Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.[CH3:10]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.N1[C:53]2[CH2:52][CH2:51][NH:50][CH2:49][C:48]=2[CH:47]=[CH:46][C:45]=1[C:54]([O:56][CH3:57])=[O:55]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:50]1[CH2:51][CH2:52][C:53]2[C:48](=[CH:47][CH:46]=[C:45]([C:54]([O:56][CH3:57])=[O:55])[CH:10]=2)[CH2:49]1)=[O:9]
Reactant: Cn1cccc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1ccc2c(n1)CCNC2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CCN(C(=O)c1cccn1C)C2
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a vial containing N-methylpyrrole-2-carboxylic acid (0.0206 g, 0.165 mmol) was added HATU (0.0627 g, 0.165 mmol) in DMF (1.00 mL) followed by DIPEA (0.157 mL, 0.9 mmol) in DMF (0.5 mL). The mixture was shaken at rt for 30 min before methyl 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride (0.0343 g, 0.15 mmol) in DMF (1.00 mL) was added. The solution was then shaken at rt for 13 h. The solvent was evaporated and to the residue was added DCE (3 mL), water (1 mL), and a few drops of ammonia in MeOH (7 N). After being thoroughly mixed, the layers were separated and the aqueous layer was extracted with DCE (3 mL). The combined organic phases were then concentrated to give a solid residue.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([NH:11][CH2:12][C:13]2[CH:14]=[C:15]([C:21]3[CH:22]=[CH:23][C:24]4[O:28][N:27]=[C:26]([NH:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]=4[CH:35]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:10][CH2:9]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH:8]1([N:11]([CH2:12][C:13]2[CH:14]=[C:15]([C:21]3[CH:22]=[CH:23][C:24]4[O:28][N:27]=[C:26]([NH:29][CH2:30][C:31]([CH3:32])([CH3:34])[CH3:33])[C:25]=4[CH:35]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[S:37]([CH3:36])(=[O:39])=[O:38])[CH2:9][CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2ccc3onc(NCC(C)(C)C)c3c2)cc1CNC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc3onc(NCC(C)(C)C)c3c2)cc1CN(C1CC1)S(C)(=O)=O
Temperature: -70 °C
Reaction time: 15 h
Yield: 69.5 %

Procedure:
Triethylamine (0.14 mL, 0.99 mmol, 1.5 equiv.) was added to a solution of 5-(3-((cyclopropylamino)methyl)-4-methoxyphenyl)-N-neopentylbenzo[d]isoxazol-3-amine (exemplary compound 45) (0.25 g, 0.66 mmol, 1 equiv.) in DCM (10 mL) and the mixture was subsequently cooled to −70° C. Methanesulphonic acid chloride (0.06 mL, 0.79 mmol, 1.2 equiv.) was added in drops and the mixture was heated slowly to RT and stirred for 15 hours. The reaction mixture was diluted with DCM (50 mL) and extracted with sat. aq. sodium hydrogen carbonate sol. (1×10 mL) and sat. aq. NaCl solution (1×10 mL), dried (MgSO4) and the solvent removed in a vacuum. After column-chromatographic purification (EtOAc/DCM; 1:1), the desired product (0.21 g, >99%) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[CH:38]([Mg]Br)=[CH2:39].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]([OH:9])[CH:38]=[CH2:39]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(C=O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 6-(N-(3-chloro-4-formylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1.17 g, 2.16 mmol) in THF (20 mL) was cooled to 0° and treated with vinylmagnesium bromide (1 M in THF, 4.76 mL). The reaction mixture was allowed to warm to rt as the bath melted. An additional portion of vinylmagnesium bromide (0.43 mL,) was added after a few h. Stirring was continued and the reaction mixture was poured into saturated ammonium chloride and extracted with EtOAc (2×). