Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CCOCC.Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1)[CH3:2]
Reactant: Brc1ccc(Br)nc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethylmagnesium bromide in dry ether (3M; 100 ml, 0.30 mol) was added dropwise to a stirred, ice-cooled solution of anhydrous zinc chloride (40.9 g, 0.30 mol) in dry tetrahydrofuran (500 ml) under nitrogen and the resulting solution stirred for a further 1 hour before the sequential addition of tetrakis (triphenylphosphine)palladium(0) (1.0 g, 0.87 mmol) and a solution of 2,5-dibromopyridine (50 g, 0.21 mol) in dry tetrahydrofuran (200 ml). The resulting yellow suspension was stirred at room temperature for 18 hours, quenched by the addition of water (200 ml) and evaporated under reduced pressure. The residue was partitioned between dichloromethane (500 ml) and a suspension of ethylenediaminetetraacetic acid (200 g) in water (1 l). The organic phase was separated, combined with a dichloromethane extract (500 ml) of the aqueous phase, dried (MgSO4) and evaporated under reduced pressure. Distillation under reduced pressure of the residue gave the title compound (28.8 g) as a colourless oil, b.p. 123-124° C./8 kPa (60 mm Hg). δ(CDCl3): 1.30(3H,t), 2.80(2H,q), 7.10(1H,d), 7.70(1H,dd), 8.60(1H,d).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]([CH3:10])[CH3:9].[OH:11][C:12]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[C:24]([CH3:27])([CH3:26])[CH3:25]>C(O)C>[OH:11][C:12]1[C:19]([C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:18][C:15]([CH:16]=[N:2][N:3]2[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]([CH3:10])[CH3:9])=[CH:14][C:13]=1[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CC(C)c1nccn1N
Agent: Cl
Solvent: CCO
Product: CC(C)c1nccn1N=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.65 g of the above crude 1-amino-2-isopropylimidazole hydrochloride is dissolved in 30 ml of ethanol, 0.94 g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde is added and the mixture is stirred at room temperature for 2 hours. The resulting solution is evaporated in a vacuum. The residue is partitioned between methylene chloride and water. The aqueous phase is treated with sodium bicarbonate solution up to a neutral reaction (pH=7) and the methylene chloride phase is separated, dried, filtered and evaporated. The residue is stirred with ether, whereupon the solid is removed by filtration and dried; there is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-2-isopropylimidazole of m.p. 159°-160°.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH3:12]>C(O)C>[NH2:12]/[C:3](/[CH:2]([CH3:11])[CH3:1])=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: N
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: CCO
Product: CCOC(=O)/C=C(/N)C(C)C
Reaction time: 16 h

Procedure:
Ethyl 4-methyl-3-oxopentanoate (2.0 g, 13 mmol) was treated with 2M ammonia in ethanol (20 mL), heated to 80 C. in a sealed tube for 16 hours and concentrated to dryness to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[N:6][CH:7]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>>[CH3:17][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:4]1[CH:3]=[C:2]([NH:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH:7]=[N:6][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(N)c2)cc2ccccc21
Product: Cn1c(-c2cncc(NS(C)(=O)=O)c2)cc2ccccc21

Procedure:
2-(5-amino-pyridin-3-yl)-1-methyl-1H-indole (Example 100) and methanesulfonyl chloride are processed according to the methods described in Example 225a and 225c to give methanesulfonic acid [5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.15 (s, 3H), 3.77 (s, 3H), 6.71 (s, 1H), 7.06-7.13 (m, 1H), 7.23 (ddd, J=8.2, 7.1, 1.1 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.79 (t, J=2.2 Hz, 1H), 8.48 (d, J=2.3 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H), 10.18 (s, 1H). HRMS: (ESI) m/z 302.0966 [(M+H)+ Calcd for C15H16N3O2S 302.0958].
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([NH:19]N)=O>>[Cl:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]1[NH:19][N:10]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:9]=1
Reactant: NNC(=O)c1sccc1Cl
Reactant: N=C(N)c1ccccc1
Agent: Cl
Product: Clc1ccsc1-c1nc(-c2ccccc2)n[nH]1

