Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[NH:13]([C@@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1)[C:14]([CH3:16])=[O:15].O[N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([O:23][N:25]2[C:29](=[O:30])[C:28]3[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]2=[O:35])[CH2:19][CH2:18]1)[C:14]([CH3:16])=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(=O)N[C@H]1CC[C@@H](O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CC[C@H](ON2C(=O)c3ccccc3C2=O)CC1
Reaction time: 6 h

Procedure:
A solution of 39.5 ml (0.2413 mol) of diethyl azodicarboxylate (95%) in 300 ml of tetrahydrofuran is added dropwise to a mixture of 36.13 g (0.2298 mol) of cis-4-acetaminocyclohexanol [Ber. Dtsch. Chem. Ges. 72, 995 (1939)], 37.49 g (0.2298 mol) of N-hydroxyphthalimide, 60.28 g of triphenylphosphine and 1500 ml of tetrahydrofuran at 20°-30° C., while stirring. After stirring at room temperature for 14 hours, in each case 20% of the amount of triphenylphosphine and diethyl azodicarboxylate originally employed is again added to the reaction mixture, stirring is continued for 6 hours and the reaction mixture is left to stand at room temperature for 2.5 days. The crystalline precipitate formed is filtered off and washed with tetrahydrofuran. The title compound thus obtained melts at 210°-213° C. The yield can be increased by further recrystallization or chromatography of the mother liquor.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8](OC)=[O:9])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:1][NH:2][CH2:3][C:5]1[CH:6]=[C:7]([CH2:8][OH:9])[CH:12]=[CH:13][CH:14]=1
Reactant: CNC(=O)c1cccc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNCc1cccc(CO)c1

Procedure:
A stirred solution of methyl 3-[(methylamino)carbonyl]benzoate (preparation 11) (5.0 g, 20.7 mmol) in THF (120 ml) was treated dropwise with a solution of lithium aluminium hydride (1M, 30 ml, 30 mmol) in THF. The resultant slurry was stirred under reflux overnight, cooled and treated with water (1.1 ml), 15% NaOH (1.8 ml) and water (2.5 ml). The resultant gel was removed by filtration, the liquors concentrated in vacuo and taken up in ethyl acetate (120 ml). The organic layer was washed with sat aq brine (100 ml) and dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave an oil which was purified by chromatography (SiO2, gradient elution with CH2Cl2; 95:5 CH2Cl2:MeOH; 90:10 CH2Cl2:MeOH; 90:10:1 CH2Cl2:MeOH:NH3; 85:15:1 CH2Cl2:MeOH:NH3). The second eluted material proved to be the correct product (2.9 g, 69%,). 1H NMR (CDCl3) δ 2.20 (s, 2H), 2.40 (s, 3H), 3.70 (s, 2H), 4.60 (s, 2H), 7.20-7.40 (m, 4H). LRMS m/z=152.4 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNC(=O)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(C2CNC2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A mixture of 3-(3-oxopiperazin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (400 mg, 1.57 mmol) and TFA (3 mL) in DCM (6 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 4-Azetidin-3-ylpiperazin-2-one as a white solid (227 mg, 93%). 1H NMR (CDCl3, 300 MHz): δ 6.08 (s, 1 H); 3.63-3.56 (m, 3 H); 3.42-3.35 (m, 3 H); 3.31 (t, J=6.74 Hz, 1 H); 3.03 (s, 2 H); 2.59-2.51 (m, 2 H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=2)=[C:8]([F:28])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl[C:30]1[C:31]2[N:38]=[CH:37][N:36]([CH:39]([CH3:41])[CH3:40])[C:32]=2[N:33]=[N:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([C:30]3[C:31]4[N:38]=[CH:37][N:36]([CH:39]([CH3:41])[CH3:40])[C:32]=4[N:33]=[N:34][CH:35]=3)[CH:13]=2)=[C:8]([F:28])[CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2F)c(F)c1
Reactant: CC(C)n1cnc2c(Cl)cnnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cc(-c3cnnc4c3ncn4C(C)C)ccc2F)c(F)c1
Temperature: 120 °C
Yield: 80 %

