Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:13])=[CH:5][C:6](=[O:12])[S:7]2.C(N(CC)CC)C.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][N:26]=[C:27]=[O:28])[CH3:22]>C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:29])[CH2:25][NH:26][C:27]([C:5]1[C:6](=[O:12])[S:7][C:8]2[C:3]([C:4]=1[OH:13])=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=2)=[O:28])[CH3:22]
Reactant: CCOC(=O)CN=C=O
Reactant: O=c1cc(O)c2c(F)cccc2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1c(O)c2c(F)cccc2sc1=O
Temperature: 120 °C
Reaction time: 3 h

Procedure:
5-Fluoro-4-hydroxy-thiochromen-2-one (500 mg, 2.55 mmol) was placed in a CEM Microwave vessel and suspended in anhydrous DCM (5 mL.) Triethylamine (710 uL, 5.1 mmol) and isocyanato-acetic acid ethyl ester (572 uL, 5.1 mmol) were added in one portion and the reaction heated to 120° C. in a CEM Discovery Microwave system. After three hours, the reaction was cooled diluted with 10 volumes of dichloromethane, washed with an equal volume of 1N HCl and dried over magnesium sulfate to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][NH:3]1.[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>[OH-].[K+]>[CH3:1][CH:2]1[CH2:4][N:3]1[S:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CN1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)N2CC2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
2-Methylaziridine (3.6 ml, 51 mmol) was added to a 10% aqueous KOH solution (30 ml) and cooled in an ice bath for 30 min. To this solution p-toluenesulfonyl chloride (9.9 g, 52 mmol) was added rapidly while maintaining the temperature below 4° C. The resulting mixture was stirred for 30 min at 0° C., then stirred at room temperature overnight. The white precipitate was washed multiple times with cold water and dried under vacuum. The washed product was dissolved in hot petroleum ether and allowed to crystallize at 0° C., yielding colorless crystals (6.3 g, 57% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:10]=2)=[N:7][CH:8]=1.[C:32](Cl)(=[O:37])[O:33][CH2:34][CH:35]=[CH2:36]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([N:25]([C:32]([O:33][CH2:34][CH:35]=[CH2:36])=[O:37])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[N:10]=2)=[N:7][CH:8]=1
Reactant: C=CCOC(=O)Cl
Reactant: COc1cnc(-c2nn(C(=O)OC(C)(C)C)c3ccccc23)nc1Nc1ccncc1
Solvent: c1ccncc1
Product: C=CCOC(=O)N(c1ccncc1)c1nc(-c2nn(C(=O)OC(C)(C)C)c3ccccc23)ncc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
96.3 mg of tert-butyl 3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazole-1-carboxylate (1-8-1, 0.23 mmol, 1 eq.) was suspended in 7 ml of pyridine. 27.7 mg of prop-2-en-1-yl carbonochloridate (0.23 mmol, 1 eq.) were added and stirred for two hours at room temperature. Twice 27.7 mg of prop-2-en-1-yl carbonochloridate (0.23 mmol, 1 eq.) were added again and stirred the first time for 24 hours and the second time for three days at room temperature. The reaction mixture was concentrated in vacuo. To the residue was added water and acidified with 1M aq. hydrogen chloride solution. This aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over a silicone filter and concentrated under vacuo. Purification by flash chromatography (ethyl acetate/methanol 0-50%) provided 50.8 mg (0.09 mmol, 39.97%) of the analytically pure target compound.
Reaction SMILES: [O:1]=[C:2]([CH2:11][O:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[N:23]([O-])=[O:24].[Na+].C(OCC)(=O)C>C(O)(=O)C>[OH:24][N:23]=[C:3]([C:2](=[O:1])[CH2:11][O:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: O=N[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC(=O)CC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)OCC(=O)C(=NO)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 33.9 %

