Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([P:14](=[O:23])([O:19][CH:20]([CH3:22])[CH3:21])[O:15][CH:16]([CH3:18])[CH3:17])[P:4](=[O:13])([O:9][CH:10]([CH3:12])[CH3:11])[O:5][CH:6]([CH3:8])[CH3:7].[CH2:24](Br)/[CH:25]=[C:26](/[CH2:28][CH2:29]/[CH:30]=[C:31](/[CH2:33][CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])\[CH3:32])\[CH3:27].O>C(COC)OC>[CH2:24]([CH:3]([P:4](=[O:13])([O:9][CH:10]([CH3:11])[CH3:12])[O:5][CH:6]([CH3:8])[CH3:7])[P:14](=[O:23])([O:15][CH:16]([CH3:18])[CH3:17])[O:19][CH:20]([CH3:22])[CH3:21])/[CH:25]=[C:26](/[CH2:28][CH2:29]/[CH:30]=[C:31](/[CH2:33][CH2:34][CH:35]=[C:36]([CH3:37])[CH3:38])\[CH3:32])\[CH3:27]
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
Oily sodium hydride (60%, 0.24 g) was added to a solution of tetraisopropyl methylenebisphosphonate (3.44 g) in dimethoxyethane (25 ml). The mixture was stirred at room temperature for 1 hour. Then, a solution of (E,E)-farnesyl bromide (1.43 g) in dimethoxyethane (5 ml) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 hour, then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), and then the solvent was distilled off under reduced pressure. The oily residue was subjected to column chromatography on silica gel. Tetraisopropyl (E,E)-farnesylmethylenebisphosphonate (1.67 g, 60.9%) was obtained as an oil from the fractions obtained by elution with ethyl acetate-chloroform (1:1, v/v).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]2([OH:30])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([CH3:12])([CH3:11])[CH3:10].[N:31]#[C:32]Br>C(O)C>[NH2:31][C:32]1[N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:7]2[CH:6]=[CH:5][C:4]([C:13]3([OH:30])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[N:14]3[CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C)(C)Nc1ccc(C2(O)c3ccccc3C(=O)N2Cc2ccccc2)cc1N
Reactant: N#CBr
Solvent: CCO
Product: CC(C)(C)n1c(N)nc2cc(C3(O)c4ccccc4C(=O)N3Cc3ccccc3)ccc21
Temperature: 25 °C
Yield: 0.7 %

Procedure:
A solution of 3-{3-amino-4-[(1,1-dimethylethyl)amino]phenyl}-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (347 mg, 0.862 mmol) and cyanogen bromide (100 mg, 0.948 mmol) in anhydrous ethanol (10 mL) was heated to reflux for 6 h, at which time it was cooled to room temperature and concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate and brine then dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC to afford 3-[2-amino-1-(1,1-dimethylethyl)-1H-benzimidazol-5-yl]-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (2.7 mg). 1H NMR (400 MHz, d6-DMSO): 7.76 (d, 1H), 7.61 (d, 1H), 7.56-7.53 (m, 2H), 7.32 (br s, 1H), 7.30 (d, 1H), 7.09-7.07 (m, 5H), 6.92 (d, 1H), 4.41 (d, 1H), 4.22 (d, 1H), 1.73 (s, 9H); MS (EI) for C26H26N4O2: 427 (MH+).
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:13][C:14]([O:16]CC)=O)[CH2:12][CH:11]2[CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10]2)([O-])=O>CO.[Ni]>[NH:1]1[C:14](=[O:16])[CH2:13][C@@:5]2([CH2:12][C@H:11]3[C@@H:6]2[CH2:7][CH2:8][CH2:9][CH2:10]3)[CH2:4]1
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])CC2CCCCC21
Agent: [Ni]
Solvent: CO
Product: O=C1C[C@]2(CN1)C[C@@H]1CCCC[C@@H]12
Yield: 97.9 %

