
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (141.28 mL of a 0.31M stock solution, 43.8 mmol) cooled to −78° C. was treated with (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid (4.44 g, 20.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (49.68 mL, 3:1). The resulting solution was then stirred at −78° C. for 1 h. At this time, the reaction was treated with a solution of iodomethylcyclopentane (4.64 g, 22.09 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.6 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. This solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution. The product was extracted into ethyl acetate (3×400 mL) and diethyl ether (1×200 mL). The combined organic layers were dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate with acetic acid) afforded 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (3.37 g, 55.4%) as a white solid: mp 66-68° C.; EI-HRMS m/e calcd for C15H16F4O2 (M+) 305.1165, found 305.1174.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8](Cl)(=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[NH:1]([C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:22])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCC(=O)N[C@@H](CS)C(=O)O

Procedure:
20 g (0.1652 mol) of Cys are reacted with 36.6 g (0.1487 mol) of myristoyl chloride analogously to Stage 6.1 to form tetradecanoyl-Cys: m.p.=63°-65°, Rf =0.13 (CH2Cl2 :acetone=8:2).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:10][N:11]([CH3:16])[S:12](Cl)(=[O:14])=[O:13].C(Cl)Cl.C(N(CC)CC)C>O>[CH2:1]([C:5]1[N:9]([S:12]([N:11]([CH3:16])[CH3:10])(=[O:14])=[O:13])[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCCCc1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCc1nccn1S(=O)(=O)N(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
12.4 g of butylimidazole and 13.3 g of N,N-dimethylsulfamoyl chloride were introduced into 200 ml of methylene chloride, and 9.7 g of triethylamine was added at room temperature. The mixture was stirred for 20 hours at room temperature and for 2 hours at 40° C., 200 ml of water was added and the phases were separated. The organic phase was washed with water, dried with Na2SO4 and concentrated by evaporation to give 22.2 g of product in the form of a red oil. The yield was 96 percent. Other data concerning the product was:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[C:23](/[CH3:30])=[CH:24]\[C:25](OCC)=[O:26])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>CCOCC.O>[CH2:16]([O:15][C:13]1[CH:12]=[C:11]([CH:23]([CH3:30])[CH2:24][CH2:25][OH:26])[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)/C=C(/C)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CC(CCO)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
A solution of ethyl 3-(3,5-dibenzyloxyphenyl)crotonate (24.1 g., 60 mM) in ether (250 ml.) is added to a mixture of lithium aluminum hydride (3.42 g., 90 mM) and ether (250 ml.). Aluminum chloride (0.18 g., 1.35 mM) is added and the mixture refluxed for 12 hours and then cooled. Water (3.4 ml.), sodium hydroxide (3.4 ml. of 6 N) and water (10 ml.) are then added successively to the reaction mixture. The inorganic salts which precipitate are filtered off and the filtrate is then concentrated in vacuo to give the desired alcohol as an oil--2.4 g. (98%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:18]=[N:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO>[Cl:1][C:2]1[C:3]2[N:4]([CH:18]=[N:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([CH:8]([NH2:27])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Temperature: 65 °C
Yield: 41.9 %

Procedure:
1-[8-Chloro-5-(3-fluorophenyl)imidazo[1,5-a]pyridine-6-yl]ethanone (0.12 g, 0.42 mmol) and ammonium acetate (0.32 g, 4.2 mmol) were stirred in methanol (4.6 mL) and heated to 65° C. for 1 hour. Sodium cyanoborohydride (78 mg, 1.3 mmol) was added and the mixture was heated at 65° C. for 16 hours. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (51 mg, 42%). LCMS calculated for C15H14ClFN3 (M+H)+: m/z=290.1. found: 290.0. 1H NMR (300 MHz, DMSO-d6): δ 7.63 (m, 2H), 7.41 (m, 3H), 7.35 (m, 2H), 3.60 (m, 1H), 1.18 (m, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13])(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[C:10]([N+:16]([O-:18])=[O:17])=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[C:12]([F:15])([F:13])[F:14])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To 2-acetamido-5-bromobenzotrifluoride (665 mg, 2.436 mmol) in concentrated H2SO4 (4 mL) at 0° C. was added dropwise 70% HNO3 (0.4 mL, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 3 h and it was poured into ice water (15 g). The precipitate was collected by filtration, affording 700 mg (90%) of crude 2-acetamido-5-bromo-3-nitrobenzotrifluoride. It was crystallized from EtOH/H2O to offer 610 mg (78.8%) of pure compound as white needles. Mp: 193°-5° C., 1H NMR (CDCl3): δ2.250 (s, 3H), 7.346 (s, 1H), 8.039 (s, 1H); 8.247 (s, 1H).
Reaction SMILES: [CH:1]1([C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=O)[CH2:2]1.C(OC(=O)C)(=O)C.[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)[CH2:27][CH2:26]1.O.Cl>O.C1(C)C(C)=CC=CC=1>[N:32]1[CH:33]=[CH:34][N:35]=[CH:36][C:31]=1[N:28]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[C:7](=[O:9])[CH:3]3[CH2:2][CH:1]([CH2:6][CH2:5][CH2:4]3)[C:10]2=[O:12])[CH2:30][CH2:29]1
Reactant: O=C(O)C1CCCC(C(=O)O)C1
Reactant: NCCCCN1CCN(c2cnccn2)CC1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: O=C1C2CCCC(C2)C(=O)N1CCCCN1CCN(c2cnccn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,3-Cyclohexane dicarboxylic acid (1.65 g., 9.6 mmole) was dissolved in 75 ml. of acetic anhydride and refluxed for 3 hours under N2. The solvent was removed in vacuum and replaced with 250 ml. of methylene chloride. 1-(4-Aminobutyl)-4-(2-pyrazinyl)piperazine (2.35 g., 10 mmole) was added and the mixture was stirred for 30 minutes at room temperature. The solvent was then replaced with 200 ml. xylene and the mixture was refluxed for 24 hours with water removal via a Dean-Stark trap. The product was concentrated to an oil in vacuum and column chromatographed in 100 g. silica gel with a gradient elution proceeding from methylene chloride to 5% isopropanol/methylene chloride. Evaporation of the relevant fractions gave 1.4 g. of the title compound, which was recrystallized from isopropanol with the addition of 4N isopropanolic HCl to give 900 mg. of monohydrochloride monohydrate; m.p. 226°-229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccc(Cl)cc1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cccnc1Nc1ccc(Cl)cc1
Reaction time: 6 h

