Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1([CH3:22])[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:31])[C:5]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:4]=2[O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CN(Cc2ccccn2)c2cc([N+](=O)[O-])ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CN(Cc2cccc[n+]2[O-])c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 4 ml of methylene chloride was dissolved 0.33 g of 3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-pyridylmethyl)-2H-1,4-benzoxazine followed by addition of 0.26 g of m-chloroperbenzoic acid, and the mixture was stirred at room temperature overnight. This reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude crystals of 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)methylpyridine N-oxide. Recrystallization from ethanol-chloroform gave 0.2 g of the object compound. This compound was found to have the following physicochemical properties.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([F:14])[CH:8]=1)C.FC(F)(F)C(O)=O.CO[CH2:25][N:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:27][Si](C)(C)C.[OH-].[Na+]>ClCCl.C(O)C.O>[CH2:32]([N:26]1[CH2:27][C:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([F:14])[CH:8]=2)=[C:5]([C:4]([OH:3])=[O:15])[CH2:25]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C#Cc1ccc(Cl)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=C(c2ccc(Cl)c(F)c2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.6 %

Procedure:
To a solution of (4-chloro-3-fluoro-phenyl)-propynoic acid ethyl ester (57.08 g, 252 mmol) in dichloromethane (240 mL) was added trifluoroacetic acid (1.9 mL, 25.2 mmol). The reaction mixture was cooled with a water bath at ambient temperature and a solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (93.43 g, 378 mmol) in dichloromethane (185 mL) was added dropwise over a period of 3 h. After stirring for 20 h at ambient temperature further N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (15.6 g, 63.0 mmol) in dichloromethane (30 mL) was added and stirring was continued for another 4 h. The solvent was removed and the residue was dissolved in dioxane (540 mL). After addition of water (270 mL) and aqueous sodium hydroxide (32%, 64.8 ml, 700 mmol), it was stirred for 44 h at ambient temperature. After concentration the resulting residue was diluted with water (225 mL) and extracted with tert-butylmethylether (225 mL). The organic layer was washed with water (225 mL) and the aqueous layer was cooled to 5° C. and set to pH=1.5 with aqueous hydrogen chloride (25%, 112 mL). After stirring for 1 h at 5° C., the resulting solid was filtered and washed with water (795 mL) and ethanol (225 mL). Drying gave a light yellow solid which was stirred with ethanol (4 L) for 1 h at 85° C. The resulting suspension was filtered and the filtrate was concentrated. Trituration with tert-butylmethylether (2 L) afforded the title compound (62.34 g, 67%) as an off-white solid. MS m/e: 330.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[F:14].[F:15][C:16]([F:21])([F:20])[C@@H:17]1[CH2:19][O:18]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][N:10]([CH2:19][C@H:17]([OH:18])[C:16]([F:21])([F:20])[F:15])[CH2:11][CH2:12][O:13]2)=[CH:4][C:3]=1[F:14]
Reactant: Fc1cc([C@@H]2CNCCO2)ccc1Cl
Reactant: FC(F)(F)[C@@H]1CO1
Solvent: ClCCl
Product: O[C@@H](CN1CCO[C@H](c2ccc(Cl)c(F)c2)C1)C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
(R)-2-(4-chloro-3-fluorophenyl)morpholine (230 mg, 1.07 mmol) was mixed with (S)-2-(trifluoromethyl)oxirane (180 mg, 1.6 mmol) in 1 mL of dichloromethane in a tube. The tube was sealed and stirred at 60° C. overnight. The solution was evaporated to dryness to afford (S)-3-((R)-2-(4-chloro-3-fluorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol as an oil (340 mg), which was used as is in the next step. (M+H)+=328 m/e.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH3:21])=[CH:15][C:13]=1[NH2:14]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][C:13]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([Cl:19])=[CH:18][C:12]=2[O:11][CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1cc(Cl)c(OC)cc1N
Product: COc1cc(Nc2nc(Cl)ncc2F)c(OC)cc1Cl

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 2,5-dimethoxy-4-chloroaniline gave 2-chloro-N4-(2,5-dimethoxy-4-chlorophenyl)-5-fluoro-4-pyrimidineamine. LCMS: purity: 97%; MS (m/e): 316 (M−2H) and 320 (M+2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:12][C:13]([NH2:15])=[S:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:17]1([C:21](OCC)=[O:22])[CH2:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:12][C:13]3[S:14][C:17]4([C:21](=[O:22])[N:15]=3)[CH2:20][CH2:19][CH2:18]4)[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: NC(=S)NC1(c2ccc(Cl)cc2)CCC1
Product: O=C1N=C(NC2(c3ccc(Cl)cc3)CCC2)SC12CCC2