Procedure:
The title compound was prepared from benzamidine hydrochloride and 3-chloro-thiophene-2-carboxylic acid hydrazide by a procedure similar to Example 88b as a yellowish solid (0.141 g, 37%). 1H NMR (DMSO-d6): 8.04 (d, J=9.6 Hz, 2H), 7.80 (d, J=6.0 Hz, 1H), 7.55 (d, J=7.80 Hz, 3H), 7.19 (d, J=5.70 Hz, 1H).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)[CH2:14]1.Br>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)[CH2:14]1
Reactant: Oc1cccc(C2CCCNC2)c1
Reactant: BrCC1COc2ccccc2O1
Agent: Br
Solvent: CC#N
Product: Oc1cccc(C2CCCN(CC3COc4ccccc4O3)C2)c1

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (54 mg, 0.24 mmol), 3-(piperidin-3-yl)phenol.HBr (60 mg, 0.23 mmol) and KHCO3 (84 mg, 0.84 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 160° C. for 5.5 h. The mixture was absorbed on silica and purified by flash chromatography using a gradient of DCM and MeOH (1% triethylamine) as eluent to give 74 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][O:11][C:12]1[N:16]([C:17]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[CH:19][N:18]=2)[N:15]=[CH:14][CH:13]=1.[C:26](#N)C.O>>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][O:11][C:12]1[N:16]([C:17]2[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][N:18]=2)[N:15]=[CH:14][CH:13]=1
Reactant: CC#N
Reactant: Cc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)c(F)c1F
Solvent: O
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C)c(F)c2F)c1

Procedure:
The title compound was prepared from 2-[5-[(2,3-difluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid (EXAMPLE 94) according to the procedure for the preparation of Example 62. 1H NMR (400 MHz, CDCl3): δ 2.31 (3H, s), 3.96 (3H, s), 5.27 (2H, s), 5.80 (1H, d, J=6.4 Hz), 6.94-6.97 (1H, m), 7.13-7.17 (1H, m), 7.58 (1H, s), 7.76 (1H, d, J=4.0 Hz), 8.30 (1H, s), 8.69 (1H, d, J=2.4 Hz). LCMS (mobile phase: 30%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=3.485 min. [M+H] Calc'd for C18H15F2N3O3, 360. Found, 360.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][S:38]([NH:41][C:42]1[CH:47]=[CH:46][C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][CH:43]=1)(=[O:40])=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:45]2[CH:44]=[CH:43][C:42]([NH:41][S:38]([CH3:37])(=[O:39])=[O:40])=[CH:47][CH:46]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 89 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.15 g, 0.28 mmol), 4-(methanesulfonylamino)phenyl boronic acid pinacol ester (0.21 g, 0.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21 mg, 0.03 mmol) in dioxane (3 mL) was added an aqueous sodium carbonate solution (2 M, 0.36 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded N-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-methanesulfonamide (130 mg, 96%) as a white solid: LC/MS m/e calcd for C27H27N3O4S2 [M+H]+ 522.66, observed 522.3.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)[C:5]=2[O:4][CH2:3][CH2:2]1.O.NN>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][NH2:14])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc2c1OCCO2
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCOc1cccc2c1OCCO2

Procedure:
Cleavage of the phthalimide group of the compound obtained in Step B is carried out in ethanol in the presence of an aqueous 98% hydrazine hydrate solution (2 eq. per 1.5 g of product). It is preferable to add the latter after 10 minutes' refluxing. When the reaction is complete, the alcohol is removed under reduced pressure. The dry residue is taken up in dichloromethane in the cold in order to precipitate the phthalic hydrazide that has formed. The latter may then be removed by filtration and the recovered and concentrated filtrate is washed several times to obtain the pule product by thin-layer chromatography.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:1][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:3])[CH:10]=1
Reactant: Nc1ccccc1F
Reactant: BrBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Product: Nc1ccc(Br)cc1F
Reaction time: 0.5 h