Procedure:
4.5 g of t-butyl 3-oxo-4-p-toluenesulphonyloxybutyrate were dissolved in 40 ml of acetic acid, and then 1.42 g of sodium nitrite were added, at room temperature, to the solution over a period of 10 minutes. The mixture was then stirred at room temperature for 50 minutes, after which 200 ml of ethyl acetate were added and the mixture was then washed with an aqueous solution of sodium chloride. The ethyl acetate solution was dried over magnesium sulphate and, after filtering off the drying agent, the filtrate was concentrated by evaporation under reduced pressure to give a brown, oily substance. This oily substance was purified by column chromatography through silica gel, eluted with a 4:1 by volume mixture of cyclohexane and ethyl acetate, affording 1.66 g of t-butyl 2-hydroxyimino-3-oxo-4-p-toluenesulphonyloxybutyrate, in the form of colourless crystals, melting at 106°-108° C. (with decomposition, recrystallized from a 1:1 by volume mixture of diethyl ether and petroleum ether).
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:14]2[C:9](=[CH:10][C:11]([N:15]3[C:19]4=[N:20][CH:21]=[CH:22][CH:23]=[C:18]4[N:17]=[CH:16]3)=[CH:12][CH:13]=2)[C:8](=[O:24])[CH2:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1>[N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:15]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7][C:8]3=[O:24])[CH:16]=1
Reactant: CCOC(=O)C1CC(=O)c2cc(-n3cnc4cccnc43)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CC(C(=O)O)c2ccc(-n3cnc4cccnc43)cc21

Procedure:
A solution of 5-imidazo[4,5-b]pyridine-3-yl-3-oxo-indan-1-carboxylic acid ethyl ester (297 mg, 0.924 mmol) and 1N LiOH (1 mL, 1 mmol) in THF (1.7 mL) is stirred at rt for 15 min. THF is removed in vacuo, the residue taken up in EtOAC and washed with 1N LiOH. The aqueous layer was acidified with 1M HCl and extracted with EtOAc. The organic layer was washed with brine, dried with MgSO4, filtered and concentrated. (R/S)-5-Imidazo[4,5-b]pyridine-3-yl-3-oxo-indan-1-carboxylic acid is obtained as a brown solid. Title compound: 1H NMR (DMSO-d6): 9.0 (s, 1H), 8.5 (d, 1H), 8.4 (d, 1H), 8.3 (s, 1H), 8.2 (d, 1H) 7.9 (d, 1H), 7.4 (dd, 1H) 4.4 (m, 1H), 3.0 (m, 2H); tR=0.9 min (System 2).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)([O:9][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([Br:3])=[CH:5][CH:6]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OCc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.1 %

Procedure:
Sodium hydride (257 mg, (428 mg of 60% dispersion), 10.6 mmol, 2 eq) was added to a solution of p-bromobenzyl alcohol (1 g, 5.3 mmol) in dry toluene (30 mL). Once the concomitant effervescing had ceased, p-toluenesulphonyl chloride (2.04 g, 10.6 mmol, 2 eq) was added and the mixture stirred at room temperature, 12 hours. The toluene was removed in vacuo and the residue taken up in water and extracted into ethyl acetate portions. The combined organic layers were washed (brine), dried (MgSO4), filtered, and concentrated in vacuo to give the crude product which was purified by column chromatography (silica gel, eluant:ethyl acetate/heptane mixtures) to give the p-bromobenzyl tosylate as a white solid (yield: 400 mg, 22%);
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([CH:24]4[CH2:26][CH2:25]4)[CH:23]=2)[O:20][C:19]([CH3:28])([CH3:27])[CH2:18][C:17]3([CH3:30])[CH3:29])=[CH:8][C:7]=1[F:31])C.CO.[OH-].[Na+].O>C(#N)C>[CH:24]1([C:22]2[CH:23]=[C:14]([CH2:13][CH2:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:32])=[O:3])=[C:7]([F:31])[CH:8]=3)[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([CH3:27])([CH3:28])[CH2:18][C:17]3([CH3:30])[CH3:29])[CH2:25][CH2:26]1
Reactant: CCOC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(C)(C)c2cc(CCc3ccc(CC(=O)O)c(F)c3)cc(C3CC3)c2O1

Procedure:
Following general procedure L and using [4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-2-fluorophenyl]acetic acid ethyl ester (Compound 37, 0.14 g, 0.323 mmol), 5 mL of methanol and 1M sodium hydroxide solution (2 mL) followed by reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a solid (0.110 g, 80%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]4[N:36]=[C:37]([CH3:39])[N:38]=[C:12]34)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37]([CH3:39])[N:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCO)CC2)c2nc(C)nn12

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.0 g), sodium cyanoborohydride (0.32 g), boron trifluoride etherate (0.64 mL) and tetrahydrofuran (20 mL) was heated under reflux for 15 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.60 g, 58%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:17][CH2:18][OH:19].C1COCC1.Br[CH2:33][C:34]#[N:35].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:17][CH2:18][O:19][CH2:33][C:34]#[N:35]
Reactant: CC(C)(C)S(=O)NC1(CCO)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Reactant: N#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(CCOCC#N)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Reaction time: 0.08 h

