Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:37](=[O:38])[N:6]2[C:7]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19]([CH2:21][CH2:22][OH:23])=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].P([O-])([O-])([O-])=[O:40].[Na+].[Na+].[Na+].[H][H]>C1COCC1.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:37](=[O:38])[N:6]2[C:7]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19]([CH2:21][CH2:22][OH:23])(=[O:40])=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(S(=O)CCO)c4s3)[C@H](C)[C@H]12
Reactant: [H][H]
Reactant: O=P([O-])([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(S(=O)(=O)CCO)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-hydroxyethyl)sulfinylimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers) (50.1 mg) was dissolved in 1.8 ml of THF and 1.8 ml of a 1/15 M sodium phosphate buffer (pH 6.6). 10% Pd-C (54.7 mg) was added to the solution. The air in the reaction vessel was replaced by hydrogen, and the contents of the reaction vessel were stirred at room temperature for 50 min. The catalyst was removed by filtration on Celite, and was washed with water. The filtrate was adjusted to pH 7.0 by the addition of an aqueous sodium hydrogencarbonate solution, and was then washed with ethyl acetate. The aqueous layer was then purified by column chromatography on Cosmosil 40C18-PREP (only water) to prepare 21.4 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:21])[CH2:6][CH2:5]2.I.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](SC)=[NH:29]>C(O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[N:15]1([CH2:14][CH2:13][CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2]([NH:1][C:28]([C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)=[NH:29])=[CH:11][CH:10]=3)[CH2:5][CH2:6][C:7]2=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCCC1)c1cccs1
Reaction time: 64 h

Procedure:
A solution of 6-amino-1-(3-(piperidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (0.065 g, 0.226 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.129 g, 0.452 mmol) at room temperature and the resulting mixture was stirred for 64 hours. The reaction was transferred to a separatory funnel and diluted with ethyl acetate (30 mL) and saturated sodium hydrogen carbonate (20 mL). The aqueous was partitioned twice more with ethyl acetate (2×20 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 0-1:10-9). The product was dried under high vacuum. Yield: 46 mg of yellow solid (51%). 1H NMR (DMSO-d6) δ: 8.02 (d, J=3.9 Hz, 1H), 7.99 (d, J=3 Hz, 1H), 7.32 (d, J =4.8 Hz, 1H), 7.28 (d, J=6.3 Hz, 1H), 7.20 (s, 1H), 7.17 (s, 1H), 4.32 (br s, 2H), 3.98−3.93 (m, 2H), 3.45-3.40 (m, 4H), 3.16-3.10 (m, 4H), 2.95-2.90 (m, 4H), 2.61-2.56(m, 2H), 2.01-1.90 (m, 2H). MS (ESI): 397.2 (M+1). ESI-HRMS calculated for C22H29N4SO (MH+): 397.2056, Observed: 397.2073.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 4-bromobenzenesulfonamide [CAS 701-34-8] (307 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (325 mg, 64%). MS (ISP) 511.3 [(M+H)+]; mp 266-267° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[N:23]#[N:24].CCO[C:28]([CH3:30])=O>CC(N(C)C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:23]1[N:24]=[CH:5][N:6]([C:7]2[CH:8]=[C:9]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:11]=[CH:28][CH:30]=2)[CH:2]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CCOC(C)=O
Reactant: N#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccn2c(-c3cccc(-n4cnnc4)c3)cnc2n1
Temperature: 65 °C
Yield: 40 %

