Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH2:8][CH2:9][CH3:10])[CH2:6][CH3:7])=[O:3].[S:11]1[CH:15]=[C:14]([C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[N:13]=[CH:12]1>N1C=CC=CC=1>[CH3:7][CH2:6][CH:5]([O:4][C:2]([N:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=[C:16]1[C:14]1[N:13]=[CH:12][S:11][CH:15]=1)=[O:3])[CH2:8][CH2:9][CH3:10]
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Reactant: CCCC(CC)OC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(CC)OC(=O)n1c(-c2cscn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
28.3 G. (0.172 moles) of 3-hexyl chloroformate is added dropwise with protection from moisture to a stirred suspension of 33.1 g. (0.165 moles) of 2-(4-thiazolyl)-benzimidazole in 200 ml. of anhydrous pyridine. The 3-hexyl chloroformate is added over a period of 20 minutes during which time the reaction mixture initially becomes a clear solution followed by the precipitation of pyridine hydrochloride. The reaction mixture is stirred overnight at room temperature filtered to remove pyridine hydrochloride which is washed with some additional anhydrous pyridine and the combined filtrates and washings evaporated to dryness in vacuo. An oil is obtained which is dissolved in 300 ml. of methylene chloride and filtered. The filtrate is washed twice with a 250 ml. of 0.25 N-hydrochloric acid containing ice followed by a washing with 200 ml. of saturated sodium bicarbonate solution. The methylenechloride is dried, treated with charcoal, filtered and evaporated to dryness in vacuo affording 39.2 g. of an orange oil which solidified on standing. The solid material is recrystallized from hexane affording 33.5 g. (62%) of 1-(3-hexyloxycarbonyl)-2-(4-thiazolyl)-benzimidazole melting point 79.5 to 81° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:16]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:19]2[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=2[N:17]=1>CN(C)C=O>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]2[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=[C:16]2[O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:27][CH:26]=1
Reactant: Fc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Reactant: CCOC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Oc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To a stirred mixture of 3.5 parts of ethyl 4-hydroxy-1-piperidinecarboxylate and 135 parts of N,N-dimethylformamide was added 1 part of a sodium hydride dispersion 50% and stirring was continued for 2 hours at room temperature. After the addition of 5.2 parts of 2-chloro-1-[(4-fluorophenyl)methyl]-1H-benzimidazole, the whole was further stirred overnight at room temperature. The reaction mixture was poured into ice water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 2.5 parts (31.5%) of ethyl 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]oxy]-1-piperidinecarboxylate; mp. 94.0° C. (26).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22].O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][CH2:22][CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(OC(F)(F)F)cc1Br

Procedure:
To a solution of 2-bromo-4-trifluoromethoxyphenol (Description 11; 8 g, 0.03 mol) and K2CO3 (8.6 g, 0.06 mol) in dimethylformamide (100 ml) was added allyl bromide (4 ml, 0.045 mol). The solution was stirred for 4 h. at room temperature undre nitrogen whereupon water (400 ml) and ethyl acetate (3×100 ml) were added and the combined organic phase was washed with water (200 ml), saturated brine (200 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (eluting with 5% ethyl acetate in hexane) to give the title compound as a yellow oil 1H NMR (250 MHz, CDCl3) δ4.60 (2H, dt, J 5, 1.6 Hz), 5.33 (1H, dq, J 10.5, 1.4 Hz), 5.48 (1H, dq, J 17.3, 1.6 Hz), 6.04 (1H, m), 6.86 (1H, d, J 9 Hz, 7.13 (1H, dd, J 8.4, 2.7 Hz), and 7.45 (1H, d, J 2.8 Hz).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][C:11]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)([C:14]1[C:22]2[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH2:12][CH3:13])(=O)=O.O.ClCCl>CS(C)=O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:11]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)([CH2:12][CH3:13])[CH2:10][CH2:9][C:1]#[N:2])=[CH:31][CH:30]=1
Reactant: CCC(CCOS(C)(=O)=O)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Reactant: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CCC(CCC#N)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Temperature: 80 °C
Reaction time: 12 h

