Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Mg]Br.[Br:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>O1CCCC1.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>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:13][CH:12]=1
Reactant: Brc1ccc(I)cc1
Reactant: Cc1ccccc1[Mg]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(Br)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A stirred solution of 21.0 mL of (2-methylphenyl)magnesium bromide (42.0 mmol, 2.0M in diethyl ether) was evaporated in situ at room temperature. The syrupy residue was redissolved in 50 mL of THF and cooled to -20° C. under argon. To this solution was added a solution of 6.84 g (50.0 mmol) of thrice-fused zinc chloride in 50 mL of tetrahydrofuran (THF). The resulting thick white slurry was warmed to room temperature and stirred for 1 hour. After cooling to -78° C., a solution of 11.32 g (40.0 mmol) 1-bromo-4-iodobenzene and 500 mg (0.4 mmol) of tetrakis(triphenylphosphine)palladium in 50 mL of THF was added over the course of thirty minutes. After an additional 20 minutes, the cooling bath was removed, the reaction stirred at room temperature for 2 hours and then quenched with 100 mL of 1M hydrochloric acid. The mixture was extracted twice with hexanes, the extracts combined, washed once with saturated sodium bicarbonate solution and once with 10% sodium thiosulfate. The organic extract was dried (MgSo4) and evaporated. The crude product (11.3 g) was purified by distillation (bp 93°-95° C. at 0.5 Torr) to give 8.06 g (82%) of title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[N:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:38]>O1CCCC1>[Cl:38][C:15]1[N:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)[N:22]=3)=[C:11]2[CH:12]=[CH:13][C:14]=1[C:16]([F:19])([F:17])[F:18]
Reactant: Fc1ccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(N3CCCC3)n2)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn3c(Cl)c(C(F)(F)F)ccc3c2-c2ccnc(N3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 59 %

Procedure:
To a cold (−78° C.) solution of 2-(4-fluorophenyl)-3-[2-(1-pyrrolidinyl)-4-pyrimidinyl]-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (86 mg, 0.20 mmol) in tetrahydrofuran (5 mL) was added n-butyllithium (0.30 mL, 1.6 M in hexane, 0.48 mmol) dropwise. The dark solution was stirred for 3 minutes, and then carbon tetrachloride (1 mL) was added. After 15 minutes, the bath was removed and the solution allowed to warm to room temperature and stirred an additional 15 minutes. Water was added then ether. The organics were washed with brine, and the aqueous layer was extracted with ether. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (4:1 hexanes-ethyl acetate) to give 7-chloro-2-(4-fluorophenyl)-3-[2-(1-pyrrolidinyl)-4-pyrimidinyl]-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (55 mg, 59%) as a solid. 1H NMR (CDCl3): δ 8.50 (d, 1 H), 8.11 (d, 1 H), 7.62 (dd, 2 H), 7.50 (d, 1 H), 7.11 (t, 2 H), 6.22 (d, 1 H), 3.62 (m, 4 H), 2.01 (m, 4 H); MS m/z 462 (M+1).
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[SH2:22]>CCCCCC>[SH:22][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1]([O:20][CH3:21])=[O:19]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: S
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCC(S)C(=O)OC
Yield: 57 %

Procedure:
The reaction of methyl oleate with hydrogen sulfide in hexane at -70° for 4 hours and +25° C. for 7 hours results in the formation of 89% and 57% methyl mercaptostearate, respectively, when catalyzed by boron trifluoride. Methyl linoleate reacts with hydrogen sulfide under the same conditions to form a mixture of the cyclic sufides in yield of 83.8% and 64.5%, respectively. Temperature programmed gas-liquid chromatography (GLC) of the above reaction products reveals that essentially all components are eluted at temperatures below 250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C:13]=3[CH:26]=2)[CH:5]=[N:6][C:7]=1[NH2:8].[CH3:27][O:28][C:29]([NH:31][C:32](=NC(OC)=O)SC)=[O:30]>C(O)(=O)C>[CH3:27][O:28][C:29]([NH:31][C:32]1[NH:1][C:2]2[C:7]([N:8]=1)=[N:6][CH:5]=[C:4]([C:9]1[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:14][C:13]=3[CH:26]=1)[CH:3]=2)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c(N)c3)cc2C1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc2[nH]1
Temperature: 65 °C
Yield: 84.5 %