Procedure:
Cycle 1. Methylene chloride, 125 ml, and 32.2 g (0.1 mol) tetrabutylammonium bromide were mixed in a 200-ml, 3-necked roundbottom flask, equipped with a mechanical stirrer, a thermometer, an addition funnel and a water condenser leading to a mineral oil bubbler. Bromine, 16.0 g (0.1 mol), was added to the mixture over 15 minutes at room temperature. The temperature of the mixture rose from 24° C. to 30° C. The contents of the flask were stirred for 30 minutes. 2-Fluoroaniline, 11.1 g (0.1 mol), at room temperature was added to the mixture in one portion. The temperature of the mixture rose to 40° C. The orange solution immediately turned yellowish. After stirring for 15 minutes, the solution turned milky and the temperature was 32° C. After 30 more minutes solids were observed. The solution was filtered and the solids washed with ice-cold methylene chloride until white. On air-drying 9 g of product (Solid I) was obtained. The melting point was >200° C. LC analysis showed only desired product with a trace of impurity. LC analysis of the mother liquor (I) showed that it contained some desired product and some dibrominated compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25]O)=[CH:23][N:24]=2)[CH:3]=1.[Br-:27].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.C(=O)([O-])O.[Na+]>ClCCl>[Br:27][CH2:25][C:22]1[O:21][C:20]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]3[C:5]=2[CH:6]=[N:7][N:8]3[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:24][CH:23]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3ncc(CO)o3)cc(Cl)cc21
Reactant: [Br-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ncc2c(-c3ncc(CBr)o3)cc(Cl)cc21
Temperature: 3 °C
Reaction time: 0.17 h

Procedure:
(2-(6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methanol (1.0 eq., 1 wt, 34.0 g) and triphenylphosphine dibromide (1.3 eq., 1.32 wt, 45.0 g) are stirred in dichloromethane (15 vols, 510 ml) at 20 (±3° C.) under a nitrogen atmosphere for 1 hr. The reaction is then checked by HPLC for completion. Once complete methanol (0.8 vols, 27.2 ml) is added to the reaction, with vigorous stirring 8% w/w sodium hydrogen carbonate solution (10 vols, 340 ml) is added drop wise over 15 minutes (check aqueous pH>7). The mixture is heated to 30° C. (±3° C.) and stirred together for 10 minutes, then separated, the aqueous is back extracted with dichloromethane (5 vols, 170 ml) and the combined dichloromethane layers are washed with water (5 vols, 170 ml). The dichloromethane solution is then evaporated under reduced pressure to a volume of approximately 4 vols. To the solution is added methanol (15 vols, 510 ml) and the solution evaporated under reduced pressure at 260 mbar, 20° C. to remove the remaining dichloromethane down to −15 vols. The suspension is then stirred at 20° C. for at least 6 hrs. The solid is filtered, washed with methanol (2×1 vols, 2×34 ml), sucked dry for 20 minutes, then dried under high vacuum at 30° C. (±3° C.) to constant probe temperature to afford 5-(bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazole as a beige solid.
Reaction SMILES: C(OC(COC1C=CC(F)=CC=1)C#CCNS(C)(=O)=O)(=O)C.C(OC(COC1C=CC(F)=CC=1)CCCNS(C)(=O)=O)(=O)C.BrCCCCCCC(OCC)=O.BrCC#CCCCC(OCC)=O.C([O:72][CH:73]([CH2:93][O:94][C:95]1[CH:100]=[CH:99][C:98]([F:101])=[CH:97][CH:96]=1)[C:74]#[C:75][CH2:76][N:77]([CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][C:88]([O:90]CC)=[O:89])[S:78]([CH3:81])(=[O:80])=[O:79])(=O)C>>[OH:72][CH:73]([CH2:93][O:94][C:95]1[CH:100]=[CH:99][C:98]([F:101])=[CH:97][CH:96]=1)[C:74]#[C:75][CH2:76][N:77]([CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][C:88]([OH:90])=[O:89])[S:78]([CH3:81])(=[O:80])=[O:79]
Reactant: CCOC(=O)CCCCCCN(CC#CC(COc1ccc(F)cc1)OC(C)=O)S(C)(=O)=O
Agent: CC(=O)OC(C#CCNS(C)(=O)=O)COc1ccc(F)cc1
Agent: CC(=O)OC(CCCNS(C)(=O)=O)COc1ccc(F)cc1
Agent: CCOC(=O)CCCC#CCBr
Product: CS(=O)(=O)N(CC#CC(O)COc1ccc(F)cc1)CCCCCCC(=O)O

Procedure:
This compound is prepared by the procedure described in Example 2, Step I, except that N-[4-acetoxy-5-(4-fluorophenoxy)-2-pentynyl]methanesulfonamide is substituted for the N-[4-acetoxy-5-(4-fluorophenoxy)pentyl]methanesulfonamide and ethyl 7-bromoheptanoate is substituted for ethyl 7-bromo-5-heptynoate. The product is thus ethyl 7-{N-[4-acetoxy-5-(4-fluorophenoxy)-2-pentynyl]methanesulfonamido}heptanoate. The subsequent hydrolysis (Example 2, Step J) affords the subject compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[CH:15][CH:14]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[CH:15][CH:14]=1
Reactant: N#CCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2nc(COc3ccc(Cc4nnn[nH]4)cc3)ccc2c1
Yield: 33.2 %