Procedure:
Ethyl [(1RS,6RS,7SR)-7-(nitromethyl)bicyclo[4.2.0]oct-7-yl]acetate (preparation 21) (4.70 g, 18.4 mmol) was shaken in methanol (150 ml) at 30° C. over Raney Nickel catalyst under an atmosphere of hydrogen gas at 483 kPa (70 p.s.i.). After 4 hrs the catalyst was removed by filtration through celite and the solvent removed under reduced pressure to give 3.23 g of the title compound as a clear oil which solidified on standing.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH:9]([C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][CH2:20][CH2:21][N:22]=[C:23]=[S:24])[N:17]=1)[C:10]([NH2:12])=[NH:11].Cl.Cl.[NH2:27][CH2:28][CH2:29][C:30]1[N:31]=[CH:32][NH:33][CH:34]=1.C(N(CC)CC)C>CO>[OH2:5].[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH:9]([C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][CH2:20][CH2:21][NH:22][C:23]([NH:27][CH2:28][CH2:29][C:30]2[N:31]=[CH:32][NH:33][CH:34]=2)=[S:24])[N:17]=1)[C:10]([NH2:12])=[NH:11].[NH:9]([C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][CH2:20][CH2:21][NH:22][C:23]([NH:27][CH2:28][CH2:29][C:30]2[N:31]=[CH:32][NH:33][CH:34]=2)=[S:24])[N:17]=1)[C:10]([NH2:12])=[NH:11].[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5]
Reactant: N=C(N)Nc1nc(CSCCN=C=S)cs1
Reactant: NCCc1c[nH]cn1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: N=C(N)Nc1nc(CSCCNC(=S)NCCc2c[nH]cn2)cs1
Product: O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-guanidinothiazol-4-ylmethylthio)ethyl isothiocyanate hydrogen maleate (0.712 g), 4-(2-aminoethyl)imidazole dihydrochloride (histamine dihydrochloride) (0.404 g), triethylamine (0.808 g) and methanol (35 ml) was stirred at room temperature overnight. The mixture was purified by preparative thin layer chromatography on Merck 60 F-254 plates using as solvent ethyl acetate/ethanol/ammonia (s.g. 0.88) 6:1:1 v/v/v, eluting the band of RF 0.4 from the plates with ethanol. Evaporation of the filtered extract followed by treatment with maleic acid in acetone gave a white solid which was filtered off and washed with acetone followed by a little cold ethanol to give 1-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl]-3-[2-(imidazol-4-yl)ethyl]thiourea dimaleate hemihydrate, m.p. 100° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.CC(O)=O>C1COCC1.[Zn]>[CH3:11][C:2]([C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)([CH3:1])[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CC(C)(CCN1CCOCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(CCN1CCOCC1)c1ccc(N)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-[3-methyl-3-(4-nitro-phenyl)-butyl]-morpholine (0.50 g, 1.8 mmol, Step E) in THF (40 mL) was added AcOH (1.97 mmol, 34.5 mmol) followed by zinc (9.1 g, 137 mmol). The mixture was stirred for 1 h and filtered on Celite®. The mixture was diluted with H2O, and aqueous NaHCO3 and the THF was evaporated. The residue was extracted with EtOAc, dried and evaporated to give the title intermediate. Calc'd for C15H24N2O:248.19.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1)=[O:2].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:18][CH3:19])=[O:8])=[C:5]([CH3:12])[CH:4]=1)=[O:2]
Reactant: CCO
Reactant: Cc1cc(C=O)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C=O)cc1C
Temperature: 80 °C
Yield: 80 %

Procedure:
To a stirred solution of 4-formyl-2-methylbenzoic acid (3 g, 18.2 mmol) in ethyl alcohol (EtOH; 30 mL) was added sulfuric acid (H2SO4, x M; 2 mL), and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water. The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a solid (2.8 g, 80%): 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.04 (m, 1H), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m, 3H).
Reaction SMILES: O[C:2]1([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[C:9]2[N:5]([CH:6]=[N:7][CH:8]=2)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH:8]1[N:7]=[CH:6][N:5]2[CH2:4][CH2:3][CH:2]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=3)[C:9]=12
Reactant: N#Cc1ccc(C2(O)CCn3cncc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(C2CCn3cncc32)cc1
Temperature: 25 °C

