Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:18]3[S:23][C:22]([CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)=[CH:21][C:19]=3[N:20]=2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.CO>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[C:18]3[S:23][C:22]([CH2:24][CH2:25][NH2:26])=[CH:21][C:19]=3[N:20]=2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCc1cc2nc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)nc(N3CCOCC3)c2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2nc(N3CCOCC3)c3sc(CCN)cc3n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-butyl 2-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethylcarbamate (10.0 mg, 1.0 eq.) was solved in 3 ml of TFA:DCM (1:1). The reaction mixture was stirred at room temperature for 2 h. The silica column chromatography (DCM:MeOH/95:5) gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH2:21][C:22]4[S:26][C:25]([CH3:27])=[N:24][C:23]=4[CH3:28])=[C:12](C(N)=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:29][CH3:30])=[C:5]([CH3:31])[O:4][N:3]=1.C1C=CC=CC=1.[OH2:38].[C:39](#[N:41])C>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:29][CH3:30])=[CH:9][C:10]3[C:11]4[N:20]([CH2:21][C:22]5[S:26][C:25]([CH3:27])=[N:24][C:23]=5[CH3:28])[C:39](=[O:38])[NH:41][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: O
Reactant: CC#N
Reactant: COc1cc2c(NCc3sc(C)nc3C)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Solvent: c1ccccc1
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1[nH]c(=O)n(Cc3sc(C)nc3C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(3,5-dimethyl-4-isoxazolyl)-4-{[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see intermediate 65, 0.3 g) in acetonitrile (50 ml) was added bis(trifluoroacetoxy)iodo]benzene (0.443 g) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated to dryness to give an orange oil. The residue was purified by flash chromatography on silica gel eluting with DCM/methanol (98: 2 then 97:3) give a sticky pale yellow solid, which was triturated in hot diisopropylether to give 7-(3,5-dimethyl-4-isoxazolyl)-1-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-8-(methyloxy)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (0.21 g) as a cream coloured solid.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:15])=[CH:10][CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Cl>>[CH2:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[CH:10][CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CCc2ccc(O)cc2C1=O
Reactant: ClCc1ccccn1
Agent: Cl
Product: CCCCC1CCc2ccc(OCc3ccccn3)cc2C1=O

Procedure:
By the method of Example 10, the title product of Example 9 (5.70 g, 34.3 mmol) and 2-picolyl chloride hydrochloride (5.63 g, 34.3 mmol) were converted to present title product, 4.37 g (41%), m.p. 56-60° C.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[N+:13]([C:16]1[C:17]([NH2:23])=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>CC#N>[N+:13]([C:16]1[C:17]2[NH:23][C:5](=[O:11])[NH:22][C:18]=2[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Product: O=c1[nH]c2cccc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C

Procedure:
Triphosgene (56 g, 188.8 mol) was added portionwise over 15 min to a solution of 3-nitro-1,2-phenylenediamine (25.5 g, 167 mol) in CH3CN (400 mL) at 0° C. and the mixture was allowed to warm to ambient temperature after 30 min. The reaction was concentrated in vacuo, diluted with toluene (100 mL) and the solid precipitate was collected by filtration to give the title compound. MS: m/z=180 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.N1(C(N2C=CN=C2)=S)C=CN=[CH:13]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:32]1[NH:33][C:34]2[CH:40]=[C:39]([C:41]([NH:43][NH2:44])=[O:42])[CH:38]=[CH:37][C:35]=2[N:36]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:32]1[NH:33][C:34]2[CH:40]=[C:39]([C:41]3[O:42][C:13]([NH:1][C:2]4[CH:3]=[N:4][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:6][CH:7]=4)=[N:44][N:43]=3)[CH:38]=[CH:37][C:35]=2[N:36]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)cn1
Reaction time: 6.5 h

