Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.OCCOCN1C=C(C=C)C(=O)NC1=O.[N-]=[N+]=[N-].[Na+].[OH:28][CH2:29][CH2:30][O:31][CH2:32][N:33]1[CH:40]=[C:39]([CH:41]([N:44]=[N+:45]=[N-:46])[CH2:42]Br)[C:37](=[O:38])[NH:36][C:34]1=[O:35]>COCCOC.O>[OH:28][CH2:29][CH2:30][O:31][CH2:32][N:33]1[CH:40]=[C:39]([CH:41]([N:44]=[N+:45]=[N-:46])[CH2:42][Cl:1])[C:37](=[O:38])[NH:36][C:34]1=[O:35]
Reactant: [N-]=[N+]=NC(CBr)c1cn(COCCO)c(=O)[nH]c1=O
Reactant: O=C1CCC(=O)N1Cl
Agent: C=Cc1cn(COCCO)c(=O)[nH]c1=O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: [N-]=[N+]=NC(CCl)c1cn(COCCO)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
N-Chlorosuccinimide (NCS, 88 mg, 0.65 mmol) was added slowly to a precooled (−5° C.) suspension prepared by mixing a solution of 1 (116 mg, 0.55 mmol) in 1,2-dimethoxyethane (20 ml) with a solution of sodium azide (143 mg, 2.2 mmol) in water (0.35 ml). The reaction was stirred for 3 h at 0° C. Completion of the reaction, as described for the isolation of 2a, gave a residue which was purified by silica gel column chromatography. Elution with chloroform:methanol (97:3, v/v) as eluent yielded 2b as a syrup (56 mg, 35%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([C:25]([F:28])([F:27])[F:26])([O:20][Si](C)(C)C)[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([Cl:17])[C:11]=1[O:18][CH3:19])([CH3:9])[CH3:8])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[CH2:1]([O:3][C:4](=[O:29])[C:5]([C:25]([F:26])([F:27])[F:28])([OH:20])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([Cl:17])[C:11]=1[O:18][CH3:19])([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(=O)C(CC(C)(C)c1ccc(C)c(Cl)c1OC)(O[Si](C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccc(C)c(Cl)c1OC)C(F)(F)F
Temperature: 25 °C
Yield: 34 %

Procedure:
4.4 g (9.67 mmol) of (rac.) 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentanoic acid ethyl ester is dissolved in 56 ml of tetrahydrofuran and mixed with 3.05 g (9.67 mmol) of tetrabutylammonium fluoride trihydrate and stirred for one and one-half hours at room temperature. The reaction mixture is diluted with water and extracted twice with diethyl ether. The organic phases are washed with water and with brine. After drying, the solvent is spun off, and the remaining residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 1.26 g of the desired compound is isolated.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH2:12][CH:11]([C:13](Cl)=[O:14])[O:10][N:9]=2)[CH:3]=1.C(N(CC)CC)C.[OH:23][N:24]=[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.O>C1COCC1>[OH:23]/[N:24]=[C:25](\[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)/[C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:13]([CH:11]2[O:10][N:9]=[C:8]([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)[CH2:12]2)=[O:14])=[CH:30][CH:31]=1
Reactant: O=C(Cl)C1CC(c2cccnc2)=NO1
Reactant: Nc1ccc(C(=NO)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(/C(=N/O)c2ccccc2)cc1)C1CC(c2cccnc2)=NO1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 12.9 %

