Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]2[O:6][C:7]([CH3:9])=[CH:8][C:4]=2[CH:3]=1.N12CCCN=C1CCCCC2.[CH2:23]([OH:26])[C:24]#[CH:25].Cl>O1CCCC1.[Cu]I.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.O>[CH3:9][C:7]1[O:6][C:5]2[CH:10]=[CH:11][C:2]([C:25]#[C:24][CH2:23][OH:26])=[CH:3][C:4]=2[CH:8]=1
Reactant: C#CCO
Reactant: Cc1cc2cc(I)ccc2o1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc2cc(C#CCO)ccc2o1
Temperature: 0 °C

Procedure:
A solution of 5-iodo-2-methylbenzo[b]furan (12.1 g, 46.9 mmol) in dry tetrahydrofuran (50 mL) was degassed and copper(I)iodide (280 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium (1.7 g, 1.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (9.1 g, 60.0 mmol) were added. The reaction solution was degassed again and propargyl alcohol (3.4 g, 60.7 mmol) was added under inert atmosphere at ambient temperature. The reaction mixture was stirred (initially under cooling with ice water) for 48 h, then treated with water (20 mL) and acidified with 2 M hydrochloric acid (20 mL). The organic phase was separated and the aqueous phase was extracted with ether (4×30 mL). The combined organic phases were dried with anhydrous magnesium sulfate and concentrated in vacuo yielding brown solid. The residue was purified by column chromatography (silica gel Fluka 60, benzene) yielding 3-(2-methylbenzo[b]furan-5-yl)prop-2-yn-1-ol.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]2[S:11][CH2:12][C:13](=[O:15])[N:14]=2)=[N:6][CH:7]=1.[N:16]1[C:25]2[C:20](=[N:21][C:22]([CH:26]=O)=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]2[S:11][C:12](=[CH:26][C:22]3[CH:23]=[CH:24][C:25]4[C:20](=[CH:19][CH:18]=[CH:17][N:16]=4)[N:21]=3)[C:13](=[O:15])[N:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(CNC2=NC(=O)CS2)cn1
Reactant: O=Cc1ccc2ncccc2n1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: Cc1cnc(CNC2=NC(=O)C(=Cc3ccc4ncccc4n3)S2)cn1
Temperature: 130 °C
Yield: 18.3 %

Procedure:
To a suspension of 2-[(5-methyl-pyrazin-2-ylmethyl)-amino]-thiazol-4-one (35.6 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 130° C. with microwave for 10 min., then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give 2-[(5-methyl-pyrazin-2-ylmethyl)-amino]-5-[1,5] naphthyridin-2-ylmethylene-thiazol-4-one as a brown solid (10.6 mg, 18.3%). HR-ES (+) m/e calcd. for C18H14N6OS: (M+H)+ 363.1023. Found: 363.1022.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([C:37]3([C:40]([O:42]C(C)C)=[O:41])[CH2:39][CH2:38]3)[N:36]=2)[N:33]=1>CN(C)C(=O)C>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([C:37]5([C:40]([OH:42])=[O:41])[CH2:39][CH2:38]5)[N:36]=4)[N:33]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)OC(=O)C1(c2cn3nc(Cl)ccc3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)C1(c2cn3nc(OCCCN4CCC(OC(c5ccccc5)c5ccccc5)CC4)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
1.14 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 15 ml of N,N-dimethylacetamide; 140 mg of a 60% dispersion of sodium hydride in mineral oil was added, followed by stirring at room temperature under reduced pressure for 30 minutes. To the reaction mixture, 980 mg of isopropyl 1-(6-chloroimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxylate was added under ice cooling conditions, followed by stirring at constant temperature for 4 hours. Ice water was added, followed by saturation with sodium chloride and subsequent extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated under reduced pressure to yield 496 mg of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:20])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:12]O)=[CH:9][C:4]=2[O:3][CH2:2]1.[ClH:21].[H][H]>C(O)C.O.[Pd]>[ClH:21].[ClH:21].[NH2:12][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:20]
Reactant: O=C(C(=NO)c1ccccn1)c1ccc2c(c1)OCO2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC(C(=O)c1ccc2c(c1)OCO2)c1ccccn1
Yield: 59 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-2-pyridin-2-yl-ethane-1,2-dione 2-oxime (2 g, 7.75 mmol) was dissolved in ethanol (100 ml) and hydrochloric acid (2 ml of a 36% solution in water) was added. Palladium on charcoal catalyst (0.5 g) was added and the reaction mixture was stirred under a positive pressure of hydrogen for 1.5 hours. The catalyst was removed by filtration through Kieselguhr and the resulting filtrate evaporated to dryness under reduced pressure. Trituration under anhydrous diethyl ether gave the title compound as a pale yellow solid (1.5 g, 59%); m/z (API) 257 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18](O)=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:24][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18](=[O:19])[N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: C1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCC(=O)N1CCCCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (200 mg, 0.49 mmol) from example 210 and piperidine (50.0 mg, 0.59 mmol). The title compound was obtained as a solid (45.0 mg, 22% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.06 (1H, m), 8.98 (2H, m), 8.51 (1H, s), 4.06 (2H, m), 3.38 (4H, m), 1.57 (2H, m), 1.48 (2H, m), 1.24 (2H, m). MS m/z: 475.08, 477.08 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:22][CH:23]([OH:41])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:22][CH:23]([OH:41])[CH2:24][O:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[NH:8][C:4]=3[CH:3]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: O=c1[nH]c2ccc(Br)cc2[nH]1
Reactant: CC1(C)OB(c2cccc(OCC(O)CN3CCc4ccccc4C3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(-c3cccc(OCC(O)CN4CCc5ccccc5C4)c3)cc2[nH]1
Temperature: 100 °C
Yield: 72.9 %