Procedure:
A solution of 4 mmol of 4-(7-hydroxyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)benzonitrile and 8 mmol of thionyl chloride in 30 ml of chloroform is heated at reflux for 15 hours. The reaction mixture is cooled to room temperature and poured into saturated sodium hydrogen carbonate solution. The phases are separated and the organic phase is washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COc1ccc(Cl)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(4-chlorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:47])[CH2:25][CH2:26][N:27]([CH2:35][CH2:36][C:37]([O:39]CC1C=CC=CC=1)=[O:38])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6](=[O:48])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:47])[CH2:25][CH2:26][N:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCNC(=O)CCN(CCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCNC(=O)CCN(CCC(=O)O)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 102.6 %

Procedure:
17-{3-[(2-Benzyloxycarbonylethyl)tert-butoxycarbonylamino]propionylamino}heptadecanoic acid tert-butyl ester (0.135 g, 0.2 mmol) was dissolved in THF (10 mL) in a flask. The flask was filled with nitrogen and purged under vacuum several times. Pd/C, wet 10% (0.03 g) was added and the flask was equipped with a balloon filled with the mixture was stirred for 16 h. The mixture was filtered through a celite, eluting with THF. The filtrate was concentrated under vacuum. TLC indicated the reaction was not complete, so the process was repeated twice more. The filtrate was concentrated under vacuum to yield a yellow oil (0.12 g)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[N:24]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:34](O)=[O:35])[C:28]=2[CH:27]=[CH:26][CH:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:29]3[C:28]4[CH:27]=[CH:26][CH:25]=[N:24][C:33]=4[CH:32]=[CH:31][CH:30]=3)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: O=C(O)c1cccc2ncccc12
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4ncccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with quinoline-5-carboxylic acid. LC-MS (basic): tR=0.75 min; [M+H]+=488.2.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:30]1([CH:37]2[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.O.C1[CH2:49][O:48][CH2:47]C1>>[CH3:2][O:3][CH:4]=[C:33]1[CH2:34][CH2:35][CH:30]([CH:37]2[CH2:42][CH2:41][C:40](=[CH:47][O:48][CH3:49])[CH2:39][CH2:38]2)[CH2:31][CH2:32]1
Reactant: O=C1CCC(C2CCC(=O)CC2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: COC=C1CCC(C2CCC(=COC)CC2)CC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
882.3 g of methoxymethyl triphenylphosphonium chloride was dispersed in 2600 mL of THF, and was cooled to −10° C. While keeping the internal temperature, 313.2 g of potassium-t-butoxide was added thereto. While keeping the internal temperature, the solution was stirred for 1 hour, and then THF (800 mL) solution containing 200.0 g of bicyclohexyl-4,4′-dione was added dropwise. While keeping the internal temperature, the solution was stirred for 1 hour, and then water was added to stop the reaction. The solvent was evaporated under reduced pressure. Then, the residue was added with hexane, was vigorously stirred, and was subjected to filtration (twice). The resultant product was mixed with the filtrate, then washed with 50% methanol aqueous solution and saturated saline in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to obtain 231.8 g of a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([NH2:16])[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:31])=[O:30])[CH:20]=1>>[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([NH:16][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([Cl:18])=[CH:20][C:21]=1[NH:28][S:29]([C:32]1[C:33]2[N:34]=[CH:35][CH:36]=[N:37][C:38]=2[CH:39]=[CH:40][CH:41]=1)(=[O:31])=[O:30])[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1
Reactant: COC(=O)[C@@H](N)Cc1csc2ccccc12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1csc2ccccc12)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
3-Benzo[b]thiophen-3-yl-2-(tert-butoxycarbonylamino)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (S)-2-amino-3-benzo[b]thiophen-3-yl-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled to 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=10.33 min. MS (ESI−): mass calcd. for C27H21ClN4O5S2, 580.06; m/z found, 579/581 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.35 (s, 1H), 8.94 (d, J=1.8, 1H), 8.85 (d, J=1.8, 1H), 8.58 (dd, J=7.3, 1.4, 1H), 8.31 (dd, J=8.5, 1.3, 1H), 7.90-7.86 (m, 2H), 7.77 (d, J=2.0, 1H), 7.72-7.70 (m, 1H), 7.37-7.26 (m, 2H), 7.09 (s, 1H), 7.00 (d, J=8.4, 1H), 6.83 (dd, J=8.4, 2.0, 1H), 6.45 (d, J=7.1, 1H), 5.09-5.05 (m, 1H), 3.77 (s, 3H), 3.53 (dd, J=14.7, 5.8, 1H), 3.45 (dd, J=14.8, 5.2, 1H).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[C:25]([O:24][C:22]([NH:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[CH:14]=[C:15]([CH3:16])[C:7]2[CH:6]([CH2:5][C:4]([OH:29])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=1)=[O:23])([CH3:27])([CH3:28])[CH3:26]
Reactant: CCOC(=O)CC1OB(O)c2cc(OCCCNC(=O)OC(C)(C)C)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCCCNC(=O)OC(C)(C)C)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.9 %