Procedure:
To a cooled stirred suspension of (±)-4,5-dihydro-3-(3-pyridinyl)-5-isoxazole carbonylchloride monohydrochloride (0.016 mol) in dry THF (100 ml), triethylamine (0.040 mol) was added. The reaction mixture was cooled to 0° C. 4-[(Hydroxyimino)phenylmethyl]benzeneamine (0.018 mol) was added in one portion. Stirring was continued for 2.5 hours. Water was added to the reaction mixture and this mixture was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was stirred in CH3OH/CH2Cl2 5/95. The precipitate was filtered off, washed with CH3OH/CH2Cl2 5/95 and dried. The product (1.6 g) was stirred in boiling ethyl acetate (25 ml) and crystallized from ethyl acetate (150 ml). The volume was reduced to 75 ml. The precipitate was filtered off, washed with ethyl acetate and DIPE, then dried, yielding 0.8 g of (±)-(E)-4,5-dihydro-N-[4-[(hydroxyimino)phenylmethyl]phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide. (compound 301)
Reaction SMILES: ClC1C=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.C[O:46]C(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.O1C=CC=C1B(O)O>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[CH:9]=[C:8]([O:39][CH3:40])[CH:7]=[CH:6][C:5]=2[C:4]2[O:46][CH:43]=[CH:42][CH:41]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: OB(O)c1ccco1
Product: COc1ccc(-c2ccco2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 5 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 2-furanboronic acid (30 mg, 0.2625 mmol) to produce the title compound (5 mg, 5% yield).
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH2:3][C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>CC(C)=O>[OH:1][CH:2]([CH3:14])[CH2:3][C:4]1[N:8]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1cc(CC(C)O)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(CC(C)O)n(COCC[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a flask containing ethyl 5-(2-hydroxypropyl)-1H-pyrazole-3-carboxylate (15.65 mmol, 3.2 g) in acetone (60 ml), Cs2CO3 (13.7 g, 99.1 mmol), SEM-Cl (9.3 ml, 51.6 mmol) were added and stirred at RT overnight. The reaction mixture was quenched by the addition of H2O and extracted with EtOAc. The organic layer was concentrated and purified by column-chromatography. Yield 3.8 g. 1H-NMR (400 MHz; CDCl3): δ −0.05 (s, 9H), 0.89 (t, 2H), 1.25 (d, 3H), 1.40 (t, 3H), 2.71-2.83 (m, 3H), 3.57 (t, 2H), 4.34 (q, 2H), 5.79 (s, 2H), 6.74 (s, 1H). LC-MS: [M+1]=329.14.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]4([CH2:18][CH2:19][C:5]=3[C:4]=2[CH:3]=1)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29]>C(#N)C.C(OCC)(=O)C>[OH2:1].[CH3:26][N:27]([CH3:31])[C:28]([O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]4([CH2:18][CH2:19][C:5]=3[C:4]=2[CH:3]=1)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)=[O:29].[CH3:26][N:27]([C:28]([O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]4([CH2:18][CH2:19][C:5]=3[C:4]=2[CH:3]=1)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)=[O:29])[CH3:31]
Reactant: CN(C)C(=O)Cl
Reactant: Cn1c2c(c3cc(O)ccc31)CCC21CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Oc1ccc2c(c1)c1c(n2C)C2(CCNCC2)CC1
Product: O
Yield: 18.7 %

Procedure:
To a solution of 1,4-dihydro-7-hydroxy4-methylspiro[cyclopent[b]indole-3(2H), 4′-piperidine] (0.61 g) and cesium carbonate (1.55 g) in acetonitrile (100 ml) was added dimethylcarbamyl chloride (0.25 g), under nitrogen, with stirring. The reaction mixture was stirred for 24 hrs, diluted with ethyl acetate, and the mixture was washed with saturated sodium chloride solution. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flash chromatographed (silica), eluting with 5% methanol/dichloromethane. The appropriate fractions were collected and concentrated. The residue was recrystallized from ethyl acetate/petroleum ether. The precipitate was flash chromatographed (silica), eluting with 25% ethyl acetate/dichloromethane to give 0.1 g (15%) of product, mp 110-111° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([OH:26])=O)[CH:22]=2)[NH:17][C:16]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:78]1[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:11])[N:12]([CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([N:78]3[CH2:83][CH2:82][O:81][CH2:80][CH2:79]3)=[O:26])[CH:22]=2)[NH:17][C:16]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)O)cc3c2CCN(CCCCc2ccncc2)C(=O)OCc2ccccc2)c1
Reactant: C1COCCN1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCN(CCCCc2ccncc2)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 100 mg (0.163 mmol) of 3-[2-[benzyloxycarbonyl-[4-(pyridin-4-yl)butyl]amino]ethyl]-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid hydrochloride 101.7 mg (0.196 mmol) of PyBOP reagent, 0.085 mL (85.2 mg, 0.978 mmol) of morpholine, and 1 mL of dry methylene chloride was stirred under nitrogen at room temperature in a stoppered flask. After 5 days, the solution was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the crude product by flash chromatography on silica gel (gradient elution with 1-4% MeOH in CH2Cl2) afforded a quantitative yield of the title compound as a yellow gum; homogeneous by TLC in 95:5 CH2Cl2-MeOH. 500 MHz 1H NMR (CDCl3) was complex, owing to rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e=645.6 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>O1CCCC1.O>[OH:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: NCCCCO
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCCCCO
Yield: 100 %