Procedure:
A mixture of 5-bromo-1H-benzo[d]imidazol-2(3H)-one (200 mg, 0.489 mmol), 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (100 mg), Pd(dppf)Cl2 (36 mg, 0.049 mmol), K2CO3 (202 mg, 1.47 mmol) in H2O-dioxane (1 mL/3 mL) was stirred and heated in am microwave reactor to 100° C. for 15 min. Once cooled, the solvent was removed by concentration and the crude product purified by HPLC separation to give the title compound (74 mg, 36.5%). 1HNMR (CH3OD, 400 MHz) δ: 7.49-7.10 (m, 10H), 6.98-6.92 (m, 1H), 4.76-4.42 (m, 3H), 4.20-4.09 (m, 2H), 3.98-3.89 (m, 1H), 3.62-3.48 (m, 3H), 3.36-3.14 (m, 2H). LCMS (m/z): 416.2 [M+H]+
Reaction SMILES: [CH3:1][NH:2][C:3]([CH3:9])=[CH:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](=[O:21])[C:4](=[C:3]([NH:2][CH3:1])[CH3:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CNC(C)=CC(=O)OC
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CNC(C)=C(C(=O)OC)C(=O)c1ccc(F)cc1Cl
Temperature: 2.5 °C

Procedure:
To a mixture of methyl 3-(methylamino)-2-butenoate (i.e. the product of Step A) (10.25 g, 79.43 mmol) and triethylamine (13.26 mL, 9.63 g, 95.31 mmol) in toluene (125 mL) at 0° C. was added dropwise 2-chloro-4-fluorobenzoyl chloride (15.25 g, 79.48 mol) in toluene (25 mL) over 30 minutes while maintaining the temperature of the reaction mixture between about 0 to 5° C. The reaction mixture was allowed to warm to room temperature and stirred over night. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting dark yellow oil was triturated with hexanes and filtered to provide the title compound as a white solid (15.91 g).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[N+:5]([C:8]1[CH:9]=[CH:10][C:11](Cl)=[N:12][CH:13]=1)([O-:7])=[O:6]>C1COCC1.O>[CH2:1]([S:3][C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][N:12]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCSc1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of sodium ethanethiolate (15.9 g; 0.189 mol) in 250 mL of THF and 100 mL of water at 0° C.-5° C. was added 5-nitro-2-chloropyridine (25.0 g; 0.158 mol). After 2 hours, the mixture was poured into 1200 mL of ice water, stirred for 15 minutes, and filtered. The solid was washed with water and dried in vacuo to provide 2-ethylsulfanyl-5-nitropyridine which was used without additional purification (28.1 g; 96%).
Reaction SMILES: [CH3:1]B1OB(C)OB(C)O1.[B:10](OCCCC)([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH3:1][B:10]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCCCOB(OCCCC)OCCCC
Product: CCCCOB(C)OCCCC
Reaction time: 0.5 h
Yield: 150.4 %