Procedure:
A mixture of 3-bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine (139 mg, 0.53 mmol), the foregoing boronate ester (269 mg, 1.05 mmol) and K3PO4 (483 mg, 2.1 mmol) in DMA (3 ml) was degassed with a stream of N2 for 5 min and then tetrakis(triphenylphosphine)palladium(0) (60 mg, 10 mol %) was added and the reaction heated at 65° C. for 70 min. EtOAc (100 ml) was added and the mixture washed with H2O (3×100 ml) and brine (100 ml), dried (MgSO4) and concentrated under reduced pressure while dry loading onto silica. The residue was purified by column chromatography on silica using 5% MeOH in dichloromethane to yield 3-[3-([1,2,4]triazol-4-yl)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine (70 mg, 40%), which was then recrystallised from EtOAc/isohexanes: δH (400 MHz, d6-DMSO) 7.55 (1H, d, J 7.2), 7.70-7.90 (3H, m), 8.16 (1H, s), 8.39 (1H, s), 9.24 (2H, s), 9.48 (1H, d, J 7.2); m/z (ES+) 331 (M+H+).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].II.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)[CH2:15][CH2:14]1.Cl>>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][C:24]3[N:1]=[C:2]([NH2:4])[S:3][C:23]=3[CH2:22]2)[CH2:17][CH2:18]1
Reactant: NC(N)=S
Reactant: O=C1CCC(CCN2CCN(c3ccccn3)CC2)CC1
Agent: Cl
Agent: II
Product: Nc1nc2c(s1)CC(CCN1CCN(c3ccccn3)CC1)CC2
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
Thiourea (7.56 g) and iodine (12.61 g) are mixed and stirred mechanically under a stream of nitrogen. To this mixture is added 4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanone (9.52 g) (Example J) and the temperature gradually increased to 150° C. Following 30 minutes at this temperature, the mixture is cooled to room temperature and treated with 250 ml of a 10% solution of hydrochloric acid. Some insoluble material is filtered, the filtrate made basic with ammonium hydroxide, and extracted with chloroform (2×500 ml). The combined organic extracts are dried over magnesium sulfate and concentrated. The crude reaction mixture is purified by MPLC (silica; 5% methanol, 95% chloroform) to give the title compound as a light yellow solid; mp 194°-197° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10]Cl)[C:4]=1[OH:12].[CH3:13][N:14]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][N:17]([CH3:23])[CH2:16][CH2:15]1.[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])C.[OH-].[Na+]>CO>[CH3:23][N:17]1[CH2:16][CH2:15][N:14]([CH3:13])[CH2:22][CH2:21][N:20]([CH2:2][C:3]2[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][N:17]3[CH2:30][CH2:29][N:26]([CH3:24])[CH2:27][CH2:28][N:14]([CH3:13])[CH2:15][CH2:16]3)[C:4]=2[OH:12])[CH2:19][CH2:18]1
Reactant: Cc1cc(CCl)c(O)c(CCl)c1
Reactant: CN1CCNCCN(C)CC1
Reactant: CCN(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CN2CCN(C)CCN(C)CC2)c(O)c(CN2CCN(C)CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
At 0° C., 3.26 g (16 mmol) of 2,6-bischloromethyl4-methylphenol are added in portions to a solution of 5 g (32 mmol) of 1,4-dimethyl-1,4,7-triazacyclononane and 3.21 g (32 mmol) of triethylamine in 150 ml of methanol, and the mixture is stirred for 4 days at room temperature. For work-up, 1.28 g (32 mmol) of sodium hydroxide are added, and the sodium chloride which forms is filtered off. The solvent is removed under reduced pressure and the product is dried for one day under a high vacuum. Yield: 6.1 g (86%). Analysis: 1H-NMR:δ=2.24 (s,3 H, Carom.—CH3); 2.35 (s,12 H, N-CH3); 2.64 (m, 8 H, Carom.—CH2—N—CH2—CH2—N); 2.67 (s, 8 H, H3C—N—CH2—CH2—N—CH3); 2.87 (m, 8 H, Carom.—CH2N—CH2—CH2—N); 3.73 (s, 4 H, Carom.—CH2N); 6.82 (s, 2 H, Carom—H) 13C-NMR: 6=20.4 (Carom.—CH3); 45.4 (N—CH3); 53.0; 55.9; 56.2; (N—CH2—CH2—N); 58.6 (Carom.—CH2—N); 123.0 (Carom.—CH2—N); 127.4 (Carom.—CH3); 130.0 (Carom.—H), 154.7 (Carom.—OH) MS: (electrospray) m/e=447 (M+H⊕, 100%)
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[CH3:32][S:33]([CH2:36][CH2:37][NH2:38])(=[O:35])=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:38][CH2:37][CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CS(=O)(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 38.6 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 30 mg, 0.070 mmol),2-(methylsulfonyl)ethanamine (12.85 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.5 min) to provide 2-hydroxy-N-(2-(methylsulfonyl)ethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (15 mg, 0.027 mmol, 38.2% yield) as a single enantiomer. LCMS=537.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.58 Hz), 7.54-7.74 (7 H, m), 5.14 (1 H, s), 3.73 (2 H, t, J=6.60 Hz), 3.35 (2 H, t, J=6.60 Hz), 2.97 (3 H, s); HPLC peak RT=9.3 min (Method A).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([NH:11][C@@H:12]([CH2:17][C:18]([F:21])([F:20])[CH3:19])[C:13]([O:15]C)=[O:14])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO>[CH2:2]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([NH:11][C@@H:12]([CH2:17][C:18]([F:21])([F:20])[CH3:19])[C:13]([OH:15])=[O:14])=[O:10])[CH2:5][CH2:4]2)[CH2:1]1
Reactant: COC(=O)[C@H](CC(C)(F)F)NC(=O)N1CCC2(CC1)CC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(F)(F)C[C@H](NC(=O)N1CCC2(CC1)CC2)C(=O)O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
365.0 mg of methyl (S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoropentanoate (1.2 mmol) were dissolved in a mixture of 10.8 ml of THF and 3.6 ml of methanol. 3.6 ml of an aqueous 1 M LiOH solution (3 eq.) were added to this solution. The mixture was stirred at 45° C. (bath temperature) for one hour and then 3.6 ml of 1 M HCl solution were added. The mixture was concentrated under reduced pressure and codistilled with DMF twice more. The (S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoropentanoic acid thus obtained was clean enough for the next reaction. Yield: 400 mg (quant.)
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1([CH3:14])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH2:5]1>C(O)=O>[CH3:3][C:4]1([CH3:14])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6](=[O:1])[CH2:5]1
Reactant: OO
Reactant: CC1(C)CC=Cc2ccccc21
Solvent: O=CO
Product: CC1(C)CC(=O)Cc2ccccc21
Temperature: 25 °C
Yield: 40 %