Procedure:
To a solution of N-(4-chlorophenyl)-3-nitropyridin-2-amine (C8) (2.68 g, 10.7 mmol) in ethyl acetate (100 mL) was added Raney nickel (1.5 g), and the mixture was degassed with hydrogen. After 6 hours of hydrogenation at room temperature, the reaction mixture was filtered; concentration of the filtrate in vacuo afforded the product as a black solid. Yield: 1.8 g, 8.2 mmol, 77%. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (br s, 1H), 7.67 (d, J=8.9 Hz, 2H), 7.50 (br d, J=4 Hz, 1H), 7.25 (d, J=8.9 Hz, 2H), 6.91 (br d, J=7.5 Hz, 1H), 6.64 (dd, J=7.3, 4.8 Hz, 1H), 5.08 (br s, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([C:4]#[C:5][CH:6]([OH:13])[C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:3]>C1C=CC=CC=1.[O-2].[O-2].[O-2].[Ni+3].[Ni+3]>[CH3:11][C:9]([CH3:12])([C:8]#[C:7][C:6](=[O:13])[C:5]#[C:4][C:2]([CH3:14])([CH3:3])[CH3:1])[CH3:10]
Reactant: CC(C)(C)C#CC(O)C#CC(C)(C)C
Agent: [Ni+3]
Agent: [O-2]
Solvent: c1ccccc1
Product: CC(C)(C)C#CC(=O)C#CC(C)(C)C
Temperature: 7.5 °C
Reaction time: 0.5 h

Procedure:
The 2,2,8,8-tetramethylnona-3,6-diyn-5-ol prepared in Part A (7.0 g, 36 mmole) was dissolved in 150 mL of benzene, cooled to 5-10° C. and nickel peroxide (18.15 g, 200 mmole) was added over a period of 20 minutes. After the addition had been completed, the reaction mixture was stirred at room temperature for 30 minutes, then filtered, and the nickel peroxide left on the filter was washed well with benzene and then with dichloromethane. The filtrate was evaporated to give a yellow solid, which was recrystallized from benzene to give 2,2,8,8-tetramethylnona-3,6-diyn-5-one as pale yellow crystals (4.2 g). The structure of this product was confirmed by fast atom bombardment (FAB) mass spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:44]/[O:45][C:46](=[O:48])[CH3:47])/[C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:27])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60]>ClCCl>[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60].[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60].[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:44]/[O:45][C:46](=[O:48])[CH3:47])/[C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cccnc3)CS[C@H]12)c1csc(N)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCc3cccnc3)CS[C@H]12)c1csc(N)n1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a solution of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetamido]-3-[(3-pyridyl)methylthio]-3-cephem-4-carboxylate (3.32 g, 4.83 m mol) and anisole (3.3 ml) in dichloromethane (16.6 ml) was added trifluoroacetic acid (6.6 ml) at 5° C. The mixture was stirred at 5° C. for 1.5 hours. The reaction mixture was poured into IPE. The resulting precipitates were collected by filtration, washed with IPE, and dried in vacuo to give 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetamido]-3-[(3-pyridyl)methylthio]-3-cephem-4-carboxylic acid bis(trifluoroacetic acid) salt (3.88 g, 5.08 m mol).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][N:29]3[C:33](=[O:34])[C:32]4=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]4[C:30]3=[O:39])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:30]1(=[O:39])[N:29]([CH2:28][C:26]2[N:27]=[C:23]([N:21]3[CH2:20][CH:19]([OH:18])[CH2:22]3)[S:24][CH:25]=2)[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]12
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN3C(=O)c4ccccc4C3=O)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1csc(N2CC(O)C2)n1
Reaction time: 1 h
Yield: 106.6 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-phthalimidomethyl-1,3-thiazol-2-yl)azetidine (1.52 g, 2.57 mmol) (obtained as described in Reference Example 68(1)) in anhydrous tetrahydrofuran (76 ml) was added a 1.0 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (3.29 ml, 3.29 mmol) in an ice bath and the mixture was stirred in an ice bath for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 1-(4-phthalimidomethyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (864 mg, yield 100%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:9]=1[C:24](OCC)=[O:25]>C1(C)C=CC=CC=1>[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][C:9]=1[C:24]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:25]
Reactant: Nc1nccs1
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Solvent: Cc1ccccc1
Product: O=C(Nc1nccs1)C1=C(O)c2ccccc2N(c2ccccc2)C1
Yield: 67.1 %