Procedure:
A solution of methyl 2-chloro-3-nitrobenzoate (53.5 g, 248 mmol), triethylamine (41.5 mL, 298 mmol), and 4-amino-1-butanol (45.7 mL, 496 mmol) in tetrahydrofuran (400 mL) was stirred for 60 h at 50° C. The mixture was diluted with water, concentrated in vacuo, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate (short column) to give the title compound as a yellow oil (66.5 g, 248 mmol, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]([O-])(C)[CH3:31].[K+].C(Br)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH:30]([CH3:31])[CH3:29])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(S)cc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)Br
Product: CC(C)Sc1ccc(NC(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.00 g (2.21 mmol) of 5-chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-mercapto-phenyl)-benzamide were dissolved in 25 ml of dimethylformamide and 0.25 g (2.21 mmol) of potassium tert-butylate were added. The mixture was stirred at room temperature for 15 min, then 0.27 g (2.21 mmol) of isopropyl bromide were added dropwise, and the mixture was heated to 60° C. for 8 h. For working up it was poured onto water and extracted with ethyl acetate. The combined extracts were evaporated and the residue was purified by chromatography over silica with hexane/ethyl acetate (3:1). 420 mg (39%) of the title compound having a melting point of 168-169° C. were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])=[C:4]([CH3:14])[CH:3]=1.[O-:15][CH2:16][CH3:17].[Na+]>>[CH2:16]([O:15][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])=[C:4]([CH3:14])[CH:3]=1)[CH3:17]
Reactant: CCOC(=O)Nc1nnc(Cl)cc1C
Reactant: CC[O-]
Agent: [Na+]
Product: CCOC(=O)Nc1nnc(OCC)cc1C
Temperature: 110 °C
Yield: 69.3 %

Procedure:
A 20 mL microwavable vial was charged with ethyl (6-chloro-4-methylpyridazin-3-yl)carbamate (550 mg, 2.55 mmol) and sodium ethoxide (3.11 mL, 17.85 mmol), then stirred and heated at 110° C. for 12 h. The reaction mixture was then concentrated and partitioned between ammonium chloride and DCM. The layers were separated and the aqueous layers were washed with DCM (2×). The combined organic layers were washed with water, brine, and eluted through a phase separator. The organic layers were concentrated to afford ethyl (6-ethoxy-4-methylpyridazin-3-yl)carbamate (398 mg, 65.8% yield).
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([CH2:18][CH2:19][CH3:20])[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:21])=[CH:5][N:6]=1
Reactant: CCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: NC1CCOCC1
Product: CCCc1noc(C)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 19 %

Procedure:
As described for example 1e, 6-(5-methyl-3-propyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (145 mg, 0.50 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (35 mg, 19%) which was obtained as a white solid after purification by chromatography (silica, 0-6% methanol in dichloromethane) and after trituration with diisopropyl ether. MS: m/e=360.3 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(N(CC)CC)C.[NH2:35][CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:40]1[CH:41]=[CH:42][C:37]([CH2:36][NH:35][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:2])=[CH:38][CH:39]=1
Reactant: NCc1ccncc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)NCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (15.4 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (30 μL) was added followed by 4-aminomethylpyridine (14 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.8 mg) and 4-dimethylaminopyridine (˜1 mg). The mixture was stirred at room temperature for 19 h then eluted directly on silica gel column (2-10%MeOH in CH2Cl2) to yield 8.9 mg of the title compound. 1H NMR (500 MHz, CDCl3,partial): δ 8.56 (m, 2H); 8.46 (br s, 1H); 8.39 (d, J=5.5 Hz, 1H); 7.96 (s, 1H); 7.81 (d, J=7.9 Hz, 1H); 7.71 (d, J=7.8 Hz, 1H); 7.63 (d, J=7.8 Hz, 1H); 7.47 (t, J=7.7 Hz, 1H); 7.24 (d, J=5.9 Hz, 1H); 6.79 (d, J=5.5 Hz, 1H); 6.64 (br s, 1H); 5.77 (br s, 1H); 5.5.24 (br s, 1H); 4.65 (m, 2H); 1.66 (d, J=7.1 Hz, 3H). Mass Spectrum (ESI): m/e 450.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[C:22](Cl)(Cl)=[O:23].[NH3:26]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([O:20][C:22](=[O:23])[NH2:26])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: N
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCC(O)CC1
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Product: NC(=O)OC1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-chloro-3-(4-hydroxypiperidinocarbonylmethyl)benzothiazolin-2-one (3.2 g) in dry dioxane (70 ml) was gradually dropped in a phosgene solution in dry dioxane (10 ml), under cooling. The mixture was left for two hours at room temperature. After cooling, to the mixture was gradually dropwise added 28% aqueous ammonia (5 ml) and the resultant was stirred for two hours at room temperature. Dioxane was evaporated off under vacuum from the reaction mixture. The residue was washed with water and then recrystallized from a mixture of dioxane and ethanol to yield the title compound as colorless crystals (2.8 g). m.p. 210°-212° C.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:34]2[N:35]=[C:36]([NH:39][CH:40]=[O:41])[S:37][CH:38]=2)[C:7]([NH:9][C@@H:10]2[C:32](=[O:33])[N:12]3[C:13]([C:19]([O:21]CC4C=CC([N+]([O-])=O)=CC=4)=[O:20])=[C:14]([O:17][CH3:18])[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.[H][H].O1CCCC1.C(O)(=O)C>[Pd].CO>[CH:1]1([O:4][N:5]=[C:6]([C:34]2[N:35]=[C:36]([NH:39][CH:40]=[O:41])[S:37][CH:38]=2)[C:7]([NH:9][C@@H:10]2[C:32](=[O:33])[N:12]3[C:13]([C:19]([OH:21])=[O:20])=[C:14]([O:17][CH3:18])[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)C(=NOC3CC3)c3csc(NC=O)n3)[C@H]2SC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC3CC3)c3csc(NC=O)n3)[C@H]2SC1
Yield: 50.1 %