Procedure:
A 100 mL RBF was charged with N-(7-bromo-3-chloro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamide (625 mg, 1.359 mmol), tetrabutylammonium hydrogen sulfate (138 mg, 0.408 mmol), THF (6.80 mL), and bromoacetonitrile (0.852 mL, 12.23 mmol) to give a cloudy, light brown solution. The resulting solution was stirred vigorously for 5 min. Then a 2N aq. solution of sodium hydroxide (13.600 mL, 27.2 mmol) was added in one portion. The solution changed into dark brown color. 3 Hrs later, LCMS showed an incomplete conversion (SM: product=1:1.5). 1 additional molar equivalent of BrCH2CN was added, and the mixture was stirred for 1 hr. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered and concentrated to give the crude material as a brown solid. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 25 to 40 to 80% DCM/MeOH/NH4OH (90:10:1) in 40% EtOAc in heptane to yield N-(7-bromo-3-chloro-5-(2-(cyanomethoxy)ethyl)-5H-chromeno[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamide as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.12 (m, 9 H) 2.59 (d, J=9.49 Hz, 2 H) 3.03 (s, 2 H) 4.10 (s, 2 H) 6.52 (s, 1 H) 7.10-7.20 (m, 1 H) 7.51-7.59 (m, 1 H) 7.72-7.80 (m, 1 H) 7.93 (d, J=2.45 Hz, 1 H) 8.33-8.40 (m, 1 H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([O:12]C)=[O:11])[CH:7]=[N:6][C:5]=12.[Li+].[OH-].Cl>CO>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[N:6][C:5]=12
Reactant: COC(=O)c1cnc2nccn2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc2nccn2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 39 %

Procedure:
A mixture of 6-bromoimidazo[1,2-a]pyrimidine (1.17 g, 6 mmol), BINAP (18 mg, 0.06 mmol), PdCl2 (6 mg) in MeOH (30 mL) and triethylamine (1.8 mL) was heated to 80° C. under CO (50 psi) for 12 hours in DMF (97.5 mL). DMF-DMA (70.6 mL, 495.8 mmol) was added and the mixture heated to 130° C. for 12 hours. The mixture was filtered and concentrated to give methyl imidazo[1,2-a]pyrimidine-6-carboxylate (365 mg, 35%) as a yellow solid which was used in the next step without further purification. To a solution of methyl imidazo[1,2-a]pyrimidine-6-carboxylate (365 mg, 2.1 mmol) in methanol was added 1M aq. LiOH (9.0 mL) and the resulting mixture was stirred for 10 hours at room temperature. The pH was adjusted to 5-6 using aq. HCl and the whole mixture extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuo to give the title compound as white solid in 39% yield, 133 mg
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([C:19]#[N:20])=[CH:15][N:14]=1)=[O:12])[CH3:9].Cl.[NH2:22][OH:23]>CCO>[NH2:20][C:19](=[N:22][OH:23])[C:16]1[N:17]=[CH:18][C:13]([C:11]([O:10][CH2:8][CH3:9])=[O:12])=[N:14][CH:15]=1
Reactant: CCOC(=O)c1cnc(C#N)cn1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(C(N)=NO)cn1
Temperature: 80 °C
Reaction time: 12 h
Yield: 62.1 %

Procedure:
Triethylamine (7.08 mL, 51.9 mmol) was added to a solution of 5-cyano-pyrazine-2-carboxylic acid ethyl ester (4.0 g, 22.6 mmol), hydroxylamine hydrochloride (3.45 g, 49.7 mmol) and EtOH (32 mL) and stirred at 80° C. for 12 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo and dissolved in H2O (30 mL). The aqueous solution was extracted with CHCl3 (3×30 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound (2.95 g, 62%) as a yellow solid.
Reaction SMILES: [PH5].[C:2]([O:5][CH2:6][C@@H:7]1[O:11][C@H:10]([C:12]2[CH2:13][S:14][C@@H:15]3[C@H:31]([NH:32][C:33](=[O:41])[CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:30](=[O:42])[N:16]3[C:17]=2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])[CH2:9][CH2:8]1)(=[O:4])[CH3:3].[N+](C1C=C(C=CC=1)CO)([O-])=O.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC.C(Cl)(Cl)Cl>[C:2]([O:5][CH2:6][CH:7]1[O:11][CH:10]([C:12]2[CH2:13][S:14][C@@H:15]3[C@H:31]([NH:32][C:33](=[O:41])[CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:30](=[O:42])[N:16]3[C:17]=2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])[CH2:9][CH2:8]1)(=[O:4])[CH3:3]
Reactant: COc1ccc(COC(=O)C2=C([C@@H]3CC[C@H](COC(C)=O)O3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: CC(=O)[O-]
Agent: O=[N+]([O-])c1cccc(CO)c1
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C2=C(C3CCC(COC(C)=O)O3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1