Procedure:
Combine 3-amino-6-trifluoromethyl-pyridine (98 mg, 0.606 mmol) and di -imidazol-1-yl-methanethione (108 mg, 0.606 mmol) in DMF (1.5 mL) and stir overnight. Add 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) and DMF (1 mL). Stir for 6.5 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 1 hr. Upon cooling, dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Purify the residue by silica gel chromatography (3-6% MeOH/DCM) to afford the title compound as an off white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62-7.68 (m, 1 H) 7.71 (d, J=1.01 Hz, 1 H) 7.73 (t, J=1.77 Hz, 1 H) 7.78 (tautomer, d, J=8.59 Hz, 1 H) 7.82-7.87 (tautomer, m, 1 H) 7.90-7.94 (m, 1 H) 7.96 (d, J=8.72 Hz, 1 H) 8.08 (tautomer, d, J=0.88 Hz, 1 H) 8.21 (tautomer, s, 1 H) 8.38 (d, J=8.59 Hz, 1 H) 8.90 (d, J=2.27 Hz, 1 H) 11.51 (s, 1 H) 13.32 (d, J=2.91 Hz, 1 H); MS m/z=490.9 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH:16]=[CH:15][C:14]2[O:17][C:18]([CH3:20])=[CH:19][C:13]=2[C:12]1=[O:21].Br[CH2:23][CH2:24][CH2:25][Cl:26].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:26][CH2:25][CH2:24][CH2:23][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH:16]=[CH:15][C:14]2[O:17][C:18]([CH3:20])=[CH:19][C:13]=2[C:12]1=[O:21]
Reactant: ClCCCBr
Reactant: Cc1cc2c(=O)n(Cc3nc4ccccc4[nH]3)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc2c(=O)n(Cc3nc4ccccc4n3CCCCl)ccc2o1
Temperature: 25 °C

Procedure:
5-(1H-Benzimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one(0.75 g), 1-bromo-3-chloropropane(1.3 ml), and potassium carbonate(0.95 g) were added to 50% hydrous acetonitrile(16 ml). The mixture was heated overnight under reflux. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1→0:1). The purified product was condensed to dryness under reduced pressure to give the title compound(0.18 g) as a colorless oily matter.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])(=O)=O.[I:16][C:17]1[CH:18]=[C:19](O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.CCCCCC>[I:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][CH:18]=1)[O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: Oc1cccc(I)c1
Reactant: COCCOCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOCCOCCOc1cccc(I)c1
Temperature: 68 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a solution of 1-[(methanesulfonyl)-oxy]-3,6,9-trioxadecane (11.6 g, 47.9 mmol) in dry DMF (145 ml) was added 3-iodophenol (10.6 g, 48.2 mmol) and potassium carbonate (6.6 g, 47.8 mmol). The reaction was immersed in an oil bath which was warmed to 68° C. over a period of 0.5 hr. The reaction was stirred at this temperature under an N2 atmosphere for 16 hrs and then at 82° C. for an additional 2 hrs. At the end of this period, the reaction was cooled, diluted with DMF, filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up into ethyl acetate (500 ml), washed with water (200 ml), 1N aqueous sodium hydroxide (200 ml) and brine (200 ml), dried (Na2SO4), filtered and evaporated in vacuo to provide a light brown oil. Flash column chromatography (silica, 1:3 to 1:2; EtOAc:hexane) provided 1 -(3-iodophenoxy)-3,6,9-trioxadecane as a light yellow oil (10.8 g, 37.1%).
Reaction SMILES: COC(=O)CCC1(C)CCCCC1=O.COC(=O)CCC1(CC)CCCCC1=O.[CH3:30][O:31][C:32](=[O:45])[CH2:33][CH2:34][C:35]1([CH2:42][CH2:43][CH3:44])[CH2:40][CH2:39][CH2:38][CH2:37][C:36]1=O.COC(=O)CCC1(CC)CCCCC21[C:56](=[O:57])[CH2:55][CH2:54][C:53]2=[O:58]>>[CH3:30][O:31][C:32](=[O:45])[CH2:33][CH2:34][C:35]1([CH2:42][CH2:43][CH3:44])[CH2:40][CH2:39][CH2:38][CH2:37][C:36]21[C:56](=[O:57])[CH2:55][CH2:54][C:53]2=[O:58]
Reactant: CCCC1(CCC(=O)OC)CCCCC1=O
Reactant: CCC1(CCC(=O)OC)CCCCC12C(=O)CCC2=O
Agent: CCC1(CCC(=O)OC)CCCCC1=O
Agent: COC(=O)CCC1(C)CCCCC1=O
Product: CCCC1(CCC(=O)OC)CCCCC12C(=O)CCC2=O