Procedure:
A solution of 4.08 g of 2-aminothiazole and 8.0 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 250 ml of toluene was refluxed for 30 hours in a soxhlet apparatus containing 10 g of 4 Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: 1:25 ethyl acetate-dichloromethane as the eluent). The resultant solution was degassed and evaporated. Recrystallization of the residue from diethyl ether yielded 6.35 g (67%) of 1,2-dihydro-4-hydroxy-1-phenyl-N-(2-thiazolyl)-3-quinolinecarboxamide, m.p. 220° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2)[C:6]([OH:8])=O.C(Cl)CCl.C1C=CC2N(O)N=[N:35][C:33]=2C=1.CN.CCN(C(C)C)C(C)C>CO.CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2)[C:6]([NH:35][CH3:33])=[O:8]
Reactant: On1nnc2ccccc21
Reactant: COc1cc(C(=O)O)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Agent: CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1ccc(-c2cc(C(F)(F)F)cc3[nH]ncc23)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.8 %

Procedure:
A 20 mL vial was charged with 3-methoxy-4-(6-(trifluoromethyl)-1H-indazol-4-yl)benzoic acid (0.04 g, 0.119 mmol), EDC (0.034 g, 0.178 mmol), HOBt (0.027 g, 0.178 mmol), methanamine (0.178 mL, 0.357 mmol), DMA (1 mL), and DIPEA (0.062 mL, 0.357 mmol). The vial was capped and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was subsequently diluted with methanol and purified via preparative HPLC, eluting with a gradient of 35-55% ACN (containing 0.1% formic acid) in H2O (containing 0.1% formic acid). The product fractions were collected and dried in vacuo to give a formic acid salt of the title compound as a white solid (23.6 mg, 56.8%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.84 (d, J=4.29 Hz, 3H), 3.83 (s, 3H), 7.37 (s, 1H), 7.49-7.56 (m, 1H), 7.56-7.62 (m, 1H), 7.65 (s, 1H), 7.94 (s, 1H), 7.97 (s, 1H), 8.60 (d, J=4.55 Hz, 1H), 13.61 (br s, 1H); ESI-MS m/z [M+H]+ calc'd for C17H14F3N3O2, 350.1. found 350.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:9]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:8][S:7][CH:6]=1.C([O-])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[K+]>C(O)C1C=CC=CC=1>[CH2:1]([O:2][C:3](=[O:19])[CH2:4][C:5]1[C:9]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:8][S:7][CH:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1cscc1Nc1c(Cl)cccc1Cl
Reactant: [O-]Cc1ccccc1
Agent: [K+]
Solvent: OCc1ccccc1
Product: O=C(Cc1cscc1Nc1c(Cl)cccc1Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
316 mg (1 mmole) of 4-(2,6-dichloroanilino)-3-thiophenacetic acid methyl ester are introduced into a solution of 10 mg of potassium benzyl alcoholate in 20 ml of benzyl alcohol. The mixture is stirred at room temperature for 2 hours, excess alcohol is distilled off in vacuo and 4-(2,6-dichloroanilino)-3-thiophenacetic acid benzyl ester is obtained as the residue.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:37][C:38]2[C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:37][C:38]4[C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:43][CH:42]=[CH:41][C:39]=4[N:40]=3)[CH2:14][C@H:13]2[NH:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Reactant: CCN[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 47.1 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(ethylamino)piperidine-1-carboxylate obtained in Example (207a) (25.0 mg, 0.063 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (21 mg, 0.075 mmol) and sodium carbonate (66 mg, 0.625 mmol), to obtain 15 mg of the title compound (48%) as a colorless solid.