Procedure:
To a solution of 1,1-dimethylethyl 7-(5,6-diaminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.51 g, 1.4 mmol) in acetic acid (5 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.3 g, 1.4 mmol). The reaction mixture was heated 65° C. for 18 h and then concentrated. The resulting residue was suspended in water and basified with portion wise addition of solid sodium bicarbonate. After complete neutralization of the aqueous mixture the insoluble solid was collected by filtration and washed with water then 50% ethyl acetate in hexanes and the filter cake dried to give 1,1-dimethylethyl 7-(2-{[(methyloxy)carbonyl]amino}-1H-imidazo[4,5-b]pyridin-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.52 g, 83% yield), MS (EI) for C22H25N5O5: 440 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)CCC>CS(C)=O>[CH2:12]([NH:19][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH2:11])[N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Solvent: CCCCO
Solvent: CS(C)=O
Product: Nc1nc(NCc2ccccc2)nc2[nH]cnc12
Temperature: 170 °C

Procedure:
2-chloroadenine (1) (2.81 g, 16.67 mmol) was divided among three microwave vials (10-20 mL), each containing Benzylamine (6 mL), 1-Butanol (8 mL,), and DMSO (1 mL). Each vial was heated to 170° C. for 90 minutes. After reaction completion the solvent was removed by rotary evaporation and triteration with diethylether gave 5.85 g of 71 as an off white solid pure enough for the next step. LCMS: m/z for C12H12N6++H observed 241.2 at 1.45 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6]1)=[O:4].C(N(CC)CC)C.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([F:39])[CH:38]=1)[C:33](Cl)=[O:34]>C(Cl)Cl>[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([F:39])[CH:38]=1)[C:33]([NH:1][CH2:2][C:3](=[O:4])[N:5]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)[CH2:6]1)=[O:34]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: NCC(=O)N1CCC(N2CCC(c3ccccc3)CC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCC(N2CCC(c3ccccc3)CC2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
To a solution of 2-amino-1-[3-(4-phenyl-piperidin-1-yl)-pyrrolidin-1-yl]-ethanone (preparation #9) (0.026 g, 0.09 mmol) and triethylamine (0.025 mL, 0.18 mmol) in DCM (0.7 mL) was added a solution of 3,5-difluoro-benzoyl chloride (0.016 g, 0.09 mmol) in dichloromethane (0.2 mL). The reaction mixture was stirred at ambient temperature for about 3 h then concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 10% MeOH/EtOAc as the mobile phase to give 3,5-difluoro-N-{2-oxo-2-[3-(4-phenyl-piperidin-1-yl)-pyrrolidin-1-yl]-ethyl}-benzamide (0.021 g, 55%). RP-HPLC (Table 1, Method b) Rt 1.51 min; m/z: (M+H)+ 428.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>C1(C)C=CC=CC=1.ClCCl>[Cl:17][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=c1ccnc(-c2ccc(Cl)cc2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2nccc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
2-(4-chlorophenyl)pyrimidin-4(3H)-one (100 mg, 0.4840 mmol), suspended in toluene (2 ml), was treated with phosphoryl trichloride (443.0 μl, 4.840 mmol) at ambient temperature. The suspension was heated to reflux at which point the reaction became a colorless solution. After 4 hours, the reaction was cooled to ambient temperature and concentrated in vacuo to afford a white solid. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organics were dried with sodium sulfate, filtered, concentrated, and purified on silica gel. Elution with 2-20% ethyl acetate/hexanes provided the title compound (99 mg, 0.4399 mmol, 90.89% yield) as a white solid.
Reaction SMILES: [Cl-].C[SiH](C)C.[F:6][C:7]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:8]=1[CH2:9]Br.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:16][C:17]1[CH:22]=[C:21]([CH2:9][C:8]2[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:7]=2[F:6])[N:20]=[CH:19][N:18]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Clc1cc(Cl)ncn1