Procedure:
In the same manner but replacing 1-methyl-2-oxocyclohexane-propionic acid methyl ester with an equivalent amount of 1-ethyl-2-oxocyclohexanepropionic acid methyl ester or 1-propyl-2-oxocyclohexanepropionic acid methyl ester, described in Example 6, 6-ethyl-1,4-dioxospiro[4.5]decane-6-propionic acid methyl ester, νmaxCHCl3 1730 cm-1 and 6-propyl-1,4-dioxospiro[4.5]decane-6-propionic acid methyl ester, νmaxCHCl3 1735 cm-1, are obtained, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][CH:14]=3)=[C:9]([CH2:23][CH2:24][CH3:25])[CH:8]=2)=[CH:4][CH:3]=1.[C:28]([O:33]C)(=[O:32])[C@@H:29]([CH3:31])O>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([O:22][C@@H:29]([CH3:31])[C:28]([OH:33])=[O:32])[CH:20]=[CH:21][C:16]=4[O:15][CH:14]=3)=[C:9]([CH2:23][CH2:24][CH3:25])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C)O
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1coc2ccc(O)cc12
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1coc2ccc(O[C@@H](C)C(=O)O)cc12

Procedure:
The title compound was prepared according to the following general procedure using the phenol from Step 11 and methyl (R)-lactate as the substrates.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([Li])CCC.[O:21]=[C:22]1[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:24][CH2:23]1>C1COCC1>[CH3:33][C:30]([O:29][C:27]([NH:26][C@@H:25]([CH2:24][CH2:23][C:22](=[O:21])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)[C:34]([O:36][CH3:37])=[O:35])=[O:28])([CH3:31])[CH3:32]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCC(=O)c1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 32.3 %

Procedure:
To a solution of commercially available (Sigma Aldrich Ltd.) 1-bromo-4-[(phenylmethyl)oxy]benzene (390 mg, 1.48 mmol) in dry THF (2 ml) at −78° C., under nitrogen atmosphere, was added dropwise n-butyllithium 1.6M solution in hexanes (0.88 ml, 1.4 mmol). The resulting suspension was stirred at −78° C. for 40 minutes and then it was added dropwise to a solution of 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D1, 300 mg, 1.23 mmol) in dry THF (2.4 ml) previously cooled to −78° C. The mixture was stirred at −78° C. for 40 minutes and at −40° C. for 1 h, then it was quenched at −40° C. with a saturated aqueous ammonium chloride solution. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was then washed with brine, dried (Na2SO4), and evaporated under vacuo to give the crude material, which was then purified by chromatography on silica gel eluting with cyclohexane:ethyl acetate (95:5), thus affording the title compound as a white solid (170 mg, 32%); Rf (cyclohexane:ethyl acetate 8:2): 0.30; 1H NMR (300 MHz, CDCl3) δ(ppm): 7.95 (d, 2H), 7.50-7.33 (m, 5H), 7.03 (d, 2H), 5.20 (bs, 1H), 5.15 (s, 2H), 4.45-4.35 (m, 1H), 3.78 (s, 3H), 3.15-2.95 (m, 2H), 2.36-2.26 (m, 1H), 2.16-2.02 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[N:8]=[CH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:5].CO.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[Br:23][C:24]1[N:25]=[CH:26][C:27]([CH2:30][NH:1][C:2]2[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=2[C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:5])=[CH:28][CH:29]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: Nc1ccccc1C(=O)Nc1cc2ccccc2cn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(Nc1cc2ccccc2cn1)c1ccccc1NCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
3.46 g (13.17 mmol) of 2-amino-N-isoquinolin-3-yl-benzamide is introduced into 50 ml of methanol, mixed with 1.5 ml of glacial acetic acid as well as 2.45 g (13.17 mmol) of 2-bromopyridine-5-carbaldehyde and stirred for 24 hours under argon and in a moisture-free environment at room temperature. Then, it is mixed with 828 mg (13.17 mmol) of sodium cyanoborohydride and stirred for another 24 hours at room temperature. After concentration by evaporation under vacuum, the residue is taken up in dilute sodium bicarbonate solution and suctioned off. The residue that is obtained is absorptively precipitated in a little ethyl acetate and suctioned off repeatedly. The residue that is obtained in this case is chromatographed on silica gel with hexane:ethyl acetate=1:1 as an eluant. 3.27 g (57% of theory) of 2-[(6-bromo-pyridin-3-ylmethyl)-amino]-N-isoquinolin-3-yl-benzamide is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:17](/[CH:20]([CH2:23]O)[CH2:21][OH:22])=[CH:18]\[CH3:19].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH:17](/[C@@H:20]1[CH2:21][O:22][C@@H:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[CH2:14][CH2:13]2)[O:16][CH2:23]1)=[CH:18]\[CH3:19]
Reactant: C/C=C/C(CO)CO
Reactant: O=C[C@H]1CC[C@H](c2ccc(F)c(F)c2)CC1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C/C=C/[C@H]1CO[C@H]([C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)OC1
Reaction time: 1.25 h

