Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:23][C:24]([C:26]1([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:22]=[CH:21][C:14]3[O:15][CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:23][C:24]([C:26]1([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:22]=[CH:21][C:14]3[O:15][CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)#[N:1]
Reactant: CN1C(=O)COc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CN1C(=O)COc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)cc3)cc21
Yield: 104 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 10, step (iii), 155 mg) in dichloromethane (8 mL) was stirred at room temperature for 18 h with Burgess' reagent (134 mg). The solvent was partially evaporated and the mixture was absorbed onto silica for purification on a silica column using ethyl acetate/isohexane 1:1 as eluent to yield the sub-titled compound as a solid (156 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:46][N:47]([CH2:54][C@H:55]1[CH2:60][CH2:59][C@H:58]([NH2:61])[CH2:57][CH2:56]1)[CH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:61][C@H:58]4[CH2:57][CH2:56][C@H:55]([CH2:54][N:47]([CH3:46])[CH:48]5[CH2:53][CH2:52][O:51][CH2:50][CH2:49]5)[CH2:60][CH2:59]4)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N[C@H]2CC[C@H](CN(C)C4CCOCC4)CC2)CCO3)cc1
Reaction time: 2 h

Procedure:
Into a suspension of 7-(4-methylphenyl)-2,3-dihydrobenzooxepine-4-carboxylic acid (200 mg) and 1-hydroxybenzotriazole (145 mg) in acetonitrile (10 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (205 mg), and the resulting mixture was stirred for 2 hours. To the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (320 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (326 mg) and triethylamine (0.2 ml) in acetonitrile (10 ml), and the resulting mixture was stirred for 4 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent and the residue was then subjected to purification using column chromatography (ethanol/ethyl acetate 1:1) and to recrystallization (ethyl acetate/hexane) to obtain trans-7-(4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 63) (233 mg) as colorless crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][Si:16]([CH2:23]Cl)([CH3:22])[O:17][Si:18]([CH3:21])([CH3:20])[CH3:19].O>C(OCC)(=O)C>[C:3]([C:4]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:19][Si:18]([CH3:21])([CH3:20])[O:17][Si:16]([CH3:23])([CH3:22])[CH2:15]1)([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C[Si](C)(C)O[Si](C)(CCl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)C[Si](C)(C)O[Si](C)(C)C1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Reaction method: To a dry 1 L 3-neck round bottom flask equipped with a reflex condenser, addition funnel and a N2 gas inlet was added di(ethyleneglycol) diethyl ether (diethyl carbitol) (650 mL, 590.85 g). To the solvent was added sodium hydride (28.80 g, 1.20 mol) under a N2 atmosphere, and the suspension was cooled to ˜5° C. in an ice/water bath. To the cooled suspension was added diethyl malonate (192.00 g, 1.20 mol) dropwise through the addition funnel. (CAUTION: A large quantity of H2 gas is evolved.) When the addition of the diethyl malonate was complete, the suspension had turned to a clear solution. The reaction mixture was heated to 50° C. and stirring was continued for 30 minutes at 50° C. To the solution at 50° C. was then added bis(chloromethyl)tetramethyldisiloxane (138.76 g, 0.6 mol) over a 5 minute period through the addition funnel. The reaction mixture was then heated to 112-115° C., and stirring was continued under a N2 atmosphere while the reaction was monitored by GC. After 20 hr, GC showed that a trace amount of bis(chloromethyl)-tetramethyldisiloxane remained (retention time: 11.5 min.). The mixture was cooled to room temperature and the mixture was transferred to a separatory funnel. Water (500 mL) and ethyl acetate were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (400 mL), and the combined organic layers were washed with water (2×500 mL) and saturated aqueous sodium chloride (500 mL). The organic layer was separated, and the ethyl acetate was removed using a rotary evaporator. The remaining solution was vacuum distilled to remove the di(ethyleneglycol) diethyl ether (b.p. 70° C. @ 8 mm Hg). The solution was concentrated to a final weight of 182 g of crude CDS_E. GC of the crude CDS_E solution was obtained (retention time: 15.2 min.). The solution of the crude product was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[C:15]([CH:17]=[C:18]([O-])[CH3:19])#[N:16].[Na+].[NH2:22][C:23]([CH3:33])=[CH:24][C:25](=[O:32])[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)(=O)C>CC(O)C>[CH:27]1([CH2:26][C:25]([C:24]2[CH:13]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[O:3][C:2]([CH3:1])=[CH:11][C:10]4=[O:12])[C:17]([C:15]#[N:16])=[C:18]([CH3:19])[NH:22][C:23]=2[CH3:33])=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(N)=CC(=O)CC1CCCC1
Reactant: CC([O-])=CC#N
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)CC2CCCC2)=C(C)N1