Procedure:
To a solution [6-(3-tert-butoxycarbonylamino-propoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.445 g, 1.09 mmol) in THF (14 mL) was added a solution of LiOH (0.229 g, 5.44 mmol) in water (5 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours then acidified to pH=2 with 6M HCl and extracted with EtOAc (3×25 mL). The organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (20% EtOAc/hexane) to give [6-(3-tert-butoxycarbonylamino-propoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.450 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (s, 1H), 7.00 (d, J=1.90 Hz, 1H), 6.87 (br. s., 1H), 6.81 (s, 1H), 5.41 (dd, J=9.52, 2.22 Hz, 1H), 3.93 (t, J=6.19 Hz, 2H), 3.06 (t, J=6.34 Hz, 2H), 3.00 (dd, J=15.55, 2.54 Hz, 1H), 2.23 (s, 3H), 2.03 (dd, J=15.39, 9.68 Hz, 1H), 1.80 (t, J=6.66 Hz, 2H), 1.35 (s, 9H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:21]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[CH:11]([C:16]([OH:18])=[O:17])[CH:12](O)[CH2:13][S:14][C@H:9]12)=[O:6].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>C(C(C)=O)C(C)C>[CH3:1][O:2][N:3]=[C:4]([C:21]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[C:11]([C:16]([OH:18])=[O:17])=[CH:12][CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: CC(=O)OC(C)=O
Product: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Yield: 69.7 %

Procedure:
7-(2-Methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 5 g), acetic anhydride (4.55 ml), sodium acetate (1.45 g), and methyl isobutyl keton (50 ml) were treated in a similar manner to that of Example 43 to give 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 3.36 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:4]=[CH:3]1.C1C(=O)N([Cl:22])C(=O)C1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:22][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1
Reactant: Cn1cnc(-c2ccc(C#N)cc2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(-c2ccc(C#N)cc2)c1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To 4-(1-methyl-1H-imidazol-4-yl)benzonitrile (Step 2, 1.05 g, 5.73 mmol) in methylene chloride (15 mL) was added NCS (765 mg, 5.73 mmol) and 3 drops of TFA. After stirring at 50° C. for 3 hrs, the reaction was diluted with 20 mL of methylene chloride and quenched with aq NaHCO3. The organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated to give 4-(5-chloro-1-methyl-1H-imidazol-4-yl)benzonitrile. LCMS: [M+1]=218.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]2[C:18]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[C:24]([OH:31])[CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:19][N:20]=[C:14]2[CH:13]=1.[C@@H:32]12[O:37][C@@H:36]1[CH2:35][N:34]([C:38]([O:40][CH2:41][C:42]1[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=1)=[O:39])[CH2:33]2>CN(C=O)C>[OH:37][C@H:32]1[C@H:36]([O:31][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:23]=2[N:22]=[C:21]([C:18]2[N:15]4[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][O:8][CH3:7])=[CH:13][C:14]4=[N:20][CH:19]=2)[CH:30]=[CH:29]3)[CH2:35][N:34]([C:38]([O:40][CH2:41][C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=2)=[O:39])[CH2:33]1
Reactant: O=C(OCc1ccc2ccccc2c1)N1C[C@@H]2O[C@@H]2C1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5O)c4n3)cnc2c1
Temperature: 100 °C