Procedure:
A solution of 3.0 g of trans-4-(3,4-difluorophenyl)cyclohexanecarboxaldehyde (prepared in accordance with Example 2) and 2.4 g of 2-(1E-propenyl)-1,3-propanediol in 75 ml of toluene was treated with 3 drops of 10 percent (v/v) sulphuric acid and the reaction mixture was heated to boiling for 1.25 hours, whereby moist toluene was distilled off and replaced by fresh toluene. Then, the reaction mixture was neutralized with triethylamine and, after cooling, washed three times with water, dried over sodium sulphate and concentrated. Chromatographic purification of the residue on 100 g of silica gel with hexane/ethyl acetate (vol. 49:1) and repeated recrystallization of the trans/cis mixture from hexane gave 0.8 g of pure trans-5-(1E-propenyl)-2-[trans-4-(3,4-difluoro-phenyl)cyclohexyl]-1,3-dioxane; m.p. (C-N) 96.0° C., cl.p. (N-I) 125.5° C., Δε (115° C.)=12.4.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(O[O:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])(=O)CC.[Si:23]([O:30][CH2:31][CH2:32][CH2:33][C@@H:34]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C@H:35]([CH3:38])[CH:36]=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].[CH2:49]1C[O:52][CH2:51][CH2:50]1>>[Si:23]([O:30][CH2:31][CH2:32][CH2:33][C@@H:34]([O:39][CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=1)[C@H:35]([CH3:38])[C@@H:36]([OH:37])[C@@H:50]([CH3:49])[C:51]([O:14][C:15]1[C:16]([CH3:22])=[CH:17][CH:18]=[CH:19][C:20]=1[CH3:21])=[O:52])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: C1CCOC1
Reactant: COc1ccc(CO[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H](C)C=O)cc1
Reactant: CCC(=O)OOc1c(C)cccc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COc1ccc(CO[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H](C)[C@@H](O)[C@@H](C)C(=O)Oc2c(C)cccc2C)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
LDA (2M in THF, 3.1 mL, 6.2 mmol) was added to a solution of 2,6-dimethylphenoxy propionate (1.10 g, 6.2 mmol) in anhydrous THF (12.4 mL) at −78° C., followed by stirring for 1 h at −78° C. The crude aldehyde 27 (4.1 mmol) from above dissolved in anhydrous THF (10 mL) was added slowly at −78° C. After 2 h at room temperature, the mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic layer was dried over anhydrous MgSO4, evaporated and chromatographed (hexane/EtOAc 4:1) to yield 29 (1.67 g, 2.99 mmol) as a colorless oil: IR (CHCl3) 3120, 2857, 1744, 1514, 1216, 1099 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.26 (d, 2H, J=8.4 Hz), 6.87 (d, 2H, J=8.4 Hz), 4.62 (d, 1H, J=11.1 Hz), 4.40 (d, 1H, J=11.1 Hz), 4.06 (d, 1H, J=6.8 Hz), 3.79 (s, 3H), 3.66–3.61 (m, 3H), 2.89 (m, 1H), 2.19 (s, 6H), 1.86 (m, 2H), 1.55 (m, 3H); 1.27 (d, 3H, J=6.8 Hz), 1.01 (d, 3H, J=6.9 Hz), 0.93 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 173.5, 159.2, 148.0, 130.0, 129.9, 129.4, 128.4, 125.6, 113.8, 83.5, 70.7, 62.9, 55.1, 44.0, 35.6, 28.7, 26.6, 25.8, 18.2, 16.3, 14.2, 5.7, −5.3; HRMS (EI) calcd for C32H50O6Si 558.3377, found 558.3392.
Reaction SMILES: C([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=O)CC.COCC=O>>[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:5][C:6]1=[O:14]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Agent: COCC=O
Product: O=c1[nH]c2ccccc2o1

Procedure:
Is prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolone with methoxyacetaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][S:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCc1ncc(Br)cc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: CCc1ncc(Br)cc1NS(=O)(=O)c1ccc(OC)cc1
Yield: 87.4 %

