Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:69])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](=[O:68])[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][C@@H:39]([C:61]([O:63]C(C)(C)C)=[O:62])[NH:40][C:41](=[O:60])[NH:42][C@H:43]([C:53]([O:55]C(C)(C)C)=[O:54])[CH2:44][CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])(C)(C)C.C(Cl)Cl>C(O)(C(F)(F)F)=O>[C:6]([CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](=[O:68])[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([C:61]([OH:63])=[O:62])[NH:40][C:41](=[O:60])[NH:42][CH:43]([C:53]([OH:55])=[O:54])[CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH2:15][C:16]([OH:18])=[O:17])([OH:69])=[O:5]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCCCCCN(CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(NC(=O)NC(CCCCNC(=O)CCCCCCCCCCN(CC(=O)O)Cc1nccn1CC(=O)O)C(=O)O)C(=O)O

Procedure:
[Re(CO)3][(19S,23 S)-2-((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylic acid] (221). A solution of (19S,23S)-tetra-tert-butyl 2-((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylate (18.8 mg, 0.019 mmol) in TFA (1.0 mL)/DCM (1.0 mL) was stirred at room temperature for overnight. The solvent was evaporated to give 19S,23 S)-2-((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylic acid as a colorless oil. To a solution of the above deprotected product in water (1.0 mL) that was adjusted to pH=9 by 2 N NaOH was added Re(CO)3(H2O)OTf (0.50 mL, 0.10 mL/mmol). The reaction mixtures were stirred at room temperature for overnight and purified by HPLC to afford the title compound (4.0 mg, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 7.70 (t, J=5.6 Hz, 1H), 7.33 (s, 1H), 7.13 (s, 2H), 6.29 (d, J=8.4 Hz, 1H), 6.26 (d, J=8.4 Hz, 1H), 4.96 (d, J=4.8 Hz, 2H), 4.56 (d, J=16.4 Hz, 1H), 4.12 (d, J=16.8 Hz, 1H), 4.07-3.90 (m, 2H), 3.70 (d, J=17.2 Hz, 1H), 3.40 (d, J=17.2 Hz, 1H), 2.98-2.94 (m, 4H), 2.21 (q, J=7.73, 2H), 1.99 (t, J=7.6 Hz, 2H), 1.70-1.22 (m, 24H); MS (ESI), 485.2 (M/2-H)+.
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[CH3:26])[C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][C:4]=1[CH3:14].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClC(Cl)C.N1C=CC=CC=1>[N:9]1([C:7]2[CH:6]=[CH:5][C:4]([CH3:14])=[C:3]([CH:8]=2)[CH:2]([C:15]2[C:16]([CH3:26])=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][C:24]=2[CH3:25])[O:1][C:39](=[O:40])[C@@H:38]([NH:37][S:34]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH3:42])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: C[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Cl
Reactant: COC(=O)c1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(C)c(C(OC(=O)[C@H](C)NS(=O)(=O)c2ccc(Cl)cc2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Reaction time: 3 h
Yield: 100.3 %