Procedure:
Synthesis was performed from N-[1-(4-chlorophenyl)cyclobutyl]thiourea and ethyl 1-bromocyclobutanecarboxylate according to Method D.
Reaction SMILES: C([NH:9][C:10]1[CH:23]=[C:22]2[O:24][CH2:25][O:26][C:21]2=[CH:20][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])(=O)C1C=CC=CC=1.[OH-].[Na+]>C(O)C>[NH2:9][C:10]1[CH:23]=[C:22]2[O:24][CH2:25][O:26][C:21]2=[CH:20][C:11]=1[C:12]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: O=C(Nc1cc2c(cc1C(=O)c1ccccc1)OCO2)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc2c(cc1C(=O)c1ccccc1)OCO2

Procedure:
To a flask equipped with a stirrer and condenser are charged 40 g. of 2-benzoylamino-4,5-methylenedioxybenzophenone, 150 ml. of ethanol and 100 ml. of 50% sodium hydroxide. The mixture is stirred and refluxed for 2 hours. The solution is treated with 400 ml. of water and the resulting solid is filtered off to give 2-amino-4,5-methylenedioxybenzophenone m.p. 160°-161°C.
Reaction SMILES: [CH3:1][S:2]([C:5](C(OC)=O)([CH2:16][CH2:17][CH2:18][CH:19]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:4])=[O:3].[Cl-].[Na+].CN(C)C=O>O>[CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:4])=[O:3]
Reactant: COC(=O)CCCCCCC(CCCC(COc1ccc(F)cc1)OCc1ccccc1)(C(=O)OC)S(C)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCC(CCCC(COc1ccc(F)cc1)OCc1ccccc1)S(C)(=O)=O
Temperature: 160 °C

Procedure:
A mixture of methyl 8-methylsulfonyl-8-methoxycarbonyl-12-benzyloxy-13-(4-fluorophenoxy)tridecanoate (2.60 g., 4.5 mmoles), sodium chloride (0.5 g., 8.5 mmoles), dimethylformamide (8 ml.) and water (0.2 ml.) is heated with an oil bath at 160° C. overnight (ca. 15 hours). The reaction mixture is allowed to cool to room temperature, quenched with cold water, and then extracted with chloroform three times. The combined extracts are washed with brine and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation in vacuo leaving the desired product as a viscous oil residue (2.30 g., 4.4 mmoles, 98%). ir (neat) 3.40, 5.72, 6.20, 6.62, 6.87, 7.71, 8.00, 8.28, 8.90, 12.04, 13.17, 14.37μ; pmr CCl4)δ1.0-2.9 (22H, m, containing a methyl singlet at 2.60δ), 3.54 (3H, s); 3.5-4.1 (3H, m), 4.47 (1H, d, J=12Hz), 4.70 (1H, d, J=12Hz), 6.6-7.1 (4H, m), 7.20 (5H, s).
Reaction SMILES: [C:1]1(=[O:16])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5](=[O:14])[C:4]=2[C:3](=[O:15])O1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[C:18]1([N:17]2[C:1](=[O:16])[C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[NH:6][C:5](=[O:14])[C:4]=3[C:3]2=[O:15])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1OC(=O)c2c1c(=O)[nH]c1ccccc21
Reactant: Nc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C1c2c(c3ccccc3[nH]c2=O)C(=O)N1c1ccccc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A mixture of Furo[3,4-c]quinoline-1,3,4(5H)-trione (215 mg) and aniline (93 mg) in dry dimethylformamide (3 mL) was heated at 100° C. for 5 min. After coolong to room temperature 1,1'-Carbonyidiimidazole (200 mg) was added. The reaction mixture was then heated again to 100° C.. for an additional 5 min. After cooling the reaction mixture was poured onto water to afford 2-Phenyl-pyrrolo[3,4-c]quinoline-1,3,4(5H)-trione (Compound 1) as yellow crystals melting at >390° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[C:12]#[N:13].C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C.Cl>O1CCCC1>[C:12]([C:11]1[CH:14]=[C:7]([B:21]([OH:22])[OH:20])[CH:8]=[CH:9][C:10]=1[O:15][CH3:16])#[N:13]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)cc1C#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1C#N
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
16.23 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 5.00 g of 5-bromo-2-methoxybenzonitrile in 90 ml of dry tetrahydrofuran at −78° C. After stirring at this temperature for 45 minutes, 6.71 ml of triisopropylborate are added, and the mixture is then slowly warmed to −20° C. 50 ml of 1N HCl are added to the reaction mixture. The phase is separated and the aqueous phase is extracted three more times with 100 ml of diethyl ether each time. The combihled organic phases are dried with sodium sulphate, filtered and evaporated. The remaining oil is mixed with pentane, and the precipitate which separates out is filtered off with suction and washed once with a little dichloromethane. Drying under high vacuum affords the title compound as a white solid. Rt=2.74.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:8][C:7]([C:20](OC)=[O:21])=[CH:6][N:5]2[C:24]=1[CH3:25].[CH2:26]([CH2:28][NH2:29])[OH:27].[C-]#N.[Na+]>C(COC)OC>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:8][C:7]([C:20]([NH:29][CH2:28][CH2:26][OH:27])=[O:21])=[CH:6][N:5]2[C:24]=1[CH3:25]
Reactant: COC(=O)c1cc(NCc2c(C)cccc2C)c2nc(C)c(C)n2c1
Reactant: NCCO
Agent: [C-]#N
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc(C)c1CNc1cc(C(=O)NCCO)cn2c(C)c(C)nc12
Yield: 85.2 %