Procedure:
A solution of the phosphorane from Example 31(g) (517 mg) in dry toluene (100 ml) was heated at reflux under dry argon for 8 hours and evaporated. the residue was chromatographed on silica gel eluting with ethyl acetate/hexane mixtures to give two fractions. The less polar fraction contained 4-methoxybenzyl (6R, 7R) -3- [ (2S, 5R) -5-acetoxymethyltetrahydro-furan-2-yl]-7-phenylacetamidoceph-3-em-4-carboxylate, a foam (105 mg); νmax (CHCl3) 3410, 1784, 1726 and 1683 cm-1 ; δH (CDCl3) 1.53-1.83 (3 H, m), 2.09 (3 H, s), 2.19-2.36 (1 H, m), 3.30 and 3.55 (2 H, ABq, J 18.9 Hz), 3.60 and 3.69 (2 H, ABq, J 16.2 Hz), 3.81 (3 H, s), 4.01-4.21 (3 H, m), 4.90 (1 H, d, J 4.8 Hz), 4.96 (1 H, dd, J 8.3, 6.7 Hz), 5.12 and 5.17 (2 H, AA'q, J 12.5 Hz), 5.81 (1 H, dd, J 9.2, 4.8 Hz), 5.97 (1 H, d, J 9.2 Hz), 6.85-6.92 (2 H, m), 7.25-7.41 (7 H, m). (Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MH+ (581), MNa+ (603)]. The more polar fraction contained 4-methoxybenzyl (6R,7R)-3-[(2R,SS)-5-acetoxymethyl-tetrahydrofuran-2-yl]-7-phenylacetamidoceph-3-em-4-carboxylate, a solid (19lmg), m.p. 185-187° C. (needles ex ethyl acetate/hexane); νmax (CHC13) 3407, 1785, 1731 and 1682 cm-1 ; δH (CDCl3) 1.53-1.78 (2 H, m), 1.90-2.05 (2 H, m), 2.08 (3 H, s), 3.35 and 3.57 (2 H, ABq, 3 18.0 Hz), 3.61 and 3.69 (2 H, ABq, J 16.2 Hz), 3.80 (3 H, s), 4.01-4.19 (3 H, m), 4.91 (1 H, d, J 4.8 Hz), 5.12-5.27 (3 H, m), 5.74 (1 H, dd, J 4.8, 9.0 Hz), 6.04 (1 H, d, J 9.0 Hz), 6.85-6.91 (2 H, m), 7.25- 7.41 (7 H, m). (Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MH+ (581), MNa+ (603)].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:12]3[CH:13]=[C:14]4[C:27](=[C:28]([F:29])[C:11]=3[O:10][N:9]=2)[N:26]2[CH2:30][C@@H:31]([CH3:35])[O:32][C@@H:33]([CH3:34])[C@@H:25]2[C:16]2([C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18][C:17]2=[O:24])[CH2:15]4)[CH:5]=[N:4][CH:3]=1.[CH3:36][NH:37][CH3:38]>C1COCC1>[CH3:36][N:37]([CH3:38])[C:2]1[N:7]=[C:6]([C:8]2[C:12]3[CH:13]=[C:14]4[C:27](=[C:28]([F:29])[C:11]=3[O:10][N:9]=2)[N:26]2[CH2:30][C@@H:31]([CH3:35])[O:32][C@@H:33]([CH3:34])[C@@H:25]2[C:16]2([C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18][C:17]2=[O:24])[CH2:15]4)[CH:5]=[N:4][CH:3]=1
Reactant: CNC
Reactant: C[C@@H]1CN2c3c(cc4c(-c5cncc(Cl)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Solvent: C1CCOC1
Product: C[C@@H]1CN2c3c(cc4c(-c5cncc(N(C)C)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting materials: (2R,4S,4aS)-rel-8-(6-chloropyrazin-2-yl)-11-fluoro-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 79) and 2N dimethylamine in THF.
Reaction SMILES: Br[C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C[N:16](C1CCCCC1)[CH:17]1CCC[CH2:19][CH2:18]1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(#N)C=C>O1CCOCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17](/[CH:18]=[CH:19]/[C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])#[N:16]
Reactant: CN(C1CCCCC1)C1CCCCC1
Reactant: COC(=O)c1sc2ccccc2c1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: C=CC#N
Product: COC(=O)c1sc2ccccc2c1/C=C/C#N
Temperature: 50 °C