Procedure:
150 mg (0.79 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 84 mg (0.79 mmol) of sodium 1-cyanoprop-1-en-2-olate, 133 mg (0.79 mmol) of 4-amino-1-cyclopentylpent-3-en-2-one and 68 μl (1.19 mmol) of acetic acid in 4 ml of 2-propanol and heated under reflux under argon for 4 h. After cooling, the suspension is filtered with suction and the remaining solid is washed with diethyl ether (20 ml). 240 mg (75% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: Cl.C([NH:5][C:6]1[C:7]([F:28])=[CH:8][C:9]2[N:13]=[N:12][N:11]([C:14]3[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[C:10]=2[CH:27]=1)(=O)C.O>CO.S(=O)(=O)(O)O>[NH2:5][C:6]1[C:7]([F:28])=[CH:8][C:9]2[N:13]=[N:12][N:11]([C:14]3[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[C:10]=2[CH:27]=1
Reactant: COC(=O)C(C)Oc1ccc(-n2nnc3cc(F)c(NC(C)=O)cc32)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)C(C)Oc1ccc(-n2nnc3cc(F)c(N)cc32)cc1
Temperature: 25 °C

Procedure:
Concentrated hydrochloric acid (6.3 mL) is added to a solution of methyl 2-[p-(6-acetamido-5-fluoro-1H -benzotriazol-1-yl)phenoxy]propionate (4.77 g, 0.013 mol) in methanol. The reaction mixture is refluxed for 18 hours, cooled to room temperature and concentrated in vacuo to obtain a solid. 1HNMR spectral analysis of the solid indicates that ester hydrolysis has occurred. A solution of the solid, sulfuric acid (4 drops) and methanol is refluxed for 6 hours, cooled to room temperature and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a brown powder which is identified by NMR spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][N:3]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: Nc1ncc(-c2cccc3c2CC(=O)N3)cn1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cnc(N)nc4)c32)c1C

Procedure:
4-(2-Aminopyrimidin-5-yl)-1,3-dihydroindol-2-one (55 mg) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (65 mg) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][OH:8])[CH:3]=1.Br[C:10]1[C:11]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:12][CH:13]=[C:14]([CH3:16])[N:15]=1>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:11]1[C:10]([O:8][CH2:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[N:15][C:14]([CH3:16])=[CH:13][N:12]=1)(=[O:19])=[O:20]
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Reactant: Cc1cc(CO)no1
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2cc(C)on2)n1

Procedure:
Prepared by the method of Example 20 using (5-methyl-3-isoxazolyl)methanol (0.05 g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.1 g). Yield 0.05 g.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][C:6]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.[OH-].[Na+]>>[C:12]([C:6]1([CH2:5][C:4]([OH:14])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)#[N:13]
Reactant: CCOC(=O)CC1(C#N)CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: N#CC1(CC(=O)O)CCCCC1

Procedure:
(1-Cyanocyclohexyl)acetic acid ethyl ester is reacted with aqueous sodium hydroxide solution using the methodology disclosed at Column 15, Method C, Step B of U.S. Pat. No. 5,132,451 which is herein incorporated by reference to afford the title product.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2].[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH2:22]([NH:24][C:25]([NH:21][C:17]1[CH:16]=[C:15]([C:5]2[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=2[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[CH:20]=[CH:19][N:18]=1)=[O:26])[CH3:23]
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Reactant: CCN=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCNC(=O)Nc1cc(-c2sc(CC)nc2-c2cccc(C)c2)ccn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 46.5 %