Procedure:
Methyl 2,3-dimethyl-8-(2,6-dimethylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylate (0.12 g, 0.33 mmol), ethanolamine (0.2 g, 3.3 mmol) and sodium cyanide (10 mg, 0.2 mmol) were refluxed in dimethoxyethane (2 ml) for 20 h. The solvent was evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride:methanol (92:8) as eluent gave the product which was washed with diethyl ether to give 103 mg (79%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]=[CH:14][C:15]([OH:17])=[O:16])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: O=CC1CCC2(CC1)OCCO2
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=CC1CCC2(CC1)OCCO2

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decane-8-carbaldehyde (3.1 g, 18.4 mmol, prepared as in STEP B above), malonic acid (3.8 g, 36.5 mmol), piperidine (0.182 mL, 1.8 mmol) in pyridine (20 mL) was stirred at 70° C. under an argon atmosphere. After 3 h the resulting solution was concentrated. The residue obtained was partitioned between ethyl acetate and water. The layers were separated, and the ethyl acetate layer was washed successively with water and brine. The ethyl acetate layer was dried over sodium sulfate and was filtered, concentrated, and dried in vacuo to yield 3-(1,4-dioxa-spiro[4.5]dec-8-yl)-acrylic acid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH:10]=1)(=[O:4])=[O:3]
Reactant: O=C1CCCN1c1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccc(N2CCCC2=O)c1
Reaction time: 2 h
Yield: 93 %

Procedure:
Methanesulfonyl chloride (0.124 mL) was added dropwise to a stirred solution of 1-[3-(2-hydroxyethyl)phenyl]-2-pyrrolidinone (0.30 g) and triethylamine (0.42 mL) in dichloromethane (10 mL) at room temperature under an inert atmosphere. The solution was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL), aqueous hydrochloric acid (1N, 2×50 mL), a saturated aqueous solution of sodium hydrogencarbonate (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, eluting with ethyl acetate-cyclohexane (50:50) to afford the title compound in 93% yield (0.384 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7](B(O)O)([CH3:9])=[CH2:8].Cl[C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][NH:27][C:28](=[O:49])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[O:36][C:37]5[C:43]([CH:44]([CH3:46])[CH3:45])=[CH:42][C:41]([C:47]#[N:48])=[CH:40][C:38]=5[N:39]=4)=[CH:31][CH:30]=3)[CH2:22][CH2:21]2)[CH:17]=[CH:16][N:15]=1.O>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C(O)C>[C:47]([C:41]1[CH:42]=[C:43]([CH:44]([CH3:46])[CH3:45])[C:37]2[O:36][C:35]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([NH:27][CH2:26][CH:23]4[CH2:24][CH2:25][N:20]([C:18]5[CH:17]=[CH:16][N:15]=[C:14]([C:7]([CH3:9])=[CH2:8])[N:19]=5)[CH2:21][CH2:22]4)=[O:49])=[CH:30][CH:31]=3)=[N:39][C:38]=2[CH:40]=1)#[N:48]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5ccnc(Cl)n5)CC4)cc3)oc12
Reactant: C=C(C)B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=C(C)c1nccc(N2CCC(CNC(=O)c3ccc(-c4nc5cc(C#N)cc(C(C)C)c5o4)cc3)CC2)n1
Temperature: 150 °C
Yield: 60.6 %