Procedure:
To a solution of 2-[4′-(ethylsulfonyl)-2′,6-difluorobiphenyl-3-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 47, 48 mg, 0.12 mmol) and 4-chloro-7-isopropyl-7H-imidazo[4,5-c]pyridazine (Preparation 6, 22 mg, 0.11 mmol) in anhydrous dioxane (0.56 mL) was added aqueous Na2CO3 solution (2M, 0.17 mL, 0.34 mmol) and a stream of nitrogen gas was bubbled through the suspension for 5 minutes. Tetrakistriphenylphosphine palladium(0) (2.3 mg, 0.002 mmol) was added and the mixture was heated under microwave irradiation at 120° C. for a total of 15 minutes. The reaction mixture was cooled, diluted with water (20 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and the filtrate was evaporated in vacuo to leave a tan sticky solid that was purified by silica gel column chromatography eluting with heptane:EtOAc to afford the title compound as a tan solid in 80% yield, 40 mg.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([Cl:25])=[C:6]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C:9]2=[O:24])[CH:7]=1.[C:27](Cl)(Cl)=[O:28]>C1(C)C=CC=CC=1>[Cl:25][C:5]1[CH:4]=[C:3]([F:26])[C:2]([N:1]=[C:27]=[O:28])=[CH:7][C:6]=1[N:8]1[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C:9]1=[O:24]
Reactant: O=C(Cl)Cl
Reactant: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N=C=O)c(F)cc2Cl)c1=O

Procedure:
A mixture of isopropyl 3-(5-amino-2-chloro-4-fluorophenyl)tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (4.0 g, 0.0103 mol) in toluene is treated with a 1.93M solution of phosgene in toluene (19 mL), refluxed for 3 hours, cooled, partially concentrated in vacuo, diluted with toluene, partially concentrated in vacuo, diluted with toluene and concentrated in vacuo to give the title product as a yellow foam which is identified by 1H NMR spectral analysis.
Reaction SMILES: [CH3:1]I.[N+:3]([CH:6]([CH2:8][CH:9]([CH2:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:7])([O-:5])=[O:4].[OH-].[Na+]>CC(C)=O>[N+:3]([CH:6]([CH2:8][CH:9]([CH2:18][C:19]([N:21]([CH3:1])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:7])([O-:5])=[O:4]
Reactant: CCCCCCCCC(CC(=O)Nc1ccccc1)CC(C)[N+](=O)[O-]
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCCCCCC(CC(=O)N(C)c1ccccc1)CC(C)[N+](=O)[O-]
Reaction time: 0.13 h
Yield: 97.6 %