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient of 0 to 60% EtOAc in hexanes) afforded the title compound (0.87 g, 71%) as a white foam. Enantiomers were separated by supercritical fluid chromatography (Chiral Tech ADH, 30% methanol, 140 bar, 40° C., 90 mL/min). Both enantiomers were white foams. The earlier eluting enantiomer 1 weighed 380 mg and the later eluting enantiomer 2 weighed 370 mg. Enantiomer #1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (q, 1H), 8.11 (s, 1H), 7.93-8.01 (m, 2H), 7.35-7.55 (m, 5H), 7.18 (s, 1H), 5.90 (ddd, 1H), 5.70 (d, 1H), 5.35 (t, 1H), 5.22 (dt, 1H), 5.08 (dt, 1H), 3.40 (s, 3H), 2.83 (d, 3H), 2.10-2.20 (m, 1H), 0.77-1.06 (m, 3H), 0.40-0.53 (m, 1H). LCMS (m/z, ES+)=569 (M+H+). Enantiomer #2 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (q, 1H), 8.11 (s, 1H), 7.93-8.01 (m, 2H), 7.36-7.56 (m, 5H), 7.18 (s, 1H), 5.90 (ddd, 1H), 5.70 (d, 1H), 5.35 (t, 1H), 5.22 (dt, 1H), 5.08 (dt, 1H), 3.40 (s, 3H), 2.83 (d, 3H), 2.09-2.20 (m, 1H), 0.76-1.06 (m, 3H), 0.40-0.54 (m, 1H). LCMS (m/z, ES+)=569 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[C:14]([O-:17])([O-])=[O:15].[K+].[K+].[C:20](#N)[CH3:21]>CN(C=O)C.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:10]([O:9][C:7]([C:6]1[CH:12]=[CH:13][C:3]([CH2:2][O:8][CH2:7][C:6]2[CH:12]=[CH:13][C:3]([C:14]([O:17][CH2:20][CH3:21])=[O:15])=[CH:4][CH:5]=2)=[CH:4][CH:5]=1)=[O:8])[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(COCc2ccc(C(=O)OCC)cc2)cc1
Yield: 71 %

Procedure:
Although a low yield of impure XXVIII can be obtained directly by heating XXVI and XXVII in DMF at 100° for 70 hr., it is better to do the esterification and furan ring closure in separate steps. 65 mg XXVI (0.1 mmole), 50 mg ethyl 4-bromomethylbenzoate (XXVII), 0.2 g K2CO3, and 10 mg tetrabutylammonium hydrogen sulfate were stirred overnight under reflux in acetonitrile. The product, the 4-ethoxycarbonylbenzyl ether of XXVI, was isolated by preparative layer chromatography with petroleum ether-ethyl acetate 1:1, giving 57 mg, 71% yield, m.p. 109°-110°. NMR (CDCl3, 90 MHz) 10.34, s, 1H; 8.06, d, 8 Hz, 2H; 7.47, d, 8 Hz, 2H; 7.3, s, partly obscured by CHCl;3; m, 6.8-6.55, 3H; 6.3, s, 1H; 5.16, s, 2H; 4.37, q, 7 Hz, 4.21, s, 4.14, s, 4.05, q, 7 Hz, 4.02, q, 7 Hz, total 22H; 2.23, s, 3H; 1.38, t, 7 Hz, 1.17, t, 7 Hz, 1.15, t, 7 Hz, total 15H. 39 mg of this ether (0.05 mmole) was stirred with potassium fluoride/alumina reagent (see reference 22) in 1 ml dimethylformamide for 2 hrs. at 150°. The fluorescent product was isolated in 21 mg (54%) yield by preparative layer chromatography on silica with toluene-ethyl acetate 1:1. More prolonged reaction times in DMF lead to increasing ester hydrolysis. NMR (CDCl3, 90 MHz): 8.15, d, 9 Hz, 7.89, d, 9 Hz, total 4-5H; 7.15-7.05, m, 6.78, m, total 6-7H; m, 3.9-4.5, 20-22H; 2.23, s, 3H; 1.0-1.4, m, 13-17H.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[OH-].[Na+].Br[CH2:17][Cl:18]>C1COCC1>[Cl:18][CH2:17][O:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11]
Reactant: ClCBr
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1OCCl
Temperature: 64 °C
Yield: 74 %

Procedure:
A four-necked 500 mL round bottom flask was equipped with a mechanical stirrer, nitrogen inlet, condenser and thermometer. It was charged with 17.8 grams (0.10 moles) of 2,6-diisopropylphenol, 200 mL of THF, 8.0 grams (0.20 mole) of sodium hydroxide pellets, and 387 grams (3.0 moles, 194 mL) of bromochloromethane. The reaction mixture was heated to 64° C. and held for 2-3 hours until no more 2,6-diisopropylphenol was present as measured by GC. After cooling to 25° C., the suspension was filtered and the filter cake was washed with THF. The THF was removed by rotary evaporation and the resultant oil was distilled under vacuum (0-1 torr, b.p.=80° C.) to give 16.9 grams (0.074 moles, 75% yield) of O-chloromethyl 2,6-diisopropyl phenol.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[N:12]1[C:16]2[C:17](=[O:28])[N:18]([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[CH2:19][CH2:20][C:15]=2[C:14]([C:29]([F:32])([F:31])[F:30])=[N:13]1.[OH-].[Na+].Cl>O1CCCC1>[I:27][C:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:19][CH2:20][C:15]3[C:14]([C:29]([F:30])([F:32])[F:31])=[N:13][N:12]([C:5]4[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=4[C:3]([NH:12][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:15]=4)=[O:33])[C:16]=3[C:17]2=[O:28])=[CH:26][CH:25]=1.[I:27][C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:19][CH2:20][C:15]3[C:14]([C:29]([F:31])([F:32])[F:30])=[N:13][N:12]([C:5]4[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=4[C:3]([OH:33])=[O:2])[C:16]=3[C:17]2=[O:28])=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(OC)ccc1-n1nc(C(F)(F)F)c2c1C(=O)N(c1ccc(I)cc1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2)CC3)c(C(=O)Nc2cccnc2)c1