Procedure:
223 mg (3.43 mmol) of potassium cyanide were added to 775 mg (1.71 mmol) of the compound from Example 115A in 12 ml of DMSO. The mixture was stirred at 80° C. for 12 h, water and dichloromethane were added to the reaction solution, and the phases were separated. The organic phase was extracted with dichloromethane, and the combined organic phases were freed of solvent. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 551 mg (84% of theory) of the target compound were obtained.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]2[O:29][CH:30]=[C:31]([CH2:33]Cl)[N:32]=2)=[CH:22][CH:21]=1>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]2[O:29][CH:30]=[C:31]([CH2:33][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:32]=2)=[CH:22][CH:21]=1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Reactant: ClCc1coc(C=Cc2ccc(Cl)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
25 mg (1.0 mmol) of 95% sodium hydride were given to a solution of 219 mg (1.0 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 5 ml N,N-dimethylformamide and stirred for 15 min at room temperature. Then 254 mg (1.0 mmol) 2-[2-(4-chloro-phenyl)-vinyl]-4-chloromethyl-oxazole were added and stirring continued over night. The mixture was quenched with water, stirred for 1 h and the precipitate isolated by filtration. After washing with water, little methanol, ethyl acetate/heptane 2:1 and ether, and drying at 40° C. in vacuo, 341 mg (78%) 1-[2-(4-{2-[2-(E)-(4-chloro-phenyl)-vinyl]-oxazol-4-ylmethoxy}-benzyloxy)-ethyl]-1H-[1,2,3]triazole were obtained.
Reaction SMILES: [CH:1]1([N:4]([CH3:12])[C:5]([C@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=O)[CH2:3][CH2:2]1.B.Cl>C1COCC1>[CH:1]1([N:4]([CH3:12])[CH2:5][C@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:3][CH2:2]1
Reactant: CN(C(=O)[C@H]1CCCN1)C1CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CN(C[C@H]1CCCN1)C1CC1
Temperature: 25 °C

Procedure:
To a solution of (R)-pyrrolidine-2-carboxylic acid cyclopropyl-methyl-amide (540 mg, 3.21 mmol) in THF (5 mL) at 0° C. was added borane (6.4 mL, 2 eq., 1 M in THF) dropwise. The mixture was allowed to warm up to rt then heated to reflux for 24 hours. The cooled reaction was acidified with HCl and heated at 75° C. for 10 mins. The mixture was concentrated, basified with 2N NaOH and extracted with 10% methanol in DCM. The combined DCM was dried and concentrated to give cyclopropyl-methyl-(R)-1-pyrrolidin-2-ylmethyl-amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[C:10]([CH3:18])[N:9]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[C:10]([CH3:18])[N+:9]=2[O-:27])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)nc1-c1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(C)[n+]([O-])c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Methyl 2-(4-fluorophenyl)-6-methylpyridin-3-carboxylate (17.3 g) was dissolved in dichloromethane (600 ml), the solution cooled to 0° C. and MCPBA (24.3 g) added in portions over 25 minutes. The solution was then warmed to ambient temperature and stirred for 16 hours washed with saturated aqueous sodium bicarbonate (500 ml), dried and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with methanol/ethyl acetate (1:12) to give 2-(4-fluorophenyl)-3-(methoxycarbonyl)-6-methylpyridine-1-oxide as a pale yellow oil which crystallised on standing (18.6 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C@H:7]1[C:10](=[O:11])[NH:9][C@@H:8]1[C:12]([OH:14])=[O:13])=[N+]=[N-]>CN(C=O)C.C(O)(=O)C.[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][C@H:7]1[C:10](=[O:11])[NH:9][C@@H:8]1[C:12]([OH:14])=[O:13]
Reactant: [N-]=[N+]=NCCC[C@H]1C(=O)N[C@@H]1C(=O)O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: NCCC[C@H]1C(=O)N[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 146 (0.59 g, 1.0 eq.) in DMF (5 mL) and acetic acid (1 mL) was added 10% Pd/C (300 mg). The flask was evacuated and flushed with hydrogen. The reaction was then stirred at room temperature under an atmosphere of hydrogen for 16 hours. The reaction was then filtered through Celite and crude amine 147 was immediately used in the next step as a solution in DMF.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:15])[NH:8][C:9]1([C:12](=[NH:14])[NH2:13])[CH2:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].CN(C)[CH:18]=[C:19]([Br:22])[CH:20]=O.CCO>CO>[C:2]([O:6][C:7](=[O:15])[NH:8][C:9]1([C:12]2[N:13]=[CH:20][C:19]([Br:22])=[CH:18][N:14]=2)[CH2:11][CH2:10]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C(=N)N)CC1
Reactant: CN(C)C=C(Br)C=O
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ncc(Br)cn2)CC1
Temperature: 80 °C