Procedure:
A solution of methyl iodide (130 g) in acetone (160 ml) was added to a stirred mixture of 2-nitro-4-dodecylacetanilide (196 g) and sodium hydroxide (130 g) in acetone (1100 ml) at room temperature. The mixture was heated rapidly and allowed to boil for 8 minutes, filtered hot and the filtrate evaporated to a semi-solid which was partitioned between toluene (800 ml) and water (400 ml). The organic layer was washed with water, dried and evaporated to give 199 g of 2-nitro-4-dodecyl-N-methylacetanilide as a dark oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[N:15][C:14]=3[CH:31]=2)=[CH:6][C:5]=1[F:32])(=[O:3])[NH2:2].[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[F:32][C:5]1[CH:6]=[C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[CH:31]=2)[CH:8]=[CH:9][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(F)c4)ccc3o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(-c2ccc3oc(C4CCNCC4)nc3c2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl 4-[5-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate (190 mg, 0.32 mmol) dissolved in DCM (40 ml) and added trifluoroacetic acid (1.5 ml). This mixture stirred at rt for 3 h. After completion of the reaction, DCM removed on rotavapour and residue was co-distilled with ether to obtain 2-fluoro-4-(2-(piperidin-4-yl)-benzo[d]oxazol-5-yl)-benzamide 2,2,2-trifluoroacetate (190 mg). 2-Fluoro-4-(2-(piperidin-4-yl)-benzo[d]oxazol-5-yl)-benzamide 2,2,2-trifluoroacetate (190 mg, 0.42 mmol) was dissolved in DMF (7 ml) and added isobutyric acid (47 mg, 0.46 mmol), EDC.HCl (200 mg, 1.04 mmol), HOBt (70 mg, 0.5 mmol) and TEA (0.7 ml, 3.3 mmol). After completion of the reaction, water added to the reaction mixture to obtain solid. Solid was filtered and washed with ether to obtain the titled compound (120 mg) as a brown solid. M.P.: 193-196° C. MS (m/z): 410.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[C:34](Br)=[CH:33][C:32]([F:36])=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2.[OH-].[Na+]>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].CN(C=O)C>[N:15]12[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[C:34]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=4)=[CH:33][C:32]([F:36])=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(Br)c2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(-c3ccc(OC(F)(F)F)cc3)c2o1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
A mixture of 40 mg (0.29 mmol) of 4-(trifluoromethoxy)phenylboronic acid, 70 mg (0.19 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7-bromo-1-benzofuran-2-carboxamide (Example 5A), 0.57 ml (0.57 mmol) of 1N sodium hydroxide solution, 14 mg (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 ml of DMF is heated at 85° C. overnight. The solvent is removed under reduced pressure. The crude product is mixed with 1N sodium hydroxide solution and extracted three times with a total of 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is removed under reduced pressure. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 20 min. The loaded ion exchanger is washed three times with 30 ml of methanol each time, then with water, again with methanol, with dichloromethane, again with methanol, with THF and finally once more with methanol. The product is eluted with methanol/triethylamine 95:5. The solvent is removed in a rotary evaporator under reduced pressure. Silica gel 60 (Merck, Darmstadt; eluent: dichloromethane/triethylamine 100:1, then dichloromethane/methanol/triethylamine 100:1:1 to dichloromethane/methanol/triethylamine 100:10:1) is used for final purification. The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 52 mg (61% of theory) of the title compound are isolated.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:16]([CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:15]([S:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)[N:14]([CH:33]([CH3:35])[CH3:34])[N:13]=1)=O)C.O.[OH-].[Na+]>O1CCCC1>[Cl:32][C:27]1[CH:26]=[C:25]([S:24][C:15]2[N:14]([CH:33]([CH3:35])[CH3:34])[N:13]=[C:12]([CH2:10][OH:9])[C:16]=2[CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH:30]=[C:29]([Cl:31])[CH:28]=1
Reactant: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1Cc1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1nc(CO)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A solution containing 0.4 ml of lithium aluminium hydride (1M solution in THF) in 2 ml of anhydrous tetrahydrofuran at 0° C. under nitrogen was treated dropwise with a solution of 154 mg of 5-(3,5-Dichloro-phenylsulfanyl)-1-isopropyl-4-pyridin-4-ylmethyl-1H-pyrazole-3-carboxylic acid ethyl ester in 2 ml of anhydrous tetrahydrofuran. The mixture was stirred at 0° C. for 0.5 h then treated with 0.012 ml of water, 0.012 ml of 2N sodium hydroxide solution and then 0.018 ml of water. The mixture was stirred for 0.5 h at 0° C.; the mixture was filtered and then the solvent removed. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (1:19) for the elution to give 90 mg of 5-(3,5dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H -pyrazole-3-methanol as a white gum. Mass spectrum (ESI) m/z 408 [M+H]+. 1H NMR (DMSO) 1.30 (d, 6H), 3.90 (s, 2H), 4.55 (d, 2H), 4.72 (m, 1H), 5.30 (t, 1H), 6.85 (s, 2H), 7.15 (d, 2H), 7.35 (s, 1H), 8.30 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:30](=[CH:31][CH:32]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[C@@H:17]4[CH2:18][C@@H:14]([CH2:15][CH2:16]4)[N:13]3[C:19](=[O:29])[C@@H:20]([NH:24][C:25](=[O:28])[O:26][CH3:27])[CH:21]([CH3:23])[CH3:22])=[N:11][C:7]=1[CH:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[NH:51][C:50]([C@@H:52]4[CH2:56][CH2:55][CH2:54][N:53]4[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[N:49][CH:48]=3)=[CH:43][CH:42]=2)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:27][O:26][C:25]([NH:24][C@@H:20]([CH:21]([CH3:23])[CH3:22])[C:19]([N:13]1[C@H:12]([C:10]2[NH:9][C:8]3[C:30]4[C:4]([CH:5]=[CH:6][C:7]=3[N:11]=2)=[CH:3][C:2]([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[NH:51][C:50]([C@@H:52]5[CH2:56][CH2:55][CH2:54][N:53]5[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[N:49][CH:48]=3)=[CH:45][CH:46]=2)=[CH:32][CH:31]=4)[C@@H:17]2[CH2:18][C@H:14]1[CH2:15][CH2:16]2)=[O:29])=[O:28]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Temperature: 85 °C
Yield: 41.6 %