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2)CC3)c(C(=O)O)c1
Yield: 100 %

Procedure:
The title compound was prepared from 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid methyl ester as obtained in Example 1. The ester (270 mg, 0.47 mmol) was stirred in tetrahydrofuran (1 mL) and 10% sodium hydroxide (1 mL) for 5 h. The reaction was acidified with 1N hydrochloric acid to pH 3 and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with water (2×5 mL), dried over sodium sulfate, filtered, and evaporated to give 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid (263 mg, 100%) as a colorless solid. The acid (263 mg, 0.47 mmol) was dissolved in dimethylformamide (3 mL) to which were added triethylamine (233 mL, 1.68 mmol) and 3-aminopyridine (54 mg, 0.58 mmol). After 10 minutes benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) was added and stirring continued for 24 hr. The reaction was poured into ethyl acetate/water, and the phases were separated. The aqueous was extracted twice with ethyl acetate. The combined organics were washed with water (4×) and once with brine, dried over sodium sulfate, filtered, and evaporated to give 278 mg (91%) of a light orange colored solid. The material was purified by preparative HPLC to give the title compound as a colorless solid. MS (ES+) 634.0 (M+H)+(100%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: C1=COCCC1
Reactant: OCCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: BrCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-bromopentanol (8 g) was dissolved in dichloromethane (100 mL) and was chilled in an ice bath. Dihydropyran (9 g) was added dropwise followed by p-Toluene sulfonic acid monohydrate (1 g). The mixture was allowed to slowly warm to room temperature and stirred for 18 hours. The mixture was diluted with 200 mL ether, washed with 10% NaOH (100 mL) and dried over MgSO4 to give the title compound. δC (CDCl3, 62.9 MHz): 19.7, 25.0, 25.5, 28.9, 30.7, 32.6, 33.7, 62.4, 67.2 and 89.9.
Reaction SMILES: [CH2:1]=[O:2].[CH:3](=[O:7])[CH:4]([CH3:6])[CH3:5].CN(C)C>C(O)=O>[OH:7][CH2:3][C:4]([CH3:1])([CH3:6])[C:5]([O:2][CH2:1][C:4]([CH3:6])([CH3:5])[CH2:3][OH:7])=[O:2]
Reactant: CC(C)C=O
Reactant: C=O
Agent: CN(C)C
Solvent: O=CO
Product: CC(C)(CO)COC(=O)C(C)(C)CO
Temperature: 60 °C

Procedure:
101 g (1.25 mol) of 37% strength aqueous formaldehyde solution and 99 g (1.37 mol) of isobutyraldehyde were mixed at 40° C. under nitrogen with 4.2 g (0.03 mol) of 40% strength aqueous trimethylamine solution by stirring. The temperature of the mixture rose to 93° to 94° in the course of from 15 to 20 minutes. The mixture was stirred at that temperature for a further 10 minutes, and the trimethylamine, excess isobutyraldehyde and 58 g of water were then distilled off under reduced pressure. The remaining solution of hydroxypivalinaldehyde was then cooled down to 60° C., and 1.9 g (0.025 mol) of finely pulverulent calcium hydroxide were then added with vigorous stirring. After the exothermic reaction had ceased and a further, short period of stirring, 2.5 g (0.054 mol) of 100% strength formic acid were added at 70° C., and the mixture was stirred 70° C. for 10 minutes. The aqueous phase was then separated off, and the organic phase was subjected to fractional distillation. 110 g (0.54 mol) were isolated of 2,2-dimethyl-1,3-propanediol hydroxypivalate, corresponding to 86.5% of theory, based on starting formaldehyde.