Procedure:
To a stirred mixture of 30% hydrogen peroxide (5 ml) and 97% formic acid (20 ml) in a round bottom flask equipped with an additional funnel, thermometer, and an ice water bath was added 1,2-dihydro-1,1-dimethylnaphthalene (4.5 g, 28 mmoles) dropwise at 5° C. under a nitrogen atmosphere. When the addition was complete, the reaction vessel was raised above the cooling bath to allow the reaction temperature to rise to just below 35° C. at which point the flask was immersed again. In this manner the temperature of the reaction was maintained between 30° and 35° C. for 45 minutes. After this time the exothermic phase of the reaction ended and the mixture was allowed to cool to room temperature. A solution of 10% aqueous ferric sulfate was added in portions of a few milliliters each until cloudiness persisted in the stired mixture and then all solvent was removed under reduced pressure. The viscous brown residue was refluxed with 20% H2SO4 (20 ml) for 4 hours and then cooled, extracted three times with ether (75 ml each), dried over magnesium sulfate, filtered and evaporated to leave a brown oil. This was purified using silica gel column chromatography eluting with ethyl acetate:hexane (7:93) to give 4,4-dimethyl-2-tetralone. (3.4 g, 74%). Overall yield=40%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:3]=1.[CH3:18][NH2:19]>O>[CH3:18][NH:19][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:3]=1
Reactant: CN
Reactant: Clc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Solvent: O
Product: CNc1cc(Oc2ccc3[nH]ccc3c2)ncn1

Procedure:
Dissolved in 6 ml methylamin solution (2 M in THF), 245 mg (1.0 mMol) 5-(6-chloro-pyrimidin-4-yloxy)-indole (WO 03/099771; Stage 163.1) are stirred for 24 h at rt and 8.5 h at 50° C. The concentrated reaction mixture is dissolved in water and EtOAC, the aqueous layer separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; EtOAc/hexane 1:1→3:1) gives the title compound: MS: [M+1]+=241; TLC(EtOAc): Rf=0.15.
Reaction SMILES: [Br-].[CH:2]1([Zn+])[CH2:5][CH2:4][CH2:3]1.Br[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=1>>[CH:2]1([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: [Zn+]C1CCC1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: [Br-]
Product: COC(=O)c1ccc(C2CCC2)cc1C
Temperature: 65 °C

Procedure:
Cyclobutylzinc(II) bromide (50 ml, 0.5 M in THF, 25.0 mmol) was added to a mixture of methyl 4-bromo-2-methylbenzoate (compound 152.1, 5.2 g, 22.7 mmol) and PdCl2(dppf)CH2Cl2 (1.85 g, 2.27 mmol). The mixture was degassed and the flask was filled with argon through a balloon. The mixture was heated at 65° C. under argon for 24 hours. The mixture was cooled to 0° C. and quenched with water (10 ml). The mixture was diluted with EtOAc (200 ml), washed with water then with brine. The EtOAc layer was dried (Na2SO4), concentrated under reduced pressure, and purified using column (silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1). Yield: 4.1 g, clear oil, 89.1%. 1H NMR (400 MHz, Chloroform-d) δ 7.86 (d, 1H), 7.12-7.02 (m, 2H), 3.88 (s, 3H), 3.59-3.48 (m, 1H), 2.59 (s, 3H), 2.35 (m, 2H), 2.22-1.96 (m, 3H), 1.86-1.84 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1>ClCCl>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:43])=[CH:37][CH:36]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 4-methoxyphenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 mins. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methoxy-phenyl)-amide as a white solid. (Yield 35 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[C:43]([NH2:51])(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[N:46][CH:45]=1.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:46]4[CH:47]=[CH:48][CH:49]=[C:44]([C:43](=[O:50])[NH2:51])[CH:45]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: NC(=O)c1cccnc1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3cccc(C(N)=O)c3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 3.9 %