Procedure:
5-Bromo-2-ethyl-3-pyridinamine (285 mg, 1.42 mmol, prepared according to WO 2008157191 A2 20081224) was treated with 4-methoxybenzene-1-sulfonyl chloride (323 mg, 1.56 mmol) according to the method described In Preparation 15b to give 461 mg (75% yield) of the title compound as an oil. Purity 85%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:22]2[N:23]=[C:24]([NH:27][CH:28]=[O:29])[S:25][CH:26]=2)[C:19]([OH:21])=O)=[O:14])[CH:7]=1.[NH2:30][CH:31]1[C:49](=[O:50])[N:33]2[C:34]([C:46]([OH:48])=[O:47])=[C:35]([CH2:38][S:39][C:40]3[N:44]([CH3:45])[N:43]=[N:42][N:41]=3)[CH2:36][S:37][C@H:32]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:22]2[N:23]=[C:24]([NH:27][CH:28]=[O:29])[S:25][CH:26]=2)[C:19]([NH:30][CH:31]2[C:49](=[O:50])[N:33]3[C:34]([C:46]([OH:48])=[O:47])=[C:35]([CH2:38][S:39][C:40]4[N:44]([CH3:45])[N:43]=[N:42][N:41]=4)[CH2:36][S:37][C@H:32]23)=[O:21])=[O:14])[CH:7]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=CNc1nc(C(=NOCC(=O)Nc2cccnc2)C(=O)O)cs1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)Nc3cccnc3)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 40 °C
Yield: 34.2 %

Procedure:
A mixture of phosphorus oxychloride (1.6 g.) and N,N-dimethylformamide (31 ml.) was warmed at 40° C. for 30 minutes followed by cooling to -10° C. To the mixture was added 2-[N-(3-pyridyl)carbamoylmethoxyimino]-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (3.1 g.) followed by stirring for an hour at -10° to -7° C. On the other hand, a mixture of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3.2 g.) and trimethylsilylacetamide (7 g.) in methylene chloride (60 ml.) was stirred for 30 minutes at room temperature and then cooled to -15° C. To the mixture was added the above obtained dimethylformamide mixture followed by stirring for 1.5 hours at -15° to -10° C. To the reaction mixture were added ice-cold water and sodium bicarbonate. The aqueous layer (pH 7 to 8) was separated and washed with ethyl acetate and then thereto was added ethyl acetate. After the pH was adjusted to 3 to 4 with 10% hydrochloric acid, the precipitates were collected and then dissolved in an aqueous solution of sodium bicarbonate. The resulting mixture was treated with activated charcoal and the aqueous layer was separated and then adjusted to pH 3 to 4 with 10% hydrochloric acid. The precipitates were collected by filtration and dried to give the title compound (2.0 g.).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:12]>CS(C)=O>[NH2:12][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N
Reactant: Clc1cnc2ccccc2n1
Solvent: CS(C)=O
Product: Nc1cnc2ccccc2n1
Reaction time: 8 h

Procedure:
Three g. of 2-chloroquinoxaline (commercially available) was dissolved in 50 ml. of dimethylsulfoxide and heated on the steam bath while anhydrous ammonia was bubbled into the mixture. The mixture was heated and stirred overnight on the steam bath. It was poured into 150 ml. of a mixture of ice and water, and the solid which precipitated was collected by filtration. This solid was recovered starting material and was discarded. The filtrate was cooled in an ice bath and the solid which precipitated was filtered off. This solid was identified by infrared spectrum as the desired compound, 2-aminoquinoxaline. It was used as is without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.Cl.[F:11][C:12]1([F:16])[CH2:15][NH:14][CH2:13]1.C(N(C(C)C)C(C)C)C.FC(F)(F)C(O)=O.CN(C)[CH:35]=[C:36]([N:42]1[CH:46]=[C:45]([C:47]#[N:48])[N:44]=[N:43]1)[C:37](OCC)=[O:38]>O>[F:11][C:12]1([F:16])[CH2:15][N:14]([C:2]2[N:3]=[CH:4][N:5]=[C:6]([N:8]3[C:37](=[O:38])[C:36]([N:42]4[CH:46]=[C:45]([C:47]#[N:48])[N:44]=[N:43]4)=[CH:35][NH:9]3)[CH:7]=2)[CH2:13]1
Reactant: CCOC(=O)C(=CN(C)C)n1cc(C#N)nn1
Reactant: FC1(F)CNC1
Reactant: NNc1cc(Cl)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CC(F)(F)C4)ncn3)c2=O)nn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 120 mg (0.8 mmol) of the compound from Example 11A, 129 mg (1.0 mmol) of 3,3-difluoroazetidine hydrochloride and 174 ml (129 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine in 3 ml of water is stirred at 100° C. for 16 h. Following the addition of 32 μl (47 mg, 0.4 mmol) of trifluoroacetic acid and 194 mg (0.8 mmol) of the compound from Example 7A, the reaction mixture is stirred at 100° C. for 16 h. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried under reduced pressure. Yield: 51 mg (18% of theory)