Reaction SMILES: C(O)C.[BH4-].[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[N:18]1[C:22](=[N:23][CH:24]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)Cl)[CH:21]=[C:20]([C:32]#[N:33])[NH:19]1.O>C(OCC)(=O)C>[Cl:17][C:9]1[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=[C:7]([Cl:6])[C:8]=1[N:18]1[C:22]([NH:23][CH2:24][C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:20]([C:32]#[N:33])=[N:19]1
Reactant: N#Cc1cc(=NC(Cl)c2cnccn2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(NCc2cnccn2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To an ethanol (2 ml) suspension of 85 mg (2.2 mmol) of sodium borohydride was gradually added 0.5 g (1.1 mmol) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(pyrazin-2-ylchloromethylimino)pyrazole-3-carbonitrile at 20° C. or less. After 1 hour of stirring at room temperature, the mixture was gradually poured into 40 ml of water to precipitate crystals. After 30 minutes of stirring, the crystals were filtrated and washed with water until the pH of the filtrate became 6. The crystals thus obtained were dissolved in ethyl acetate and the solution was extracted after the addition of saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated. The resulting crystals were filtrated, washed with a small amount of hexane and ethyl acetate, and dried to obtain 0.42 g (yield 92%) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(pyrazin-2-ylmethylamino)pyrazole-3-carbonitrile.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([N:30]([O:42][CH3:43])[C:31](=[O:41])[CH2:32][C:33]3[N:34]=[C:35]([NH:38][CH:39]=[O:40])[S:36][CH:37]=3)[C:28](=[O:44])[N:10]2[C:11]=1[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([N:30]([O:42][CH3:43])[C:31](=[O:41])[CH2:32][C:33]3[N:34]=[C:35]([NH:38][CH:39]=[O:40])[S:36][CH:37]=3)[C:28](=[O:44])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CON(C(=O)Cc1csc(NC=O)n1)C1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(C)=O)CS[C@H]12
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON(C(=O)Cc1csc(NC=O)n1)C1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
In methylene chloride (10 ml) is dissolved diphenylmethyl 3-acetoxymethyl-7-[N-methoxy-2-(2-formylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylate (535 mg). Under ice-cooling, anisole (1 ml) and trifluoroacetic acid (1.5 ml) are added and the mixture is stirred for 1.5 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in ethyl acetate and extracted with a dilute aqueous solution of sodium hydrogen carbonate. The water layer is adjusted to pH 1 with dil HCl and extracted with ethyl acetate. The extract is washed with aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is washed with isopropyl ether to give a powder of 3-acetoxymethyl-7-[N-methoxy-2-(2-formylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (390 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]([N:9]=[N+]=[N-])[CH3:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([CH:7]([NH2:9])[CH3:8])=[CH:4][CH:3]=1
Reactant: CC(N=[N+]=[N-])c1ccc(Cl)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1ccc(Cl)s1
Temperature: 60 °C
Yield: 75.5 %

Procedure:
A mixture of 1-(5-chloro-2-thienyl)ethyl azide (991 mg, 5.3 mmol) and triphenylphosphine (1.4 g, 5.3 mmol) in THF (10 mL) and water (0.4 mL) was heated to 60° C. for 1 h. After cooling to rt, the solution was concentrated in vacuo. The resulting residue was purified by flash chromatography (90% DCM: 10% methanol) to provide the desired 1-(5-chloro-2-thienyl)ethanamine (646 mg, 4.0 mmol, 75% yield) as a pink liquid. 