Procedure:
A mixture of 8.6 g of 4(2-quinolylmethyloxy)phenylacetonitrile, 6.1 g of sodium azide and 5.0 g of ammonium chloride was heated with 70 ml of dry dimethylformamide at 140° C. for twenty hours. The reaction mixture was poured onto ice, basified with 1N sodium hydroxide and extracted 2 times with ethyl acetate. The aqueous fraction was extracted 2 times with ethyl acetate. Removal of solvent left 10.3 g of crude product. This was crystallized from methanol:ethyl acetate to yield 3.3 g of pure product of m.p. 173°-175° C.
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)=[CH2:2].[NH2:22][NH2:23]>C(O)C>[CH2:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:22][NH2:23])=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NN
Reactant: C=Cc1ccc(CN2CCN(CC(=O)OCC)CC2)cc1
Solvent: CCO
Product: CCc1ccc(CN2CCN(CC(=O)NN)CC2)cc1

Procedure:
Synthesized according to General Procedure C: 9 (3.23 g, 11.2 mmol, 1 equiv.), anhydrous hydrazine (1.1 mL, 33.6 mmol, 3 equiv.), ethanol (22.6 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{28} (1.92 g, 62%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.14 (br s, 1H), 7.20 (d, 2H, J=8.0 Hz), 7.14 (d, 2H, J=8.0 Hz), 3.84 (d, 2H, J=4.0 Hz), 3.47 (s, 2H), 3.06 (s, 2H), 2.63 (q, 2H, J=7.5 Hz), 2.53 (br s, 4H), 2.45 (br s, 4H), 1.22 (t, 3H, J=7.5 Hz). 13C-NMR (125 MHz, CDCl3): δ 170.5, 143.1, 134.9, 129.1, 127.7, 62.6, 60.5, 53.6, 52.9, 28.5, 15.5.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[C:3]([O:5][CH:6](I)[CH3:7])=[O:4].[CH3:11][O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[CH:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23](=[O:36])[N:18]2[C:19]=1[C:20]([O-:22])=[O:21].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[CH3:11][O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[CH:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23](=[O:36])[N:18]2[C:19]=1[C:20]([O:22][CH:6]([O:5][C:3](=[O:4])[C:2]([CH3:10])([CH3:9])[CH3:1])[CH3:7])=[O:21]
Reactant: CC(I)OC(=O)C(C)(C)C
Reactant: COCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCC1=C(C(=O)OC(C)OC(=O)C(C)(C)C)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 25 °C

