Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].CCN(CC)CC.[C:18](OCl)([CH3:20])=[O:19]>ClCCl.O>[C:18]([O:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1])(=[O:19])[CH3:20]
Reactant: CC(=O)OCl
Reactant: Cc1ccc(CO)c(Cl)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1ccc(C)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of (2-chloro-4-methylphenyl)methanol (365 mg, 2.331 mmol) and Et3N (0.390 mL, 2.80 mmol) in Dichloromethane (DCM) (10 mL) at 0° C. AcOCl (0.331 mL, 4.66 mmol) was slowly added and the mixture was left under stirring at 0° C. for 1 hour then at room temperature overnight. Next morning HPLC showed no starting material remaining volatiles were removed under vacuum and resulting crude was dissolved in DCM washed several times with water. Organic layers were dried over Na2SO4 and volatiles removed to afford 453 mg of the final compound as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(C)(C)O[C:9]2=[O:15])=[CH:4][CH:3]=1.Cl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=1.C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(c2ccc(Br)cc2)O1
Reactant: COc1cc(CCN)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(CCNC(=O)C(O)c2ccc(Br)cc2)ccc1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-(4-Bromophenyl)-2,2-dimethyl-1,3-dioxolan-4-one (15 g; 55 mmol) is dissolved in 50 ml of methanol. 4-(2-Aminoethyl)-2-methoxyphenol hydrochloride (14 g; 69 mmol) and triethylamine (7 g; 69 mmol) are added and the mixture is stirred for 72 hours at room temperature. The solvent is removed in vacuum and the residue is extracted with ethyl acetate and the combined organic phases are washed with brine, dried over sodium sulfate and evaporated to dryness. The remaining 2-(4-bromophenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide is purified by chromatography on silica gel.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:38]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)=[O:39])[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)Nc3ccc(F)cc3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
83 mg (50% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 23 mg (0.17 mmol, 1.2 eq.) of 4-fluorophenyl isocyanate were reacted according to General Method 4. Yield: 44 mg (67% of theory)
Reaction SMILES: Cl[CH:2]([C:6](=O)[CH3:7])[CH2:3][C:4]#[N:5].[NH2:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.C(N(CC)CC)C>C(O)C>[CH2:17]([O:16][C:15]1[C:10]2[N:11]([C:2]([CH2:3][C:4]#[N:5])=[C:6]([CH3:7])[N:9]=2)[CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)C(Cl)CC#N
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc2c(OCc3ccccc3)cccn2c1CC#N

Procedure:
A solution of 0.86 g. of 3-chloro-4-oxopentanonitrile, 0.92 g. of 2-amino-3-phenylmethoxypyridine and 0.5 ml. of triethylamine in 15 ml. of ethanol was stirred for 16 hours, then concentrated to remove the triethylamine and ethanol. The residue was dissolved in methylene chlorideand washed with water. The methylene chloride was concentrated and the residual oil was dissolved in 20 ml. of boiling acetonitrile, filtered, cooled, and treated with hydrogen chloride/methanol with cooling to give 0.22 g. of the desired product (m.p. 163°-166° C.).
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[Cl:40])=[O:29])[CH2:24][CH:23]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.Cl.O1CCOCC1>>[ClH:40].[Cl:40][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:31]=1[NH:30][C:28]([N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:23]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:24]1)=[O:29])[C:35]([OH:37])=[O:36]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)Nc2ccc(C(=O)O)cc2Cl)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CCN(C(=O)Nc2ccc(C(=O)O)cc2Cl)CC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 302 mg of the crude product of 4-({[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}amino)-3-chlorobenzoic acid was added 2.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was then added isopropanol, followed by heating under reflux. The mixture was cooled to room temperature, and the precipitate was then isolated by filtration, and dried under reduced pressure to obtain 147 mg of 3-chloro-4-({[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}amino)benzoic acid hydrochloride as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]([CH3:39])([C:37]#[CH:38])[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31].N(CC)CC>[Cu]I.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.CCN(CC)CC>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:38]#[C:37][C:29]([CH3:28])([CH3:39])[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: C#CC(C)(C)C(=O)OCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCNCC
Product: CCCCOC(=O)C(C)(C)C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Yield: 17.6 %