Procedure:
Trimethylboroxin (50 ml of 50 wt % solution in THF, 170 mmol) was placed in a round bottom flask with distillation head and receiver under nitrogen. Tri-n-butyl borate (92 ml, 340 mmol) was added and the mixture stirred 30 min. Methyidi-n-butoxyborane and THF were distilled from the tri-n-butoxyboroxin. The methyidi-n-butoxyborane and THF were separated by further distillation to obtain 44 g of methyidi-n-butoxyborane, 50% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:13][C:11]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:3][CH2:1][CH3:2])[CH:12]=1
Reactant: CCOc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOc1cc(N)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
Iron (16.19 g, 290 mmol) was added to a slurry mixture of 2-ethoxy-4-nitrobenzoic acid (24.00 g, 114 mmol) in ethanol (200 mL) and saturated aqueous solution of ammonium chloride (120 mL). The mixture was stirred at 80° C. for 2 h. The reaction mixture was cooled to room temperature and filtered through Celite. It was rinsed with methylene chloride and the combined filtrate diluted with water and extracted with methylene chloride and dried over anhydrous sodium sulfate. Evaporation of the solvent and chromatography of the brown residue over silica gel using 1-5% methanol in methylene chloride produced 4-amino-2-ethoxybenzoic acid as a yellow solid (14.94 g, 73%).
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].[Cl:7][C:8]1[C:9]([C:30]([F:33])([F:32])[F:31])=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH:19]=O)[N:13]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:12]=2[CH:29]=1.[CH3:34][C:35]1([CH3:61])[O:39][C@@H:38]2[C@@H:40]([CH2:56][NH:57][CH:58]([CH3:60])[CH3:59])[CH2:41][C@@H:42]([N:43]3[C:47]4[N:48]=[CH:49][N:50]=[C:51]([NH:52][CH:53]5[CH2:55][CH2:54]5)[C:46]=4[CH:45]=[CH:44]3)[C@@H:37]2[O:36]1.C([O-])(O)=O.[Na+]>ClCCCl.[Cl-].[Na+].O>[Cl:7][C:8]1[C:9]([C:30]([F:33])([F:31])[F:32])=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][N:57]([CH2:56][C@@H:40]3[C@H:38]4[O:39][C:35]([CH3:61])([CH3:34])[O:36][C@H:37]4[C@H:42]([N:43]4[C:47]5[N:48]=[CH:49][N:50]=[C:51]([NH:52][CH:53]6[CH2:55][CH2:54]6)[C:46]=5[CH:45]=[CH:44]4)[CH2:41]3)[CH:58]([CH3:59])[CH3:60])[N:13]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:12]=2[CH:29]=1
Reactant: CC(C)NC[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reactant: C[Si](C)(C)CCOCn1c(CCCC=O)nc2cc(C(F)(F)F)c(Cl)cc21
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CC(C)N(CCCCc1nc2cc(C(F)(F)F)c(Cl)cc2n1COCC[Si](C)(C)C)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
MgSO4 (450 mg, 3.74 mmol) was added to a solution of 4-[6-chloro-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]butanal (189 mg, 0.45 mmol) and 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-[(propan-2-ylamino)methyl]-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (145 mg, 0.37 mmol) in DCE (10 ml) at RT and stirred for 15 mins. Na(AcO)3BH (111 mg, 0.52 mmol) was then added and continued stirring at RT for 2 hours. Sat. NaHCO3 (30 ml) was added to the reaction mixture and stirred for 5 mins. Brine (10 ml) was added to the reaction mixture, the organic layer was separated and the aqueous was further extracted with DCM (30 ml). The combined organic layers was dried over Na2SO4, filtered and evaporated. The crude mixture was dissolved in MeCN:H2O (8:2) (4 ml) and purified by preparative HPLC under acidic conditions to give a colourless oil (105 mg, 42%); MS (ESI+) for C39H55ClF3N7O3Si m/z 790.35 [M+H]+: HPLC purity 90% (ret. time, 1.90 min): 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 10.98 (1H, br. s.), 8.07 (6.98-7.10 (1H, m), 1H, d, J=1.89 Hz), 7.87-8.01 (1H, m), 7.70 (1H, s), 7.16-7.25 (1H, m), 5.50-5.69 (2H, m), 4.96 (2H, br. s.), 4.66 (1H, br. s.), 4.28-4.39 (1H, m), 3.82 (1H, br. s.), 3.55-3.69 (2H, m), 3.15-3.33 (5H, m), 3.05-3.14 (1H, m), 2.94-3.03 (1H, m), 2.49-2.83 (2H, m), 2.23-2.49 (1H, m), 1.83-2.16 (4H, m), 1.53 (3H, d, J=11.51 Hz), 1.33-1.46 (6H, m), 1.28 (3H, d, J=7.72 Hz), 0.99-1.10 (2H, m), 0.94 (4H, dd, J=3.39, 1.18 Hz), −0.26-0.15 (9H, m)
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:5][CH:4]1[C:15]1[N:19]2[C:20]3[CH:26]=[CH:25][N:24](S(C4C=CC(C)=CC=4)(=O)=O)[C:21]=3[N:22]=[CH:23][C:18]2=[N:17][N:16]=1)[CH3:2].[OH-].[Na+].Cl>O1CCOCC1>[CH2:1]([C@@H:3]1[CH2:7][C@H:6]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:5][C@@H:4]1[C:15]1[N:19]2[C:20]3[CH:26]=[CH:25][NH:24][C:21]=3[N:22]=[CH:23][C:18]2=[N:17][N:16]=1)[CH3:2]
Reactant: CCC1CC(OC2CCOCC2)CC1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](OC2CCOCC2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 47.4 %