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(Cc2cc(Cl)ncn2)c(F)c1
Reaction time: 0.33 h
Yield: 39.2 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 2.1 g of 2,4-difluorobenzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution H). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution H was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.95 g of 4-chloro-6-(2,4-difluorobenzyl)pyrimidine.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[S:9][CH2:10][CH2:11][C:12]([OH:14])=O.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>O>[O:14]=[C:12]1[CH2:11][CH2:10][S:9][C@@H:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]2[NH:2]1
Reactant: N[C@@H]1CCCC[C@H]1SCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: O
Product: O=C1CCS[C@@H]2CCCC[C@H]2N1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To (±)-trans-2-amino-1-[2-(carboxy)ethylthio]-cyclohexane hydrochloride (0.240 g, 1 mmol) dissolved in 2 mL of dimethylformaamide at 0° C. was successively added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.356 g, 1.2 mmol), 1-hydroxy-7-azabenzotriazole (0.164 g, 1.2 mmol) and then finally N-methylmorpholine (0.252 g, 2.5 mmol). After stirring for an additional 5 mins., the reaction mixture was warmed to room temperature and stirred overnight at the same temperature. The following day the reaction mixture was diluted with water and extracted with methylene chloride.
Reaction SMILES: C1C2C(COC([N:18]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@H:19]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=3)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=O)C3C(=CC=CC=3)C=2C=CC=1.[OH:57][C:58]1[CH:59]=[C:60]([CH:64]=[CH:65][C:66]=1[OH:67])[C:61]([OH:63])=O>>[OH:57][C:58]1[CH:59]=[C:60]([CH:64]=[CH:65][C:66]=1[OH:67])[C:61]([N:18]([C:38]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C@H:19]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=1)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=[O:63]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: CNC(=O)CC[C@@H](C(=O)NCc1ccc(O)c(O)c1)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CNC(=O)CC[C@@H](C(=O)NCc1ccc(O)c(O)c1)N(C(=O)c1ccc(O)c(O)c1)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-methyltrityl-L-glutaminyl]-3,4-dihydroxybenzylamine (576 mg, 0.8 mmol, example 26, step A) as described for example 26 (step B) using 3,4-dihydroxybenzoic acid (178 mg, 1.2 mmol) instead of 4-hydroxy-3-nitrobenzoic acid. The crude material was purified by flash chromatography using a solvent gradient from 30% to 60% EtOAc/CH2Cl2/1% AcOH. The title compound was obtained as white crystals (190 mg, 32%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33](=[O:35])[NH2:34])/[C:27]([OH:29])=O)[N:25]=1)([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.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:61][C@@H:62]1[C:80](=[O:81])[N:64]2[C:65]([C:77]([OH:79])=[O:78])=[C:66]([CH2:69][S:70][C:71]3[N:75]([NH2:76])[N:74]=[N:73][N:72]=3)[CH2:67][S:68][C@H:63]12.C(N(CC)CC)C.NC1SC=C(/C(=N/OCCCC)/C(N[C@@H]2C(=O)N3C(C(O)=O)=C(CSC4N(N)N=NN=4)CS[C@H]23)=O)N=1>CC(N(C)C)=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33](=[O:35])[NH2:34])/[C:27]([NH:61][C@@H:62]2[C:80](=[O:81])[N:64]3[C:65]([C:77]([OH:79])=[O:78])=[C:66]([CH2:69][S:70][C:71]4[N:75]([NH2:76])[N:74]=[N:73][N:72]=4)[CH2:67][S:68][C@H:63]23)=[O:29])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Reactant: NC(=O)CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(N)n1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: NC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 69.3 %