Procedure:
(1-Carbamimidoyl-cyclopropyl)-carbamic acid tert-butyl ester hydrochloride (1.0 g, 4.2 mmol) (prepared according to the procedure described in patent application WO 2009/070485 A1) and 3-dimethylamino-2-bromo-propenal (1.1 g, 6.4 mmol) are added to EtOH (2 mL) in a pressure tube. The reaction vessel is capped and the mixture is heated at 80° C. for 24 hours. The mixture is cool to room temperature and methanol (20 mL) is added. The resulting solids are filtered and the filtrate is concentrated in vacuo. The residue is dissolved with CH2Cl2 (50 mL) and the solids are filtered. The filtrate is concentrated and the residue is purified by silica gel chromatography using a gradient of 0-50% EtOAc in hexanes to afford [1-(5-bromo-pyrimidin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester as a solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:22])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=2[N:4]=1)[CH3:2].[CH3:33][C:34](=O)[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:22])[CH2:21][N:20]([CH:34]([CH3:35])[CH3:33])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CNC3)n(C)c2n1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CN(C(C)C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.7 %

Procedure:
A mixture of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-azetidin-3-ol (100 mg, 0.23 mmol), propan-2-one (34 μL, 27 mg, 0.46 mmol) and 4 Å powdered molecular sieves (150 mg) in DCE (3 mL) was stirred for 3 h before sodium triacetoxyborohydride (96 mg, 0.46 mmol) was added. The resulting mixture was stirred for 16 h at r.t., then filtered through Celite®, washing with DCM. The filtrate was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 50-70%) affording 738 as a white solid (15 mg, 13%). LCMS (method I): RT 2.43 min, [M+H]+ 477.2. 1H NMR (MeOD, 400 MHz): δ 8.01-8.01 (1 H, m), 7.64-7.61 (1 H, m), 7.29-7.28 (2 H, m), 4.39 (5 H, s), 4.19-4.17 (2 H, m), 3.85 (4 H, s), 3.46 (2 H, d, J=8.87 Hz), 3.31-3.30 (5 H, m), 2.56-2.54 (1 H, m), 1.39 (3 H, t, J=7.50 Hz), 1.01 (6 H, d, J=6.25 Hz)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH:23][CH:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)=[O:6]
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a mixture of 2-fluoro-5-methoxy-4-nitrobenzoic acid (53.8 g, 250 mmol), 1-methylpiperidin-4-amine (31.4 g, 275 mmol), DIEA (134 mL, 750 mmol) in 1 L of DCM at 0° C. was added HATU (114 g, 300 mmol) in four batches. The reaction mixture was stirred at room temp. for 16 h. After which, it was concentrated and diluted to IL of a mixture of MeOH in water (5%). The suspension was stirred vigorously for 2 h until seen a suspension of fine powder. The solid was filtered, washed with more water and dried to give 55 g of light yellow product. The filtrate was extracted with EtOAc, concentrated and re-suspended in water (5% of MeOH) and repeating the same procedure as above, after which another batch of solid was obtained (total 67 g, 86%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (m, 2 H) 1.81 (m, 2 H) 2.04 (m, 2 H) 2.19 (s, 3 H) 2.77 (d, J=8 Hz, 2 H) 3.73 (m, 1 H) 3.94 (s, 3 H) 7.42 (d, J=5.6 Hz, 1 H) 7.98 (d, J=8.8 Hz, 1 H) 8.51 (d, J=7.6 Hz, 1 H). [M+H] calc'd for C14H18FN3O4, 312; found 312.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].CC1(C)C(C)(C)OB([C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:2]([C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC1(C)OB(c2ccn[nH]2)OC1(C)C
Reactant: CCOC(=O)c1c(Br)cccc1OC
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1c(OC)cccc1-c1ccn[nH]1
Temperature: 100 °C
Yield: 33 %