Procedure:
To a solution of 1-(2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.145 g, 0.285 mmol) in p-dioxane (6.00 mL) was added an aqueous solution of NaOH (1 N, 1.50 mL, 1.50 mmol). The reaction mixture was stirred at about 55° C. for about 45 min, then cooled to ambient temperature. The reaction mixture was acidified to about pH 2 by the addition of aqueous HCl (1 N, 6 mL). The aqueous layer was extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concd to give a brown residue. The crude material was purified by silica gel chromatography using a gradient of 1-10% MeOH in DCM. The stereoisomers were separated using AA (Table 2, Method 32, Rt=15.5 min, or =negative) to give 1-((1S,2R,4S)-2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.048 g, 48%): LC/MS (Table 1, Method a) Rt=1.70 min; MS m/z: 356 (M+H)+.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH2:21][OH:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])(C)(C)C.C1(C)C=CC=CC=1.N1C=CC=CC=1.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>ClC(Cl)C.ClCCl>[O:7]=[C:6]1[NH:8][C@@H:9]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:21][O:22]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(C[C@H]1COC(=O)N1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The alcohol 2 (500 mg, 1.616 mmol) was azeotroped with toluene, and then dissolved in dichloroethane (5 mL). Pyridine (1.44 mL, 17.78 mmol) was added and the mixture was cooled to 0° C. Anhydrous p-toluenesulfonic anhydride (580 mg, 1.778 mmol) was added and the mixture was warmed to room temperature and stirred for 1 hour. A condenser was adapted to the reaction flask and the mixture heated to 90° C. for two hours. Added additional 0.5 equivalents (290 mg) of p-toluenesulfonic anhydride and heated at 90° C. overnight. The mixture was cooled, diluted with dichloromethane and washed with 1 N HCl (2×3 mL), then water. The organic layer was dried with sodium sulfate and filtered over a small silica plug, rinsing with ethyl acetate. The solvents were removed in vacuo to afford an oil that crystallizes. LC-MS m/z=253 (M+NH4+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[S:32][C:33]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=4)=[CH:34][C:35]=3[CH3:36])=[CH:25][CH:24]=2)[CH2:7][C:8](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:9])=[N:2]1.OO.[Li+].[OH-].Cl.[C:52]([O-])([O-])=[O:53].[K+].[K+].IC>C1COCC1.CCOC(C)=O>[O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]3[S:32][C:33]([C:37]4[CH:38]=[CH:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=4)=[CH:34][C:35]=3[CH3:36])=[CH:27][CH:28]=2)[CH2:7][C:8]([O:53][CH3:52])=[O:9])=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1)c1ccon1
Temperature: 0 °C
Yield: 85.1 %