Procedure:
A microwave vial was charged with (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.12 mmol), butyl 2,2-dimethylbut-3-ynoate (40 mg, 0.23 mmol), CuI (2.2 mg, 0.012 mmol), PdCl2(PPh3)2 (5 mg, 0.008 mmol), Et3N (2 mL) and Et2NH (0.2 mL). The mixture was sparged with N2 for 10 min and heated at 100 C for 2 h. The mixture was concentrated, redissolved in EtOAc (90 mL), washed with 5% aq HCl (20 mL) and brine (20 mL), and dried over Na2SO4. Removal of the solvent left an oil (75 mg) which was purified by prep HPLC to afford butyl 4-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-2,2-dimethylbut-3-ynoate (11 mg, 19%). LC-MS Method 1 tR=2.13 min, m/z=520, 462.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[C:16]([O:19][C:20]([CH3:26])([CH2:22][CH2:23][CH:24]=O)[CH3:21])(=[O:18])[CH3:17].C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Ti](Cl)(Cl)(Cl)Cl>[C:16]([O:19][C:20]([CH3:26])([CH2:22][CH2:23][CH2:24][N:8]1[CH2:7][C@@H:6]2[CH2:12][O:13][CH2:14][CH2:15][N:5]2[C:4]2[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]1=2)[CH3:21])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)(C)CCC=O
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC(C)(C)CCCN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x3, 200 mg, 0.882 mmol) and 2-methyl-5-oxopentan-2-yl acetate (55.8 mg, 0.353 mmol) were combined in a 25 mL pear flask to give an orange suspension. Titanium(IV) chloride in DCM (1M, 0.971 mL, 0.971 mmol) was added at room temperature to give a deep-red suspension, which was stirred at room temperature for 1 hour before being cooled to 0° C. Sodium triacetoxyborohydride (281 mg, 1.324 mmol) was added at 0° C. in portions. The thick suspension slowly turned into a thinner, orange one with gas evolution. UPLC showed the reaction proceeded more than half-way after about 20 minutes. The reaction mixture was carefully quenched with brine, and was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted a second time with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C17H25ClN4O3, 369.17. found 396.2.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.[CH2:10]([NH2:12])[CH3:11]>O>[CH2:10]([NH:12][C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9])[CH3:11]
Reactant: CCN
Reactant: Cn1cc(C(=O)O)cn1
Solvent: O
Product: CCNC(=O)c1cnn(C)c1
Yield: 54.7 %

Procedure:
N-Ethyl-1-methyl-1H-pyrazole-4-carboxamide was prepared from 1-methyl-1H-pyrazole-4-carboxylic acid and 70% ethylamine in water using the methods of steps a and b of Example 248. The product was purified by flash chromatography with 10% ethyl acetate-hexane and recovered as a white solid in 54.7% yield. m.p. 103-106° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]#[N:19])[C:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[F:17])=[CH:6][CH:7]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]([C:5]2[C:4]([C:18]#[N:19])=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:13]=1
Reactant: N#Cc1cc(F)ccc1-c1cc([N+](=O)[O-])ccc1F
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cc(F)ccc1-c1cc(N)ccc1F
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A suspension of 4,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile (26 g, 100 mmol) in ethanol (180 ml) and ethyl acetate (180 ml) was treated with platinum(IV) oxide (1.02 g, 4.5 mmol) and then shaken under an atmosphere of hydrogen (40 psi) for 1 h. [The reaction was very exothermic and complete solution is brought about by the increase in temperature]. The catalyst was removed by filtration through glass microfibre filter paper [if any crystalline product is present the filter cake is washed with dichloromethane] and the filtrate evaporated to dryness to afford 5′-amino-4,2′-difluorobiphenyl-2-carbonitrile as a straw-coloured solid (23 g, 100%): 1H NMR (360 MHz, CDCl3) δ 3.66 (2H, s), 6.66-6.70 (1H, m), 6.71-6.74 (1H, m), 7.00 (1H, dd, J 9, 9 Hz), 7.33-7.38 (1H, m), 7.44-7.49 (1H, m).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]([NH:16]C(OC(C)(C)C)=O)([CH3:15])[C:10]2([CH2:12][CH2:11]2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>C1(C)C=CC=CC=1>[NH2:16][C:13]1([CH3:15])[C:10]2([CH2:12][CH2:11]2)[C:9](=[O:24])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1(C)CN(Cc2ccccc2)C(=O)C12CC2
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(N)CN(Cc2ccccc2)C(=O)C12CC2
Reaction time: 0.5 h
Yield: 70 %