Procedure:
Sodium carbonate (120 uL, 2M aqueous), isopropenylboronic acid (21 mg), and N-{[1-(2-chloropyrimidin-4-yl)piperidin-4-yl]methyl}-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (31 mg, EXAMPLE 7) were dissolved in toluene (2.1 ml), water (0.6 ml) and ethanol (0.3 ml). To this solution was added palladium tetrakis(triphenylphosphine) (10 mg). The mixture was heated to 150° C. for 25 min in a microwave reactor. Upon cooling, the mixture was then concentrated in vacuo, taken up in dichloromethane, and purified via flash chromatography on a Biotage Horizon, 25 M column, eluting with 10 column volumes of ethyl acetate to provide the title compound (19 mg, 61%). Mass spectrum (ESI) 521.4 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.34 (d, J=8.5 Hz, 2H), 8.23 (d, J=6.2 Hz, 1H), 7.95 (d, J=8.0 Hz, 3H), 7.52 (s, 1H), 6.38 (d, J=6.2 Hz, 1H), 6.31 (t, J=6.0 Hz, 1H), 6.30 (s, 1H), 5.41 (s, 1H), 4.52 (d, J=8.7 Hz, 2H), 3.46 (m, 3H), 2.91 (t, J=12.4 Hz, 2H), 2.19 (s, 3H), 2.00 (m, 2H), 1.90 (d, J=12.2 Hz, 2H), 1.46 (d, J=7.0, 6H), 1.33 (m, 2H).
Reaction SMILES: C(OC([CH:8]([NH2:35])[C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][S:13][C@@H:12]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:10])=O)(C)(C)C.C1(C2C=CC=CC=2C2N[C@H]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])CS2)C=CC=CC=1.C(OC(NCC(O)=O)=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>>[C:56]([O:55][C:53]([NH:35][CH2:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:14][S:13][C@@H:12]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:10])=[O:54])([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)(C)OC(=O)C(N)C(=O)N1[C@@H](c2ccccc2-c2ccccc2)SC[C@H]1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@@H]1CSC(c2ccccc2-c2ccccc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)NCC(=O)O
Product: CC(C)(C)OC(=O)NCC(=O)N1[C@@H](c2ccccc2-c2ccccc2)SC[C@H]1C(=O)OC(C)(C)C

Procedure:
C tert-Butyl (2R,4R)-3-(2-tert-butoxycarbonyl-aminoacetyl)-2-(2-phenylphenyl)-4-thiazolidinecarboxylate may be prepared in a manner similar to that described in Example 1C, but starting with 5.44 g of tert-butyl (2RS,4R)-2-(2-phenylphenyl)-4-thiazolidinecarboxylate, 2.8 g of 2-tert-butoxycarbonylaminoacetic acid and 3.3 g of N,N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica [eluent: cyclohexane/ethyl acetate (80:20 by volume)]. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure at 40° C. 4.42 g of tert-butyl (2R,4R)-3-(2-tert-butoxycarbonylaminoacetyl)-2-(2-phenylphenyl)-4-thiazolidinecarboxylate are thereby obtained in the form of a white foam, which is used in the subsequent syntheses without further treatment.
Reaction SMILES: [CH3:1][C:2](=[CH2:10])[CH2:3][O:4][CH2:5][C:6]([F:9])([F:8])[F:7].C1N2CCN(CC2)C1>C(O)C.O.CCCCC>[CH3:1][C:2]([CH3:10])=[CH:3][O:4][CH2:5][C:6]([F:9])([F:8])[F:7]
Reactant: C=C(C)COCC(F)(F)F
Agent: C1CN2CCN1CC2
Solvent: CCCCC
Solvent: O
Solvent: CCO
Product: CC(C)=COCC(F)(F)F