Procedure:
To A solution of 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.50 g, 1.7 mmol) in N,N-dimethylacetamide (10 mL) was added ethyl isocyanate (0.20 mL, 2.5 mmol) and the reaction mixture was stirred at 80° C. for 20 hours. The reaction mixture was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extracts were washed with aqueous sodium hydrogen carbonate solution and brine. The resulting solution was dried, and concentrated under reduced pressure. The obtained crude crystal was recrystallized from ethyl acetate-hexane to give a title compound (0.29 g, yield 47%).
Reaction SMILES: [CH3:1][C:2]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>>[CH3:1][C:2]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:22][CH:21]=2)=[CH:13][CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)(Oc1ccccc1)C(=O)O
Yield: 61.9 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-methyl-2-phenoxy-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (930 mg), which is the product of Example 15, was reacted with aqueous sodium hydroxide solution (1N, 3.60 ml) at 70° C. and the reaction mixture was treated to give the title compound (545 mg) as a white powder.
Reaction SMILES: CC([O:4][CH2:5][C@H:6]1[O:11][C@H:10]([O:12][C:13]([CH3:15])=O)[C@H:9]([O:16]C(C)=O)[C@@H:8]([O:20]C(C)=O)[C@@H:7]1[O:24][C@@H:25]1[O:30][C@H:29]([CH2:31][O:32]C(C)=O)[C@@H:28]([O:36]C(C)=O)[C@H:27]([O:40]C(C)=O)[C@H:26]1[O:44]C(C)=O)=O.[CH2:48](O)C=C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[O-].[Na+]>C(Cl)Cl.O>[C@@H:25]1([O:24][C@@H:7]2[C@@H:6]([CH2:5][OH:4])[O:11][CH:10]([O:12][CH2:13][CH:15]=[CH2:48])[C@H:9]([OH:16])[C@H:8]2[OH:20])[O:30][C@H:29]([CH2:31][OH:32])[C@@H:28]([OH:36])[C@H:27]([OH:40])[C@H:26]1[OH:44]
Reactant: C=CCO
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCOC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.6 %

Procedure:
α-D-cellobiose octaacetate (48.59 g, 71.6 mmol) was dissolved in methylene chloride (600 mL), and allyl alcohol (29 ml, 0.43 mol) and trimethylsilyl trifluoromethanesulfonate (16 mL, 86.0 mmol) were added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 1.5 hours. Water (200 mL) was added to the reaction mixture and the mixture was extracted with methylene chloride (200 mL). The extract was washed with a saturated aqueous NaCl solution (100 mL) and after it was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (300 mL) and sodium methoxide (28 mL, 0.14 mol) was added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 2 hours. Dowex 50w×8 was added to the reaction mixture until the reaction mixture became neutral and after it was filtered, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 8:2:1, V/V) to obtain the desired title compound (24.8 g, yield: 91%) as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:43])[C:15]([C:18]3[N:19]=[C:20]([NH:23][C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:21][CH:22]=3)=[N:16][OH:17])[C:11](=[O:44])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].C(Cl)Cl.Br[CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51].Cl>O>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:43])[C:15]([C:18]3[N:19]=[C:20]([NH:23][C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[S:21][CH:22]=3)=[N:16][O:17][CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:11](=[O:44])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH2:5]([NH:6][CH2:7][CH3:2])[CH3:12]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Product: CCNCC
Reaction time: 0.08 h