Procedure:
Methyl (±)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoate (9.2 g) was suspended in dichloroethane (110 ml) and pyridine (3.15 ml), and a solution of (S)-2-(4-chlorobenzenesulfonylamino)propionyl chloride (8.9 g) in dichloroethane (25 ml) was added dropwise over 5 minutes with siring under ice-cooling. The mixture was sired at room temperature for 3 hours and the reaction mixture was washed successively with water, 5% citric acid, 5% potassium carbonate and water. The organic layer was separated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 15.7 g of methyl (±)-4-[5-(1-imidazolyl)-α-{(S)-2-(4-chlorobenzenesulfonylamino)propionyloxy}-2-methylbenzyl]-3,5-dimethylbenzoate as a pale-yellow oil. This was crystallized from ethyl acetate (27 ml) and isopropyl ether (108 ml) and the obtained crystals were recrystallized from ethyl acetate (15 ml) and isopropyl ether (30 ml) to give 5.2 g of methyl (S)-4-[5-(1-imidazolyl)-α-{(S)-2-(4-chlorobenzenesulfonylamino)propionyloxy}-2-methylbenzyl]-3,5-dimethylbenzoate as white crystals, melting point 126-128° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:23]O>>[CH3:23][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=1[NH2:1]
Reactant: CO
Reactant: Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 28 g (112 mmol) of 2-amino-5-nitro-4-trifluoromethyl-benzoic acid in 550 ml of methanol is cooled to 0° C. under nitrogen and concentrated H2SO4 is added dropwise in order to keep the temperature around 20° C. Upon completion of the addition, the mixture is heated to reflux for 24 hours. It is then allowed to cool to room temperature and the mixture is concentrated in vacuo to about 50 ml. This residue is poured onto ice and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product is recrystallized in toluene to give 26.7 g (90%) of 2-amino-5-nitro-4-trifluoromethyl-benzoic acid methyl ester as yellow crystals, m.p. 174-175° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=O.O>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]2[O:9][C:1](=[O:10])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[N:4]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1ccccc1C(=O)O
Solvent: O
Solvent: c1ccncc1
Product: O=c1oc(-c2cccc(Cl)c2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a stirred solution of 76.5 g (0.56 mole) of anthranilic acid in 1000 ml of pyridine at room temperature was added 197 g (1.12 mole) of m-chlorobenzoyl chloride at a rapid dropwise rate. The temperature rose to 45°-50° and, midway through the addition, a precipitate began forming. After stirring one hour at room temperature the slurry was poured into 1500 ml of water and the precipitate was filtered, washed well with water and air dried to give 139 g (96.5%) of 2-(m-chlorophenyl)-4H-3,1-benzoxazin-4-one, m.p. 158°-60°. Crystallization from ethanol gave an analytical sample, m.p. 159°-60°.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.O1CCOCC1>[I:16][C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:17]=[CH:18][C:2]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:3][CH:4]=2)[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: C1COCCN1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)nc2)cc1I

Procedure:
A mixture of 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide (50 mg, 0.13 mmol) and morpholine (35 mg, 0.42 mmol), diisopropylethyl amine (0.07 mL, 0.42 mmol) and a catalytic amount of DMAP in dioxane (5 mL) was heated at 120° C. in a sealed tube until consumption of the limiting reagent. The mixture was then cooled and partitioned between EtOAc and water. Organic layer was removed, dried over Na2SO4 filtered and concentrated to a residue that after a silica gel column with 20-40% EtOAc in hexanes gradient afforded the product. HRMS m/z calcd for C17H18N3O2I [M+H]+: 424.0517. Found: 424.0516.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].CS(C)=O.C[C:21](C)([O-:23])C.[K+]>CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:23][CH3:21])[C:3]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15]
Reactant: CC(C)(C)[O-]
Reactant: O=C1NC(=O)C(c2c(F)cccc2F)O1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: COc1cccc(F)c1C1OC(=O)NC1=O
Temperature: 155 °C