Procedure:
In 100 ml 20% ethanol/water is added 11 g (71.4 mmol) 2,2,2-trifluoroethyl 2-methyl-2-propenyl ether and 0.59 g (0.642 mmol) 1,4-diazobicyclo(2,2,2)octane. Rhodium tris-triphenylphosphine chloride (16 g, 142.8 mmol) is then added to the stirring mixture, and the solution is heated to 90° for 4 hr. The reaction is then cooled, brought up in pentane, filtered, washed with water and brine and dried over sodium sulfate. The crude product is distilled, yielding 2,2,2-trifluoroethyl 2-methyl-1-propenyl ether.
Reaction SMILES: [NH2:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH2:9][S:10]/[CH:11]=[CH:12]\[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:36][C:37]1[S:38][CH:39]=[C:40]([C:42](=[N:46][O:47][CH:48]2[CH2:51][S:50][CH2:49]2)[C:43](O)=[O:44])[N:41]=1.C(N(C(C)C)CC)(C)C.S(Cl)(C)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C.O>[NH2:36][C:37]1[S:38][CH:39]=[C:40]([C:42](=[N:46][O:47][CH:48]2[CH2:49][S:50][CH2:51]2)[C:43]([NH:1][CH:2]2[C:22](=[O:23])[N:4]3[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH2:9][S:10]/[CH:11]=[CH:12]\[C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)[CH2:7][S:8][C@H:3]23)=[O:44])[N:41]=1
Reactant: Nc1nc(C(=NOC2CSC2)C(=O)O)cs1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CS/C=C\c3cccnc3)CS[C@H]12
Agent: CS(=O)(=O)Cl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nc(C(=NOC2CSC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CS/C=C\c4cccnc4)CS[C@H]23)cs1
Yield: 20.9 %

Procedure:
To a suspension of 7-amino-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylic acid (0.72 g) in dry tetrahydrofuran (10 ml) was added bis(trimethylsilyl)acetamide (1.7 ml) at ambient temperature and the mixture was stirred at the same temperature for an hour. On the other hand, to a solution of 2-(2-aminothiazol-4-yl)-2-(3-thietanyloxyimino)acetic acid (syn isomer) (0.42 g) and diisopropylethylamine in N,N-dimethylformamide (15 ml) was added mesyl chloride (0.25 ml) at -55° C. and the mixture was stirred for half an hour. This solution was added to the above mentioned reaction mixture at -30° C. The mixture was stirred at -30° to 0° C. for an hour and added to a mixture of water and ethyl acetate under stirring. The mixture was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate. Aqueous layer was separated, concentrated in vacuo to remove ethyl acetate and subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP 20" (20 ml). After the column was washed with water, the elution was carried out with 20% aqueous isopropyl alcohol. The fractions containing the object compound were collected, evaporated to remove isopropyl alcohol under reduced pressure and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-(3-thietanyloxyimino)acetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylic acid (anti isomer) (0.2 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:3]([OH:26])[CH2:4][C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[CH3:41][C@@H:42]([CH2:64][CH3:65])[C@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:56]=[CH:55][CH:54]=2)[C:48]1=[O:63])[C:44](O)=[O:45].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][C@H:3]([OH:26])[C@@H:2]([NH:1][C:44](=[O:45])[C@@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:56]=[CH:55][CH:54]=2)[C:48]1=[O:63])[CH:42]([CH3:41])[CH2:64][CH3:65])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2ccnc3ccccc23)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2ccnc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.5 %

Procedure:
A solution containing the product from Example 3D (0.078 g, 0.171 mmol) in DMF (0.5 mL) was treated with the product from Example 4A (0.070 g, 0.205 mmol), EDAC (0.050 g, 0.261 mmol), HOBT (0.035 g, 0.259 mmol), and NMM (0.060 mL, 0.546 mmol) at 0° C., stirred at 25° C. for 16 hours and partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid, diluted sodium bicarbonate, and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.030 g, 23% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.79 (m, 15 H), 1.00 (m, 1 H), 1.25 (m, 1 H), 1.51 (m, 2 H), 1.82 (m, 1 H), 2.64 (m, 5 H), 3.02 (m, 3 H), 3.55 (s, 3 H), 3.63 (m, 1 H), 3.82 (d, J=9.93 Hz, 1 H), 3.99 (d, J=11.03 Hz, 1 H), 4.13 (m, 2 H), 4.64 (d, J=7.72 Hz, 1 H), 4.80 (m, 2 H), 6.62 (d, J=9.93 Hz, 1 H), 6.98 (m, 5 H), 7.14 (m, 5 H), 7.32 (d, J=9.56 Hz, 1 H), 7.41 (d, J=4.41 Hz, 1 H), 7.62 (t, J=7.54 Hz, 1 H), 7.76 (m, 2 H), 8.06 (d, J=7.72 Hz, 1 H), 8.30 (d, J=8.46 Hz, 1 H), 8.88 (d, J=4.41 Hz, 1 H).