Procedure:
In a flask under nitrogen was placed tris(dibenzylideneacetone)dipalladium(0) (313 mg, 0.34 mmol) in 25 mL of 1,4-dioxane followed by the product obtained from Example 97A (4.5 g, 16.7 mmol), N-methyldicyclohexylamine (3.91 g, 20.0 mmol), tri-tert-butylphosphine (0.68 mL of a 1.0 M solution in toluene, 0.68 mmol) and acrylonitrile (1.06 g, 20.0 mmol). The mixture was stirred and heated at 50° C. under nitrogen for 90 minutes and then cooled and diluted with 100 mL of ethyl acetate and stirred for 15 minutes. The mixture was filtered and the precipitate washed with 25 mL of ethyl acetate. The filtrate was concentrated and worked up as described in Example 55B to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.92 (s, 3H) 6.55 (d, J=17.29 Hz, 1H) 7.54-7.66 (m, 2H) 8.13-8.25 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:28]([NH:32][CH2:33][C:34]1[CH:46]=[CH:45][C:37]([O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:36]([CH3:47])[CH:35]=1)[CH2:29][CH2:30][CH3:31]>C(Cl)Cl>[CH2:28]([N:32]([CH2:33][C:34]1[CH:46]=[CH:45][C:37]([O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:36]([CH3:47])[CH:35]=1)[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:29][CH2:30][CH3:31]
Reactant: Cc1c(Cl)ncnc1-c1ccc(C(F)(F)F)cc1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(C(F)(F)F)cc2)c1C
Temperature: 100 °C
Yield: 43.9 %

Procedure:
A mixture of 4-chloro-5-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (0.229 g, 0.84 mmol), N,N-diisopropylethylamine (0.293 mL, 1.68 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.35 g, 1.26 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The reaction mixture was then allowed to come to room temperature, and the residue dissolved in CH2Cl2 (50 mL), the organic extract was washed water (20 mL) and passed through a hydrophobic frit then concentrated in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting with 1:19–1:9 EtOAc:cyclohexane afforded the title compound as a colourless oil (0.19 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10]C)=O)=[N:6][CH:7]=1.[CH3:12][NH2:13]>CO.O1CCCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([NH:13][CH3:12])=[O:10])=[N:4][CH:3]=1
Reactant: CN
Reactant: COC(=O)c1ncc(Br)cn1
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 5-bromopyrimidine-2-carboxylate (94 mg, 0.43 mmol) was dissolved in a mixture of methanol (1 mL) and tetrahydrofuran (2 mL). An aqueous solution of methylamine (40%, 0.5 mL) was added. The reaction was stirred at room temperature for three days, and was evaporated to dryness in vacuo. The title compound was obtained as a white solid (94 mg).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[F:33][C:34]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C(#N)C>[F:33][C:34]1([F:40])[CH2:39][CH2:38][N:37]([C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[CH:4][CH:3]=2)[CH2:36][CH2:35]1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)nc3)cc2)CCN1C(=O)OC(C)(C)C
Reactant: FC1(F)CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(N4CCC(F)(F)CC4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
A mixture of 1,1-dimethylethyl (2S)-4-({4-[[(6-bromo-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D108) (0.050 g, 0.0993 mmol), 4,4-difluoropiperidine (0.141 g, 0.894 mmol) and triethylamine (0.138 mL, 0.993 mmol) in acetonitrile (4 mL) was heated in a microwave at 150° C. for 12 h. Further portions of 4,4-difluoropiperidine (4 eq.) and triethylamine (5 eq.) were added and the reaction heated at 150° C. for 1 h. The reaction mixture was concentrated and the residue dissolved in DCM/water. The aqueous layer was further extracted with DCM (×3) and the combined organics were dried (Na2SO4) and concentrated to give a yellow gum which was purified by column chromatography. Elution with 0-100% EtOAc/hexane gave a colourless gum which was a mixture (˜9:1) of the title compound and unreacted D109 (0.0485 g). MS (ES): MH+ 544.2.