Procedure:
Methyl (S)-1-((1R,3S,4S)-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (122 mg, 0.24 mmol) and (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (114 mg, 0.26 mmol) were combined in DME (3 mL). Pd(PPh3)4 (28 mg, 0.024 mmol) and K2CO3 (2M H2O, 0.4 mL, 0.79 mmol) were added, and the solution was degassed with N2 for 10 min. The solution was heated to 85° C. and stirred o/n. The following morning, the solution was cooled to rt. The solution was diluted with EtOAc, washed with sat. NaHCO3, brine, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (73 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][CH3:45])/[C:8]([NH:10][CH:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([O:27]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:26])=[C:15]([C:18]4[C:21](=[O:22])[C:20](=[O:23])[C:19]=4[CH3:24])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][CH3:45])/[C:8]([NH:10][CH:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([OH:27])=[O:26])=[C:15]([C:18]4[C:21](=[O:22])[C:20](=[O:23])[C:19]=4[CH3:24])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(C)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(c3c(C)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Reaction time: 0.66 h
Yield: 86.5 %

Procedure:
Diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(3,4-dioxo-2-methyl-1-cyclobutenyl)-3-cephem-4-carboxylate (550 mg) was added to stirred and cooled (ice/H2O bath) trifluoroacetic acid (5 mL) containing anisole (1mL). The cooling bath was removed, and stirring was continued for 0.66 hr at ambient temperatures. The solution was added to stirred diisopropyl ether to precipitate the trifluoroacetic acid salt of the title compound (353 mg, 70% yield) as a yellow powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:12]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH:26]([CH2:29]O)[CH2:27][OH:28])=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O>[CH2:12]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH:26]2[CH2:27][O:28][CH:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[O:11][CH2:29]2)=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCc1ccc(CCC(CO)CO)cc1
Reactant: O=Cc1ccc2c(c1)OCO2
Solvent: O
Product: CCCCCCc1ccc(CCC2COC(c3ccc4c(c3)OCO4)OC2)cc1

Procedure:
By reaction of benzo[1,3]dioxole-5-carbaldehyde with 2-[2-(4-hexylphenyl)ethyl]propane-1,3-diol with acid catalysis on a water separator.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:23]3[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(3,4-dichlorophenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.43 (m, 1H), 7.90-8.04 (m, 2H), 7.72-7.75 (m, 1H), 7.58-7.70 (m, 6H), 7.38 (dd, J=8.3, 2.1 Hz, 1H), 3.75 (s, 2H); MS (ESI−) M/Z 456 (M−H)−.
Reaction SMILES: [CH2:1]([P:3]([CH:6]=[CH:7][CH3:8])(=[O:5])[OH:4])[CH3:2].[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4:29]>C1(C)C=CC=CC=1>[Ti+4:29].[CH2:1]([P:3]([CH:6]=[CH:7][CH3:8])(=[O:4])[O-:5])[CH3:2].[CH2:1]([P:3]([CH:6]=[CH:7][CH3:8])(=[O:4])[O-:5])[CH3:2].[CH2:1]([P:3]([CH:6]=[CH:7][CH3:8])(=[O:4])[O-:5])[CH3:2].[CH2:1]([P:3]([CH:6]=[CH:7][CH3:8])(=[O:4])[O-:5])[CH3:2]
Reactant: CC=CP(=O)(O)CC
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: Cc1ccccc1
Product: CC=CP(=O)([O-])CC
Yield: 91.8 %