Procedure:
In a microwave vial was dissolved ethyl 2-bromo-6-methoxybenzoate (500 mg, 1.54 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (330 mg, 1.70 mmol) in DME (10 mL) and water (2 mL). Na2CO3 (259 mg, 3.09 mmol) was then added followed by Pd(PPh3)4 (89 mg, 0.077 mmol) and the reaction mixture was degassed with N2 for 10 minutes. The reaction mixture was then heated at 100° C. for 1 h in the microwave. The mixture was cooled to room temperature, filtered through Celite and washed with EtOAc and DCM. The crude solution was concentrated in vacuo and directly purified via silica gel chromatography (10-80% EtOAc in hexanes) to afford the title compound (125 mg, 33%). MS (ESI) mass calcd. for C13H14N2O3, 246.3. m/z found 247.1 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J=2.2 Hz, 1H), 7.44-7.37 (m, 1H), 7.24 (d, J=8.1 Hz, 1H), 6.94 (dd, J=8.3, 0.9 Hz, 1H), 6.53 (d, J=2.3 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 3.88 (s, 3H), 1.25-1.16 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.[CH2:9]([Mg]Br)[CH3:10].B(F)(F)F.[OH-].[Na+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2([NH2:8])[CH2:10][CH2:9]2)[N:6]=1
Reactant: CC[Mg]Br
Reactant: Cc1nc(C#N)co1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C2(N)CC2)co1
Reaction time: 0.17 h

Procedure:
2-Methyloxazole-4-carbonitrile (5 g, 46.1 mmol, 1 eq) was dissolved in dry THF at room temperature, and to which titanium(IV) isopropoxide (16 ml, 655 mmol, 1.2 eq) was added dropwise over a period of 15 minutes. The resulting mixture was stirred for 10 min and ethyl magnesium bromide (85 ml, 17 volumes) was added slowly dropwise at ambient temperature and the reaction was stirred for 1 h. Later BF3.etherate (16.7 ml, 115 mmol, 2.5 eq) was added slowly at ambient temperature and the above solution was stirred at ambient temperature for 3 h. Finally water was added and the pH was brought to 10 using 10% sodium hydroxide solution. The reaction mixture was extracted with dichloromethane, concentrated and purified by combiflash chromotography. Yield: 1.5 g (20%). 1H NMR (400 MHz, DMSO-d6): δ 0.93 (m, 2H), 1.00 (m, 2H), 1.98 (br s, 2H), 2.39 (s, 3H), 7.33 (s, 1H). LCMS: (ES+) m/z=138.9 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.CN(C)C=O.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:21][Si:22]([C:25]#[C:26][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:24])[CH3:23]
Reactant: Brc1ccccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)C#Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 105.9 %