Procedure:
25.7 g (100 mmol) of 1-iodoethyl 2,2-dimethylpropionate are added to 42.8 g (107 mmol) of sodium 3-methoxymethyl7-phenoxyacetamido-3-cephem-4-carboxylate in 430 ml of dry dimethylformamide. The reaction mixture is stirred at room temperature for a further hour and then poured onto a mixture of 2.5 1 of water and 1.5 1 of ethyl acetate. The aqueous phase is extracted again with ethyl acetate. The combined organic phases are washed with saturated sodium chloride-solution, dried over magnesium sulfate and evaporated in vacuo.
Reaction SMILES: [C:1](=[O:35])([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][N+:32]([O-:34])=[O:33])[O:2][CH2:3]/[C:4](/[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)=[C:5](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)\[CH2:6][OH:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:38].CC(=CC)C.P(=O)(O)(O)O.[O-]Cl=O.[Na+]>ClCCl.C1COCC1.CC(O)(C)C>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14](/[C:4](/[CH2:3][O:2][C:1]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][N+:32]([O-:34])=[O:33])=[O:35])=[C:5](\[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)/[C:6]([OH:38])=[O:7])=[CH:15][CH:16]=1)(=[O:21])=[O:22]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCCCO[N+](=O)[O-])=C(/CO)c2ccccc2)cc1
Agent: CC=C(C)C
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCCCO[N+](=O)[O-])=C(/C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4.5 g of (2Z)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-yl 6-(nitrooxy)hexyl carbonate in 100 mL of dichloromethane was treated with 4.5 g of Dess-Martin reagent at 25° C. for 75 min. The reaction was quenched by 1 mL of water, and stirred at RT for 30 min. Then the mixture was filtered through a pad of silica gel and evaporated. The crude thus obtained was dissolved in a solvent mixture of THF and t-BuOH (100 mL/100 mL). To the resulting solution was added 5.3 mL of 2-methyl-2-butene followed by the addition of 13 mL of phosphoric acid (1.2 M soln) and 13 mL of NaClO2 (1M soln). The resulting mixture was stirred at RT for 30 min. The organic phase was separated and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over Na2SO4, filtered, and then evaporated. The crude was purified by flash chromatography to afford titled compound as a white solid. 1H NMR (acetone-d6, 500 MHz): δ 11.8 (bs, 1 H), 7.76 (d, 2 H), 7.43 (d, 2 H), 7.17–7.11 (m, 5 H), 5.34 (s, 2 H), 4.52 (t, 2 H), 4.04 (t, 2 H), 3.05 (s, 3 H), 1.71 (m, 2 H), 1.57 (m, 2 H), 1.40 (m, 2 H), 1.34 (m, 2 H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:10][CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:13])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[CH3:19][C:17]([CH3:20])([O:16][C:14]([N:12]([CH3:13])[CH2:11][CH2:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:15])[CH3:18]
Reactant: COC(=O)C1(CCN(C)C(=O)OC(C)(C)C)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(CCC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a solution of 1-[2-[[(1,1-dimethylethoxy)carbonyl](methyl)amino]ethyl]cyclopentane carboxylic acid methyl ester (4.00 g, 14.0 mmol) in THF/MeOH (2:1, 24 mL) was added a solution of LiOH (1.50 g, 35.0 mmol) in water (8 mL). The mixture was stirred overnight at 50° C. and then cooled to room temperature. The reaction mixture was poured into a round bottom flask and concentrated in vacuo. The mixture was diluted with H2O (50 mL) and acidified with 1M HCl. The aqueous phase was extracted with ethyl acetate (3×150 mL) and the combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography, using hexane-ethyl acetate (5:1), afforded (3.60 g, 95%) of a white powder. HR MS (C14H25NO4): Calcd mass, 272.1862. Obs mass, 272.1872 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH:15]=3)=[CH:9][O:10][C:4]=2[C:3]=1[O:29][CH:30]([C:32]1[C:37]([Cl:38])=[C:36]([F:39])[CH:35]=[C:34]([F:40])[C:33]=1[Cl:41])[CH3:31].Cl>O1CCOCC1>[Cl:41][C:33]1[C:34]([F:40])=[CH:35][C:36]([F:39])=[C:37]([Cl:38])[C:32]=1[CH:30]([O:29][C:3]1[C:4]2[O:10][CH:9]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)[CH:15]=3)[C:5]=2[CH:6]=[N:7][C:2]=1[NH2:1])[CH3:31]
Reactant: CC(Oc1c(N)ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)coc12)c1c(Cl)c(F)cc(F)c1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CC(Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1c(Cl)c(F)cc(F)c1Cl
Temperature: 47.5 °C
Reaction time: 2 h

Procedure:
Into a round bottom flask were added tert-Butyl 4-(4-{6-amino-7-[1-(2,6-dichloro-3,5-difluorophenyl)ethoxy]furo[3,2-c]pyridin-3-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (12.0 mg, 0.0197 mmol) and 1,4-Dioxane (3.0 mL, 38 mmol). 4 M HCl in 1,4-Dioxane (0.2 mL) was added slowly at 0° C. and the reaction mixture was stirred at rt (1 h), 30° C. (2 h), and 45-50° C. until completion. The reaction mixture was passed through SCX-2 and then purified by HPLC to afford the title compound. 1H NMR (400 MHz, CD3OD): δ=1.91 (d, J=6.8 Hz, 3H), 2.15-2.41 (m, 4H), 3.10-3.27 (m, 2H), 3.46-3.63 (m, 2H), 4.50-4.67 (m, 1H), 6.54 (q, J=6.7 Hz, 1H), 7.34 (t, J=8.7 Hz, 1H), 7.78 (s, 1H), 7.87 (s, 1H), 8.12 (s, 2H), 8.16 (s, 1H). MS (ES+): m/z 507.95/509.96 (40/24) [MH+]. HPLC: tR=2.56 min (ZQ3, polar—5 min).