Procedure:
5-Benzyl-7-t-butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane (43.63 g) was dissolved in toluene, and the solution was stirred under ice-cooling. 37% Concentrated hydrochloric acid (100 mL) was added dropwise thereto, followed by stirring. After 0.5 hours, water was added to the reaction mixture. The mixture was stirred and left to stand so as to separate the aqueous layer from the organic layer. Sodium hydroxide (54 g) was added to and dissolved in the separated aqueous layer so as to alkalify the layer. The aqueous layer was extracted several times with toluene repeatedly. All the toluene layers were combined and washed with saturated brine. The washed toluene layer was dried with sodium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure, to thereby yield the title product (21.29 g, yield: 90.2%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C@H:16]3[CH2:21][CH2:20][C@@H:19]([C:22]([F:25])([F:24])[F:23])[CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.N1(S(N)(=O)=O)CCC1.[CH:34]1([S:37]([NH2:40])(=[O:39])=[O:38])[CH2:36][CH2:35]1>>[CH:1]1([C:4]2[C:5]([O:14][CH2:15][C@H:16]3[CH2:17][CH2:18][C@@H:19]([C:22]([F:25])([F:23])[F:24])[CH2:20][CH2:21]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([NH:40][S:37]([CH:34]2[CH2:36][CH2:35]2)(=[O:39])=[O:38])=[O:11])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(C2CC2)c(OC[C@H]2CC[C@@H](C(F)(F)F)CC2)cc1F
Agent: NS(=O)(=O)N1CCC1
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OC[C@H]2CC[C@@H](C(F)(F)F)CC2)cc1F

Procedure:
Following the procedure as described in Example 218 step 5, and making variations as required to replace trans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acid with cis-5-cyclopropyl-2-fluoro-4-((4-(trifluoromethyl)cyclohexyl)-methoxy)benzoic acid and to replace azetidine-1-sulfonamide with cyclopropanesulfonamide, the title compound was obtained as colorless solid (0.11 g, 79%): 1H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.04 (d, J=13.1 Hz, 1H), 4.06 (d, J=7.1 Hz, 2H), 3.11-3.03 (m, 1H), 2.42-2.26 (m, 1H), 2.14 (brs, 1H), 2.06-1.97 (m, 1H), 1.74-1.56 (m, 8H), 1.13-1.09 (m, 4H), 0.91-0.85 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 464.1 (M+1); MS (ES−) m/z 462.2 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]=[CH:11][C:12](C(C(O)=O)C(O)=O)=[O:13].[CH3:21][CH:22]([CH2:42][CH2:43][CH:44]=[C:45]([CH3:47])[CH3:46])[CH2:23][CH2:24][O:25][C:26](=[O:41])[CH2:27][C:28]([O:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:39])[CH3:38])=[O:29].CC1CCCC(C)(C)C=1C=CC(Cl)=O.[H-].[Na+]>>[CH3:21][CH:22]([CH2:42][CH2:43][CH:44]=[C:45]([CH3:47])[CH3:46])[CH2:23][CH2:24][O:25][C:26](=[O:41])[CH:27]([C:12](=[O:13])[CH:11]=[CH:10][C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])[C:28]([O:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:38])[CH3:39])=[O:29]
Reactant: CC1=C(C=CC(=O)C(C(=O)O)C(=O)O)C(C)(C)CCC1
Reactant: CC(C)=CCCC(C)CCOC(=O)CC(=O)OCCC(C)CCC=C(C)C
Agent: CC1=C(C=CC(=O)Cl)C(C)(C)CCC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)=CCCC(C)CCOC(=O)C(C(=O)C=CC1=C(C)CCCC1(C)C)C(=O)OCCC(C)CCC=C(C)C