Procedure:
p-Nitrobenzyl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-methoxy-3-cephem-4-carboxylate (syn isomer) (0.9 g) was hydrogenated under 1 atmospheric pressure of hydrogen in the presence of 10% palladium on carbon (0.9 g) in a mixture of methanol (20 ml), tetrahydrofuran (400 ml), and acetic acid (0.01 ml) at ambient temperature for 2 hours. The catalyst was filtered off and washed successively diluted aqueous solution of sodium bicarbonate and tetrahydrofuran. The filtrate and the washings were combined and washed with ethyl acetate. The aqueous solution was adjusted to pH 3 with 1N hydrochloric acid and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo, and triturated in diisopropyl ether to give 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer) (0.35 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cccc(Cl)c1
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cccc(Cl)c1

Procedure:
Following General Procedure G′ above and using 3-Chlorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18])(=O)C.Cl>O1CCOCC1>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:14])([F:15])([F:16])([F:13])[F:12])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Yield: 98.7 %

Procedure:
4-Acetamido-3-nitrophenylsulphur pentafluoride (29.0 g) was heated at reflux with hydrochloric acid (6N) and dioxan for 40 minutes and concentrated to low volume, basified with sodium carbonate solution and extracted (ether). The extract was washed (water), dried (magnesium sulphate) and evaporated to give 4-amino-3-nitrophenylsulphur pentafluoride (24.7 g), m.p.132°-1350° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][C:30]=3[F:38])[CH:20]=2)=[N:15][CH:14]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>CO.O.[Zn]>[C:1]([O:5][C:6](=[O:39])[N:7]([CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=3[F:38])[CH:20]=2)=[N:15][CH:14]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 274.9 %

Procedure:
To a solution of 45 (1.1 g, 0.717 mmol) in MeOH (30 mL) and water (10 mL) was added ammonium chloride (211 mg, 3.95 mmol) and zinc (1.61 g, 17.76 mmol) and the reaction mixture was heated to reflux for 24 hours. The reaction mixture was cooled to RT then concentrated to dryness. The residue was partitioned between DCM and water and the organic phase was collected, dried over Na2SO4, filtered and concentrated to afford the title compound 46 (1.04 g, 100% yield), which was used crude in the next step with no additional purification. MS (m/z): 528.1 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.CO.[OH-].[Li+].Cl>O.O1CCCC1>[F:34][CH:32]([F:33])[O:31][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:35])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(S(=O)(=O)CC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(S(=O)(=O)CC)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of [4-difluoromethoxy-3-(4-ethanesulfonylbenzyl)-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.080 g), methanol (2.0 mL), tetrahydrofuran (2.0 mL), water (2.0 mL) and lithium hydroxide (0.006 mg) was stirred at room temperature for 45 minutes. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid and purified by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water to afford title compound as an off-white solid, 0.025 g.