Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]2[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:14]=12)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:26][N:23]1[CH2:24][CH2:25][C:14]2=[C:13]([C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)=[O:1])[C:21]3[C:16]([N:15]2[CH2:22]1)=[CH:17][CH:18]=[CH:19][CH:20]=3
Reactant: COC(=O)c1ccc(C(O)c2c3n(c4ccccc24)CN(C)CC3)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)c2c3n(c4ccccc24)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
To a solution of methyl 4-(hydroxy(2-methyl-1,2,3,4-tetrahydropyrimido[1,6-a]indol-5-yl)methyl)benzoate (400 mg) in 60 mL of CH2Cl2 was added 0.5 g of Dess-Martin reagent. After stirring for 10 min at r.t., the reaction was quenched with 25 mL of saturated aqueous solution of NaHCO3 and the CH2Cl2 phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with up to 10% MeOH/EtOAc to give 80 mg of the title product as white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH2:4][CH3:5].[F:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:23])=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:22](=[O:23])[C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6]([CH2:3][CH2:4][CH3:5])=[CH:7]3)(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[CH:34][CH:35]=1
Reactant: CCCc1c[nH]c2ccccc12
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1cn(S(=O)(=O)c2ccc(C(=O)NCc3ccc(F)cc3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Add NaH 60% in mineral oil (0.080 g, 2.0 mmol) to a stirred solution of 3-propyl-indole (0.266 g, 1.67 mmol) in dr THF (25 mL) under N2. Stir the reaction mixture at ambient temperature for 45 min. Add 4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (0.547 g, 1.67 mmol) portion wise at ambient temperature. Stir the reaction mixture overnight at ambient temperature. Pour the reaction mixture into a two-phase mixture of EtOAc (150 mL) and saturated solution of NaHCO3 (50 mL). Separate the organic layer, wash with brine, separate and dry (MgSO4). Filter and evaporate the filtrate. Purify the residue on the chromatron using a 4 mm plate and eluting with a gradient hexane-EtOAC system to give 0.262 g (34%) of N-(4-fluoro-benzyl)-4-([3-propyl-indole-1-sulfonyl]-benzamide. Mass spectrum (m/e) M+1) 451.1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([OH:3])=O.[C:14]([NH:21][CH2:22][CH2:23][NH2:24])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.C(Cl)CCl>CN(C=O)C>[C:14]([NH:21][CH2:22][CH2:23][NH:24][C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)NCCNC(=O)OC(C)(C)C)c1
Reaction time: 16 h

Procedure:
A solution of methyl 3-carboxybenzoate (16-3) (Aldrich) (0.9 g, 5 mmol), 16-2 (0.8 g, 5 mmol), and HOBT (0.74 g, 5.5 mmol) in DMF (20 ml) was treated with Et3N (1.0 g, 10 mmol) followed by EDC (1.15 g, 6.0 mmol). After stirring for 16 h the solvent was removed, the residue was taken up in H2O (100 mL), and extracted with 3×75 ml portions of EtOAc. The organic extract was washed consecutively with 10% KHSO4, brine, satd. NaHCO3, brine, and dried (Na2 SO4). Solvent removal gave a residue that was purified by flash chromatography (silica, 95% hexanes/EtOAc) to give crude 16-4. This was further purified by chromatography (silica, 70%/acetone/hexanes) to give pure 16-4.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C([O:24][CH2:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][C:27]=1[N:41]1[N:50]=[CH:49][C:48]2[C:43](=[C:44]([F:55])[CH:45]=[C:46]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:47]=2)[C:42]1=[O:56])(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C.CCCCCC>[C:51]([C:46]1[CH:47]=[C:48]2[C:43](=[C:44]([F:55])[CH:45]=1)[C:42](=[O:56])[N:41]([C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:26]=1[CH2:25][OH:24])[N:50]=[CH:49]2)([CH3:54])([CH3:52])[CH3:53]
Reactant: Cn1nc(Cl)cc(Nc2ccc(S(C)(=O)=O)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(S(C)(=O)=O)cn2)c1=O
Temperature: 130 °C
Reaction time: 8 h