Procedure:
To a solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) in DMSO (2 ml) was added nicotinamide (244 mg, 2 mmoles), and the mixture was stirred at ambient temperature for 1.5 hours and poured into ethyl acetate (200 ml) with stirring. The resulting precipitate was collected by filtration. The quaternized salt (500 mg) was dissolved in HCOOH (5 ml) in the presence of sodium bisulfite (50 mg), and the mixture was heated at 40°-50° C. for 40 minutes, with stirring, and evaporated to dryness. The residue was dissolved in water (40 ml) and an insoluble solid was filtered off and washed with a small amount of water. The filtrate and wash were combined and chromatographed on a reverse phase column, PrepPAK-500/C18 (100 ml). After elution with water and 5%, 10% and 20% aqueous CH3OH, successively, the fractions containing the desired material were combined, concentrated in vacuo and freeze-dried to yield 21 mg (3.8%) of the title compound (I-1G) (E) as a yellow powder. Mp. >175° C. (dec.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[C:20]3[C:21]4[CH:35]=[C:34]([C:36]5[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=5)[CH:33]=[N:32][C:22]=4[N:23](COCC[Si](C)(C)C)[C:19]=3[CH:18]=[N:17][C:16]=2[C:42]#[N:43])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:41][N:39]1[CH:40]=[C:36]([C:34]2[CH:33]=[N:32][C:22]3[NH:23][C:19]4[CH:18]=[N:17][C:16]([C:42]#[N:43])=[C:15]([S:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[C:20]=4[C:21]=3[CH:35]=2)[CH:37]=[N:38]1
Reactant: Cn1cc(-c2cnc3c(c2)c2c(SC4CCN(C(=O)OC(C)(C)C)CC4)c(C#N)ncc2n3COCC[Si](C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2cnc3[nH]c4cnc(C#N)c(SC5CCNCC5)c4c3c2)cn1
Temperature: 25 °C
Reaction time: 22 h
Yield: 32.5 %

Procedure:
A mixture of 4-[6-cyano-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester (106 mg, 0.17 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (9 mL) was stirred at ambient temperature for 22 h. The reaction mixture was concentrated in vacuo and the resultant residue partitioned between dichloromethane (10 mL) and a saturated aqueous solution of sodium hydrogen carbonate (10 mL). The organic phase was concentrated in vacuo and the residue was adsorbed onto HM-N then purified by flash chromatography (silica, 25 g column, Si-SPE, 0-13% (2M ammonia in MeOH) in DCM) to afford the title compound as a pale yellow solid (21.5 mg, 25%). NMR (DMSO-D6, 300 MHz): 9.04 (d, J=2.2 Hz, 1H), 9.02-8.97 (m, 2H), 8.29 (s, 1H), 7.98 (s, 1H), 3.93 (s, 3H), 3.54-3.21 (m, 1H), 2.97-2.86 (m, 2H), 2.49-2.36 (m, 2H), 1.89-1.77 (m, 2H), 1.65-1.47 (m, 2H). LCMS (Method F): RT=7.08 min, M+H+=390.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C[Al](C)C.C1(C)C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[CH:22][N:23]2[C:28]=1[C:27](=[O:29])[O:26][C:25]([CH2:30][N:31]1[CH:39]=[N:38][C:37]3[C:32]1=[N:33][CH:34]=[N:35][C:36]=3[N:40](C(OC(C)(C)C)=O)[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:24]2.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>ClCCl.O>[Cl:19][C:20]1[CH:21]=[CH:22][N:23]([NH:24][C:25](=[O:26])[CH2:30][N:31]2[CH:39]=[N:38][C:37]3[C:32]2=[N:33][CH:34]=[N:35][C:36]=3[NH:40][C:41](=[O:42])[O:43][C:44]([CH3:47])([CH3:45])[CH3:46])[C:28]=1[C:27](=[O:29])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Nc1ccncc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2c1ncn2Cc1nn2ccc(Cl)c2c(=O)o1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ncnc2c1ncn2CC(=O)Nn1ccc(Cl)c1C(=O)Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.6 %

Procedure:
To a suspension of 4-aminopyridine (164 mg, 1.74 mmol) in 3.3 mL of dichloromethane under inert atmosphere was added a 2M solution of trimethyl aluminium in toluene (0.87 mL, 1.74 mmol) and the mixture was stirred during 20 minutes at room temperature. Next, this mixture was cooled in an ice-water bath and a solution of di-tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimidodicarbonate (150 mg, 0.29 mmol) in 2.2 mL of dry dichloromethane was added stirring the mixture during 3 days at room temperature. At the end of this period, the reaction mixture was cooled-down with an ice-water bath and mL of water were added followed by a 5% aqueous solution disodium tartrate dihydrate. The resulting mixture was purified directly by reverse phase chromatography (C-18 silica from Waters, water/1:1 acetonitrile-methanol as eluents 0% to 100%). After purification were obtained 139 mg of tert-butyl 9-(2-(3-chloro-2-(pyridin-4-ylcarbamoyl)-1H-pyrrol-1-ylamino)-2-oxoethyl)-9H-purin-6-ylcarbamate (93% yield).