Procedure:
According to the procedure of Example 45, 2-[3-(2,6,6-trimethyl-cyclohex-1-enyl)-acryloyl]-malonic acid bis-3,7-dimethyl-oct-6-enyl) ester was prepared from malonic acid bis-(3,7-dimethyl-oct-6-enyl) ester, 3-(2,6,6-trimethyl-cyclohex-1-enyl)acryloyl chloride (Shimasaki et al., Chem. Pharm. Bull., 43 (1995) 1, 100-107) and sodium hydride.
Reaction SMILES: C[C:2](C)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C(C)(C)C.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[O:45]1CC[NH:47][C:46]1=O>O1CCCC1.C(N(CC)CC)C>[CH2:2]([C@H:3]1[CH2:4][O:5][C:46](=[O:45])[NH:47]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NCCO1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1N[C@@H](Cc2ccccc2)CO1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3,3-dimethyl-3-phenyl propionic acid (10 g, 57 mmol, from Reference Example 22) in anhydrous tetrahydrofuran (120 mL) is added under inert atmosphere triethylamine (10 mL) and the mixture is cooled to −78° C. in a dry-ice acetone bath. Pivaloyl chloride (7.4 mL, 60 mmol) is added dropwise, causing the immediate formation of a white precipitate. The reaction mixture is allowed to sit for 15 minutes at −78° C. and is then stirred at 0° C. in an ice-water bath. In a separate flask, a solution of (S)-4-benzyl-2-oxazolidinone (9.9 g, 56 mmol) in anhydrous tetrahydrofuran (130 mL) is prepared under inert atmosphere and cooled to −35° C. in a dry-ice/acetone bath. A small amount of triphenylmethane (<5 mg) is added as an indicator of deprotonation. n-Butyllithium (1.6 M solution in hexanes, 40 mL, 64 mmol) is added dropwise via syringe. After 30 minutes of stirring at 0° C., the flask containing the mixed anhydride is re-cooled to −78° C. in a dry-ice/acetone bath. The solution of the lithium anion of the oxazolidinone is added to the mixed anhydride solution via cannula. The source flask is washed twice with tetrahydrofuran (4 mL×2) and these washings are also transferred via cannula to the mixed anhydride solution. The reaction mixture is stirred at −78° C. for 1 hour and at 0° C. for 1 hour. Water (100 mL) is added and stirring is continued for 15 minutes. The aqueous phase is extracted thrice with diethyl ether. The combined extracts are washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, decanted, and concentrated under reduced pressure to afford 20 g of a white paste. The crude material is purified by flash chromatography (ethyl acetate/hexanes) to afford 11 g (56%) of a flocculent white solid. MS (ES+): (M+H)=338.1
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:8][CH:7](OS(C)(=O)=O)[CH2:6][N:5]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:3].C1COCC1.[F-:26].C([N+](CCCC)(CCCC)CCCC)CCC.O>ClCCl>[NH2:1][C:2]([C@@H:4]1[CH2:8][C@H:7]([F:26])[CH2:6][N:5]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)CC1C(N)=O
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Temperature: 0 °C

Procedure:
In a 5.0 L 4-necked RB flask, fitted with a mechanical stirrer and reflux condenser, were added tert-butyl 2-(aminocarbonyl)-4-[(methylsulfonyl)oxy]pyrrolidine-1-carboxylate (100 gm, 0.32 M), THF (500 ml), a tetrabutylammonium fluoride solution (153.4 gm, 0.48 mol in 500 ml THF) and water (35 ml) at 25-35° C. while stirring. The reaction mixture was brought to 55-60° C. and maintained for 48-60 hrs while stirring. The progress of the reaction was monitored by HPLC and after ascertaining completion, the reaction mixture was poured slowly into an ice cold water (1.5 L) and dichloromethane (0.72 L) mixture. The aqueous layer was washed with additional MDC (210 ml×3). The organic layers were combined and washed with a saturated brine solution (0.5 L). The dichloromethane layer was distilled below 40° C. under vacuum and hexane (500 ml) was added to the resulting mass. The trace dichloromethane was distilled off. The resulting mass was taken as such to the next stage.
Reaction SMILES: C(=[N:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2[F:25])[CH2:12][CH2:11]1)C1C=CC=CC=1>Cl>[F:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(N2CCC(CN=Cc3ccccc3)CC2)c(F)c1
Agent: Cl
Product: NCC1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Yield: 98.5 %