Procedure:
4.7 g of the product of Step B were added to 70 ml of methylene chloride and then 70 ml of distilled water were added thereto. 21 ml of trithylamine were added thereto with stirring and under reduced pressure and after 5 minutes of stirring, 15.3 ml of tert.-butyl bromoacetate were added thereto all at once. The mixture was vigorously stirred at 25°-30° C. for 30 minutes and was then acidified at 15°-20° C. by addition of 8 ml of hydrochloric acid. The decanted aqueous phase was extracted twice with 20 ml of methylene chloride and the combined organic phases were washed 3 times with 50 ml of distilled water, was dried over magnesium sulfate and was vacuum filtered. The filtrate was rinsed and the filtrate was evaporated to dryness under reduced pressure. The 9.8 g of gum were dissolved in 30 ml of ethyl acetate and the mixture was stirred at 20° C. until dissolution occured. 0.75 ml of diethylamine were added thereto followed by the addition of 60 ml of isopropyl ether and the mixture was stirred at 20°-25° C. for 15 minutes and was then vacuum filtered. The recovered product was washed twice with 5 ml of a 1-2 ethyl acetate-isopropyl ether mixture and 3 times with 10 ml of isopropyl ether and was dried to obtain 4.31 g of the syn isomer of diethylamine 3-methyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(tert.-butoxycarbonylmethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate melting at 140° C. (decomposition).
Reaction SMILES: [CH2:1](N(CC)CC)C.C(OCC)(=O)CC(OCC)=O.[Cl-].[Mg+2].[Cl-].[Cl:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:22][C:23]1[C:24]([C:25](=[O:26])[CH3:1])=[CH:28][CH:29]=[CH:30][N:31]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CCOC(=O)CC(=O)OCC
Product: CC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
Triethylamine (7.4 g, 73 mmol) was added to a solution of diethyl malonate (5.6 g, 35 mmol) and anhydrous magnesium chloride (1.9 g, 20 mmol) in toluene (15 ml) under inert atmosphere. After stirring for 1 hr at room temperature, a solution of 2-chloro nicotinoyl chloride (5.2 g, 29 mmol) in toluene (5 ml) was added and the reaction mixture was stirred at room temperature for a further 1 hr. The reaction was quenched with ice cold 2N hydrochloric acid (20 ml), and the organic layer was separated and concentrated to dryness. The resultant residue was dissolved in a mixture of 3:2 DMSO-water and heated at 120-130° C. for 6 hr. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 ml). The organic layer was washed once with bicarbonate solution, then several times with water, and finally with brine. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to yield 1-(2-chloro-pyridin-3-yl)ethanone (1 g, 25%) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[P:31]([O:43][CH2:44][CH2:45][N:46]([CH3:76])[CH2:47][CH2:48][C@@H:49]([NH:58][C:59]1[CH:64]=[CH:63][C:62]([S:65](=[O:68])(=[O:67])[NH2:66])=[CH:61][C:60]=1[S:69]([C:72]([F:75])([F:74])[F:73])(=[O:71])=[O:70])[CH2:50][S:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[P:31]([O:43][CH2:44][CH2:45][N:46]([CH2:47][CH2:48][C@@H:49]([NH:58][C:59]1[CH:64]=[CH:63][C:62]([S:65](=[O:68])(=[O:67])[NH:66][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[OH:30])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)=[CH:61][C:60]=1[S:69]([C:72]([F:74])([F:75])[F:73])(=[O:71])=[O:70])[CH2:50][S:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH3:76])([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:32]
Reactant: CN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reactant: O=C(O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Product: CN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Yield: 61.5 %

Procedure:
A similar procedure to that described for INTERMEDIATE 55 utilizing (R)-4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 40, 63 mg, 0.14 mmol) and (R)-di-tert-butyl 2-(methyl(4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butyl)amino)ethyl phosphate (INTERMEDIATE 54, 105 mg, 0.14 mmol) as starting materials was followed, with subsequent purification by column chromatography (ISCO, 0→100% EtOAc/hexane followed by 0→10% MeOH/EtOAc) to give the title product (98 mg, yield: 60%).
Reaction SMILES: [C:1]([C:5]([C:9]([O:11]C)=[O:10])([O:7][CH3:8])[F:6])([F:4])([F:3])[F:2].[OH-].[K+].Cl>O>[CH3:8][O:7][C:5]([F:6])([C:1]([F:2])([F:3])[F:4])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(F)(OC)C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(F)(C(=O)O)C(F)(F)F
Yield: 79.9 %

Procedure:
A mixture of methyl 2-methoxytetrafluoropropionate formed in Example 1 (41.9 g), water (500 ml) and potassium hydroxide (56 g) was refluxed for 3 hours. The reaction mixture was acidified with 100 ml of equal parts hydrochloric acid and water and extracted with three 200 ml portions of ether. The combined ether extracts were dried over sodium sulfate. After evaporation of the ether, fractional distillation gave 2-methoxytetrafluoropropionic acid (31.0 g. 80%), b.p. 67°-68° (12 mm Hg).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(O[C:43]([N:45]1[CH2:51][CH2:50][CH2:49][N:48]([C:52](=O)[CH2:53]Cl)[CH2:47][CH2:46]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:53][CH2:52][N:48]2[CH2:49][CH2:50][CH2:51][N:45]([CH3:43])[CH2:46][CH2:47]2)=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)CCl)CC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCN(C)CC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 44.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(2-chloroacetyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.6 mg) was obtained.