Procedure:
6-Chloro-4-(5-methanesulfonyl-pyridin-2-ylamino)-2-methyl-2H-pyridazin-3-one (40 mg, 127 μmol, Eq: 1.00), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (136 mg, 165 μmol, Eq: 1.3) and cesium carbonate (145 mg, 445 μmol, Eq: 3.5) were dissolved in 10% aq. dioxane solution (3.3 ml). The reaction mixture was heated to 130° C. for 30 min in the microwave. Reaction mixture was filtered over celite. Filtrate was extracted with ethyl acetate, washed with water, and then with brine. Organic phase was dried over sodium sulfate; filtered; concentrated to give light brown solid. The crude material was dissolved in ethyl acetate, and treated with hexane until a precipitate was formed. Precipitate was collected by filtration to give an off-white solid. Solid was dissolved in dioxane (2 ml) and 1 M sodium hydroxide solution (191 μl, 191 μmol, Eq: 1.5) was added and stirred at room temperature overnight+
Reaction SMILES: ClCCl.C(N(CC)CC)C.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:19][C:20]1([CH3:45])[C:24](=O)[CH2:23][CH2:22][CH:21]1[NH:26][C:27]1[C:28]2[N:29]([CH:36]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:38]=2)[N:30]=[CH:31][C:32]=1[C:33]([NH2:35])=[O:34]>C1C=CC=CC=1.C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:11]([N:18]=[C:24]1[CH2:23][CH2:22][CH:21]([NH:26][C:27]2[C:28]3[N:29]([CH:36]=[C:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:38]=3)[N:30]=[CH:31][C:32]=2[C:33]([NH2:35])=[O:34])[C:20]1([CH3:45])[CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)C(=O)CCC1Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Reactant: NCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)C(=NCc2ccccc2)CCC1Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Temperature: 25 °C
Yield: 31 %

Procedure:
A 1.0 M dichloromethane solution of titanium(IV) chloride (0.025 mL, 0.025 mmol) was added to a solution of triethylamine (0.042 mL, 0.298 mmol) and benzylamine (6.39 mg, 0.060 mmol) in benzene (5 mL) at room temperature. The mixture was heated to reflux. A solution of 4-((2,2-dimethyl-3-oxocyclopentyl)amino)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide (18 mg, 0.050 mmol, from Example 144) in benzene (1 mL) was added to the above mixture. The resultant mixture was kept at reflux for 3 h, cooled to room temperature, diluted with ethyl acetate (80 mL), washed with water, brine, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography, eluting with 30 to 80% ethyl acetate in hexanes, to give 4-(3-(benzylimino)-2,2-dimethylcyclopentylamino)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide (7 mg, 31% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 10.66 (1 H, d, J=8.80 Hz), 7.80-8.02 (2 H, m), 7.55-7.76 (2 H, m), 7.20-7.53 (8 H, m), 7.10 (1 H, d, J=1.76 Hz), 5.59 (2 H, br. s.), 4.41-4.51 (1 H, m), 2.56-2.78 (1 H, m), 2.34-2.60 (2 H, m), 1.92-2.01 (1 H, m), 1.19-1.43 (6 H, m); MS (ES+) m/z: 452.3 (M+H).
Reaction SMILES: C[Si]([I:5])(C)C.O[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH2:26][CH3:27])[CH:20]=2)[NH:13][C:12]1=[O:28].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[I:5][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH2:26][CH3:27])[CH:20]=2)[NH:13][C:12]1=[O:28]
Reactant: C[Si](C)(C)I
Reactant: CCc1cc(Nc2cc(=O)n(CCCCO)c(=O)[nH]2)ccc1C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(Nc2cc(=O)n(CCCCI)c(=O)[nH]2)ccc1C