Procedure:
134 g (1 mol) of ethylpropenylphosphinic acid (produced as in Example 12) and 85 g of titanium tetrabutoxide are refluxed in 500 ml of toluene for 40 hours. The resulting butanol is distilled off from time to time with proportions of toluene. The solution formed is subsequently freed of solvent to leave 133 g (92% of theory) of ethylpropenylphosphinic acid titanium salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.N>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC1CCN(c2ccc(Br)cn2)CC1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC1CCN(c2ccc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 6.9 g (17.95 mmol) of tert-butyl 2-(5′-bromo-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl)ethylcarbamate obtained in step 8.1., in 100 ml of dichloromethane, cooled by an ice/water bath, is admixed slowly with 20.47 g (179.54 mmol) of trifluoroacetic acid. Stirring is continued at ambient temperature for 2 hours. The reaction mixture is poured into a mixture of ice-water and 28% aqueous ammonia. The mixture is decanted, the aqueous phase is extracted twice with dichloromethane, and the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][C:2](Cl)([CH2:4][CH2:5][C:6]([CH3:9])(Cl)[CH3:7])[CH3:3].[CH:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18]>[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)CCl>[OH:17][C:16]1[C:15]2[C:6]([CH3:9])([CH3:7])[CH2:5][CH2:4][C:2]([CH3:3])([CH3:1])[C:14]=2[CH:13]=[C:12]([CH3:18])[CH:11]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Cc1cccc(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
2,5-Dimethyl-2,5-dichlorohexane (183 g, 1 mol) was stirred with m-cresol (129.6 g, 1.2 mol) and aluminium chloride (4 g) was added in one portion. The mixture was heated at 95° C., with stirring for 1.5 h, after which ethylene dichloride (100 mL) was added and then the heating was continued. After 1 h the mixture was cooled to 20° C. and poured onto an ice-water/hydrochloric acid mixture (150 mL, 10% HCl solution). The mixture was then extracted with toluene (500 mL). The organic layer was separated, washed with brine (3×50 mL) and dried (Na2SO4). The solvent was removed by distillation and the residue was crystallized from a hexane/benzene solvent mixture to give 1-hydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (171 g), mp 133°-134° C., GLC purity 99%+, exhibiting the expected spectral data.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[CH3:11][C:12]([CH3:15])([O-])C.[K+].BrC1CC1>CN(C=O)C>[CH:15]1([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)[O-]
Reactant: c1ccc2c(c1)NCCO2
Agent: BrC1CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)OCCN2C1CC1
Reaction time: 0.08 h
Yield: 68.2 %

Procedure:
To a stirred solution of 3,4-dihydro-2H-benzo[1,4]oxazine (5 g, 37.0 mmol) in DMF (20 mL) was added potassium tert-butoxide (6.22 g, 55.55 mmol) at 0° C. After stirring for 5 min, bromo-cyclopropane (4.44 mL, 55.55 mmol) was added and the reaction mixture was stirred for another 4 h at room temperature. The reaction was quenched by addition of water and extracted with ethyl acetate (50×2 mL). The organic layer was washed with water (20 mL), concentrated and purified by silica gel column chromatography to furnish 4-Cyclopropyl-3,4-dihydro-2H-benzo[1,4]oxazine (4.42 g).