Procedure:
Cs2CO3. (0.2201 g, 1.141 mmol) was added to a solution of 2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol (0.294 g, 0.878 mmol) and (cis)-naphthalen-2-ylmethyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.260 g, 0.966 mmol) in DMF (4.5 mL). The reaction was heated to 100° C. overnight, then cooled and poured into 30 mL of ice water. This mixture was extracted with 25%. IP A in CH2Cl2, and the organic layer was dried over sodium sulfate and condensed. The residue was purified by silica gel chromatography, eluting with gradient from 1% to 25% MeOH (with 6% NH4OH) in EtOAc, to collect 223 mg of the desired product. MS APCI (+) m/z 605.1 (M+1) detected.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:20])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[CH3:10].Cl[CH2:29][N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[N:31]1>CN(C=O)C>[N:30]1([CH2:29][N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:15]2[CH2:16][CH2:17][CH2:18][N:14]2[S:11]([C:6]2[CH:7]=[CH:8][C:9]([CH3:10])=[C:4]([Cl:3])[CH:5]=2)(=[O:13])=[O:12])=[O:20])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[N:31]1
Reactant: ClCn1nnc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)N2CCCC2C(=O)Nc2ccccc2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCCC2C(=O)N(Cn2nnc3ccccc32)c2ccccc2)cc1Cl
Reaction time: 1 h
Yield: 42.8 %

Procedure:
Under inert atmosphere, to a stirred solution of NaH (12 mg, 0.31 mmol) in 0.20 ml anhydrous DMF at 0° C., was added a solution of parent compound 1-((3-chloro-4-methylphenyl)sulfonyl)-N-phenylpyrrolidine-2-carboxamide (0.040 g, 0.11 mmol) in 0.60 ml anhydrous DMF. After 1 h at 0° C., a solution of 1-(chloromethyl)-1H-benzotriazole (0.052 g, 0.31 mmol) in 0.50 ml anhydrous DMF was added to the reaction mixture. This mixture was stirred for 16 h, and then solvent was completely removed. The crude was chromatographically purified over SiO2 using Hexane/AcOEt as the eluant, yielding 0.024 g (46%) of the desired product.
Reaction SMILES: CO[C:3](=[O:10])[CH2:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:8][CH:6]([CH3:7])[C:5](=[O:9])[CH2:4][C:3]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10]
Reactant: C1COCCN1
Reactant: COC(=O)CC(=O)C(C)C
Product: CC(C)C(=O)CC(=O)N1CCOCC1
Yield: 88.9 %

Procedure:
0.351 mol (49.6 ml) of 4-methyl-3-oxovaleric acid methyl ester and 0.369 mol (32.3 ml) morpholine were stirred for 14 hours at 110° C. in a Dean-Stark apparatus. 8 ml methanol were collected. Subsequently, the excess starting materials was distilled off for 3 h on a rotary evaporator (80° C. water bath, 2 mbar). The crude product was dissolved in 500 ml toluene and extracted with 50 ml of 1 M NaOH and 3 times with 50 ml water, and the organic phase was concentrated on a rotary evaporator to dryness. After drying, 62.2 g of the title compound were obtained.