Procedure:
5-(2,6-Difluorophenyl)oxazolidine-2,4-dione (2.0 g., 9.4 mmoles) was dissolved in 50 ml. of dimethylsulfoxide. Methanol (5 ml.) and then potassium tert-butoxide (2.11 g., 18.8 mmoles) were then added and the reaction mixture heated in an oil bath maintained at 155° C. for 4 hours. The reaction mixture was cooled to room temperature, poured into 200 ml. of 1 N hydrochloric acid and extracted with three portions of ethyl acetate. The combined organic extracts were washed with water and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated to solids. The solids were taken up in 1 N sodium hydroxide, and the solution washed with three portions of ethyl acetate and then acidified with 1 N hydrochloric acid to precipitate purified 5-(2-fluoro-6-methoxyphenyl)oxazolidine-2,4-dione (1.32 g., 62%; m.p. 138°-142° C.). For analysis, the product was recrystallized from toluene (930 mg. recovered; m.p. 139°-141° C.).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.CCN(CC)CC.[O:19](C(C(F)(F)F)=O)[C:20]([C:22]([F:25])([F:24])[F:23])=O>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:20]([N:3]1[CH2:2][CH2:1][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4]1)=[O:19]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccc2c(c1)CCNCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N1CCc2ccccc2CC1)C(F)(F)F
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a stirred solution of 2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.25 g, 1.7 mmol) in anhydrous CH2Cl2 (5 ml), Et3N (0.28 ml, 2 mmol) was added at 0° C. and under N2, followed by (CF3CO)2O (0.29 ml, 2 mmol) and the resulting mixture was stirred for 1 h, than washed with aqueous NaHCO3 and H2O. The organic layer was dried over MgSO4, filtered and the filtrate was evaporated to dryness to give the title product (0.418 g, 100%), as pale oil. 1H-NMR (CDCl3) 3.6-3.97 (m, 8H); 7.11-7.19 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]2([CH3:15])[CH2:13][S:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:7]=1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:47]=[CH:46][C:29]([C:30](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1>ClCCl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:30]([C:29]2[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[NH:14][C:10]2[CH2:11][S:12][CH2:13][C@:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:16])([CH3:15])[N:9]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CSCC(N)=N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)CSC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution (R)-5-(5-bromo-2-fluorophenyl)-5-methyl-5,6-dihydro-2H-1,4-thiazin-3-amine (910 mg, 3 mmol, Eq: 1.00) and triethylamine (607 mg, 836 μl, 6.00 mmol, Eq: 2) in dichloromethane (30.0 ml) at 23° C. was added 4,4′-dimethoxytrityl chloride (1.12 g, 3.3 mmol, Eq: 1.1) and the mixture was stirred at 23° C. for 2 h. The solution was concentrated in vacuum and directly subjected to silica gel flash chromatography with n-heptane and ethyl acetate to give the (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-bromo-2-fluorophenyl)-5-methyl-5,6-dihydro-2H-1,4-thiazin-3-amine (1.67 g, 2.76 mmol, 91.9% yield) as an off-white foam. MS (ISP): m/z=605.1 [M+H]+ and 607.2 [M+2+H]+.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:21](OC(=O)C)(=[O:23])[CH3:22]>C([O-])(=O)C.[Na+].O>[CH2:1]([NH:11][C:12]([CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:21](=[O:23])[CH3:22])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCNC(=O)CCCOCCO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCNC(=O)CCCOCCOC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
In a glass reaction vessel 17.7 grams (0.0616 mole) of N-decyl-4-(2-hydroxyethoxy)butyramide was admixed with 25.3 grams (0.25 mole) of acetic anhydride in the presence of 4 grams sodium acetate catalyst. This mixture was heated to 100° C. on a steam bath until a reaction was completed within a period of 3 hours. The mixture was then drowned in water, salted out and phase separated. The upper liquid phase was dried to 17.8 grams of liquid product having a refractive index ηd25 =1.4586 and an IR of 6.09 mu.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(#N)C>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2)CC1
Reaction time: 5 h
Yield: 125.8 %