Procedure:
Trimethylsilyl iodide (19.4 g, 47 mmol) was added to a stirred solution of 3-(4-hydroxybutyl)-6-(3-ethyl-4-methylanilino)uracil (7.7 g, 24.3 mmol) in dry chloroform (300 ml). The reaction mixture was stirred at reflux for 12 h, until disappearance of starting material (TLC). A saturated solution of aqueous sodium sulfite was added to decolorize the brown-purple solution. After separation of layers, the aqueous solution was extracted with chloroform, and the combined organic extracts were reduced to about one fourth volume. The solid was filtered and washed with water and acetone to give 9.9 g (95%) of IB-EMAU.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:5])=O.O.ON1C2C=CC=CC=2N=N1.[NH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.CN(C)C=O>[OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:3]([NH:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:5]
Reactant: O=C(O)C(O)(c1ccccc1)c1cccnc1
Reactant: NN1CCOCC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(NN1CCOCC1)C(O)(c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
A mixture of 2-hydroxy-2-phenyl-2-(3-pyridinyl)acetic acid (3.48 g, 0. 015 mole) , 1-hyrdoxybenzotriazole hydrate (4.10 g, 0.03 mole), 1,3-Dicyclohexycarbodiimide (3.09 g, 0.015 mole), 4-aminomorpholine (1.45 ml, 0.015 mole), sodium bicarbonate (1.26 g, 0.015 mole), N,N-dimethyformamide (36 ml) and dioxane (36 ml) were stirred at room temperature overnight. The volatiles were removed in vacuo, dichloromethane (170 ml) was added and following filtration, the organic layer was washed with saturated sodium bicarbonate and brine. After drying, filtration and concentration, the residue was purified by column chromatography using 10% methanol in chloroform to give 3.92 g of the product as a white foam. High Res. Mass Spec. Calcd. for C17H19N3O3 :314.1505 (M+H). Found: 314.1501.
Reaction SMILES: C(OC([C:8]1[NH:17][C:16]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:11](=[O:26])[C:10]=2[C:9]=1[CH3:27])=O)(C)(C)C.Cl>C(O)C>[CH3:27][C:9]1[C:10]2[C:11](=[O:26])[N:12]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:13][CH2:14][CH2:15][C:16]=2[NH:17][CH:8]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Agent: Cl
Solvent: CCO
Product: Cc1c[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 57 %