Procedure:
To a solution of 62.8 (94 mg, 0.15 mmol) in THF (1.5 mL) were added 30% H2O2 (0.17 mL, 1.50 mmol) and 1N LiOH (0.73 mL, 0.73 mmol) at 0° C. The mixture was stirred for 1 Hour at 0° C., adjusted to pH 3 with aqueous HCl, and extracted with EtOAc. The combined organics were washed with 1N Na2SO3 (pH 3) and brine, dried (Na2SO4), and concentrated. The residue was dissolved in 9:1 MeCN/DMF (1.5 mL), and to the solution were added K2CO3 (30 mg, 0.22 mmol) and iodomethane (20 μL, 0.22 mmol). The mixture was stirred overnight at room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and concentrated. The crude product was chromatographed on silica gel (0-40% EtOAc/hexane) to afford 62.9 (64 mg, 88%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, 1H), 7.65 (d, 2H), 7.60 (d, 2H), 7.20 (d, 2H), 7.15 (s, 1H), 6.95 (d, 2H), 6.08 (d, 1H), 5.10 (s, 2H), 4.59 (t, 1H), 3.64 (s, 3H), 3.31 (dd, 1H), 2.95 (dd, 1H), 2.28 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:46][O:47][CH3:48])[C:15]([NH:17][CH:18]2[C:44](=[O:45])[N:20]3[C:21]([C:28]([O:30]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:29])=[C:22](/[CH:25]=[CH:26]/[Cl:27])[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[CH3:48][O:47][N:46]=[C:14]([C:12]1[N:13]=[C:9]([NH2:8])[S:10][CH:11]=1)[C:15]([NH:17][CH:18]1[C:44](=[O:45])[N:20]2[C:21]([C:28]([OH:30])=[O:29])=[C:22](/[CH:25]=[CH:26]/[Cl:27])[CH2:23][S:24][C@H:19]12)=[O:16]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12)c1csc(N)n1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(/C=C/Cl)CS[C@H]12)c1csc(N)n1
Reaction time: 0.67 h
Yield: 64.8 %

Procedure:
Trifluoroacetic acid (6 ml) was added to a solution of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (syn isomer) (1.4 g) in methylene chloride (4 ml) and anisole (1.4 ml) under ice-cooling and the mixture was stirred at the same temperature for 40 minutes. The resulting solution was added dropwise to diisopropyl ether (200 ml) and the resultant precipitates were collected by filtration. The precipitates were added to a mixture of water (30 ml) and ethyl acetate (30 ml) and the solution was adjusted to pH 7.0 with 5% aqueous solution of sodium bicarbonate. The separated aqueous layer was adjusted to pH 2.7 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylic acid (syn isomer) (0.66 g).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH2:37][CH2:38]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:38][CH2:37][C:27]2[N:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:30][C:26]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1OC
Product: COc1ccccc1OC(C)(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxy-phenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3): • 7.99-7.97 (m, 2H), 7.47 (dd, 3H, J=5.08 Hz, 1.96 Hz), 7.18 (d, 2H, J=8.60), 7.07 (td, 1H, J=6.65 Hz, 1.56 Hz), 6.89-6.80 (m, 4H), 6.63 (dd, 1H, J=7.82 Hz, 1.56 Hz), 4.21 (t, 2H, J=6.26 Hz), 3.82 (s, 3H), 3.30 (d, 1H, J=14.1 Hz), 3.10-3.04 (m, 3H), 2.41 (s, 3H), 1.30 (s, 3H). MS [ES+] m/z exact mass calcd for C29H30NO6 488.2073, found 488.2086.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13]>>[CH:2]1([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: BrC1C=CCCC1
Reactant: O=Cc1cccc(O)c1
Product: O=Cc1cccc(OC2C=CCCC2)c1

Procedure:
3-Bromo-1-cyclohexene and 3-hydroxybenzaldehyde were processed as described in Example 58A to provide the title compound.