Procedure:
To a stirring solution of 1-Boc-piperidine-4-carboxaldehyde (2.4 g, 11.3 mmol) in THF (60 mL) and acetonitrile (15 mL) was added piperazine (4.85 g, 56.3 mmol). After stirring for 5 h, sodium triacetoxyborohydride (2.87 g, 13.5 mmol) was added and the reaction was allowed to stir overnight. The next morning, the solvents were removed by rotary evaporation and the residue was dissolved in ethyl acetate, washed twice with satd aq. NaHCO3, followed by water, then dried over MgSO4, filtered and concentrated in vacuo. The residue was then chromatographed over silica gel, eluting with a step gradient of 2% through 15% (2 N ammonia/methanol) in dichloromethane. The product containing fractions were combined and concentrated in vacuo to give 4.03 g (48%) of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C1C(=O)N([Br:26])C(=O)C1>C(#N)C>[Br:26][C:5]1[S:1][C:2]([CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccs2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of tert-butyl 4-(thiazol-2-yl)piperidine-1-carboxylate (530 mg, 1.97 mmol) in acetonitrile (10 mL) was added NBS (1.40 g, 7.86 mmol). The mixture was stirred at RT for 14 hours and heated at 50° C. for 4 hours. The reaction mixture with some starting material recovered was poured into a solution of Na2SO3 (30 mL) and 6N NaOH (2 mL). The aqueous layer was extracted with EtOAc, dried over MgSO4, and the combined organics concentrated in vacuo. The residue was purified by silica gel chromatography to provide tert-butyl 4-(5-bromothiazol-2-yl)piperidine-1-carboxylate as a yellow oil [210 mg (0.61 mmol); 1H NMR (300 MHz, CDCl3) 7.59 (s, 1H), 4.20 (brd, J=12.9 Hz, 2H), 3.13 (tt, J=3.8, 11.5 Hz, 1H), 2.89 (t, J=11.6 Hz, 2H), 2.08 (d, J=11.7 Hz, 2H), 1.72 (dq, J=4.3, 11.9 Hz, 2H), 1.49 (s, 9H)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[N:29]1([CH2:35][CH2:36][OH:37])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([N:32]1[CH2:33][CH2:34][N:29]([CH2:35][CH2:36][OH:37])[CH2:30][CH2:31]1)=[O:21]
Reactant: OCCN1CCNCC1
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)N2CCN(CCO)CC2)c(=O)n(C)c1=O

Procedure:
Example 44 was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and 2-(piperazin-1-yl)ethanol. 1H NMR (400 MHz, CDCl3) δ 7.55 (m, 2 H) 6.95 (t, J=8.0 Hz, 1 H) 4.17 (br, 1 H) 3.86 (br, 3 H) 3.54 (br, 5 H) 3.33 (br, 1 H) 3.28 (br, 5 H) 3.10 (br, 2 H) 2.37 (br, 1 H). [M+H] calc'd for C19H23FIN5O4, 532; found, 532.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].C(N(CC)CC)C.[CH:29]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)(Cl)Cl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C1CCCC1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A solution of 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) and triethylamine (0.64 mL, 4.6 mmol) in chloroform (100 mL) was cooled with an acetone/ice bath. Cyclopentanecarbonyl chloride (0.47 mL, 3.9 mmol) was slowly added. The reaction was complete within 10 minutes. The reaction mixture was washed with water (1×100 mL) and brine (1×100 mL). The organic layer was dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was slurried with acetonitrile. The resulting solid was isolated by filtration and dried in an oven overnight to provide 1.01 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclopentanecarboxamide as a light brown solid, m.p. 178.6-179.5° C. Analysis: Calculated for C22H29N5O-0.25H2O: % C, 68.81; % H, 7.74; % N, 18.24; Found: % C, 68.77; % H, 7.87; % N, 18.19.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4].Cl[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: Clc1nc2ccccc2s1
Reactant: COC(=O)c1cc2cc(O)ccc2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(Oc3nc4ccccc4s3)ccc2o1
Yield: 80 %