Procedure:
3-Methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester 32b (953 mg, 2.54 mmol) was dissolved in 3 ml of ethanol under stirring, and added dropwise with hydrochloric acid (3.2 ml, 12 mol/L) in an ice-water bath under an argon atmosphere. Upon completion of the addition, the ice-water bath was removed, and the reaction mixture was stirred at 60° C. in an oil bath for 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was adjusted to about pH 7 with aqueous sodium hydroxide solution (10 mol/L) and concentrated under reduced pressure to evaporate ethanol. The residue was adjusted to pH 10 with aqueous sodium hydroxide solution (10 mol/L), extracted with dichloromethane (20 ml×3). The combined organic extracts were washed with saturated brine (20 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 32c (395 m, yield 57%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:25]([C:28]1[CH:29]=[C:30]([CH2:37][C:38](Cl)=[O:39])[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)([O-:27])=[O:26]>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:38](=[O:39])[CH2:37][C:30]4[CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=4)[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)N(c2nnc(C3CC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. α-(3,5-Dinitrophenyl)-acetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[α-(3,5-dinitrophenyl)acetyloxy]-2(1H)-pyrimidinone as the residue.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][N:9]=[C:10]([C:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[CH3:16])[C:11]([O:13][CH3:14])=[O:12].S(Cl)([Cl:26])(=O)=O>C(Cl)(Cl)Cl>[CH3:7][O:8][N:9]=[C:10]([C:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[CH2:16][Cl:26])[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCOC(C)(OCC)C(=NOC)C(=O)OC
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(CCl)(OCC)C(=NOC)C(=O)OC
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
Anhydrous potassium carbonate (8.89 g) was added to a solution of methyl 2-methoxyimino-3,3-diethoxybutyrate (syn isomer, 10 g) in chloroform (40 ml). Sulfuryl chloride (6.94 g) was added to the suspension at -6 to -2° C. over 50 minutes, and stirred at -5° to -2° C. for 10 minutes. After removing the solvent from the resultant mixture, ethanol (10 ml) was added to the residue and stirred for 30 minutes. Water (25 ml) was added to the mixture, and the mixture was extracted with diisopropyl ether (20 ml) twice. The extract was washed with water (10 ml) and a saturated aqueous solution of sodium chloride (5 ml) subsequently, and dried over magnesium sulfate. The solution was evaporated in vacuo to give methyl 2-methoxyimino-3,3-diethoxy-4-chlorobutyrate (syn isomer, 11.23 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCCCCC.CCOC(C)=O>CC(C)=O.C1COCC1>[CH2:21]([O:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-(2-Hydroxy-4-nitro-phenyl)-acetamide (417) (17 g, 86.7 mmol) was dissolved in a mixture of acetone (200 mL) and THF (200 mL). Potassium-carbonate (24 g, 173.4 mmol, 2 equiv.) was added as a dry powder and the solution turned deep red. Benzyl-bromide (16.3 g, 95.37 mmol, 1.1 equiv.) was added and the mixture stirred at room temperature for 20 h. TLC (Rf: 0.5 compared to Rf: 0.2–0.3 for compound 417 in 1:1 hexane/EtOAc) indicated complete alkylation at this point. The mixture was poured into ice water (˜1000 mL) and a precipitate formed while stirring for 20 min. The precipitate was collected by filtration under reduced pressure, washed with water (3×100 mL) and dried under high vacuum for 16 h to give the desired product (418) as a faintly yellow powder (13 g, 45.4 mmol, 51.7% yield). LC-MS was inconclusive. The product was used in the next step without further characterization
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH2:14])[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2].[NH2:19][C:20]([CH:30]([F:32])[F:31])([CH2:24][C:25]1[NH:29][CH:28]=[N:27][CH:26]=1)[C:21](Cl)=[O:22]>C(OCC)(=O)C>[NH2:19][C:20]([CH:30]([F:32])[F:31])([CH2:24][C:25]1[NH:29][CH:28]=[N:27][CH:26]=1)[C:21]([NH:14][CH:10]1[C:9](=[O:15])[N:8]2[CH:11]1[S:12][CH2:13][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[C:7]2[C:16]([OH:18])=[O:17])=[O:22]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: NC(Cc1cnc[nH]1)(C(=O)Cl)C(F)F
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)(Cc3cnc[nH]3)C(F)F)C2SC1

Procedure:
A mixture of 1 g of 3-acetyloxymethyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1 g of 2-amino-2-difluoromethyl-3-(5-imidazolyl)propionic acid chloride wherein the free amino groups are protected with tertiary-butoxycarbonyl in 50 ml of ethyl acetate is refluxed for 2 hours after which the solvent is removed leaving a residue which is chromatographed on silica gel using benzene-acetone as the eluant to give 7-[[2-amino-2-difluoromethyl-3-(5-imidazolyl)propionyl]amino]-3-acetoxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid wherein the amino groups are protected with tert-butoxycarbonyl. The protected cephalosporin compound is treated with trifluoroacetic acid for 1/2 hour at 25° C. under nitrogen atmosphere then diluted with ether until precipitation stops and filtered to give the di-trifluoroacetic acid salt of the title cephalosporin which can be converted to free base by use of ion exchange resin.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC>CS(C)=O.C(Cl)Cl.CCOCC>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCOCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=CCOCCc1ccccc1
Reaction time: 0.17 h