Procedure:
A mixture of 150 g of 97% bromo iodo benzene, 500 ml of anhydrous dimethylformamide, 100 ml of triethylamine, 50 g of trimethylsilyl acetylene, 2.1 g of copper iodide and 2.22 g of bis-(triphenylphosphine)-palladium (II) dichloride was stirred for 2 hours and then 500 ml of ice-cooled water were added. The mixture was extracted 3 times with 500 ml of ethyl acetate and the organic phase was washed with salt water, then dried over sodium sulfate, and evaporated under reduced pressure to obtain 136.542 g of a brown oil which was purified by distillation under reduced pressure to obtain 106.979 g of the expected product with a boiling point of 75-82° C. under 0.2 mbar and a melting point of 62° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](O)[CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1.CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([Cl:17])[CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(O)cc(C2CC2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(Cl)cc(C2CC2)n1
Yield: 104.9 %

Procedure:
14.8 g 2-tert-butyl-4-hydroxy-6-cyclopropyl-pyrimidine (76.9 mmol) were dissolved in 100 ml of toluene and 3 ml of dimethylformamide. 23.6 ml of POCl3 (153.7 mmol) were added dropwise at 10° C. After stirring overnight at room temperature most of the toluene was evaporated. The mixture was cooled with ice and 20 ml of water were added cautiously. Subsequently, an additional 200 ml of water were added and the aqueous phase was extracted four times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and then concentrated to dryness to yield 17 g of a yellowish oil (quant.).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[CH2:14][S:13]/[C:12]/1=[N:17]\[C:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[CH:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=3)[N:30]=2)=[CH:25][CH:24]=1)=[O:19])([CH3:3])[CH3:2].C1C(=O)C=CC2C=1C=C1C=2C=CC=C1.[B-](F)(F)(F)[F:60].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:60][CH:14]1[S:13]/[C:12](=[N:17]\[C:18]([NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[N:33]=[CH:32][N:31]([C:34]4[CH:35]=[CH:36][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:38][CH:39]=4)[N:30]=3)=[CH:27][CH:28]=2)=[O:19])/[N:11]([C:5]2[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:15]1=[O:16]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C1C=CC2=c3ccccc3=CC2=C1
Solvent: CC#N
Product: Cc1ccc(C(C)C)c(N2C(=O)C(F)S/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To (Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea (F5) (0.050 g, 0.080 mmol) and 2-fluorenone (0.0080 g, 0.044 mmol) in anhydrous acetonitrile (0.80 mL) was added Selectfluor® (0.062 g, 0.18 mmol). The reaction was stirred at room temperature overnight. Purification by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided the title compound as a yellow oil (0.033 g, 63%).
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1)([OH:4])=[O:3].[CH2:32]([O:39][C:40]1[C:45]([CH:46]=O)=[CH:44][CH:43]=[CH:42][N:41]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([O:39][C:40]1[C:45]([CH:46]=[CH:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:2]([OH:4])=[O:3])=[CH:10][CH:9]=2)=[CH:44][CH:43]=[CH:42][N:41]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cccnc1OCc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CC=Cc2cccnc2OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
(2-(4-Carboxyphenyl)ethyl)triphenylphosphonium bromide (10.9 g, 22.2 mmol) was suspended in THF (80 ml) and the flask was flushed with argon. Lithium bis(trimethylsilyl)amide (1M in THF, 48.8 ml) was added dropwise and the reaction stirred for 1 hour, becoming dark brown. A solution of 2-benzyloxy-3-pyridinecarbaldehyde (4.73 g, 22.2 mmol) in THF (20 ml) was added slowly. The reaction was stirred at ambient temperature for 18 hours (shielding from light alumimium foil). The reaction mixture was then partitioned between Et2O/water, the organic layer was washed with water and the aqueous layers were combined, acidified with HCl and extracted with EtOAc. The organic phase was dried (MgSO4) and evaporated and purified by colum chromtagraphy with MeOH/CH2Cl2 to give the title product.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.S(=O)(=O)(O)O.B(OC)(OC)OC>ClCCl>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 1 h

Procedure:
To 10 ml of dichloromethane were added 1.41 g of 7-ACA, 2.18 g of concentrated sulfuric acid and 1.88 ml of trimethyl borate. The reaction was conducted at 0° C. for one hour. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.63 g. The yield of the desired product was 50%.