Procedure:
A solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-carbamoylmethoxyiminoacetic acid (3.02 g, 6.2 mmol), 1-hydroxybenzotriazole (0.900 g, 6.7 mmol) and N,N'-dicyclohexylcarbodiimide (1.38 g, 6.7 mmol) in dimethylacetamide (17 ml) was stirred at 0°-5° C. for an hour. To the solution was added a solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.38 g, 7.2 mmol) and triethylamine (1.60 g, 15.8 mmol) in dimethylacetamide (12 ml) and water (2 ml) at the same temperature and allowed to react for 2 hours. Then the mixture was treated in a manner similar to that described in Example 6, (c) to give pale yellow powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-carbamoylmethoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (3.43 g, 69.3%), mp~115° C. (decomposition).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[N:11][C:4]=2[NH:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([S:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)=[CH:20]2>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([S:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:12]([C:10]3[CH:9]=[CH:8][C:5]4[S:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=4[N:11]=3)=[O:14])[CH2:32][CH2:31]1)=[CH:20]2
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)cc2c1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4ccc5c(n4)NC(=O)CS5)CC3)cc2c1

Procedure:
The title compound is prepared as a light yellow solid (64 mg, 30% yield) following Scheme 3 and in analogy to Example 53 using 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (19 mg, 0.09 mmol, 1.0 eq) and 1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine (30 mg, 0.09 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10]([CH3:11])=[CH:9][N:8]=[C:7]([NH:12][NH2:13])[C:6]1=[O:14])([OH:3])=[O:2].C([O-])(O)=O.[Na+].[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.O1CCOCC1>[CH2:20]([O:27][C:28]([NH:13][NH:12][C:7]1[C:6](=[O:14])[N:5]([CH2:4][C:1]([OH:3])=[O:2])[C:10]([CH3:11])=[CH:9][N:8]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cnc(NN)c(=O)n1CC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(NNC(=O)OCc2ccccc2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
To a solution of the compound of Example 5 (Step G) (5.0 g, 0.025 mol) and NaHCO3 (9.4 g, 0.112 mol) in water (180 mL), was added drop-wise a solution of benzylchloroformate (6.0 mL, 0.042 mol) in dioxane (300 mL). The resulting mixture was stirred at room temperature for 4 hours, diluted with water (200 mL), and washed with ether (200 mL). The aqueous phase was acidified with aqueous 2M KHSO4 and extracted with EtOAc (3×300 mL). The combined organic phases were washed with brine (400 mL), dried (Na2SO4), and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel to afford the title compound (7.35 g, 90%) as a pale brown solid. 1H NMR (DMSO-d4) δ 2.15 (s, 3H), 4.3 (br s, 1H), 4.73 (s, 2H), 5.12 (s, 2H), 6.76 (s, 1H), 7.20-7.50 (m, 5H), 9.7 (br s, 1H), 10.0 (br s, 1H). HPLC Rt 8.10 minutes (water/ACN/TFA, 5 to 75%, 0.1% TFA, 20 minutes).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][S:39][CH2:40][CH2:41][CH2:42][NH2:43]>>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][CH2:42][CH2:41][CH2:40][S:39][CH3:38])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: CSCCCN
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Product: CSCCCNc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (150 mg, 0.264 mmol) and 3-(methylthio)-1-propanamine (300 mg, 2.85 mmol), the title compound was obtained as a crude yellow foam and used directly in the next step. MS (ESI): 637.2 [M+H]+.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])OCC>[Zn+2].[I-].[I-]>[CH2:23]([O:22][CH:15]([O:19][CH2:20][CH3:21])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:24]
Reactant: C#CCCCCCCCCCCCC
Reactant: CCOC(OCC)OCC
Agent: [I-]
Agent: [Zn+2]
Product: CCCCCCCCCCCCC#CC(OCC)OCC

Procedure:
1-Tetradecyne (100 g), (EtO)3CH (200 ml) and ZnI2 (15 g) were heated together (bath temperature 170°-175°) with distillative removal of ethanol (~90 minutes). The reaction mixture was evaporated in vacuo (bath temperature 80°) to remove excess (EtO)3CH. The residue was distributed between CH2Cl2 and water. The CH2Cl2 phase was separated, washed with aqueous NaHCO3, dried (Na2SO4) and evaporated in vacuo to provide a light brown oil. Yield: 135.4 g. This product was shown to be virtually pure by TLC and PMR and it was used as such in subsequent reactions.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4].[CH:23]1([CH2:26]Br)[CH2:25][CH2:24]1>CN(C=O)C>[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:26][CH:23]3[CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: BrCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(c2cn(CC3CC3)c3ccccc23)CC1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a suspension of 0.76 g (19 mmol) of a 60% suspension of sodium hydroxide, in mineral oil, in 15 mL of anhydrous DMF, a solution of 4 g (15 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester in 5 mL of anhydrous DMF was added. After 30 minutes at room temperature, a solution of 1.71 mL (18 mmol) of cyclopropylmethyl bromide in 5 mL of DMF was added. The crude mixture was stirred at room temperature for 14 h and the solvent was removed under reduced pressure. The crude mixture was extracted between water and ethyl acetate. The organic layer was dried over magnesium sulfate, and after filtration the solvent was removed under reduced pressure affording 4.7 g of the desired product.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:13][C@H:14]1[CH:17]([CH3:18])[N:16]([S:19]([OH:22])(=[O:21])=[O:20])[C:15]1=[O:23].[OH-].[Na+]>>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([NH:13][C@H:14]2[CH:17]([CH3:18])[N:16]([S:19]([OH:22])(=[O:20])=[O:21])[C:15]2=[O:23])=[O:12])[N:8]=1)=[O:2]
Reactant: CC1[C@H](N)C(=O)N1S(=O)(=O)O
Reactant: O=CNc1nc(CC(=O)O)cs1
Agent: [Na+]
Agent: [OH-]
Product: CC1[C@H](NC(=O)Cc2csc(NC=O)n2)C(=O)N1S(=O)(=O)O
Reaction time: 20 h

Procedure:
100 mg. of a Escherichia coli acylase that is bound in a polyacrylamide matrix (Boehringer Mannheim) is mixed with an aqueous solution containing 4 mg. of 2-(formylamino)-4-thiazoleacetic acid and an aqueous solution containing 2 mg. of (3S)-3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid, inner salt in a total volume of 2 ml. The pH of the reaction mixture is adjusted to pH 4.5 by the addition of 50 mmolar sodium hydroxide. The reaction mixture is incubated at 30° C. with shaking (60 rpm) for up to 20 hours. The desired product can then be separated from the reaction mixture by thin layer chromatography using a silica gel 60 F254 plate and developing in a solvent consisting of acetonitrile, ethyl acetate, acetic acid, and water (4:4:1:1) followed by elution with water to give (3S)-3-[[[2-(formylamino)-4-thiazolyl]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, zwitterion.