Procedure:
To 2-(2-phenylethoxy)-1-ethanol (0.25 g; 1.5 mmol) [J. Med. Chem., 1570 (1983)] dissolved in DMSO/CH2Cl2 (4 ml/2 ml) is added Et3N (1 ml; 7 mmol) followed by sulfur trioxide pyridine complex (1.2 g; 7.5 mmol). After 10 minutes, the reaction mixture is then diluted with Et2O and washed with brine, 1N HCl, NaHCO3 and brine, dried (MgSO4) and concentrated in yacuo to dryness. The residue is purified by column chromatography using CH2Cl2 to obtain 2-phenylethoxyacetaldehyde which is used directly in Step B.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1.[OH-].[Na+]>C1COCC1.O>[CH3:1][NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: CN[C@H]1CC[C@@H](C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@H]1CC[C@@H](C(=O)O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
The methyl cis-4-(methylamino)cyclohexanecarboxylate (3 g, 0.0175 mol) from above was dissolved in a THF/H2O (10 mL) mixture and was cooled to 0° C. Next 2 L of a 0.025 M solution of NaOH was added slowly. The mixture was stirred a 0° C. for another 0.5 hour. The mixture was then acidified to pH 7-8 and extracted with ethyl acetate. The water layer was acidified to pH 3-4 and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give 2.49 g (0.016 mol, 90% yield) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:15])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]2O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[C:4]([CH3:15])[CH:5]=2)[N:10]=[C:9]([CH3:12])[C:8]=1[CH3:13]
Reactant: Cc1cc(Cl)c2nc(C)c(C)c(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)c2nc(C)c(C)c(Cl)c2c1

Procedure:
Prepared according to procedure S using 8-chloro-2,3,6-trimethylquinolin-4-ol (1.56 g, 7.0 mmol) and POCl3 (8.0 mL, 85.8 mmol) to afford 4,8-dichloro-2,3,6-trimethylquinoline.
Reaction SMILES: CCCCCCC=CCCC.Br[CH2:13][CH2:14][C:15]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16]>C(Cl)Cl>[O:16]=[C:15]1[CH2:14][CH2:13][C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:17]1
Reactant: CCOC(=O)C(NC(=O)CCBr)C(=O)OCC
Agent: CCCC=CCCCCCC
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
2(b) 314 μl of 1,8-diaza[5.4.0]-7-undecene were added to a solution of 620 mg of diethyl 2-(3-bromopropionamido)malonate (prepared as described above) dissolved in methylene chloride, and the mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, poured into water and then extracted with diethyl ether. The extract was washed with 5% w/v aqueous hydrochloric acid, with a 5% w/v aqueous solution of sodium bicarbonate and with water, in that order, and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give a crude product. This was purified by column chromatography through silica gel, eluted with a 2:1 by volume mixture of cyclohexane and ethyl acetate, to give 171 mg of diethyl 2-oxopyrrolidine-5,5-dicarboxylate.
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH2:44])=[O:43])=[C:40]([F:45])[C:39]([F:46])=[CH:38][CH:37]=4)[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH2:44])=[O:43])=[C:40]([F:45])[C:39]([F:46])=[CH:38][CH:37]=4)[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Temperature: 120 °C
Yield: 76.2 %

Procedure:
6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluorobenzamide (133 mg, 0.193 mmol) was dissolved in 1,4-dioxane (10 mL) and transferred to a 20 ml microwave vessel. Water (3 mL) and a solution of 6M NaOH (3 ml) and was added and reaction heated in microwave at 120° C. for 10 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid that was purified via chromatography on SiO2 to afford 6-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2,3-difluorobenzamide (79 mg, 0.147 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.19-2.31 (m, 6 H), 3.04-3.25 (m, 4 H), 3.70-3.87 (m, 3 H), 4.18 (m, 2 H), 6.24 (d, J=0.64 Hz, 1 H), 6.95 (d, J=2.29 Hz, 2 H), 7.23-7.44 (m, 1 H), 7.54 (br. s., 1 H), 8.06-8.23 (m, 2 H), 8.24-8.38 (m, 1 H), 8.64 (br. s., 1H), 9.93 (br. s., 1 H), 11.27 (br. s., 1 H). (ESIMS (M+H)+=537)