Procedure:
To a solution of 5-hydroxy-benzofuran-2-carboxylic acid methyl ester (300 mg, 1.56 mmol) in DMF (5 mL) was added 2-chlorobenzothiazole (263 mg, 1.56 mmol) and Cs2CO3 (590 mg, 1.87 mmol). The resultant suspension was warmed (50° C., 18 h). The reaction mixture was concentrated under a stream of nitrogen. The resultant residue was purified by silica gel flash chromatography using EtOAc:hexane (10-30%) to provide the title compound (406 mg, 80%). MS (ESI): mass calcd for C17H11NO4S, 325.0; m/z found, 326.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.76-7.72 (m, 2H), 7.70 (d, J=8.0, 1H), 7.67 (d, J=9.0, 1H), 7.57 (s, 1H), 7.49-7.44 (m, 1H), 7.43-7.38 (m, 1H), 7.32-7.27 (m, 1H), 4.01 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:14][NH:13][C:12]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:27][N:13]1[CH2:14][C@@H:15]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:26]
Reactant: O=C(OCc1ccccc1)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN1C[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 70 %

Procedure:
A mixture of 25 g of benzyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate, 29.3 g of anhydrous potassium carbonate, 50 g of methyl iodide and 200 ml of acetone is vigorously stirred at room temperature for 5 days. The mixture is concentrated under reduced pressure to remove solvent. Ethyl acetate and water are added to the residue, and the ethyl acetate layer is collected therefrom. The ethyl acetate solution is dried and concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography and then triturated with ether. 18.2 g of benzyl (4S)-1-methyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are thereby obtained as colorless crystals. Yield: 60.7%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[CH2:13]([N:15]([CH2:30][CH3:31])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[NH:23][C:24]([CH:28]=O)=[CH:25][C:26]=1[CH3:27])=[O:21])[CH3:14]>>[CH2:30]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[NH:23][C:24]([CH:28]=[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:8][C:7]2=[O:12])=[CH:25][C:26]=1[CH3:27])=[O:21])[CH3:31]
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)cc1C
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: CCN(CC)CCCNC(=O)c1[nH]c(C=C2C(=O)Nc3ccc(OC)cc32)cc1C
Yield: 39 %

Procedure:
5-Methoxy-1,3-dihydroindol-2-one (82.5 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide to give 80 mg (39%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([C:19]#[N:20])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][CH2:30][NH:31]2)=[CH:27][CH:26]=1.Cl.N1C=CC=CC=1>COCCO>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:24][C:25]3[CH:33]=[C:32]4[C:28]([CH2:29][CH2:30][NH:31]4)=[CH:27][CH:26]=3)=[C:14]([C:19]#[N:20])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)NCC2
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCc1ccccc1
Agent: Cl
Solvent: COCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc4c(c3)NCC4)c(C#N)cnc2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 27 %

Procedure:
A solution of 586 mg (1.60 mM) of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile, 560 mg (1.70 mM) of 6-Aminoindolin dihydrchloride salt and 208 mg (1.80 mM) of pyridine hydrochloride in 13 ml of 2-methoxyethanol was refluxed for 3 hours. The reaction was allowed to cool to room temperature and the resulting solid was isolated and washed with excess ethanol and dried under vacuum at 80° C. The resulting solid was digested in 300 ml of ethanol and the volume was reduced to 100 ml. The solid was isolated from the hot solution and the digestion process was repeated a second time. The solid was once again isolated from the hot solution to yield 206 mg of 7-benzyloxy-4-(2,3-dihydro-1H-indol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile as a tan solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[S:3]([CH2:6][C:7](O)=[O:8])(=[O:5])=[O:4].ON1C(=O)CCC1=O.[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[S:34][C:33]([CH3:35])=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12>>[F:1][C:2]([F:11])([F:10])[S:3]([CH2:6][C:7]([NH:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[S:34][C:33]([CH3:35])=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12)=[O:8])(=[O:5])=[O:4]
Reactant: O=C(O)CS(=O)(=O)C(F)(F)F
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Agent: O=C1CCC(=O)N1O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CS(=O)(=O)C(F)(F)F)[C@H]3SC2)s1

Procedure:
Using the procedure in Example 1 trifluoromethylsulfonylacetic acid is esterified with N-hydroxysuccinimide and then is reacted with 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid using the procedure of Example 3 to give the title compound.