Procedure:
1N aqueous hydrochloric acid (20 ml) was added to benzylidene[1-(2-fluoro-4-nitrophenyl)piperidine-4-ylmethyl]amine (compound of Reference Example 21; 1.15 g, 3.36 mmol), and the mixture was refluxed for 6 hours. The reaction mixture was washed with ethyl acetate and adjusted to pH=12 by addition of 2N aqueous sodium hydroxide. The water layer was saturated with sodium chloride and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.838 g, 98%) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:34][O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:5]([NH:7][CH:8]1[C:32](=[O:33])[N:10]2[C:11]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[S:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:42][C:43]([NH2:45])=[S:44].C([O-])(=O)C.[Na+].C(OCC)(=O)C>O1CCCC1.O>[NH2:45][C:43]1[S:44][CH:2]=[C:3]([C:4](=[N:34][O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:5]([NH:7][CH:8]2[C:32](=[O:33])[N:10]3[C:11]([C:16]([O:18][CH:19]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[S:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]23)=[O:6])[N:42]=1
Reactant: COC(=O)CON=C(C(=O)CCl)C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C)CS[C@H]12
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C)CS[C@H]12)c1csc(N)n1
Reaction time: 2 h
Yield: 89.1 %

Procedure:
A mixture of benzhydryl 7-[4-chloro-2-(methoxycarbonylmethoxyimino)-3-oxobutyramido]-3-methylthio-3-cephem-4-carboxylate (syn isomer) (18.97 g), thiourea (4.56 g) and sodium acetate (7.38 g) in tetrahydrofuran (150 ml) and water (80 ml) was stirred at 40° to 45° C. for 2 hours. Ethyl acetate (300 ml) was added to the reaction mixture at room temperature and the organic layer was separated. The organic layer was washed with brine and dried over magnesium sulfate. The solution was evaporated and the residue was triturated with ether to give benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-(methoxycarbonylmethoxyimino)acetamido]-3-methylthio-3-cephem-4-carboxylate (syn isomer) (17.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH2:13]([C:15]1[C:16]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=1)[CH3:14]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[C:15]([CH2:13][CH3:14])=[CH:20][C:19]([CH3:21])=[CH:18][N:17]=3)[CH2:23][CH2:24]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: CCc1cc(C)cnc1N1CCNCC1
Agent: Cl
Product: CCc1cc(C)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Yield: 65.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 8 and using 4-bromo-2-fluorobenzoyl chloride (1.1 g) and 1-(3-ethyl-5-methylpyridin-2-yl)piperazine hydrochloride (1 g) described in Preparation Example 54, the title compound (1.1 g) was obtained.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:28][C:29]1[C:30](=[O:37])[CH2:31][C:32]([CH2:35][OH:36])=[N:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:21]([O:28][C:29]1[C:30](=[O:37])[CH2:31][C:32]([CH2:35][O:36][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:33][CH:34]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1CC(CO)=NC=C1OCc1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)=NC=C1OCc1ccccc1
Temperature: 95 °C
Yield: 42.8 %

Procedure:
4-Dimethylaminopyridine (17.55 g) and trityl chloride (40.5 g) are added to a solution of 5-benzyloxy-2-hydroxymethyl-4-pyridone (30.2 g) in dry dimethylformamide and the mixture stirred and heated at 95° C. for 2 hours. After cooling the mixture is poured into iced-water (800 mL) and the precipitate collected, washed with water (2×500 mL) and sucked dry. The solid is boiled with methanol (500 mL) and after cooling the solid is collected, washed with methanol (200 mL) and diethyl ether (2×100 mL) and dried at 80° C. to give 5-benzyloxy-2-trityloxymethyl-4-pyridone (26.5 g) as a white solid, m.p. 233-5° C.