1H NMR (400 MHz, CDCl3): 6.71 (d, 1H), 6.64 (d, 1H), 4.26 (q, 1H), 1.64 (br s, 2H), 1.44 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[O:6][C@H:5]2[C@H:7]([NH:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C@H:9]([OH:10])[C@H:4]2[O:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:45][CH2:46][O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)(=O)=O)=CC=1>CN(C=O)C>[CH2:48]([O:47][CH2:46][CH2:45][O:10][C@@H:9]1[C@H:4]2[O:3][C:2]([CH3:31])([CH3:1])[O:6][C@H:5]2[C@H:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCOCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCOCc1ccccc1)C[C@H]2NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (10 g, 24.0 mmol) (3aR,4S,6R,6aS)-2,2-dimethyl-6-(tritylamino)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol in dry DMF (100 mL) under nitrogen atmosphere was cooled at 0° C. followed by addition of NaH (60%, 1.2 g, 29.0 mmol). After stirring for 30 min at 0° C., 2-(benzyloxy)ethyl 4-methylbenzenesulfonate (7.4 g, 24.0 mmol) was added and the reaction mixture was allowed to warm at room temperature. After stirring for 4 hours, the reaction mixture was quenched with water (100 mL). To the mixture was extracted 3×100 mL of EtOAc. The combined organic phases were dried over MgSO4, filtered and evaporated to the dryness. The pure IIIe was isolated from reaction mixture by chromatography on silica gel column (mobile phase: n-hexane/EtOAc).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=[O:12])[CH:8]=2)[NH:3]1.[O:14]=[C:15]1[C:20]2=[CH:21][NH:22][C:23]([CH:24]=O)=[C:19]2[CH2:18][CH2:17][NH:16]1.N1CCCCC1>C(O)C>[O:1]=[C:2]1[C:10](=[CH:24][C:23]2[NH:22][CH:21]=[C:20]3[C:19]=2[CH2:18][CH2:17][NH:16][C:15]3=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=[O:12])[CH:8]=2)[NH:3]1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C
Yield: 24.7 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (44.5 mg, 0.25 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (41 mg, 0.25 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 6 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol. The solid was then dissolved in methanol, the insoluble materials were removed and the filtrate was concentrated to give 20 mg (25%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[O:10][C:11]2[C:12](=[C:14]([C:18](O)=[O:19])[CH:15]=[CH:16][CH:17]=2)[N:13]=1.Cl.Cl.[NH2:23][CH:24]1[CH2:31][CH:30]2[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:33][N:32]1[CH:26]2[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH:24]([NH:23][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:13][C:12]=13)=[O:19])[CH2:25]2
Reactant: O=C(O)c1cccc2oc(-c3c(Cl)cccc3Cl)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4c(Cl)cccc4Cl)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.2 %

Procedure:
A mixture of 2-(2,6-dichlorophenyl)benzoxazole-4-carboxylic acid (71 mg, 0.23 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (64 mg, 0.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (88 mg, 0.46 mmol) and 1-hydroxybenzotriazole (62 mg, 0.46 mmol) in DMF (2 mL) was stirred at room temperature for 10 min, then triethylamine (0.16 mL, 1.16 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (30 mL), and then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (2×30 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2,6-dichlorophenyl)benzoxazole-4-carboxamide (39 mg, 38%) as off-white crystals: 1H NMR (500 MHz, CDCl3) δ 8.85 (s, 1H), 8.29 (d, J=7.5 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.57-7.46 (m, 4H), 4.62-4.54 (m, 1H), 3.14-3.06 (m, 2H), 2.53 (s, 3H), 2.05-1.92 (m, 3H), 1.65-1.40 (m, 5H), 1.16-1.05 (m, 2H); MS (ESI+) m/z 444 (M+H); HPLC>99% (AUC), tR=12.70 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cl:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[ClH:25].[C:26]([N:15]1[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:17][CH2:16]1)([O:28][CH2:29][CH3:30])=[O:27]
Reactant: Fc1ccc(C(CCCN2CCNCC2)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Product: Cl

Procedure:
To a solution of 3.3 g (0.01 mole) of 1-[4,4-bis(p-fluorophenyl)butyl]piperazine in 10 ml of CHCl3 was added dropwise over a period of 15 minutes 1.2 g (0.011 mole) of ethyl chloroformate in 10 ml of CHCl3. The mixture was refluxed for 2 hours and was made basic with 0.8 g of sodium hydroxide in 25 ml of water.